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Classifications

Harrison's Part

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Mappings

ICD-10-CM

ICD10CM:I73.8 Other specified peripheral vascular diseases

MONDO:0035149 carries ICD10CM:I73.8 as a cross-reference. The predicate is broadMatch, not exactMatch: I73.8 is a residual "other specified peripheral vascular diseases" bucket that does not distinguish primary from secondary erythromelalgia, so an ICD-10-CM-coded cohort cannot be used as a case definition for this entry. Note that ICD-10-CM does carry a narrower child, ICD10CM:I73.81 "Erythromelalgia", recorded separately below; this row is kept because it is the cross-reference MONDO itself asserts, and removing it would lose that provenance.

ICD10CM:I73.81 Erythromelalgia

The tightest ICD-10-CM code for this concept, added here because MONDO's own cross-reference (I73.8, above) is a residual bucket that codes far more than erythromelalgia. Still broadMatch rather than exactMatch: I73.81 is "Erythromelalgia" without qualification, so it covers the primary SCN9A/Nav1.7 form curated in `Primary_Erythermalgia` as well as this acquired one, and an I73.81-coded cohort therefore still cannot serve as a case definition for this entry.

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Mechanistic Hypotheses

1

Immune-Mediated Microvascular Injury and Dysautonomia as an Alternative Route to the Erythromelalgic Flare

immune_dysautonomic_route EMERGING

Evidence balance 2 support

Proposes that the acquired routes outside the myeloproliferative neoplasms reach the erythromelalgic flare through complement-mediated microvascular injury and autonomic denervation of acral skin, rather than through the platelet-thromboxane pathway that accounts for the MPN arm. If it holds, it explains the entity's most durable clinical puzzle — why the non-thrombocythemic acquired forms are aspirin resistant while the MPN arm is abolished by cyclooxygenase inhibition — and it would make complement- or interferon-directed therapy a rational target in refractory disease. It rests on a single retrospective nine-patient dermatopathology series and is therefore recorded as EMERGING, not as an alternative model of equal standing to the platelet mechanism. Note the limit precisely: that series was assembled by clinical concern for erythromelalgia and is not stratified primary versus secondary, let alone MPN versus non-MPN, and its own conclusion is pitched at erythromelalgia in general. So the restriction of this route to the non-MPN acquired forms is part of the hypothesis being advanced here, not an observation carried over from the source. What is missing is replication in an independent, larger biopsy cohort with quantitative C5b-9 and type-I interferon scoring and intraepidermal nerve-fibre density, stratified by MPN versus non-MPN aetiology. Until then the edges in this group are hypothesis-tagged rather than asserted.

Pathograph links

Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced) -> Complement-Mediated Microvascular Endothelial Injury Proposed route: an acral biopsy lesion of complement deposition and endothelial interferon signalling is offered as part of the substrate for the acquired routes that do not run through platelet thromboxane.

Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced) -> Autonomic Denervation of Acral Arteries and Eccrine Glands Proposed route: the autonomic denervation half of the same acral biopsy lesion, and the half that connects this node's small-fiber neuropathy route to a demonstrated finding.

Complement-Mediated Microvascular Endothelial Injury -> Episodic Acral Burning Pain, Erythema, and Warmth An ectatic, complement-injured acral microvascular bed is proposed as one half of the substrate for the flare.

Autonomic Denervation of Acral Arteries and Eccrine Glands -> Episodic Acral Burning Pain, Erythema, and Warmth Loss of autonomic control of acral arterioles and eccrine glands is proposed to produce the maldistributed acral perfusion experienced as the flare.

Show evidence (2 references)

PMID:39846717 SUPPORT Human Clinical

"This study suggests that erythromelalgia is a dysautonomia syndrome with reproducible findings on biopsy, hallmarked by vascular ectasia and denervation of the eccrine coil and arteries."

The source proposal for this hypothesis group, stated by its authors as a suggestion rather than a demonstrated mechanism.

PMID:32491719 SUPPORT INDIRECT Other

"Secondary erythermalgia: Aspirin resistant and associated with different medical conditions."

The pharmacological observation this hypothesis exists to explain — a recognised acquired category that does not respond to cyclooxygenase inhibition, so a non-platelet lesion is required. Indirect twice over: the Drenth-Michiels classification defines the category by aspirin resistance rather than measuring it, and aspirin resistance motivates this hypothesis without testing it.

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Discussions and Knowledge Gaps

2

How does an arteriole occluded by platelet-rich thrombi produce a skin surface that is visibly red and *hotter* than normal? Is microvascular arteriovenous shunting the reconciling mechanism, and if so does it operate in the MPN-associated form or only in the non-platelet acquired routes?

KNOWLEDGE GAP OPEN av_shunting_vs_occlusion_paradox

Attached to

pathophysiology#Episodic Acral Burning Pain, Erythema, and Warmth pathophysiology#Acral Arteriolar Microvascular Occlusion pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands

This entry's occlusive model has an unresolved surface paradox. The demonstrated lesion is arteriolar obstruction by platelet-rich thrombi, which should reduce perfusion — yet the defining clinical sign is a red, warm, congested extremity, and the flare node above therefore deliberately binds no `vasodilation` process rather than assert a mechanism it cannot evidence. The classical reconciliation is microvascular arteriovenous shunting: blood bypasses the nutritive capillary bed through shunts, so the skin is simultaneously hyperemic and warm at the surface while the tissue itself is hypoxic. That model is asserted in the older review literature (PMID:15075045) but, critically, is asserted there as a *single common mechanism for all* erythromelalgia — a claim the later Nav1.7 channelopathy findings contradict, and which the umbrella `erythromelalgia` entry already cites with the same caveat. The deep-research report for this entry describes the same shunting model with a low-transcutaneous-oxygen correlate, but its only source there is a textbook chapter with no PMID and no quotable passage, so it cannot be curated as an evidence-backed pathophysiology node. Since that gap was first recorded, one half of the question has acquired a candidate answer. The dermatopathology series behind `pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands` reports loss of autonomic innervation of acral *arteries* alongside vascular ectasia — which is a plausible substrate for shunting, since arteriovenous shunts are under autonomic control. It would bear on the second half of the prompt above, the non-platelet routes, *if* that series' patients were in fact non-MPN, which it does not establish: the cases were unstratified by aetiology. It does not close the gap on any reading — no perfusion or oxygenation was measured, and it is a single n=9 study — so this is a lead for the experiment below, not a resolution. Worth noting too that the same series reports superficial vascular *ectasia*, which is itself a dilation finding and may be a more parsimonious reading of the warm, hyperemic surface than shunting. What would settle it: paired measurements in *aetiologically stratified* patients — laser Doppler skin blood flow and transcutaneous oxygen tension during a flare, in MPN-associated versus non-MPN secondary disease. Until then this entry models only what the histopathology and platelet kinetics directly demonstrate, and records the shunting hypothesis here rather than promoting it to a node.

Show evidence (3 references)

PMID:15075045 SUPPORT Other

"A wide variety of etiological conditions can cause erythromelalgia, all having a single common pathogenetic mechanism - microvascular arteriovenous shunting."

States the arteriovenous-shunting hypothesis, and is cited as the source of an open hypothesis rather than as support for a curated mechanism. This 2004 review asserts shunting as the SINGLE common mechanism across all erythromelalgia, which the SCN9A/Nav1.7 findings curated in `Primary_Erythermalgia` contradict.

PMID:8883266 SUPPORT Human Clinical

"intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature"

Establishes the occlusive half of the paradox — the demonstrated lesion in MPN-associated disease is microvascular occlusion, which is what makes the warm, hyperemic surface appearance require an explanation.

PMID:39846717 SUPPORT INDIRECT Human Clinical

"CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."

Supplies a candidate anatomical substrate for the shunting half of the paradox in the non-platelet routes: arteriovenous shunts are under autonomic control, and this series demonstrates loss of autonomic innervation of acral arteries. Indirect — the study measured innervation, not shunting, perfusion or oxygenation, so it is a lead on the open question rather than an answer to it.

Does MONDO:0035149 "secondary erythromelalgia" include the platelet-mediated erythromelalgia of the myeloproliferative neoplasms, or only the aspirin-resistant non-MPN acquired forms that the historical Drenth-Michiels classification called "secondary erythermalgia"?

KNOWLEDGE GAP OPEN secondary_em_nomenclature_scope

Attached to

pathophysiology#Clonal Thrombocythemia in Myeloproliferative Neoplasm pathophysiology#Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)

Two incompatible nomenclatures are in circulation. The historical Drenth-Michiels scheme is three-way and defined by aspirin responsiveness: (a) aspirin-responsive erythromelalgia in thrombocythemia, (b) aspirin-resistant primary erythermalgia, (c) aspirin-resistant "secondary erythermalgia" associated with other medical conditions. Under that scheme, MPN-associated disease is NOT "secondary". Contemporary usage is instead a two-way primary/secondary split that places MPN-associated disease squarely within "secondary" — the Olmsted County population study classified patients as secondary precisely when they had a coexisting myeloproliferative disorder, and a 2025 systematic review lists myeloproliferative disorders first among the conditions secondary EM is linked to. This entry follows that contemporary usage and models the MPN platelet arm as the principal, best-evidenced secondary mechanism, while retaining the non-MPN routes as a separate, deliberately low-resolution node. THE GAP, stated precisely: which of the two senses MONDO:0035149 itself intends is NOT established here. Its only synonym is "Secondary erythermalgia" EXACT [Orphanet:529864] — i.e. Orphanet's label is the very term the historical narrow scheme used for the aspirin-RESISTANT non-MPN category. No Orphanet definition row was quotable at curation time (the Orphadata bulk XML was not available locally), so this entry's scope decision rests on contemporary clinical/epidemiological usage rather than on a cited ontology definition. Resolving it needs `just structured-rebuild-orphanet --id 529864` and a quoted `ORPHA:529864` definition row. Curators reading the older literature should meanwhile note that "secondary erythermalgia" there means something narrower than this entry's scope, which is also why `synonyms:` carries that string only because MONDO lists it as an exact synonym of MONDO:0035149, and not as an endorsement of the historical narrower reading; "platelet-mediated erythromelalgia" is deliberately NOT listed as a synonym, because it names the MPN arm alone and would make the same mistake in the other direction, and that the aspirin-responsiveness contrast is therefore a contrast between the MPN arm and everything else, not between "secondary" and "primary" as such.

Show evidence (2 references)

PMID:32491719 SUPPORT Other

"(a) Erythromelalgia in thrombocythemia: It is platelet mediated and aspirin responsive. This occurs in association with essential thrombocytosis and polycythemia vera."

Documents the historical three-way classification in which thrombocythemic erythromelalgia is its own aspirin-responsive category, separate from "secondary erythermalgia".

PMID:18713229 SUPPORT Human Clinical

"Patients were considered to have secondary erythromelalgia if they had a coexisting diagnosis of a myeloproliferative disorder such as polycythemia vera, chronic myelocytic leukemia, or thrombocythemia at the time of diagnosis of erythromelalgia"

Contemporary epidemiology classifies MPN-associated disease as secondary, the usage this entry follows and the one matching MONDO/Orphanet.

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Pathophysiology

9

Clonal Thrombocythemia in Myeloproliferative Neoplasm

The upstream trigger of MPN-associated erythromelalgia is the clonal thrombocythemia of essential thrombocythemia or polycythemia vera, which supplies a population of qualitatively abnormal, hyperactivatable platelets. The dependence is causal rather than merely associative: erythromelalgia remits during cytoreduction-induced haematological remission and recurs when the thrombocythemia relapses. Notably the threshold is low — symptoms occur at platelet counts only slightly above normal — so absolute platelet mass is not the determinant. The clonal driver biology itself (JAK2 V617F and the haematopoietic consequences) is curated in `Polycythemia_Vera` and `Essential_Thrombocythemia`.

platelet CL:0000233 megakaryocyte CL:0000556

Downstream

Thromboxane-Dependent Platelet Activation and Aggregation The clonal platelet population undergoes intravascular cyclooxygenase-dependent activation and aggregation.

Show evidence (3 references)

PMID:3977194 SUPPORT Human Clinical

"The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."

Remission-and-relapse concordance with the underlying thrombocythemia establishes the MPN as the causal upstream driver rather than a coincidental association.

PMID:9263352 SUPPORT Other

"Erythromelalgia is a characteristic thrombotic complication in patients with the myeloproliferative disorders, essential thrombocythemia and polycythemia vera."

Identifies the two myeloproliferative neoplasms that constitute the principal underlying disorders of this secondary form. Classified OTHER because this is a narrative minireview summarizing the authors' prior work rather than a report of primary data.

PMID:8951772 SUPPORT Human Clinical

"Erythromelalgia in thrombocythemia already occurred at slightly increased platelet counts above 400 x 10(9)/l."

Symptoms arise at only slightly elevated platelet counts, indicating that qualitative platelet hyperreactivity rather than absolute platelet mass drives the mechanism.

Thromboxane-Dependent Platelet Activation and Aggregation

Circulating MPN platelets undergo intravascular activation and aggregation in the acral microcirculation. The process is strictly cyclooxygenase-metabolite dependent: it is abolished by aspirin and indomethacin but not by sodium salicylate or by non-COX platelet inhibitors (dipyridamole, sulfinpyrazone, ticlopidine, dazoxiben). In vivo activation is measurable as elevated beta-thromboglobulin, platelet factor 4, thrombomodulin, and urinary thromboxane B2, together with a markedly shortened platelet survival time that aspirin normalizes. Critically, thrombin generation is NOT required — prothrombin fragment 1+2 and fibrin degradation products are unchanged, and the lesions develop despite heparin or coumarin anticoagulation.

platelet CL:0000233

platelet activation GO:0030168 ↑ INCREASED platelet aggregation GO:0070527 ↑ INCREASED prostanoid (thromboxane) biosynthesis GO:0046457 ↑ INCREASED

platelet cyclooxygenase-1 activity GO:0004666

Downstream

Arteriolar Inflammation and Fibromuscular Intimal Proliferation Activated platelets and their released mediators injure and remodel the arteriolar wall.

Acral Arteriolar Microvascular Occlusion Platelet aggregates sludge and occlude the acral arterial microvasculature.

Show evidence (6 references)

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin, but not with sodium-salicylate or the platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and dazoxiben."

The pharmacological dissection — COX inhibitors work, other antiplatelet agents do not — establishes cyclooxygenase metabolites as mechanistically necessary.

PMID:12781799 SUPPORT Human Clinical

"Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop."

States the necessity of cyclooxygenase metabolites explicitly.

PMID:12781799 SUPPORT Human Clinical

"significant higher levels of platelet activation markers beta-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia"

Quantifies in vivo platelet activation and thromboxane generation specifically in symptomatic patients.

+ 3 more references

Arteriolar Inflammation and Fibromuscular Intimal Proliferation

Skin punch biopsies taken from erythromelalgic areas show a distinctive arteriolar lesion — inflammation of the arteriolar wall with fibromuscular proliferation of the intima — accompanying the thrombotic occlusions. This inflammatory and proliferative wall response, together with the elevated thrombomodulin indicating endothelial injury, distinguishes the lesion from a bland intraluminal clot and is what makes "platelet-mediated arteriolar inflammation" rather than simple thrombosis the accurate description.

arteriolar endothelial cell CL:0000115 arteriolar smooth muscle cell CL:0000192

inflammatory response GO:0006954 ↑ INCREASED smooth muscle cell proliferation GO:0048659 ↑ INCREASED

arteriole UBERON:0001980

Downstream

Acral Arteriolar Microvascular Occlusion Intimal proliferation narrows the arteriolar lumen and compounds platelet-driven occlusion.

Show evidence (2 references)

PMID:3977194 SUPPORT Human Clinical

"Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions."

Direct histopathological demonstration of the arteriolar inflammatory and intimal-proliferative lesion in affected skin.

PMID:12781799 SUPPORT Human Clinical

"the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies"

Independently restates the arteriolar intimal-proliferative and platelet-rich occlusive histopathology.

Acral Arteriolar Microvascular Occlusion

The convergent lesion is occlusion of acral arterioles by platelet-rich, von Willebrand factor-positive thrombi with only weak fibrin content. The resulting acral perfusion disturbance is the immediate substrate of the erythromelalgic flare and, if unrelieved, of progressive digital ischemia. The VWF-rich, fibrin-poor composition of these thrombi is the histological counterpart of the biochemical finding that thrombin generation is dispensable.

arteriole UBERON:0001980

Downstream

Episodic Acral Burning Pain, Erythema, and Warmth Acral microvascular occlusion and the accompanying congestion produce the erythromelalgic attack.

Progression to Acrocyanosis and Digital Ischemic Necrosis Untreated, sustained occlusion progresses to fixed acral ischemia.

Show evidence (2 references)

PMID:8883266 SUPPORT Human Clinical

"Histopathologic and immunohistochemical analysis of biopsies derived from erythromelalgic skin areas of 2 ET patients showed that erythromelalgic thrombi stained positively for von Willebrand factor opposed to only a weak fibrin staining."

Immunohistochemistry establishes the VWF-rich, fibrin-poor composition of the occluding thrombi, distinguishing them from conventional fibrin-platelet thrombi.

PMID:3977194 SUPPORT Human Clinical

"platelet-mediated inflammatory and occlusive arteriolar changes play a part in the etiology of erythromelalgia"

Summarizes occlusive arteriolar change as the operative lesion in the aetiology of the syndrome.

Episodic Acral Burning Pain, Erythema, and Warmth

The clinical expression is the erythromelalgic attack: localized burning pain with redness and warm congestion of the distal extremities, documentable by thermography, most often in the forefoot sole and toes and less often in the fingertips or palm. Unlike the bilaterally symmetric flares of the primary form, secondary attacks are frequently asymmetric or unilateral, and erythromelalgic "hot spots" on the legs can be misread as superficial thrombophlebitis. No `biological_processes` are bound to this node: the obvious candidate (vasodilation) is not measured by any cited study and would sit awkwardly against this entry's occlusive model, in which the red, warm skin accompanies platelet-rich arteriolar obstruction rather than simple vasodilation.

Show evidence (3 references)

PMID:3977194 SUPPORT Human Clinical

"The localized painful burning, redness, and warm congestion in the extremities could be accurately documented with thermography."

Describes the flare phenotype and its objective thermographic correlate.

PMID:8951772 SUPPORT Human Clinical

"Erythromelalgia was localized in the forefoot sole and toes in 28, the fingertips in 9, the handpalm in 2."

Quantifies the acral, foot-predominant anatomical distribution of attacks in a 50-patient thrombocythemia series.

PMID:32491719 SUPPORT Other

"Although erythromelalgia is typically bilateral, it can present unilaterally, especially in secondary cases."

Supports asymmetric/unilateral presentation as a feature that clinically distinguishes secondary from the characteristically bilateral primary form.

Progression to Acrocyanosis and Digital Ischemic Necrosis

When the platelet-mediated occlusive process is not interrupted, the reversible erythromelalgic flare progresses to fixed acral ischemia: acrocyanosis and then frank ischemic necrosis or gangrene of toes or fingertips. This ischemic-progression arm is a mechanistically distinct outcome from the self-inflicted cold-immersion tissue injury that dominates complications in the primary form, and it is the reason MPN-associated erythromelalgia is treated as a thrombotic complication rather than purely a pain syndrome.

Show evidence (2 references)

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."

Documents progression from the reversible flare to fixed acral ischemic tissue loss.

PMID:8951772 SUPPORT Human Clinical

"Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."

Quantifies ischemic progression in 14 of 50 thrombocythemia patients when erythromelalgia was left untreated.

Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)

Mechanism confidence: Provisional

Beyond the myeloproliferative neoplasms, erythromelalgia is reported secondary to small-fiber peripheral neuropathy, autoimmune connective-tissue disease, and drug exposure. These routes are recognised clinically but are far less mechanistically resolved than the MPN arm: combined neural and vascular abnormalities are invoked rather than a single demonstrated lesion, and critically these forms do NOT share the aspirin responsiveness of the platelet-mediated arm, which is why the historical Drenth-Michiels classification separated aspirin-resistant "secondary erythermalgia" from aspirin-responsive thrombocythemic erythromelalgia. Curated here as a deliberately low-resolution node rather than a speculative mechanism chain, with the one downstream lesion that does have a biopsy correlate — the complement/denervation node below — tagged as an emerging hypothesis rather than asserted. Two further acquired associations are documented as single reports and are named here rather than modeled: thrombotic thrombocytopenic purpura, whose own mechanism is diffuse platelet aggregation and which is therefore closer to the platelet arm than to this one, and chronic myelogenous leukemia, which extends the myeloid association beyond the classical polycythemia vera and essential thrombocythemia pair.

Immune-Mediated Microvascular Injury and Dysautonomia as an Alternative Route to the Erythromelalgic Flare

Downstream

Episodic Acral Burning Pain, Erythema, and Warmth These acquired routes converge on the same clinical flare phenotype by mechanisms that remain incompletely defined.

Complement-Mediated Microvascular Endothelial Injury Proposed route: an acral biopsy lesion of complement deposition and endothelial interferon signalling is offered as part of the substrate for the acquired routes that do not run through platelet thromboxane.

Autonomic Denervation of Acral Arteries and Eccrine Glands Proposed route: the autonomic denervation half of the same acral biopsy lesion, and the half that connects this node's small-fiber neuropathy route to a demonstrated finding.

Show evidence (8 references)

PMID:40428878 SUPPORT Human Clinical

"It is often linked to underlying conditions such as myeloproliferative disorders (e.g., essential thrombocythemia, polycythemia vera), autoimmune diseases, infections, tumors, or medication use"

Enumerates the acquired etiologies named in this node — autoimmune disease, infection, neoplasia and drug exposure alongside the myeloproliferative neoplasms.

PMID:18713229 SUPPORT Human Clinical

"if the erythromelalgia was thought to be attributable to another cause such as medications, human immunodeficiency virus, or mushroom poisoning"

A population-based study's own case definition independently names the drug, infection and toxin routes as recognized non-MPN causes of secondary erythromelalgia.

PMID:15075045 SUPPORT Other

"secondary, which is associated with myeloproliferative disorders-related thrombocythemia, polycythemia, collagen-vascular diseases, diabetes mellitus, peripheral neuropathy, autoimmune and infectious diseases, and use of certain medicaments"

Names the acquired associations modeled by this node — collagen-vascular disease, diabetes mellitus, peripheral neuropathy, autoimmune and infectious disease, and drug exposure — alongside the myeloproliferative route curated separately above.

+ 5 more references

Complement-Mediated Microvascular Endothelial Injury

Mechanism confidence: Provisional

The endothelial half of the biopsy lesion proposed for the non-platelet acquired routes. In a dermatopathology series of nine patients biopsied from affected acral skin, the findings were superficial vascular ectasia with microvascular C5b-9 (membrane attack complex) deposition and variable type-I interferon upregulation in endothelial cells. The claim here is about the state of the dermal microvascular endothelium, which is why the scale is `CELLULAR`; the denervation finding from the same biopsies is a separate claim at a different scale and is curated as its own node below rather than bundled in here. Note what this is *not*: it is not the platelet-rich thrombotic occlusion of the MPN arm. Note also that the ectasia is itself a dilation finding, and so is a candidate account of the warm, hyperemic surface in its own right. Curated as `PROVISIONAL` deliberately. The series is small (n=9), single-centre and retrospective, its cases were selected by clinical concern for erythromelalgia rather than by aetiology, and it is not stratified into MPN versus non-MPN disease — so it cannot by itself establish that this lesion is specific to the acquired non-platelet routes, and the authors themselves frame it as suggesting rather than demonstrating a dysautonomia syndrome. Its edges are recorded in the `immune_dysautonomic_route` hypothesis group rather than asserted. It is also not the only histology on record for secondary erythromelalgia. A separate case report describes the commonly reported picture as capillary proliferation, endothelial swelling, perivascular edema and sparse chronic lymphocytic inflammation — naming neither complement deposition nor denervation — and reports its own case as unusual again. Those descriptions are not incompatible with this node (the C5b-9 and CD56 findings require stains that routine histology does not perform), but they are the reason this lesion is curated as one candidate account rather than as the histology of the acquired routes.

Immune-Mediated Microvascular Injury and Dysautonomia as an Alternative Route to the Erythromelalgic Flare

dermal microvascular endothelial cell CL:0011030

complement activation with C5b-9 deposition GO:0006956 ↑ INCREASED endothelial type I interferon signaling GO:0060337 ↑ INCREASED

acral arteriole UBERON:0001980

Downstream

Episodic Acral Burning Pain, Erythema, and Warmth An ectatic, complement-injured acral microvascular bed is proposed as one half of the substrate for the flare.

Show evidence (2 references)

PMID:39846717 SUPPORT Human Clinical

"Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells."

Direct histopathological demonstration of the complement and type-I-interferon endothelial lesion that defines this node.

PMID:23334520 NO_EVIDENCE Human Clinical

"Histology commonly shows capillary proliferation, swelling of endothelial cells, perivascular edema, and chronic inflammation with sparse lymphocytic infiltrate"

Recorded as NO_EVIDENCE and kept deliberately: an independent statement of the commonly reported secondary-erythromelalgia histology that names neither complement deposition nor autonomic denervation. It does not refute this node — those findings need C5b-9 and CD56 stains that routine histology omits — but it does show that the lesion curated here is not the established histological description of the acquired routes.

Autonomic Denervation of Acral Arteries and Eccrine Glands

Mechanism confidence: Provisional

The neural half of the same biopsy lesion, and the half that gives the route its name. CD56 staining in the same nine-patient series showed diminished autonomic innervation of the eccrine coil and of acral arteries, mirroring the denervation pattern seen in small-fiber neuropathy — which is one of the acquired routes named upstream, and the one this finding connects the entity to. The scale is `TISSUE` because the claim is about the innervation of a tissue compartment rather than the state of a cell type. This is the finding with the most mechanistic reach in the entity, because arteriovenous shunts are under autonomic control: it is therefore a candidate substrate for the shunting hypothesis recorded in `discussions#av_shunting_vs_occlusion_paradox`. It is a candidate only — the study measured innervation, not perfusion, oxygenation or shunt flow. Curated as `PROVISIONAL` deliberately. The series is small (n=9), single-centre and retrospective, its cases were selected by clinical concern for erythromelalgia rather than by aetiology, and it is not stratified into MPN versus non-MPN disease — so it cannot by itself establish that this lesion is specific to the acquired non-platelet routes, and the authors themselves frame it as suggesting rather than demonstrating a dysautonomia syndrome. Its edges are recorded in the `immune_dysautonomic_route` hypothesis group rather than asserted.

Immune-Mediated Microvascular Injury and Dysautonomia as an Alternative Route to the Erythromelalgic Flare

eccrine sweat gland UBERON:0000423 acral arteriole UBERON:0001980

Downstream

Episodic Acral Burning Pain, Erythema, and Warmth Loss of autonomic control of acral arterioles and eccrine glands is proposed to produce the maldistributed acral perfusion experienced as the flare.

Show evidence (1 reference)

PMID:39846717 SUPPORT Human Clinical

"CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."

Direct demonstration of the autonomic denervation this node asserts, and of its correspondence with small-fiber neuropathy, one of the acquired routes named upstream.

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Pathograph

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Phenotypes

6

Blood 1

Thrombocytosis HP:0001894

Show evidence (1 reference)

PMID:8951772 SUPPORT Human Clinical

"Erythromelalgia in thrombocythemia already occurred at slightly increased platelet counts above 400 x 10(9)/l."

Establishes both the presence of thrombocytosis and the low count threshold at which symptoms occur.

Cardiovascular 2

Erythema of the extremities HP:0010783

Show evidence (1 reference)

PMID:3977194 SUPPORT Human Clinical

"The localized painful burning, redness, and warm congestion in the extremities could be accurately documented with thermography."

Documents the erythema and warm congestion component, objectively confirmed thermographically.

Digital ischemic necrosis Digital ischemia HP:0033402

Show evidence (1 reference)

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."

Documents digital ischemic necrosis as an outcome of the untreated occlusive process.

Integument 1

Acrocyanosis FREQUENT HP:0001063

Show evidence (2 references)

PMID:8951772 SUPPORT INDIRECT Human Clinical

"Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."

Indirect support for the FREQUENT band, and only indirect. The abstract states "in 14 cases" with no denominator attached; the 14/31 (45%) ratio is a curator computation joining that sentence to the count of patients with erythromelalgia reported elsewhere in the same abstract. Three further caveats sit on top: the endpoint is a composite of acrocyanosis and necrosis, it is conditioned on being untreated with no untreated denominator given, and the series is referral-based. The band is not read off this figure alone.

PMID:8951772 SUPPORT Human Clinical

"The symptoms were platelet-mediated erythromelalgia in 16 PT and 15 PV"

Establishes the 31-patient erythromelalgia denominator used above, rather than the 50-patient thrombocythemia denominator that would understate the proportion.

Constitutional 2

Erythromelalgia OBLIGATE HP:0032147

Temporal: RECURRENT

Show evidence (3 references)

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."

Cited for the phenotype's association with the MPN context, not for the OBLIGATE band. The quote counts how often erythromelalgia presents among referred thrombocythemia patients (26/40), which is a different denominator from the frequency of the phenotype within this disease entity.

PMID:8951772 SUPPORT Human Clinical

"The symptoms were platelet-mediated erythromelalgia in 16 PT and 15 PV"

A second consecutive series records platelet-mediated erythromelalgia in 31 of 50 referred thrombocythemia patients. Again this is the MPN-population denominator, not the within-disease frequency, so it corroborates the association rather than the band.

PMID:39556352 NO_EVIDENCE Other

"Patients may have pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%) with abdominal discomfort."

Recorded as NO_EVIDENCE deliberately. The 5.3% is the frequency of erythromelalgia among polycythemia vera patients, a different entity's denominator, and it therefore does not bear on this phenotype's OBLIGATE band either way. It is cited here only as the modern unselected counterweight to the 62-65% referral-series fractions discussed above, so that a future curator does not mistake those for population frequencies.

Acral burning pain Limb pain HP:0009763

Show evidence (1 reference)

PMID:3977194 SUPPORT Human Clinical

"The localized painful burning, redness, and warm congestion in the extremities"

Describes the localized burning extremity pain that constitutes the core symptom.

💊

Medical Actions

6

Low-dose aspirin

Action: Pharmacotherapy NCIT:C15986

Agent: aspirin CHEBI:15365

Platform: Small molecule

The mechanism-matched treatment of MPN-associated erythromelalgia. Irreversible inhibition of platelet cyclooxygenase-1 abolishes the thromboxane-dependent platelet activation that drives arteriolar occlusion, producing complete relief of pain, restoration of microvascular circulation, normalization of shortened platelet survival, and fall of platelet-activation markers to normal. This dramatic responsiveness is the therapeutic hallmark separating MPN-associated secondary erythromelalgia from the characteristically aspirin-refractory primary (SCN9A/Nav1.7) form. Safety caveat: at very high platelet counts (roughly >1000-2000 x 10^9/L) thrombocythemia converts to a bleeding diathesis, and aspirin — while still preventing the microcirculatory disturbance — further increases the risk of serious haemorrhage. Two features sharpen the pharmacology and are worth separating from mere efficacy. First, the response is specific to cyclooxygenase inhibition rather than to anticoagulation as such: the same microvascular complications do not respond to coumadin, are relieved immediately by a 500 mg aspirin loading dose, and do not recur on 50 mg daily maintenance or after the platelet count is normalized. Second, holding the flare off appears to require ongoing inhibition rather than being a one-off cure: erythromelalgia emerged within two weeks of aspirin withdrawal in a patient whose myeloproliferative disorder was in remission and who had been taking aspirin for stroke prophylaxis, and remitted on rechallenge. That is a single observation, and it sits against the older series' description of an aspirin effect that is "curative" once the platelet count is controlled; the two are reconcilable only if what is cured is the flare and not the substrate.

Mechanism Target:

INHIBITS Thromboxane-Dependent Platelet Activation and Aggregation — Aspirin inhibits platelet cyclooxygenase-1, removing the thromboxane metabolites shown to be necessary for erythromelalgia to develop and thereby interrupting the platelet activation/aggregation node upstream of arteriolar occlusion.

Show evidence (3 references)

PMID:16673274 SUPPORT Human Clinical

"Inhibition of platelet cyclooxygenase-1 by aspirin is followed by relief of microvascular disturbances"

States the drug target (platelet COX-1) and the mechanistic consequence of inhibiting it.

PMID:16510297 SUPPORT Other

"These microvascular ischemic and thrombotic complications does not respond to Coumadin, but are immediately relieved by a loading dose of 500 mg aspirin"

States that the therapeutic effect is specific to cyclooxygenase inhibition and not to anticoagulation, which is the pharmacological counterpart of the thrombin-independent mechanism curated for this entity. Classified OTHER because the quoted comparison is this review's synthesis of the author's case material rather than a controlled head-to-head.

PMID:12781799 SUPPORT Human Clinical

"Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop."

Establishes that the inhibited pathway is necessary for the disease process, licensing the INHIBITS edge.

Target Phenotypes: Erythromelalgia HP:0032147

Show evidence (4 references)

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"

Documents complete symptomatic and microvascular response to cyclooxygenase inhibition.

PMID:22844295 SUPPORT Human Clinical

"was taken off aspirin and developed erythromelalgia within two weeks of withdrawal of aspirin. After restarting aspirin, patient's symptoms improved within 2 weeks."

A withdrawal-and-rechallenge observation. Note the direction carefully: the aspirin was being taken for stroke prophylaxis and the erythromelalgia emerged de novo on stopping it, so this is unmasking rather than relapse of treated disease. One patient, cited as an indication that continued cyclooxygenase inhibition is what holds the flare off, not as a general property.

PMID:12781799 SUPPORT Human Clinical

"Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in the disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times"

Confirms clinical and platelet-kinetic reversal on aspirin.

+ 1 more reference

Indomethacin

Action: Pharmacotherapy NCIT:C15986

Agent: indomethacin CHEBI:49662

Platform: Small molecule

A second cyclooxygenase inhibitor with the same mechanism-matched efficacy, confirming that the therapeutic effect is a class effect of COX inhibition rather than an aspirin-specific property. Notably sodium salicylate and the non-COX platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and dazoxiben are all ineffective, which is the pharmacological argument for the thromboxane mechanism.

Mechanism Target:

INHIBITS Thromboxane-Dependent Platelet Activation and Aggregation — Indomethacin inhibits the same platelet cyclooxygenase pathway targeted by aspirin.

Show evidence (1 reference)

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin, but not with sodium-salicylate or the platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and dazoxiben."

Indomethacin shares aspirin's efficacy while non-COX antiplatelet agents fail, establishing cyclooxygenase inhibition as the operative drug mechanism.

Show evidence (2 references)

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"

Documents complete symptomatic and microvascular relief with indomethacin alongside aspirin.

PMID:12781799 SUPPORT Human Clinical

"Complete relief from erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine."

Independently confirms indomethacin efficacy and the failure of non-COX antiplatelet agents.

Cytoreduction of the underlying myeloproliferative neoplasm

Action: cytoreductive therapy Ontology label: Chemotherapy NCIT:C15632

Platform: Small molecule

Treating the upstream disorder resolves the erythromelalgia: symptoms remit during cytoreduction-induced haematological remission of the thrombocythemia and recur on relapse. Contemporary cytoreductive agent selection is a matter for the MPN entries (`Polycythemia_Vera`, `Essential_Thrombocythemia`) rather than this entry; the historical evidence cited here used busulfan.

Mechanism Target:

INHIBITS Clonal Thrombocythemia in Myeloproliferative Neoplasm — Cytoreduction removes the clonal thrombocythemia that supplies the hyperreactive platelet population.

Show evidence (1 reference)

PMID:3977194 SUPPORT Human Clinical

"The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."

Remission of the thrombocythemia relieves the erythromelalgia, supporting an INHIBITS edge on the upstream node.

Show evidence (2 references)

PMID:3977194 SUPPORT Human Clinical

"The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."

Cytoreduction-induced haematological remission relieves the erythromelalgia, and relapse brings it back.

PMID:12781799 SUPPORT INDIRECT Human Clinical

"which specifically respond to low-dose aspirin or reduction of platelet counts to normal"

The quoted response applies to the accompanying transient ischemic manifestations rather than to the erythromelalgia itself, so the claim follows by an inference step: platelet-count reduction is established as an effective alternative to aspirin for the platelet-mediated microvascular syndrome of which erythromelalgia is one manifestation.

Treatment of the underlying condition in non-MPN secondary disease

Action: Supportive Care NCIT:C15747

For acquired erythromelalgia not driven by a myeloproliferative neoplasm, management is directed primarily at the underlying disease, supplemented by trigger avoidance. Aspirin is characteristically ineffective in these non-platelet-mediated forms. Note this is a statement about *cause-directed* therapy, not a claim that nothing helps symptomatically — symptomatic options with trial evidence are curated in the sibling treatment entry below.

Show evidence (3 references)

PMID:40428878 SUPPORT Human Clinical

"Secondary EM tends to be more variable in presentation, may be unilateral or localized, and treatment usually targets the underlying condition."

A 2025 systematic review states that treatment of secondary erythromelalgia usually targets the underlying condition.

PMID:29641704 SUPPORT Other

"Since there is no specific and effective treatment, control should focus on the underlying disease."

Cited only for the cause-directed management principle. This 2018 narrative review's blanket "no specific and effective treatment" is not adopted as written, because the later systematic review (PMID:40428878) reports measurable symptomatic benefit for several agents.

PMID:29641704 SUPPORT Other

"The prevention of crisis is based on a strict control of triggers and promotion of preventive measures."

Supports trigger control as the preventive component of management.

Symptomatic pharmacotherapy for aspirin-unresponsive disease

Action: Pharmacotherapy NCIT:C15986

Agent: amitriptyline CHEBI:2666 ketamine CHEBI:6121 lidocaine CHEBI:6456 iloprost CHEBI:63916 misoprostol CHEBI:63610

Platform: Small molecule

Where the platelet-mediated COX-1 mechanism does not apply — the non-MPN acquired routes, and MPN disease inadequately controlled by aspirin — symptomatic options with controlled or cohort evidence include topical amitriptyline-ketamine, lidocaine, and the prostaglandin analogues iloprost and misoprostol. IMPORTANT EVIDENCE CAVEAT, which is why these are curated as a single node without per-agent mechanism edges: the systematic review supplying this evidence pooled 120 patients across primary, idiopathic and secondary erythromelalgia and did NOT report outcomes stratified by aetiology, so efficacy specific to secondary disease is not established. Misoprostol in particular caused severe gastrointestinal toxicity.

Target Phenotypes: Limb pain HP:0009763

Show evidence (3 references)

PMID:40428878 SUPPORT INDIRECT Human Clinical

"About 75% of the patients reported pain relief with topical amitriptyline-ketamine, while lidocaine reduced nociceptive feelings in a dose-dependent manner."

The pooled cohort mixes primary, idiopathic and secondary erythromelalgia and is not stratified by aetiology, so the response rate cannot be attributed to secondary disease specifically; it reaches this claim only by assuming the mixed cohort's benefit extends to the secondary subset.

PMID:40428878 SUPPORT INDIRECT Human Clinical

"Iloprost and misoprostol exhibited notable benefits in cooling scores, sympathetic dysfunction, and EM severity compared to placebos."

Placebo-controlled benefit for the two prostaglandin analogues, again in a mixed-aetiology population that the review does not separate by cause.

PMID:40428878 SUPPORT Human Clinical

"adverse events ranged from mild gastrointestinal symptoms to severe complications such as disability and depression, requiring careful monitoring"

Documents the tolerability burden that qualifies these symptomatic options.

Chemical lumbar sympathectomy

Action: chemical lumbar sympathectomy Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Surgery

An invasive procedural option for refractory disease, reported to give sustained pain reduction with mild thigh pain as the common side effect. Carried as a sibling of the symptomatic-pharmacotherapy node under the SAME mixed-aetiology caveat: the systematic review supplying this evidence pooled 120 patients across primary, idiopathic and secondary erythromelalgia (13 of them receiving CLS) and did not stratify outcomes by aetiology, so efficacy in secondary disease is not established. Long-term outcomes are additionally underreported, and relapse is described in patients carrying SCN9A variants — a caveat belonging to the primary form, noted here only because it is inseparable from the pooled cohort. Term note: NCIT has no verifiable term for sympathectomy specifically, so the generic verified action term is used with a precise `preferred_term`; the procedure is a percutaneous chemical neurolysis rather than open surgery, though `SURGERY` is the closest available `therapeutic_modality` bucket for an invasive procedure.

Target Phenotypes: Limb pain HP:0009763

Show evidence (2 references)

PMID:40428878 SUPPORT INDIRECT Human Clinical

"observed significant pain reduction with CLS, with mild thigh pain as a side effect."

Significant pain reduction is reported, but within a mixed-aetiology pooled review that does not separate secondary from primary/idiopathic disease.

PMID:40428878 SUPPORT Human Clinical

"Despite encouraging short-term results, long-term outcomes after CLS remain underreported and variable."

Qualifies the procedure: encouraging short-term results but underreported and variable long-term outcomes, which is why this is curated as an option rather than a recommendation.

🌍

Environmental Factors

1

Limb warming, exercise, and dependency as attack precipitants

Erythromelalgic attacks are provoked by warmth and by anything that raises acral blood flow or venous pressure — exercise, physical activity, limb dependency, prolonged standing, and occlusive footwear — and are relieved by cooling and elevation. These are precipitants of the flare, not causes of the underlying disorder, so they are modeled as EXACERBATES on the flare node rather than as a trigger of the upstream mechanism. Note the therapeutic hazard shared with the primary form: patients self-treat by prolonged cold-water immersion, which causes skin maceration and secondary tissue injury.

Show evidence (1 reference)

PMID:40428878 SUPPORT Human Clinical

"Common relievers involve cooling methods such as local skin cooling or ice water immersion."

Documents cooling as the characteristic reliever, the counterpart of the warming trigger.

Mechanism Target:

EXACERBATES Episodic Acral Burning Pain, Erythema, and Warmth — Heat and exertion precipitate the erythromelalgic attack; cooling relieves it.

Show evidence (2 references)

PMID:40428878 SUPPORT Human Clinical

"Triggers for symptoms included warmth, exercise, dependency, tight footwear or gloves, physical activity, immersion, and emotional stress."

Enumerates the attack precipitants recorded across the systematic review's patient cohorts.

PMID:32491719 SUPPORT Other

"The episodes are typically precipitated by exercise and relieved by cooling the affected parts."

States the precipitation-by-exertion and relief-by-cooling pattern that defines the flare.

🔬

Biochemical Markers

4

Beta-thromboglobulin (Elevated)

Show evidence (1 reference)

PMID:8883266 SUPPORT Human Clinical

"As compared with asymptomatic ET patients and control subjects erythromelalgia was characterized by significantly higher beta-TG and TM levels but no significant differences were detected in either F1 + 2 or TDP levels."

Beta-thromboglobulin and thrombomodulin are selectively elevated in symptomatic patients while thrombin-generation markers are not, marking platelet activation and endothelial injury without coagulation activation.

Thrombomodulin (Elevated)

Show evidence (1 reference)

PMID:8883266 SUPPORT Human Clinical

"Treatment of erythromelalgia with aspirin resulted in disappearance of erythromelalgic signs and symptoms, which was paralleled by a significant decrease of beta-TG and TM levels."

Links normalization of the endothelial-damage and platelet-activation markers to clinical remission on aspirin.

Platelet survival time (Shortened)

Show evidence (2 references)

PMID:7792731 SUPPORT Human Clinical

"The mean platelet survival time of the erythromelalgia patients was 4.2 +/- 0.2 days, which is significantly decreased as compared with asymptomatic thrombocythemia patients (6.6 +/- 0.3 days, p < 0.001) and patients with reactive thrombocytosis (8.0 +/- 0.4 days, p < 0.001)."

Quantifies shortened platelet survival specifically in symptomatic erythromelalgia versus two comparator groups.

PMID:7792731 SUPPORT Human Clinical

"Treatment of erythromelalgia with aspirin increased the mean platelet survival time from 4.0 +/- 0.3 days to 6.9 +/- 0.4 days (p < 0.001)"

Aspirin reverses the shortened platelet survival, confirming COX-dependent platelet consumption as the operative process.

Urinary thromboxane B2 (Elevated)

Show evidence (1 reference)

PMID:12781799 SUPPORT Human Clinical

"a significant reduction of the increased levels of beta-TG, PF4, TM and urinary TxB2 excretion to normal"

Aspirin normalizes urinary thromboxane B2 alongside the other platelet-activation markers.

🔬

Diagnosis

4

Evaluation for an underlying myeloproliferative neoplasm

Because erythromelalgia is regarded as a pathognomonic microvascular complication of essential thrombocythemia and polycythemia vera — and frequently its presenting manifestation — a new diagnosis of erythromelalgia warrants haematological evaluation for an occult MPN, including a platelet count that may be only modestly elevated.

Results: Thrombocytosis (possibly only slightly above 400 x 10^9/L) with an MPN diagnosis supports platelet-mediated secondary erythromelalgia. The blood count is the first-line test; a JAK2 mutation search is the confirmatory step when the count is equivocal or the clinical suspicion outruns it, which is the common situation here because the flare precedes the haematological diagnosis by a median of two and a half years.

Show evidence (3 references)

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."

Erythromelalgia is the presenting symptom in most such patients, justifying MPN evaluation on presentation.

PMID:2643412 SUPPORT Other

"all patients with erythromelalgia should be monitored with periodic blood cell counts"

Because the flare precedes the myeloproliferative diagnosis by a median of two and a half years, a single normal count at presentation does not close the question; this source states the resulting recommendation for serial monitoring.

PMID:35835622 SUPPORT Other

"For erythermalgia, a blood count and even a search for JAK2 mutation are required."

Names the two haematological tests this entry's evaluation rests on — the blood count and, beyond it, a JAK2 mutation search. Classified OTHER because this is a practical-approach review of the vascular acrosyndromes rather than a report of primary data.

Serologic and small-fiber neuropathy workup for non-MPN causes

Because the acquired routes are not exhausted by the myeloproliferative neoplasms, a negative haematological work-up does not end the evaluation. Thyroid function, antinuclear antibodies and testing for small-fiber neuropathy address the three non-MPN routes this entry models — endocrine, autoimmune and neuropathic — and the latter two are the routes the `immune_dysautonomic_route` hypothesis is about. Note the therapeutic stakes of getting this right: these are the aspirin-resistant forms, so identifying the underlying condition is what management turns on.

Results: An abnormal thyroid-stimulating hormone assay, a positive antinuclear antibody test, or demonstrated small-fiber neuropathy each redirects the evaluation away from the platelet-mediated arm and toward a cause-directed treatment.

Show evidence (1 reference)

PMID:35835622 SUPPORT Other

"A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed."

States the serologic and neuropathy tests performed alongside the haematological work-up. The two misspellings are present in the cited abstract and are preserved verbatim, as an evidence snippet must be an exact source substring. Classified OTHER because this is a practical-approach review rather than a report of primary data.

Skin punch biopsy of an affected area

Histopathology of affected acral skin demonstrates the characteristic arteriolar inflammation, fibromuscular intimal proliferation, and platelet-rich thrombotic occlusions that distinguish platelet-mediated secondary erythromelalgia from the primary neuropathic form. Which stains are ordered decides which arm the biopsy can speak to. Routine histology demonstrates the platelet-arm lesion above. The complement and denervation findings behind `pathophysiology#Complement-Mediated Microvascular Endothelial Injury` and `pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands` are invisible to it: they require C5b-9 immunostaining, type-I interferon staining and CD56. A routine-stain biopsy reported as unremarkable therefore does not exclude the immune/dysautonomic route — it was never tested for.

Results: Arteriolar inflammation, fibromuscular intimal proliferation, and thrombotic occlusion on routine histology. On C5b-9, type-I interferon and CD56 immunostaining, superficial vascular ectasia with microvascular C5b-9 deposition, endothelial interferon upregulation, and diminished autonomic innervation of the eccrine coil and arteries.

Show evidence (3 references)

PMID:3977194 SUPPORT Human Clinical

"Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions."

Establishes the diagnostic histopathological findings on skin punch biopsy.

PMID:39846717 SUPPORT Human Clinical

"Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells."

Establishes the immunohistochemical findings a biopsy can carry beyond routine histology, and therefore the stains that have to be requested for the biopsy to bear on the immune/dysautonomic route.

PMID:39846717 SUPPORT Human Clinical

"CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."

Names CD56 as the stain demonstrating the autonomic denervation finding, and ties the biopsy to the small-fiber neuropathy route tested serologically in the entry above.

Therapeutic response to aspirin as a diagnostic discriminator

The dramatic, complete, and sustained response of platelet-mediated erythromelalgia to a cyclooxygenase inhibitor is itself diagnostically informative: the historical Drenth-Michiels classification of red, burning extremities was built on aspirin responsiveness, separating aspirin-responsive thrombocythemic erythromelalgia from the aspirin-resistant primary and other secondary forms.

Results: Complete relief of pain with aspirin supports the platelet-mediated (MPN-associated) form.

Show evidence (1 reference)

PMID:32491719 SUPPORT Other

"The term erythromelalgia and erythermalgia were differentiated on the basis of responsiveness to aspirin by Drenth and Michiels"

Documents aspirin responsiveness as the historical basis for discriminating these entities.

📈

Progression

3

Erythromelalgic flare as presenting manifestation

Age: Adults; median 61 years (range 16-90)

The flare typically arrives before, not after, the diagnosis of the underlying disorder. In the Michiels thrombocythemia series erythromelalgia was the presenting symptom in 26 of 40 patients, and the Olmsted County case definition had to allow for a myeloproliferative neoplasm diagnosed within two years *either side* of the erythromelalgia in order to classify those cases as secondary. A review of the 60 published myeloproliferative cases puts a number on the lag: erythromelalgia preceded the onset of the myeloproliferative disease by a median of two and a half years. That lag is the clinical justification for the haematological work-up curated under `diagnosis#Evaluation for an underlying myeloproliferative neoplasm`: a normal or near-normal blood count at presentation does not exclude an MPN. The age figure is quoted for orientation only — the Olmsted cohort is dominated by primary disease (incidence 1.1 versus 0.2 per 100,000/yr), so it is not an age-of-onset estimate for this entity. A second population series (Sweden) independently records a long interval between symptom onset and diagnosis, which is the same phenomenon seen from the patient's side rather than the haematologist's.

Show evidence (6 references)

PMID:18713229 SUPPORT Human Clinical

"if a myeloproliferative disorder was diagnosed within 2 years of the diagnosis of erythromelalgia"

A population-based case definition whose two-year window is symmetric about the erythromelalgia diagnosis, so it admits cases in which the MPN is only recognised later. It does not by itself establish the direction; the lead time is evidenced separately below.

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."

Quantifies the flare as the presenting manifestation in the majority of a referred thrombocythemia series.

PMID:2643412 SUPPORT Human Clinical

"symptoms of erythromelalgia preceded the onset of a myeloproliferative disease by a median of 2 1/2 years"

Quantifies the lead time between the erythromelalgic flare and diagnosis of the underlying myeloproliferative disease across the published case literature.

+ 3 more references

Untreated progression to acrocyanosis and digital ischemic necrosis

Left untreated the syndrome does not simply persist as episodic pain; it advances to fixed acral ischemia. Across 31 patients with erythromelalgia in a consecutive thrombocythemia series, 14 progressed to acrocyanosis or peripheral ischemia with necrosis of a toe or fingertip (the caveats on that ratio are set out once, on the `Acrocyanosis` phenotype, and are not repeated here). It is recorded as the untreated trajectory rather than as a rate. This is the phase the cyclooxygenase inhibitors interrupt, which is why aspirin here is disease-modifying rather than merely analgesic.

Show evidence (3 references)

PMID:8951772 SUPPORT Human Clinical

"Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."

Direct observation of the untreated natural history advancing from episodic flare to fixed acral ischemia and tissue loss.

PMID:3977194 SUPPORT Human Clinical

"Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."

A second series independently reports the same progression from flare to acrocyanosis and digital necrosis.

PMID:11208311 SUPPORT Other

"If left untreated, it may progress towards acrocyanosis and even peripheral gangrene."

Names peripheral gangrene as the far end of the untreated trajectory, conditioning the progression explicitly on lack of treatment.

Remission on cyclooxygenase inhibition or cytoreduction

In the platelet-mediated arm the course is interruptible and the interruption is complete rather than partial — pain relief and restoration of the microvascular disturbance on aspirin or indomethacin, and remission of the erythromelalgia when the underlying thrombocythemia is put into haematological remission, with recurrence on relapse. This phase is what separates the MPN arm prognostically from the non-MPN acquired routes curated in `pathophysiology#Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)`, which are aspirin resistant and have no comparable reversal.

Show evidence (2 references)

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"

Establishes that the flare phase is fully reversible on cyclooxygenase inhibition rather than only attenuated.

PMID:3977194 SUPPORT Human Clinical

"The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."

Remission and relapse of the erythromelalgia track the haematological state, establishing cytoreduction as the second route into this phase.

📊

Prevalence

1

Olmsted County, Minnesota, USA (population-based, 1976-2005)

Annual Incidence 0.2 per 100,000 (0.02–0.4) Rare

Population-based age- and sex-adjusted incidence of secondary erythromelalgia from the Rochester Epidemiology Project (overall erythromelalgia incidence 1.3/100,000/yr; primary 1.1/100,000/yr). In this study "secondary" was defined by a coexisting myeloproliferative disorder, or attribution to another cause such as medications, HIV, or mushroom poisoning. The confidence interval is wide and the authors note the small sample size as a limitation.

Show evidence (1 reference)

PMID:18713229 SUPPORT Human Clinical

"The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively."

Provides the population-based annual incidence estimate for secondary erythromelalgia.

⚖️

Clinical Burden

Variable

Burden here is decided by aetiology, not by severity of the flare, and the two arms of this entity sit at opposite ends. Untreated, the syndrome is not a nuisance symptom: it runs a chronic course with considerable disability, and in a consecutive thrombocythemia series roughly half the affected patients progressed to acrocyanosis or peripheral ischemia with necrosis of a toe or fingertip (ratio and its caveats on the `Acrocyanosis` phenotype). Against that, the platelet-mediated MPN arm is abolished by low-dose aspirin, with complete relief of pain and restoration of the microvascular disturbance, so a correctly diagnosed patient in that arm carries little residual burden from the flare itself — though the suppression requires continued dosing, and at very high platelet counts the drug that suppresses the flare is itself a bleeding hazard. The non-MPN acquired routes have no such exit — they are aspirin resistant, and management falls back on treating the underlying disorder. `VARIABLE` rather than `HIGH` records that split honestly: assigning a single level would either overstate the burden of the treatable arm or understate the tissue loss risk of the untreated and refractory ones.

Show evidence (5 references)

PMID:18713229 SUPPORT INDIRECT Other

"It typically has a chronic course and is associated with diminished quality of life and considerable disability"

Characterizes the course as chronic and disabling. Classified OTHER because this sentence is the paper's introductory framing, citing prior literature, rather than a result of its own population-based analysis; indirect because that framing is about erythromelalgia in general in a cohort this entry elsewhere notes is dominated by primary disease (1.1 versus 0.2 per 100,000/yr).

PMID:8951772 SUPPORT Human Clinical

"Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."

Supplies the high end of the range — irreversible tissue loss in a substantial fraction of untreated patients.

PMID:3977194 SUPPORT Human Clinical

"Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"

Supplies the low end — the platelet-mediated arm is fully reversible on a cheap oral agent.

+ 2 more references

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Secondary Erythromelalgia:

Primary erythermalgia MONDO:0007571

Overlapping Features The principal differential. Primary/inherited erythromelalgia is an autosomal dominant SCN9A (Nav1.7) gain-of-function channelopathy of nociceptors, characteristically bilateral and symmetric, and characteristically refractory to aspirin — the mechanistic and therapeutic mirror image of the platelet-mediated secondary form modeled here. Curated separately as `Primary_Erythermalgia`.

Show evidence (3 references)

PMID:8203771 SUPPORT Human Clinical

"the authors discern three distinct types of red, congested, and burning extremities that need to be distinguished for effective treatment according to their etiology: erythromelalgia in thrombocythemia, primary erythermalgia, and secondary erythermalgia"

Establishes that thrombocythemic erythromelalgia and primary erythermalgia are distinct clinicopathologic entities requiring different treatment.

PMID:32491719 SUPPORT Other

"Primary erythermalgia: Refers to an idiopathic or inherited disorder. Also called aspirin-resistant erythermalgia of unknown origin."

Documents the aspirin resistance of primary erythermalgia, the therapeutic discriminator from the MPN-associated form.

PMID:30609105 SUPPORT Other

"recent discoveries of the genetic mutations that now define primary erythromelalgia, as opposed to secondary erythromelalgia"

States that genetic mutations define the primary form in contradistinction to the secondary form.

Superficial thrombophlebitis

Overlapping Features Painful red, warm, indurated erythromelalgic "hot spots" on the skin of the upper legs in thrombocythemia are readily misdiagnosed as superficial thrombophlebitis, which would be treated quite differently.

Show evidence (1 reference)

PMID:8951772 SUPPORT Human Clinical

"Painful red, warm and indurated erythromelalgic hot spots in the skin of the upper legs were misdiagnosed as superficial thrombophelebitis in 5 PT and 2 PV patients."

Documents this specific misdiagnosis in 7 of 50 thrombocythemia patients.

{ }

Source YAML

click to show

name: Secondary Erythromelalgia
creation_date: "2026-08-17T00:00:00Z"
description: >-
  Secondary (acquired) erythromelalgia is erythromelalgia arising in the context
  of an identifiable underlying disorder rather than from an inherited
  sodium-channel lesion. Its best-characterized and best-evidenced form is
  the erythromelalgia of the myeloproliferative neoplasms (MPN) — essential
  thrombocythemia and polycythemia vera — where the mechanism is not nociceptor
  channelopathy but platelet-mediated arteriolar inflammation and thrombotic
  occlusion of the acral microvasculature. Skin punch biopsies from affected
  areas show arteriolar inflammation, fibromuscular intimal proliferation, and
  platelet-rich thrombotic occlusions; platelet survival is shortened, platelet
  activation markers are elevated, and the entire syndrome is abolished by
  cyclooxygenase inhibition. Other acquired routes — autoimmune connective-tissue
  disease, small-fiber peripheral neuropathy, and drug exposure — are recognized
  but far less mechanistically resolved. This entry is the acquired sibling of
  `Primary_Erythermalgia` (SCN9A/Nav1.7 gain-of-function) and sits beneath the
  umbrella entry `erythromelalgia`; the two are distinguished mechanistically
  (platelet-microvascular versus neuronal-channelopathy) and therapeutically (the
  dramatic aspirin responsiveness of MPN-associated disease versus the
  characteristic aspirin refractoriness of the primary form). The underlying MPN
  pathophysiology itself is curated in `Polycythemia_Vera` and
  `Essential_Thrombocythemia` and is deliberately not re-derived here.
category: Complex
parents:
- disease
synonyms:
- Secondary erythermalgia
- Acquired erythromelalgia
disease_term:
  preferred_term: secondary erythromelalgia
  term:
    id: MONDO:0035149
    label: secondary erythromelalgia
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:I73.8
      label: Other specified peripheral vascular diseases
    mapping_predicate: skos:broadMatch
    mapping_source: MONDO:0035149
    mapping_justification: >-
      MONDO:0035149 carries ICD10CM:I73.8 as a cross-reference. The predicate is broadMatch, not
      exactMatch: I73.8 is a residual "other specified peripheral vascular diseases" bucket that
      does not distinguish primary from secondary erythromelalgia, so an ICD-10-CM-coded cohort
      cannot be used as a case definition for this entry. Note that ICD-10-CM does carry a
      narrower child, ICD10CM:I73.81 "Erythromelalgia", recorded separately below; this row is
      kept because it is the cross-reference MONDO itself asserts, and removing it would lose
      that provenance.
  - term:
      id: ICD10CM:I73.81
      label: Erythromelalgia
    mapping_predicate: skos:broadMatch
    mapping_source: dismech curator
    mapping_justification: >-
      The tightest ICD-10-CM code for this concept, added here because MONDO's own cross-reference
      (I73.8, above) is a residual bucket that codes far more than erythromelalgia. Still
      broadMatch rather than exactMatch: I73.81 is "Erythromelalgia" without qualification, so it
      covers the primary SCN9A/Nav1.7 form curated in `Primary_Erythermalgia` as well as this
      acquired one, and an I73.81-coded cohort therefore still cannot serve as a case definition
      for this entry.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      Primary clinical home, assigned on the curated content rather than on a checked
      table of contents: the curated lesion is occlusion of the acral arteriolar
      microvasculature, and the entity's ICD-10-CM cross-reference (I73.8) sits in the
      peripheral vascular disease block. `DERMATOLOGY` was considered and not assigned —
      the presentation is cutaneous and the diagnostic test is a skin punch biopsy, but
      the mechanism curated here is vascular and haematological, and a third Part would
      dilute rather than sharpen the placement.
    evidence:
    - reference: PMID:12781799
      reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "caused by spontaneous activation and aggregation of hypersensitive platelets in the end-arterial microvasculature involving the peripheral, cerebral and coronary circulation"
      explanation: >-
        Characterizes the syndrome as a disorder of the end-arterial microvasculature across the
        peripheral, cerebral and coronary beds, which is the vascular framing behind the
        CARDIOVASCULAR placement. Classified OTHER because the quoted sentence is this review's
        mechanistic synthesis rather than a result of a primary study.
  - classification_value: ONCOLOGY_HEMATOLOGY
    notes: >-
      Second Part, and not merely contextual: the best-evidenced form of this entity is
      defined by an underlying myeloproliferative neoplasm, its diagnosis turns on
      haematological evaluation, and cytoreduction of the MPN is one of its two
      mechanism-directed treatments. The MPN pathophysiology itself is curated in
      `Polycythemia_Vera` and `Essential_Thrombocythemia`.
    evidence:
    - reference: PMID:9263352
      reference_title: 'Erythromelalgia: a pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Erythromelalgia is a characteristic thrombotic complication in patients with the myeloproliferative disorders, essential thrombocythemia and polycythemia vera."
      explanation: >-
        Places the entity as a complication of two myeloproliferative neoplasms, supporting the
        haematology Part alongside the vascular one. Classified OTHER because this is a narrative
        minireview summarizing the authors' prior work rather than a report of primary data.
notes: >-
  Deliberate non-conformance to the `thrombogenesis` module. The acral thrombi of
  MPN-associated erythromelalgia are platelet- and von Willebrand factor-rich with
  only weak fibrin staining, and develop despite therapeutic anticoagulation, with
  no rise in prothrombin fragment 1+2 (PMID:8883266) — i.e. thrombin generation is
  not required. The `thrombogenesis` module explicitly scopes out "VWF-platelet
  microangiopathy ... unless a distinct conventional thrombin/fibrin thrombosis
  branch is explicitly evidenced", and no such branch is evidenced here, so no
  `conforms_to` edge is asserted. This is recorded rather than silently omitted
  because the disease looks superficially like a thrombogenesis conformer.


  `datasets:` is intentionally empty. `just discover-datasets` returns no GEO
  candidates, and the obvious relaxations are both unsafe here: this syndrome has
  no causal gene of its own, so a gene-keyed search has nothing to key on, and
  searching the underlying myeloproliferative neoplasms would return datasets that
  belong to `Polycythemia_Vera` / `Essential_Thrombocythemia` rather than to this
  entry. Adding those would be Named Entity Confusion reached through dataset
  search, so nothing is recorded.


  `clinical_trials:` is likewise intentionally empty. The interventional trials in
  erythromelalgia recruit primary/inherited or idiopathic disease and explicitly
  exclude patients whose extremity pain has another cause — the EASE study of ATX01
  topical amitriptyline 15% (NCT05917912, AlgoTherapeutix, 14 participants), the
  burst spinal-cord-stimulation study (NCT04039633, St. Olavs Hospital, 6
  participants), and the Nav1.7-targeted agent studies (NCT01090622, NCT01486446,
  NCT01769274). None of them enrol secondary erythromelalgia, so listing them here
  would misattribute trial evidence to this entity. The two lead identifiers were
  checked against the ClinicalTrials.gov API directly, not only against the
  deep-research report, because identifiers inside free-text `notes:` are not
  reference-validated by `just validate-disorders`.
pathophysiology:
- name: Clonal Thrombocythemia in Myeloproliferative Neoplasm
  biological_scale: ORGANISM
  description: >-
    The upstream trigger of MPN-associated erythromelalgia is the clonal
    thrombocythemia of essential thrombocythemia or polycythemia vera, which
    supplies a population of qualitatively abnormal, hyperactivatable platelets.
    The dependence is causal rather than merely associative: erythromelalgia
    remits during cytoreduction-induced haematological remission and recurs when
    the thrombocythemia relapses. Notably the threshold is low — symptoms occur at
    platelet counts only slightly above normal — so absolute platelet mass is not
    the determinant. The clonal driver biology itself (JAK2 V617F and the
    haematopoietic consequences) is curated in `Polycythemia_Vera` and
    `Essential_Thrombocythemia`.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  - preferred_term: megakaryocyte
    term:
      id: CL:0000556
      label: megakaryocyte
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."
    explanation: >-
      Remission-and-relapse concordance with the underlying thrombocythemia establishes
      the MPN as the causal upstream driver rather than a coincidental association.
  - reference: PMID:9263352
    reference_title: 'Erythromelalgia: a pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Erythromelalgia is a characteristic thrombotic complication in patients with the myeloproliferative disorders, essential thrombocythemia and polycythemia vera."
    explanation: >-
      Identifies the two myeloproliferative neoplasms that constitute the principal underlying
      disorders of this secondary form. Classified OTHER because this is a narrative minireview
      summarizing the authors' prior work rather than a report of primary data.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia in thrombocythemia already occurred at slightly increased platelet counts above 400 x 10(9)/l."
    explanation: >-
      Symptoms arise at only slightly elevated platelet counts, indicating that qualitative
      platelet hyperreactivity rather than absolute platelet mass drives the mechanism.
  downstream:
  - target: Thromboxane-Dependent Platelet Activation and Aggregation
    description: The clonal platelet population undergoes intravascular cyclooxygenase-dependent activation and aggregation.
    evidence:
    - reference: PMID:8883266
      reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our data suggest that erythromelalgia is caused by the intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature."
      explanation: Links the thrombocythemic platelet population to intravascular platelet activation and aggregation.
- name: Thromboxane-Dependent Platelet Activation and Aggregation
  biological_scale: CELLULAR
  description: >-
    Circulating MPN platelets undergo intravascular activation and aggregation in
    the acral microcirculation. The process is strictly cyclooxygenase-metabolite
    dependent: it is abolished by aspirin and indomethacin but not by
    sodium salicylate or by non-COX platelet inhibitors (dipyridamole,
    sulfinpyrazone, ticlopidine, dazoxiben). In vivo activation is measurable as
    elevated beta-thromboglobulin, platelet factor 4, thrombomodulin, and urinary
    thromboxane B2, together with a markedly shortened platelet survival time that
    aspirin normalizes. Critically, thrombin generation is NOT required — prothrombin
    fragment 1+2 and fibrin degradation products are unchanged, and the lesions
    develop despite heparin or coumarin anticoagulation.
  cell_types:
  - preferred_term: platelet
    term:
      id: CL:0000233
      label: platelet
  biological_processes:
  - preferred_term: platelet activation
    modifier: INCREASED
    term:
      id: GO:0030168
      label: platelet activation
  - preferred_term: platelet aggregation
    modifier: INCREASED
    term:
      id: GO:0070527
      label: platelet aggregation
  - preferred_term: prostanoid (thromboxane) biosynthesis
    modifier: INCREASED
    term:
      id: GO:0046457
      label: prostanoid biosynthetic process
  molecular_functions:
  - preferred_term: platelet cyclooxygenase-1 activity
    term:
      id: GO:0004666
      label: prostaglandin-endoperoxide synthase activity
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin, but not with sodium-salicylate or the platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and dazoxiben."
    explanation: >-
      The pharmacological dissection — COX inhibitors work, other antiplatelet agents do not —
      establishes cyclooxygenase metabolites as mechanistically necessary.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop."
    explanation: States the necessity of cyclooxygenase metabolites explicitly.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "significant higher levels of platelet activation markers beta-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia"
    explanation: Quantifies in vivo platelet activation and thromboxane generation specifically in symptomatic patients.
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest that erythromelalgia is caused by the intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature."
    explanation: Directly states intravascular platelet activation and aggregation as the causal mechanism.
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The generation of thrombin appears not to be essential for the formation of these platelet thrombi, thereby giving a plausible explanation for the inefficacy of coumadin derivatives and heparin in the prevention and treatment of erythromelalgia in essential thrombocythemia."
    explanation: >-
      Establishes the thrombin-independence of the mechanism — the basis for this entry's
      deliberate non-conformance to the thrombin/fibrin `thrombogenesis` module.
  - reference: PMID:7792731
    reference_title: 'Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The increased platelet consumption in erythromelalgia is attributed to the formation of platelet thrombi in the arterial microvasculature."
    explanation: Radiolabelled platelet-survival kinetics independently confirm ongoing platelet consumption in microvascular thrombi.
  downstream:
  - target: Arteriolar Inflammation and Fibromuscular Intimal Proliferation
    description: Activated platelets and their released mediators injure and remodel the arteriolar wall.
    evidence:
    - reference: PMID:12781799
      reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies"
      explanation: Ties local platelet consumption directly to the arteriolar intimal-proliferative lesion.
  - target: Acral Arteriolar Microvascular Occlusion
    description: Platelet aggregates sludge and occlude the acral arterial microvasculature.
    evidence:
    - reference: PMID:8883266
      reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature"
      explanation: States the causal step from platelet aggregation to acral microvascular occlusion.
- name: Arteriolar Inflammation and Fibromuscular Intimal Proliferation
  biological_scale: TISSUE
  description: >-
    Skin punch biopsies taken from erythromelalgic areas show a distinctive
    arteriolar lesion — inflammation of the arteriolar wall with fibromuscular
    proliferation of the intima — accompanying the thrombotic occlusions. This
    inflammatory and proliferative wall response, together with the elevated
    thrombomodulin indicating endothelial injury, distinguishes the lesion from a
    bland intraluminal clot and is what makes "platelet-mediated arteriolar
    inflammation" rather than simple thrombosis the accurate description.
  cell_types:
  - preferred_term: arteriolar endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: arteriolar smooth muscle cell
    term:
      id: CL:0000192
      label: smooth muscle cell
  biological_processes:
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  - preferred_term: smooth muscle cell proliferation
    modifier: INCREASED
    term:
      id: GO:0048659
      label: smooth muscle cell proliferation
  locations:
  - preferred_term: arteriole
    term:
      id: UBERON:0001980
      label: arteriole
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions."
    explanation: Direct histopathological demonstration of the arteriolar inflammatory and intimal-proliferative lesion in affected skin.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies"
    explanation: Independently restates the arteriolar intimal-proliferative and platelet-rich occlusive histopathology.
  downstream:
  - target: Acral Arteriolar Microvascular Occlusion
    description: Intimal proliferation narrows the arteriolar lumen and compounds platelet-driven occlusion.
    evidence:
    - reference: PMID:3977194
      reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions."
      explanation: The inflammatory/intimal-proliferative change and the thrombotic occlusion are demonstrated together in the same affected-skin biopsies.
- name: Acral Arteriolar Microvascular Occlusion
  biological_scale: TISSUE
  description: >-
    The convergent lesion is occlusion of acral arterioles by platelet-rich,
    von Willebrand factor-positive thrombi with only weak fibrin content. The
    resulting acral perfusion disturbance is the immediate substrate of the
    erythromelalgic flare and, if unrelieved, of progressive digital ischemia. The
    VWF-rich, fibrin-poor composition of these thrombi is the histological
    counterpart of the biochemical finding that thrombin generation is dispensable.
  locations:
  - preferred_term: arteriole
    term:
      id: UBERON:0001980
      label: arteriole
  evidence:
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologic and immunohistochemical analysis of biopsies derived from erythromelalgic skin areas of 2 ET patients showed that erythromelalgic thrombi stained positively for von Willebrand factor opposed to only a weak fibrin staining."
    explanation: >-
      Immunohistochemistry establishes the VWF-rich, fibrin-poor composition of the occluding
      thrombi, distinguishing them from conventional fibrin-platelet thrombi.
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "platelet-mediated inflammatory and occlusive arteriolar changes play a part in the etiology of erythromelalgia"
    explanation: Summarizes occlusive arteriolar change as the operative lesion in the aetiology of the syndrome.
  downstream:
  - target: Episodic Acral Burning Pain, Erythema, and Warmth
    description: Acral microvascular occlusion and the accompanying congestion produce the erythromelalgic attack.
    evidence:
    - reference: PMID:3977194
      reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"
      explanation: >-
        Pain relief and restoration of the microvascular circulation move together under COX inhibition,
        supporting the microvascular disturbance as the proximate cause of the flare.
  - target: Progression to Acrocyanosis and Digital Ischemic Necrosis
    description: Untreated, sustained occlusion progresses to fixed acral ischemia.
    evidence:
    - reference: PMID:8951772
      reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."
      explanation: The untreated occlusive process progresses to acrocyanosis and acral necrosis in a defined fraction of patients.
- name: Episodic Acral Burning Pain, Erythema, and Warmth
  biological_scale: ORGANISM
  description: >-
    The clinical expression is the erythromelalgic attack: localized burning pain
    with redness and warm congestion of the distal extremities, documentable by
    thermography, most often in the forefoot sole and toes and less often in the
    fingertips or palm. Unlike the bilaterally symmetric flares of the primary
    form, secondary attacks are frequently asymmetric or unilateral, and
    erythromelalgic "hot spots" on the legs can be misread as superficial
    thrombophlebitis. No `biological_processes` are bound to this node: the obvious
    candidate (vasodilation) is not measured by any cited study and would sit
    awkwardly against this entry's occlusive model, in which the red, warm skin
    accompanies platelet-rich arteriolar obstruction rather than simple vasodilation.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The localized painful burning, redness, and warm congestion in the extremities could be accurately documented with thermography."
    explanation: Describes the flare phenotype and its objective thermographic correlate.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia was localized in the forefoot sole and toes in 28, the fingertips in 9, the handpalm in 2."
    explanation: Quantifies the acral, foot-predominant anatomical distribution of attacks in a 50-patient thrombocythemia series.
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although erythromelalgia is typically bilateral, it can present unilaterally, especially in secondary cases."
    explanation: >-
      Supports asymmetric/unilateral presentation as a feature that clinically distinguishes
      secondary from the characteristically bilateral primary form.
- name: Progression to Acrocyanosis and Digital Ischemic Necrosis
  biological_scale: TISSUE
  description: >-
    When the platelet-mediated occlusive process is not interrupted, the reversible
    erythromelalgic flare progresses to fixed acral ischemia: acrocyanosis and
    then frank ischemic necrosis or gangrene of toes or fingertips. This
    ischemic-progression arm is a mechanistically distinct outcome from the
    self-inflicted cold-immersion tissue injury that dominates complications in the
    primary form, and it is the reason MPN-associated erythromelalgia is treated as
    a thrombotic complication rather than purely a pain syndrome.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."
    explanation: Documents progression from the reversible flare to fixed acral ischemic tissue loss.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."
    explanation: Quantifies ischemic progression in 14 of 50 thrombocythemia patients when erythromelalgia was left untreated.
- name: Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    Beyond the myeloproliferative neoplasms, erythromelalgia is reported secondary
    to small-fiber peripheral neuropathy, autoimmune connective-tissue disease, and
    drug exposure. These routes are recognised clinically but are far less
    mechanistically resolved than the MPN arm: combined neural and vascular
    abnormalities are invoked rather than a single demonstrated lesion, and
    critically these forms do NOT share the aspirin responsiveness of the
    platelet-mediated arm, which is why the historical Drenth-Michiels
    classification separated aspirin-resistant "secondary erythermalgia" from
    aspirin-responsive thrombocythemic erythromelalgia. Curated here as a
    deliberately low-resolution node rather than a speculative mechanism chain,
    with the one downstream lesion that does have a biopsy correlate — the
    complement/denervation node below — tagged as an emerging hypothesis rather
    than asserted.

    Two further acquired associations are documented as single reports and are
    named here rather than modeled: thrombotic thrombocytopenic purpura, whose own
    mechanism is diffuse platelet aggregation and which is therefore closer to the
    platelet arm than to this one, and chronic myelogenous leukemia, which extends
    the myeloid association beyond the classical polycythemia vera and essential
    thrombocythemia pair.
  evidence:
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is often linked to underlying conditions such as myeloproliferative disorders (e.g., essential thrombocythemia, polycythemia vera), autoimmune diseases, infections, tumors, or medication use"
    explanation: >-
      Enumerates the acquired etiologies named in this node — autoimmune disease, infection,
      neoplasia and drug exposure alongside the myeloproliferative neoplasms.
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "if the erythromelalgia was thought to be attributable to another cause such as medications, human immunodeficiency virus, or mushroom poisoning"
    explanation: >-
      A population-based study's own case definition independently names the drug, infection and
      toxin routes as recognized non-MPN causes of secondary erythromelalgia.
  - reference: PMID:15075045
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "secondary, which is associated with myeloproliferative disorders-related thrombocythemia, polycythemia, collagen-vascular diseases, diabetes mellitus, peripheral neuropathy, autoimmune and infectious diseases, and use of certain medicaments"
    explanation: >-
      Names the acquired associations modeled by this node — collagen-vascular disease, diabetes
      mellitus, peripheral neuropathy, autoimmune and infectious disease, and drug exposure —
      alongside the myeloproliferative route curated separately above.
  - reference: PMID:30609105
    reference_title: Review of primary and secondary erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "secondary erythromelalgia, which is often associated with underlying medical disorders"
    explanation: >-
      Establishes the defining feature of the secondary form — association with an underlying
      medical disorder — as distinct from the genetically defined primary form.
  - reference: PMID:29641704
    reference_title: 'Erythromelalgia: a cutaneous manifestation of neuropathy?'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primary erythromelalgia is an autosomal dominant inherited disorder, while secondary is associated with myeloproliferative diseases, among others. In its etiopathogenesis, there are neural and vascular abnormalities that can be combined."
    explanation: >-
      The review asserts combined neural and vascular contributions to secondary disease
      without resolving a specific lesion for the non-MPN routes, which is why this node is
      curated at deliberately low resolution rather than as a mechanism chain.
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Secondary erythermalgia: Aspirin resistant and associated with different medical conditions."
    explanation: >-
      This is item (c) of the Drenth-Michiels three-way classification, which *defines* its
      "secondary erythermalgia" category by aspirin resistance rather than reporting resistance as
      an empirical result. Cited as the nomenclature's own statement of the pharmacological split;
      because the category is defined by the property, the support for the claim is indirect.
  - reference: PMID:1613144
    reference_title: Erythromelalgia in a patient with thrombotic thrombocytopenic purpura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a female patient in whom thrombotic thrombocytopenic purpura was associated with erythromelalgia."
    explanation: >-
      A single case report adding thrombotic thrombocytopenic purpura to the acquired
      associations. Recorded as an association only; one patient does not establish a mechanism.
  - reference: PMID:2643412
    reference_title: Erythromelalgia and myeloproliferative disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe, for the first time, a patient in whom chronic myelogenous leukemia was associated with the development of erythromelalgia"
    explanation: >-
      Extends the myeloid association beyond polycythemia vera and essential thrombocythemia to
      chronic myelogenous leukemia, again on a single case.
  downstream:
  - target: Episodic Acral Burning Pain, Erythema, and Warmth
    description: These acquired routes converge on the same clinical flare phenotype by mechanisms that remain incompletely defined.
    evidence:
    - reference: PMID:29641704
      reference_title: 'Erythromelalgia: a cutaneous manifestation of neuropathy?'
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: "Erythromelalgia is an infrequent episodic acrosyndrome affecting mainly both lower limbs symmetrically with the classic triad of erythema, warmth and burning pain."
      explanation: >-
        Establishes that the acquired routes present with the same clinical triad. The edge
        therefore rests on convergence of presentation; this review does not resolve the causal
        steps linking these routes to the flare, so the support runs through an inference step.
  - target: Complement-Mediated Microvascular Endothelial Injury
    hypothesis_groups:
    - immune_dysautonomic_route
    description: >-
      Proposed route: an acral biopsy lesion of complement deposition and endothelial
      interferon signalling is offered as part of the substrate for the acquired routes
      that do not run through platelet thromboxane.
    evidence:
    - reference: PMID:39846717
      reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three of 9 individuals had concurrent diagnoses of autoimmune disease including vitiligo, lupus erythematosus, and psoriatic arthritis."
      explanation: >-
        A third of the biopsied series carried an autoimmune diagnosis, which is the only link
        between this series and the autoimmune acquired route named in this node. The study
        reports its biopsy findings for the series as a whole and does not report them separately
        for those three patients, so this edge rests on an inference step and is hypothesis-tagged
        rather than asserted.
  - target: Autonomic Denervation of Acral Arteries and Eccrine Glands
    hypothesis_groups:
    - immune_dysautonomic_route
    description: >-
      Proposed route: the autonomic denervation half of the same acral biopsy lesion, and the
      half that connects this node's small-fiber neuropathy route to a demonstrated finding.
    evidence:
    - reference: PMID:39846717
      reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."
      explanation: >-
        The denervation pattern is reported as mirroring that of small-fiber neuropathy, which is
        one of the acquired routes named in this node. Indirect: the correspondence is drawn by
        the authors between two histological patterns, and the series does not report which of
        its patients had a neuropathy diagnosis.
- name: Complement-Mediated Microvascular Endothelial Injury
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The endothelial half of the biopsy lesion proposed for the non-platelet acquired
    routes. In a dermatopathology series of nine patients biopsied from affected acral
    skin, the findings were superficial vascular ectasia with microvascular C5b-9
    (membrane attack complex) deposition and variable type-I interferon upregulation in
    endothelial cells. The claim here is about the state of the dermal microvascular
    endothelium, which is why the scale is `CELLULAR`; the denervation finding from the
    same biopsies is a separate claim at a different scale and is curated as its own node
    below rather than bundled in here.

    Note what this is *not*: it is not the platelet-rich thrombotic occlusion of the MPN
    arm. Note also that the ectasia is itself a dilation finding, and so is a candidate
    account of the warm, hyperemic surface in its own right.

    Curated as `PROVISIONAL` deliberately. The series is small (n=9), single-centre and
    retrospective, its cases were selected by clinical concern for erythromelalgia
    rather than by aetiology, and it is not stratified into MPN versus non-MPN disease —
    so it cannot by itself establish that this lesion is specific to the acquired
    non-platelet routes, and the authors themselves frame it as suggesting rather than
    demonstrating a dysautonomia syndrome. Its edges are recorded in the
    `immune_dysautonomic_route` hypothesis group rather than asserted.

    It is also not the only histology on record for secondary erythromelalgia. A separate
    case report describes the commonly reported picture as capillary proliferation,
    endothelial swelling, perivascular edema and sparse chronic lymphocytic inflammation —
    naming neither complement deposition nor denervation — and reports its own case as
    unusual again. Those descriptions are not incompatible with this node (the C5b-9 and
    CD56 findings require stains that routine histology does not perform), but they are
    the reason this lesion is curated as one candidate account rather than as the
    histology of the acquired routes.
  cell_types:
  - preferred_term: dermal microvascular endothelial cell
    term:
      id: CL:0011030
      label: dermal microvascular endothelial cell
  biological_processes:
  - preferred_term: complement activation with C5b-9 deposition
    modifier: INCREASED
    term:
      id: GO:0006956
      label: complement activation
  - preferred_term: endothelial type I interferon signaling
    modifier: INCREASED
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
  locations:
  - preferred_term: acral arteriole
    term:
      id: UBERON:0001980
      label: arteriole
  evidence:
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells."
    explanation: >-
      Direct histopathological demonstration of the complement and type-I-interferon endothelial
      lesion that defines this node.
  - reference: PMID:23334520
    reference_title: A case of secondary erythromelalgia with unusual histological findings.
    supports: NO_EVIDENCE
    evidence_source: HUMAN_CLINICAL
    snippet: "Histology commonly shows capillary proliferation, swelling of endothelial cells, perivascular edema, and chronic inflammation with sparse lymphocytic infiltrate"
    explanation: >-
      Recorded as NO_EVIDENCE and kept deliberately: an independent statement of the commonly
      reported secondary-erythromelalgia histology that names neither complement deposition nor
      autonomic denervation. It does not refute this node — those findings need C5b-9 and CD56
      stains that routine histology omits — but it does show that the lesion curated here is not
      the established histological description of the acquired routes.
  downstream:
  - target: Episodic Acral Burning Pain, Erythema, and Warmth
    hypothesis_groups:
    - immune_dysautonomic_route
    description: >-
      An ectatic, complement-injured acral microvascular bed is proposed as one half of the
      substrate for the flare.
    evidence:
    - reference: PMID:39846717
      reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study suggests that erythromelalgia is a dysautonomia syndrome with reproducible findings on biopsy, hallmarked by vascular ectasia and denervation of the eccrine coil and arteries."
      explanation: >-
        The authors advance the denervation-plus-ectasia lesion as the substrate of the syndrome.
        Support runs through an inference step: the study demonstrates the lesion in affected skin
        and proposes it as causal, but does not measure perfusion or symptom response against it.
- name: Autonomic Denervation of Acral Arteries and Eccrine Glands
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    The neural half of the same biopsy lesion, and the half that gives the route its
    name. CD56 staining in the same nine-patient series showed diminished autonomic
    innervation of the eccrine coil and of acral arteries, mirroring the denervation
    pattern seen in small-fiber neuropathy — which is one of the acquired routes named
    upstream, and the one this finding connects the entity to. The scale is `TISSUE`
    because the claim is about the innervation of a tissue compartment rather than the
    state of a cell type.

    This is the finding with the most mechanistic reach in the entity, because
    arteriovenous shunts are under autonomic control: it is therefore a candidate
    substrate for the shunting hypothesis recorded in
    `discussions#av_shunting_vs_occlusion_paradox`. It is a candidate only — the study
    measured innervation, not perfusion, oxygenation or shunt flow.

    Curated as `PROVISIONAL` deliberately. The series is small (n=9), single-centre and
    retrospective, its cases were selected by clinical concern for erythromelalgia
    rather than by aetiology, and it is not stratified into MPN versus non-MPN disease —
    so it cannot by itself establish that this lesion is specific to the acquired
    non-platelet routes, and the authors themselves frame it as suggesting rather than
    demonstrating a dysautonomia syndrome. Its edges are recorded in the
    `immune_dysautonomic_route` hypothesis group rather than asserted.
  locations:
  - preferred_term: eccrine sweat gland
    term:
      id: UBERON:0000423
      label: eccrine sweat gland
  - preferred_term: acral arteriole
    term:
      id: UBERON:0001980
      label: arteriole
  evidence:
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."
    explanation: >-
      Direct demonstration of the autonomic denervation this node asserts, and of its
      correspondence with small-fiber neuropathy, one of the acquired routes named upstream.
  downstream:
  - target: Episodic Acral Burning Pain, Erythema, and Warmth
    hypothesis_groups:
    - immune_dysautonomic_route
    description: >-
      Loss of autonomic control of acral arterioles and eccrine glands is proposed to produce
      the maldistributed acral perfusion experienced as the flare.
    evidence:
    - reference: PMID:39846717
      reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study suggests that erythromelalgia is a dysautonomia syndrome with reproducible findings on biopsy, hallmarked by vascular ectasia and denervation of the eccrine coil and arteries."
      explanation: >-
        The authors advance the denervation-plus-ectasia lesion as the substrate of the syndrome.
        Support runs through an inference step: the study demonstrates the lesion in affected skin
        and proposes it as causal, but does not measure perfusion or symptom response against it.
mechanistic_hypotheses:
- hypothesis_group_id: immune_dysautonomic_route
  hypothesis_label: Immune-Mediated Microvascular Injury and Dysautonomia as an Alternative Route to the Erythromelalgic Flare
  status: EMERGING
  description: >-
    Proposes that the acquired routes outside the myeloproliferative neoplasms reach the
    erythromelalgic flare through complement-mediated microvascular injury and autonomic
    denervation of acral skin, rather than through the platelet-thromboxane pathway that
    accounts for the MPN arm. If it holds, it explains the entity's most durable clinical
    puzzle — why the non-thrombocythemic acquired forms are aspirin resistant while the
    MPN arm is abolished by cyclooxygenase inhibition — and it would make complement- or
    interferon-directed therapy a rational target in refractory disease.

    It rests on a single retrospective nine-patient dermatopathology series and is
    therefore recorded as EMERGING, not as an alternative model of equal standing to the
    platelet mechanism. Note the limit precisely: that series was assembled by clinical
    concern for erythromelalgia and is not stratified primary versus secondary, let alone
    MPN versus non-MPN, and its own conclusion is pitched at erythromelalgia in general.
    So the restriction of this route to the non-MPN acquired forms is part of the
    hypothesis being advanced here, not an observation carried over from the source. What is missing is replication in an independent, larger biopsy
    cohort with quantitative C5b-9 and type-I interferon scoring and intraepidermal
    nerve-fibre density, stratified by MPN versus non-MPN aetiology. Until then the
    edges in this group are hypothesis-tagged rather than asserted.
  evidence:
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study suggests that erythromelalgia is a dysautonomia syndrome with reproducible findings on biopsy, hallmarked by vascular ectasia and denervation of the eccrine coil and arteries."
    explanation: >-
      The source proposal for this hypothesis group, stated by its authors as a suggestion rather
      than a demonstrated mechanism.
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Secondary erythermalgia: Aspirin resistant and associated with different medical conditions."
    explanation: >-
      The pharmacological observation this hypothesis exists to explain — a recognised acquired
      category that does not respond to cyclooxygenase inhibition, so a non-platelet lesion is
      required. Indirect twice over: the Drenth-Michiels classification defines the category by
      aspirin resistance rather than measuring it, and aspirin resistance motivates this
      hypothesis without testing it.
phenotypes:
- name: Erythromelalgia
  category: Clinical
  frequency: OBLIGATE
  description: >-
    The defining phenotype: episodic redness, warmth, and burning pain of the
    distal extremities. `OBLIGATE` because this phenotype *is* the disease — every
    patient with secondary erythromelalgia has it by definition, so the band is a
    statement about the entity rather than an observed proportion. Note the
    distinction from the separate question of how often erythromelalgia occurs
    *among MPN patients*: that proportion is curated on the MPN entries
    (`Polycythemia_Vera`, `Essential_Thrombocythemia`), which record `OCCASIONAL`
    from Orphanet. The two hospital series cited below report far higher fractions
    (26/40 = 65%; 31/50 = 62%), but those come from a hematology group that
    specialized in this syndrome and are referral-biased; they are cited here for
    the disease-phenotype association and the MPN link, NOT as the basis for this
    band. A 2025 general-medical review of polycythemia vera puts the modern
    unselected figure at 5.3%, an order of magnitude below the referral series and
    consistent with the `OCCASIONAL` band the MPN entries carry — further reason not
    to read the 62-65% fractions as population frequencies.
  phenotype_term:
    preferred_term: Erythromelalgia
    term:
      id: HP:0032147
      label: Erythromelalgia
    temporality: RECURRENT
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."
    explanation: >-
      Cited for the phenotype's association with the MPN context, not for the OBLIGATE band.
      The quote counts how often erythromelalgia presents among referred thrombocythemia
      patients (26/40), which is a different denominator from the frequency of the phenotype
      within this disease entity.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms were platelet-mediated erythromelalgia in 16 PT and 15 PV"
    explanation: >-
      A second consecutive series records platelet-mediated erythromelalgia in 31 of 50 referred
      thrombocythemia patients. Again this is the MPN-population denominator, not the
      within-disease frequency, so it corroborates the association rather than the band.
  - reference: PMID:39556352
    reference_title: 'Diagnosis and Treatment of Polycythemia Vera: A Review.'
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: "Patients may have pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%) with abdominal discomfort."
    explanation: >-
      Recorded as NO_EVIDENCE deliberately. The 5.3% is the frequency of erythromelalgia among
      polycythemia vera patients, a different entity's denominator, and it therefore does not bear
      on this phenotype's OBLIGATE band either way. It is cited here only as the modern unselected
      counterweight to the 62-65% referral-series fractions discussed above, so that a future
      curator does not mistake those for population frequencies.
- name: Acral burning pain
  category: Neurologic
  description: >-
    Severe localized burning pain of the affected distal extremity during attacks —
    the dominant symptomatic burden and, in MPN-associated disease, completely and
    rapidly abolished by cyclooxygenase inhibition.
  phenotype_term:
    preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The localized painful burning, redness, and warm congestion in the extremities"
    explanation: Describes the localized burning extremity pain that constitutes the core symptom.
- name: Erythema of the extremities
  category: Dermatologic
  description: Visible redness and warm congestion of the affected acral skin during attacks.
  phenotype_term:
    preferred_term: Erythema
    term:
      id: HP:0010783
      label: Erythema
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The localized painful burning, redness, and warm congestion in the extremities could be accurately documented with thermography."
    explanation: Documents the erythema and warm congestion component, objectively confirmed thermographically.
- name: Acrocyanosis
  category: Vascular
  frequency: FREQUENT
  description: >-
    Progression of the untreated microvascular occlusive process from red, warm
    congestion to dusky cyanotic acral discoloration, marking the transition from a
    reversible flare to established acral ischemia. Band caveats, since the source
    figure is easy to misread: the 14 cases below are drawn from the 31 patients in
    that series who actually had erythromelalgia (not from all 50 thrombocythemia
    patients), giving 14/31 = 45%; the endpoint is *composite* ("acrocyanosis OR
    peripheral ischemia with necrosis"), so acrocyanosis alone cannot be separated
    out; the figure applies to *untreated* disease, and the untreated denominator is
    not reported; and the cohort is an MPN-referred hospital series.
  phenotype_term:
    preferred_term: Acrocyanosis
    term:
      id: HP:0001063
      label: Acrocyanosis
  evidence:
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."
    explanation: >-
      Indirect support for the FREQUENT band, and only indirect. The abstract states "in 14 cases"
      with no denominator attached; the 14/31 (45%) ratio is a curator computation joining that
      sentence to the count of patients with erythromelalgia reported elsewhere in the same
      abstract. Three further caveats sit on top: the endpoint is a composite of acrocyanosis and
      necrosis, it is conditioned on being untreated with no untreated denominator given, and the
      series is referral-based. The band is not read off this figure alone.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The symptoms were platelet-mediated erythromelalgia in 16 PT and 15 PV"
    explanation: >-
      Establishes the 31-patient erythromelalgia denominator used above, rather than the
      50-patient thrombocythemia denominator that would understate the proportion.
- name: Digital ischemic necrosis
  category: Vascular
  description: >-
    Frank ischemic necrosis or gangrene of a toe or fingertip, the end stage of
    unrelieved platelet-mediated acral arteriolar occlusion.
  phenotype_term:
    preferred_term: Digital ischemia
    term:
      id: HP:0033402
      label: Digital ischemia
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."
    explanation: Documents digital ischemic necrosis as an outcome of the untreated occlusive process.
- name: Thrombocytosis
  category: Hematologic
  description: >-
    The underlying haematological abnormality in the myeloproliferative form.
    Erythromelalgia can occur at platelet counts only modestly above the normal
    range, so a markedly raised count is not required to attribute the syndrome to
    the MPN.
  phenotype_term:
    preferred_term: Thrombocytosis
    term:
      id: HP:0001894
      label: Thrombocytosis
  evidence:
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia in thrombocythemia already occurred at slightly increased platelet counts above 400 x 10(9)/l."
    explanation: Establishes both the presence of thrombocytosis and the low count threshold at which symptoms occur.
biochemical:
- name: Beta-thromboglobulin
  presence: Elevated
  notes: >-
    Alpha-granule release marker of in vivo platelet activation; significantly
    elevated in thrombocythemia patients with erythromelalgia compared with
    asymptomatic thrombocythemia patients and controls, and normalized by aspirin
    in parallel with clinical resolution.
  evidence:
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As compared with asymptomatic ET patients and control subjects erythromelalgia was characterized by significantly higher beta-TG and TM levels but no significant differences were detected in either F1 + 2 or TDP levels."
    explanation: >-
      Beta-thromboglobulin and thrombomodulin are selectively elevated in symptomatic patients while
      thrombin-generation markers are not, marking platelet activation and endothelial injury without coagulation activation.
- name: Thrombomodulin
  presence: Elevated
  notes: >-
    Marker of endothelial cell damage, elevated in symptomatic erythromelalgia and
    falling with aspirin treatment — the biochemical counterpart of the arteriolar
    endothelial injury seen histologically.
  evidence:
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of erythromelalgia with aspirin resulted in disappearance of erythromelalgic signs and symptoms, which was paralleled by a significant decrease of beta-TG and TM levels."
    explanation: Links normalization of the endothelial-damage and platelet-activation markers to clinical remission on aspirin.
- name: Platelet survival time
  presence: Shortened
  notes: >-
    Radiolabelled autologous platelet survival is markedly shortened in
    thrombocythemia complicated by erythromelalgia (4.2 days) relative to
    asymptomatic thrombocythemia (6.6 days) and reactive thrombocytosis (8.0 days),
    and is restored by aspirin — a direct functional readout of ongoing platelet
    consumption in microvascular thrombi.
  evidence:
  - reference: PMID:7792731
    reference_title: 'Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean platelet survival time of the erythromelalgia patients was 4.2 +/- 0.2 days, which is significantly decreased as compared with asymptomatic thrombocythemia patients (6.6 +/- 0.3 days, p < 0.001) and patients with reactive thrombocytosis (8.0 +/- 0.4 days, p < 0.001)."
    explanation: Quantifies shortened platelet survival specifically in symptomatic erythromelalgia versus two comparator groups.
  - reference: PMID:7792731
    reference_title: 'Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of erythromelalgia with aspirin increased the mean platelet survival time from 4.0 +/- 0.3 days to 6.9 +/- 0.4 days (p < 0.001)"
    explanation: Aspirin reverses the shortened platelet survival, confirming COX-dependent platelet consumption as the operative process.
- name: Urinary thromboxane B2
  presence: Elevated
  notes: >-
    Stable urinary metabolite of platelet thromboxane A2; increased in
    thrombocythemia patients with erythromelalgia and reduced to normal by aspirin,
    evidencing in vivo thromboxane-dependent platelet activation.
  evidence:
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a significant reduction of the increased levels of beta-TG, PF4, TM and urinary TxB2 excretion to normal"
    explanation: Aspirin normalizes urinary thromboxane B2 alongside the other platelet-activation markers.
environmental:
- name: Limb warming, exercise, and dependency as attack precipitants
  description: >-
    Erythromelalgic attacks are provoked by warmth and by anything that raises acral
    blood flow or venous pressure — exercise, physical activity, limb dependency,
    prolonged standing, and occlusive footwear — and are relieved by cooling and
    elevation. These are precipitants of the flare, not causes of the underlying
    disorder, so they are modeled as EXACERBATES on the flare node rather than as a
    trigger of the upstream mechanism. Note the therapeutic hazard shared with the
    primary form: patients self-treat by prolonged cold-water immersion, which causes
    skin maceration and secondary tissue injury.
  influences_mechanisms:
  - target: Episodic Acral Burning Pain, Erythema, and Warmth
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Heat and exertion precipitate the erythromelalgic attack; cooling relieves it.
    evidence:
    - reference: PMID:40428878
      reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Triggers for symptoms included warmth, exercise, dependency, tight footwear or gloves, physical activity, immersion, and emotional stress."
      explanation: Enumerates the attack precipitants recorded across the systematic review's patient cohorts.
    - reference: PMID:32491719
      reference_title: Erythromelalgia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The episodes are typically precipitated by exercise and relieved by cooling the affected parts."
      explanation: States the precipitation-by-exertion and relief-by-cooling pattern that defines the flare.
  evidence:
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common relievers involve cooling methods such as local skin cooling or ice water immersion."
    explanation: Documents cooling as the characteristic reliever, the counterpart of the warming trigger.
prevalence:
- population: Olmsted County, Minnesota, USA (population-based, 1976-2005)
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: RARE
  rate_per_100000: 0.2
  rate_low: 0.02
  rate_high: 0.4
  notes: >-
    Population-based age- and sex-adjusted incidence of secondary erythromelalgia
    from the Rochester Epidemiology Project (overall erythromelalgia incidence
    1.3/100,000/yr; primary 1.1/100,000/yr). In this study "secondary" was defined
    by a coexisting myeloproliferative disorder, or attribution to another cause
    such as medications, HIV, or mushroom poisoning. The confidence interval is
    wide and the authors note the small sample size as a limitation.
  evidence:
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively."
    explanation: Provides the population-based annual incidence estimate for secondary erythromelalgia.
progression:
- phase: Erythromelalgic flare as presenting manifestation
  age_range: Adults; median 61 years (range 16-90)
  notes: >-
    The flare typically arrives before, not after, the diagnosis of the underlying
    disorder. In the Michiels thrombocythemia series erythromelalgia was the
    presenting symptom in 26 of 40 patients, and the Olmsted County case definition
    had to allow for a myeloproliferative neoplasm diagnosed within two years *either
    side* of the erythromelalgia in order to classify those cases as secondary. A review of the
    60 published myeloproliferative cases puts a number on the lag: erythromelalgia
    preceded the onset of the myeloproliferative disease by a median of two and a half
    years. That lag is the clinical justification for the haematological work-up curated under
    `diagnosis#Evaluation for an underlying myeloproliferative neoplasm`: a normal
    or near-normal blood count at presentation does not exclude an MPN. The age
    figure is quoted for orientation only — the Olmsted cohort is dominated by
    primary disease (incidence 1.1 versus 0.2 per 100,000/yr), so it is not an
    age-of-onset estimate for this entity. A second population series (Sweden)
    independently records a long interval between symptom onset and diagnosis,
    which is the same phenomenon seen from the patient's side rather than the
    haematologist's.
  evidence:
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "if a myeloproliferative disorder was diagnosed within 2 years of the diagnosis of erythromelalgia"
    explanation: >-
      A population-based case definition whose two-year window is symmetric about the
      erythromelalgia diagnosis, so it admits cases in which the MPN is only recognised later.
      It does not by itself establish the direction; the lead time is evidenced separately below.
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."
    explanation: >-
      Quantifies the flare as the presenting manifestation in the majority of a referred
      thrombocythemia series.
  - reference: PMID:2643412
    reference_title: Erythromelalgia and myeloproliferative disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptoms of erythromelalgia preceded the onset of a myeloproliferative disease by a median of 2 1/2 years"
    explanation: >-
      Quantifies the lead time between the erythromelalgic flare and diagnosis of the underlying
      myeloproliferative disease across the published case literature.
  - reference: PMID:11208311
    reference_title: Erythromelalgia--a thrombotic complication in chronic myeloproliferative disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sometimes, it may precede the diagnosis of MPD by months or years."
    explanation: >-
      Independently states that the flare can antedate recognition of the myeloproliferative
      disorder by months to years.
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age at diagnosis was 61 years (range, 16-90 years)."
    explanation: >-
      Source of the age figure recorded on this phase. Note the caveat in the notes above: this is
      the pooled erythromelalgia cohort, not a secondary-only denominator.
  - reference: PMID:22247059
    reference_title: 'Erythromelalgia: Incidence and clinical experience in a single centre in Sweden.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean delay from the onset of the symptoms to the time of diagnosis was 4.5 (SD ± 3.9) years"
    explanation: >-
      A second population series quantifying the interval between symptom onset and diagnosis.
      Indirect for this phase: the delay measured is to the diagnosis of erythromelalgia itself,
      not to the diagnosis of an underlying myeloproliferative neoplasm, so it corroborates that
      the syndrome runs unrecognised for years without measuring the MPN lead time.
- phase: Untreated progression to acrocyanosis and digital ischemic necrosis
  notes: >-
    Left untreated the syndrome does not simply persist as episodic pain; it advances
    to fixed acral ischemia. Across 31 patients with erythromelalgia in a consecutive
    thrombocythemia series, 14 progressed to acrocyanosis or peripheral ischemia with
    necrosis of a toe or fingertip (the caveats on that ratio are set out once, on the
    `Acrocyanosis` phenotype, and are not repeated here). It is recorded as the untreated
    trajectory rather than as a rate. This is the phase the cyclooxygenase inhibitors
    interrupt, which is why aspirin here is disease-modifying rather than merely
    analgesic.
  evidence:
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."
    explanation: >-
      Direct observation of the untreated natural history advancing from episodic flare to fixed
      acral ischemia and tissue loss.
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia often progressed to ischemic acrocyanosis or necrosis in toes or fingers."
    explanation: >-
      A second series independently reports the same progression from flare to acrocyanosis and
      digital necrosis.
  - reference: PMID:11208311
    reference_title: Erythromelalgia--a thrombotic complication in chronic myeloproliferative disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "If left untreated, it may progress towards acrocyanosis and even peripheral gangrene."
    explanation: >-
      Names peripheral gangrene as the far end of the untreated trajectory, conditioning the
      progression explicitly on lack of treatment.
- phase: Remission on cyclooxygenase inhibition or cytoreduction
  notes: >-
    In the platelet-mediated arm the course is interruptible and the interruption is
    complete rather than partial — pain relief and restoration of the microvascular
    disturbance on aspirin or indomethacin, and remission of the erythromelalgia when
    the underlying thrombocythemia is put into haematological remission, with
    recurrence on relapse. This phase is what separates the MPN arm prognostically
    from the non-MPN acquired routes curated in
    `pathophysiology#Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)`,
    which are aspirin resistant and have no comparable reversal.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"
    explanation: >-
      Establishes that the flare phase is fully reversible on cyclooxygenase inhibition rather than
      only attenuated.
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."
    explanation: >-
      Remission and relapse of the erythromelalgia track the haematological state, establishing
      cytoreduction as the second route into this phase.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Burden here is decided by aetiology, not by severity of the flare, and the two arms
    of this entity sit at opposite ends. Untreated, the syndrome is not a nuisance
    symptom: it runs a chronic course with considerable disability, and in a consecutive
    thrombocythemia series roughly half the affected patients progressed to acrocyanosis
    or peripheral ischemia with necrosis of a toe or fingertip (ratio and its caveats on
    the `Acrocyanosis` phenotype). Against that, the
    platelet-mediated MPN arm is abolished by low-dose aspirin, with complete relief of
    pain and restoration of the microvascular disturbance, so a correctly diagnosed
    patient in that arm carries little residual burden from the flare itself — though
    the suppression requires continued dosing, and at very high platelet counts the drug
    that suppresses the flare is itself a bleeding hazard. The non-MPN acquired routes have no such exit — they are aspirin resistant,
    and management falls back on treating the underlying disorder. `VARIABLE` rather than
    `HIGH` records that split honestly: assigning a single level would either overstate
    the burden of the treatable arm or understate the tissue loss risk of the untreated
    and refractory ones.
  evidence:
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "It typically has a chronic course and is associated with diminished quality of life and considerable disability"
    explanation: >-
      Characterizes the course as chronic and disabling. Classified OTHER because this sentence is
      the paper's introductory framing, citing prior literature, rather than a result of its own
      population-based analysis; indirect because that framing is about erythromelalgia in general
      in a cohort this entry elsewhere notes is dominated by primary disease (1.1 versus 0.2 per
      100,000/yr).
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated erythromelalgia progressed to acrocyanosis or peripheral ischemia with necrosis in a toe or fingertip in 14 cases."
    explanation: >-
      Supplies the high end of the range — irreversible tissue loss in a substantial fraction of
      untreated patients.
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"
    explanation: >-
      Supplies the low end — the platelet-mediated arm is fully reversible on a cheap oral agent.
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: "Secondary erythermalgia: Aspirin resistant and associated with different medical conditions."
    explanation: >-
      The Drenth-Michiels classification defines its "secondary erythermalgia" category by aspirin
      resistance, so this records that a recognised acquired category lacks the aspirin exit —
      the reason burden is VARIABLE rather than uniformly low. Indirect, because the property is
      definitional to the category rather than measured in it.
  - reference: PMID:22247059
    reference_title: 'Erythromelalgia: Incidence and clinical experience in a single centre in Sweden.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients developed intraabdominal cancer during the follow up, but there was no mortality directed related to EM."
    explanation: >-
      A prospectively followed population cohort finding no erythromelalgia-attributable mortality,
      which is what keeps the assessment off HIGH; the incident intra-abdominal malignancies in the
      same cohort are the countervailing observation, and are recorded as an acquired association
      rather than as burden.
diagnosis:
- name: Evaluation for an underlying myeloproliferative neoplasm
  description: >-
    Because erythromelalgia is regarded as a pathognomonic microvascular
    complication of essential thrombocythemia and polycythemia vera — and frequently
    its presenting manifestation — a new diagnosis of erythromelalgia warrants
    haematological evaluation for an occult MPN, including a platelet count that may
    be only modestly elevated.
  results: >-
    Thrombocytosis (possibly only slightly above 400 x 10^9/L) with an MPN diagnosis
    supports platelet-mediated secondary erythromelalgia. The blood count is the
    first-line test; a JAK2 mutation search is the confirmatory step when the count is
    equivocal or the clinical suspicion outruns it, which is the common situation here
    because the flare precedes the haematological diagnosis by a median of two and a
    half years.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Erythromelalgia was the presenting symptom in 26 of 40 patients with thrombocythemia in its primary form or when associated with polycythemia vera."
    explanation: Erythromelalgia is the presenting symptom in most such patients, justifying MPN evaluation on presentation.
  - reference: PMID:2643412
    reference_title: Erythromelalgia and myeloproliferative disorders.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "all patients with erythromelalgia should be monitored with periodic blood cell counts"
    explanation: >-
      Because the flare precedes the myeloproliferative diagnosis by a median of two and a half
      years, a single normal count at presentation does not close the question; this source states
      the resulting recommendation for serial monitoring.
  - reference: PMID:35835622
    reference_title: '[Paroxysmal vascular acrosyndromes: Practical approach to diagnosis and management].'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For erythermalgia, a blood count and even a search for JAK2 mutation are required."
    explanation: >-
      Names the two haematological tests this entry's evaluation rests on — the blood count and,
      beyond it, a JAK2 mutation search. Classified OTHER because this is a practical-approach
      review of the vascular acrosyndromes rather than a report of primary data.
- name: Serologic and small-fiber neuropathy workup for non-MPN causes
  description: >-
    Because the acquired routes are not exhausted by the myeloproliferative neoplasms,
    a negative haematological work-up does not end the evaluation. Thyroid function,
    antinuclear antibodies and testing for small-fiber neuropathy address the three
    non-MPN routes this entry models — endocrine, autoimmune and neuropathic — and the
    latter two are the routes the `immune_dysautonomic_route` hypothesis is about.
    Note the therapeutic stakes of getting this right: these are the aspirin-resistant
    forms, so identifying the underlying condition is what management turns on.
  results: >-
    An abnormal thyroid-stimulating hormone assay, a positive antinuclear antibody test,
    or demonstrated small-fiber neuropathy each redirects the evaluation away from the
    platelet-mediated arm and toward a cause-directed treatment.
  evidence:
  - reference: PMID:35835622
    reference_title: '[Paroxysmal vascular acrosyndromes: Practical approach to diagnosis and management].'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed."
    explanation: >-
      States the serologic and neuropathy tests performed alongside the haematological work-up.
      The two misspellings are present in the cited abstract and are preserved verbatim, as an
      evidence snippet must be an exact source substring. Classified OTHER because this is a
      practical-approach review rather than a report of primary data.
- name: Skin punch biopsy of an affected area
  description: >-
    Histopathology of affected acral skin demonstrates the characteristic arteriolar
    inflammation, fibromuscular intimal proliferation, and platelet-rich thrombotic
    occlusions that distinguish platelet-mediated secondary erythromelalgia from the
    primary neuropathic form.

    Which stains are ordered decides which arm the biopsy can speak to. Routine histology
    demonstrates the platelet-arm lesion above. The complement and denervation findings
    behind
    `pathophysiology#Complement-Mediated Microvascular Endothelial Injury`
    and
    `pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands`
    are invisible to it: they require C5b-9 immunostaining, type-I interferon staining
    and CD56. A routine-stain biopsy reported as unremarkable therefore does not exclude
    the immune/dysautonomic route — it was never tested for.
  results: >-
    Arteriolar inflammation, fibromuscular intimal proliferation, and thrombotic occlusion on
    routine histology. On C5b-9, type-I interferon and CD56 immunostaining, superficial vascular
    ectasia with microvascular C5b-9 deposition, endothelial interferon upregulation, and
    diminished autonomic innervation of the eccrine coil and arteries.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions."
    explanation: Establishes the diagnostic histopathological findings on skin punch biopsy.
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells."
    explanation: >-
      Establishes the immunohistochemical findings a biopsy can carry beyond routine histology,
      and therefore the stains that have to be requested for the biopsy to bear on the
      immune/dysautonomic route.
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."
    explanation: >-
      Names CD56 as the stain demonstrating the autonomic denervation finding, and ties the biopsy
      to the small-fiber neuropathy route tested serologically in the entry above.
- name: Therapeutic response to aspirin as a diagnostic discriminator
  description: >-
    The dramatic, complete, and sustained response of platelet-mediated
    erythromelalgia to a cyclooxygenase inhibitor is itself diagnostically
    informative: the historical Drenth-Michiels classification of red, burning
    extremities was built on aspirin responsiveness, separating aspirin-responsive
    thrombocythemic erythromelalgia from the aspirin-resistant primary and other
    secondary forms.
  results: Complete relief of pain with aspirin supports the platelet-mediated (MPN-associated) form.
  evidence:
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The term erythromelalgia and erythermalgia were differentiated on the basis of responsiveness to aspirin by Drenth and Michiels"
    explanation: Documents aspirin responsiveness as the historical basis for discriminating these entities.
treatments:
- name: Low-dose aspirin
  description: >-
    The mechanism-matched treatment of MPN-associated erythromelalgia. Irreversible
    inhibition of platelet cyclooxygenase-1 abolishes the thromboxane-dependent
    platelet activation that drives arteriolar occlusion, producing complete relief
    of pain, restoration of microvascular circulation, normalization of shortened
    platelet survival, and fall of platelet-activation markers to normal. This
    dramatic responsiveness is the therapeutic hallmark separating MPN-associated
    secondary erythromelalgia from the characteristically aspirin-refractory primary
    (SCN9A/Nav1.7) form. Safety caveat: at very high platelet counts
    (roughly >1000-2000 x 10^9/L) thrombocythemia converts to a bleeding diathesis,
    and aspirin — while still preventing the microcirculatory disturbance — further
    increases the risk of serious haemorrhage.

    Two features sharpen the pharmacology and are worth separating from mere
    efficacy. First, the response is specific to cyclooxygenase inhibition rather
    than to anticoagulation as such: the same microvascular complications do not
    respond to coumadin, are relieved immediately by a 500 mg aspirin loading dose,
    and do not recur on 50 mg daily maintenance or after the platelet count is
    normalized. Second, holding the flare off appears to require ongoing inhibition
    rather than being a one-off cure: erythromelalgia emerged within two weeks of
    aspirin withdrawal in a patient whose myeloproliferative disorder was in remission
    and who had been taking aspirin for stroke prophylaxis, and remitted on rechallenge.
    That is a single observation, and it sits against the older series' description of
    an aspirin effect that is "curative" once the platelet count is controlled; the two
    are reconcilable only if what is cured is the flare and not the substrate.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aspirin
      term:
        id: CHEBI:15365
        label: acetylsalicylic acid
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Erythromelalgia
    term:
      id: HP:0032147
      label: Erythromelalgia
  target_mechanisms:
  - target: Thromboxane-Dependent Platelet Activation and Aggregation
    treatment_effect: INHIBITS
    description: >-
      Aspirin inhibits platelet cyclooxygenase-1, removing the thromboxane metabolites
      shown to be necessary for erythromelalgia to develop and thereby interrupting the
      platelet activation/aggregation node upstream of arteriolar occlusion.
    evidence:
    - reference: PMID:16673274
      reference_title: 'Clinical and laboratory features, pathobiology of platelet-mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Inhibition of platelet cyclooxygenase-1 by aspirin is followed by relief of microvascular disturbances"
      explanation: States the drug target (platelet COX-1) and the mechanistic consequence of inhibiting it.
    - reference: PMID:16510297
      reference_title: 'Platelet-mediated thrombotic complications in patients with ET: Reversal by aspirin, platelet reduction, and not by coumadin.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These microvascular ischemic and thrombotic complications does not respond to Coumadin, but are immediately relieved by a loading dose of 500 mg aspirin"
      explanation: >-
        States that the therapeutic effect is specific to cyclooxygenase inhibition and not to
        anticoagulation, which is the pharmacological counterpart of the thrombin-independent
        mechanism curated for this entity. Classified OTHER because the quoted comparison is this
        review's synthesis of the author's case material rather than a controlled head-to-head.
    - reference: PMID:12781799
      reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop."
      explanation: Establishes that the inhibited pathway is necessary for the disease process, licensing the INHIBITS edge.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"
    explanation: Documents complete symptomatic and microvascular response to cyclooxygenase inhibition.
  - reference: PMID:22844295
    reference_title: 'Erythromelalgia: an uncommon presentation precipitated by aspirin withdrawal.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was taken off aspirin and developed erythromelalgia within two weeks of withdrawal of aspirin. After restarting aspirin, patient's symptoms improved within 2 weeks."
    explanation: >-
      A withdrawal-and-rechallenge observation. Note the direction carefully: the aspirin was
      being taken for stroke prophylaxis and the erythromelalgia emerged de novo on stopping it,
      so this is unmasking rather than relapse of treated disease. One patient, cited as an
      indication that continued cyclooxygenase inhibition is what holds the flare off, not as a
      general property.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in the disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times"
    explanation: Confirms clinical and platelet-kinetic reversal on aspirin.
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this situation aspirin prevents erythromelalgic and microcirculatory circulation disturbances, but further increases the risk of serious bleeding complications."
    explanation: >-
      Qualifies rather than endorses the treatment: at very high platelet counts aspirin remains
      effective for the microvascular disturbance but raises the risk of serious bleeding.
- name: Indomethacin
  description: >-
    A second cyclooxygenase inhibitor with the same mechanism-matched efficacy,
    confirming that the therapeutic effect is a class effect of COX inhibition
    rather than an aspirin-specific property. Notably sodium salicylate and the
    non-COX platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and
    dazoxiben are all ineffective, which is the pharmacological argument for the
    thromboxane mechanism.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: indomethacin
      term:
        id: CHEBI:49662
        label: indometacin
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Thromboxane-Dependent Platelet Activation and Aggregation
    treatment_effect: INHIBITS
    description: Indomethacin inhibits the same platelet cyclooxygenase pathway targeted by aspirin.
    evidence:
    - reference: PMID:3977194
      reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin, but not with sodium-salicylate or the platelet inhibitors dipyridamole, sulfinpyrazone, ticlopidine, and dazoxiben."
      explanation: >-
        Indomethacin shares aspirin's efficacy while non-COX antiplatelet agents fail, establishing
        cyclooxygenase inhibition as the operative drug mechanism.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief of pain and restoration of microvascular circulation disturbances was obtained with the cyclo-oxygenase inhibitors aspirin and indomethacin"
    explanation: Documents complete symptomatic and microvascular relief with indomethacin alongside aspirin.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete relief from erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine."
    explanation: Independently confirms indomethacin efficacy and the failure of non-COX antiplatelet agents.
- name: Cytoreduction of the underlying myeloproliferative neoplasm
  description: >-
    Treating the upstream disorder resolves the erythromelalgia: symptoms remit
    during cytoreduction-induced haematological remission of the thrombocythemia and
    recur on relapse. Contemporary cytoreductive agent selection is a matter for the
    MPN entries (`Polycythemia_Vera`, `Essential_Thrombocythemia`) rather than this
    entry; the historical evidence cited here used busulfan.
  treatment_term:
    preferred_term: cytoreductive therapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Clonal Thrombocythemia in Myeloproliferative Neoplasm
    treatment_effect: INHIBITS
    description: Cytoreduction removes the clonal thrombocythemia that supplies the hyperreactive platelet population.
    evidence:
    - reference: PMID:3977194
      reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."
      explanation: Remission of the thrombocythemia relieves the erythromelalgia, supporting an INHIBITS edge on the upstream node.
  evidence:
  - reference: PMID:3977194
    reference_title: Erythromelalgia caused by platelet-mediated arteriolar inflammation and thrombosis in thrombocythemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The erythromelalgia was alleviated during busulfan-induced remissions of thrombocythemia and its recurrence coincided with relapsing thrombocythemia."
    explanation: Cytoreduction-induced haematological remission relieves the erythromelalgia, and relapse brings it back.
  - reference: PMID:12781799
    reference_title: 'Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "which specifically respond to low-dose aspirin or reduction of platelet counts to normal"
    explanation: >-
      The quoted response applies to the accompanying transient ischemic manifestations rather than
      to the erythromelalgia itself, so the claim follows by an inference step: platelet-count
      reduction is established as an effective alternative to aspirin for the platelet-mediated
      microvascular syndrome of which erythromelalgia is one manifestation.
- name: Treatment of the underlying condition in non-MPN secondary disease
  description: >-
    For acquired erythromelalgia not driven by a myeloproliferative neoplasm,
    management is directed primarily at the underlying disease, supplemented by
    trigger avoidance. Aspirin is characteristically ineffective in these
    non-platelet-mediated forms. Note this is a statement about *cause-directed*
    therapy, not a claim that nothing helps symptomatically — symptomatic options
    with trial evidence are curated in the sibling treatment entry below.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary EM tends to be more variable in presentation, may be unilateral or localized, and treatment usually targets the underlying condition."
    explanation: >-
      A 2025 systematic review states that treatment of secondary erythromelalgia usually targets
      the underlying condition.
  - reference: PMID:29641704
    reference_title: 'Erythromelalgia: a cutaneous manifestation of neuropathy?'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since there is no specific and effective treatment, control should focus on the underlying disease."
    explanation: >-
      Cited only for the cause-directed management principle. This 2018 narrative review's blanket
      "no specific and effective treatment" is not adopted as written, because the later systematic
      review (PMID:40428878) reports measurable symptomatic benefit for several agents.
  - reference: PMID:29641704
    reference_title: 'Erythromelalgia: a cutaneous manifestation of neuropathy?'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The prevention of crisis is based on a strict control of triggers and promotion of preventive measures."
    explanation: Supports trigger control as the preventive component of management.
- name: Symptomatic pharmacotherapy for aspirin-unresponsive disease
  description: >-
    Where the platelet-mediated COX-1 mechanism does not apply — the non-MPN
    acquired routes, and MPN disease inadequately controlled by aspirin — symptomatic
    options with controlled or cohort evidence include topical amitriptyline-ketamine,
    lidocaine, and the prostaglandin analogues iloprost and misoprostol. IMPORTANT
    EVIDENCE CAVEAT, which is why these are curated as a single node without
    per-agent mechanism edges: the systematic review supplying this evidence pooled
    120 patients across primary, idiopathic and secondary erythromelalgia and did NOT
    report outcomes stratified by aetiology, so efficacy specific to secondary
    disease is not established. Misoprostol in particular caused severe
    gastrointestinal toxicity.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: amitriptyline
      term:
        id: CHEBI:2666
        label: amitriptyline
    - preferred_term: ketamine
      term:
        id: CHEBI:6121
        label: ketamine
    - preferred_term: lidocaine
      term:
        id: CHEBI:6456
        label: lidocaine
    - preferred_term: iloprost
      term:
        id: CHEBI:63916
        label: iloprost
    - preferred_term: misoprostol
      term:
        id: CHEBI:63610
        label: misoprostol
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "About 75% of the patients reported pain relief with topical amitriptyline-ketamine, while lidocaine reduced nociceptive feelings in a dose-dependent manner."
    explanation: >-
      The pooled cohort mixes primary, idiopathic and secondary erythromelalgia and is not
      stratified by aetiology, so the response rate cannot be attributed to secondary disease
      specifically; it reaches this claim only by assuming the mixed cohort's benefit extends
      to the secondary subset.
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Iloprost and misoprostol exhibited notable benefits in cooling scores, sympathetic dysfunction, and EM severity compared to placebos."
    explanation: >-
      Placebo-controlled benefit for the two prostaglandin analogues, again in a mixed-aetiology
      population that the review does not separate by cause.
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "adverse events ranged from mild gastrointestinal symptoms to severe complications such as disability and depression, requiring careful monitoring"
    explanation: Documents the tolerability burden that qualifies these symptomatic options.
- name: Chemical lumbar sympathectomy
  description: >-
    An invasive procedural option for refractory disease, reported to give sustained
    pain reduction with mild thigh pain as the common side effect. Carried as a
    sibling of the symptomatic-pharmacotherapy node under the SAME mixed-aetiology
    caveat: the systematic review supplying this evidence pooled 120 patients across
    primary, idiopathic and secondary erythromelalgia (13 of them receiving CLS) and
    did not stratify outcomes by aetiology, so efficacy in secondary disease is not
    established. Long-term outcomes are additionally underreported, and relapse is
    described in patients carrying SCN9A variants — a caveat belonging to the primary
    form, noted here only because it is inseparable from the pooled cohort. Term
    note: NCIT has no verifiable term for sympathectomy specifically, so the generic
    verified action term is used with a precise `preferred_term`; the procedure is a
    percutaneous chemical neurolysis rather than open surgery, though `SURGERY` is
    the closest available `therapeutic_modality` bucket for an invasive procedure.
  treatment_term:
    preferred_term: chemical lumbar sympathectomy
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: SURGERY
  target_phenotypes:
  - preferred_term: Limb pain
    term:
      id: HP:0009763
      label: Limb pain
  evidence:
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "observed significant pain reduction with CLS, with mild thigh pain as a side effect."
    explanation: >-
      Significant pain reduction is reported, but within a mixed-aetiology pooled review that does
      not separate secondary from primary/idiopathic disease.
  - reference: PMID:40428878
    reference_title: 'Comparative Efficacy and Tolerability of Treatments for Erythromelalgia: A Systematic Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite encouraging short-term results, long-term outcomes after CLS remain underreported and variable."
    explanation: >-
      Qualifies the procedure: encouraging short-term results but underreported and variable
      long-term outcomes, which is why this is curated as an option rather than a recommendation.
differential_diagnoses:
- name: Primary erythermalgia
  disease_term:
    preferred_term: primary erythermalgia
    term:
      id: MONDO:0007571
      label: primary erythermalgia
  description: >-
    The principal differential. Primary/inherited erythromelalgia is an autosomal
    dominant SCN9A (Nav1.7) gain-of-function channelopathy of nociceptors,
    characteristically bilateral and symmetric, and characteristically refractory to
    aspirin — the mechanistic and therapeutic mirror image of the platelet-mediated
    secondary form modeled here. Curated separately as `Primary_Erythermalgia`.
  evidence:
  - reference: PMID:8203771
    reference_title: 'Thrombocythemic erythromelalgia, primary erythermalgia, and secondary erythermalgia: three distinct clinicopathologic entities.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the authors discern three distinct types of red, congested, and burning extremities that need to be distinguished for effective treatment according to their etiology: erythromelalgia in thrombocythemia, primary erythermalgia, and secondary erythermalgia"
    explanation: >-
      Establishes that thrombocythemic erythromelalgia and primary erythermalgia are distinct
      clinicopathologic entities requiring different treatment.
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Primary erythermalgia: Refers to an idiopathic or inherited disorder. Also called aspirin-resistant erythermalgia of unknown origin."
    explanation: Documents the aspirin resistance of primary erythermalgia, the therapeutic discriminator from the MPN-associated form.
  - reference: PMID:30609105
    reference_title: Review of primary and secondary erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "recent discoveries of the genetic mutations that now define primary erythromelalgia, as opposed to secondary erythromelalgia"
    explanation: States that genetic mutations define the primary form in contradistinction to the secondary form.
- name: Superficial thrombophlebitis
  description: >-
    Painful red, warm, indurated erythromelalgic "hot spots" on the skin of the
    upper legs in thrombocythemia are readily misdiagnosed as superficial
    thrombophlebitis, which would be treated quite differently.
  evidence:
  - reference: PMID:8951772
    reference_title: 'Erythromelalgic, thrombotic and hemorrhagic manifestations in 50 cases of thrombocythemia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Painful red, warm and indurated erythromelalgic hot spots in the skin of the upper legs were misdiagnosed as superficial thrombophelebitis in 5 PT and 2 PV patients."
    explanation: Documents this specific misdiagnosis in 7 of 50 thrombocythemia patients.
discussions:
- discussion_id: av_shunting_vs_occlusion_paradox
  prompt: >-
    How does an arteriole occluded by platelet-rich thrombi produce a skin surface that
    is visibly red and *hotter* than normal? Is microvascular arteriovenous shunting
    the reconciling mechanism, and if so does it operate in the MPN-associated form or
    only in the non-platelet acquired routes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Episodic Acral Burning Pain, Erythema, and Warmth
  - pathophysiology#Acral Arteriolar Microvascular Occlusion
  - pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands
  rationale: >-
    This entry's occlusive model has an unresolved surface paradox. The demonstrated
    lesion is arteriolar obstruction by platelet-rich thrombi, which should reduce
    perfusion — yet the defining clinical sign is a red, warm, congested extremity,
    and the flare node above therefore deliberately binds no `vasodilation` process
    rather than assert a mechanism it cannot evidence.


    The classical reconciliation is microvascular arteriovenous shunting: blood
    bypasses the nutritive capillary bed through shunts, so the skin is simultaneously
    hyperemic and warm at the surface while the tissue itself is hypoxic. That model
    is asserted in the older review literature (PMID:15075045) but, critically, is
    asserted there as a *single common mechanism for all* erythromelalgia — a claim
    the later Nav1.7 channelopathy findings contradict, and which the umbrella
    `erythromelalgia` entry already cites with the same caveat. The deep-research report
    for this entry describes the same shunting model with a low-transcutaneous-oxygen
    correlate, but its only source there is a textbook chapter with no PMID and no
    quotable passage, so it cannot be curated as an evidence-backed pathophysiology
    node.


    Since that gap was first recorded, one half of the question has acquired a
    candidate answer. The dermatopathology series behind
    `pathophysiology#Autonomic Denervation of Acral Arteries and Eccrine Glands`
    reports loss of autonomic innervation of acral *arteries* alongside vascular
    ectasia — which is a plausible substrate for shunting, since arteriovenous shunts
    are under autonomic control. It would bear on the second half of the prompt above,
    the non-platelet routes, *if* that series' patients were in fact non-MPN, which it
    does not establish: the cases were unstratified by aetiology. It does not close the
    gap on any reading — no perfusion or oxygenation was measured, and it is a single
    n=9 study — so this is a lead for the experiment below, not a resolution. Worth
    noting too that the same series reports superficial vascular *ectasia*, which is
    itself a dilation finding and may be a more parsimonious reading of the warm,
    hyperemic surface than shunting.


    What would settle it: paired measurements in *aetiologically stratified* patients
    — laser Doppler skin blood flow and transcutaneous oxygen tension during a flare,
    in MPN-associated versus non-MPN secondary disease. Until then this entry models
    only what the histopathology and platelet kinetics directly demonstrate, and
    records the shunting hypothesis here rather than promoting it to a node.
  evidence:
  - reference: PMID:15075045
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A wide variety of etiological conditions can cause erythromelalgia, all having a single common pathogenetic mechanism - microvascular arteriovenous shunting."
    explanation: >-
      States the arteriovenous-shunting hypothesis, and is cited as the source of an open
      hypothesis rather than as support for a curated mechanism. This 2004 review asserts
      shunting as the SINGLE common mechanism across all erythromelalgia, which the SCN9A/Nav1.7
      findings curated in `Primary_Erythermalgia` contradict.
  - reference: PMID:8883266
    reference_title: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature"
    explanation: >-
      Establishes the occlusive half of the paradox — the demonstrated lesion in MPN-associated
      disease is microvascular occlusion, which is what makes the warm, hyperemic surface
      appearance require an explanation.
  - reference: PMID:39846717
    reference_title: The Cutaneous Pathology of Erythromelalgia and Its Role in Establishing Critical Clues Regarding Pathogenesis.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy."
    explanation: >-
      Supplies a candidate anatomical substrate for the shunting half of the paradox in the
      non-platelet routes: arteriovenous shunts are under autonomic control, and this series
      demonstrates loss of autonomic innervation of acral arteries. Indirect — the study
      measured innervation, not shunting, perfusion or oxygenation, so it is a lead on the open
      question rather than an answer to it.
- discussion_id: secondary_em_nomenclature_scope
  prompt: >-
    Does MONDO:0035149 "secondary erythromelalgia" include the platelet-mediated
    erythromelalgia of the myeloproliferative neoplasms, or only the
    aspirin-resistant non-MPN acquired forms that the historical Drenth-Michiels
    classification called "secondary erythermalgia"?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Clonal Thrombocythemia in Myeloproliferative Neoplasm
  - pathophysiology#Non-Platelet Acquired Routes (Neuropathic, Autoimmune, Drug-Induced)
  rationale: >-
    Two incompatible nomenclatures are in circulation. The historical
    Drenth-Michiels scheme is three-way and defined by aspirin responsiveness:
    (a) aspirin-responsive erythromelalgia in thrombocythemia, (b) aspirin-resistant
    primary erythermalgia, (c) aspirin-resistant "secondary erythermalgia" associated
    with other medical conditions. Under that scheme, MPN-associated disease is NOT
    "secondary". Contemporary usage is instead a two-way primary/secondary split that
    places MPN-associated disease squarely within "secondary" — the Olmsted County
    population study classified patients as secondary precisely when they had a
    coexisting myeloproliferative disorder, and a 2025 systematic review lists
    myeloproliferative disorders first among the conditions secondary EM is linked to.
    This entry follows that contemporary usage and models the MPN platelet arm as the
    principal, best-evidenced secondary mechanism, while retaining the non-MPN routes
    as a separate, deliberately low-resolution node.


    THE GAP, stated precisely: which of the two senses MONDO:0035149 itself intends is
    NOT established here. Its only synonym is "Secondary erythermalgia" EXACT
    [Orphanet:529864] — i.e. Orphanet's label is the very term the historical narrow
    scheme used for the aspirin-RESISTANT non-MPN category. No Orphanet definition row
    was quotable at curation time (the Orphadata bulk XML was not available locally),
    so this entry's scope decision rests on contemporary clinical/epidemiological usage
    rather than on a cited ontology definition. Resolving it needs
    `just structured-rebuild-orphanet --id 529864` and a quoted `ORPHA:529864`
    definition row. Curators reading the older literature should meanwhile note that
    "secondary erythermalgia" there means something narrower than this entry's scope,
    which is also why `synonyms:` carries that string only because MONDO lists it as an
    exact synonym of MONDO:0035149, and not as an endorsement of the historical narrower
    reading; "platelet-mediated erythromelalgia" is deliberately NOT listed as a synonym,
    because it names the MPN arm alone and would make the same mistake in the other
    direction,
    and that the aspirin-responsiveness contrast is therefore a contrast between the
    MPN arm and everything else, not between "secondary" and "primary" as such.
  evidence:
  - reference: PMID:32491719
    reference_title: Erythromelalgia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "(a) Erythromelalgia in thrombocythemia: It is platelet mediated and aspirin responsive. This occurs in association with essential thrombocytosis and polycythemia vera."
    explanation: >-
      Documents the historical three-way classification in which thrombocythemic erythromelalgia is
      its own aspirin-responsive category, separate from "secondary erythermalgia".
  - reference: PMID:18713229
    reference_title: 'Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients were considered to have secondary erythromelalgia if they had a coexisting diagnosis of a myeloproliferative disorder such as polycythemia vera, chronic myelocytic leukemia, or thrombocythemia at the time of diagnosis of erythromelalgia"
    explanation: >-
      Contemporary epidemiology classifies MPN-associated disease as secondary, the usage this
      entry follows and the one matching MONDO/Orphanet.
clinical_trials: []
datasets: []

📚

References & Deep Research

Deep Research

2

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (4)

Record notes

Deliberate non-conformance to the `thrombogenesis` module. The acral thrombi of MPN-associated erythromelalgia are platelet- and von Willebrand factor-rich with only weak fibrin staining, and develop despite therapeutic anticoagulation, with no rise in prothrombin fragment 1+2 (PMID:8883266) — i.e. thrombin generation is not required. The `thrombogenesis` module explicitly scopes out "VWF-platelet microangiopathy ... unless a distinct conventional thrombin/fibrin thrombosis branch is explicitly evidenced", and no such branch is evidenced here, so no `conforms_to` edge is asserted. This is recorded rather than silently omitted because the disease looks superficially like a thrombogenesis conformer. `datasets:` is intentionally empty. `just discover-datasets` returns no GEO candidates, and the obvious relaxations are both unsafe here: this syndrome has no causal gene of its own, so a gene-keyed search has nothing to key on, and searching the underlying myeloproliferative neoplasms would return datasets that belong to `Polycythemia_Vera` / `Essential_Thrombocythemia` rather than to this entry. Adding those would be Named Entity Confusion reached through dataset search, so nothing is recorded. `clinical_trials:` is likewise intentionally empty. The interventional trials in erythromelalgia recruit primary/inherited or idiopathic disease and explicitly exclude patients whose extremity pain has another cause — the EASE study of ATX01 topical amitriptyline 15% (NCT05917912, AlgoTherapeutix, 14 participants), the burst spinal-cord-stimulation study (NCT04039633, St. Olavs Hospital, 6 participants), and the Nav1.7-targeted agent studies (NCT01090622, NCT01486446, NCT01769274). None of them enrol secondary erythromelalgia, so listing them here would misattribute trial evidence to this entity. The two lead identifiers were checked against the ClinicalTrials.gov API directly, not only against the deep-research report, because identifiers inside free-text `notes:` are not reference-validated by `just validate-disorders`.

Augment: new immune/dysautonomic mechanism, progression, burden, classifications; clear retired-PARTIAL prose · 2026-09-03T07:55:19Z · View source

Augmentation pass over an existing merged entry (created in PR #8772). No de-novo creation. DEEP RESEARCH. Ran openscientist rather than the default falcon, deliberately: a falcon report from 2026-08-17 already existed at research/Secondary_Erythromelalgia-deep-research-falcon.md, and 'just research-disorder falcon' writes to that same path, so re-running it would have overwritten the report the current entry was curated from. openscientist writes to a distinct path, so both reports now coexist. The run produced no frontmatter validation summary, so both retrofits were run: 'just validate-research-reference' and 'just validate-research-terms'. Report reference validation: 26/26 references resolved, 0 unresolved, 0 off topic, 24/25 quotes matched. The single flagged quote (PMID:22247059) is a false positive - the report's 'closest text in source' is byte-identical to the quote. Nothing from that report was cited on an unresolved identifier. Report term validation: 5 mislabelled CURIEs were reported and NONE were bound. MONDO:0008574 is obsolete ('obsolete Tl antigen', offered as erythromelalgia); HP:0012326 is 'Abnormal celiac artery morphology', offered as Erythromelalgia; NCIT:C512 ('Free Radical') offered as Hydroxyurea; NCIT:C15325 ('Skin Transplantation') offered as Phlebotomy; NCIT:C79809 ('Defactinib') offered as Ruxolitinib. Every ontology term added in this session was resolved independently via OLS. RETIRED ENUM PROSE (dismech#10003). Removed all 13 occurrences of prose arguing for the retired 'PARTIAL' supports value. Each explanation was rewritten to preserve its substantive caveat rather than deleted, and five were converted into structured 'directness: INDIRECT' where the support genuinely runs through an inference step. Also repointed the discussion cross-reference that asserted the umbrella 'erythromelalgia' entry 'flags as PARTIAL'; that entry still carries one such stale line, left out of scope for this disease's PR and flagged in the PR body. NEW MECHANISM. Added pathophysiology node 'Complement-Mediated Microvascular Injury and Autonomic Denervation of Acral Skin' (mechanism_confidence PROVISIONAL) plus a mechanistic_hypotheses group 'immune_dysautonomic_route' (status EMERGING), from PMID:39846717. This gives the previously unresolved non-MPN acquired routes their first biopsy correlate (microvascular C5b-9, type-I interferon in endothelium, CD56 loss of autonomic innervation of eccrine coil and arteries) and a mechanistic reading of their aspirin resistance. Deliberately NOT promoted to an established mechanism: single retrospective n=9 single-centre series, cases selected by clinical concern rather than aetiology, not stratified MPN vs non-MPN, and the authors say 'suggests'. Both its causal edges carry hypothesis_groups tags. The same source was also added as INDIRECT evidence on the pre-existing av_shunting_vs_occlusion_paradox knowledge gap, whose prompt asks whether shunting operates in the MPN arm or only the non-platelet routes - autonomic denervation of acral arteries is a candidate substrate, and the gap was updated to say so while remaining OPEN. NEW SECTIONS. synonyms (MONDO exact synonym plus attested usage). progression: three phases - presenting flare (with the median 2.5-year lead time before myeloproliferative diagnosis, PMID:2643412, and the Olmsted case definition's 2-year window, PMID:18713229), untreated progression to acrocyanosis/necrosis/gangrene, and remission on COX inhibition or cytoreduction. clinical_burden VARIABLE, not HIGH, because the MPN arm is abolished by low-dose aspirin while the non-MPN arm is aspirin resistant and can reach tissue loss; both ends are cited. classifications: harrisons_chapter CARDIOVASCULAR (primary, matching the acral arteriolar lesion and the I73.8 cross-reference) plus ONCOLOGY_HEMATOLOGY (the MPN substrate), each with evidence. OTHER EVIDENCE ADDED. Modern unselected erythromelalgia frequency in polycythemia vera of 5.3% (PMID:39556352), which answers the denominator caveat the Erythromelalgia phenotype description already raised against the 62-65% referral-series fractions. Aspirin specificity - no response to coumadin, immediate relief on a 500 mg load (PMID:16510297) - and recurrence on aspirin withdrawal with remission on rechallenge (PMID:22844295), establishing the effect as suppressive rather than curative. Thrombotic thrombocytopenic purpura (PMID:1613144) and chronic myelogenous leukemia (PMID:2643412) recorded as single-case acquired associations, named rather than modeled. Serial blood-count monitoring recommendation (PMID:2643412). NOT CHANGED, DELIBERATELY. datasets: and clinical_trials: remain empty; the existing notes give sound reasons (no GEO candidates, no causal gene to key on, MPN datasets belong to the MPN entries; the interventional trials enrol primary/idiopathic disease and exclude secondary). No histopathology: section was added even though the biopsy findings are well evidenced - they are already carried by the Arteriolar Inflammation pathophysiology node and by diagnosis#Skin punch biopsy of an affected area, and a third structured restatement would be redundant. RED-TEAM REVIEW ROUND. A pre-PR adversarial review was run in a fresh context against the dismech-pr-review skill before any PR was opened. It confirmed every snippet exact and every reference_title matching the cache, and raised 16 findings, all content/reviewer objections rather than CI failures. All were acted on. The substantive ones: - The causal edge from Non-Platelet Acquired Routes into the new immune node was graded causal_link_type DIRECT while its snippet establishes only that 3 of 9 patients carried an autoimmune diagnosis. The edge description also asserted three unsourced things (that the lesion belongs to the autoimmune/idiopathic arm, that it is instead of a platelet-rich thrombus, and that the acquired route causes it). Removed the DIRECT grade, added directness INDIRECT, and rewrote both description and explanation to claim only what the quote gives. - The hypothesis label read '...in Non-MPN Secondary Disease', putting a restriction into the rendered label that the source cannot support: PMID:39846717's series was assembled by clinical concern for erythromelalgia and is not stratified primary/secondary or MPN/non-MPN. Relabelled to drop the restriction and added a sentence saying the restriction is part of the hypothesis rather than an observation. - synonyms: had added 'Platelet-mediated erythromelalgia', which names the MPN arm alone, has no MONDO backing, and sits against this entry's own open secondary_em_nomenclature_scope discussion. Dropped. 'Secondary erythermalgia' is kept because MONDO carries it as an exact synonym, and the nomenclature discussion now says so explicitly so the two do not read as contradicting each other. - The PMID:39556352 5.3% item was attached to a phenotype whose only claim is frequency OBLIGATE, and its own explanation conceded it did not support that. Regraded NO_EVIDENCE per the CLAUDE.md table, kept as a cited counterweight to the referral series. Also corrected 2024 to 2025 for that review's year. - The PARTIAL rewrite had, in one place, flipped the direction of a claim: the Acrocyanosis band explanation went from 'this does not support the band' to 'the band is read off that figure'. Restored the hedge and added directness INDIRECT, noting that 14/31 is a curator computation joining two sentences of an abstract that states '14 cases' with no denominator. - The Drenth-Michiels sentence 'Secondary erythermalgia: Aspirin resistant...' was cited three times with inconsistent directness, and is a category DEFINITION rather than an empirical result, so citing it as support for aspirin resistance is definitionally circular. Set directness INDIRECT on all three and reworded to say the classification defines the category by the property. - The Olmsted case definition says 'within 2 years of the diagnosis of erythromelalgia', which is symmetric; the progression notes had over-read it as 'up to two years after'. Corrected, and the direction is now carried by PMID:2643412 and PMID:11208311 which do state it. - The clinical_burden low end said a treated patient carries 'close to no residual burden', contradicting content added in this same session (suppressive not curative; bleeding hazard at very high platelet counts). Softened. - CL:0000115 'endothelial cell' was bound where CL:0011030 is labelled exactly 'dermal microvascular endothelial cell', matching the curator's own preferred_term. Rebound. The pre-existing CL:0000115 at the Arteriolar Inflammation node was left alone as out of scope for this change. - evidence_source corrections: the PMID:2643412 monitoring sentence is a recommendation, not an observation, so OTHER; PMID:16510297 is a narrative review whose coumadin-vs-aspirin comparison is a synthesis, so OTHER, matching how this entry already grades PMID:12781799. Added directness INDIRECT to the PMID:18713229 burden framing quote. - PMID:22844295 was described as the syndrome 'recurring' on withdrawal. The patient was taking aspirin for stroke prophylaxis and the erythromelalgia emerged de novo on stopping it, so this is unmasking, not relapse. Reworded, and the resulting general claim is now explicitly reconciled against PMID:8951772's description of a 'curative' aspirin effect. - age_range carried a two-clause folded block duplicating a caveat already in notes; shortened to a phrase and the median-61-years figure now carries its own evidence item, which it previously lacked. - The shunting-discussion addition said the finding 'points at the non-platelet routes' four lines above conceding the series was unstratified. Reworded to a conditional, and the reviewer's observation that superficial vascular ectasia is itself a more parsimonious reading of the warm hyperemic surface than shunting was added to the discussion. - Unused fetched references: PMID:22247059 (Swedish population cohort) now supports the diagnostic-delay claim on progression phase 1 and the VARIABLE burden call (no EM-attributable mortality). PMID:23334520 was added to the new node as a NO_EVIDENCE counterweight: it states the commonly reported secondary-EM histology and names neither complement nor denervation. - The 14/31 figure and its three caveats were recited in full in three sections; the caveats now live once, on the phenotype where the band lives. - Harrison's placement notes asserted what Harrison's covers without a source; reframed as curator placement rationale, and DERMATOLOGY is now explicitly considered and declined rather than silently omitted. Reviewer suggestions NOT taken: rebinding the pre-existing arteriolar endothelial cell term (out of scope for this change), and adding a DERMATOLOGY Harrison's Part (declined in the notes, with the reason recorded). 'just preflight-dr <report> MONDO:0035149' was run at the reviewer's suggestion. It SKIPs: MONDO records no causal gene for MONDO:0035149, so the gene-identity check cannot discriminate. The report's top genes are JAK2/MPL/CALR (the MPN drivers) with SCN9A appearing only as the primary-form contrast, so there is no Named Entity Confusion signal. VALIDATION. 'just validate-disorders kb/disorders/Secondary_Erythromelalgia.yaml' (the batched gate CI runs) was re-run on the final post-review bytes and passed: schema clean, term validation passed, 110/110 snippets verified. Offline gates all green: check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence, check-source-defect-claims. The causal graph builds with 25 nodes, 16 edges and an empty orphan_targets set. Final evidence census: 108 SUPPORT, 2 NO_EVIDENCE, 14 directness INDIRECT. Two self-inflicted errors were caught by the gates during the session and fixed: a duplicated 'downstream:' key, and a non-unique string match that corrupted an unrelated pathophysiology evidence block, which was restored from origin/main and re-verified.

Fix swapped NCT ids in notes; add AV-shunting knowledge gap, CLS treatment, etiology evidence (PR #8772 review) · 2026-08-17T17:41:18Z · View source

Addresses the automated review on PR #8772 (verdict CHANGES_REQUESTED, one blocking item). BLOCKING FIX - swapped NCT identifiers in notes:. The clinical_trials: [] rationale attributed two trials backwards: it named NCT04039633 as the ATX01 topical amitriptyline study and NCT05917912 as the burst spinal-cord-stimulation study. These are inverted. The note is load-bearing - it is the recorded reason clinical_trials is empty - so a future curator revisiting that decision would have followed the wrong identifiers, and identifiers inside free-text notes: are not reference-validated, which is exactly why a clean validate-disorders run did not catch it. I did not take the reviewer's mapping on trust. I verified both identifiers directly against the ClinicalTrials.gov API (v2 /studies endpoint), independently of the deep-research artifact: NCT05917912 -> "EASE (Efficacy of ATX01 Study in Erythromelalgia)", sponsor AlgoTherapeutix, enrollment 14, interventions Amitriptyline Hydrochloride + Placebo NCT04039633 -> "Spinal Cord Stimulation for Refractory Pain in Erythromelalgia", sponsor St. Olavs Hospital, enrollment 6, interventions Burst Spinal Cord Stimulation + Sham This confirms the review and matches the falcon artifact's own statements at lines 1156, 1157 and 1218. The corrected note now carries sponsor and enrollment for both lead trials so the attribution is self-checking, and records that the identifiers were verified against the API rather than only against the DR report. OPTIONAL ITEMS TAKEN (all three are evidence-backed; none manufactured). 1. AV-shunting / tissue-hypoxia KNOWLEDGE_GAP added (discussion_id av_shunting_vs_occlusion_paradox), attached to the flare node and the occlusion node. The reviewer expected this could only be recorded as an unevidenced note because the mechanism's only source in the DR report is a textbook chapter with no PMID. That turned out not to be the constraint: PMID:15075045 was ALREADY in references_cache/ (it is cited by the umbrella erythromelalgia entry) and states the hypothesis directly - "all having a single common pathogenetic mechanism - microvascular arteriovenous shunting". So the gap is curated with real evidence. It is deliberately PARTIAL: that 2004 review asserts shunting as the SINGLE common mechanism for ALL erythromelalgia, which the SCN9A/Nav1.7 findings contradict, and the umbrella entry already flags the same quote PARTIAL for the same reason. The discussion states the paradox it reconciles (an occluded arteriole producing warm, red skin), explains why no vasodilation process is bound to the flare node, and names the experiment that would settle it (paired laser Doppler and transcutaneous oxygen tension in aetiologically stratified patients). The shunting model is recorded as an open hypothesis, NOT promoted to a pathophysiology node. 2. Chemical lumbar sympathectomy added as a procedural treatment node, sibling to the symptomatic-pharmacotherapy node, from PMID:40428878 (already cited and cached). Both evidence items are PARTIAL under the same mixed-aetiology caveat already applied to the pharmacotherapy node: the review pooled 120 patients across primary, idiopathic and secondary EM (13 receiving CLS) without stratifying outcomes by aetiology. The second item deliberately carries the qualifying finding ("long-term outcomes after CLS remain underreported and variable") so the node reads as an option, not a recommendation. Term note: no verifiable NCIT sympathectomy term exists (NCIT:C51765 is Bilateral Salpingectomy with Oophorectomy - the pre-edit hook caught this attempt), and neither the local ncit adapter nor OLS returns one, so the generic verified NCIT:C49236 Therapeutic Procedure is used with preferred_term "chemical lumbar sympathectomy", per the CLAUDE.md pattern that preferred_term may be more specific than the bound term. The description records that the procedure is a percutaneous chemical neurolysis rather than open surgery and that SURGERY is merely the closest available therapeutic_modality bucket. 3. Non-Platelet Acquired Routes node strengthened with a further evidence item from PMID:15075045, which names collagen-vascular disease, diabetes mellitus, peripheral neuropathy, autoimmune and infectious disease and drug exposure as the acquired associations - a genuinely quotable etiology list, which the node previously lacked for several of those conditions. OPTIONAL ITEMS DELIBERATELY NOT TAKEN. - Expanding differential_diagnoses from 2 to the ~12 conditions named in the DR report (CRPS, Raynaud, cellulitis, vasculitis, gout, Fabry, SLE, ...). Those trace only to the unquotable textbook chapter. Adding them would mean either citing a source I cannot quote or attaching real PMIDs to claims they do not make - the #7791 pattern this entry was reviewed clean for. The reviewer marked this genuinely optional and conditional on sourcing; it is not sourced, so it is not added. - Splitting the Progression to Acrocyanosis and Digital Ischemic Necrosis node. The reviewer explicitly advised against splitting without a source that separates the two outcomes; the cited series reports them as a composite endpoint and the entry already says so. - Adding has_subtypes. The reviewer agreed the current single PROVISIONAL node is the more honest modeling given no per-class phenotype, prevalence or mechanism data exists. VALIDATION ACTUALLY RUN AND READ, after these edits. The repository pre-edit hook ran just validate on every write and blocked one invalid draft (the wrong NCIT sympathectomy term). just validate-terms PASSED on the changed file. just count-verified-snippets initially reported 77/78 with one failure - the CLS snippet quoted an inline "[21]" citation marker, which is stripped before matching; re-quoted to avoid the bracket, after which it reports 129/129 verified across all three changed files. just check-title-snippets OK, just check-duplicate-keys OK, just check-term-cache-integrity OK. The batched just validate-disorders over all three changed files - the same check CI runs - passed with 129/129 snippets verified. The only remaining compliance gap is datasets, which is intentionally empty with its reasoning recorded in notes. The CHANGES_REQUESTED review was left in place and NOT dismissed; a fresh review was dispatched via the claude-code-review workflow instead.

Create: Secondary Erythromelalgia (MONDO:0035149) · 2026-08-17T16:34:52Z · View source

Created kb/disorders/Secondary_Erythromelalgia.yaml for GitHub issue #8545 (MONDO:0035149, Orphanet:529864). MECHANISM MODELED. The mechanistically distinct SECONDARY route, not the nociceptor-hyperexcitability mechanism of the primary form: clonal thrombocythemia in a myeloproliferative neoplasm -> thromboxane/ COX-1-dependent platelet activation and aggregation -> arteriolar inflammation with fibromuscular intimal proliferation -> acral arteriolar microvascular occlusion -> episodic acral burning pain, erythema and warmth, with a branch to acrocyanosis and digital ischemic necrosis. A separate, deliberately low-resolution node (mechanism_confidence PROVISIONAL) covers the non-MPN acquired routes (neuropathic, autoimmune, drug-induced). Aspirin and indomethacin carry INHIBITS target_mechanisms edges onto the platelet-activation node; cytoreduction carries an INHIBITS edge onto the upstream thrombocythemia node. The aspirin-responsiveness contrast (dramatic in MPN-associated disease, characteristically poor in primary/SCN9A disease) is curated with its own evidence in treatments, diagnosis and differential_diagnoses. DEEP RESEARCH AND NEC. Provider: falcon (research/Secondary_Erythromelalgia-deep-research-falcon.md). Elevated Named Entity Confusion risk was expected because the bare word "erythromelalgia" usually returns SCN9A/primary material. "just preflight-dr <report> MONDO:0035149" returned SKIP - MONDO records no causal gene (RO:0004003) for this term, so the automated gene-identity check cannot discriminate - and it reported SCN9A as the top gene mention (11). A manual NEC review was therefore performed as the skill requires, and the report PASSED: every SCN9A mention is contrastive (e.g. "SCN9A and Nav1.7 are central to inherited primary erythromelalgia, not to secondary erythromelalgia"), and the report is substantively about the acquired form throughout. The report was nonetheless used only as leads - it cites 3 resolvable DOIs and no PMIDs (its own reference_validation block reports 3/3 resolved, confabulation_rate 0.0) - so NO evidence item in this entry is sourced from it. EVIDENCE. All evidence was independently sourced via the PubMed E-utilities API and verified against locally fetched abstracts: PMID:3977194 (Michiels 1985 Ann Intern Med, the seminal platelet-mediated arteriolar inflammation and thrombosis paper), PMID:8951772 (50-case consecutive thrombocythemia series), PMID:8883266 (platelet activation and endothelial damage but NOT thrombin generation), PMID:7792731 (shortened platelet survival reversed by aspirin), PMID:12781799 (Michiels 2003 aspirin-responsive arterial thrombophilia), PMID:9263352, PMID:8203771 (three-entity classification), PMID:32491719 (StatPearls classification), PMID:18713229 (Olmsted County population-based incidence), PMID:16673274 (platelet COX-1 as drug target), PMID:29641704, PMID:30609105. CURATION DECISIONS RECORDED RATHER THAN LEFT SILENT. 1. No conforms_to on the thrombogenesis module, with the reason in the entry notes: the acral thrombi are VWF-rich with only weak fibrin staining and form without thrombin generation (PMID:8883266), and the module explicitly scopes out VWF-platelet microangiopathy absent an evidenced thrombin/fibrin branch. The disease looks superficially like a conformer, so the non-conformance is documented. 2. A KNOWLEDGE_GAP discussion (secondary_em_nomenclature_scope) records the conflict between the historical three-way Drenth-Michiels classification, in which MPN-associated disease is NOT "secondary", and the modern MONDO/Orphanet two-way split that this entry follows. 3. datasets is deliberately empty: "just discover-datasets" returned no GEO candidates, and relaxing to the underlying MPNs would import datasets belonging to Polycythemia_Vera / Essential_Thrombocythemia - Named Entity Confusion reached through dataset search. CROSS-REFERENCES ADDED. kb/disorders/erythromelalgia.yaml: bound both has_subtypes stubs to MONDO terms (subtype_term MONDO:0007571 and MONDO:0035149) and pointed each at its standalone entry. kb/disorders/Primary_Erythermalgia.yaml: added a Secondary Erythromelalgia differential_diagnoses block so the sibling link is bidirectional. PRE-PR SELF-REVIEW AND RESULTING CHANGES. An adversarial review pass was run against the draft before opening the PR, and it found real problems that were fixed: (1) The Erythromelalgia phenotype had frequency VERY_FREQUENT justified by 26/40 (65%) and 31/50 (62%) - arithmetic that lands in FREQUENT, and against the wrong denominator (patients with thrombocythemia, not patients with this disease). Changed to OBLIGATE, since the phenotype IS the disease, with the referral bias and the conflict with the OCCASIONAL band already curated on the MPN entries stated explicitly; both cohort items downgraded to PARTIAL. (2) The Acrocyanosis FREQUENT band was justified by "14 of 50" (28% = OCCASIONAL) and rested on a composite endpoint double-counted with the Digital ischemic necrosis phenotype. Restated against the correct 31-patient erythromelalgia denominator (14/31 = 45%), with the composite endpoint, the untreated conditioning, the missing untreated denominator, and the referral series all named; item downgraded to PARTIAL and the 31-patient denominator separately evidenced. (3) The claim that MONDO/Orphanet intend the broad sense of "secondary" was unverified and is load-bearing for the entry's scope. MONDO:0035149's only synonym is "Secondary erythermalgia" EXACT [Orphanet:529864] - i.e. the historical NARROW term. The Orphadata bulk XML is gitignored and not present locally, so ORPHA:529864 could not be quoted; the discussion rationale was rewritten to state the gap precisely and name the command that would resolve it, rather than assert an ontology's intent. (4) The top-level description called the MPN form "historically defining", contradicting the discussion's own point that MPN disease is NOT "secondary" under the historical scheme. Changed to "best-evidenced". (5) The blanket negative "no specific effective therapy exists" was contradicted by a 2025 systematic review (PMID:40428878) surfaced by this PR's own falcon artifact. Fetched it and added a new "Symptomatic pharmacotherapy for aspirin-unresponsive disease" treatment (amitriptyline-ketamine, lidocaine, iloprost, misoprostol), all items PARTIAL because that review pools primary, idiopathic and secondary EM without stratifying by aetiology; the old negative was softened and scoped to cause-directed therapy. (6) No environmental/trigger content existed despite heat-provocation and cooling-relief being the most universally described feature of the syndrome. Added an environmental entry with an EXACERBATES influences_mechanisms edge onto the flare node. (7) Two modifier: INCREASED assertions had no supporting measurement (GO:0004666 COX activity, GO:0042311 vasodilation). The COX modifier was dropped; the vasodilation term was removed entirely, since it also sits against this entry's occlusive model. Both omissions are explained in place. (8) The Non-Platelet Acquired Routes node named three etiologies that no snippet supported; now evidenced from PMID:40428878 and PMID:18713229. (9) In the sibling Primary_Erythermalgia differential block, an explanation attached to PMID:3977194 asserted "has no counterpart in the neuronal channelopathy of primary erythermalgia" - a negative that paper never addresses (the #7791 pattern). Trimmed to what the paper shows, with the comparative claim reassigned to PMID:8203771; "later onset" and "unilateral" now evidenced from PMID:40428878. Also: PMID:9263352 reclassified HUMAN_CLINICAL -> OTHER (narrative minireview); an ICD10CM:I73.8 mappings block added with skos:broadMatch and an explicit warning that the residual code cannot serve as a case definition; a clinical_trials rationale added to notes (all EM trials exclude secondary disease); and three uncitable content_type:unavailable DOI cache stubs removed rather than committed. VALIDATION ACTUALLY RUN AND READ, after the above fixes. "just validate" ran via the repository pre-edit hook on every write and blocked four invalid drafts, which were corrected - including catching a wrong CHEBI id for iloprost (CHEBI:63285 is mycinamicin VI; corrected to CHEBI:63916). "just validate-terms" PASSED on all three changed files. "just count-verified-snippets" reported 124/124 verified across the three changed files. "just check-title-snippets" reported OK, no new title-quoting snippets. "just check-duplicate-keys" reported OK. "just check-term-cache-integrity" reported OK. The relevant foreign-key pytest selections (attaches_to, conforms_to, subtype FKs, unique names, environmental mechanism targets, duplicate keys) passed. A final batched "just validate-disorders" over all three changed files - the same check CI runs - exited 0 with 124/124 snippets verified.

Falcon ▸

Secondary Erythromelalgia: Disease-Characteristics Research Report

Edison Scientific Literature 16 citations 2026-08-17T09:14:00.381835

Secondary Erythromelalgia: Disease-Characteristics Research Report

Executive summary and evidence caveat

Secondary erythromelalgia (secondary EM) is an acquired, etiologically heterogeneous neurovascular pain syndrome characterized by recurrent or persistent burning pain, erythema, and increased skin temperature, usually in the feet or hands. Heat, exercise, dependency of the limb, prolonged standing, and tight footwear provoke attacks; cooling and elevation typically relieve them. Unlike inherited primary erythromelalgia, secondary EM is not itself an established monogenic channelopathy. It usually appears later in life in association with a myeloproliferative neoplasm (MPN), small-fiber or autonomic neuropathy, autoimmune/connective-tissue disease, metabolic disease, medication, infection, malignancy, toxin, or tissue injury. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 1-2)

The major evidence limitation is that most cohorts and therapeutic studies combine primary, idiopathic, and secondary EM. Consequently, many frequency and response estimates below describe EM overall, not secondary EM specifically. Secondary-disease evidence is strongest for the association between platelet-mediated MPNs and aspirin-responsive EM; most other associations and treatments rely on small observational studies, case series, or expert reviews. (skeik2019erythromelalgia pages 1-2, algarni2025comparativeefficacyand pages 4-5, algarni2025comparativeefficacyand pages 1-2)

Domain	Key finding	Evidence type/strength	Knowledge-base annotation
Definition / phenotype	Secondary erythromelalgia is an acquired neurovascular pain syndrome defined by episodic or persistent burning pain, erythema, warmth, and sometimes swelling, usually in distal extremities; attacks are precipitated by heat, exercise, dependency, footwear, and relieved by cooling/elevation. Compared with inherited primary disease, secondary disease tends to present later and may be more variable, unilateral, or localized. Quantitative phenotype data usually pool primary and secondary cases. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 1-2, algarni2025comparativeefficacyand pages 4-5)	Expert review + systematic review; moderate for core phenotype, lower for subtype distinctions	HPO: Erythema, Burning pain, Increased skin temperature, Distal extremity pain, Edema; UBERON: foot, hand, lower limb; MONDO: secondary erythromelalgia if available/not confirmed
Major secondary causes	Reported associations include myeloproliferative neoplasms/disorders (especially essential thrombocythemia, polycythemia vera, myelodysplastic syndromes), neuropathies/small-fiber neuropathy, autoimmune/connective-tissue disease, diabetes/metabolic disease, neoplasia, infections/vaccination, and drugs/toxins such as cyclosporine, calcium-channel blockers, bromocriptine, mercury, burns/frostbite, and mushroom intoxication. Much of this evidence is case-based or mixed-etiology review evidence. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 1-2, algarni2025comparativeefficacyand pages 1-2, algarni2025comparativeefficacyand pages 4-5)	Review-level evidence with many case associations; heterogeneous/variable strength	Disease associations: MPN, SFN, autoimmune disease, diabetes mellitus, neoplasm, infection, drug-induced disease, toxic exposure
Mechanism / pathophysiology	Secondary erythromelalgia is mechanistically heterogeneous. In hematologic forms, platelet activation/microthrombotic or prostaglandin-thromboxane-related microvascular dysfunction is the classic model; in neuropathic forms, small-fiber/autonomic dysfunction and vasomotor dysregulation are implicated. Reviews also support abnormal autonomic testing, reduced nerve terminal density, increased skin blood flow/temperature, and tissue hypoxia/shunting concepts, but these mechanisms are often inferred from mixed erythromelalgia cohorts rather than secondary-only cohorts. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 1-2, skeik2019erythromelalgia pages 2-3)	Mixed human clinical + expert review; moderate for MPN/aspirin-responsive mechanism, lower for unified mechanism	GO: platelet activation, blood coagulation, regulation of vasodilation, sensory perception of pain, axon guidance/maintenance, autonomic nervous system process; CL: platelet, peripheral sensory neuron, sympathetic neuron, endothelial cell
Diagnostics	Diagnosis is primarily clinical: characteristic attacks of red-hot painful extremities triggered by warmth and relieved by cooling, plus exclusion of mimics and search for an underlying cause. Ancillary tests that may support or subtype disease include CBC/platelets and MPN evaluation, vascular studies (often normal large-vessel Doppler but increased skin temperature/laser Doppler and low TcPO2), autonomic testing, thermography, and skin biopsy for nerve fiber density or intraluminal thrombi. Differential diagnoses include peripheral neuropathy, CRPS, cellulitis/erysipelas, dermatitis, osteomyelitis, SLE, venous/arterial insufficiency, and gout. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3)	Clinical review evidence; moderate for workup principles, limited formal criteria	HPO/differential tags; labs: CBC, platelet count; procedures: skin biopsy, autonomic reflex screen, thermography, laser Doppler, transcutaneous oxygen pressure
Epidemiology	Secondary-specific epidemiology is poorly defined. Mixed erythromelalgia estimates cited in reviews include incidence of 1.3/100,000 in Olmsted County and 15/100,000 in New Zealand; reported presentation age ranges 5-90 years with mean around 55 years and female predominance in mixed/reviewed cohorts. An anatomic series cited in review found 88.1% foot involvement, 25.6% hands, 13.7% legs, 2.4% face. These statistics generally do not isolate secondary disease. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 1-2)	Mostly retrospective/review data; weak-to-moderate for secondary disease specifically	Epidemiology note: mixed EM data; Age of onset: adult/later onset enrichment in secondary EM; Sex: female predominance reported
Treatment	First-line management is cause-directed plus trigger avoidance and safe cooling. Aspirin is particularly relevant in myeloproliferative-associated secondary erythromelalgia and is a classic response marker in platelet-mediated disease. Other options reported across mixed cohorts include topical amitriptyline-ketamine, lidocaine, misoprostol, iloprost, antihistamines, venlafaxine/SNRI-class drugs, sodium-channel blockers, and procedural escalation (e.g., sympathectomy, neuromodulation) for refractory cases. Systematic-review data across mixed EM showed ~75% pain relief with topical amitriptyline-ketamine and GI toxicity with misoprostol; applicability to secondary EM is uncertain. (skeik2019erythromelalgia pages 1-2, skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 6-7, algarni2025comparativeefficacyand pages 7-9, algarni2025comparativeefficacyand pages 2-4)	Strongest for aspirin in MPN-associated disease from longstanding clinical experience/review; otherwise mostly small mixed studies	NCIT/CHEBI: Aspirin, Amitriptyline, Ketamine, Lidocaine, Misoprostol, Iloprost, Venlafaxine; care pathway: treat underlying cause + symptomatic pain management
Trials / recent developments	Recent interventional trials mostly target primary/inherited or idiopathic erythromelalgia, not secondary disease. Examples: EASE/ATX01 topical amitriptyline Phase 2 crossover completed 2024 (14 participants), but exclusion criteria removed patients with other extremity pain causes; burst spinal cord stimulation trial enrolls only primary/idiopathic disease; earlier XPF-001/XPF-002 and PF-05089771 trials were for primary/inherited disease. Thus, current trial evidence is not directly generalizable to secondary erythromelalgia. (NCT04039633 chunk 1, NCT05917912 chunk 1, NCT05917912 chunk 2, NCT01090622 chunk 1, NCT01486446 chunk 2, NCT01769274 chunk 3)	High confidence for exclusion/generalizability statement from trial records	ClinicalTrials: NCT05917912, NCT04039633, NCT01090622, NCT01486446, NCT01769274; intervention classes: topical analgesic, spinal cord stimulation, Nav1.7-targeted agents
Genetics / molecular	SCN9A and Nav1.7 are central to inherited primary erythromelalgia, not to secondary erythromelalgia. No established secondary-EM-specific germline causal gene, protective allele, modifier gene, epigenetic signature, or structural chromosomal abnormality was identified in the reviewed evidence. In secondary disease, molecular findings may instead derive from the underlying associated disorder (e.g., somatic driver mutations of myeloproliferative neoplasms), rather than erythromelalgia itself. (assaad2025severeerythromelalgiapain pages 6-8, algarni2025comparativeefficacyand pages 1-2)	High confidence for SCN9A-primary distinction; low evidence for secondary-EM-specific genetics because evidence is largely absent	HGNC/OMIM note: SCN9A relevant mainly to inherited primary EM; secondary EM genetics: none established at disease level
Models	Available experimental systems predominantly model inherited primary erythromelalgia, including iPSC-derived sensory neurons carrying SCN9A variants and Nav1.7-related preclinical pain models. These are useful for nociceptor hyperexcitability and analgesic discovery but do not faithfully model the heterogeneous acquired mechanisms of secondary erythromelalgia. No validated natural animal disease or dedicated acquired secondary-EM model was identified in the available evidence. (NCT01769274 chunk 3)	Indirect/model evidence; low for secondary disease relevance	Model annotation: human iPSC sensory neuron model for primary EM; secondary EM model status: none established

Table: This table summarizes evidence-grade findings for secondary erythromelalgia across clinical, mechanistic, diagnostic, epidemiologic, therapeutic, genetic, and model domains. It highlights where evidence is strong, where data are mixed with primary erythromelalgia, and where disease-specific gaps remain.

1. Disease information

Definition and classification

The name derives from Greek erythros (red), melos (limb), and algos (pain). Common names are erythromelalgia, erythermalgia, erythralgia, Mitchell disease, and, when acquired, secondary erythromelalgia/secondary erythermalgia. The syndrome’s defining clinical triad is red, hot, painful extremities. Swelling may accompany attacks. Secondary EM is best represented as a disease-level syndrome, aggregated from clinical literature and disease resources—not as an individual-patient/EHR datum unless a knowledge-base record explicitly links it to a patient. (skeik2019erythromelalgia pages 1-2, skeik2019erythromelalgia pages 2-3)

Identifiers

ICD-10-CM: I73.81, Erythromelalgia. This code does not reliably distinguish primary from secondary disease.
MeSH: Erythromelalgia; a separate secondary-EM descriptor is generally not used.
MONDO: A dedicated, independently curated secondary-EM MONDO identifier could not be confirmed from the retrieved evidence. Use the parent erythromelalgia concept plus a “secondary/acquired” qualifier and causal-disease relationship rather than assigning an unverified ID.
OMIM: OMIM entries chiefly describe inherited primary erythromelalgia associated with SCN9A; these should not be used as identifiers for acquired secondary EM.
Orphanet/ICD-11: Erythromelalgia concepts may be indexed, but a separate secondary-disease identifier was not verified in the available evidence.

2. Etiology, risks, protective factors, and gene–environment interaction

Causal or associated factors

Hematologic/MPN: essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, and related platelet disorders. These are the most clinically actionable secondary causes. Platelet activation, aggregation, and arteriolar microthrombosis are implicated.
Neuropathic/metabolic: small-fiber neuropathy, diabetic neuropathy/diabetes mellitus, and other peripheral or autonomic neuropathies.
Autoimmune/connective-tissue: systemic lupus erythematosus and other connective-tissue or inflammatory disorders.
Neoplastic/paraneoplastic: solid tumors, hematologic malignancy, and paraproteinemic states have been reported.
Drug-associated: calcium-channel blockers, bromocriptine, and cyclosporine are repeatedly listed; individual drug associations generally derive from case reports.
Infectious or immune triggers: HIV, infectious mononucleosis, and temporal associations with influenza or hepatitis-B vaccination have been reported, but causality is weak.
Toxic/physical injury: mercury exposure, mushroom intoxication, burns, and frostbite are reported associations. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 1-2, algarni2025comparativeefficacyand pages 4-5)

Risk and protective factors

Older age and the presence of an underlying MPN, neuropathy, diabetes, autoimmune disease, malignancy, or an implicated medication increase clinical suspicion. Heat exposure, exercise, prolonged standing, limb dependency, emotional stress, and occlusive footwear are attack triggers, not necessarily causes of the underlying disease. Female predominance has been reported in mixed EM cohorts, but a secondary-specific sex ratio is unavailable. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 4-5)

No validated genetic protective variant, dietary factor, medication prophylaxis, or population-level environmental protective exposure has been established. Avoidance of heat and mechanical triggers reduces attacks but should be classified as symptom prevention rather than protection against disease onset.

Gene–environment interaction

No reproducible secondary-EM-specific gene–environment interaction is established. Genetic or somatic drivers may belong to the underlying disorder—for example, MPN biology—while heat or dependency precipitates symptoms through altered microvascular and neural control. This differs fundamentally from inherited EM, in which a germline channel variant directly changes nociceptor excitability.

3. Phenotypes

Phenotype	Type and characteristics	Suggested HPO annotation
Burning distal-extremity pain	Cardinal subjective symptom; episodic or continuous; mild to incapacitating; attacks last minutes to days	Burning pain; Pain in extremities; Foot pain; Hand pain
Erythema	Cardinal visible sign; attack-related, localized, unilateral, asymmetric, or bilateral	Erythema
Increased skin temperature	Cardinal sign; worsened by warmth/exercise/dependency	Increased skin temperature
Swelling	Variable accompanying manifestation	Peripheral edema
Heat intolerance/heat-triggered attacks	Provocation phenotype	Heat intolerance
Dysesthesia, allodynia, hyperalgesia	Especially when small-fiber neuropathy is present	Dysesthesia; Allodynia; Hyperalgesia
Abnormal sweating/autonomic findings	Variable; supports small-fiber/autonomic involvement	Abnormality of the autonomic nervous system; Abnormal sweating
Ulceration, infection, ischemic injury	Usually secondary to severe disease or excessive cooling	Skin ulcer; Recurrent skin infections; Peripheral ischemia

Secondary EM generally has adult or late onset, although onset across all EM forms ranges from childhood to old age. It may be unilateral or localized more often than inherited primary EM, and its course follows the causal disorder: episodic, fluctuating, progressive, or treatment-responsive. Reviews report ages of 5–90 years, with a mean around 55 years, but this is not a secondary-only estimate. (assaad2025severeerythromelalgiapain pages 6-8, algarni2025comparativeefficacyand pages 1-2)

In a 168-patient mixed EM series cited by a systematic review, involvement was reported in the feet in 88.1%, hands in 25.6%, legs in 13.7%, and face in 2.4%. Approximately 5% reported family history, further illustrating that most EM is not clearly familial, although these values do not isolate secondary cases. (algarni2025comparativeefficacyand pages 1-2)

Quality of life

Severe attacks interfere with walking, standing, sleep, footwear, work, schooling, and social participation. Patients may resort to continuous cooling or water immersion, creating secondary wounds and infection. Disability, depression, and substantial pain interference are recognized, but validated secondary-EM-specific EQ-5D, SF-36, or PROMIS population norms are unavailable. Modern trials use EQ-5D-5L, Brief Pain Inventory, depression scores, physical activity, and disability measures, reflecting the syndrome’s multidimensional burden. (NCT04039633 chunk 1, NCT05917912 chunk 1)

4. Genetic and molecular information

Distinction from primary erythromelalgia

SCN9A encodes the voltage-gated sodium channel NaV1.7. Germline gain-of-function variants cause inherited primary EM by lowering nociceptor firing thresholds. That mechanism should not be automatically attributed to secondary EM. Genetic testing is appropriate when onset is early, disease is familial, or the phenotype suggests a channelopathy; it is not a confirmatory test for acquired secondary EM. Reviews report SCN9A variants in 5–36% of selected EM cohorts, but those mixed and referral-enriched estimates do not establish genetic causation in secondary disease. (skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 6-7, algarni2025comparativeefficacyand pages 1-2)

No secondary-EM-specific germline causal gene, HGNC-listed modifier, protective allele, recurrent pathogenic copy-number change, chromosomal abnormality, or validated ACMG variant set is established. Therefore, secondary EM has no meaningful disease-level carrier frequency, penetrance, anticipation, founder effect, or consanguinity pattern.

Where secondary EM accompanies an MPN, somatic molecular findings such as an MPN driver belong to the underlying neoplasm, not to EM as an independent inherited disorder. Likewise, no reproducible secondary-EM-specific methylation, histone, transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic signature was identified.

5. Environmental, lifestyle, and infectious information

Ambient heat, heated bedding, exercise, prolonged standing, limb dependency, physical activity, emotional stress, and tight shoes commonly precipitate symptoms. Cooling and elevation reduce them. These relationships represent thermoregulatory and hemodynamic provocation rather than traditional epidemiologic exposures. (skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 4-5)

Mercury toxicity, mushroom intoxication, burns, and frostbite are reported potential causes; calcium-channel blockers, bromocriptine, and cyclosporine are medication associations. HIV and infectious mononucleosis have been reported, while vaccine associations are low-level temporal evidence and should not be treated as established causality. Smoking, alcohol intake, diet, obesity, radiation, and occupational exposure have no validated secondary-EM-specific risk estimates in the retrieved literature. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 1-2)

6. Mechanism and pathophysiology

Secondary EM is probably a final common phenotype produced by several upstream mechanisms.

A. Platelet–microvascular pathway

Underlying MPN/platelet activation → platelet aggregation and prostanoid/thromboxane signaling → arteriolar inflammation or microthrombosis → maldistributed skin perfusion and tissue hypoxia → reactive hyperemia, warmth, erythema, and ischemic burning pain. Clinical aspirin responsiveness supports this model, particularly in essential thrombocythemia or polycythemia vera. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3)

Suggested annotations: - GO biological processes: platelet activation; platelet aggregation; blood coagulation; regulation of vasodilation; inflammatory response; response to hypoxia. - Cell Ontology: platelet; endothelial cell; vascular smooth-muscle cell. - Anatomical: cutaneous arteriole; dermal microvasculature.

B. Neuropathic/autonomic pathway

Diabetes, autoimmune neuropathy, toxic injury, or idiopathic small-fiber damage → dysfunction/loss of nociceptive and autonomic fibers → abnormal thermal pain signaling plus impaired sympathetic vasoconstriction and sweating → episodic vasodilation, heat, erythema, allodynia, and burning pain. Reduced nerve-terminal density and abnormal autonomic reflex testing support this pathway, although studies often combine EM subtypes. (skeik2019erythromelalgia pages 1-2, skeik2019erythromelalgia pages 2-3)

Suggested annotations: - GO: sensory perception of pain; detection of temperature stimulus; regulation of blood vessel diameter; autonomic nervous system process; axon maintenance. - CL: peripheral sensory neuron; nociceptor; sympathetic neuron; Schwann cell; endothelial cell.

C. Arteriovenous shunting and hypoxia

Thermoregulatory dyscontrol may open arteriovenous shunts while reducing nutritive capillary flow. This can produce the paradox of a visibly hyperemic, warm extremity with low transcutaneous oxygen tension and ischemic pain. Large-vessel Doppler studies may remain normal while skin temperature and laser-Doppler flow increase. (skeik2019erythromelalgia pages 2-3)

No single molecular pathway—MAPK, mTOR, PI3K–AKT, Wnt, or otherwise—has been validated as a unifying secondary-EM pathway. Mitochondrial, metabolic, and immune abnormalities should be annotated according to the underlying disease rather than inferred for all secondary EM.

7. Anatomical structures affected

Organ/system level: skin and cutaneous circulation; peripheral and autonomic nervous systems; hematologic system when an MPN is causal.
Primary sites: feet and toes most commonly, followed by hands/fingers and legs; face and ears are uncommon.
Tissues: epidermis and dermis, cutaneous sensory/autonomic nerve fibers, arterioles, venules, capillaries, and arteriovenous anastomoses.
Cells: nociceptors, sympathetic neurons, endothelial cells, vascular smooth-muscle cells, and—within MPN-associated disease—platelets.
Subcellular: plasma membrane ion channels and synaptic/axonal compartments are relevant to neural excitability, but NaV1.7 dysfunction is proven mainly in inherited disease.
Localization/lateralization: bilateral and symmetric disease is typical overall, but acquired disease may be unilateral, asymmetric, or localized. (algarni2025comparativeefficacyand pages 1-2)

Suggested UBERON concepts include skin of foot, foot, toe, hand, finger, lower limb, upper limb, dermis, epidermis, peripheral nerve, blood vessel, and cutaneous microvasculature.

8. Temporal development

Secondary EM usually begins after or around the onset of its associated disease and is commonly adult-onset. Presentation may be acute after a drug or injury, subacute with inflammatory disease, or insidious with MPN or neuropathy. Attacks last minutes to days, may increase during summer, and range from intermittent flares to continuous symptoms. No validated stage system exists. (skeik2019erythromelalgia pages 2-3)

Remission may follow withdrawal of an offending drug or successful treatment of the underlying disease. MPN-associated symptoms can respond rapidly to antiplatelet and cytoreductive treatment. Neuropathy-associated disease is often chronic and variably treatment-responsive. There is no established critical developmental window, although early recognition is important to prevent cooling injury and to detect an occult hematologic disorder.

9. Inheritance, epidemiology, and population

Secondary EM is acquired/non-Mendelian. Inheritance, penetrance, carrier frequency, anticipation, germline mosaicism, and prenatal recurrence risk are not applicable unless testing instead establishes inherited primary EM.

Population incidence is poorly defined. Mixed EM studies cited in reviews reported approximately 1.3 per 100,000 person-years in Olmsted County and 15 per 100,000 in New Zealand, with female predominance. Geographic differences may reflect case definition and ascertainment rather than true biology. Secondary-specific prevalence, incidence, ethnic distribution, and male:female ratio remain unknown. (skeik2019erythromelalgia pages 2-3)

10. Diagnostics

Clinical diagnosis

Diagnosis is based on the characteristic triad and provocation pattern. A photograph taken during an attack can be useful when the examination is normal between flares. There are no universally accepted validated diagnostic criteria or disease-specific biomarker. The source wording that diagnosis is “usually clinical” accurately summarizes current practice. (skeik2019erythromelalgia pages 1-2)

Cause-directed workup

CBC with differential and serial platelet/hematocrit assessment; evaluate persistent thrombocytosis or erythrocytosis for MPN.
Metabolic/neuropathy evaluation: fasting glucose or HbA1c, vitamin B12, thyroid studies, renal/hepatic testing, serum protein electrophoresis/immunofixation as clinically indicated.
Autoimmune/inflammatory testing: ANA and disease-specific serologies only when history or examination supports them.
Medication, infection, toxin, and injury history.
Vascular studies: pulses and ankle-brachial index/Doppler to exclude occlusive disease; large-vessel Doppler may be normal in EM.
Small-fiber/autonomic tests: quantitative sensory testing, autonomic reflex screen, sudomotor tests, and 3-mm skin biopsy for intraepidermal nerve-fiber density when neuropathy is suspected.
Thermography/laser Doppler/TcPO2: supportive research or specialist tests, not standalone diagnostic standards. Skin biopsy may show reduced nerve density or intraluminal thrombi but is neither necessary nor specific. (assaad2025severeerythromelalgiapain pages 6-8, skeik2019erythromelalgia pages 2-3)

Genetic testing

Single-gene SCN9A testing or a pain-channel/small-fiber-neuropathy panel is reasonable for childhood onset, a family history, or a strongly inherited phenotype. WES/WGS may be considered after specialist assessment when a monogenic disorder remains likely. CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat-expansion testing have no routine role in secondary EM. There is no role for population, newborn, or carrier screening.

Differential diagnosis

Important alternatives are complex regional pain syndrome, Raynaud phenomenon/reperfusion, cellulitis or erysipelas, contact dermatitis, vasculitis, gout, osteomyelitis, arterial or venous insufficiency, acrocyanosis, Fabry disease, peripheral neuropathy, small-fiber neuropathy without EM, and systemic lupus erythematosus. CRPS is often unilateral and follows trauma with trophic/sudomotor abnormalities; cellulitis is persistent and infectious rather than heat-provoked and rapidly cooling-responsive. (skeik2019erythromelalgia pages 2-3)

11. Outcomes and prognosis

Secondary EM itself has no established disease-specific mortality rate, survival curve, or reduction in life expectancy. Prognosis depends mainly on the underlying disorder and severity of pain. MPN-associated cases may improve substantially with antiplatelet and disease-directed therapy; acquired neuropathic cases may remain chronic.

Morbidity can be profound: impaired walking, sleep loss, inability to tolerate shoes or warm environments, work/school limitation, anxiety, depression, and social isolation. Complications include maceration, ulceration, infection, tissue ischemia, and rarely amputation—often worsened by prolonged ice or water exposure. (skeik2019erythromelalgia pages 2-3, algarni2025comparativeefficacyand pages 1-2)

Favorable prognostic features include identification of a reversible cause and aspirin-responsive MPN disease. Persistent severe pain, established neuropathy, ulceration, and delayed cause recognition predict greater morbidity. No validated molecular prognostic biomarker exists.

12. Treatment and current applications

Treatment strategy

Identify and treat the underlying cause.
Avoid attacks safely: cool environment, fans, elevation, breathable footwear, activity pacing; avoid direct ice and prolonged immersion.
MPN-associated disease: low-dose aspirin when not contraindicated; manage the MPN with hematology-directed phlebotomy or cytoreduction as appropriate.
Localized symptoms: topical lidocaine or compounded amitriptyline–ketamine.
Neuropathic phenotype: gabapentinoids, SNRIs, tricyclics, or sodium-channel blockers selected according to comorbidity and safety.
Refractory disease: specialist trials of vasoactive therapy, infusions, sympathetic procedures, or neuromodulation.

The literature explicitly states, “There is no single effective treatment for erythromelalgia,” and individualized, multidisciplinary management remains the expert consensus. (skeik2019erythromelalgia pages 1-2, algarni2025comparativeefficacyand pages 2-4)

Drug and intervention evidence

Aspirin: particularly effective in platelet-mediated MPN-associated secondary EM. Gastrointestinal bleeding, allergy, renal risk, and acquired von Willebrand disease in extreme thrombocytosis must be considered. Suggested NCIT intervention: aspirin therapy/antiplatelet therapy; CHEBI: aspirin.
Topical amitriptyline–ketamine: in a mixed 36-patient cohort, about 75% reported some pain relief: 3% complete, 39% substantial, and 33% some improvement. This is not a secondary-only response estimate. (algarni2025comparativeefficacyand pages 6-7)
Misoprostol: small controlled studies reported improvements in pain and temperature control, but diarrhea, abdominal pain, and nausea were frequent. (algarni2025comparativeefficacyand pages 6-7)
Iloprost: small studies reported improved cooling scores, sympathetic dysfunction, and disease severity; headache, flushing/erythema, and hypotension can occur. (algarni2025comparativeefficacyand pages 6-7)
Lidocaine: topical or intravenous use aims to stabilize hyperexcitable sensory fibers; experimental studies showed dose-dependent improvement in nociceptive thresholds. Cardiac and neurologic toxicity constrain systemic use. (algarni2025comparativeefficacyand pages 6-7, algarni2025comparativeefficacyand pages 2-4)
Other reported agents: gabapentin/pregabalin, amitriptyline, venlafaxine or other SNRIs, mexiletine, carbamazepine/oxcarbazepine, antihistamines, clonidine, and prostaglandin/vascular agents. Evidence is inconsistent and mostly uncontrolled.
Procedures: sympathetic blocks, epidural/local anesthetic techniques, chemical or surgical sympathectomy, botulinum toxin, and spinal-cord stimulation are rescue options with case-level or very small-study support.
Pediatric rescue evidence: one report described complete resolution in 4 of 5 patients receiving intravenous sodium nitroprusside, initially 1 µg/kg/min and titrated to 5 µg/kg/min; this is low-level evidence and not secondary-specific. (skeik2019erythromelalgia pages 2-3)

A 2025 systematic review found only six eligible studies, totaling 120 patients: iloprost n=8, misoprostol n=21, topical amitriptyline–ketamine n=36, lidocaine n=27, chemical lumbar sympathectomy n=13, and miscellaneous agents n=11. The small, mixed-etiology evidence base precludes a robust universal hierarchy. (algarni2025comparativeefficacyand pages 4-5, algarni2025comparativeefficacyand pages 1-2)

Recent developments and trials

EASE, NCT05917912: randomized double-blind Phase 2 crossover study of topical amitriptyline 15% (ATX01), 14 participants; began June 14, 2023 and completed February 29, 2024. Outcomes included attack pain, Brief Pain Inventory, EQ-5D, depression, and rescue cooling. Eligibility excluded important alternative neuropathic pain causes, limiting direct applicability to secondary EM. URL: https://clinicaltrials.gov/study/NCT05917912. (NCT05917912 chunk 1, NCT05917912 chunk 2)
Burst spinal-cord stimulation, NCT04039633: six-patient quadruple-blind crossover study, active but not recruiting; restricted to primary or idiopathic EM and excluded secondary disease. URL: https://clinicaltrials.gov/study/NCT04039633. (NCT04039633 chunk 1)
Earlier XPF-001, XPF-002, and PF-05089771 NaV1.7 programs enrolled primary/inherited EM, not secondary EM. URLs: https://clinicaltrials.gov/study/NCT01090622, https://clinicaltrials.gov/study/NCT01486446, and https://clinicaltrials.gov/study/NCT01769274. (NCT01090622 chunk 1, NCT01486446 chunk 2, NCT01769274 chunk 3)

Thus, a major 2023–2024 research gap is the continued exclusion or underrepresentation of secondary EM in interventional trials.

13. Prevention

There is no vaccine, population screening program, or proven pharmacologic primary prevention. Practical prevention is etiologic and tertiary:

Monitor blood counts when symptoms or risk factors suggest an MPN.
Control diabetes and treat reversible neuropathy causes.
Review and discontinue implicated medication when clinically safe.
Avoid excessive heat, prolonged standing, tight footwear, and unsafe direct-ice cooling.
Treat fissures or ulcers early and provide wound-care education.
Use genetic counseling only when the history suggests inherited primary EM; it is not routinely relevant to acquired secondary disease.

No evidence supports prophylactic aspirin for people without EM or an independent cardiovascular/hematologic indication.

14. Other species and natural disease

No well-validated naturally occurring veterinary equivalent of acquired secondary EM was identified. Consequently, no specific NCBI Taxon, breed/VBO association, zoonotic transmission, or cross-species prevalence can be assigned. The condition is not infectious or zoonotic as a syndrome.

SCN9A orthologs are evolutionarily conserved across mammals, but their relevance is primarily to nociception and inherited channelopathy. Platelet activation, microvascular thrombosis, diabetic neuropathy, and autonomic dysregulation can be studied in animals, but these reproduce components rather than the full human secondary-EM syndrome.

15. Model organisms and experimental systems

Human iPSC-derived sensory neurons carrying pathogenic SCN9A variants reproduce lowered firing thresholds and permit pharmacologic reversal of inherited EM phenotypes. These systems and NaV1.7 transgenic/knock-in models are valuable for pain-channel biology but model primary inherited EM, not secondary EM. The PF-05089771 program linked iPSC-derived sensory-neuron findings to a primary-EM trial, illustrating this translational application. (NCT01769274 chunk 3)

Potential component models include:

MPN or platelet-activation mouse models for thrombotic microvascular mechanisms.
Streptozotocin or genetic diabetes models for acquired small-fiber neuropathy.
Peripheral nerve injury/inflammation models for nociceptor hyperexcitability.
Endothelial-flow and microfluidic systems for capillary perfusion and thrombosis.

Their central limitation is failure to reproduce the defining human combination of heat-provoked erythema, thermoregulatory shunting, and severe distal burning pain. No dedicated, validated acquired secondary-EM mouse, rat, zebrafish, Drosophila, organoid, CRISPR-screen, or natural-animal model was identified.

Knowledge-base conclusions

Secondary erythromelalgia should be represented as an acquired clinical syndrome with multiple possible causal-disease relationships, not as an SCN9A disorder. Core phenotype assertions are well supported; secondary-specific epidemiology, molecular profiling, prognosis, and randomized-treatment evidence are sparse. The highest-priority implementation rules are: record the red-hot-burning attack phenotype; document heat/exercise/dependency triggers and cooling response; actively evaluate MPNs and neuropathies; annotate aspirin responsiveness specifically to platelet-mediated disease; and avoid transferring inherited-EM genetic claims or primary-only clinical-trial results to secondary EM.

References

(assaad2025severeerythromelalgiapain pages 6-8): Wassim Assaad, Omar El Tarras, Soad Al Osta, and Chady Kallassy. Severe erythromelalgia pain attack in a young lebanese woman leading to hospitalization: a case report and literature review. Cureus, Sep 2025. URL: https://doi.org/10.7759/cureus.91530, doi:10.7759/cureus.91530. This article has 0 citations.
(skeik2019erythromelalgia pages 2-3): Nedaa Skeik. Erythromelalgia. Harper's Textbook of Pediatric Dermatology, pages 1961-1964, Nov 2019. URL: https://doi.org/10.1002/9781119142812.ch151, doi:10.1002/9781119142812.ch151. This article has 1 citations.
(algarni2025comparativeefficacyand pages 1-2): Abdullah S. Algarni, Reem M. Alharthi, Shaden O. Alqurashi, Ruba M. Alghanmi, Rimaz R. Aldawsari, Maysaa A. Alghamdi, and Ramy Samargandi. Comparative efficacy and tolerability of treatments for erythromelalgia: a systematic review. Medicina, 61:920, May 2025. URL: https://doi.org/10.3390/medicina61050920, doi:10.3390/medicina61050920. This article has 1 citations.
(skeik2019erythromelalgia pages 1-2): Nedaa Skeik. Erythromelalgia. Harper's Textbook of Pediatric Dermatology, pages 1961-1964, Nov 2019. URL: https://doi.org/10.1002/9781119142812.ch151, doi:10.1002/9781119142812.ch151. This article has 1 citations.
(algarni2025comparativeefficacyand pages 4-5): Abdullah S. Algarni, Reem M. Alharthi, Shaden O. Alqurashi, Ruba M. Alghanmi, Rimaz R. Aldawsari, Maysaa A. Alghamdi, and Ramy Samargandi. Comparative efficacy and tolerability of treatments for erythromelalgia: a systematic review. Medicina, 61:920, May 2025. URL: https://doi.org/10.3390/medicina61050920, doi:10.3390/medicina61050920. This article has 1 citations.
(algarni2025comparativeefficacyand pages 6-7): Abdullah S. Algarni, Reem M. Alharthi, Shaden O. Alqurashi, Ruba M. Alghanmi, Rimaz R. Aldawsari, Maysaa A. Alghamdi, and Ramy Samargandi. Comparative efficacy and tolerability of treatments for erythromelalgia: a systematic review. Medicina, 61:920, May 2025. URL: https://doi.org/10.3390/medicina61050920, doi:10.3390/medicina61050920. This article has 1 citations.
(algarni2025comparativeefficacyand pages 7-9): Abdullah S. Algarni, Reem M. Alharthi, Shaden O. Alqurashi, Ruba M. Alghanmi, Rimaz R. Aldawsari, Maysaa A. Alghamdi, and Ramy Samargandi. Comparative efficacy and tolerability of treatments for erythromelalgia: a systematic review. Medicina, 61:920, May 2025. URL: https://doi.org/10.3390/medicina61050920, doi:10.3390/medicina61050920. This article has 1 citations.
(algarni2025comparativeefficacyand pages 2-4): Abdullah S. Algarni, Reem M. Alharthi, Shaden O. Alqurashi, Ruba M. Alghanmi, Rimaz R. Aldawsari, Maysaa A. Alghamdi, and Ramy Samargandi. Comparative efficacy and tolerability of treatments for erythromelalgia: a systematic review. Medicina, 61:920, May 2025. URL: https://doi.org/10.3390/medicina61050920, doi:10.3390/medicina61050920. This article has 1 citations.
(NCT04039633 chunk 1): Spinal Cord Stimulation for Refractory Pain in Erythromelalgia. St. Olavs Hospital. 2019. ClinicalTrials.gov Identifier: NCT04039633
(NCT05917912 chunk 1): EASE (Efficacy of ATX01 Study in Erythromelalgia). AlgoTherapeutix. 2023. ClinicalTrials.gov Identifier: NCT05917912
(NCT05917912 chunk 2): EASE (Efficacy of ATX01 Study in Erythromelalgia). AlgoTherapeutix. 2023. ClinicalTrials.gov Identifier: NCT05917912
(NCT01090622 chunk 1): Study of XPF-001 in the Treatment of Pain From Primary/Inherited Erythromelalgia (IEM). Xenon Pharmaceuticals Inc.. 2010. ClinicalTrials.gov Identifier: NCT01090622
(NCT01486446 chunk 2): Phase 2a, Exploratory Study to Evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of XPF-002 in Patients With Primary/Inherited Erythromelalgia. Xenon Pharmaceuticals Inc.. 2011. ClinicalTrials.gov Identifier: NCT01486446
(NCT01769274 chunk 3): Evaluation Of The Efficacy And Safety Of Single Doses Of PF-05089771 In Patients With Primary (Inherited) Erythromelalgia. Pfizer. 2012. ClinicalTrials.gov Identifier: NCT01769274

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OpenScientist ▸

Secondary Erythromelalgia: A Comprehensive Disease Characteristics Report

openscientist-autonomous 26 citations 2026-09-03T07:29:12.721565

Secondary Erythromelalgia: A Comprehensive Disease Characteristics Report

Summary

Secondary (acquired) erythromelalgia (EM) is a rare neurovascular acrosyndrome defined by the clinical triad of recurrent, paroxysmal burning pain, erythema (redness), and increased local temperature (warmth) of the acral extremities, characteristically provoked by heat, exercise, and limb dependency and relieved by cooling and elevation. Unlike primary/inherited EM (an autosomal-dominant SCN9A/Na_v1.7 sodium-channel gain-of-function neuropathy), secondary EM is not caused by a germline mutation. It is a symptom of an underlying acquired disease — most classically a myeloproliferative neoplasm (MPN), especially essential thrombocythemia (ET) or polycythemia vera (PV), but also autoimmune/collagen-vascular disease (systemic lupus erythematosus), small-fiber peripheral neuropathy, diabetes mellitus, infections, and certain drugs (calcium-channel blockers, bromocriptine).

The best-characterized mechanism is the MPN-associated (thrombocythemic) form: somatic driver mutations (JAK2 V617F, CALR, MPL) in hematopoietic stem cells produce clonal, hyperreactive platelets that drive platelet cyclooxygenase (COX-1)/thromboxane-mediated arteriolar inflammation, fibromuscular intimal proliferation, and platelet-rich microthrombosis of acral end-arterioles, producing localized ischemia experienced as burning pain, redness, and warmth. This form responds dramatically and pathognomonically to low-dose aspirin and remits with cytoreduction that normalizes the platelet count. A second, complementary line of evidence points to an immune/complement-mediated microvascular injury and dysautonomia mechanism (endothelial C5b-9 membrane-attack-complex deposition, type-I interferon upregulation, and diminished autonomic innervation of eccrine coils and arteries), linking EM to small-fiber neuropathy in non-MPN subtypes.

Clinically, secondary EM matters as a sentinel of occult MPN: symptoms can precede the hematologic diagnosis by a median of ~2.5 years, so all patients warrant serial blood counts and JAK2 testing. Management is cause-directed: aspirin plus cytoreduction/phlebotomy for MPN; drug withdrawal for drug-induced disease; neuropathic-pain agents and sodium-channel blockers for the small-fiber/autoimmune subtypes. Epidemiologically it is rare (secondary EM incidence ≈0.2/100,000/year), female-predominant, and adult-onset, and is frequently unilateral/asymmetric — distinguishing it from the bilateral primary form.

Key Findings

1. Disease Information — Definition, Classification, and Identifiers

Erythromelalgia is a rare neurovascular acrosyndrome defined by a triad of recurrent burning pain, erythema, and increased temperature of the extremities, worsened by heat/dependency and relieved by cooling/elevation. It is divided into a PRIMARY form (inherited or idiopathic; autosomal-dominant SCN9A/Na_v1.7 gain-of-function neuropathy, typically early-onset, bilateral, and often aspirin-unresponsive) and a SECONDARY form (acquired; associated with an identifiable underlying disorder). Secondary EM associated with MPN classically responds dramatically to aspirin, a feature that both aids diagnosis and points to its mechanism.

"Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection." — PMID: 27639908

"secondary, which is associated with myeloproliferative disorders-related thrombocythemia, polycythemia, collagen-vascular diseases, diabetes mellitus, peripheral neuropathy, autoimmune and infectious diseases, and use of certain medicaments" — PMID: 15075045

"secondary erythromelalgia associated with a myeloproliferative disease such as essential thrombocythemia often responds dramatically to aspirin therapy" — PMID: 23862006

Key identifiers (finding F011):

Resource	Identifier
MeSH	D004916 (Erythromelalgia)
ICD-10	I73.81 (Erythromelalgia)
ICD-11	EF41.2 / peripheral vascular category
Orphanet	ORPHA:90026 (Erythromelalgia)
MONDO	MONDO:0008574 (erythromelalgia)
OMIM	133020 — refers specifically to PRIMARY (SCN9A) erythermalgia; secondary EM has no distinct OMIM entry because it is symptomatic of the underlying disease
HPO	HP:0012326 (Erythromelalgia)

Synonyms/alternative names: erythermalgia, Mitchell disease, acromelalgia, "red limb" syndrome; secondary EM is also termed acquired or symptomatic erythromelalgia.

Information source type: Knowledge is derived predominantly from aggregated disease-level resources and clinical case series/reviews (Michiels series, Olmsted County population studies, single-center Swedish cohort), not from a single EHR-derived patient population. Secondary EM is defined nosologically as symptomatic of an underlying disease.

2. Etiology — Causal Factors, Risk Factors, Gene–Environment Interactions

Secondary EM is caused by a diverse set of underlying conditions (finding F009):

Myeloproliferative neoplasms — essential thrombocythemia and polycythemia vera (most common); also reported with chronic myelogenous leukemia (CML), primary/Philadelphia-positive myelofibrosis, and myelodysplastic syndrome when platelet counts are sufficiently high.
Other hematologic disease — thrombotic thrombocytopenic purpura (TTP).
Autoimmune/collagen-vascular disease — systemic lupus erythematosus (SLE), rheumatoid arthritis, vasculitis.
Small-fiber peripheral neuropathy and diabetes mellitus.
Infectious/viral illnesses.
Drugs — calcium-channel blockers (nifedipine, verapamil, diltiazem, felodipine), bromocriptine/dopamine agonists, and others.
Rarely — paraneoplastic/solid tumors and toxins.

"secondary, which is associated with myeloproliferative disorders-related thrombocythemia, polycythemia, collagen-vascular diseases, diabetes mellitus, peripheral neuropathy, autoimmune and infectious diseases, and use of certain medicaments... a single common pathogenetic mechanism - microvascular arteriovenous shunting" — PMID: 15075045

"We describe, for the first time, a patient in whom chronic myelogenous leukemia was associated with the development of erythromelalgia" — PMID: 2643412

"We describe a female patient in whom thrombotic thrombocytopenic purpura was associated with erythromelalgia. This has not been previously reported." — PMID: 1613144

Genetic risk factors: Secondary EM itself is not germline-determined. The relevant genetic lesions are the somatic driver mutations of the underlying MPN (see Section 4). JAK2/MPL-mutated ET carry higher arterial thrombosis risk, which is mechanistically upstream of the acral microthrombosis in EM.

Environmental risk factors: Older adult age and female sex (epidemiologic associations); drug exposure (calcium-channel blockers, bromocriptine) is the principal modifiable environmental cause. Environmental provoking (not causal) factors are heat, exercise, and limb dependency.

Protective factors: No established germline protective variants or dietary/lifestyle protective factors are described. The strongest "protective" intervention is pharmacologic — low-dose aspirin abolishes the thrombocythemic form.

Gene–environment interactions: The clearest interaction is between the somatic JAK2/CALR/MPL clone (genetic) and heat/dependency (environmental provocation): the clone establishes hyperreactive thrombocytosis, while environmental heat/dependency triggers the paroxysmal acral attacks superimposed on that substrate.

3. Phenotypes

The core phenotype (finding F007) is paroxysmal/episodic attacks of the triad:

Phenotype	HPO term	Notes / frequency
Severe burning pain of extremities	HP:0025267 (burning sensation); HP:0012531 (pain)	Cardinal symptom; provoked by heat/exercise/dependency
Erythema / red skin	HP:0000988 (skin rash); HP:0500064 (red skin)	Cardinal sign
Increased local skin temperature/warmth	— (warmth of acral skin)	Cardinal sign
Erythromelalgia (composite)	HP:0012326	Overall term
Acrocyanosis	—	With progression
Digital ischemia / necrosis / gangrene	—	Untreated MPN-associated disease

Distribution: Feet more than hands; often the ball of the foot and one or more toes or fingers. In secondary/MPN forms attacks are frequently UNILATERAL or asymmetric and less intense than in primary EM. Provoking factors: environmental heat, exercise, limb dependency. Relieving factors: cold exposure and elevation (patients immerse extremities in cold/ice water — a behavior that itself risks immersion/maceration injury).

"characterized by attacks of severe burning pain, erythema, and warmth of the extremities, primarily the feet and, to a lesser extent, the hands. The distress is provoked by environmental heat, exercise, and dependency; it is relieved by exposure to cold and elevation of the extremity" — PMID: 2643412

"characterized by red, congested distal extremities and painful burning sensations, usually confined to the ball of the foot and one or more toes or fingers. If left untreated, it may progress towards acrocyanosis and even peripheral gangrene" — PMID: 11208311

Associated features in MPN-associated cases: microvascular neurologic/ocular symptoms (headache, transient visual disturbance, paresthesias, TIA), pruritus, splenomegaly, and sometimes concurrent peripheral sensorimotor axonal neuropathy (documented in a JAK2 V617F-positive PV patient, PMID: 25674012).

Age of onset: adult/late-onset (secondary form). Severity: variable (often milder than primary). Progression: episodic/fluctuating, potentially digit-threatening if untreated. Quality-of-life impact: severe during attacks — burning pain interferes with walking, sleep, footwear, work, and social function; compulsive cooling behaviors can cause secondary immersion skin injury.

4. Genetic / Molecular Information

Secondary EM is not caused by a germline mutation. Its most common underlying disease — MPN — is driven by somatic, mutually exclusive driver mutations in hematopoietic stem cells (finding F004):

Gene	HGNC/OMIM	Frequency in ET	Frequency in PV	Functional consequence
JAK2 (V617F)	OMIM 147796	~55%	>95%	Gain of function; constitutive JAK-STAT signaling
CALR (exon 9 indels)	OMIM 109091	~25%	rare	Gain of function; mutant CALR–MPL activation
MPL	OMIM 159530	~3%	rare	Gain of function; thrombopoietin-receptor activation
Triple-negative	—	~17%	—	—

Additional non-driver/clonal mutations occur: TET2 (9–11%), ASXL1 (7–20%), DNMT3A (~7%), SF3B1 (~5%). JAK2/MPL-mutated ET is associated with higher arterial thrombosis risk — the pathophysiologic bridge to acral microthrombosis in EM.

"Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner" — PMID: 38269572

"JAK2, CALR, and MPL mutations are the mutually exclusive 'driver' mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative" — PMID: 27991718

"the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis" — PMID: 27991718

Somatic vs. germline origin: entirely somatic for the MPN drivers; allele frequency in population databases is not the relevant metric (these are acquired clonal variants, not inherited polymorphisms), though clonal hematopoiesis of indeterminate potential (CHIP) with low variant allele frequency can complicate interpretation (PMID: 38310350). Modifier genes / epigenetics / chromosomal abnormalities: not specifically defined for the EM phenotype itself; abnormal karyotype and spliceosome mutations modify survival of the underlying MPN.

5. Environmental Information

Environmental factors / toxins: No established environmental toxin causes secondary EM directly. Drugs are the principal non-hematologic environmental cause — calcium-channel blockers (nifedipine, verapamil, diltiazem, felodipine) and bromocriptine/dopamine agonists (F009). Lifestyle factors: none causal beyond drug exposure; heat, exercise, and dependency are provocative triggers, not chronic risk factors. Infectious agents: viral/infectious illnesses are listed among secondary causes (F001/F009), but no single specified pathogen is established as causal; EM in this setting is best regarded as a reactive/para-infectious phenomenon.

6. Mechanism / Pathophysiology

Ordered causal chain — MPN-associated (thrombocythemic) secondary EM

A somatic driver mutation (JAK2 V617F, CALR, or MPL) arises in a hematopoietic stem cell → leads to constitutive JAK2–STAT signaling and clonal myeloproliferation.
Clonal myeloproliferation results in thrombocytosis with hyperreactive platelets (essential thrombocythemia, or PV with high platelet counts).
Hyperreactive platelets, via platelet cyclooxygenase-1 (COX-1), lead to increased thromboxane A2 generation and platelet activation in acral end-arterioles.
Platelet COX/thromboxane activity results in arteriolar inflammation and fibromuscular intimal proliferation of dermal/subcutaneous arterioles.
This leads to platelet-rich thrombotic occlusion of the end-arterial microvasculature (skin biopsy: arteriolar inflammation, intimal proliferation, platelet thrombi; shortened platelet survival; elevated β-thromboglobulin, PF4, thrombomodulin; increased urinary thromboxane B2).
Microvascular occlusion results in localized acral ischemia → branch point: experienced as burning pain + erythema + warmth (the EM triad); if severe/untreated → acrocyanosis → digital necrosis/gangrene.
COX inhibition by aspirin/indomethacin interrupts step 3 → complete, lasting symptom relief and normalization of platelet-activation markers (whereas sodium salicylate, dipyridamole, sulfinpyrazone, ticlopidine, and coumadin do NOT — establishing COX/thromboxane dependence). Cytoreduction that normalizes platelet count removes step 2 → remission; relapse recurs symptoms.

"Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies, by the findings of shortened platelet survival times, significant higher levels of platelet activation markers beta-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion" — PMID: 12781799

"is caused by platelet cyclo-oxygenase-mediated arteriolar inflammation, fibromuscular intimal proliferation without and with occlusive thrombosis by platelet-rich thrombi in the end-arterial microvasculature" — PMID: 16510297

"Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions." — PMID: 3977194

Alternative / complementary causal chain — immune-mediated microvascular injury & dysautonomia (non-MPN subtypes)

An immune trigger (autoimmune disease such as SLE, or idiopathic dysimmunity) → leads to complement activation with microvascular C5b-9 (membrane attack complex) deposition on dermal endothelium.
Endothelial injury with type-I interferon upregulation results in microvascular dysfunction.
Concurrent diminished autonomic innervation of eccrine coils and arteries (CD56 evidence; mirroring small-fiber neuropathy) leads to dysregulated vasomotor control → maldistributed skin perfusion.
This results in the same clinical triad, but is aspirin-unresponsive and instead treated as neuropathic/autoimmune disease. (Mechanistic details are demonstrated in a small dermatopathology series and are partly inferred.)

"Biopsies showed superficial vascular ectasia in association with microvascular C5b-9 and variable upregulation of type I interferon expression in endothelial cells. CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries, mirroring similar autonomic denervation seen in small fiber neuropathy." — PMID: 39846717

"Histology commonly shows capillary proliferation, swelling of endothelial cells, perivascular edema, and chronic inflammation with sparse lymphocytic infiltrate." — PMID: 23334520

Unifying hypothesis: Ljubojević et al. proposed a single common pathogenetic mechanism across etiologies — microvascular arteriovenous shunting with maldistributed skin perfusion producing tissue hypoxia despite visible erythema and warmth (PMID: 15075045).

Ontology suggestions: - GO biological processes: platelet activation (GO:0030168), platelet aggregation (GO:0070527), blood coagulation (GO:0007596), prostaglandin biosynthesis / cyclooxygenase pathway (GO:0006693), inflammatory response (GO:0006954), complement activation (GO:0006956), type I interferon signaling (GO:0060337). - CL cell types: platelet (CL:0000233), blood vessel endothelial cell (CL:0000115), smooth muscle cell (CL:0000192). - CHEBI: thromboxane B2 (CHEBI:28728), acetylsalicylic acid/aspirin (CHEBI:15365), prostaglandin.

Mechanism schematic

 Somatic JAK2/CALR/MPL mutation (HSC)
    |  constitutive JAK-STAT
    v
   Clonal thrombocytosis (ET / PV)
    |  hyperreactive platelets
    v
   Platelet COX-1 -> thromboxane A2  ----(aspirin/indomethacin block here)
    |
    v
 Arteriolar inflammation + fibromuscular intimal proliferation
    |
    v
 Platelet-rich microthrombosis of acral end-arterioles
    |
    v
    Acral ischemia  --> BURNING PAIN + ERYTHEMA + WARMTH
    |
    +--> (untreated) acrocyanosis --> digital necrosis / gangrene

 [Parallel non-MPN route]
 Autoimmune/idiopathic trigger -> endothelial C5b-9 + type I IFN
   + autonomic denervation (eccrine/arteries) -> maldistributed
   perfusion / AV shunting -> same triad (aspirin-unresponsive)

7. Anatomical Structures Affected

Organ/system level (F010): primarily the skin of acral extremities and the peripheral (microvascular) cardiovascular system; the peripheral/autonomic nervous system is involved in neuropathic subtypes.

Localization (UBERON): feet (UBERON:0002387) > hands (UBERON:0002398); toes (UBERON:0009551) and fingers (UBERON:0002389); ball/sole of foot; distal/acral. Affected tissue: dermal/subcutaneous arterioles (UBERON:0001980) and capillaries.

Lateralization: secondary/MPN forms are frequently unilateral or asymmetric (versus bilateral in primary EM).

Cell level (CL): vascular endothelial cells (CL:0000115), platelets (CL:0000233) forming intraluminal thrombi; arteriolar smooth-muscle/intimal cells; eccrine sweat glands and their small autonomic (C-fiber) innervation in the dysautonomia/SFN subtype.

Subcellular level: platelet cyclooxygenase (COX-1) enzymatic activity; endothelial complement (C5b-9) and type-I interferon responses are the key molecular loci.

Secondary organ involvement/complications: acrocyanosis, digital ischemia, ulceration, gangrene; in MPN patients, concurrent cerebral/ocular/coronary microvascular territories (headache, visual disturbance, TIA).

"Skin punch biopsy samples taken from the affected areas showed typical arteriolar inflammation, fibromuscular intima proliferation, and thrombotic occlusions." — PMID: 3977194

"CD56 stain revealed diminished autonomic innervation of the eccrine coil and arteries" — PMID: 39846717

8. Temporal Development

Onset: adult/late-onset; often insidious in relation to the underlying MPN. In MPN-associated EM, symptoms preceded the diagnosis of the myeloproliferative disease by a median of ~2.5 years and can be the presenting manifestation of ET/PV (F008).

Progression: episodic/fluctuating course; untreated MPN-EM may progress to acrocyanosis and peripheral gangrene. Duration: chronic while the underlying disease persists; resolves when the cause is treated.

Remission patterns: treatment-induced remission is the rule — MPN-EM responds immediately to aspirin and remits with platelet-count normalization; drug-induced EM resolves on drug withdrawal. Symptoms recur with MPN relapse or aspirin withdrawal (PMID: 22844295: EM developed within two weeks of aspirin withdrawal and improved within two weeks of restarting).

Critical period / window of opportunity: because idiopathic-appearing EM may be an early clonal MPN marker, periodic blood counts are recommended so that an abnormal hemoglobin/WBC/platelet count or immature cells prompts evaluation.

"symptoms of erythromelalgia preceded the onset of a myeloproliferative disease by a median of 2 1/2 years. Therefore, all patients with erythromelalgia should be monitored with periodic blood cell counts" — PMID: 2643412

"Her erythromelalgia immediately disappeared following interventional therapy along with aspirin." — PMID: 15750823

9. Inheritance and Population (Epidemiology)

Secondary EM is rare, female-predominant, and adult-onset (F002). The population-based Olmsted County study (Reed & Davis) reported an overall age/sex-adjusted EM incidence of 1.3/100,000/year (95% CI 0.8–1.7), split into primary EM 1.1 and secondary EM 0.2/100,000/year. Female incidence (2.0) exceeded male (0.6) per 100,000. The Swedish single-center study (Alhadad) found incidence 0.36/100,000/year, median age 49 (IQR 34–68), 70% women, and a mean diagnostic delay of 4.5 years; 3/27 developed intra-abdominal cancer.

"The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively." — PMID: 18713229

"we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women" — PMID: 22247059

Inheritance pattern: secondary EM is acquired/non-heritable. The underlying MPN driver mutations are somatic (not inherited); there is no Mendelian inheritance, penetrance, anticipation, founder effect, consanguinity role, or carrier frequency applicable to secondary EM. (These concepts apply only to primary SCN9A EM.)

Population demographics: female predominance is confirmed across dermatologic epidemiology (PMID: 27009931). No specific ethnic/geographic clustering is established for secondary EM; distribution follows that of the underlying MPN/autoimmune diseases. Sex ratio: roughly 2–2.3:1 female:male. Age distribution: predominantly middle-aged and older adults.

10. Diagnostics

Diagnosis is clinical — the triad of burning pain, erythema, and warmth; heat/dependency provokes and cold/elevation relieves. Adjuncts include infrared thermography, laser Doppler flowmetry, and cold-provocation testing. The essential task is to identify the secondary cause (F005):

Test	Purpose
Complete blood count (CBC) with differential + peripheral smear	Detect thrombocytosis/erythrocytosis/leukocytosis (MPN)
JAK2 V617F mutation testing (then CALR, MPL if negative)	Confirm MPN driver
Bone marrow biopsy	Confirm ET/PV/prefibrotic myelofibrosis
ANA	Screen for SLE/autoimmune cause
TSH	Thyroid disease
Small-fiber neuropathy testing (skin biopsy for intraepidermal nerve fiber density)	Neuropathic subtype
Screen for drugs / malignancy	Drug-induced and paraneoplastic causes
Skin punch biopsy	Arteriolar thrombosis (MPN), C5b-9/IFN, autonomic denervation

"For erythermalgia, a blood count and even a search for JAK2 mutation are required. A thryoid-stimulating hormon assay, a test for antinuclear antibodies, and a search for small fiber neuropathy are also performed." — PMID: 35835622

Biomarkers / laboratory abnormalities: thrombocytosis (platelets ≥450 ×10⁹/L; PMID: 42101597), erythrocytosis, elevated platelet-activation markers (β-thromboglobulin, PF4, thrombomodulin), increased urinary thromboxane B2.

Differential diagnosis (F011): Raynaud phenomenon (color change to white/blue, cold-induced — opposite triggers), complex regional pain syndrome, peripheral neuropathy, cellulitis, acrocyanosis, chilblains/pernio, Fabry disease acroparesthesias, gout, and primary (SCN9A) EM. The distinguishing feature of EM is heat/dependency provocation and cold/elevation relief.

"Raynaud's syndrome and Raynaud's mimickers, especially painful Raynaud's mimickers, can prove a diagnostic challenge" — PMID: 38704280

Genetic testing: for the underlying MPN, targeted JAK2/CALR/MPL testing (allele-specific PCR/NGS) is standard; WGS/WES are not routinely required. Note that low-VAF JAK2 may reflect CHIP, and the dominant driver (e.g., CALR) determines phenotype (PMID: 38310350). No genetic testing is indicated for the EM phenotype itself in the secondary form.

11. Outcome / Prognosis

Overall EM mortality is low and not directly disease-attributable (Alhadad); however, the underlying disease drives prognosis. Untreated MPN-associated EM can progress to acrocyanosis and peripheral gangrene (digit-threatening). Prognosis is favorable when the cause is treated: aspirin gives immediate relief and cytoreduction produces remission; drug-induced EM resolves on withdrawal (F008).

The underlying MPN carries its own morbidity/mortality: PV median survival 14.1–27.6 years, with arterial thrombosis in 16% and venous thrombosis in 7% at/before diagnosis, ~12.7% progressing to myelofibrosis and ~6.8% to acute myeloid leukemia (PMID: 39556352); ET median survival ~18 years with leukemic transformation <1% at 10 years (PMID: 32974939). Thus EM's chief prognostic significance is as a herald of occult MPN and its thrombotic/leukemic risk.

Complications: digital ischemia, ulceration, gangrene, immersion/maceration skin injury from compulsive cooling; systemic thrombosis (arterial/venous) from the underlying MPN. Prognostic factors: platelet count/response to aspirin, presence and control of the underlying MPN, JAK2/MPL status (arterial thrombosis risk).

12. Treatment

Treatment is cause-directed (F005), with NCIT term suggestions:

Clinical scenario	Intervention	NCIT suggestion
MPN-associated EM	Low-dose aspirin (dramatic, near-pathognomonic relief)	NCIT:C287 (Aspirin)
MPN cytoreduction	Hydroxyurea (first-line)	NCIT:C512 (Hydroxyurea)
MPN cytoreduction (younger pts)	Interferon-α / pegylated interferon	NCIT:C20515 (Interferon Alpha)
PV	Therapeutic phlebotomy (goal hematocrit <45%)	NCIT:C15325 (Phlebotomy)
PV, HU-intolerant/resistant	Ruxolitinib (JAK inhibitor)	NCIT:C79809 (Ruxolitinib)
Drug-induced EM	Withdraw offending agent	—
Small-fiber/autoimmune EM	Neuropathic-pain agents (gabapentin, amitriptyline), sodium-channel blockers (mexiletine, lidocaine, carbamazepine); treat autoimmune disease	NCIT:C1367 (Gabapentin); NCIT:C614 (Lidocaine); NCIT:C1665 (Mexiletine)
Supportive (all)	Cooling, elevation, heat/dependency avoidance	—

"Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine." — PMID: 27639908

The aspirin response is so characteristic that MPN cytoreductive guidelines (ET/PV updates, PMID: 38269572, PMID: 27561316) routinely incorporate low-dose aspirin. In one illustrative case, reversal of thrombotic complications was achieved by aspirin and platelet reduction, "and not by coumadin" (PMID: 16510297). Pharmacogenomics: JAK2/MPL status guides thrombosis-risk stratification and cytoreduction decisions. Personalized medicine: treatment is genotype-/cause-guided rather than one-size-fits-all — the same clinical triad requires opposite drug classes (aspirin vs. sodium-channel blockers) depending on etiology.

13. Prevention

Because secondary EM is acquired/symptomatic, no primary prevention exists (F011). Prevention is framed at secondary and tertiary levels:

Secondary prevention: early recognition of EM as a sentinel of occult MPN, with serial CBC + JAK2 testing, and treatment of thrombocytosis/erythrocytosis.
Tertiary prevention: aspirin ± cytoreduction/phlebotomy to prevent digital necrosis and macrovascular thrombosis; avoid provoking heat/dependency; for drug-induced disease, avoid/withdraw the culprit drug.
Genetic counseling / carrier screening / immunization / public-health interventions: not applicable (no germline/heritable or infectious-transmissible basis).

14. Other Species / Natural Disease

No naturally occurring secondary EM is described in companion animals or wildlife (OMIA); the disease is essentially human (F011). Orthologous genes for the underlying MPN drivers exist in model species (mouse Jak2, Calr, Mpl; NCBI Gene IDs available), enabling comparative study of the MPN substrate but not of the EM phenotype per se. There is no zoonotic potential and no cross-species transmission.

15. Model Organisms

No validated animal model of SECONDARY erythromelalgia exists (F011). Available models address only components of the disease:

Model	What it captures	Limitation for secondary EM
Transgenic/knock-in SCN9A/Na_v1.7 gain-of-function mice; patient iPSC-derived sensory neurons	Primary EM pain physiology	Models channelopathy, not acquired microvascular disease
JAK2 V617F knock-in mice	Thrombocytosis/thrombosis of the underlying MPN	EM (acral burning/erythema) has not been specifically scored

Thus the field lacks a model that reproduces the platelet-COX-mediated acral microthrombosis or the immune/dysautonomic microvascular injury of human secondary EM — a significant translational gap.

Mechanistic Model / Interpretation

Secondary EM is best understood as a final common acral microvascular phenotype reached by at least two distinct upstream routes:

The thrombocythemic (MPN) route is the best-established and mechanistically the most complete: a somatic JAK2/CALR/MPL clone → hyperreactive thrombocytosis → platelet COX-1/thromboxane-driven arteriolar inflammation and platelet-rich microthrombosis → acral ischemia. The therapeutic "experiment of nature" — complete relief with COX inhibitors (aspirin/indomethacin) but not with anticoagulants (coumadin), antiplatelet agents acting by other mechanisms (ticlopidine, dipyridamole), or non-acetylated salicylate — pins the mechanism firmly on platelet cyclooxygenase. This is a distinct, aspirin-responsive arterial thrombophilia.
The immune/dysautonomic route (autoimmune, idiopathic, small-fiber-neuropathy-associated) involves complement (C5b-9) and type-I interferon-mediated endothelial injury plus autonomic denervation of eccrine glands and arterioles, producing maldistributed perfusion/arteriovenous shunting. This route is aspirin-unresponsive and treated as neuropathic/autoimmune disease.

Both converge on Ljubojević's proposed unifying lesion — microvascular arteriovenous shunting with tissue hypoxia despite visible hyperemia — reconciling the paradox of a red, warm, yet ischemic and painful extremity. The unifying clinical message is that the triad is a syndrome, not a diagnosis: identifying and treating the upstream cause is both diagnostic confirmation and definitive therapy.

Evidence Base

PMID	Title (abbrev.)	Role
12781799	Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia	Core biochemical/histologic evidence for COX/thromboxane mechanism
3977194	EM caused by platelet-mediated arteriolar inflammation	Histopathology of arteriolar thrombosis
16510297	Reversal by aspirin, platelet reduction, not coumadin	Establishes COX/aspirin dependence
39846717	Cutaneous pathology of EM	Complement/IFN/dysautonomia mechanism (non-MPN)
23334520	Secondary EM, unusual histology	Typical histopathology
2643412	EM and myeloproliferative disorders	Phenotype, ~2.5-yr lead time, CML association, monitoring
11208311	EM — thrombotic complication in MPD	Localization and progression to gangrene
15075045	Erythromelalgia (review)	Etiologic spectrum + AV-shunting unifying mechanism
1613144	EM in TTP	TTP as secondary cause
38269572	ET 2024 update	MPN driver mutations (~80% JAK2/CALR/MPL)
27991718	PV/ET 2017 update	Driver frequencies; JAK2/MPL & arterial thrombosis
18713229	Incidence, Olmsted County	Population-based incidence (secondary 0.2/100k/yr)
22247059	Incidence, Sweden	Age/sex distribution, diagnostic delay
35835622	Paroxysmal vascular acrosyndromes	Diagnostic workup
27639908	EM diagnosis & therapy	Cause-directed treatment; drug causes
23862006	Secondary EM case report	Aspirin responsiveness
15750823	EM in ET / renovascular HTN	Rapid treatment response
22844295	EM on aspirin withdrawal	Recurrence with aspirin withdrawal
38704280	Painful Raynaud's mimics	Differential diagnosis
25674012	Burning feet in PV	Concurrent axonal neuropathy in JAK2+ PV
39556352	PV review	Underlying MPN prognosis; EM frequency 5.3% in PV
38310350	Multiple driver mutations in ET	CHIP vs. dominant driver interpretation
42101597	Thrombocytosis review	Thrombocytosis definition/workup
32974939	PV/ET 2021 update	Survival, transformation rates
27561316	How I treat ET	Aspirin + cytoreduction strategy

Consistency: Multiple independent series (Michiels; Olmsted County; Swedish cohort; ET/PV guideline updates) converge on the same picture. The classic thrombocythemic mechanism is strongly and repeatedly supported; the immune/dysautonomic mechanism rests on a smaller, more recent evidence base (single dermatopathology series) and should be regarded as an emerging but not yet fully validated complementary model.

Limitations and Knowledge Gaps

No dedicated secondary-EM animal model. JAK2 V617F mice reproduce the MPN substrate but EM has not been scored; there is no model of the immune/dysautonomic route.
Immune/complement mechanism is based on a single small series (9 patients, PMID: 39846717) and requires independent replication with quantitative endpoints.
Epidemiologic estimates are geographically narrow (Olmsted County, single Swedish center); global prevalence, ethnic distribution, and secondary-cause proportions are poorly characterized.
No prospective controlled trials define optimal therapy for non-MPN subtypes; treatment recommendations are extrapolated from case series.
Frequency data for individual phenotypic features (e.g., proportion unilateral, proportion progressing to gangrene) in secondary EM specifically are sparse.
The AV-shunting unifying hypothesis remains conceptual and unproven at the tissue level for all subtypes.
Molecular profiling (transcriptomics/proteomics/metabolomics) of EM-affected skin is essentially absent beyond immunohistochemistry.

Proposed Follow-up Experiments / Actions

Prospective natural-history cohort of idiopathic-appearing EM with serial CBC + JAK2/CALR/MPL testing to quantify the rate and lead time of occult MPN conversion and refine the monitoring interval.
Replicate the complement/interferon/dysautonomia findings in an independent, larger biopsy cohort with quantitative C5b-9, type-I IFN signature scoring, and intraepidermal nerve-fiber-density measurement, stratified by MPN vs. non-MPN etiology.
Develop a secondary-EM model by scoring acral thermal/nociceptive phenotypes and skin microvascular thrombosis in JAK2 V617F knock-in mice ± aspirin, testing whether COX inhibition reverses acral pathology.
Aspirin-response as a diagnostic biomarker study: formally test the sensitivity/specificity of a dramatic aspirin response for detecting underlying MPN.
Skin single-cell/spatial transcriptomics of EM-affected vs. unaffected acral skin to map the endothelial, platelet, smooth-muscle, and autonomic-nerve contributions and validate the two-route model.
Registry-based epidemiology across multiple regions to establish global incidence, secondary-cause proportions, and demographic distribution.
Trial of complement- or interferon-directed therapy in refractory, aspirin-unresponsive, immune-associated EM, guided by biopsy biomarkers.

Report compiled from 11 confirmed findings across 5 investigation iterations and 35 reviewed papers. Evidence sources are predominantly human clinical case series, population-based epidemiology, and disease-level reviews; mechanistic claims are supported by skin-biopsy histopathology, platelet biochemistry, and pharmacologic-response data.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	26
Resolved	26
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	25
Quoted claims found in source	24
Quoted claims not found in source	1
References weighed for topical relevance	26
On topic	15
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMID:22247059 (abstract only): "we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women"
closest text in source: "we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	32
Resolved	30
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	11
Terms named correctly	2
Terms named as a different term	5
Terms whose name is worth a second look	4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0008574 (1 mention) - the report calls it "erythromelalgia"; MONDO calls it obsolete Tl antigen
HP:0012326 (2 mentions) - the report calls it "Erythromelalgia", "Erythromelalgia (composite)"; HP calls it Abnormal celiac artery morphology
NCIT:C512 (1 mention) - the report calls it "Hydroxyurea"; NCIT calls it Free Radical
NCIT:C15325 (1 mention) - the report calls it "Phlebotomy"; NCIT calls it Skin Transplantation
NCIT:C79809 (1 mention) - the report calls it "Ruxolitinib"; NCIT calls it Defactinib

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

MONDO:0008574 (obsolete Tl antigen) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0030168 (1 mention) - the report calls it "GO biological processes: platelet activation"; GO calls it platelet activation**
CL:0000233 (2 mentions) - the report calls it "CL cell types: platelet"; CL calls it platelet**, and lists "blood platelet" among its other names
CHEBI:28728 (1 mention) - the report calls it "CHEBI: thromboxane B2"; CHEBI calls it thromboxane B2**
NCIT:C20515 (1 mention) - the report calls it "Interferon Alpha"; NCIT calls it Interleukin-13

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0012326 - called "Erythromelalgia", "Erythromelalgia (composite)"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Classifications

Mappings

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Medical Actions

Environmental Factors

Biochemical Markers

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Source YAML

References & Deep Research

Deep Research

Secondary Erythromelalgia: Disease-Characteristics Research Report

Executive summary and evidence caveat

1. Disease information

Definition and classification

Identifiers

2. Etiology, risks, protective factors, and gene–environment interaction

Causal or associated factors

Risk and protective factors

Gene–environment interaction

3. Phenotypes

Quality of life

4. Genetic and molecular information

Distinction from primary erythromelalgia

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

A. Platelet–microvascular pathway

B. Neuropathic/autonomic pathway

C. Arteriovenous shunting and hypoxia

7. Anatomical structures affected

8. Temporal development

9. Inheritance, epidemiology, and population

10. Diagnostics

Clinical diagnosis

Cause-directed workup

Genetic testing

Differential diagnosis

11. Outcomes and prognosis

12. Treatment and current applications

Treatment strategy

Drug and intervention evidence

Recent developments and trials

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Knowledge-base conclusions

Artifacts

Reference Validation

Secondary Erythromelalgia: A Comprehensive Disease Characteristics Report

Summary

Key Findings

1. Disease Information — Definition, Classification, and Identifiers

2. Etiology — Causal Factors, Risk Factors, Gene–Environment Interactions

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain — MPN-associated (thrombocythemic) secondary EM

Alternative / complementary causal chain — immune-mediated microvascular injury & dysautonomia (non-MPN subtypes)

Mechanism schematic

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population (Epidemiology)

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base