| 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. (pqac-00000000, pqac-00000002, pqac-00000003, pqac-00000005) | 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. (pqac-00000000, pqac-00000001, pqac-00000003, pqac-00000005) | 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. (pqac-00000000, pqac-00000001, pqac-00000004) | 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. (pqac-00000000, pqac-00000004) | 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. (pqac-00000000, pqac-00000004, pqac-00000007) | 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. (pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000008, pqac-00000009) | 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. (pqac-00000011, pqac-00000013, pqac-00000014, pqac-00000010, pqac-00000012, pqac-00000015) | 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. (pqac-00000000, pqac-00000003, pqac-00000007) | 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. (pqac-00000015) | 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.*