Idiopathic Multicentric Castleman Disease

🔗

Mappings

MONDO

MONDO:0018702 Castleman-Kojima disease Not Yet Curated

◆

Subtypes

3

iMCD with Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Organomegaly MONDO:0018702

Acute, severe clinical subtype of iMCD presenting as a rapid-onset cytokine storm with thrombocytopenia, anasarca, fever, renal dysfunction or bone marrow reticulin fibrosis, and organomegaly, often with small-volume lymphadenopathy. Serum immunoglobulins are normal or low, distinguishing it from iMCD-IPL. It carries the highest requirement for dialysis, mechanical ventilation, and transfusion, and most iMCD deaths occur in this subtype.

Show evidence (2 references)

PMID:29157612 SUPPORT Human Clinical

"Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."

Identifies the immunoglobulin-level contrast that separates TAFRO from the other iMCD subtypes.

PMID:29157612 SUPPORT Human Clinical

"TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment."

Establishes the aggressive course and the absence of a standard regimen.

iMCD with Idiopathic Plasmacytic Lymphadenopathy

Indolent clinical subtype of iMCD characterized by polyclonal hypergammaglobulinemia, thrombocytosis, plasmacytic or mixed lymph node histopathology, and anemia of inflammation. Despite a higher measured inflammatory state than other iMCD-NOS patients, survival is longer, and IL-6-blocking and myeloma-like regimens outperform lymphoma-like regimens. It is the subtype most often confused with IgG4-related disease. Whether it should be formally split out of iMCD-NOS is still contested; it is recorded here as a subtype because the international expert review and the largest cohort both treat it as one.

Show evidence (2 references)

PMID:38356434 SUPPORT Human Clinical

"Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival."

The 228-patient cohort quantifies the paradoxical combination of higher inflammation with better survival that defines this subtype.

PMID:38356434 SUPPORT Human Clinical

"This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL."

Establishes that IPL accounts for roughly half of what is otherwise labeled iMCD-NOS.

iMCD, Not Otherwise Specified

iMCD that meets neither the TAFRO nor the IPL pattern. Clinically it often mimics indolent lymphoma or an autoimmune condition. In the ACCELERATE registry, NOS patients were hospitalized far less than TAFRO patients but spent a significantly greater proportion of their follow-up in active disease flare, so a milder acute presentation does not mean a lower long-term symptom burden.

Show evidence (2 references)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Those who have iMCD not meeting criteria for TAFRO or IPL have iMCD‐NOS, which often mimics indolent lymphoma or autoimmune conditions."

Defines iMCD-NOS as the residual category and names its usual clinical mimics.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004)."

Quantifies the chronic flare burden of NOS relative to TAFRO.

◈

Mechanistic Hypotheses

6

Immune-Stromal Dysregulation and Molecular Endotypes

immune_stromal_dysregulation EMERGING iMCD-TAFRO iMCD-IPL iMCD-NOS

Evidence balance 2 support

Molecular endotypes defined by differential pathway activation (IL-6 vs. CXCL13 vs. TNF vs. PI3K/AKT/mTOR signaling) underlie clinical and therapeutic heterogeneity in iMCD. Single-cell transcriptomics and spatial biology identify immune-stromal dysregulation involving fibroblastic reticular cells and endothelial dysfunction as core mechanistic components.

Pathograph links

Unknown iMCD Initiating Process -> Lymph Node Stromal Cell Activation and Expansion INDIRECT UNKNOWN INTERMEDIATES Whatever the trigger, the observed tissue consequence is activation and expansion of the lymph node stromal compartment.

CXCL13 Chemokine Axis Elevation -> Plasma Cell / B Cell Proliferation INDIRECT UNKNOWN INTERMEDIATES

Show evidence (2 references)

PPR:PPR1286884 Preprint · not peer-reviewed SUPPORT Other

"Recent discoveries have transformed Castleman disease from a clinicopathological entity largely defined by interleukin-6 excess into a complex disorder of immune–stromal dysregulation. Single-cell transcriptomics and spatial biology have identified fibroblastic reticular cells, endothelial..."

Narrative review synthesizing recent molecular and immunological discoveries, establishing immune-stromal dysregulation as an organizing framework for contemporary pathophysiology.

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"CD shows increased stromal cells that form unique microenvironments."

Spatial proteomic and transcriptomic mapping of 22 Castleman lymph nodes provides the primary tissue evidence for a stromal-centred model.

Lymph Node Stromal Cells as the Source of IL-6 and VEGF

stromal_cytokine_source EMERGING iMCD-TAFRO iMCD-IPL iMCD-NOS

Evidence balance 2 support

The cells that oversupply IL-6 and VEGF in iMCD are lymph node stromal cells - PDGFRA+ T-zone reticular cells and ACTA2+ perivascular reticular cells, with CXCL13+ follicular dendritic cells contributing inside follicles - rather than the hematopoietic compartment that earlier immunohistochemical work implicated. The T-zone and perivascular subsets are the ones that expand in multicentric disease, in contrast to the B-zone reticular cells that dominate the unicentric form. The evidence is a single spatial multi-omic study of 22 cases with no functional perturbation, so the causal direction (stromal activation driving the cytokine storm versus responding to it) is not established.

Pathograph links

Unknown iMCD Initiating Process -> Lymph Node Stromal Cell Activation and Expansion INDIRECT UNKNOWN INTERMEDIATES Whatever the trigger, the observed tissue consequence is activation and expansion of the lymph node stromal compartment.

Lymph Node Stromal Cell Activation and Expansion -> Follicular Dendritic Cell Meshwork Expansion DIRECT

Lymph Node Stromal Cell Activation and Expansion -> Stromal VEGF Overproduction and Neovascularization DIRECT

Lymph Node Stromal Cell Activation and Expansion -> IL-6 Overproduction DIRECT Under the stromal-source hypothesis, activated perivascular and T-zone reticular cells are a principal origin of the IL-6 signal in MCD.

Follicular Dendritic Cell Meshwork Expansion -> Angiofollicular Lymph Node Hyperplasia DIRECT Meshwork interdigitation between concentric mantle-zone B cell layers is the proposed structural basis of onion-skinning.

Follicular Dendritic Cell Meshwork Expansion -> Plasma Cell / B Cell Proliferation INDIRECT KNOWN INTERMEDIATES

Show evidence (2 references)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."

Establishes that distinct stromal subsets dominate the unicentric and multicentric forms, the core claim of this hypothesis group.

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."

States the prior interpretation this hypothesis displaces: follicular dendritic cells as passive remnants rather than activated drivers.

Autoantibody-Driven Etiology of iMCD

autoimmune_etiology EMERGING iMCD-TAFRO iMCD-IPL iMCD-NOS

Evidence balance 2 support

iMCD is initiated by autoimmunity, with autoantibodies against connective tissue disease antigens and against cytokines themselves driving the hypercytokinemia. Supporting observations are an enrichment of CTD-associated and anti-cytokine IgG autoantibodies in iMCD sera relative to healthy controls, and the long-standing clinical overlap between iMCD and connective tissue disease. The autoantibodies detected are heterogeneous rather than a shared specificity, and no pathogenic mechanism has been demonstrated, so this remains one of several competing candidate etiologies.

Pathograph links

Unknown iMCD Initiating Process -> Autoantibody-Mediated Immune Dysregulation INDIRECT UNKNOWN INTERMEDIATES Under the autoimmune candidate, the initiating process is loss of tolerance producing the autoantibody repertoire seen in iMCD sera.

Autoantibody-Mediated Immune Dysregulation -> Lymph Node Stromal Cell Activation and Expansion INDIRECT UNKNOWN INTERMEDIATES Proposed route by which loss of tolerance would produce chronic nodal immune activation. No intermediate step has been demonstrated.

Show evidence (2 references)

PMID:40181993 SUPPORT Human Clinical

"IgG autoantibodies binding autoantigens associated with common CTDs and cytokines are elevated in iMCD patients compared to HC, suggesting that autoimmunity may be involved in iMCD pathogenesis."

The authors state the autoimmune hypothesis as a suggestion drawn from a case-control serology comparison, matching the EMERGING status recorded here.

PMID:24622327 SUPPORT Human Clinical

"We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus."

Places the autoantibody mechanism as one of three explicitly competing candidate drivers, which is why this is recorded as EMERGING rather than canonical.

Clonal Somatic Mutation as a Driver of iMCD

clonal_stromal_origin EMERGING iMCD-TAFRO iMCD-IPL iMCD-NOS

Evidence balance 2 support

Recurrent somatic mutations - notably NCOA4 L261F in about 23% of iMCD, with chromatin-organization and methylation abnormalities clustering in this form - make iMCD at least partly a clonal process rather than a purely reactive one. The alleles are recurrent and enriched, but they are present in a minority of cases, the functional consequence of NCOA4 L261F in this disease has not been characterized, no functional model has shown that it initiates the lymph node lesion, and its cell of origin within the node is unresolved.

Pathograph links

Somatic Stromal Cell Mutation -> Lymph Node Stromal Cell Activation and Expansion INDIRECT UNKNOWN INTERMEDIATES Under the clonal hypothesis, an activating stromal mutation is what makes the stromal compartment expand autonomously.

Show evidence (2 references)

PMID:33804823 SUPPORT Human Clinical

"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"

Quantifies the recurrent somatic alleles this hypothesis rests on, and the minority frequencies that keep it from being canonical.

PMID:33804823 SUPPORT Human Clinical

"However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."

The same review states that the mechanistic significance of these genetic findings is not established, limiting the hypothesis to EMERGING status.

PI3K/AKT/mTOR Signaling in IL-6-Blockade-Refractory iMCD

il6_independent_mtor EMERGING iMCD-TAFRO

Evidence balance 2 support

In the substantial fraction of iMCD patients who do not respond to anti-IL-6 therapy, the disease is driven by PI3K/AKT/mTOR signaling with CD8+ T cell activation and VEGF-A elevation rather than by IL-6 itself. The supporting evidence is a three-patient precision-medicine study in which mTOR pathway activity was elevated and sirolimus produced durable remissions; a prospective single-arm trial (NCT03933904) was designed to test it.

Pathograph links

PI3K/AKT/mTOR Pathway Activation -> Stromal VEGF Overproduction and Neovascularization INDIRECT UNKNOWN INTERMEDIATES mTOR inhibition lowers circulating VEGF-A, placing VEGF downstream of this pathway in the refractory setting.

Show evidence (2 references)

PMID:31408438 SUPPORT Human Clinical

"Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity."

Reports the pathway activation on which this hypothesis rests.

PMID:31408438 SUPPORT Human Clinical

"This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD."

The authors' own framing of the finding as a first identification in three patients rather than an established mechanism.

Subtype-Specific Cellular Source of IL-6

subtype_specific_il6_source EMERGING iMCD-IPL iMCD-TAFRO

Evidence balance 2 support

The cell producing IL-6 differs between iMCD subtypes, and this explains their divergent response to IL-6 blockade. In iMCD-IPL, plasma cells are the dominant IL-6 source under XBP1-driven endoplasmic reticulum stress and plasma cell differentiation, consistent with the good response of IPL to siltuximab or tocilizumab. In iMCD-TAFRO, IL-6 comes predominantly from vascular endothelial cells, which would make the elevated serum IL-6 a secondary consequence of the cytokine storm rather than its driver. Evidence is tissue expression profiling without functional perturbation.

Show evidence (2 references)

PMID:40931874 SUPPORT Human Clinical

"Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO."

The direct tissue observation of a subtype-specific IL-6 source.

PMID:40931874 SUPPORT Human Clinical

"In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."

States the strong form of the hypothesis - that IL-6 is secondary in TAFRO - in the authors' own hedged terms.

?

Discussions and Knowledge Gaps

8

What initiates idiopathic multicentric Castleman disease - autoimmunity, an ectopic clonal cytokine source, a non-HHV-8 infection, or a germline inflammatory predisposition?

KNOWLEDGE GAP OPEN gap_imcd_initiating_process

Attached to

pathophysiology#Unknown iMCD Initiating Process pathophysiology#Autoantibody-Mediated Immune Dysregulation pathophysiology#Somatic Stromal Cell Mutation

This is the field's central unanswered question and everything downstream depends on it. Three candidate processes were formally proposed in 2014 and none has been confirmed or excluded since. Viral-Track sequencing of 22 UCD and 19 iMCD nodes found no shared viral signature, weakening the infectious candidate; autoantibody enrichment supports but does not establish the autoimmune candidate; and recurrent somatic alleles support but do not establish a clonal candidate. Because the etiology is unknown, iMCD is defined by exclusion, has no diagnostic biomarker, and is treated with a single-cytokine blockade that fails in most patients.

Proposed experiments

Paired serologic, viral, and clonality screen across adjudicated iMCD subtypes

exp_imcd_paired_multiomic_etiology_screen

In a prospectively enrolled, expert-adjudicated iMCD cohort stratified by TAFRO/IPL/NOS, run in parallel on the same patients: unbiased autoantigen-array and functional receptor-blocking serology, metagenomic and viral-capture sequencing of lymph node and plasma, and deep targeted sequencing of sorted stromal, plasma cell, and T cell fractions for clonality. Testing the three candidate etiologies on shared samples is what makes them comparable; the existing evidence for each comes from separate cohorts.

Would support

pathophysiology#Autoantibody-Mediated Immune Dysregulation pathophysiology#Somatic Stromal Cell Mutation

Supporting outcome

A candidate process is enriched in one subtype and co-segregates with disease activity, with the other two candidates negative in the same patients.

Refuting outcome

All three candidate processes are negative or are equally present in disease controls, indicating the initiating process lies outside the three proposed categories.

Show evidence (2 references)

PMID:24622327 SUPPORT Human Clinical

"Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases."

States the gap as an explicit research priority. Two of the four priorities listed (consensus criteria, registry) have since been met; the first two have not.

DOI:10.1038/s41598-025-85193-x SUPPORT Computational

"While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown."

Confirms the gap is still open as of a 2025 sequencing study.

Can a cell-culture or animal model be built that reproduces the Castleman lymph node lesion, and until one exists how can any proposed mechanism be tested causally?

KNOWLEDGE GAP OPEN gap_imcd_no_disease_model

Attached to

pathophysiology#Lymph Node Stromal Cell Activation and Expansion pathophysiology#Follicular Dendritic Cell Meshwork Expansion pathophysiology#Stromal VEGF Overproduction and Neovascularization

Every mechanism node in this entry derives from human tissue association - spatial transcriptomics, immunohistochemistry, serum proteomics - with no perturbation experiment behind it, because no validated model system exists. The authors of the largest spatial study state this limitation directly and note that the disease may have no genetic basis to engineer, being instead immune-driven by antigenic stimuli whose origin is unknown. This is the upstream reason the causal direction of the stromal model cannot be settled: stromal activation could be driving the cytokine storm or responding to it.

Proposed experiments

Human lymphoid organoid with defined stromal perturbation

exp_cd_lymphoid_organoid_stromal_perturbation

Build a human lymphoid organoid or lymph-node-on-chip containing primary follicular dendritic cells, T-zone and perivascular reticular cells, naive B cells, and endothelium, then perturb single stromal populations (constitutive PDGFRB N666S expression, forced VEGFA or IL6 expression, lymphotoxin-beta receptor stimulation, DLL4-NOTCH1 blockade) and score for the defining tissue readouts: CD21 meshwork expansion, concentric mantle-zone B cell layering, perifollicular neovascularization, and plasmablast output.

Would support

pathophysiology#Lymph Node Stromal Cell Activation and Expansion pathophysiology#Follicular Dendritic Cell Meshwork Expansion

Supporting outcome

Perturbing a single stromal population reproduces the onion-skinning and penetrating-vessel architecture, establishing stromal activation as sufficient rather than reactive.

Refuting outcome

No stromal perturbation reproduces the architecture, indicating the lesion requires a systemic or hematopoietic input absent from the organoid.

Show evidence (1 reference)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"The absence of accurate cell culture or murine models limits functional studies of CD."

States the gap in the authors' own words.

What drives disease in the majority of iMCD patients who do not respond to IL-6 blockade, and can non-responders be identified before weeks of failed therapy have passed?

KNOWLEDGE GAP OPEN gap_imcd_anti_il6_nonresponse

Attached to

pathophysiology#IL-6 Overproduction pathophysiology#PI3K/AKT/mTOR Pathway Activation pathophysiology#CXCL13 Chemokine Axis Elevation

Siltuximab produced a durable response in 34% of patients in the registration trial and is effective in roughly 34-50% of cases, so most patients treated with the only approved drug do not benefit from it, and severe patients have a narrow window before escalation to cytotoxic chemotherapy is needed. Two partial answers exist and neither is complete: PI3K/AKT/mTOR activation identified in three refractory TAFRO patients, and an early CXCL13 fall that predicts response by day 8. What drives the remaining non-responders is not known.

Proposed experiments

Pretreatment endotype stratification with response-adaptive assignment

exp_imcd_pretreatment_endotype_stratified_trial

Profile serum proteome, lymph node spatial transcriptome, and PBMC phospho-signaling before first-line therapy in an iMCD cohort, assign a candidate endotype (IL-6-high, CXCL13-high, TNF-high, mTOR-high), then randomize within endotype to IL-6 blockade versus the endotype-matched agent (sirolimus for mTOR-high, JAK inhibition for broad gp130 signaling). A day-8 CXCL13 readout is embedded as a prespecified early futility rule.

Would support

mechanistic_hypotheses#immune_stromal_dysregulation mechanistic_hypotheses#il6_independent_mtor

Supporting outcome

Endotype-matched assignment beats uniform IL-6 blockade on durable response, and day-8 CXCL13 identifies non-responders before week 3.

Refuting outcome

Response rates are the same regardless of pretreatment endotype, indicating the proposed endotypes are descriptive rather than predictive.

Show evidence (2 references)

PMID:36433996 SUPPORT Human Clinical

"Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking."

States both halves of the gap - unexplained non-response and missing early biomarkers.

PMID:31408438 SUPPORT Human Clinical

"The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist."

The explicit statement of the gap that motivated the mTOR work.

Are activated lymph node stromal cells the source that drives the Castleman cytokine excess, or do they expand and secrete in response to a cytokine excess generated elsewhere?

OPEN QUESTION OPEN gap_stromal_cytokine_source_causality

Attached to

pathophysiology#Lymph Node Stromal Cell Activation and Expansion pathophysiology#Stromal VEGF Overproduction and Neovascularization pathophysiology#IL-6 Overproduction

The spatial data establish where VEGF and IL-6 transcripts are, not what started them. The question is not academic: if stromal cells are the driver, stroma-directed agents (lymphotoxin-beta receptor fusion proteins, VEGF inhibitors, NOTCH inhibitors) are rational; if they are responders, those agents treat a consequence. The evidence is one observational cohort of 22 cases with no perturbation, and the subtype-specific IL-6 source data point the other way for TAFRO, where endothelial IL-6 is proposed to be secondary to the cytokine storm.

Show evidence (2 references)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"A limitation of the study is the moderate sample size and its observational nature."

The authors' own statement of the limitation that leaves causal direction unresolved.

PMID:40931874 SUPPORT Human Clinical

"In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."

Argues explicitly for the responder interpretation in at least one subtype, which is why the question is recorded as open rather than settled.

Should iMCD-IPL be recognized as a formal subtype separate from iMCD-NOS, and if so, does the CDCN severity classification apply to it?

CONTROVERSY OPEN controversy_imcd_ipl_as_subtype

Attached to

has_subtypes#iMCD-IPL has_subtypes#iMCD-NOS

The CDCN consensus criteria recognize only TAFRO and NOS, but IPL accounted for 45.2% of 228 iMCD-NOS patients in the largest cohort and behaved differently: higher inflammatory state, longer overall survival, better response to myeloma-like and IL-6-blocking regimens than to lymphoma-like ones, and - importantly - no survival difference between CDCN-severe and CDCN-non-severe patients, meaning the severity classification does not stratify this group. The 2026 expert perspective now lists IPL as one of three iMCD subtypes. Recording it as a subtype here follows that, but the formal criteria have not been revised.

Show evidence (3 references)

PMID:38356434 SUPPORT Human Clinical

"Whether these patients should be excluded from the current classification system lacks sufficient evidence."

States the controversy directly.

PMID:38356434 SUPPORT Human Clinical

"No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification."

The specific finding that the existing severity classification fails to stratify IPL patients, which is the practical stake in this controversy.

DOI:10.1002/art.43269 SUPPORT Human Clinical

"The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."

The expert review that treats IPL as a subtype, which this entry follows.

Does iMCD raise the risk of subsequent myeloid and solid malignancy, or is the reported excess an artifact of misclassifying malignancy-associated reactive lymphadenopathy as iMCD?

CONTROVERSY OPEN controversy_imcd_malignancy_risk

Attached to

has_subtypes#iMCD-TAFRO has_subtypes#iMCD-NOS

A systematic review and a claims-based study both reported increased myeloid and solid malignancy after iMCD, but in the expert-adjudicated ACCELERATE cohort only one patient developed a myeloid malignancy and no patient developed diffuse large B-cell lymphoma, with a malignancy rate comparable to the claims study's controls. The two readings have opposite implications: an excess means iMCD warrants cancer surveillance, whereas an artifact means claims-based iMCD cohorts contain patients who only ever had a malignancy. Because iMCD diagnostic criteria explicitly exclude concurrent malignancy, strict adjudication could also be excluding genuine iMCD patients who then developed cancer, so neither cohort settles it.

Show evidence (2 references)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"In this cohort, few patients developed a malignancy following the diagnosis of iMCD."

The adjudicated-registry finding on one side of the controversy.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Conversely, our strict inclusion criteria might have inadvertently excluded true iMCD patients who also developed malignancies."

The authors' own statement of why their negative result does not settle the question either.

Which mediator causes the glomerular endothelial injury of TAFRO, and would targeting it prevent the dialysis requirement?

KNOWLEDGE GAP OPEN gap_tafro_renal_lesion_mechanism

Attached to

pathophysiology#Endothelial Injury and Renal Thrombotic Microangiopathy phenotypes#Acute Renal Failure

Renal failure is the most common post-diagnosis morbidity in iMCD (48%) and 27% of patients require dialysis, so the renal lesion drives a large share of the disease's burden. The histology - membranoproliferative-like injury and thrombotic microangiopathy - points at glomerular endothelium, and IL-6 and VEGF are the proposed mediators, but the review that summarizes this states plainly that their role in renal injury is not well understood. No therapy is directed at the renal lesion specifically.

Proposed experiments

Spatial mediator mapping of TAFRO renal biopsies

exp_tafro_renal_biopsy_mediator_mapping

Apply the same spatial transcriptomic and in situ hybridization panel used on Castleman lymph nodes to banked TAFRO kidney biopsies, localizing IL6, VEGFA, complement components, and endothelial injury markers to glomerular compartments, and compare with thrombotic microangiopathy from other causes and with membranoproliferative glomerulonephritis controls.

Would support

pathophysiology#Endothelial Injury and Renal Thrombotic Microangiopathy

Supporting outcome

A specific mediator localizes to injured glomerular endothelium in TAFRO but not in the comparator lesions, nominating a renal-directed target.

Refuting outcome

The TAFRO renal lesion is indistinguishable from other causes of thrombotic microangiopathy, indicating a shared final common pathway rather than a Castleman-specific mediator.

Show evidence (3 references)

PMID:34208103 SUPPORT Human Clinical

"The role of these cytokines in renal injury, however, is not well understood."

States the mechanistic gap directly.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Following the iMCD diagnosis, 48% (n=49) of the cohort developed acute renal failure"

Quantifies why this gap matters clinically.

PMID:34208103 SUPPORT Human Clinical

"Therefore, it is suggested that there are factors other than IL-6 and VEGF, which dominate the glomerular injury."

Narrows the gap: the review concludes the two cytokines usually invoked are not the dominant cause of the glomerular lesion, so the mediator is unidentified.

Is there a serum or tissue marker that can establish a diagnosis of iMCD, rather than the current diagnosis by exclusion?

KNOWLEDGE GAP OPEN gap_imcd_diagnostic_biomarker

Attached to

diagnosis#International consensus diagnostic criteria for iMCD biochemical#C-X-C Motif Chemokine Ligand 13 (CXCL13) biochemical#Interleukin-6 (IL-6)

iMCD is diagnosed on non-specific clinical features plus characteristic but non-specific histopathology, after excluding infection, malignancy, and autoimmune disease - and Castleman-like nodal changes occur in all three of those. There is no known diagnostic serum biomarker, which the natural history study names as a contributor to underdiagnosis. CXCL13 is the closest candidate but was validated as a predictor of siltuximab response, not as a diagnostic discriminator, and the reported comparison groups included related diseases rather than the full mimic set a diagnostic test would face.

Proposed experiments

Biomarker discovery against the full iMCD mimic set

exp_imcd_diagnostic_biomarker_mimic_cohort

Compare serum proteomes of adjudicated iMCD against each mimic the diagnostic criteria require excluding - IgG4-related disease, HHV-8+ MCD, POEMS, lymphoma, SLE, and HLH - powered per comparator rather than pooling them as "related diseases", and evaluate candidate markers including CXCL13 as a diagnostic classifier with prespecified sensitivity and specificity targets.

Would support

biochemical#C-X-C Motif Chemokine Ligand 13 (CXCL13)

Supporting outcome

A marker or panel separates iMCD from every individual mimic at clinically useful sensitivity and specificity.

Refuting outcome

Candidate markers separate iMCD from healthy controls but not from individual mimics, confirming that diagnosis by exclusion is unavoidable with serum markers alone.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Underdiagnosis is likely as diagnostic criteria were not developed until 2017, and there is no known diagnostic serum biomarker."

States the absence of a diagnostic biomarker and its consequence.

⚙

Pathophysiology

17

Unknown iMCD Initiating Process

The event that starts idiopathic multicentric Castleman disease has not been identified. Three candidate processes have been proposed and none has been excluded: systemic inflammatory disease driven by autoantibodies or germline inflammatory gene variants; a paraneoplastic mechanism in which a clonal cell population ectopically secretes cytokine; and infection by a virus other than HHV-8. Viral-Track analysis of 22 UCD and 19 iMCD lymph nodes found no shared viral signature, which weighs against the third candidate without excluding a hit-and-run or non-transcribed agent. This node is deliberately kept in the graph as an explicit unknown so that everything downstream is not implicitly attributed to IL-6.

Autoantibody-Driven Etiology of iMCD Immune-Stromal Dysregulation and Molecular Endotypes Lymph Node Stromal Cells as the Source of IL-6 and VEGF

Downstream

Autoantibody-Mediated Immune Dysregulation Under the autoimmune candidate, the initiating process is loss of tolerance producing the autoantibody repertoire seen in iMCD sera.

Lymph Node Stromal Cell Activation and Expansion Whatever the trigger, the observed tissue consequence is activation and expansion of the lymph node stromal compartment.

Show evidence (2 references)

PMID:24622327 SUPPORT Human Clinical

"We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus."

Enumerates the three candidate initiating processes named in this node.

DOI:10.1038/s41598-025-85193-x SUPPORT Computational

"These results suggest that active viral infection is unlikely to be a pathological driver of UCD or iMCD."

Argues against the non-HHV-8 virus candidate specifically, leaving the initiating process unresolved.

Somatic Stromal Cell Mutation

Recurrent somatic mutations are found in the lesional tissue of both unicentric and idiopathic multicentric CD. PDGFRB N666S, an activating receptor tyrosine kinase allele, is present in about 10% of UCD, and NCOA4 L261F in about 23% of iMCD. In paraneoplastic-pemphigus-associated UCD, whole-exome sequencing found IL6ST (encoding gp130) and PDGFRB as the most frequently mutated genes at 32% each, with IL6ST variants predicting worse overall survival. More broadly, MAPK and interleukin signaling pathway abnormalities cluster in UCD while chromatin-organization and methylation abnormalities cluster in iMCD. Whether these alleles initiate the lesion or accumulate within it is unresolved.

Clonal Somatic Mutation as a Driver of iMCD

Genetic context variant_origin: SOMATIC functional_impact_category: GAIN_OF_FUNCTION

PDGFRB N666S is an activating allele; IL6ST encodes the gp130 subunit shared by IL-6 and vIL-6 signaling. The functional consequence of NCOA4 L261F in this disease has not been characterized.

MAPK cascade GO:0000165 ↑ INCREASED

Downstream

Lymph Node Stromal Cell Activation and Expansion Under the clonal hypothesis, an activating stromal mutation is what makes the stromal compartment expand autonomously.

Show evidence (3 references)

PMID:33804823 SUPPORT Human Clinical

"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"

Gives the recurrent alleles and their frequencies in each subtype.

PMID:33804823 SUPPORT Human Clinical

"Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD."

Supports the subtype-specific pathway clustering described in this node.

PMID:37839777 SUPPORT Human Clinical

"Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."

Whole-exome sequencing of 37 PNP-associated UCD samples identifies the two recurrently mutated genes named in this node.

Autoantibody-Mediated Immune Dysregulation

IgG autoantibodies against connective tissue disease autoantigens are found in 47% of iMCD patients versus 17% of healthy controls, and anti-cytokine autoantibodies in 38% versus 10%. One sample showed receptor-blocking activity against interferon-omega. The autoantibodies are heterogeneous rather than a single shared specificity, and no pathogenic mechanism linking them to lymph node pathology has been shown, so this node records an association-level candidate mechanism rather than an established step.

Autoantibody-Driven Etiology of iMCD

Immunoglobulin production GO:0002377 ↑ INCREASED

Downstream

Lymph Node Stromal Cell Activation and Expansion Proposed route by which loss of tolerance would produce chronic nodal immune activation. No intermediate step has been demonstrated.

Show evidence (2 references)

PMID:40181993 SUPPORT Human Clinical

"We found that an increased proportion of iMCD patients (47%) tested positive for at least one CTD-associated autoantibody compared to healthy controls (HC) (17%)."

Quantifies the CTD autoantibody enrichment stated in this node.

PMID:40181993 SUPPORT Human Clinical

"ACAs were also detected in a greater proportion of iMCD patients (38%) compared to HC (10%)"

Quantifies the anti-cytokine autoantibody enrichment stated in this node.

Lymph Node Stromal Cell Activation and Expansion

Spatial proteomic and single-nuclei transcriptomic mapping shows that the non-lymphoid stromal compartment of the multicentric Castleman lymph node expands and forms microenvironments absent from reactive nodes. The subsets that expand here are PDGFRA+ T-zone reticular cells and ACTA2+ perivascular reticular cells, in contrast to the B-zone reticular cells that dominate the unicentric form. These stromal populations, not the hematopoietic compartment, carry the highest VEGFA and IL-6-module expression, and they activate JAK-STAT, TGF-beta, and MAPK programs. Plasma cells, plasmablasts, endothelium, lymphatics, monocytes and macrophages are also increased.

Lymph Node Stromal Cells as the Source of IL-6 and VEGF

Follicular dendritic cell CL:0000442 T-zone reticular cell CL:0009105 B-zone reticular cell CL:0009104 Perivascular reticular cell CL:4033054 Fibroblastic reticular cell CL:0009101

Extracellular matrix remodeling GO:0030198 ↑ INCREASED MAPK cascade GO:0000165 ↑ INCREASED TGF-beta receptor signaling GO:0007179 ↑ INCREASED

Downstream

Follicular Dendritic Cell Meshwork Expansion

Stromal VEGF Overproduction and Neovascularization

IL-6 Overproduction Under the stromal-source hypothesis, activated perivascular and T-zone reticular cells are a principal origin of the IL-6 signal in MCD.

Show evidence (2 references)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"CD shows increased stromal cells that form unique microenvironments."

The primary observation of stromal expansion that this node records.

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."

Supports the subtype-specific stromal subset assignment described here.

Follicular Dendritic Cell Meshwork Expansion

CD21+ follicular dendritic cell meshworks are larger, brighter, and more structurally complex in both UCD and MCD than in reactive lymph nodes. Interdigitation of the expanded meshwork between concentric layers of mantle zone B cells is the proposed structural basis of the "onion-skinning" appearance, and the resulting sustained antigen presentation is proposed to drive B cell activation and plasma cell differentiation. This reinterprets the prominent FDCs of Castleman histology as an active driver rather than a passive remnant of an attenuated germinal center.

Lymph Node Stromal Cells as the Source of IL-6 and VEGF

Follicular dendritic cell CL:0000442 Mantle zone B cell CL:0000236

Germinal center formation GO:0002467 ↓ DECREASED Plasma cell differentiation GO:0002317 ↑ INCREASED

Downstream

Angiofollicular Lymph Node Hyperplasia Meshwork interdigitation between concentric mantle-zone B cell layers is the proposed structural basis of onion-skinning.

Plasma Cell / B Cell Proliferation

Show evidence (2 references)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."

The direct observation behind this node's mechanism.

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."

States the earlier interpretation that this node replaces, which is why the reinterpretation is flagged in the description.

Stromal VEGF Overproduction and Neovascularization

VEGFA is expressed at its highest levels by perivascular and T-zone reticular cells in MCD and by CXCL13+ follicular dendritic cells inside follicles in UCD. In UCD the expression is confined to follicles; in MCD it extends into the interfollicular space. The resulting perifollicular neovascularization and penetrating vessels are the structural basis of the diagnostic "lollipop" follicle, and hypervascularization supports the stromal remodeling and nodal expansion. Systemically, VEGF contributes to vascular permeability and to the POEMS phenotype.

Perivascular reticular cell CL:4033054 Blood endothelial cell CL:0000115

Vascular endothelial growth factor production GO:0010573 ↑ INCREASED Angiogenesis GO:0001525 ↑ INCREASED

Downstream

Angiofollicular Lymph Node Hyperplasia

Vascular Hyperpermeability and Third-Space Fluid Accumulation

Show evidence (2 references)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"VEGF expression was highest in PRCs and TRCs of MCD cases."

Identifies the stromal cells carrying the VEGF signal in MCD.

PMID:31408438 SUPPORT Human Clinical

"Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."

Shows circulating VEGF-A is elevated and pharmacologically reducible in IL-6-refractory iMCD, supporting VEGF as an actionable node.

PI3K/AKT/mTOR Pathway Activation

In IL-6-blockade-refractory iMCD, quantitative serum proteomics, cytokine panels, flow cytometry, and phospho-S6 immunohistochemistry showed increased CD8+ T cell activation, elevated VEGF-A, and PI3K/AKT/mTOR pathway activity. Sirolimus attenuated CD8+ T cell activation, lowered VEGF-A, and produced durable clinical benefit in all three patients studied. This is the first pharmacologically targetable process identified for patients whose disease does not respond to IL-6 blockade, and it is the mechanistic rationale for NCT03933904. The supporting series is three patients.

PI3K/AKT/mTOR Signaling in IL-6-Blockade-Refractory iMCD

CD8+ T cell CL:0000625

PI3K/AKT signal transduction GO:0043491 ↑ INCREASED TOR signaling GO:0031929 ↑ INCREASED

Downstream

Stromal VEGF Overproduction and Neovascularization mTOR inhibition lowers circulating VEGF-A, placing VEGF downstream of this pathway in the refractory setting.

Show evidence (2 references)

PMID:31408438 SUPPORT Human Clinical

"Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity."

The observation defining this node, in a three-patient series.

PMID:31408438 SUPPORT Human Clinical

"Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months."

The pharmacological reversal that makes this node causally interpretable rather than a correlation.

IL-6 Overproduction

Endogenous human IL-6 is overproduced from a trigger that has not been identified. The producing cell appears to differ by subtype: plasma cells in iMCD-IPL, under an XBP1-driven endoplasmic reticulum stress and plasma-cell-differentiation program, and vascular endothelial cells in iMCD-TAFRO, where the serum elevation may be secondary to the cytokine storm rather than its cause. That difference is the leading explanation for why IL-6 blockade works well in IPL and poorly in TAFRO, and it is why this node is not treated as the single unifying driver of the disease.

Plasma cell CL:0000786 Vascular endothelial cell CL:0000115

Interleukin-6 production GO:0032635 ↑ INCREASED

Downstream

JAK-STAT3 Signaling Activation

Show evidence (3 references)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"

Expert-perspective review identifies excess IL-6 as the shared driver of the multicentric forms of CD (the "they" of the quoted sentence are the MCD subtypes, of which this entry is one); IL-6 is typically normal in unicentric disease, so the quote does not establish an all-subtype claim.

PMID:40931874 SUPPORT Human Clinical

"Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO."

Supports the subtype-specific producing cell stated in this node.

PMID:40931874 SUPPORT Human Clinical

"Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation."

Identifies the XBP1/ER-stress transcriptional program named in this node for iMCD-IPL.

JAK-STAT3 Signaling Activation

IL-6 and vIL-6 bind gp130 and activate downstream JAK kinases and STAT3 transcription factor signaling. This pathway is therapeutically targeted by anti-IL-6 (siltuximab), anti-IL-6R (tocilizumab), and JAK1/2 inhibitors (ruxolitinib).

Interleukin-6-mediated signaling pathway GO:0070102 ↑ INCREASED JAK-STAT signaling GO:0007259 ↑ INCREASED

Downstream

Plasma Cell / B Cell Proliferation

CXCL13 Chemokine Axis Elevation Serum CXCL13 falls early after siltuximab in responders, placing it downstream of IL-6/JAK-STAT signaling in patients whose disease is IL-6-driven.

CXCL13 Chemokine Axis Elevation

In a comparison of 1,178 serum proteins across 88 iMCD patients, 60 patients with related diseases, and 42 healthy participants, CXCL13 was the protein most prominently up-regulated in iMCD. CXCL13 is the follicular dendritic cell chemokine that organizes B cell follicles, so its elevation connects the stromal compartment to the B cell expansion seen histologically. A 17% reduction in CXCL13 by day 8 of siltuximab predicts later response, making this node the best-supported pharmacodynamic readout in the disease.

Immune-Stromal Dysregulation and Molecular Endotypes

Chemokine-mediated signaling GO:0070098 ↑ INCREASED

Downstream

Plasma Cell / B Cell Proliferation

Show evidence (1 reference)

PMID:36433996 SUPPORT Human Clinical

"C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD."

The proteomic finding that defines this node.

Plasma Cell / B Cell Proliferation

JAK-STAT3 signaling drives proliferation of B cells and plasma cells within affected lymph nodes. Immunoglobulin output from the expanded plasma cell compartment is polyclonal, class-switched, and somatically hypermutated, consistent with a driven germinal-centre-type response rather than antigen-independent activation.

B cell CL:0000236 Plasma cell CL:0000786 Plasmablast CL:0000980

B cell proliferation GO:0042100 ↑ INCREASED Immunoglobulin production GO:0002377 ↑ INCREASED

Downstream

Angiofollicular Lymph Node Hyperplasia

Polyclonal Hypergammaglobulinemia Expanded polyclonal plasma cells are the direct source of the hypergammaglobulinemia that defines the iMCD-IPL pattern.

Hepatic Acute-Phase Response

IL-6 signaling reprogrammes hepatic protein synthesis: C-reactive protein and fibrinogen are induced, albumin synthesis falls, and hepcidin induction restricts iron availability. This is a separate effector arm from the B-lineage one - a different cell lineage with a different clinical read-out - and its markers normalize earlier on IL-6 blockade than immunoglobulin does.

Hepatocyte CL:0000182

Acute-phase response GO:0006953 ↑ INCREASED

Downstream

Anemia IL-6-driven hepcidin induction and the acute-phase response produce the anemia of inflammation seen in 85% of iMCD patients at diagnosis.

Hypoalbuminemia Reprioritized hepatic protein synthesis during the acute-phase response lowers serum albumin, present in 79% of iMCD patients at diagnosis.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical

"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"

Shows the acute-phase outputs of this node reversing on IL-6 blockade, and places them earlier in the sequence than the immunoglobulin read-out.

Angiofollicular Lymph Node Hyperplasia

The unifying histopathologic feature across all CD subtypes: lymph nodes show abnormal germinal centers (regressed/atretic in hyaline-vascular UCD, hyperplastic with plasma cell infiltrates in plasma-cell variant MCD), penetrating "lollipop" vessels, mantle-zone expansion ("onion-skinning"), and interfollicular plasmacytosis and vascular proliferation driven by IL-6 and VEGF.

Plasma cell CL:0000786 Follicular dendritic cell CL:0000442

Angiogenesis GO:0001525 ↑ INCREASED

Downstream

Generalized Lymphadenopathy

Vascular Hyperpermeability and Third-Space Fluid Accumulation

VEGF-driven and cytokine-driven endothelial permeability, compounded by hypoalbuminemia, causes fluid to leave the vascular space. Clinically this is the anasarca of iMCD-TAFRO, with pleural effusion, ascites, and generalized edema. Fluid retention was present in 84% of iMCD patients in the ACCELERATE registry, and 46% required paracentesis.

Vascular endothelial cell CL:0000115

Regulation of vascular permeability GO:0043114 ↑ INCREASED

Downstream

Generalized Edema (Anasarca)

Ascites

Pleural Effusion

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."

Quantifies fluid retention as the dominant clinical consequence of this node.

Endothelial Injury and Renal Thrombotic Microangiopathy

Renal involvement is common in MCD and especially in TAFRO. Where kidney biopsy is performed, membranoproliferative glomerulonephritis-like injury and thrombotic microangiopathy are the findings most often reported, implicating glomerular endothelial injury rather than a primary tubular or immune-complex process. IL-6 and VEGF have both been proposed as the mediators, but their specific role in the renal lesion has not been established. Thrombotic microangiopathy was diagnosed after iMCD onset in 6.9% of the ACCELERATE cohort, predominantly TAFRO patients.

Glomerular endothelial cell CL:0000115

Blood coagulation GO:0007596 ↑ INCREASED

Downstream

Renal Dysfunction

Show evidence (3 references)

PMID:34208103 SUPPORT Human Clinical

"Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy."

Establishes the two dominant renal histopathologic patterns named in this node.

PMID:34208103 SUPPORT Human Clinical

"The role of these cytokines in renal injury, however, is not well understood."

The review states directly that the mediator-to-lesion link is unresolved, which is why the mechanism is hedged here.

PMID:34208103 SUPPORT Human Clinical

"Therefore, it is suggested that there are factors other than IL-6 and VEGF, which dominate the glomerular injury."

Argues that the two cytokines this entry models as the systemic drivers are not sufficient to explain the renal lesion, so an unidentified mediator is implied at this node.

Marrow Stromal Fibrotic Remodeling

In iMCD-TAFRO the bone marrow stroma lays down excess reticulin - the "R" of the TAFRO acronym - typically with megakaryocytic hyperplasia. What drives the fibrotic response in this setting has not been established.

Extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Bone Marrow Reticulin Fibrosis

Show evidence (1 reference)

PMID:29157612 SUPPORT Human Clinical

"TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."

Names reticulin fibrosis as one of the five defining TAFRO features.

Peripheral Platelet Consumption

Platelet counts fall in iMCD-TAFRO despite adequate marrow megakaryocyte numbers, so the deficit is peripheral rather than a failure of production. This distinguishes TAFRO sharply from iMCD-IPL and iMCD-NOS, where thrombocytosis rather than thrombocytopenia is typical. Kept separate from the marrow fibrosis node because the two are different claims - one about stromal remodeling in the marrow, one about platelet survival in the circulation - and neither is established as causing the other. The mechanism of the consumption has not been established; endothelial injury and thrombotic microangiopathy are the leading candidates in this subtype.

Negative regulation of megakaryocyte differentiation GO:0045653 ↑ INCREASED

Downstream

Thrombocytopenia

Show evidence (1 reference)

PMID:29157612 SUPPORT Human Clinical

"Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."

Supports the contrast with the other iMCD subtypes stated in this node.

✶

Histopathology

5

Angiofollicular Lymph Node Hyperplasia, Plasma-Cell Variant

Plasma-cell histologic variant predominates in MCD. Features hyperplastic germinal centers, sheets of mature plasma cells in the interfollicular zone, and increased interfollicular vascularity. Mantle-zone onion-skinning is less prominent than in the hyaline-vascular variant. This is the pattern associated with iMCD-IPL and with polyclonal hypergammaglobulinemia.

Mixed Histopathologic Variant

Nodes carrying features of both the hyaline-vascular and plasma-cell patterns. In the ACCELERATE registry the histopathologic distribution across 102 adjudicated iMCD cases was hypervascular/hyaline vascular 61.8%, mixed 26.5%, and plasmacytic 6.9%; TAFRO cases were predominantly hypervascular and none were plasmacytic. The clinical significance of the histopathologic subtype is not established.

Show evidence (1 reference)

PMID:36433996 SUPPORT Human Clinical

"Patients are also classified according to histopathologic subtype, including hyaline vascular/hypervascular, plasmacytic, or mixed, though the clinical implications of defining histopathologic subtype is unclear."

States both the three-way histopathologic classification and that its clinical meaning is unresolved.

IgG4-Positive Plasma Cell Infiltrate

Lymph nodes in iMCD-IPL can contain enough IgG4-positive plasma cells to satisfy the histological diagnostic criteria for IgG4-related disease: in one series 13 of 39 iMCD-IPL cases (33.3%) did so, and serum IgG4 levels did not separate the two conditions. The serum IgG4/IgG ratio, with a cut-off of 19.0%, is the discriminator that did.

Show evidence (2 references)

PMID:38378248 SUPPORT Human Clinical

"Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups."

Quantifies the histological overlap and the failure of serum IgG4 to discriminate.

PMID:38378248 SUPPORT Human Clinical

"However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%."

Gives the discriminating ratio and its cut-off.

Expanded CD21-Positive Follicular Dendritic Cell Meshwork

CD21 immunostaining shows follicular dendritic cell meshworks of greater area, intensity, and structural complexity (image entropy) in both UCD and MCD than in reactive lymph nodes, and UCD follicles show reduced cellular diversity consistent with FDC predominance. This is an immunohistochemical correlate of the stromal-activation model rather than a routine diagnostic criterion.

Show evidence (1 reference)

DOI:10.1038/s41467-025-61214-1 SUPPORT Human Clinical

"CD shows increased stromal cells that form unique microenvironments."

Records the increased stromal content quantified by CD21 meshwork imaging in this study.

Bone Marrow Reticulin Fibrosis with Megakaryocytic Hyperplasia

Bone marrow biopsy in iMCD-TAFRO shows increased reticulin fibrosis, often with megakaryocytic hyperplasia despite peripheral thrombocytopenia. Marrow examination is part of the TAFRO workup and helps exclude a primary myeloproliferative or myelodysplastic cause of the cytopenias.

Show evidence (1 reference)

PMID:29157612 SUPPORT Human Clinical

"TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."

Names reticulin fibrosis on marrow biopsy as a defining TAFRO feature.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

22

Blood 5

Anemia VERY_FREQUENT HP:0001903

Anemia of inflammation. Present in 85.3% of iMCD patients at diagnosis in the ACCELERATE registry, with a median hemoglobin of 7.8 g/dL.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"

Gives the anemia frequency at diagnosis in a 102-patient adjudicated iMCD cohort.

Thrombocytopenia VERY_FREQUENT HP:0001873

The "T" of iMCD-TAFRO and the feature that most sharply separates it from iMCD-IPL and iMCD-NOS, where thrombocytosis is typical. Platelet transfusion was required by 21.6% of the ACCELERATE iMCD cohort, almost entirely TAFRO patients.

Show evidence (2 references)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."

Identifies thrombocytopenia as a hallmark feature of iMCD-TAFRO.

PMID:29157612 SUPPORT Human Clinical

"Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."

Establishes thrombocytopenia as TAFRO-specific rather than general to iMCD.

Thrombocytosis HP:0001894

Thrombocytosis, with polyclonal hypergammaglobulinemia, defines the iMCD-IPL pattern and is the mirror image of the TAFRO platelet phenotype. It was the first abnormality to normalize in siltuximab responders.

Show evidence (2 references)

PMID:40181993 SUPPORT Human Clinical

"iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL) involving hypergammaglobulinemia and thrombocytosis"

Defines thrombocytosis as part of the iMCD-IPL pattern.

DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical

"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"

Places thrombocytosis first in the sequence of laboratory normalization on siltuximab.

Polyclonal Hypergammaglobulinemia Polyclonal elevation of circulating IgG HP:0032288

Severe polyclonal hyperimmunoglobulinemia is the defining laboratory feature of idiopathic plasmacytic lymphadenopathy. Serum IgG above roughly 5,000 mg/dL is associated with enough IgG4-positive cells to also satisfy the histological criteria for IgG4-related disease, which is the main source of diagnostic confusion for this subtype.

Show evidence (1 reference)

PMID:38378248 SUPPORT Human Clinical

"iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed."

Gives the serum IgG level associated with IgG4-RD-like histology in iMCD-IPL.

Bone Marrow Reticulin Fibrosis Myelofibrosis HP:0011974

The "R" of TAFRO in its original formulation. Bone marrow biopsy showing reticulin fibrosis with megakaryocytic hyperplasia is part of the TAFRO diagnostic workup.

Show evidence (1 reference)

PMID:29157612 SUPPORT Human Clinical

"TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."

Names reticulin fibrosis as one of the five defining TAFRO features.

Cardiovascular 2

Generalized Lymphadenopathy HP:0008940

Multiple enlarged lymph node regions, which is a required criterion for the diagnosis. Lymphadenopathy in iMCD-TAFRO is characteristically small-volume, so node size does not track disease severity.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."

Establishes the multiple-region criterion that makes this disease multicentric and distinguishes it from the unicentric form.

Splenomegaly FREQUENT HP:0001744

48.2% in iMCD versus 89.2% in HHV8+ MCD by meta-analysis; 72% at diagnosis in the ACCELERATE iMCD cohort.

Show evidence (2 references)

DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical

"patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"

Meta-analysis quantifies splenomegaly frequencies at 48.2% in iMCD and 89.2% in HHV8+ MCD.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."

Independent registry frequency for splenomegaly at iMCD diagnosis.

Digestive 3

Anorexia HP:0002039

Loss of appetite is one of the 16 items on the validated MCD symptom score used in the siltuximab trial and the ACCELERATE registry.

Hepatomegaly FREQUENT HP:0002240

Present in 60% of iMCD patients at diagnosis in the ACCELERATE registry.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."

Gives the hepatomegaly frequency at iMCD diagnosis.

Ascites HP:0001541

Component of the anasarca that hallmarks iMCD-TAFRO. Paracentesis was required by 46% of the ACCELERATE iMCD cohort.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."

Anasarca (which includes ascites) is identified as a hallmark feature of iMCD-TAFRO.

Genitourinary 3

Renal Dysfunction FREQUENT Renal insufficiency HP:0000083

Renal dysfunction/reticulin fibrosis is the "R" of iMCD-TAFRO; component of the defining TAFRO pentad. Renal dysfunction was reported in 36.9% of iMCD versus 17.4% of HHV8+ MCD by meta-analysis, and 26.5% of the ACCELERATE iMCD cohort required dialysis.

Show evidence (2 references)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."

Renal dysfunction/reticulin fibrosis is codified as the "R" component of the iMCD-TAFRO pentad.

DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical

"Renal dysfunction was significantly more common in patients with iMCD than in patients with HHV8+ MCD before adjustment (36.9% vs 17.4%; P = .04; adjusted P = .1)."

Quantifies the iMCD/HHV8+ difference in renal dysfunction, and records that the difference did not survive multiplicity adjustment.

Acute Renal Failure Acute kidney injury HP:0001919

The most common iMCD-related morbidity arising after diagnosis, affecting 48% of the ACCELERATE cohort. It occurred in both TAFRO and NOS patients.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Following the iMCD diagnosis, 48% (n=49) of the cohort developed acute renal failure"

Quantifies acute renal failure as the leading post-diagnosis morbidity.

Proteinuria HP:0000093

Reflects the membranoproliferative glomerulonephritis-like and thrombotic microangiopathic glomerular injury reported on renal biopsy.

Show evidence (1 reference)

PMID:34208103 SUPPORT Human Clinical

"Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy."

Establishes the glomerular lesions underlying proteinuria in this setting.

Metabolism 6

Fever FREQUENT Recurrent fever HP:0001954

Constitutional symptoms including fever were present in 46.6% of iMCD patients in a 1,998-patient meta-analysis - substantially less than the 98.6% seen in HHV-8-associated disease. Fever, or an elevated C-reactive protein in its place, is one of the five defining TAFRO features.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2024013548 SUPPORT INDIRECT Human Clinical

"patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"

Meta-analysis quantifies constitutional symptoms (including fever) as substantially more frequent in HHV8+ MCD than iMCD.

Hypoalbuminemia VERY_FREQUENT HP:0003073

Present in 79.4% of iMCD patients at diagnosis (median albumin 2.2 g/dL). Hypoalbuminemia is a minor criterion in the international iMCD diagnostic criteria and contributes to the third-space fluid accumulation.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"

Gives the hypoalbuminemia frequency at diagnosis in the same adjudicated iMCD cohort.

Elevated C-Reactive Protein Elevated circulating C-reactive protein concentration HP:0011227

Elevated CRP is the "F" of TAFRO in the CDCN formulation (fever/elevated C-reactive protein) and a minor criterion for iMCD. It is the routine marker used to follow disease activity and treatment response.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical

"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"

Post hoc analysis of the siltuximab trial confirms elevated CRP as one of the tracked abnormalities and places it early in the normalization sequence.

Elevated Erythrocyte Sedimentation Rate HP:0003565

Pleural Effusion HP:0002202

Component of the anasarca of iMCD-TAFRO.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."

Fluid retention, of which pleural effusion is a component, was the most frequent clinical abnormality at iMCD diagnosis.

Generalized Edema (Anasarca) HP:0000969

Generalized edema/anasarca is a hallmark of iMCD-TAFRO. Fluid retention was present in 84% of iMCD patients at diagnosis in the ACCELERATE registry.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."

Anasarca is identified as a hallmark feature of iMCD-TAFRO.

Constitutional 2

Night Sweats HP:0030166

Fatigue HP:0012378

Growth 1

Weight Loss HP:0001824

🧬

Genetic Associations

1

NCOA4

Gene: NCOA4 hgnc:7671 relationship_type: SOMATIC_DRIVER variant_origin: SOMATIC

Show evidence (1 reference)

PMID:33804823 SUPPORT Human Clinical

"specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"

Gives the recurrence frequency of NCOA4 L261F in iMCD.

💊

Medical Actions

6

Siltuximab

Action: anti-IL-6 monoclonal antibody therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: siltuximab NCIT:C61084

Platform: Monoclonal antibody

Anti-IL-6 monoclonal antibody. FDA-approved first-line therapy across all iMCD subtypes (TAFRO, IPL, NOS). Directly binds and neutralizes human IL-6. Durable tumor and symptomatic response occurred in 34% of treated patients in the registration trial, and progression-free survival was significantly prolonged. It is also recommended for unresectable UCD with an inflammatory syndrome. Despite this it reached only 8.7% of US iMCD patients in a claims analysis.

Mechanism Target:

INHIBITS IL-6 Overproduction — Neutralizes circulating human IL-6 before it engages gp130.

Show evidence (1 reference)

PMID:25042199 SUPPORT Human Clinical

"Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6."

States the target of the antibody and the rationale for blocking it.

INHIBITS CXCL13 Chemokine Axis Elevation — Serum CXCL13 falls by day 8 in responders, and a 17% fall predicts later response, so CXCL13 is a downstream pharmacodynamic readout of IL-6 blockade.

Show evidence (1 reference)

PMID:36433996 SUPPORT Human Clinical

"Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points."

Demonstrates the pharmacodynamic effect on this node.

Show evidence (5 references)

NCIT:C61084 SUPPORT Other

"Siltuximab | Accepted_Therapeutic_Use_For | - | - | multicentric Castleman's disease (MCD)"

NCI Thesaurus asserts accepted therapeutic use of siltuximab for multicentric Castleman disease.

DOI:10.1002/art.43269 SUPPORT Human Clinical

"The first‐line therapy for all subtypes of iMCD is siltuximab, an IL‐6 antagonist."

Establishes siltuximab as the cross-iMCD first-line therapy regardless of TAFRO/IPL/NOS subtyping.

PMID:25042199 SUPPORT Human Clinical

"Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012)."

The randomised placebo-controlled result, which is also the source of the 34% response rate quoted in the description.

+ 2 more references

Tocilizumab

Action: anti-IL-6 receptor monoclonal antibody therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: tocilizumab NCIT:C84217

Platform: Monoclonal antibody

Anti-IL-6-receptor monoclonal antibody. Approved in Japan for MCD; recommended internationally as alternative when siltuximab is unavailable.

Mechanism Target:

INHIBITS JAK-STAT3 Signaling Activation — Blocks the IL-6 receptor, preventing gp130-dependent JAK-STAT3 activation.

Show evidence (1 reference)

PMID:30181172 SUPPORT Human Clinical

"The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD."

Establishes tocilizumab as the substitute first-line agent where siltuximab is unavailable.

Corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Given with anti-IL-6 therapy as part of preferred first-line iMCD treatment. Corticosteroid monotherapy is explicitly not the recommended approach - in a US claims analysis 39% of iMCD patients received corticosteroid monotherapy while only 9.8% received IL-6-targeted therapy, which the authors identify as a major unmet treatment need.

Show evidence (2 references)

PMID:30181172 SUPPORT Human Clinical

"The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD."

Places corticosteroids as an adjunct to anti-IL-6 therapy rather than a standalone treatment.

DOI:10.1182/bloodadvances.2021004441 SUPPORT Human Clinical

"Among patients with iMCD, 39% received corticosteroid monotherapy, 33.1% received no iMCD-directed treatment, and 9.8% received interleukin-6 (IL-6)–targeted therapy with tocilizumab or siltuximab."

Quantifies the real-world over-reliance on corticosteroid monotherapy described here.

Combination Cytotoxic Chemotherapy

Action: chemotherapy Ontology label: Chemotherapy NCIT:C15632

Platform: Small molecule

Adjuvant multiagent cytotoxic chemotherapy is recommended for the most severe iMCD, and for severe disease that fails first-line IL-6 blockade. In iMCD-IPL specifically, myeloma-like and IL-6-blocking regimens gave higher response rates and longer time to next treatment than lymphoma-like regimens, so regimen choice should follow the subtype.

Show evidence (2 references)

PMID:30181172 SUPPORT Human Clinical

"In the most severe cases, adjuvant combination chemotherapy is recommended."

The guideline statement placing chemotherapy in severe iMCD.

PMID:38356434 SUPPORT Human Clinical

"Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment."

Supports the subtype-dependent regimen choice described here.

Sirolimus

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

Platform: Small molecule

mTOR inhibitor for anti-IL-6-refractory iMCD, with a mechanistic rationale from PI3K/AKT/mTOR pathway activation in refractory iMCD-TAFRO. In the three-patient index series sirolimus attenuated CD8+ T cell activation, lowered VEGF-A, and produced remissions of 66, 19, and 19 months. A single-arm Phase II trial (NCT03933904) is testing it prospectively.

Mechanism Target:

INHIBITS PI3K/AKT/mTOR Pathway Activation — Direct mTOR inhibition, the mechanism this treatment was selected for.

Show evidence (1 reference)

PMID:31408438 SUPPORT Human Clinical

"Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."

Demonstrates the pharmacodynamic effect on the targeted pathway.

Show evidence (2 references)

PMID:31408438 SUPPORT Human Clinical

"Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months."

Gives the clinical responses in the index series.

PMID:31408438 SUPPORT Human Clinical

"Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904)."

Links the mechanism to the registered prospective trial.

Ruxolitinib

Action: Pharmacotherapy NCIT:C15986

Agent: ruxolitinib CHEBI:66919

Platform: Small molecule

JAK1/2 inhibitor under investigation as second-line therapy in iMCD patients refractory or intolerant to anti-IL-6 therapy; multicenter Phase II trial NCT07085039 enrolling since 2025. Acting on JAK rather than on IL-6 itself would in principle cover signaling driven by other gp130 ligands.

Mechanism Target:

INHIBITS JAK-STAT3 Signaling Activation — Inhibits JAK1/2 downstream of gp130, the shared node for IL-6, vIL-6, and other gp130-family cytokines.

🔬

Biochemical Markers

7

Interleukin-6 (IL-6) (Elevated)

Context: Markedly elevated in MCD (both HHV-8+ and iMCD); typically normal in UCD. IL-6 levels correlate with disease activity. The producing cell differs by iMCD subtype - plasma cells in IPL, vascular endothelium in TAFRO - and in TAFRO the serum elevation may be a downstream consequence of the cytokine storm rather than its driver. There is no validated diagnostic serum biomarker for iMCD, and serum IL-6 is not one.

Show evidence (1 reference)

PMID:40931874 SUPPORT Human Clinical

"In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."

Supports the caveat that serum IL-6 may be secondary in the TAFRO subtype.

C-Reactive Protein (CRP) (Elevated)

Context: Acute-phase reactant driven by IL-6 signaling. Elevated in MCD; useful biomarker for disease activity and prognosis, and a component of the fever/elevated-CRP criterion in the CDCN TAFRO formulation.

C-X-C Motif Chemokine Ligand 13 (CXCL13) (Elevated)

Context: Of 1,178 serum proteins compared across 88 iMCD patients, 60 disease controls, and 42 healthy participants, CXCL13 was the most prominently up-regulated protein in iMCD. A 17% fall by day 8 of siltuximab predicts later response, making CXCL13 the best-supported pharmacodynamic marker in the disease. It has not been established as a diagnostic marker.

Show evidence (2 references)

PMID:36433996 SUPPORT Human Clinical

"C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD."

Establishes CXCL13 as the top differentially elevated serum protein in iMCD.

PMID:36433996 SUPPORT Human Clinical

"Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points."

Supports the predictive-response use described here.

Vascular Endothelial Growth Factor A (VEGF-A) (Elevated)

Context: Elevated in MCD and central to the POEMS phenotype. In IL-6-blockade refractory iMCD-TAFRO, VEGF-A was elevated alongside PI3K/AKT/mTOR pathway activity and fell on sirolimus, alongside clinical response. Lymph node stromal cells (perivascular and T-zone reticular cells, and follicular dendritic cells) are the tissue source.

Show evidence (1 reference)

PMID:31408438 SUPPORT Human Clinical

"Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."

Supports both the elevation of VEGF-A and its pharmacological reversibility.

Serum Albumin (Decreased)

Context: Hypoalbuminemia is a minor criterion for iMCD and one of the laboratory abnormalities tracked for treatment response. Median albumin at iMCD diagnosis in the ACCELERATE registry was 2.2 g/dL.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"

Quantifies hypoalbuminemia at diagnosis in an adjudicated iMCD cohort.

Serum Immunoglobulin G (Elevated)

Context: Polyclonal IgG elevation is characteristic of iMCD-IPL and iMCD-NOS and is the last abnormality to normalize on siltuximab. It is normal or low in iMCD-TAFRO, which is a practical way of separating the subtypes at presentation.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical

"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"

Places elevated IgG last in the normalization sequence on siltuximab.

Serum Fibrinogen (Elevated)

Context: Hyperfibrinogenemia is an acute-phase abnormality that normalizes late on siltuximab, after the symptomatic and lymph node responses.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2022007112 SUPPORT Human Clinical

"the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"

Identifies hyperfibrinogenemia as a tracked abnormality with a late normalization time.

🔬

Diagnosis

5

Excisional lymph node biopsy

Diagnosis requires characteristic lymph node histopathology; there is no diagnostic serum biomarker. Excisional biopsy is preferred over core or fine needle sampling because architectural features - regressed or hyperplastic germinal centers, mantle-zone onion-skinning, penetrating vessels, interfollicular plasmacytosis - cannot be assessed on a fragment. Histology alone is not sufficient: reactive Castleman-like changes occur in autoimmune disease, lymphoma, and infection, so the findings must be combined with clinical and laboratory data.

lymph node biopsy NCIT:C51900

Results: Angiofollicular lymph node hyperplasia of hyaline-vascular, plasma-cell, or mixed type.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."

States directly why histology alone cannot establish the diagnosis.

International consensus diagnostic criteria for iMCD

The CDCN evidence-based criteria, derived from 244 clinical cases and 88 tissue samples, require multicentric lymphadenopathy with the defined histopathology, at least two of eleven clinical or laboratory minor criteria, and exclusion of the infectious, malignant, and autoimmune conditions that mimic iMCD - in particular HHV-8-associated MCD, POEMS syndrome, lymphoma, and IgG4-related disease.

Results: Diagnosis of iMCD when both major criteria, at least two minor criteria, and all exclusions are satisfied.

Show evidence (2 references)

DOI:10.1182/blood-2016-10-746933 SUPPORT Human Clinical

"The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics."

States the three-part structure of the criteria described here.

DOI:10.1182/blood-2016-10-746933 SUPPORT Human Clinical

"An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples."

Establishes the evidence base behind the criteria.

Bone marrow biopsy

Performed in suspected iMCD-TAFRO to document reticulin fibrosis with megakaryocytic hyperplasia and to exclude a primary marrow disorder as the cause of the cytopenias. TAFRO also has its own Japanese diagnostic criteria (Iwaki, and the Masaki 2019 update), separate from the CDCN iMCD criteria, in which thrombocytopenia is a major criterion; the two criteria sets are not identical and a case can satisfy one without the other.

bone marrow biopsy NCIT:C15193

Results: Reticulin fibrosis, often with megakaryocytic hyperplasia.

Show evidence (2 references)

PMID:34208103 SUPPORT Human Clinical

"the presence of thrombocytopenia fulfills one of the major diagnostic criteria"

In the source sentence this refers to the Iwaki and Masaki TAFRO definitions, establishing that TAFRO has its own diagnostic criteria in which thrombocytopenia is a major criterion. The numeric citation markers in the original sentence are omitted from the quote because the reference validator strips bracketed spans before matching.

PMID:29157612 SUPPORT Human Clinical

"Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular-type CD."

Supports the exclusion-focused role of tissue sampling in TAFRO. Note the quote refers to lymph node biopsy; the marrow finding is the "R" of the TAFRO acronym.

Cross-sectional and FDG-PET imaging

CT of the neck, chest, abdomen, and pelvis, or FDG-PET/CT, establishes whether disease is unicentric or multicentric - the single most consequential branch point in management, since unicentric disease is surgically curable. Imaging also selects the biopsy target and, in UCD, determines resectability.

positron emission tomography NCIT:C17007

Results: A single involved nodal region indicates UCD; multiple involved regions indicate MCD.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."

The distinction that imaging is performed to establish.

Serum IgG4 to IgG ratio

Used to separate iMCD-IPL from IgG4-related disease when the lymph node contains numerous IgG4-positive plasma cells. Absolute serum IgG4 does not discriminate; the IgG4/IgG ratio does, with a reported cut-off of 19.0%.

Results: A serum IgG4/IgG ratio above roughly 19% favors IgG4-related disease over iMCD-IPL.

Show evidence (1 reference)

PMID:38378248 SUPPORT Human Clinical

"However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%."

Gives the discriminating test and threshold.

🩻

Imaging Findings

2

FDG-Avid Multicentric Lymphadenopathy

FDG-PET/CT demonstrates avid lymphadenopathy in multiple nodal stations in MCD and is used both to establish multicentricity and to select the node to biopsy. Uptake is typically moderate, and marked focal uptake in a single node raises concern for lymphomatous transformation rather than Castleman disease itself.

Pet Diagnostic

Serosal Effusions and Organomegaly

Cross-sectional imaging in iMCD-TAFRO shows pleural effusions, ascites, generalized subcutaneous edema, and hepatosplenomegaly, often with only modest lymph node enlargement. The imaging pattern of severe third-spacing with small nodes is a recognizable TAFRO signature.

Ct iMCD-TAFRO

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."

Establishes the combination of anasarca with small-volume lymphadenopathy that this imaging pattern reflects.

📈

Progression

5

Presentation and diagnostic delay

Diagnosis rests on non-specific clinical features plus characteristic lymph node histopathology, with no diagnostic serum biomarker and diagnostic criteria that did not exist before 2017, so underdiagnosis is expected. Patients are hospitalized a median of 5 days in the 6 months before the diagnostic biopsy. iMCD occurs at all ages; in the ACCELERATE cohort the youngest patient was diagnosed at 1.8 years and the oldest at 74.4, with a median of 35.3 years.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Notably, we found iMCD in individuals of all ages, with the youngest patient in the cohort diagnosed at 1.8 years and the oldest at 74.4."

Gives the age range at diagnosis quoted here.

Severe presentation at diagnosis

Most patients are already severely ill when diagnosed: 77% met the guideline definition of severe iMCD at diagnosis, rising to 93% of TAFRO patients and still 51% of NOS patients. Severity is bimodal by age, with patients under 30 and over 60 more likely to present severely.

Show evidence (2 references)

PMID:38205523 SUPPORT Human Clinical

"Of the 100 patients with sufficient information to determine disease severity at diagnosis, 77 (77%) initially presented with severe disease."

Quantifies severe presentation at diagnosis.

PMID:38205523 SUPPORT Human Clinical

"Patients <30 and patients >60 years old were more likely to have severe disease (94.6% and 90.0%, respectively) as compared to patients between 30 and 60 years old (62.2%)"

Supports the bimodal age-severity pattern described here.

Acute multiorgan failure (TAFRO)

iMCD-TAFRO

TAFRO patients spend a median of 36 days in hospital in the year surrounding diagnosis (versus 0 for NOS), and 27% require dialysis and 17% mechanical ventilation at some point. Most iMCD deaths occur here: of eight deaths in the ACCELERATE cohort, six were TAFRO patients and five of those died within two years of diagnosis.

Show evidence (2 references)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO."

Quantifies the life-sustaining interventions required in this phase.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"Of the eight deceased patients in this cohort, six had TAFRO and five of these TAFRO patients died within 2 years of diagnosis."

Establishes that mortality concentrates in the TAFRO subtype and early after diagnosis.

Chronic relapsing-remitting course

iMCD-NOS

NOS patients are hospitalized much less than TAFRO patients but spend a median 52.3% of their post-onset follow-up in active flare, versus 18.9% for TAFRO. A milder acute presentation is therefore not a lower long-term symptom burden, just a differently distributed one.

Show evidence (1 reference)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004)."

Quantifies the chronic flare burden that characterizes this phase.

Long-term survival

Across the whole disease, 2-, 5-, and 10-year overall survival in a 113-patient two-centre series was 92%, 76%, and 59%. Survival separates sharply by category: 5-year survival was 91% for UCD, 90% for MCD with the osteosclerotic POEMS variant, 65% for MCD without POEMS, and 27% for MCD with POEMS but without osteosclerotic lesions.

Show evidence (2 references)

PMID:22791417 SUPPORT Human Clinical

"For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively."

Gives the overall survival figures quoted here.

PMID:22791417 SUPPORT Human Clinical

"(1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%)."

Gives the category-specific 5-year survival stratification.

📊

Prevalence

2

United States

Annual Incidence 0.34 per 100,000 (0.14–0.92) <1 in 1,000,000 per year

iMCD only. Estimated from 30.7 million enrollees using the D47.Z2 CD-specific ICD-10 code plus at least two claims codes matching the international iMCD minor criteria. 3.4 cases per million per year (95% CI 1.4-9.2).

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2021004441 SUPPORT Human Clinical

"we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively"

Source for both the incidence recorded here and the prevalence recorded below.

United States

Point Prevalence 0.69 per 100,000 (0.37–1.33) <1 in 1,000,000

iMCD only. 6.9 cases per million (95% CI 3.7-13.3) in the same claims-based analysis.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2021004441 SUPPORT Human Clinical

"we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively"

The prevalence estimate converted to the normalized rate above.

⚖️

Clinical Burden

Variable

Burden spans nearly the whole available range depending on subtype. iMCD-TAFRO is a life-threatening cytokine storm: 93% of patients present with severe disease, 27% require dialysis and 17% mechanical ventilation, median hospitalization in the year around diagnosis is 36 days, and most deaths occur within two years. iMCD-NOS sits between them, with less acute intensity but a majority of follow-up time spent in active flare and quality of life inversely tracking symptom score years after diagnosis. Access to effective therapy is itself part of the burden: only 8.7% of US iMCD patients in a claims analysis received siltuximab, the only approved and guideline-recommended first-line drug, while 33% received no iMCD-directed treatment at all.

Show evidence (4 references)

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO."

Supports the organ-support burden at the severe end of the range.

DOI:10.3324/haematol.2023.283603 SUPPORT Human Clinical

"QOL scores were inversely correlated with MCD symptom score (R=-0.69; P<0.001)"

Supports the persistent quality-of-life impact measured a median 3.9 years after diagnosis.

DOI:10.1182/bloodadvances.2021004441 SUPPORT Human Clinical

"Siltuximab, which is the only US Food and Drug Administration–approved treatment and established first-line treatment recommendation, was used in only 8.7% of patients with iMCD."

Supports the treatment-access component of the burden described above.

+ 1 more reference

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Idiopathic Multicentric Castleman Disease:

HHV-8-associated multicentric Castleman disease

Overlapping Features Not a different disease from Castleman disease but the branch point within it, and the exclusion that defines iMCD. Distinguished by HHV-8 LANA-1 immunohistochemistry on the node, usually with HIV co-infection, higher rates of constitutional symptoms and splenomegaly, and a different first-line therapy (rituximab rather than siltuximab).

Distinguishing Features

HHV-8 LANA-1-positive plasmablasts on lymph node immunohistochemistry; detectable plasma KSHV viral load; usual HIV co-infection.

Show evidence (1 reference)

DOI:10.1182/bloodadvances.2024013548 SUPPORT Human Clinical

"patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"

Quantifies the clinical features that differ between the two subtypes.

POEMS syndrome

Overlapping Features A clonal plasma cell disorder that can present with Castleman-like lymphadenopathy. Distinguished by peripheral neuropathy, a monoclonal (usually lambda-restricted) paraprotein, osteosclerotic bone lesions, and endocrinopathy - none of which belong to iMCD, where the immunoglobulin elevation is polyclonal. The distinction changes prognosis sharply: MCD with non-osteosclerotic POEMS had 27% 5-year survival versus 65% for MCD without POEMS.

Distinguishing Features

Monoclonal plasma cell disorder, peripheral polyneuropathy, osteosclerotic lesions, endocrinopathy.

Show evidence (1 reference)

PMID:22791417 SUPPORT Human Clinical

"Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome."

Establishes how often the POEMS distinction actually has to be made in an MCD population.

Lymphoma

Overlapping Features Hodgkin and non-Hodgkin lymphoma both produce lymphadenopathy with systemic symptoms and can generate reactive Castleman-like nodal changes; iMCD-NOS in particular mimics indolent lymphoma. Lymphoma is a formal exclusion in the iMCD diagnostic criteria. The relationship also runs the other way in HHV-8+ MCD, where concurrent KSHV-driven lymphoma occurs at 28 cases per 1,000 patient-years.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."

Names lymphoma among the conditions producing Castleman-like reactive nodes.

Hemophagocytic lymphohistiocytosis MONDO:0015540

Overlapping Features iMCD-TAFRO presents as an acute cytokine storm with fever, cytopenias, organomegaly, and multiorgan failure that is clinically close to HLH or to sepsis. Both require urgent treatment and the therapies differ, so the distinction is made on ferritin, soluble IL-2 receptor, hemophagocytosis on marrow, HLH genetic and trigger workup, and above all the lymph node histopathology.

Distinguishing Features

Lymph node biopsy showing Castleman histopathology; absence of the ferritin and hemophagocytosis profile typical of HLH.

Show evidence (1 reference)

DOI:10.1002/art.43269 SUPPORT Human Clinical

"Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."

Names HLH and sepsis as the clinical mimics of iMCD-TAFRO.

Systemic lupus erythematosus and other connective tissue diseases MONDO:0007915

Overlapping Features Autoimmune disease produces lymphadenopathy with Castleman-like reactive nodal changes and is a formal exclusion for iMCD. The overlap is not only diagnostic: 47% of iMCD patients carry at least one CTD-associated autoantibody versus 17% of healthy controls, which is part of why an autoimmune etiology for iMCD remains under active consideration.

Show evidence (1 reference)

PMID:40181993 SUPPORT Human Clinical

"For example, connective tissue disorders (CTDs) and iMCD share many clinical features, and autoantibodies have been anecdotally reported in individual iMCD patients."

States the clinical and serologic overlap that makes this differential difficult.

📊

Related Datasets

4

Common Connective Tissue Disorder and Anti-Cytokine Autoantibodies are Enriched in Idiopathic Multicentric Castleman Disease Patients [CTD Array version 3] geo:GSE290549

We measued IgG autoantibodies associated with Connective Tissue Diseases (CTDs) and Anti-Cytokine Antibodies (ACA) in idiopathic Multicentric Castleman Disease (iMCD) patients and healthy controls who received the BNT162b2 vaccine.

human PROTEOMICS n=151

PMID:40181993

Identified by GEO DataSets index search for Castleman Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values. This is the autoantibody array underlying the autoimmune_etiology hypothesis group.

Whole-genome sequencing of twins with Castleman disease and an unaffected sibling. ega:EGAS00001007388

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Single cell landscape of Multicentric Castleman Disease in monozygotic twins ega:EGAS00001007390

human SINGLE CELL RNA SEQ

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

WGS data of an individual with Unicentric Castleman Disease ega:EGAS00001007557

human WGS

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

🔬

Clinical Trials

2

NCT03933904 PHASE_II UNKNOWN

A Phase II, single-arm, open-label, multi-center study of sirolimus in previously-treated idiopathic multicentric Castleman disease.

Show evidence (1 reference)

clinicaltrials:NCT03933904 SUPPORT Other

"The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease."

ClinicalTrials.gov-listed Phase II trial evaluating sirolimus in previously-treated iMCD.

NCT07085039 PHASE_II RECRUITING

A Phase II, single-arm, open-label, multi-center study of ruxolitinib in adults with iMCD that has not improved with siltuximab or tocilizumab, or who cannot take those medications.

Show evidence (1 reference)

clinicaltrials:NCT07085039 SUPPORT Other

"The research study is being done to look at the effects of ruxolitinib in adults with idiopathic Multicentric Castleman Disease (iMCD) that has not gotten better from taking siltuximab or tocilizumab, or who cannot take those medications."

ClinicalTrials.gov-listed Phase II trial evaluating ruxolitinib as second-line therapy in iMCD.

{ }

Source YAML

click to show

name: Idiopathic Multicentric Castleman Disease
creation_date: "2026-08-26T00:00:00Z"
category: Complex
disease_term:
  preferred_term: idiopathic multicentric Castleman disease
  term:
    id: MONDO:0035838
    label: idiopathic multicentric Castleman disease
parents:
- Castleman Disease
- Lymphoproliferative Disease
synonyms:
- iMCD
- HHV-8-negative multicentric Castleman disease
- Human herpesvirus-8-negative multicentric Castleman disease
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018702
      label: Castleman-Kojima disease
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    notes: >-
      TAFRO syndrome / Castleman-Kojima disease, curated here as the
      "iMCD-TAFRO" subtype rather than as a separate entry.
references:
- reference: DOI:10.1038/s41572-021-00317-7
  title: Castleman disease
- reference: DOI:10.1016/j.bvth.2024.100006
  title: Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy
- reference: DOI:10.1016/j.hoc.2017.09.001
  title: Epidemiology of Castleman Disease
- reference: DOI:10.1182/asheducation-2018.1.318
  title: Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
- reference: DOI:10.14740/jh1343
  title: "Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience"
- reference: DOI:10.7759/cureus.73156
  title: "The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis"
description: >-
  Idiopathic multicentric Castleman disease (iMCD) is the HHV-8-negative
  multicentric form, and the one whose cause is unknown. It presents with
  multicentric lymphadenopathy, characteristic angiofollicular lymph node
  histopathology, cytopenias, and a systemic inflammatory syndrome that can
  progress to multiorgan failure. Diagnosis is by the international consensus
  criteria and is a diagnosis of exclusion: there is no diagnostic serum
  biomarker, and infection, malignancy and autoimmune disease - all of which can
  produce Castleman-like nodal changes - must be ruled out first.
  Three clinical subtypes with materially different courses are recognized:
  iMCD-TAFRO, an acute cytokine storm with thrombocytopenia, anasarca, renal
  dysfunction and marrow fibrosis; iMCD-IPL, an indolent form with polyclonal
  hypergammaglobulinemia and thrombocytosis that closely mimics IgG4-related
  disease; and iMCD-NOS. First-line therapy across all three is the anti-IL-6
  antibody siltuximab, the only approved drug, but it produces a durable response
  in only about a third of patients and what drives the remainder is not known.
  An emerging framework proposes immune-stromal dysregulation - activated
  follicular dendritic, T-zone and perivascular reticular cells supplying VEGF
  and IL-6 - alongside molecular endotypes defined by IL-6, CXCL13, TNF and
  PI3K/AKT/mTOR pathway activation. That framework is recorded here as EMERGING
  rather than as settled pathophysiology, and the absence of any validated
  animal or cell-culture model is the reason it cannot yet be tested causally.
mechanistic_hypotheses:
- hypothesis_group_id: immune_stromal_dysregulation
  hypothesis_label: Immune-Stromal Dysregulation and Molecular Endotypes
  status: EMERGING
  description: >-
    Molecular endotypes defined by differential pathway activation (IL-6 vs.
    CXCL13 vs. TNF vs. PI3K/AKT/mTOR signaling) underlie clinical and
    therapeutic heterogeneity in iMCD. Single-cell transcriptomics and spatial
    biology identify immune-stromal dysregulation involving fibroblastic
    reticular cells and endothelial dysfunction as core mechanistic components.
  applies_to_subtypes:
  - iMCD-TAFRO
  - iMCD-IPL
  - iMCD-NOS
  evidence:
  - reference: PPR:PPR1286884
    reference_title: "Castleman Disease: Updated Pathophysiology, Diagnostic Approach and Therapeutic Strategies"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recent discoveries have transformed Castleman disease from a
      clinicopathological entity largely defined by interleukin-6 excess into a
      complex disorder of immune–stromal dysregulation. Single-cell
      transcriptomics and spatial biology have identified fibroblastic reticular
      cells, endothelial dysfunction and dysregulated immune-cell communication
      as central pathogenic components.
    explanation: >-
      Narrative review synthesizing recent molecular and immunological
      discoveries, establishing immune-stromal dysregulation as an organizing
      framework for contemporary pathophysiology.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD shows increased stromal cells that form unique microenvironments."
    explanation: >-
      Spatial proteomic and transcriptomic mapping of 22 Castleman lymph nodes
      provides the primary tissue evidence for a stromal-centred model.
- hypothesis_group_id: stromal_cytokine_source
  hypothesis_label: Lymph Node Stromal Cells as the Source of IL-6 and VEGF
  status: EMERGING
  description: >-
    The cells that oversupply IL-6 and VEGF in iMCD are lymph node stromal cells
    - PDGFRA+ T-zone reticular cells and ACTA2+ perivascular reticular cells,
    with CXCL13+ follicular dendritic cells contributing inside follicles -
    rather than the hematopoietic compartment that earlier immunohistochemical
    work implicated. The T-zone and perivascular subsets are the ones that expand
    in multicentric disease, in contrast to the B-zone reticular cells that
    dominate the unicentric form. The evidence is a single spatial multi-omic
    study of 22 cases with no functional perturbation, so the causal direction
    (stromal activation driving the cytokine storm versus responding to it) is
    not established.
  applies_to_subtypes:
  - iMCD-TAFRO
  - iMCD-IPL
  - iMCD-NOS
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
    explanation: >-
      Establishes that distinct stromal subsets dominate the unicentric and
      multicentric forms, the core claim of this hypothesis group.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
    explanation: >-
      States the prior interpretation this hypothesis displaces: follicular
      dendritic cells as passive remnants rather than activated drivers.
- hypothesis_group_id: autoimmune_etiology
  hypothesis_label: Autoantibody-Driven Etiology of iMCD
  status: EMERGING
  description: >-
    iMCD is initiated by autoimmunity, with autoantibodies against connective
    tissue disease antigens and against cytokines themselves driving the
    hypercytokinemia. Supporting observations are an enrichment of
    CTD-associated and anti-cytokine IgG autoantibodies in iMCD sera relative to
    healthy controls, and the long-standing clinical overlap between iMCD and
    connective tissue disease. The autoantibodies detected are heterogeneous
    rather than a shared specificity, and no pathogenic mechanism has been
    demonstrated, so this remains one of several competing candidate etiologies.
  applies_to_subtypes:
  - iMCD-TAFRO
  - iMCD-IPL
  - iMCD-NOS
  evidence:
  - reference: PMID:40181993
    reference_title: "Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgG autoantibodies binding autoantigens associated with common CTDs and cytokines are elevated in iMCD patients compared to HC, suggesting that autoimmunity may be involved in iMCD pathogenesis."
    explanation: >-
      The authors state the autoimmune hypothesis as a suggestion drawn from a
      case-control serology comparison, matching the EMERGING status recorded here.
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus."
    explanation: >-
      Places the autoantibody mechanism as one of three explicitly competing
      candidate drivers, which is why this is recorded as EMERGING rather than canonical.
- hypothesis_group_id: clonal_stromal_origin
  hypothesis_label: Clonal Somatic Mutation as a Driver of iMCD
  status: EMERGING
  description: >-
    Recurrent somatic mutations - notably NCOA4 L261F in about 23% of iMCD, with
    chromatin-organization and methylation abnormalities clustering in this form
    - make iMCD at least partly a clonal process rather than a purely reactive
    one. The alleles are recurrent and enriched, but they are present in a
    minority of cases, the functional consequence of NCOA4 L261F in this disease
    has not been characterized, no functional model has shown that it initiates
    the lymph node lesion, and its cell of origin within the node is unresolved.
  applies_to_subtypes:
  - iMCD-TAFRO
  - iMCD-IPL
  - iMCD-NOS
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: >-
      Quantifies the recurrent somatic alleles this hypothesis rests on, and the
      minority frequencies that keep it from being canonical.
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process."
    explanation: >-
      The same review states that the mechanistic significance of these genetic
      findings is not established, limiting the hypothesis to EMERGING status.
- hypothesis_group_id: il6_independent_mtor
  hypothesis_label: PI3K/AKT/mTOR Signaling in IL-6-Blockade-Refractory iMCD
  status: EMERGING
  description: >-
    In the substantial fraction of iMCD patients who do not respond to anti-IL-6
    therapy, the disease is driven by PI3K/AKT/mTOR signaling with CD8+ T cell
    activation and VEGF-A elevation rather than by IL-6 itself. The supporting
    evidence is a three-patient precision-medicine study in which mTOR pathway
    activity was elevated and sirolimus produced durable remissions; a
    prospective single-arm trial (NCT03933904) was designed to test it.
  applies_to_subtypes:
  - iMCD-TAFRO
  evidence:
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity."
    explanation: Reports the pathway activation on which this hypothesis rests.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically-targetable pathogenic process in IL-6-blockade refractory iMCD."
    explanation: >-
      The authors' own framing of the finding as a first identification in three
      patients rather than an established mechanism.
- hypothesis_group_id: subtype_specific_il6_source
  hypothesis_label: Subtype-Specific Cellular Source of IL-6
  status: EMERGING
  description: >-
    The cell producing IL-6 differs between iMCD subtypes, and this explains
    their divergent response to IL-6 blockade. In iMCD-IPL, plasma cells are the
    dominant IL-6 source under XBP1-driven endoplasmic reticulum stress and
    plasma cell differentiation, consistent with the good response of IPL to
    siltuximab or tocilizumab. In iMCD-TAFRO, IL-6 comes predominantly from
    vascular endothelial cells, which would make the elevated serum IL-6 a
    secondary consequence of the cytokine storm rather than its driver. Evidence
    is tissue expression profiling without functional perturbation.
  applies_to_subtypes:
  - iMCD-IPL
  - iMCD-TAFRO
  evidence:
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO."
    explanation: The direct tissue observation of a subtype-specific IL-6 source.
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."
    explanation: >-
      States the strong form of the hypothesis - that IL-6 is secondary in TAFRO -
      in the authors' own hedged terms.
has_subtypes:
- name: iMCD-TAFRO
  display_name: iMCD with Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Organomegaly
  description: >-
    Acute, severe clinical subtype of iMCD presenting as a rapid-onset cytokine
    storm with thrombocytopenia, anasarca, fever, renal dysfunction or bone
    marrow reticulin fibrosis, and organomegaly, often with small-volume
    lymphadenopathy. Serum immunoglobulins are normal or low, distinguishing it
    from iMCD-IPL. It carries the highest requirement for dialysis, mechanical
    ventilation, and transfusion, and most iMCD deaths occur in this subtype.
  subtype_term:
    preferred_term: Castleman-Kojima disease
    term:
      id: MONDO:0018702
      label: Castleman-Kojima disease
  evidence:
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."
    explanation: >-
      Identifies the immunoglobulin-level contrast that separates TAFRO from the
      other iMCD subtypes.
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment."
    explanation: Establishes the aggressive course and the absence of a standard regimen.
- name: iMCD-IPL
  display_name: iMCD with Idiopathic Plasmacytic Lymphadenopathy
  description: >-
    Indolent clinical subtype of iMCD characterized by polyclonal
    hypergammaglobulinemia, thrombocytosis, plasmacytic or mixed lymph node
    histopathology, and anemia of inflammation. Despite a higher measured
    inflammatory state than other iMCD-NOS patients, survival is longer, and
    IL-6-blocking and myeloma-like regimens outperform lymphoma-like regimens.
    It is the subtype most often confused with IgG4-related disease. Whether it
    should be formally split out of iMCD-NOS is still contested; it is recorded
    here as a subtype because the international expert review and the largest
    cohort both treat it as one.
  evidence:
  - reference: PMID:38356434
    reference_title: "Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival."
    explanation: >-
      The 228-patient cohort quantifies the paradoxical combination of higher
      inflammation with better survival that defines this subtype.
  - reference: PMID:38356434
    reference_title: "Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL."
    explanation: Establishes that IPL accounts for roughly half of what is otherwise labeled iMCD-NOS.
- name: iMCD-NOS
  display_name: iMCD, Not Otherwise Specified
  description: >-
    iMCD that meets neither the TAFRO nor the IPL pattern. Clinically it often
    mimics indolent lymphoma or an autoimmune condition. In the ACCELERATE
    registry, NOS patients were hospitalized far less than TAFRO patients but
    spent a significantly greater proportion of their follow-up in active
    disease flare, so a milder acute presentation does not mean a lower
    long-term symptom burden.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Those who have iMCD not meeting criteria for TAFRO or IPL have iMCD‐NOS, which often mimics indolent lymphoma or autoimmune conditions."
    explanation: Defines iMCD-NOS as the residual category and names its usual clinical mimics.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004)."
    explanation: Quantifies the chronic flare burden of NOS relative to TAFRO.
pathophysiology:
- name: Unknown iMCD Initiating Process
  description: >-
    The event that starts idiopathic multicentric Castleman disease has not been
    identified. Three candidate processes have been proposed and none has been
    excluded: systemic inflammatory disease driven by autoantibodies or germline
    inflammatory gene variants; a paraneoplastic mechanism in which a clonal cell
    population ectopically secretes cytokine; and infection by a virus other than
    HHV-8. Viral-Track analysis of 22 UCD and 19 iMCD lymph nodes found no shared
    viral signature, which weighs against the third candidate without excluding a
    hit-and-run or non-transcribed agent. This node is deliberately kept in the
    graph as an explicit unknown so that everything downstream is not implicitly
    attributed to IL-6.
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that 1 or more of the following 3 candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus."
    explanation: Enumerates the three candidate initiating processes named in this node.
  - reference: DOI:10.1038/s41598-025-85193-x
    reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "These results suggest that active viral infection is unlikely to be a pathological driver of UCD or iMCD."
    explanation: >-
      Argues against the non-HHV-8 virus candidate specifically, leaving the
      initiating process unresolved.
  downstream:
  - target: Autoantibody-Mediated Immune Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - autoimmune_etiology
    description: >-
      Under the autoimmune candidate, the initiating process is loss of
      tolerance producing the autoantibody repertoire seen in iMCD sera.
  - target: Lymph Node Stromal Cell Activation and Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - immune_stromal_dysregulation
    - stromal_cytokine_source
    description: >-
      Whatever the trigger, the observed tissue consequence is activation and
      expansion of the lymph node stromal compartment.
- name: Somatic Stromal Cell Mutation
  description: >-
    Recurrent somatic mutations are found in the lesional tissue of both
    unicentric and idiopathic multicentric CD. PDGFRB N666S, an activating
    receptor tyrosine kinase allele, is present in about 10% of UCD, and NCOA4
    L261F in about 23% of iMCD. In paraneoplastic-pemphigus-associated UCD,
    whole-exome sequencing found IL6ST (encoding gp130) and PDGFRB as the most
    frequently mutated genes at 32% each, with IL6ST variants predicting worse
    overall survival. More broadly, MAPK and interleukin signaling pathway
    abnormalities cluster in UCD while chromatin-organization and methylation
    abnormalities cluster in iMCD. Whether these alleles initiate the lesion or
    accumulate within it is unresolved.
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  genetic_context:
    variant_origin: SOMATIC
    functional_impact_category: GAIN_OF_FUNCTION
    notes: >-
      PDGFRB N666S is an activating allele; IL6ST encodes the gp130 subunit
      shared by IL-6 and vIL-6 signaling. The functional consequence of NCOA4
      L261F in this disease has not been characterized.
  biological_processes:
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: Gives the recurrent alleles and their frequencies in each subtype.
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD."
    explanation: Supports the subtype-specific pathway clustering described in this node.
  - reference: PMID:37839777
    reference_title: "Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%)."
    explanation: >-
      Whole-exome sequencing of 37 PNP-associated UCD samples identifies the two
      recurrently mutated genes named in this node.
  downstream:
  - target: Lymph Node Stromal Cell Activation and Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - clonal_stromal_origin
    description: >-
      Under the clonal hypothesis, an activating stromal mutation is what makes
      the stromal compartment expand autonomously.
- name: Autoantibody-Mediated Immune Dysregulation
  description: >-
    IgG autoantibodies against connective tissue disease autoantigens are found
    in 47% of iMCD patients versus 17% of healthy controls, and anti-cytokine
    autoantibodies in 38% versus 10%. One sample showed receptor-blocking
    activity against interferon-omega. The autoantibodies are heterogeneous
    rather than a single shared specificity, and no pathogenic mechanism linking
    them to lymph node pathology has been shown, so this node records an
    association-level candidate mechanism rather than an established step.
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: Immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  evidence:
  - reference: PMID:40181993
    reference_title: "Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that an increased proportion of iMCD patients (47%) tested positive for at least one CTD-associated autoantibody compared to healthy controls (HC) (17%)."
    explanation: Quantifies the CTD autoantibody enrichment stated in this node.
  - reference: PMID:40181993
    reference_title: "Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ACAs were also detected in a greater proportion of iMCD patients (38%) compared to HC (10%)"
    explanation: Quantifies the anti-cytokine autoantibody enrichment stated in this node.
  downstream:
  - target: Lymph Node Stromal Cell Activation and Expansion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - autoimmune_etiology
    description: >-
      Proposed route by which loss of tolerance would produce chronic nodal
      immune activation. No intermediate step has been demonstrated.
- name: Lymph Node Stromal Cell Activation and Expansion
  description: >-
    Spatial proteomic and single-nuclei transcriptomic mapping shows that the
    non-lymphoid stromal compartment of the multicentric Castleman lymph node
    expands and forms microenvironments absent from reactive nodes. The subsets
    that expand here are PDGFRA+ T-zone reticular cells and ACTA2+ perivascular
    reticular cells, in contrast to the B-zone reticular cells that dominate the
    unicentric form. These stromal populations, not the hematopoietic
    compartment, carry the highest VEGFA and IL-6-module expression, and they
    activate JAK-STAT, TGF-beta, and MAPK programs. Plasma cells, plasmablasts,
    endothelium, lymphatics, monocytes and macrophages are also increased.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: T-zone reticular cell
    term:
      id: CL:0009105
      label: T cell zone reticular cell
  - preferred_term: B-zone reticular cell
    term:
      id: CL:0009104
      label: B cell zone reticular cell
  - preferred_term: Perivascular reticular cell
    term:
      id: CL:4033054
      label: perivascular cell
  - preferred_term: Fibroblastic reticular cell
    term:
      id: CL:0009101
      label: fibroblastic reticular cell
  biological_processes:
  - preferred_term: Extracellular matrix remodeling
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: MAPK cascade
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD shows increased stromal cells that form unique microenvironments."
    explanation: The primary observation of stromal expansion that this node records.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC)."
    explanation: Supports the subtype-specific stromal subset assignment described here.
  downstream:
  - target: Follicular Dendritic Cell Meshwork Expansion
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    evidence:
    - reference: DOI:10.1038/s41467-025-61214-1
      reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
      explanation: Links stromal activation to the FDC meshwork phenotype in the next node.
  - target: Stromal VEGF Overproduction and Neovascularization
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    evidence:
    - reference: DOI:10.1038/s41467-025-61214-1
      reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "VEGF expression was highest in PRCs and TRCs of MCD cases."
      explanation: Identifies the expanded stromal subsets as the VEGF source.
  - target: IL-6 Overproduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    description: >-
      Under the stromal-source hypothesis, activated perivascular and T-zone
      reticular cells are a principal origin of the IL-6 signal in MCD.
- name: Follicular Dendritic Cell Meshwork Expansion
  description: >-
    CD21+ follicular dendritic cell meshworks are larger, brighter, and more
    structurally complex in both UCD and MCD than in reactive lymph nodes.
    Interdigitation of the expanded meshwork between concentric layers of mantle
    zone B cells is the proposed structural basis of the "onion-skinning"
    appearance, and the resulting sustained antigen presentation is proposed to
    drive B cell activation and plasma cell differentiation. This reinterprets
    the prominent FDCs of Castleman histology as an active driver rather than a
    passive remnant of an attenuated germinal center.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  - preferred_term: Mantle zone B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: Germinal center formation
    term:
      id: GO:0002467
      label: germinal center formation
    modifier: DECREASED
  - preferred_term: Plasma cell differentiation
    term:
      id: GO:0002317
      label: plasma cell differentiation
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation."
    explanation: The direct observation behind this node's mechanism.
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, prominent FDCs in CD were considered remnants of attenuated germinal centers."
    explanation: >-
      States the earlier interpretation that this node replaces, which is why the
      reinterpretation is flagged in the description.
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
    hypothesis_groups:
    - stromal_cytokine_source
    description: >-
      Meshwork interdigitation between concentric mantle-zone B cell layers is
      the proposed structural basis of onion-skinning.
  - target: Plasma Cell / B Cell Proliferation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - stromal_cytokine_source
- name: Stromal VEGF Overproduction and Neovascularization
  description: >-
    VEGFA is expressed at its highest levels by perivascular and T-zone
    reticular cells in MCD and by CXCL13+ follicular dendritic cells inside
    follicles in UCD. In UCD the expression is confined to follicles; in MCD it
    extends into the interfollicular space. The resulting perifollicular
    neovascularization and penetrating vessels are the structural basis of the
    diagnostic "lollipop" follicle, and hypervascularization supports the stromal
    remodeling and nodal expansion. Systemically, VEGF contributes to vascular
    permeability and to the POEMS phenotype.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Perivascular reticular cell
    term:
      id: CL:4033054
      label: perivascular cell
  - preferred_term: Blood endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Vascular endothelial growth factor production
    term:
      id: GO:0010573
      label: vascular endothelial growth factor production
    modifier: INCREASED
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "VEGF expression was highest in PRCs and TRCs of MCD cases."
    explanation: Identifies the stromal cells carrying the VEGF signal in MCD.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."
    explanation: >-
      Shows circulating VEGF-A is elevated and pharmacologically reducible in
      IL-6-refractory iMCD, supporting VEGF as an actionable node.
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
  - target: Vascular Hyperpermeability and Third-Space Fluid Accumulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: PI3K/AKT/mTOR Pathway Activation
  description: >-
    In IL-6-blockade-refractory iMCD, quantitative serum proteomics, cytokine
    panels, flow cytometry, and phospho-S6 immunohistochemistry showed increased
    CD8+ T cell activation, elevated VEGF-A, and PI3K/AKT/mTOR pathway activity.
    Sirolimus attenuated CD8+ T cell activation, lowered VEGF-A, and produced
    durable clinical benefit in all three patients studied. This is the first
    pharmacologically targetable process identified for patients whose disease
    does not respond to IL-6 blockade, and it is the mechanistic rationale for
    NCT03933904. The supporting series is three patients.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: CD8+ T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: PI3K/AKT signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Studies of three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity."
    explanation: The observation defining this node, in a three-patient series.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months."
    explanation: >-
      The pharmacological reversal that makes this node causally interpretable
      rather than a correlation.
  downstream:
  - target: Stromal VEGF Overproduction and Neovascularization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - il6_independent_mtor
    description: >-
      mTOR inhibition lowers circulating VEGF-A, placing VEGF downstream of this
      pathway in the refractory setting.
- name: IL-6 Overproduction
  conforms_to: "il6_hypercytokinemia#Sustained Interleukin-6 Oversupply"
  description: >-
    Endogenous human IL-6 is overproduced from a trigger that has not been
    identified. The producing cell appears to differ by subtype: plasma cells in
    iMCD-IPL, under an XBP1-driven endoplasmic reticulum stress and
    plasma-cell-differentiation program, and vascular endothelial cells in
    iMCD-TAFRO, where the serum elevation may be secondary to the cytokine storm
    rather than its cause. That difference is the leading explanation for why
    IL-6 blockade works well in IPL and poorly in TAFRO, and it is why this node
    is not treated as the single unifying driver of the disease.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Interleukin-6 production
    term:
      id: GO:0032635
      label: interleukin-6 production
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
    explanation: >-
      Expert-perspective review identifies excess IL-6 as the shared driver of the
      multicentric forms of CD (the "they" of the quoted sentence are the MCD
      subtypes, of which this entry is one); IL-6 is typically normal in
      unicentric disease, so the quote does not establish an all-subtype claim.
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO."
    explanation: Supports the subtype-specific producing cell stated in this node.
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation."
    explanation: Identifies the XBP1/ER-stress transcriptional program named in this node for iMCD-IPL.
  downstream:
  - target: JAK-STAT3 Signaling Activation
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
      explanation: >-
        Establishes the excess-IL-6 drive that is upstream of this edge. The quote
        does not itself mention gp130 or JAK-STAT3, so it supports the source node
        rather than the signal-transduction step asserted here.
- name: JAK-STAT3 Signaling Activation
  conforms_to: "il6_hypercytokinemia#JAK-STAT3 Activation in Responder Cells"
  description: >-
    IL-6 and vIL-6 bind gp130 and activate downstream JAK kinases and
    STAT3 transcription factor signaling. This pathway is therapeutically
    targeted by anti-IL-6 (siltuximab), anti-IL-6R (tocilizumab), and
    JAK1/2 inhibitors (ruxolitinib).
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Interleukin-6-mediated signaling pathway
    term:
      id: GO:0070102
      label: interleukin-6-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  downstream:
  - target: Plasma Cell / B Cell Proliferation
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
      explanation: >-
        Documents the cytokine-storm clinical picture (anasarca, thrombocytopenia,
        lymphadenopathy) that hallmarks iMCD-TAFRO, i.e. the downstream
        consequence. Attributing that picture to JAK-STAT3-driven proliferation is
        the entry's mechanistic reading, not something the quote states.
  - target: CXCL13 Chemokine Axis Elevation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Serum CXCL13 falls early after siltuximab in responders, placing it
      downstream of IL-6/JAK-STAT signaling in patients whose disease is
      IL-6-driven.
    evidence:
    - reference: PMID:36433996
      reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points."
      explanation: >-
        The fall of CXCL13 on IL-6 blockade, only in responders, is the evidence
        for placing CXCL13 downstream of the IL-6 axis.
- name: CXCL13 Chemokine Axis Elevation
  description: >-
    In a comparison of 1,178 serum proteins across 88 iMCD patients, 60 patients
    with related diseases, and 42 healthy participants, CXCL13 was the protein
    most prominently up-regulated in iMCD. CXCL13 is the follicular dendritic
    cell chemokine that organizes B cell follicles, so its elevation connects the
    stromal compartment to the B cell expansion seen histologically. A 17%
    reduction in CXCL13 by day 8 of siltuximab predicts later response, making
    this node the best-supported pharmacodynamic readout in the disease.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Chemokine-mediated signaling
    term:
      id: GO:0070098
      label: chemokine-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD."
    explanation: The proteomic finding that defines this node.
  downstream:
  - target: Plasma Cell / B Cell Proliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - immune_stromal_dysregulation
- name: Plasma Cell / B Cell Proliferation
  conforms_to: "il6_hypercytokinemia#B-Lineage Differentiation and Immunoglobulin Output"
  description: >-
    JAK-STAT3 signaling drives proliferation of B cells and plasma cells within
    affected lymph nodes. Immunoglobulin output from the expanded plasma cell
    compartment is polyclonal, class-switched, and somatically hypermutated,
    consistent with a driven germinal-centre-type response rather than
    antigen-independent activation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Plasmablast
    term:
      id: CL:0000980
      label: plasmablast
  biological_processes:
  - preferred_term: B cell proliferation
    term:
      id: GO:0042100
      label: B cell proliferation
    modifier: INCREASED
  - preferred_term: Immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
    modifier: INCREASED
  downstream:
  - target: Angiofollicular Lymph Node Hyperplasia
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although they are all driven by excessive cytokines such as interleukin‐6 (IL‐6)"
      explanation: >-
        Supports the excess-IL-6 drive upstream of this edge. The quoted review
        sentence does not describe the angiofollicular histology, so the histologic
        consequence remains uncited here.
  - target: Polyclonal Hypergammaglobulinemia
    causal_link_type: DIRECT
    description: >-
      Expanded polyclonal plasma cells are the direct source of the
      hypergammaglobulinemia that defines the iMCD-IPL pattern.
- name: Hepatic Acute-Phase Response
  conforms_to: "il6_hypercytokinemia#Hepatic Acute-Phase Reprogramming"
  description: >-
    IL-6 signaling reprogrammes hepatic protein synthesis: C-reactive protein
    and fibrinogen are induced, albumin synthesis falls, and hepcidin induction
    restricts iron availability. This is a separate effector arm from the
    B-lineage one - a different cell lineage with a different clinical read-out -
    and its markers normalize earlier on IL-6 blockade than immunoglobulin does.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: Acute-phase response
    term:
      id: GO:0006953
      label: acute-phase response
    modifier: INCREASED
  evidence:
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: >-
      Shows the acute-phase outputs of this node reversing on IL-6 blockade, and
      places them earlier in the sequence than the immunoglobulin read-out.
  downstream:
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      IL-6-driven hepcidin induction and the acute-phase response produce the
      anemia of inflammation seen in 85% of iMCD patients at diagnosis.
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Reprioritized hepatic protein synthesis during the acute-phase response
      lowers serum albumin, present in 79% of iMCD patients at diagnosis.
- name: Angiofollicular Lymph Node Hyperplasia
  description: >-
    The unifying histopathologic feature across all CD subtypes: lymph
    nodes show abnormal germinal centers (regressed/atretic in
    hyaline-vascular UCD, hyperplastic with plasma cell infiltrates in
    plasma-cell variant MCD), penetrating "lollipop" vessels, mantle-zone
    expansion ("onion-skinning"), and interfollicular plasmacytosis and
    vascular proliferation driven by IL-6 and VEGF.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: Follicular dendritic cell
    term:
      id: CL:0000442
      label: follicular dendritic cell
  biological_processes:
  - preferred_term: Angiogenesis
    term:
      id: GO:0001525
      label: angiogenesis
    modifier: INCREASED
  downstream:
  - target: Generalized Lymphadenopathy
    causal_link_type: DIRECT
    evidence:
    - reference: DOI:10.1002/art.43269
      reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
      explanation: Angiofollicular lymph node hyperplasia drives clinically detectable lymphadenopathy, localized in UCD and generalized in MCD.
- name: Vascular Hyperpermeability and Third-Space Fluid Accumulation
  conforms_to: "cytokine_storm_hyperinflammation#Endothelial Activation and Capillary Leak"
  description: >-
    VEGF-driven and cytokine-driven endothelial permeability, compounded by
    hypoalbuminemia, causes fluid to leave the vascular space. Clinically this is
    the anasarca of iMCD-TAFRO, with pleural effusion, ascites, and generalized
    edema. Fluid retention was present in 84% of iMCD patients in the ACCELERATE
    registry, and 46% required paracentesis.
  biological_scale: ORGANISM
  cell_types:
  - preferred_term: Vascular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Regulation of vascular permeability
    term:
      id: GO:0043114
      label: regulation of vascular permeability
    modifier: INCREASED
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: Quantifies fluid retention as the dominant clinical consequence of this node.
  downstream:
  - target: Generalized Edema (Anasarca)
    causal_link_type: DIRECT
  - target: Ascites
    causal_link_type: DIRECT
  - target: Pleural Effusion
    causal_link_type: DIRECT
- name: Endothelial Injury and Renal Thrombotic Microangiopathy
  description: >-
    Renal involvement is common in MCD and especially in TAFRO. Where kidney
    biopsy is performed, membranoproliferative glomerulonephritis-like injury and
    thrombotic microangiopathy are the findings most often reported, implicating
    glomerular endothelial injury rather than a primary tubular or immune-complex
    process. IL-6 and VEGF have both been proposed as the mediators, but their
    specific role in the renal lesion has not been established. Thrombotic
    microangiopathy was diagnosed after iMCD onset in 6.9% of the ACCELERATE
    cohort, predominantly TAFRO patients.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Glomerular endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Blood coagulation
    term:
      id: GO:0007596
      label: blood coagulation
    modifier: INCREASED
  evidence:
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy."
    explanation: Establishes the two dominant renal histopathologic patterns named in this node.
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The role of these cytokines in renal injury, however, is not well understood."
    explanation: >-
      The review states directly that the mediator-to-lesion link is unresolved,
      which is why the mechanism is hedged here.
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it is suggested that there are factors other than IL-6 and VEGF, which dominate the glomerular injury."
    explanation: >-
      Argues that the two cytokines this entry models as the systemic drivers are
      not sufficient to explain the renal lesion, so an unidentified mediator is
      implied at this node.
  notes: >-
    Unmined lead: Lossos et al. 2024 (DOI:10.1016/j.bvth.2024.100006) report high
    SVEP1, tissue factor and endotheliopathy in iMCD-TAFRO, which would be a
    candidate for the unidentified mediator this node records - and would connect
    the endothelial injury here to the PI3K/AKT/mTOR node, since SVEP1 is an mTOR
    activator. Not curated as evidence because the cached record for that paper
    has no retrievable abstract, so no exact quote can be taken. Carried in
    `references:` so the lead is not lost.
  downstream:
  - target: Renal Dysfunction
    causal_link_type: DIRECT
- name: Marrow Stromal Fibrotic Remodeling
  description: >-
    In iMCD-TAFRO the bone marrow stroma lays down excess reticulin - the "R" of
    the TAFRO acronym - typically with megakaryocytic hyperplasia. What drives
    the fibrotic response in this setting has not been established.
  notes: >-
    Named for the stromal process rather than the biopsy finding it produces,
    which is carried as the phenotype this node points at.
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."
    explanation: Names reticulin fibrosis as one of the five defining TAFRO features.
  downstream:
  - target: Bone Marrow Reticulin Fibrosis
    causal_link_type: DIRECT
- name: Peripheral Platelet Consumption
  description: >-
    Platelet counts fall in iMCD-TAFRO despite adequate marrow megakaryocyte
    numbers, so the deficit is peripheral rather than a failure of production.
    This distinguishes TAFRO sharply from iMCD-IPL and iMCD-NOS, where
    thrombocytosis rather than thrombocytopenia is typical. Kept separate from
    the marrow fibrosis node because the two are different claims - one about
    stromal remodeling in the marrow, one about platelet survival in the
    circulation - and neither is established as causing the other. The mechanism
    of the consumption has not been established; endothelial injury and
    thrombotic microangiopathy are the leading candidates in this subtype.
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: Negative regulation of megakaryocyte differentiation
    term:
      id: GO:0045653
      label: negative regulation of megakaryocyte differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."
    explanation: Supports the contrast with the other iMCD subtypes stated in this node.
  downstream:
  - target: Thrombocytopenia
    causal_link_type: DIRECT
phenotypes:
- category: Constitutional
  name: Generalized Lymphadenopathy
  diagnostic: true
  notes: >-
    Multiple enlarged lymph node regions, which is a required criterion for the
    diagnosis. Lymphadenopathy in iMCD-TAFRO is characteristically small-volume,
    so node size does not track disease severity.
  phenotype_term:
    preferred_term: Generalized lymphadenopathy
    term:
      id: HP:0008940
      label: Generalized lymphadenopathy
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
    explanation: >-
      Establishes the multiple-region criterion that makes this disease
      multicentric and distinguishes it from the unicentric form.
- category: Constitutional
  name: Fever
  notes: >-
    Constitutional symptoms including fever were present in 46.6% of iMCD
    patients in a 1,998-patient meta-analysis - substantially less than the 98.6%
    seen in HHV-8-associated disease. Fever, or an elevated C-reactive protein in
    its place, is one of the five defining TAFRO features.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: DOI:10.1182/bloodadvances.2024013548
    reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"
    explanation: Meta-analysis quantifies constitutional symptoms (including fever) as substantially more frequent in HHV8+ MCD than iMCD.
- category: Constitutional
  name: Night Sweats
  phenotype_term:
    preferred_term: Night sweats
    term:
      id: HP:0030166
      label: Night sweats
- category: Constitutional
  name: Fatigue
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Constitutional
  name: Weight Loss
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
- category: Constitutional
  name: Anorexia
  phenotype_term:
    preferred_term: Loss of appetite
    term:
      id: HP:0002039
      label: Anorexia
  notes: >-
    Loss of appetite is one of the 16 items on the validated MCD symptom score
    used in the siltuximab trial and the ACCELERATE registry.
- category: Hematologic
  name: Anemia
  frequency: VERY_FREQUENT
  notes: >-
    Anemia of inflammation. Present in 85.3% of iMCD patients at diagnosis in
    the ACCELERATE registry, with a median hemoglobin of 7.8 g/dL.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
    explanation: Gives the anemia frequency at diagnosis in a 102-patient adjudicated iMCD cohort.
- category: Hematologic
  name: Hypoalbuminemia
  frequency: VERY_FREQUENT
  notes: >-
    Present in 79.4% of iMCD patients at diagnosis (median albumin 2.2 g/dL).
    Hypoalbuminemia is a minor criterion in the international iMCD diagnostic
    criteria and contributes to the third-space fluid accumulation.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
    explanation: Gives the hypoalbuminemia frequency at diagnosis in the same adjudicated iMCD cohort.
- category: Laboratory
  name: Elevated C-Reactive Protein
  diagnostic: true
  notes: >-
    Elevated CRP is the "F" of TAFRO in the CDCN formulation
    (fever/elevated C-reactive protein) and a minor criterion for iMCD. It is the
    routine marker used to follow disease activity and treatment response.
  phenotype_term:
    preferred_term: Elevated C-reactive protein
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: >-
      Post hoc analysis of the siltuximab trial confirms elevated CRP as one of
      the tracked abnormalities and places it early in the normalization sequence.
- category: Laboratory
  name: Elevated Erythrocyte Sedimentation Rate
  phenotype_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
- category: Abdominal
  name: Splenomegaly
  frequency: FREQUENT
  notes: >-
    48.2% in iMCD versus 89.2% in HHV8+ MCD by meta-analysis; 72% at diagnosis
    in the ACCELERATE iMCD cohort.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: DOI:10.1182/bloodadvances.2024013548
    reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"
    explanation: Meta-analysis quantifies splenomegaly frequencies at 48.2% in iMCD and 89.2% in HHV8+ MCD.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: Independent registry frequency for splenomegaly at iMCD diagnosis.
- category: Abdominal
  name: Hepatomegaly
  frequency: FREQUENT
  notes: Present in 60% of iMCD patients at diagnosis in the ACCELERATE registry.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: Gives the hepatomegaly frequency at iMCD diagnosis.
- category: Hematologic
  name: Thrombocytopenia
  subtype: iMCD-TAFRO
  frequency: VERY_FREQUENT
  notes: >-
    The "T" of iMCD-TAFRO and the feature that most sharply separates it from
    iMCD-IPL and iMCD-NOS, where thrombocytosis is typical. Platelet transfusion
    was required by 21.6% of the ACCELERATE iMCD cohort, almost entirely TAFRO
    patients.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
    explanation: Identifies thrombocytopenia as a hallmark feature of iMCD-TAFRO.
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS)."
    explanation: Establishes thrombocytopenia as TAFRO-specific rather than general to iMCD.
- category: Hematologic
  name: Thrombocytosis
  subtype: iMCD-IPL
  notes: >-
    Thrombocytosis, with polyclonal hypergammaglobulinemia, defines the
    iMCD-IPL pattern and is the mirror image of the TAFRO platelet phenotype.
    It was the first abnormality to normalize in siltuximab responders.
  phenotype_term:
    preferred_term: Thrombocytosis
    term:
      id: HP:0001894
      label: Thrombocytosis
  evidence:
  - reference: PMID:40181993
    reference_title: "Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iMCD with idiopathic plasmacytic lymphadenopathy (iMCD-IPL) involving hypergammaglobulinemia and thrombocytosis"
    explanation: Defines thrombocytosis as part of the iMCD-IPL pattern.
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: Places thrombocytosis first in the sequence of laboratory normalization on siltuximab.
- category: Immunologic
  name: Polyclonal Hypergammaglobulinemia
  subtype: iMCD-IPL
  notes: >-
    Severe polyclonal hyperimmunoglobulinemia is the defining laboratory feature
    of idiopathic plasmacytic lymphadenopathy. Serum IgG above roughly
    5,000 mg/dL is associated with enough IgG4-positive cells to also satisfy the
    histological criteria for IgG4-related disease, which is the main source of
    diagnostic confusion for this subtype.
  phenotype_term:
    preferred_term: Polyclonal hypergammaglobulinemia
    term:
      id: HP:0032288
      label: Polyclonal elevation of circulating IgG
  evidence:
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed."
    explanation: Gives the serum IgG level associated with IgG4-RD-like histology in iMCD-IPL.
- category: Abdominal
  name: Ascites
  subtype: iMCD-TAFRO
  notes: >-
    Component of the anasarca that hallmarks iMCD-TAFRO. Paracentesis was
    required by 46% of the ACCELERATE iMCD cohort.
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
    explanation: Anasarca (which includes ascites) is identified as a hallmark feature of iMCD-TAFRO.
- category: Respiratory
  name: Pleural Effusion
  subtype: iMCD-TAFRO
  notes: Component of the anasarca of iMCD-TAFRO.
  phenotype_term:
    preferred_term: Pleural effusion
    term:
      id: HP:0002202
      label: Pleural effusion
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A large majority of patients presented with fluid retention (84%), splenomegaly (72%), and/or hepatomegaly (60%)."
    explanation: >-
      Fluid retention, of which pleural effusion is a component, was the most
      frequent clinical abnormality at iMCD diagnosis.
- category: Cardiovascular
  name: Generalized Edema (Anasarca)
  subtype: iMCD-TAFRO
  notes: >-
    Generalized edema/anasarca is a hallmark of iMCD-TAFRO. Fluid retention was
    present in 84% of iMCD patients at diagnosis in the ACCELERATE registry.
  phenotype_term:
    preferred_term: Anasarca
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
    explanation: Anasarca is identified as a hallmark feature of iMCD-TAFRO.
- category: Renal
  name: Renal Dysfunction
  frequency: FREQUENT
  notes: >-
    Renal dysfunction/reticulin fibrosis is the "R" of iMCD-TAFRO; component
    of the defining TAFRO pentad. Renal dysfunction was reported in 36.9% of
    iMCD versus 17.4% of HHV8+ MCD by meta-analysis, and 26.5% of the
    ACCELERATE iMCD cohort required dialysis.
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."
    explanation: Renal dysfunction/reticulin fibrosis is codified as the "R" component of the iMCD-TAFRO pentad.
  - reference: DOI:10.1182/bloodadvances.2024013548
    reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal dysfunction was significantly more common in patients with iMCD than in patients with HHV8+ MCD before adjustment (36.9% vs 17.4%; P = .04; adjusted P = .1)."
    explanation: >-
      Quantifies the iMCD/HHV8+ difference in renal dysfunction, and records that
      the difference did not survive multiplicity adjustment.
- category: Renal
  name: Acute Renal Failure
  notes: >-
    The most common iMCD-related morbidity arising after diagnosis, affecting
    48% of the ACCELERATE cohort. It occurred in both TAFRO and NOS patients.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the iMCD diagnosis, 48% (n=49) of the cohort developed acute renal failure"
    explanation: Quantifies acute renal failure as the leading post-diagnosis morbidity.
- category: Renal
  name: Proteinuria
  subtype: iMCD-TAFRO
  notes: >-
    Reflects the membranoproliferative glomerulonephritis-like and thrombotic
    microangiopathic glomerular injury reported on renal biopsy.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, membranoproliferative glomerulonephritis (MPGN)-like injury and thrombotic microangiopathy (TMA) are the most reported histopathologic findings of renal biopsy."
    explanation: >-
      Establishes the glomerular lesions underlying proteinuria in this setting.
- category: Hematologic
  name: Bone Marrow Reticulin Fibrosis
  subtype: iMCD-TAFRO
  diagnostic: true
  notes: >-
    The "R" of TAFRO in its original formulation. Bone marrow biopsy showing
    reticulin fibrosis with megakaryocytic hyperplasia is part of the TAFRO
    diagnostic workup.
  phenotype_term:
    preferred_term: Reticulin fibrosis of the bone marrow
    term:
      id: HP:0011974
      label: Myelofibrosis
  evidence:
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."
    explanation: Names reticulin fibrosis as one of the five defining TAFRO features.
histopathology:
- name: Angiofollicular Lymph Node Hyperplasia, Plasma-Cell Variant
  description: >-
    Plasma-cell histologic variant predominates in MCD. Features
    hyperplastic germinal centers, sheets of mature plasma cells in the
    interfollicular zone, and increased interfollicular vascularity.
    Mantle-zone onion-skinning is less prominent than in the
    hyaline-vascular variant. This is the pattern associated with iMCD-IPL and
    with polyclonal hypergammaglobulinemia.
  context: MCD
  subtype: iMCD-IPL
- name: Mixed Histopathologic Variant
  description: >-
    Nodes carrying features of both the hyaline-vascular and plasma-cell
    patterns. In the ACCELERATE registry the histopathologic distribution across
    102 adjudicated iMCD cases was hypervascular/hyaline vascular 61.8%, mixed
    26.5%, and plasmacytic 6.9%; TAFRO cases were predominantly
    hypervascular and none were plasmacytic. The clinical significance of the
    histopathologic subtype is not established.
  context: MCD
  evidence:
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients are also classified according to histopathologic subtype, including hyaline vascular/hypervascular, plasmacytic, or mixed, though the clinical implications of defining histopathologic subtype is unclear."
    explanation: >-
      States both the three-way histopathologic classification and that its
      clinical meaning is unresolved.
- name: IgG4-Positive Plasma Cell Infiltrate
  description: >-
    Lymph nodes in iMCD-IPL can contain enough IgG4-positive plasma cells to
    satisfy the histological diagnostic criteria for IgG4-related disease: in one
    series 13 of 39 iMCD-IPL cases (33.3%) did so, and serum IgG4 levels did not
    separate the two conditions. The serum IgG4/IgG ratio, with a cut-off of
    19.0%, is the discriminator that did.
  context: iMCD-IPL
  subtype: iMCD-IPL
  evidence:
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups."
    explanation: Quantifies the histological overlap and the failure of serum IgG4 to discriminate.
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%."
    explanation: Gives the discriminating ratio and its cut-off.
- name: Expanded CD21-Positive Follicular Dendritic Cell Meshwork
  description: >-
    CD21 immunostaining shows follicular dendritic cell meshworks of greater
    area, intensity, and structural complexity (image entropy) in both UCD and
    MCD than in reactive lymph nodes, and UCD follicles show reduced cellular
    diversity consistent with FDC predominance. This is an immunohistochemical
    correlate of the stromal-activation model rather than a routine diagnostic
    criterion.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CD shows increased stromal cells that form unique microenvironments."
    explanation: >-
      Records the increased stromal content quantified by CD21 meshwork imaging
      in this study.
- name: Bone Marrow Reticulin Fibrosis with Megakaryocytic Hyperplasia
  description: >-
    Bone marrow biopsy in iMCD-TAFRO shows increased reticulin fibrosis, often
    with megakaryocytic hyperplasia despite peripheral thrombocytopenia. Marrow
    examination is part of the TAFRO workup and helps exclude a primary
    myeloproliferative or myelodysplastic cause of the cytopenias.
  context: iMCD-TAFRO
  subtype: iMCD-TAFRO
  evidence:
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O)."
    explanation: Names reticulin fibrosis on marrow biopsy as a defining TAFRO feature.
imaging_findings:
- name: FDG-Avid Multicentric Lymphadenopathy
  modality: PET
  description: >-
    FDG-PET/CT demonstrates avid lymphadenopathy in multiple nodal stations in
    MCD and is used both to establish multicentricity and to select the node to
    biopsy. Uptake is typically moderate, and marked focal uptake in a single
    node raises concern for lymphomatous transformation rather than Castleman
    disease itself.
  diagnostic: true
- name: Serosal Effusions and Organomegaly
  modality: CT
  description: >-
    Cross-sectional imaging in iMCD-TAFRO shows pleural effusions, ascites,
    generalized subcutaneous edema, and hepatosplenomegaly, often with only
    modest lymph node enlargement. The imaging pattern of severe third-spacing
    with small nodes is a recognizable TAFRO signature.
  subtype: iMCD-TAFRO
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
    explanation: >-
      Establishes the combination of anasarca with small-volume lymphadenopathy
      that this imaging pattern reflects.
biochemical:
- name: Interleukin-6 (IL-6)
  presence: Elevated
  context: >-
    Markedly elevated in MCD (both HHV-8+ and iMCD); typically normal in
    UCD. IL-6 levels correlate with disease activity. The producing cell differs
    by iMCD subtype - plasma cells in IPL, vascular endothelium in TAFRO - and in
    TAFRO the serum elevation may be a downstream consequence of the cytokine
    storm rather than its driver. There is no validated diagnostic serum
    biomarker for iMCD, and serum IL-6 is not one.
  evidence:
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."
    explanation: Supports the caveat that serum IL-6 may be secondary in the TAFRO subtype.
- name: C-Reactive Protein (CRP)
  presence: Elevated
  context: >-
    Acute-phase reactant driven by IL-6 signaling. Elevated in MCD; useful
    biomarker for disease activity and prognosis, and a component of the
    fever/elevated-CRP criterion in the CDCN TAFRO formulation.
- name: C-X-C Motif Chemokine Ligand 13 (CXCL13)
  presence: Elevated
  context: >-
    Of 1,178 serum proteins compared across 88 iMCD patients, 60 disease
    controls, and 42 healthy participants, CXCL13 was the most prominently
    up-regulated protein in iMCD. A 17% fall by day 8 of siltuximab predicts
    later response, making CXCL13 the best-supported pharmacodynamic marker in
    the disease. It has not been established as a diagnostic marker.
  evidence:
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD."
    explanation: Establishes CXCL13 as the top differentially elevated serum protein in iMCD.
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points."
    explanation: Supports the predictive-response use described here.
- name: Vascular Endothelial Growth Factor A (VEGF-A)
  presence: Elevated
  context: >-
    Elevated in MCD and central to the POEMS phenotype. In IL-6-blockade
    refractory iMCD-TAFRO, VEGF-A was elevated alongside PI3K/AKT/mTOR pathway
    activity and fell on sirolimus, alongside clinical response. Lymph node
    stromal cells (perivascular and T-zone reticular cells, and follicular
    dendritic cells) are the tissue source.
  evidence:
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."
    explanation: Supports both the elevation of VEGF-A and its pharmacological reversibility.
- name: Serum Albumin
  presence: Decreased
  context: >-
    Hypoalbuminemia is a minor criterion for iMCD and one of the laboratory
    abnormalities tracked for treatment response. Median albumin at iMCD
    diagnosis in the ACCELERATE registry was 2.2 g/dL.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-seven (85.3%) patients had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis"
    explanation: Quantifies hypoalbuminemia at diagnosis in an adjudicated iMCD cohort.
- name: Serum Immunoglobulin G
  presence: Elevated
  context: >-
    Polyclonal IgG elevation is characteristic of iMCD-IPL and iMCD-NOS and is
    the last abnormality to normalize on siltuximab. It is normal or low in
    iMCD-TAFRO, which is a practical way of separating the subtypes at
    presentation.
  subtype: iMCD-IPL
  evidence:
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: Places elevated IgG last in the normalization sequence on siltuximab.
- name: Serum Fibrinogen
  presence: Elevated
  context: >-
    Hyperfibrinogenemia is an acute-phase abnormality that normalizes late on
    siltuximab, after the symptomatic and lymph node responses.
  evidence:
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the median time to normalization of abnormal laboratory tests and clinical end points occurred in the following sequence: thrombocytosis, symptomatic response, elevated C-reactive protein, hypoalbuminemia, anemia, lymph node response, hyperfibrinogenemia, and elevated immunoglobulin G"
    explanation: Identifies hyperfibrinogenemia as a tracked abnormality with a late normalization time.
prevalence:
- population: United States
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.34
  rate_low: 0.14
  rate_high: 0.92
  notes: >-
    iMCD only. Estimated from 30.7 million enrollees using the D47.Z2 CD-specific
    ICD-10 code plus at least two claims codes matching the international iMCD
    minor criteria. 3.4 cases per million per year (95% CI 1.4-9.2).
  evidence:
  - reference: DOI:10.1182/bloodadvances.2021004441
    reference_title: "Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively"
    explanation: Source for both the incidence recorded here and the prevalence recorded below.
- population: United States
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.69
  rate_low: 0.37
  rate_high: 1.33
  notes: >-
    iMCD only. 6.9 cases per million (95% CI 3.7-13.3) in the same claims-based
    analysis.
  evidence:
  - reference: DOI:10.1182/bloodadvances.2021004441
    reference_title: "Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 254 patients with iMCD, with an estimated annual incidence and prevalence of 3.4 (95% confidence interval [CI], 1.4-9.2) and 6.9 (95% CI, 3.7-13.3) cases per million, respectively"
    explanation: The prevalence estimate converted to the normalized rate above.
progression:
- phase: Presentation and diagnostic delay
  notes: >-
    Diagnosis rests on non-specific clinical features plus characteristic lymph
    node histopathology, with no diagnostic serum biomarker and diagnostic
    criteria that did not exist before 2017, so underdiagnosis is expected.
    Patients are hospitalized a median of 5 days in the 6 months before the
    diagnostic biopsy. iMCD occurs at all ages; in the ACCELERATE cohort the
    youngest patient was diagnosed at 1.8 years and the oldest at 74.4, with a
    median of 35.3 years.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, we found iMCD in individuals of all ages, with the youngest patient in the cohort diagnosed at 1.8 years and the oldest at 74.4."
    explanation: Gives the age range at diagnosis quoted here.
- phase: Severe presentation at diagnosis
  notes: >-
    Most patients are already severely ill when diagnosed: 77% met the guideline
    definition of severe iMCD at diagnosis, rising to 93% of TAFRO patients and
    still 51% of NOS patients. Severity is bimodal by age, with patients under
    30 and over 60 more likely to present severely.
  evidence:
  - reference: "PMID:38205523"
    reference_title: >-
      Longitudinal, natural history study reveals the disease burden of idiopathic multicentric
      Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 100 patients with sufficient information to determine disease severity at diagnosis, 77 (77%) initially presented with severe disease."
    explanation: Quantifies severe presentation at diagnosis.
  - reference: "PMID:38205523"
    reference_title: >-
      Longitudinal, natural history study reveals the disease burden of idiopathic multicentric
      Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients <30 and patients >60 years old were more likely to have severe disease (94.6% and 90.0%, respectively) as compared to patients between 30 and 60 years old (62.2%)"
    explanation: Supports the bimodal age-severity pattern described here.
- phase: Acute multiorgan failure (TAFRO)
  subtype: iMCD-TAFRO
  notes: >-
    TAFRO patients spend a median of 36 days in hospital in the year surrounding
    diagnosis (versus 0 for NOS), and 27% require dialysis and 17% mechanical
    ventilation at some point. Most iMCD deaths occur here: of eight deaths in
    the ACCELERATE cohort, six were TAFRO patients and five of those died within
    two years of diagnosis.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO."
    explanation: Quantifies the life-sustaining interventions required in this phase.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the eight deceased patients in this cohort, six had TAFRO and five of these TAFRO patients died within 2 years of diagnosis."
    explanation: Establishes that mortality concentrates in the TAFRO subtype and early after diagnosis.
- phase: Chronic relapsing-remitting course
  subtype: iMCD-NOS
  notes: >-
    NOS patients are hospitalized much less than TAFRO patients but spend a
    median 52.3% of their post-onset follow-up in active flare, versus 18.9% for
    TAFRO. A milder acute presentation is therefore not a lower long-term
    symptom burden, just a differently distributed one.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004)."
    explanation: Quantifies the chronic flare burden that characterizes this phase.
- phase: Long-term survival
  notes: >-
    Across the whole disease, 2-, 5-, and 10-year overall survival in a
    113-patient two-centre series was 92%, 76%, and 59%. Survival separates
    sharply by category: 5-year survival was 91% for UCD, 90% for MCD with the
    osteosclerotic POEMS variant, 65% for MCD without POEMS, and 27% for MCD
    with POEMS but without osteosclerotic lesions.
  evidence:
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For all patients, 2, 5, and 10-year OS was 92%, 76%, 59%, respectively."
    explanation: Gives the overall survival figures quoted here.
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%)."
    explanation: Gives the category-specific 5-year survival stratification.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Burden spans nearly the whole available range depending on subtype.
    iMCD-TAFRO is a life-threatening cytokine storm: 93% of
    patients present with severe disease, 27% require dialysis and 17%
    mechanical ventilation, median hospitalization in the year around diagnosis
    is 36 days, and most deaths occur within two years. iMCD-NOS sits between
    them, with less acute intensity but a majority of follow-up time spent in
    active flare and quality of life inversely tracking symptom score years
    after diagnosis. Access to effective therapy is itself part of the burden:
    only 8.7% of US iMCD patients in a claims analysis received siltuximab, the
    only approved and guideline-recommended first-line drug, while 33% received
    no iMCD-directed treatment at all.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO."
    explanation: Supports the organ-support burden at the severe end of the range.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "QOL scores were inversely correlated with MCD symptom score (R=-0.69; P<0.001)"
    explanation: >-
      Supports the persistent quality-of-life impact measured a median 3.9 years
      after diagnosis.
  - reference: DOI:10.1182/bloodadvances.2021004441
    reference_title: "Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Siltuximab, which is the only US Food and Drug Administration–approved treatment and established first-line treatment recommendation, was used in only 8.7% of patients with iMCD."
    explanation: Supports the treatment-access component of the burden described above.
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(1) unicentric CD (91%); (2) multicentric CD associated with the osteosclerotic variant of POEMS syndrome (90%); (3); multicentric CD without POEMS syndrome (65%); and (4) multicentric CD with POEMS syndrome without osteosclerotic lesions (27%)."
    explanation: Supports the survival spread across categories that motivates the VARIABLE assignment.
diagnosis:
- name: Excisional lymph node biopsy
  description: >-
    Diagnosis requires characteristic lymph node histopathology; there is no
    diagnostic serum biomarker. Excisional biopsy is preferred over core or fine
    needle sampling because architectural features - regressed or hyperplastic
    germinal centers, mantle-zone onion-skinning, penetrating vessels,
    interfollicular plasmacytosis - cannot be assessed on a fragment. Histology
    alone is not sufficient: reactive Castleman-like changes occur in
    autoimmune disease, lymphoma, and infection, so the findings must be
    combined with clinical and laboratory data.
  diagnosis_term:
    preferred_term: lymph node biopsy
    term:
      id: NCIT:C51900
      label: Lymph Node Biopsy
  results: >-
    Angiofollicular lymph node hyperplasia of hyaline-vascular, plasma-cell, or
    mixed type.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
    explanation: States directly why histology alone cannot establish the diagnosis.
- name: International consensus diagnostic criteria for iMCD
  description: >-
    The CDCN evidence-based criteria, derived from 244 clinical cases and 88
    tissue samples, require multicentric lymphadenopathy with the defined
    histopathology, at least two of eleven clinical or laboratory minor criteria,
    and exclusion of the infectious, malignant, and autoimmune conditions that
    mimic iMCD - in particular HHV-8-associated MCD, POEMS syndrome, lymphoma,
    and IgG4-related disease.
  results: >-
    Diagnosis of iMCD when both major criteria, at least two minor criteria, and
    all exclusions are satisfied.
  evidence:
  - reference: DOI:10.1182/blood-2016-10-746933
    reference_title: "International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics."
    explanation: States the three-part structure of the criteria described here.
  - reference: DOI:10.1182/blood-2016-10-746933
    reference_title: "International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples."
    explanation: Establishes the evidence base behind the criteria.
- name: Bone marrow biopsy
  description: >-
    Performed in suspected iMCD-TAFRO to document reticulin fibrosis with
    megakaryocytic hyperplasia and to exclude a primary marrow disorder as the
    cause of the cytopenias. TAFRO also has its own Japanese diagnostic criteria
    (Iwaki, and the Masaki 2019 update), separate from the CDCN iMCD criteria, in
    which thrombocytopenia is a major criterion; the two criteria sets are not
    identical and a case can satisfy one without the other.
  diagnosis_term:
    preferred_term: bone marrow biopsy
    term:
      id: NCIT:C15193
      label: Bone Marrow Biopsy
  results: Reticulin fibrosis, often with megakaryocytic hyperplasia.
  evidence:
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the presence of thrombocytopenia fulfills one of the major diagnostic criteria"
    explanation: >-
      In the source sentence this refers to the Iwaki and Masaki TAFRO
      definitions, establishing that TAFRO has its own diagnostic criteria in
      which thrombocytopenia is a major criterion. The numeric citation markers
      in the original sentence are omitted from the quote because the reference
      validator strips bracketed spans before matching.
  - reference: PMID:29157612
    reference_title: TAFRO Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular-type CD."
    explanation: >-
      Supports the exclusion-focused role of tissue sampling in TAFRO. Note the
      quote refers to lymph node biopsy; the marrow finding is the "R" of the
      TAFRO acronym.
- name: Cross-sectional and FDG-PET imaging
  description: >-
    CT of the neck, chest, abdomen, and pelvis, or FDG-PET/CT, establishes
    whether disease is unicentric or multicentric - the single most consequential
    branch point in management, since unicentric disease is surgically curable.
    Imaging also selects the biopsy target and, in UCD, determines resectability.
  diagnosis_term:
    preferred_term: positron emission tomography
    term:
      id: NCIT:C17007
      label: Positron Emission Tomography
  results: >-
    A single involved nodal region indicates UCD; multiple involved regions
    indicate MCD.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unicentric CD (UCD) involves one enlarged lymph node region, whereas multicentric CD (MCD) involves multiple enlarged lymph node regions."
    explanation: The distinction that imaging is performed to establish.
- name: Serum IgG4 to IgG ratio
  description: >-
    Used to separate iMCD-IPL from IgG4-related disease when the lymph node
    contains numerous IgG4-positive plasma cells. Absolute serum IgG4 does not
    discriminate; the IgG4/IgG ratio does, with a reported cut-off of 19.0%.
  results: >-
    A serum IgG4/IgG ratio above roughly 19% favors IgG4-related disease over
    iMCD-IPL.
  evidence:
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%."
    explanation: Gives the discriminating test and threshold.
differential_diagnoses:
- name: IgG4-related disease
  description: >-
    The closest mimic of iMCD-IPL. Both present with lymphadenopathy, polyclonal
    hypergammaglobulinemia, and IgG4-positive plasma cell infiltrates, and a
    third of iMCD-IPL lymph nodes meet the histological criteria for IgG4-RD.
    Serum IgG4 alone does not separate them; the serum IgG4/IgG ratio (cut-off
    19.0%) does. IgG4-RD additionally shows storiform fibrosis and characteristic
    extranodal organ involvement (pancreas, salivary and lacrimal glands).
  disease_term:
    preferred_term: IgG4-related disease
    term:
      id: MONDO:0017287
      label: immunoglobulin G4-related sclerosing disease
  evidence:
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD)."
    explanation: Names IgG4-RD as the principal mimic of this iMCD subtype.
  - reference: PMID:38378248
    reference_title: "Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL."
    explanation: States the combined approach needed to separate the two.
- name: HHV-8-associated multicentric Castleman disease
  description: >-
    Not a different disease from Castleman disease but the branch point within
    it, and the exclusion that defines iMCD. Distinguished by HHV-8 LANA-1
    immunohistochemistry on the node, usually with HIV co-infection, higher rates
    of constitutional symptoms and splenomegaly, and a different first-line
    therapy (rituximab rather than siltuximab).
  distinguishing_features:
  - >-
      HHV-8 LANA-1-positive plasmablasts on lymph node immunohistochemistry; detectable plasma KSHV viral load; usual HIV co-infection.
  evidence:
  - reference: DOI:10.1182/bloodadvances.2024013548
    reference_title: "The clinical picture of Castleman disease: a systematic review and meta-analysis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with HHV8+ MCD had significantly higher rates of constitutional symptoms (46.6% vs 98.6%; P = .038) and splenomegaly (48.2% vs 89.2%; P = .031)"
    explanation: Quantifies the clinical features that differ between the two subtypes.
- name: POEMS syndrome
  description: >-
    A clonal plasma cell disorder that can present with Castleman-like
    lymphadenopathy. Distinguished by peripheral neuropathy, a monoclonal
    (usually lambda-restricted) paraprotein, osteosclerotic bone lesions, and
    endocrinopathy - none of which belong to iMCD, where the immunoglobulin
    elevation is polyclonal. The distinction changes prognosis sharply: MCD with
    non-osteosclerotic POEMS had 27% 5-year survival versus 65% for MCD without
    POEMS.
  distinguishing_features:
  - >-
      Monoclonal plasma cell disorder, peripheral polyneuropathy, osteosclerotic lesions, endocrinopathy.
  evidence:
  - reference: PMID:22791417
    reference_title: "The clinical spectrum of Castleman's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the patients with multicentric CD, 32% had criteria sufficient for a diagnosis of POEMS syndrome."
    explanation: >-
      Establishes how often the POEMS distinction actually has to be made in an
      MCD population.
- name: Lymphoma
  description: >-
    Hodgkin and non-Hodgkin lymphoma both produce lymphadenopathy with systemic
    symptoms and can generate reactive Castleman-like nodal changes; iMCD-NOS in
    particular mimics indolent lymphoma. Lymphoma is a formal exclusion in the
    iMCD diagnostic criteria. The relationship also runs the other way in
    HHV-8+ MCD, where concurrent KSHV-driven lymphoma occurs at 28 cases per
    1,000 patient-years.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with autoimmune disease, lymphoma, and infections can experience Castleman‐like changes in reactive lymph nodes, and thus histologic findings must be combined with clinical and laboratory findings to accurately diagnose iMCD."
    explanation: Names lymphoma among the conditions producing Castleman-like reactive nodes.
- name: Hemophagocytic lymphohistiocytosis
  disease_term:
    preferred_term: hemophagocytic lymphohistiocytosis
    term:
      id: MONDO:0015540
      label: hemophagocytic syndrome
  description: >-
    iMCD-TAFRO presents as an acute cytokine storm with fever, cytopenias,
    organomegaly, and multiorgan failure that is clinically close to HLH or to
    sepsis. Both require urgent treatment and the therapies differ, so the
    distinction is made on ferritin, soluble IL-2 receptor, hemophagocytosis on
    marrow, HLH genetic and trigger workup, and above all the lymph node
    histopathology.
  distinguishing_features:
  - >-
      Lymph node biopsy showing Castleman histopathology; absence of the ferritin and hemophagocytosis profile typical of HLH.
  evidence:
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rapid onset cytokine storm with severe inflammation, anasarca, thrombocytopenia, and small volume lymphadenopathy, similar to hemophagocytic lymphohistiocytosis or sepsis, are the hallmarks of iMCD‐TAFRO."
    explanation: Names HLH and sepsis as the clinical mimics of iMCD-TAFRO.
- name: Systemic lupus erythematosus and other connective tissue diseases
  description: >-
    Autoimmune disease produces lymphadenopathy with Castleman-like reactive
    nodal changes and is a formal exclusion for iMCD. The overlap is not only
    diagnostic: 47% of iMCD patients carry at least one CTD-associated
    autoantibody versus 17% of healthy controls, which is part of why an
    autoimmune etiology for iMCD remains under active consideration.
  disease_term:
    preferred_term: systemic lupus erythematosus
    term:
      id: MONDO:0007915
      label: systemic lupus erythematosus
  evidence:
  - reference: PMID:40181993
    reference_title: "Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For example, connective tissue disorders (CTDs) and iMCD share many clinical features, and autoantibodies have been anecdotally reported in individual iMCD patients."
    explanation: States the clinical and serologic overlap that makes this differential difficult.
genetic:
- name: NCOA4
  gene_term:
    preferred_term: NCOA4
    term:
      id: hgnc:7671
      label: NCOA4
  relationship_type: SOMATIC_DRIVER
  variant_origin: SOMATIC
  presence: Somatic mutation in lesional tissue
  frequency: L261F in about 23% of idiopathic multicentric CD.
  notes: >-
    The most frequently reported recurrent somatic allele in iMCD. Its functional
    consequence in this disease has not been characterized and no mechanism links
    it to the lymph node lesion, so it is recorded as a recurrence observation.
  evidence:
  - reference: PMID:33804823
    reference_title: "A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases"
    explanation: Gives the recurrence frequency of NCOA4 L261F in iMCD.
treatments:
- name: Siltuximab
  description: >-
    Anti-IL-6 monoclonal antibody. FDA-approved first-line therapy across
    all iMCD subtypes (TAFRO, IPL, NOS). Directly binds and neutralizes
    human IL-6. Durable tumor and symptomatic response occurred in 34% of
    treated patients in the registration trial, and progression-free survival was
    significantly prolonged. It is also recommended for unresectable UCD with an
    inflammatory syndrome. Despite this it reached only 8.7% of US iMCD patients
    in a claims analysis.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: IL-6 Overproduction
    treatment_effect: INHIBITS
    description: Neutralizes circulating human IL-6 before it engages gp130.
    evidence:
    - reference: PMID:25042199
      reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6."
      explanation: States the target of the antibody and the rationale for blocking it.
  - target: CXCL13 Chemokine Axis Elevation
    treatment_effect: INHIBITS
    description: >-
      Serum CXCL13 falls by day 8 in responders, and a 17% fall predicts later
      response, so CXCL13 is a downstream pharmacodynamic readout of IL-6 blockade.
    evidence:
    - reference: PMID:36433996
      reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points."
      explanation: Demonstrates the pharmacodynamic effect on this node.
  evidence:
  - reference: NCIT:C61084
    reference_title: "Siltuximab (NCIT)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Siltuximab | Accepted_Therapeutic_Use_For | - | - | multicentric Castleman's disease (MCD)"
    explanation: >-
      NCI Thesaurus asserts accepted therapeutic use of siltuximab for
      multicentric Castleman disease.
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first‐line therapy for all subtypes of iMCD is siltuximab, an IL‐6 antagonist."
    explanation: Establishes siltuximab as the cross-iMCD first-line therapy regardless of TAFRO/IPL/NOS subtyping.
  - reference: PMID:25042199
    reference_title: "Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012)."
    explanation: >-
      The randomised placebo-controlled result, which is also the source of the
      34% response rate quoted in the description.
  - reference: DOI:10.1182/bloodadvances.2022007112
    reference_title: "Siltuximab is associated with improved progression-free survival in idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progression-free survival (PFS) was significantly improved in siltuximab-treated patients compared with those receiving placebo (P = .0001)."
    explanation: Post hoc analysis establishing the progression-free survival benefit.
  - reference: PMID:33284946
    reference_title: "International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome."
    explanation: Extends the siltuximab recommendation to inflammatory unresectable UCD.
  treatment_term:
    preferred_term: anti-IL-6 monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: siltuximab
      term:
        id: NCIT:C61084
        label: Siltuximab
- name: Tocilizumab
  description: >-
    Anti-IL-6-receptor monoclonal antibody. Approved in Japan for MCD;
    recommended internationally as alternative when siltuximab is
    unavailable.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  target_mechanisms:
  - target: JAK-STAT3 Signaling Activation
    treatment_effect: INHIBITS
    description: Blocks the IL-6 receptor, preventing gp130-dependent JAK-STAT3 activation.
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD."
    explanation: Establishes tocilizumab as the substitute first-line agent where siltuximab is unavailable.
  treatment_term:
    preferred_term: anti-IL-6 receptor monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
- name: Corticosteroids
  description: >-
    Given with anti-IL-6 therapy as part of preferred first-line iMCD treatment.
    Corticosteroid monotherapy is explicitly not the recommended approach - in a
    US claims analysis 39% of iMCD patients received corticosteroid monotherapy
    while only 9.8% received IL-6-targeted therapy, which the authors identify
    as a major unmet treatment need.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD."
    explanation: Places corticosteroids as an adjunct to anti-IL-6 therapy rather than a standalone treatment.
  - reference: DOI:10.1182/bloodadvances.2021004441
    reference_title: "Epidemiology and treatment patterns of idiopathic multicentric Castleman disease in the era of IL-6–directed therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among patients with iMCD, 39% received corticosteroid monotherapy, 33.1% received no iMCD-directed treatment, and 9.8% received interleukin-6 (IL-6)–targeted therapy with tocilizumab or siltuximab."
    explanation: Quantifies the real-world over-reliance on corticosteroid monotherapy described here.
- name: Combination Cytotoxic Chemotherapy
  description: >-
    Adjuvant multiagent cytotoxic chemotherapy is recommended for the most severe
    iMCD, and for severe disease that fails first-line IL-6 blockade. In
    iMCD-IPL specifically, myeloma-like and IL-6-blocking regimens gave higher
    response rates and longer time to next treatment than lymphoma-like regimens,
    so regimen choice should follow the subtype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:30181172
    reference_title: "International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the most severe cases, adjuvant combination chemotherapy is recommended."
    explanation: The guideline statement placing chemotherapy in severe iMCD.
  - reference: PMID:38356434
    reference_title: "Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment."
    explanation: Supports the subtype-dependent regimen choice described here.
- name: Sirolimus
  description: >-
    mTOR inhibitor for anti-IL-6-refractory iMCD, with a mechanistic rationale
    from PI3K/AKT/mTOR pathway activation in refractory iMCD-TAFRO. In the
    three-patient index series sirolimus attenuated CD8+ T cell activation,
    lowered VEGF-A, and produced remissions of 66, 19, and 19 months. A
    single-arm Phase II trial (NCT03933904) is testing it prospectively.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: PI3K/AKT/mTOR Pathway Activation
    treatment_effect: INHIBITS
    description: Direct mTOR inhibition, the mechanism this treatment was selected for.
    evidence:
    - reference: PMID:31408438
      reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels."
      explanation: Demonstrates the pharmacodynamic effect on the targeted pathway.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  evidence:
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sirolimus induced clinical benefit responses in all three patients with durable and ongoing remissions of 66, 19, and 19 months."
    explanation: Gives the clinical responses in the index series.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904)."
    explanation: Links the mechanism to the registered prospective trial.
- name: Ruxolitinib
  description: >-
    JAK1/2 inhibitor under investigation as second-line therapy in iMCD
    patients refractory or intolerant to anti-IL-6 therapy; multicenter
    Phase II trial NCT07085039 enrolling since 2025. Acting on JAK rather than
    on IL-6 itself would in principle cover signaling driven by other gp130
    ligands.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: JAK-STAT3 Signaling Activation
    treatment_effect: INHIBITS
    description: >-
      Inhibits JAK1/2 downstream of gp130, the shared node for IL-6, vIL-6, and
      other gp130-family cytokines.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
clinical_trials:
- name: NCT03933904
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    A Phase II, single-arm, open-label, multi-center study of sirolimus
    in previously-treated idiopathic multicentric Castleman disease.
  evidence:
  - reference: clinicaltrials:NCT03933904
    reference_title: "A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease."
    explanation: ClinicalTrials.gov-listed Phase II trial evaluating sirolimus in previously-treated iMCD.
- name: NCT07085039
  phase: PHASE_II
  status: RECRUITING
  description: >-
    A Phase II, single-arm, open-label, multi-center study of
    ruxolitinib in adults with iMCD that has not improved with
    siltuximab or tocilizumab, or who cannot take those medications.
  evidence:
  - reference: clinicaltrials:NCT07085039
    reference_title: "A Phase II, Single-Arm Open-Label Multi-Center Study of Ruxolitinib in Previously Treated Idiopathic Multicentric Castleman Disease"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The research study is being done to look at the effects of ruxolitinib in adults with idiopathic Multicentric Castleman Disease (iMCD) that has not gotten better from taking siltuximab or tocilizumab, or who cannot take those medications."
    explanation: ClinicalTrials.gov-listed Phase II trial evaluating ruxolitinib as second-line therapy in iMCD.
discussions:
- discussion_id: gap_imcd_initiating_process
  prompt: >-
    What initiates idiopathic multicentric Castleman disease - autoimmunity, an
    ectopic clonal cytokine source, a non-HHV-8 infection, or a germline
    inflammatory predisposition?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Unknown iMCD Initiating Process
  - pathophysiology#Autoantibody-Mediated Immune Dysregulation
  - pathophysiology#Somatic Stromal Cell Mutation
  rationale: >-
    This is the field's central unanswered question and everything downstream
    depends on it. Three candidate processes were formally proposed in 2014 and
    none has been confirmed or excluded since. Viral-Track sequencing of 22 UCD
    and 19 iMCD nodes found no shared viral signature, weakening the infectious
    candidate; autoantibody enrichment supports but does not establish the
    autoimmune candidate; and recurrent somatic alleles support but do not
    establish a clonal candidate. Because the etiology is unknown, iMCD is
    defined by exclusion, has no diagnostic biomarker, and is treated with a
    single-cytokine blockade that fails in most patients.
  evidence:
  - reference: PMID:24622327
    reference_title: "HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases."
    explanation: >-
      States the gap as an explicit research priority. Two of the four priorities
      listed (consensus criteria, registry) have since been met; the first two have not.
  - reference: DOI:10.1038/s41598-025-85193-x
    reference_title: "No evidence for active viral infection in unicentric and idiopathic multicentric Castleman disease by Viral-Track analysis"
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "While uncontrolled infection with human herpesvirus-8 (HHV-8) is responsible for the cytokine storm in a portion of multicentric CD (HHV-8-associated MCD) cases, the etiology of unicentric CD (UCD) and HHV-8-negative/idiopathic MCD (iMCD) is unknown."
    explanation: Confirms the gap is still open as of a 2025 sequencing study.
  proposed_experiments:
  - experiment_id: exp_imcd_paired_multiomic_etiology_screen
    name: Paired serologic, viral, and clonality screen across adjudicated iMCD subtypes
    description: >-
      In a prospectively enrolled, expert-adjudicated iMCD cohort stratified by
      TAFRO/IPL/NOS, run in parallel on the same patients: unbiased
      autoantigen-array and functional receptor-blocking serology, metagenomic
      and viral-capture sequencing of lymph node and plasma, and deep targeted
      sequencing of sorted stromal, plasma cell, and T cell fractions for
      clonality. Testing the three candidate etiologies on shared samples is what
      makes them comparable; the existing evidence for each comes from separate
      cohorts.
    would_support:
    - pathophysiology#Autoantibody-Mediated Immune Dysregulation
    - pathophysiology#Somatic Stromal Cell Mutation
    supporting_outcome:
    - >-
        A candidate process is enriched in one subtype and co-segregates with disease activity, with the other two candidates negative in the same patients.
    refuting_outcome:
    - >-
        All three candidate processes are negative or are equally present in disease controls, indicating the initiating process lies outside the three proposed categories.
- discussion_id: gap_imcd_no_disease_model
  prompt: >-
    Can a cell-culture or animal model be built that reproduces the Castleman
    lymph node lesion, and until one exists how can any proposed mechanism be
    tested causally?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Lymph Node Stromal Cell Activation and Expansion
  - pathophysiology#Follicular Dendritic Cell Meshwork Expansion
  - pathophysiology#Stromal VEGF Overproduction and Neovascularization
  rationale: >-
    Every mechanism node in this entry derives from human tissue association -
    spatial transcriptomics, immunohistochemistry, serum proteomics - with no
    perturbation experiment behind it, because no validated model system exists.
    The authors of the largest spatial study state this limitation directly and
    note that the disease may have no genetic basis to engineer, being instead
    immune-driven by antigenic stimuli whose origin is unknown. This is the
    upstream reason the causal direction of the stromal model cannot be settled:
    stromal activation could be driving the cytokine storm or responding to it.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The absence of accurate cell culture or murine models limits functional studies of CD."
    explanation: States the gap in the authors' own words.
  proposed_experiments:
  - experiment_id: exp_cd_lymphoid_organoid_stromal_perturbation
    name: Human lymphoid organoid with defined stromal perturbation
    description: >-
      Build a human lymphoid organoid or lymph-node-on-chip containing primary
      follicular dendritic cells, T-zone and perivascular reticular cells, naive
      B cells, and endothelium, then perturb single stromal populations
      (constitutive PDGFRB N666S expression, forced VEGFA or IL6 expression,
      lymphotoxin-beta receptor stimulation, DLL4-NOTCH1 blockade) and score for
      the defining tissue readouts: CD21 meshwork expansion, concentric mantle-zone
      B cell layering, perifollicular neovascularization, and plasmablast output.
    would_support:
    - pathophysiology#Lymph Node Stromal Cell Activation and Expansion
    - pathophysiology#Follicular Dendritic Cell Meshwork Expansion
    supporting_outcome:
    - >-
        Perturbing a single stromal population reproduces the onion-skinning and penetrating-vessel architecture, establishing stromal activation as sufficient rather than reactive.
    refuting_outcome:
    - >-
        No stromal perturbation reproduces the architecture, indicating the lesion requires a systemic or hematopoietic input absent from the organoid.
- discussion_id: gap_imcd_anti_il6_nonresponse
  prompt: >-
    What drives disease in the majority of iMCD patients who do not respond to
    IL-6 blockade, and can non-responders be identified before weeks of failed
    therapy have passed?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#IL-6 Overproduction
  - pathophysiology#PI3K/AKT/mTOR Pathway Activation
  - pathophysiology#CXCL13 Chemokine Axis Elevation
  rationale: >-
    Siltuximab produced a durable response in 34% of patients in the registration
    trial and is effective in roughly 34-50% of cases, so most patients treated
    with the only approved drug do not benefit from it, and severe patients have
    a narrow window before escalation to cytotoxic chemotherapy is needed. Two
    partial answers exist and neither is complete: PI3K/AKT/mTOR activation
    identified in three refractory TAFRO patients, and an early CXCL13 fall that
    predicts response by day 8. What drives the remaining non-responders is not
    known.
  evidence:
  - reference: PMID:36433996
    reference_title: CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking."
    explanation: States both halves of the gap - unexplained non-response and missing early biomarkers.
  - reference: PMID:31408438
    reference_title: "Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular underpinnings of interleukin-6(IL-6)-blockade refractory patients remain unknown; no targeted therapies exist."
    explanation: The explicit statement of the gap that motivated the mTOR work.
  proposed_experiments:
  - experiment_id: exp_imcd_pretreatment_endotype_stratified_trial
    name: Pretreatment endotype stratification with response-adaptive assignment
    description: >-
      Profile serum proteome, lymph node spatial transcriptome, and PBMC
      phospho-signaling before first-line therapy in an iMCD cohort, assign a
      candidate endotype (IL-6-high, CXCL13-high, TNF-high, mTOR-high), then
      randomize within endotype to IL-6 blockade versus the endotype-matched
      agent (sirolimus for mTOR-high, JAK inhibition for broad gp130 signaling).
      A day-8 CXCL13 readout is embedded as a prespecified early futility rule.
    would_support:
    - mechanistic_hypotheses#immune_stromal_dysregulation
    - mechanistic_hypotheses#il6_independent_mtor
    supporting_outcome:
    - >-
        Endotype-matched assignment beats uniform IL-6 blockade on durable response, and day-8 CXCL13 identifies non-responders before week 3.
    refuting_outcome:
    - >-
        Response rates are the same regardless of pretreatment endotype, indicating the proposed endotypes are descriptive rather than predictive.
- discussion_id: gap_stromal_cytokine_source_causality
  prompt: >-
    Are activated lymph node stromal cells the source that drives the Castleman
    cytokine excess, or do they expand and secrete in response to a cytokine
    excess generated elsewhere?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - pathophysiology#Lymph Node Stromal Cell Activation and Expansion
  - pathophysiology#Stromal VEGF Overproduction and Neovascularization
  - pathophysiology#IL-6 Overproduction
  rationale: >-
    The spatial data establish where VEGF and IL-6 transcripts are, not what
    started them. The question is not academic: if stromal cells are the driver,
    stroma-directed agents (lymphotoxin-beta receptor fusion proteins, VEGF
    inhibitors, NOTCH inhibitors) are rational; if they are responders, those
    agents treat a consequence. The evidence is one observational cohort of
    22 cases with no perturbation, and the subtype-specific IL-6 source data
    point the other way for TAFRO, where endothelial IL-6 is proposed to be
    secondary to the cytokine storm.
  evidence:
  - reference: DOI:10.1038/s41467-025-61214-1
    reference_title: "Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A limitation of the study is the moderate sample size and its observational nature."
    explanation: >-
      The authors' own statement of the limitation that leaves causal direction
      unresolved.
  - reference: PMID:40931874
    reference_title: "Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype."
    explanation: >-
      Argues explicitly for the responder interpretation in at least one subtype,
      which is why the question is recorded as open rather than settled.
- discussion_id: controversy_imcd_ipl_as_subtype
  prompt: >-
    Should iMCD-IPL be recognized as a formal subtype separate from iMCD-NOS, and
    if so, does the CDCN severity classification apply to it?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - has_subtypes#iMCD-IPL
  - has_subtypes#iMCD-NOS
  rationale: >-
    The CDCN consensus criteria recognize only TAFRO and NOS, but IPL accounted
    for 45.2% of 228 iMCD-NOS patients in the largest cohort and behaved
    differently: higher inflammatory state, longer overall survival, better
    response to myeloma-like and IL-6-blocking regimens than to lymphoma-like
    ones, and - importantly - no survival difference between CDCN-severe and
    CDCN-non-severe patients, meaning the severity classification does not
    stratify this group. The 2026 expert perspective now lists IPL as one of
    three iMCD subtypes. Recording it as a subtype here follows that, but the
    formal criteria have not been revised.
  evidence:
  - reference: PMID:38356434
    reference_title: "Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whether these patients should be excluded from the current classification system lacks sufficient evidence."
    explanation: States the controversy directly.
  - reference: PMID:38356434
    reference_title: "Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification."
    explanation: >-
      The specific finding that the existing severity classification fails to
      stratify IPL patients, which is the practical stake in this controversy.
  - reference: DOI:10.1002/art.43269
    reference_title: "Expert Perspective: Diagnosis and Treatment of Castleman Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three subtypes are iMCD–thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, organomegaly (TAFRO); iMCD–idiopathic plasmacytic lymphadenopathy (IPL); and iMCD–not otherwise specified (NOS)."
    explanation: The expert review that treats IPL as a subtype, which this entry follows.
- discussion_id: controversy_imcd_malignancy_risk
  prompt: >-
    Does iMCD raise the risk of subsequent myeloid and solid malignancy, or is
    the reported excess an artifact of misclassifying malignancy-associated
    reactive lymphadenopathy as iMCD?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - has_subtypes#iMCD-TAFRO
  - has_subtypes#iMCD-NOS
  rationale: >-
    A systematic review and a claims-based study both reported increased myeloid
    and solid malignancy after iMCD, but in the expert-adjudicated ACCELERATE
    cohort only one patient developed a myeloid malignancy and no patient
    developed diffuse large B-cell lymphoma, with a malignancy rate comparable to
    the claims study's controls. The two readings have opposite implications: an
    excess means iMCD warrants cancer surveillance, whereas an artifact means
    claims-based iMCD cohorts contain patients who only ever had a malignancy.
    Because iMCD diagnostic criteria explicitly exclude concurrent malignancy,
    strict adjudication could also be excluding genuine iMCD patients who then
    developed cancer, so neither cohort settles it.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this cohort, few patients developed a malignancy following the diagnosis of iMCD."
    explanation: The adjudicated-registry finding on one side of the controversy.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conversely, our strict inclusion criteria might have inadvertently excluded true iMCD patients who also developed malignancies."
    explanation: >-
      The authors' own statement of why their negative result does not settle the
      question either.
- discussion_id: gap_tafro_renal_lesion_mechanism
  prompt: >-
    Which mediator causes the glomerular endothelial injury of TAFRO, and would
    targeting it prevent the dialysis requirement?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Endothelial Injury and Renal Thrombotic Microangiopathy
  - phenotypes#Acute Renal Failure
  rationale: >-
    Renal failure is the most common post-diagnosis morbidity in iMCD (48%) and
    27% of patients require dialysis, so the renal lesion drives a large share of
    the disease's burden. The histology - membranoproliferative-like injury and
    thrombotic microangiopathy - points at glomerular endothelium, and IL-6 and
    VEGF are the proposed mediators, but the review that summarizes this states
    plainly that their role in renal injury is not well understood. No therapy is
    directed at the renal lesion specifically.
  evidence:
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The role of these cytokines in renal injury, however, is not well understood."
    explanation: States the mechanistic gap directly.
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following the iMCD diagnosis, 48% (n=49) of the cohort developed acute renal failure"
    explanation: Quantifies why this gap matters clinically.
  - reference: PMID:34208103
    reference_title: "TAFRO Syndrome with Renal Thrombotic Microangiopathy: Insights into the Molecular Mechanism and Treatment Opportunities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therefore, it is suggested that there are factors other than IL-6 and VEGF, which dominate the glomerular injury."
    explanation: >-
      Narrows the gap: the review concludes the two cytokines usually invoked are
      not the dominant cause of the glomerular lesion, so the mediator is unidentified.
  proposed_experiments:
  - experiment_id: exp_tafro_renal_biopsy_mediator_mapping
    name: Spatial mediator mapping of TAFRO renal biopsies
    description: >-
      Apply the same spatial transcriptomic and in situ hybridization panel used
      on Castleman lymph nodes to banked TAFRO kidney biopsies, localizing IL6,
      VEGFA, complement components, and endothelial injury markers to glomerular
      compartments, and compare with thrombotic microangiopathy from other causes
      and with membranoproliferative glomerulonephritis controls.
    would_support:
    - pathophysiology#Endothelial Injury and Renal Thrombotic Microangiopathy
    supporting_outcome:
    - >-
        A specific mediator localizes to injured glomerular endothelium in TAFRO but not in the comparator lesions, nominating a renal-directed target.
    refuting_outcome:
    - >-
        The TAFRO renal lesion is indistinguishable from other causes of thrombotic microangiopathy, indicating a shared final common pathway rather than a Castleman-specific mediator.
- discussion_id: gap_imcd_diagnostic_biomarker
  prompt: >-
    Is there a serum or tissue marker that can establish a diagnosis of iMCD,
    rather than the current diagnosis by exclusion?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - diagnosis#International consensus diagnostic criteria for iMCD
  - biochemical#C-X-C Motif Chemokine Ligand 13 (CXCL13)
  - biochemical#Interleukin-6 (IL-6)
  rationale: >-
    iMCD is diagnosed on non-specific clinical features plus characteristic but
    non-specific histopathology, after excluding infection, malignancy, and
    autoimmune disease - and Castleman-like nodal changes occur in all three of
    those. There is no known diagnostic serum biomarker, which the natural
    history study names as a contributor to underdiagnosis. CXCL13 is the closest
    candidate but was validated as a predictor of siltuximab response, not as a
    diagnostic discriminator, and the reported comparison groups included related
    diseases rather than the full mimic set a diagnostic test would face.
  evidence:
  - reference: DOI:10.3324/haematol.2023.283603
    reference_title: "Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Underdiagnosis is likely as diagnostic criteria were not developed until 2017, and there is no known diagnostic serum biomarker."
    explanation: States the absence of a diagnostic biomarker and its consequence.
  proposed_experiments:
  - experiment_id: exp_imcd_diagnostic_biomarker_mimic_cohort
    name: Biomarker discovery against the full iMCD mimic set
    description: >-
      Compare serum proteomes of adjudicated iMCD against each mimic the
      diagnostic criteria require excluding - IgG4-related disease, HHV-8+ MCD,
      POEMS, lymphoma, SLE, and HLH - powered per comparator rather than pooling
      them as "related diseases", and evaluate candidate markers including CXCL13
      as a diagnostic classifier with prespecified sensitivity and specificity
      targets.
    would_support:
    - biochemical#C-X-C Motif Chemokine Ligand 13 (CXCL13)
    supporting_outcome:
    - >-
        A marker or panel separates iMCD from every individual mimic at clinically useful sensitivity and specificity.
    refuting_outcome:
    - >-
        Candidate markers separate iMCD from healthy controls but not from individual mimics, confirming that diagnosis by exclusion is unavoidable with serum markers alone.
datasets:
- accession: geo:GSE290549
  title: Common Connective Tissue Disorder and Anti-Cytokine Autoantibodies are Enriched in Idiopathic Multicentric Castleman Disease Patients [CTD Array version 3]
  description: We measued IgG autoantibodies associated with Connective Tissue Diseases (CTDs) and Anti-Cytokine Antibodies (ACA) in idiopathic Multicentric Castleman Disease (iMCD) patients and healthy controls who received the BNT162b2 vaccine.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PROTEOMICS
  sample_count: 151
  publication: PMID:40181993
  notes: Identified by GEO DataSets index search for Castleman Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values. This is the autoantibody array underlying the autoimmune_etiology hypothesis group.
- accession: ega:EGAS00001007388
  title: Whole-genome sequencing of twins with Castleman disease and an unaffected sibling.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001007390
  title: Single cell landscape of Multicentric Castleman Disease in monozygotic twins
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001007557
  title: WGS data of an individual with Unicentric Castleman Disease
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: WGS
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Castleman Disease"); description-level mentions were not accepted. EGA study_type: Whole Genome Sequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
notes: >-
  Scope note: this entry covers the HHV-8-negative idiopathic multicentric form
  only. It was split out of the former umbrella `Castleman_Disease` entry,
  together with `Unicentric_Castleman_Disease` and
  `HHV-8-Associated_Multicentric_Castleman_Disease`, because those forms have
  different causes, different first-line therapy, and different confirmatory
  tests - differences that live in `pathophysiology`, `treatments` and
  `diagnosis`, none of which carry a `subtype:` discriminator. The curated union
  is kept in `kb/groupings/Castleman_Disease.yaml`.

  Subtype note: iMCD-TAFRO, iMCD-IPL and iMCD-NOS are kept as `has_subtypes`
  rather than as separate entries because they share an etiology (unknown), the
  same diagnostic criteria, and the same first-line drug. TAFRO is the closest
  to the line - it has its own MONDO term (MONDO:0018702), its own Japanese
  diagnostic criteria, and two pathophysiology nodes here that do not apply to
  its siblings - and should be promoted to its own entry if a subtype-specific
  first-line therapy is established, plausibly sirolimus via NCT03933904.
  Whether iMCD-IPL should be a formal subtype at all is contested and recorded
  as `controversy_imcd_ipl_as_subtype`.

  Evidence note: the stromal, autoantibody, mTOR and subtype-specific IL-6-source
  nodes rest on human tissue or serum association without any perturbation
  experiment, because no validated animal or cell-culture model of Castleman
  disease exists. That limitation is recorded as its own knowledge gap
  (gap_imcd_no_disease_model) and is why those nodes carry EMERGING hypothesis
  groups and, where applicable, HYPOTHETICAL mechanism confidence rather than
  being asserted as established mechanism.

📚

References & Deep Research

References

6

DOI:10.1038/s41572-021-00317-7

Castleman disease

No top-level findings curated for this source.

DOI:10.1016/j.bvth.2024.100006

Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

No top-level findings curated for this source.

DOI:10.1016/j.hoc.2017.09.001

Epidemiology of Castleman Disease

No top-level findings curated for this source.

DOI:10.1182/asheducation-2018.1.318

Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease

No top-level findings curated for this source.

DOI:10.14740/jh1343

Siltuximab in Idiopathic Multicentric Castleman Disease: Real-World Experience

No top-level findings curated for this source.

DOI:10.7759/cureus.73156

The Enigma of Idiopathic Multicentric Castleman Disease: An Elusive Diagnosis

No top-level findings curated for this source.

Idiopathic Multicentric Castleman Disease

Ask OpenScientist

OpenScientist Report

Mappings

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Related Datasets

Clinical Trials

Source YAML

References & Deep Research

References