Eosinophilic Fasciitis

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Classifications

Harrison's Chapter

🔗

Mappings

MONDO

MONDO:0009175 eosinophilic fasciitis

Primary MONDO disease identifier for eosinophilic fasciitis (Shulman syndrome). MONDO records the Orphanet:3165 and OMIM:226350 cross-references; the schema mappings block has no dedicated Orphanet slot, so the Orphanet:3165 equivalence is captured here as provenance.

NCIT

NCIT:C112116 Eosinophilic Fasciitis

NCI Thesaurus concept for Eosinophilic Fasciitis (Shulman syndrome), cross-referenced by the MONDO term.

NCIT

NCIT:C112116 Eosinophilic Fasciitis

NCI Thesaurus concept for Eosinophilic Fasciitis (Shulman syndrome), cross-referenced by the MONDO term.

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Discussions and Knowledge Gaps

1

Eosinophilic fasciitis is associated with hematologic disorders, especially aplastic anemia; how should this paraneoplastic/associated marrow disease be represented and surveilled?

INTERPRETATION ef-hematologic-association

A minority of EF patients have an associated hematologic disorder (aplastic anemia, myelodysplastic syndrome, lymphoma, monoclonal gammopathy). This association carries prognostic weight and warrants surveillance for cytopenias, but EF itself is not caused by these clonal diseases. Modeled as a discussion because dismech has no top-level comorbidity slot on the Disease class.

Show evidence (1 reference)

PMID:9283913 SUPPORT Human Clinical

"Eosinophilic fasciitis (EF) is a rare connective tissue disorder which is frequently associated with hematologic disorders, especially aplastic anemia"

Establishes the recognized association between EF and hematologic disorders, especially aplastic anemia.

⚙

Pathophysiology

4

Type 2 Immune Activation and Eosinophil Recruitment

A triggering insult (commonly strenuous exertion, drug exposure such as immune checkpoint inhibitors, or infection) drives a Th2-skewed immune response in the deep fascia with recruitment of eosinophils and T cells. Eosinophils are detected within the fascia and degranulate, releasing effector molecules. Activators of the Th2-M2 pathway (STAT6, IL-4) are upregulated at the muscle-fascia interface.

Eosinophil CL:0000771 T cell CL:0000084 M2 macrophage (CD206+) CL:0000890

Eosinophil degranulation GO:0043308 ↑ INCREASED Adaptive (type 2) immune response GO:0002250 ↑ INCREASED

Downstream

TGF-beta-Driven Fascial Fibroblast Activation

Show evidence (3 references)

PMID:36130069 SUPPORT Human Clinical

"CD206+ macrophages predominate and eosinophils are detected within the fascia in the majority of cases"

Direct human biopsy study showing eosinophil infiltration and M2 macrophage predominance in the fascia, supporting type 2 immune activation.

PMID:36130069 SUPPORT Human Clinical

"Activators of the so-called Th2-M2 pathway like STAT6 and IL-4 are upregulated leading to high expression levels of CD206."

Documents upregulation of the Th2-M2 axis (STAT6/IL-4) in EF fascia, supporting the type 2 immune mechanism.

PMID:40399177 SUPPORT Human Clinical

"ICIs can exceptionally induce eosinophilic fasciitis (EF)."

Supports immune checkpoint inhibitors as a drug trigger of EF, consistent with checkpoint blockade unleashing the type 2 immune/eosinophil response.

TGF-beta-Driven Fascial Fibroblast Activation

Eosinophil effector molecules and type 2 cytokines (including TGF-beta, IL-4, IL-13) activate resident fascial fibroblasts, driving their differentiation toward collagen-producing myofibroblasts. This is the central profibrotic effector step shared with other scleroderma-like fibrosing disorders.

Fascial fibroblast CL:0000057 Myofibroblast CL:0000186

TGF-beta receptor signaling GO:0007179 ↑ INCREASED Positive regulation of fibroblast proliferation GO:0048146 ↑ INCREASED

Downstream

Fascial Collagen Deposition and Fibrosis

Show evidence (2 references)

PMID:11890876 SUPPORT Human Clinical

"Activation of eosinophils and disordered regulation of fibroblast collagen synthesis, apoptosis, and proliferation are recurrent findings in these disorders."

Establishes eosinophil activation coupled to dysregulated fibroblast collagen synthesis/proliferation as a recurrent mechanism in eosinophilic fasciitis and related scleroderma-like disorders.

PMID:11890876 SUPPORT Human Clinical

"Cytokines such as transforming growth factor-beta, interleukin-4, interleukin-13, and connective tissue growth factor contribute to fibrosis in these disorders"

Supports TGF-beta and type 2 cytokine signaling as drivers of the fibrotic response in the scleroderma-like disorders including EF.

Fascial Collagen Deposition and Fibrosis

Activated myofibroblasts deposit excess collagen and extracellular matrix in the deep fascia and subcutaneous septa, producing fascial thickening and fibrosis with an accompanying inflammatory infiltrate.

Myofibroblast CL:0000186

Collagen fibril organization GO:0030199 ↑ INCREASED Extracellular matrix organization GO:0030198 ↑ INCREASED

Downstream

Fascial Induration and Joint Contractures

Show evidence (1 reference)

PMID:36130069 SUPPORT Human Clinical

"EF is a rare disease characterized by fibrosis and inflammation of the fascia"

Confirms fibrosis and inflammation of the fascia as the defining pathological end-state of EF.

Fascial Induration and Joint Contractures

Progressive fascial fibrosis produces woody skin induration, peau d'orange texture, and the groove sign, and ultimately restricts joint mobility, leading to flexion contractures and disability, the clinical end-state of the disease.

Show evidence (1 reference)

PMID:41763542 SUPPORT Human Clinical

"Clinical presentations range from rapidly advancing fibrosis leading to joint contractures to fluctuating inflammatory episodes."

Supports progression of fascial fibrosis to joint contractures as the disabling clinical end-state.

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Histopathology

1

Thickened Fascia with Inflammatory Infiltrate and Fibrosis

Fascial thickening with an inflammatory infiltrate composed predominantly of lymphocytes and plasma cells, with or without eosinophils, and fibrosis; eosinophilic infiltration of the fascia is seen in roughly half of cases and is more likely early in the disease.

Show evidence (2 references)

PMID:32913886 SUPPORT Human Clinical

"findings consist of hypertrophied fascia with inflammatory cell infiltration (lymphocytes and plasma cells)"

Describes the characteristic histopathology: hypertrophied fascia with a lymphoplasmacytic inflammatory infiltrate.

PMID:32913886 SUPPORT Human Clinical

"Eosinophilic infiltration of the fascia is observed in approximately 50% of cases and more likely to be found in early stages of the disease."

Documents that fascial eosinophilic infiltration is present in only ~50% of cases and is stage-dependent, so it is supportive but not required.

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Pathograph

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

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Phenotypes

8

Blood 1

Peripheral Eosinophilia FREQUENT Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"Eosinophilia was found in 31 patients (68.9%)."

A 45-patient cohort found peripheral eosinophilia in 68.9% of patients, supporting a FREQUENT band.

Integument 3

Symmetric Skin Induration VERY_FREQUENT Thickened skin HP:0001072

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"subcutaneous swelling and induration (95.6%)"

Cohort data show subcutaneous swelling and induration in 95.6% of EF patients, the core cutaneous manifestation.

Peau d'Orange Skin Texture OCCASIONAL Thickened skin HP:0001072

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"peau d'orange appearance (13.3%)"

Documents peau d'orange appearance as a characteristic (if less frequent) cutaneous sign in the EF cohort.

Groove Sign FREQUENT Thickened skin HP:0001072

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"groove sign (42.2%)"

Cohort reports the characteristic groove sign in 42.2% of EF patients.

Metabolism 1

Limb Edema Peripheral edema HP:0012398

Show evidence (1 reference)

PMID:32913886 SUPPORT Human Clinical

"Clinical presentation of eosinophilic fasciitis consists of nonpitting edema, indurated skin, and pathognomonic venous furrowing, known as “groove sign”"

Describes nonpitting edema with indurated skin and the groove sign as the characteristic clinical presentation of EF.

Musculoskeletal 1

Joint Contractures FREQUENT Flexion contracture HP:0001371

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"hand joint contractures (42.2%)"

Cohort reports hand joint contractures in 42.2% of patients, supporting contractures as a frequent disabling complication.

Constitutional 1

Arthralgia and Arthritis FREQUENT Arthralgia HP:0002829

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"arthralgia and arthritis (55.6%)"

Cohort reports arthralgia and arthritis in 55.6% of EF patients.

Other 1

Hypergammaglobulinemia FREQUENT Increased circulating IgG concentration HP:0003237

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"Hypergammaglobulinemia was seen in 23/44 (52.3%)"

Cohort reports hypergammaglobulinemia in 52.3% of EF patients.

💊

Medical Actions

5

Systemic Corticosteroids

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382 methylprednisolone CHEBI:6888

Systemic glucocorticoids (e.g., prednisone, often 0.5-1 mg/kg/day, or pulse methylprednisolone for severe disease) are the first-line treatment and are often effective in the inflammatory phase.

Mechanism Target:

Type 2 Immune Activation and Eosinophil Recruitment

Show evidence (1 reference)

PMID:32913886 SUPPORT Human Clinical

"Systemic corticosteroids remain the first-line treatment for eosinophilic fasciitis"

Directly states that systemic corticosteroids are the first-line treatment for EF.

Methotrexate

Action: Pharmacotherapy NCIT:C15986

Agent: methotrexate CHEBI:44185

Methotrexate (typically 15-25 mg/week) is the most commonly used steroid-sparing agent; early combination of corticosteroids with methotrexate is the prevailing initial regimen, particularly for morphea-like lesions or inadequate steroid response.

Mechanism Target:

Type 2 Immune Activation and Eosinophil Recruitment

Show evidence (2 references)

PMID:32913886 SUPPORT Human Clinical

"methotrexate is the most commonly used steroid-sparing agent"

Establishes methotrexate as the most commonly used steroid-sparing agent in EF.

PMID:23040360 SUPPORT Human Clinical

"oral corticosteroids remain the mainstay treatment and may be associated to an immunosuppressive drug such as methotrexate"

Supports corticosteroids as mainstay therapy combined with methotrexate as a steroid-sparing immunosuppressant.

Anti-IL-5 Biologic Therapy

Action: anti-IL-5 monoclonal antibody therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: monoclonal antibody NCIT:C20401

Anti-IL-5 monoclonal antibodies (reslizumab, mepolizumab, benralizumab) target the IL-5/eosinophil axis and have produced responses in refractory, eosinophilia-associated EF. IL-5 is the major cytokine for eosinophil growth, recruitment, activation, and survival.

Mechanism Target:

Type 2 Immune Activation and Eosinophil Recruitment

Show evidence (1 reference)

PMID:32913886 SUPPORT Human Clinical

"The addition of this medication at 3 mg/kg intravenously every 4 weeks led to the stabilization of her symptoms, and her prednisone was tapered to discontinuation."

Reports successful treatment of refractory EF with the anti-IL-5 antibody reslizumab, with symptom stabilization and steroid discontinuation.

Sirolimus (mTOR Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

The mTOR inhibitor sirolimus produced remarkable efficacy in a case of immune checkpoint inhibitor (nivolumab)-triggered EF, implicating mTOR/T-cell metabolic signaling in refractory/ICI-related disease.

Mechanism Target:

Type 2 Immune Activation and Eosinophil Recruitment

Show evidence (1 reference)

PMID:32127188 SUPPORT Human Clinical

"Eosinophilic Fasciitis Triggered by Nivolumab: A Remarkable Efficacy of the mTOR Inhibitor Sirolimus"

Case report documenting remarkable efficacy of the mTOR inhibitor sirolimus in nivolumab-triggered EF.

Physical Therapy

Action: Physical Therapy NCIT:C15302

Physical and occupational therapy are essential throughout the disease course to prevent and treat joint contractures and preserve range of motion.

Show evidence (1 reference)

PMID:32913886 SUPPORT Human Clinical

"The patient initially began receiving 60 mg of prednisone, which was slowly tapered to 10 mg daily, and started to improve quickly with physical therapy."

Documents physical therapy as part of EF management contributing to functional improvement.

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Biochemical Markers

3

Peripheral Blood Eosinophilia (INCREASED)

Show evidence (1 reference)

PMID:36768300 SUPPORT Human Clinical

"the lab results (eosinophilia, increased inflammatory markers)"

Identifies eosinophilia and increased inflammatory markers as the key laboratory abnormalities supporting the diagnosis.

Elevated Erythrocyte Sedimentation Rate (INCREASED)

Show evidence (1 reference)

PMID:36768300 SUPPORT Human Clinical

"the lab results (eosinophilia, increased inflammatory markers)"

Increased inflammatory markers (including ESR) are characteristic laboratory findings in active EF.

Polyclonal Hypergammaglobulinemia (INCREASED)

Show evidence (1 reference)

PMID:36856224 SUPPORT Human Clinical

"Hypergammaglobulinemia was seen in 23/44 (52.3%)"

Cohort data establish polyclonal hypergammaglobulinemia as a frequent laboratory abnormality.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Eosinophilic Fasciitis:

systemic sclerosis MONDO:0005100

Overlapping Features The principal differential. EF and systemic sclerosis both produce scleroderma-like skin induration, but EF spares the fingers and face, lacks Raynaud phenomenon and nailfold capillary changes, lacks anti-centromere and anti-Scl-70 autoantibodies, and lacks visceral organ involvement, and the fibrosis is centered on the deep fascia rather than the dermis.

Distinguishing Features

EF spares the fingers and face, whereas systemic sclerosis characteristically involves the fingers (sclerodactyly).
EF lacks Raynaud phenomenon and nailfold capillary changes typical of systemic sclerosis.
EF lacks anti-centromere and anti-Scl-70 (topoisomerase) autoantibodies.
EF lacks the visceral (lung, GI, kidney, heart) organ involvement seen in systemic sclerosis.
EF fibrosis is centered on the deep fascia; diagnosis requires a full-thickness fascial biopsy.

Show evidence (1 reference)

PMID:32913886 SUPPORT Human Clinical

"patients lack the classic features of scleroderma, including extracutaneous organ involvement, sclerodactyly, Raynaud disease, and nail-fold capillary changes"

Directly enumerates the scleroderma features that EF lacks (extracutaneous organ involvement, sclerodactyly, Raynaud, nailfold capillary changes), the basis for distinguishing EF from systemic sclerosis.

eosinophilia-myalgia syndrome Not Yet Curated MONDO:0004941

Overlapping Features A toxic eosinophilic syndrome historically caused by contaminated L-tryptophan ingestion, with prominent myalgia and eosinophilia that can mimic EF but is a distinct toxic entity.

Distinguishing Features

Eosinophilia-myalgia syndrome follows L-tryptophan ingestion and features prominent severe myalgia.
EF myalgia is typically milder and the disorder is centered on fascial fibrosis rather than diffuse myalgia.

Show evidence (1 reference)

PMID:23040360 SUPPORT Human Clinical

"Differential diagnoses should be ruled out, including eosinophilia-myalgia syndrome (EMS) after L-tryprophane ingestion"

Lists eosinophilia-myalgia syndrome after L-tryptophan ingestion as a key differential to exclude.

hypereosinophilic syndrome MONDO:0015691

Overlapping Features A group of disorders with persistent marked peripheral eosinophilia and multi-organ eosinophilic infiltration; shares eosinophilia with EF but differs in systemic organ involvement and lack of the fascial fibrosis pattern.

Distinguishing Features

Hypereosinophilic syndrome features sustained marked eosinophilia with end-organ eosinophilic damage across multiple organs.
EF eosinophilia is often transient and the disease is anatomically restricted to the deep fascia.

Show evidence (1 reference)

PMID:23040360 SUPPORT Human Clinical

"Differential diagnoses should be ruled out, including eosinophilia-myalgia syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes (HES), systemic sclerosis"

Lists hypereosinophilic syndromes among the differentials to exclude in suspected EF.

eosinophilic granulomatosis with polyangiitis MONDO:0015943

Overlapping Features An eosinophilic ANCA-associated vasculitis (Churg-Strauss syndrome) with asthma, eosinophilia, and multi-organ vasculitic involvement; shares eosinophilia with EF but is a systemic vasculitis rather than a fascia-restricted fibrosing disorder.

Distinguishing Features

EGPA is a systemic eosinophilic vasculitis with asthma and frequent pulmonary, cardiac, neurologic, and ANCA-associated features.
EF is anatomically restricted to the deep fascia with fibrosis and lacks vasculitis and asthma.

Show evidence (1 reference)

PMID:23040360 SUPPORT Human Clinical

"Differential diagnoses should be ruled out, including eosinophilia-myalgia syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes (HES), systemic sclerosis, Churg-Strauss syndrome"

Lists Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) among the differentials to exclude in suspected EF.

{ }

Source YAML

click to show

name: Eosinophilic Fasciitis
creation_date: "2026-06-30T00:00:00Z"
category: Complex
disease_term:
  preferred_term: Eosinophilic Fasciitis
  term:
    id: MONDO:0009175
    label: eosinophilic fasciitis
description: >-
  Eosinophilic fasciitis (Shulman syndrome) is a rare acquired, immune-mediated
  fibrosing connective-tissue disorder of the deep fascia. It is characterized by
  symmetric, painful swelling that progresses to woody induration of the
  extremities (classically sparing the fingers and face), a "peau d'orange" skin
  texture and a pathognomonic "groove sign", inflammation and thickening of the
  deep fascia, peripheral blood eosinophilia, polyclonal hypergammaglobulinemia,
  and elevated erythrocyte sedimentation rate. Onset is frequently preceded by
  strenuous physical exertion, and the disorder may be triggered by drugs
  (notably immune checkpoint inhibitors). It is regarded as a scleroderma-spectrum
  disease but is distinguished from systemic sclerosis by sparing of the fingers
  and face, absence of Raynaud phenomenon and nailfold capillary changes, and
  lack of visceral organ involvement. EF is not a Mendelian/genetic disorder and
  has no established causal gene.
notes: >-
  EF is associated with hematologic disorders, especially aplastic anemia, in a
  minority of patients (also reported with myelodysplastic syndrome, lymphoma,
  and monoclonal gammopathy); this association is captured as a discussion with
  cited evidence below. No GeneReviews article exists for EF (acquired,
  non-Mendelian disease); a PubMed title search returned no GeneReviews chapter.
pathophysiology:
- name: Type 2 Immune Activation and Eosinophil Recruitment
  description: >-
    A triggering insult (commonly strenuous exertion, drug exposure such as
    immune checkpoint inhibitors, or infection) drives a Th2-skewed immune
    response in the deep fascia with recruitment of eosinophils and T cells.
    Eosinophils are detected within the fascia and degranulate, releasing
    effector molecules. Activators of the Th2-M2 pathway (STAT6, IL-4) are
    upregulated at the muscle-fascia interface.
  cell_types:
  - preferred_term: Eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: M2 macrophage (CD206+)
    term:
      id: CL:0000890
      label: M2 macrophage
  biological_processes:
  - preferred_term: Eosinophil degranulation
    term:
      id: GO:0043308
      label: eosinophil degranulation
    modifier: INCREASED
  - preferred_term: Adaptive (type 2) immune response
    term:
      id: GO:0002250
      label: adaptive immune response
    modifier: INCREASED
  evidence:
  - reference: PMID:36130069
    reference_title: "Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CD206+ macrophages predominate and eosinophils are detected within the
      fascia in the majority of cases
    explanation: >-
      Direct human biopsy study showing eosinophil infiltration and M2
      macrophage predominance in the fascia, supporting type 2 immune activation.
  - reference: PMID:36130069
    reference_title: "Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activators of the so-called Th2-M2 pathway like STAT6 and IL-4 are
      upregulated leading to high expression levels of CD206.
    explanation: >-
      Documents upregulation of the Th2-M2 axis (STAT6/IL-4) in EF fascia,
      supporting the type 2 immune mechanism.
  - reference: PMID:40399177
    reference_title: "Immune checkpoint inhibitor-related eosinophilic fasciitis: 3 case reports with literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ICIs can exceptionally induce  eosinophilic fasciitis (EF).
    explanation: >-
      Supports immune checkpoint inhibitors as a drug trigger of EF, consistent
      with checkpoint blockade unleashing the type 2 immune/eosinophil response.
  downstream:
  - target: TGF-beta-Driven Fascial Fibroblast Activation
- name: TGF-beta-Driven Fascial Fibroblast Activation
  description: >-
    Eosinophil effector molecules and type 2 cytokines (including TGF-beta,
    IL-4, IL-13) activate resident fascial fibroblasts, driving their
    differentiation toward collagen-producing myofibroblasts. This is the
    central profibrotic effector step shared with other scleroderma-like
    fibrosing disorders.
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  cell_types:
  - preferred_term: Fascial fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: Myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  - preferred_term: Positive regulation of fibroblast proliferation
    term:
      id: GO:0048146
      label: positive regulation of fibroblast proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:11890876
    reference_title: "Scleroderma-like cutaneous syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Activation of eosinophils and disordered regulation of fibroblast collagen
      synthesis, apoptosis, and proliferation are recurrent findings in these
      disorders.
    explanation: >-
      Establishes eosinophil activation coupled to dysregulated fibroblast
      collagen synthesis/proliferation as a recurrent mechanism in
      eosinophilic fasciitis and related scleroderma-like disorders.
  - reference: PMID:11890876
    reference_title: "Scleroderma-like cutaneous syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cytokines such as transforming growth factor-beta, interleukin-4,
      interleukin-13, and connective tissue growth factor contribute to fibrosis
      in these disorders
    explanation: >-
      Supports TGF-beta and type 2 cytokine signaling as drivers of the
      fibrotic response in the scleroderma-like disorders including EF.
  downstream:
  - target: Fascial Collagen Deposition and Fibrosis
- name: Fascial Collagen Deposition and Fibrosis
  description: >-
    Activated myofibroblasts deposit excess collagen and extracellular matrix in
    the deep fascia and subcutaneous septa, producing fascial thickening and
    fibrosis with an accompanying inflammatory infiltrate.
  cell_types:
  - preferred_term: Myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: Collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:36130069
    reference_title: "Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EF is a rare disease characterized by fibrosis and inflammation of the
      fascia
    explanation: >-
      Confirms fibrosis and inflammation of the fascia as the defining
      pathological end-state of EF.
  downstream:
  - target: Fascial Induration and Joint Contractures
- name: Fascial Induration and Joint Contractures
  description: >-
    Progressive fascial fibrosis produces woody skin induration, peau d'orange
    texture, and the groove sign, and ultimately restricts joint mobility,
    leading to flexion contractures and disability, the clinical end-state of
    the disease.
  evidence:
  - reference: PMID:41763542
    reference_title: "Eosinophilic Fasciitis in Pediatric Patients: A Rare but Distinct Autoimmune Fibrosing Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical presentations range from rapidly advancing fibrosis leading to
      joint contractures to fluctuating inflammatory episodes.
    explanation: >-
      Supports progression of fascial fibrosis to joint contractures as the
      disabling clinical end-state.
phenotypes:
- category: Laboratory
  name: Peripheral Eosinophilia
  description: >-
    Elevated peripheral blood eosinophil count, often present early and
    transient; not required for diagnosis and not correlated with severity.
  phenotype_term:
    preferred_term: Peripheral eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  frequency: FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophilia was found in 31 patients (68.9%)."
    explanation: >-
      A 45-patient cohort found peripheral eosinophilia in 68.9% of patients,
      supporting a FREQUENT band.
- category: Cutaneous
  name: Symmetric Skin Induration
  description: >-
    Symmetric "woody" induration and thickening of the skin and subcutaneous
    tissue of the extremities, typically sparing the hands, feet, and face.
  phenotype_term:
    preferred_term: Skin induration
    term:
      id: HP:0001072
      label: Thickened skin
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "subcutaneous swelling and induration (95.6%)"
    explanation: >-
      Cohort data show subcutaneous swelling and induration in 95.6% of EF
      patients, the core cutaneous manifestation.
- category: Cutaneous
  name: Peau d'Orange Skin Texture
  description: >-
    Orange-peel (peau d'orange) dimpled skin texture overlying indurated fascia.
  phenotype_term:
    preferred_term: Orange-peel (peau d'orange) skin texture
    term:
      id: HP:0001072
      label: Thickened skin
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peau d'orange appearance (13.3%)"
    explanation: >-
      Documents peau d'orange appearance as a characteristic (if less frequent)
      cutaneous sign in the EF cohort.
- category: Musculoskeletal
  name: Joint Contractures
  description: >-
    Flexion contractures, especially of the elbows, wrists, knees, and ankles,
    arising from fascial fibrosis; a major cause of disability.
  phenotype_term:
    preferred_term: Joint contractures
    term:
      id: HP:0001371
      label: Flexion contracture
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hand joint contractures (42.2%)"
    explanation: >-
      Cohort reports hand joint contractures in 42.2% of patients, supporting
      contractures as a frequent disabling complication.
- category: Musculoskeletal
  name: Arthralgia and Arthritis
  description: Joint pain and inflammatory arthritis affecting a substantial minority of patients.
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  frequency: FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arthralgia and arthritis (55.6%)"
    explanation: >-
      Cohort reports arthralgia and arthritis in 55.6% of EF patients.
- category: Cutaneous
  name: Groove Sign
  description: >-
    Linear depression along the course of superficial veins, accentuated by limb
    elevation, reflecting tethering of skin to indurated fascia; relatively
    specific for EF.
  phenotype_term:
    preferred_term: Groove sign (venous furrowing)
    term:
      id: HP:0001072
      label: Thickened skin
  frequency: FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "groove sign (42.2%)"
    explanation: >-
      Cohort reports the characteristic groove sign in 42.2% of EF patients.
- category: Laboratory
  name: Hypergammaglobulinemia
  description: Polyclonal hypergammaglobulinemia with elevated serum immunoglobulins.
  phenotype_term:
    preferred_term: Hypergammaglobulinemia (increased IgG)
    term:
      id: HP:0003237
      label: Increased circulating IgG concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypergammaglobulinemia was seen in 23/44 (52.3%)"
    explanation: >-
      Cohort reports hypergammaglobulinemia in 52.3% of EF patients.
- category: Cutaneous
  name: Limb Edema
  description: Early inflammatory-phase non-pitting edema and swelling of the extremities.
  phenotype_term:
    preferred_term: Peripheral edema of extremities
    term:
      id: HP:0012398
      label: Peripheral edema
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical presentation of eosinophilic fasciitis consists of nonpitting
      edema, indurated skin, and pathognomonic venous furrowing, known as
      “groove sign”
    explanation: >-
      Describes nonpitting edema with indurated skin and the groove sign as the
      characteristic clinical presentation of EF.
biochemical:
- name: Peripheral Blood Eosinophilia
  biomarker_term:
    preferred_term: Eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  presence: INCREASED
  notes: Elevated absolute eosinophil count on complete blood count, characteristically early and transient.
  evidence:
  - reference: PMID:36768300
    reference_title: "Eosinophilic Fasciitis: Current and Remaining Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the lab results (eosinophilia, increased inflammatory markers)
    explanation: >-
      Identifies eosinophilia and increased inflammatory markers as the key
      laboratory abnormalities supporting the diagnosis.
- name: Elevated Erythrocyte Sedimentation Rate
  biomarker_term:
    preferred_term: Erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
  presence: INCREASED
  notes: Elevated ESR reflecting systemic inflammation in the active phase.
  evidence:
  - reference: PMID:36768300
    reference_title: "Eosinophilic Fasciitis: Current and Remaining Challenges."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the lab results (eosinophilia, increased inflammatory markers)
    explanation: >-
      Increased inflammatory markers (including ESR) are characteristic
      laboratory findings in active EF.
- name: Polyclonal Hypergammaglobulinemia
  biomarker_term:
    preferred_term: Serum IgG concentration
    term:
      id: HP:0003237
      label: Increased circulating IgG concentration
  presence: INCREASED
  notes: Increased serum IgG/gammaglobulins, a frequent laboratory finding.
  evidence:
  - reference: PMID:36856224
    reference_title: "[Clinical characteristics, ultrasonic diagnosis, treatment and outcomes of eosinophilic fasciitis: a retrospective single-center analysis of 45 cases]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypergammaglobulinemia was seen in 23/44 (52.3%)"
    explanation: >-
      Cohort data establish polyclonal hypergammaglobulinemia as a frequent
      laboratory abnormality.
diagnosis:
- name: Full-Thickness Skin-to-Fascia Biopsy
  description: >-
    A full-thickness incisional (en bloc) biopsy extending to and including the
    deep muscular fascia is the diagnostic gold standard, revealing fascial
    thickening with a lymphoplasmacytic infiltrate with or without eosinophils.
    Tissue eosinophilia is supportive but not required.
  diagnosis_term:
    preferred_term: Full-thickness skin-to-fascia biopsy
    term:
      id: NCIT:C51692
      label: Skin Biopsy
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic histologic diagnosis of eosinophilic fasciitis requires a
      full-thickness skin biopsy, including the underlying muscle and fascia
    explanation: >-
      Establishes the full-thickness skin-to-fascia biopsy as the classic
      confirmatory diagnostic procedure.
  - reference: PMID:41763542
    reference_title: "Eosinophilic Fasciitis in Pediatric Patients: A Rare but Distinct Autoimmune Fibrosing Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Definitive diagnosis depends on deep skin and fascial biopsy, revealing
      eosinophil-rich lymphoplasmacytic infiltrates and fibrosis.
    explanation: >-
      Confirms deep skin-and-fascial biopsy as the definitive diagnostic test,
      showing lymphoplasmacytic infiltrate and fibrosis.
- name: Fascial MRI
  description: >-
    MRI of the affected limb demonstrates fascial thickening, T2 hyperintensity
    (edema), and post-contrast fascial enhancement; it supports diagnosis and
    guides biopsy site selection.
  diagnosis_term:
    preferred_term: Magnetic resonance imaging
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  evidence:
  - reference: PMID:23040360
    reference_title: "Eosinophilic fasciitis (Shulman disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis might be helped by a muscle magnetic resonance imaging which
      typically may evidence an increased signal intensity within the fascia and
      marked fascia enhancement after gadolinium administration
    explanation: >-
      Documents the characteristic MRI findings (increased fascial signal and
      gadolinium enhancement) used to support EF diagnosis.
  - reference: PMID:35651918
    reference_title: "MRI Findings of Eosinophilic Fasciitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eosinophilic fasciitis (EF) is a rare sclerodermiform disease
      characterized by upper- and lower-limbs oedema and hardness, which should
      be confirmed by skin biopsy and MRI in case of clinical suspicion.
    explanation: >-
      Confirms MRI (alongside skin biopsy) as a recommended confirmatory test
      when EF is clinically suspected.
histopathology:
- name: Thickened Fascia with Inflammatory Infiltrate and Fibrosis
  description: >-
    Fascial thickening with an inflammatory infiltrate composed predominantly of
    lymphocytes and plasma cells, with or without eosinophils, and fibrosis;
    eosinophilic infiltration of the fascia is seen in roughly half of cases and
    is more likely early in the disease.
  finding_term:
    preferred_term: Fascial fibrosis with lymphoplasmacytic infiltrate
    term:
      id: NCIT:C3044
      label: Fibrosis
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      findings consist of hypertrophied fascia with inflammatory cell
      infiltration (lymphocytes and plasma cells)
    explanation: >-
      Describes the characteristic histopathology: hypertrophied fascia with a
      lymphoplasmacytic inflammatory infiltrate.
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eosinophilic infiltration of the fascia is observed in approximately 50%
      of cases and more likely to be found in early stages of the disease.
    explanation: >-
      Documents that fascial eosinophilic infiltration is present in only ~50%
      of cases and is stage-dependent, so it is supportive but not required.
treatments:
- name: Systemic Corticosteroids
  description: >-
    Systemic glucocorticoids (e.g., prednisone, often 0.5-1 mg/kg/day, or pulse
    methylprednisolone for severe disease) are the first-line treatment and are
    often effective in the inflammatory phase.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
    - preferred_term: methylprednisolone
      term:
        id: CHEBI:6888
        label: 6alpha-methylprednisolone
  target_mechanisms:
  - target: Type 2 Immune Activation and Eosinophil Recruitment
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Systemic corticosteroids remain the first-line treatment for eosinophilic
      fasciitis
    explanation: >-
      Directly states that systemic corticosteroids are the first-line treatment
      for EF.
- name: Methotrexate
  description: >-
    Methotrexate (typically 15-25 mg/week) is the most commonly used
    steroid-sparing agent; early combination of corticosteroids with
    methotrexate is the prevailing initial regimen, particularly for
    morphea-like lesions or inadequate steroid response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methotrexate
      term:
        id: CHEBI:44185
        label: methotrexate
  target_mechanisms:
  - target: Type 2 Immune Activation and Eosinophil Recruitment
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      methotrexate is the most commonly used steroid-sparing agent
    explanation: >-
      Establishes methotrexate as the most commonly used steroid-sparing agent
      in EF.
  - reference: PMID:23040360
    reference_title: "Eosinophilic fasciitis (Shulman disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      oral corticosteroids remain the mainstay treatment and may be associated
      to an immunosuppressive drug such as methotrexate
    explanation: >-
      Supports corticosteroids as mainstay therapy combined with methotrexate as
      a steroid-sparing immunosuppressant.
- name: Anti-IL-5 Biologic Therapy
  description: >-
    Anti-IL-5 monoclonal antibodies (reslizumab, mepolizumab, benralizumab)
    target the IL-5/eosinophil axis and have produced responses in refractory,
    eosinophilia-associated EF. IL-5 is the major cytokine for eosinophil
    growth, recruitment, activation, and survival.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: anti-IL-5 monoclonal antibody therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: monoclonal antibody
      term:
        id: NCIT:C20401
        label: Monoclonal Antibody
  target_mechanisms:
  - target: Type 2 Immune Activation and Eosinophil Recruitment
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The addition of this medication at 3 mg/kg intravenously every 4 weeks led
      to the stabilization of her symptoms, and her prednisone was tapered to
      discontinuation.
    explanation: >-
      Reports successful treatment of refractory EF with the anti-IL-5 antibody
      reslizumab, with symptom stabilization and steroid discontinuation.
- name: Sirolimus (mTOR Inhibitor)
  description: >-
    The mTOR inhibitor sirolimus produced remarkable efficacy in a case of
    immune checkpoint inhibitor (nivolumab)-triggered EF, implicating
    mTOR/T-cell metabolic signaling in refractory/ICI-related disease.
  notes: >-
    Evidence is a single case-report letter (PMID:32127188); the cached source
    carries only the title, with no structured abstract. This is anecdotal,
    hypothesis-generating support for an emerging therapy in ICI-related EF, not
    cohort- or trial-level evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Type 2 Immune Activation and Eosinophil Recruitment
  evidence:
  - reference: PMID:32127188
    reference_title: "Eosinophilic Fasciitis Triggered by Nivolumab: A Remarkable Efficacy of the mTOR Inhibitor Sirolimus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eosinophilic Fasciitis Triggered by Nivolumab: A Remarkable Efficacy of
      the mTOR Inhibitor Sirolimus
    explanation: >-
      Case report documenting remarkable efficacy of the mTOR inhibitor
      sirolimus in nivolumab-triggered EF.
- name: Physical Therapy
  description: >-
    Physical and occupational therapy are essential throughout the disease
    course to prevent and treat joint contractures and preserve range of motion.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient initially began receiving 60 mg of prednisone, which was
      slowly tapered to 10 mg daily, and started to improve quickly with
      physical therapy.
    explanation: >-
      Documents physical therapy as part of EF management contributing to
      functional improvement.
differential_diagnoses:
- name: systemic sclerosis
  disease_term:
    preferred_term: systemic sclerosis
    term:
      id: MONDO:0005100
      label: systemic sclerosis
  description: >-
    The principal differential. EF and systemic sclerosis both produce
    scleroderma-like skin induration, but EF spares the fingers and face, lacks
    Raynaud phenomenon and nailfold capillary changes, lacks anti-centromere and
    anti-Scl-70 autoantibodies, and lacks visceral organ involvement, and the
    fibrosis is centered on the deep fascia rather than the dermis.
  distinguishing_features:
  - EF spares the fingers and face, whereas systemic sclerosis characteristically involves the fingers (sclerodactyly).
  - EF lacks Raynaud phenomenon and nailfold capillary changes typical of systemic sclerosis.
  - EF lacks anti-centromere and anti-Scl-70 (topoisomerase) autoantibodies.
  - EF lacks the visceral (lung, GI, kidney, heart) organ involvement seen in systemic sclerosis.
  - EF fibrosis is centered on the deep fascia; diagnosis requires a full-thickness fascial biopsy.
  evidence:
  - reference: PMID:32913886
    reference_title: "Successful treatment of refractory eosinophilic fasciitis with reslizumab."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients lack the classic features of scleroderma, including extracutaneous
      organ involvement, sclerodactyly, Raynaud disease, and nail-fold capillary
      changes
    explanation: >-
      Directly enumerates the scleroderma features that EF lacks (extracutaneous
      organ involvement, sclerodactyly, Raynaud, nailfold capillary changes),
      the basis for distinguishing EF from systemic sclerosis.
- name: eosinophilia-myalgia syndrome
  disease_term:
    preferred_term: eosinophilia-myalgia syndrome
    term:
      id: MONDO:0004941
      label: eosinophilia-myalgia syndrome
  description: >-
    A toxic eosinophilic syndrome historically caused by contaminated
    L-tryptophan ingestion, with prominent myalgia and eosinophilia that can
    mimic EF but is a distinct toxic entity.
  distinguishing_features:
  - Eosinophilia-myalgia syndrome follows L-tryptophan ingestion and features prominent severe myalgia.
  - EF myalgia is typically milder and the disorder is centered on fascial fibrosis rather than diffuse myalgia.
  evidence:
  - reference: PMID:23040360
    reference_title: "Eosinophilic fasciitis (Shulman disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Differential diagnoses should be ruled out, including eosinophilia-myalgia
      syndrome (EMS) after L-tryprophane ingestion
    explanation: >-
      Lists eosinophilia-myalgia syndrome after L-tryptophan ingestion as a key
      differential to exclude.
- name: hypereosinophilic syndrome
  disease_term:
    preferred_term: hypereosinophilic syndrome
    term:
      id: MONDO:0015691
      label: hypereosinophilic syndrome
  description: >-
    A group of disorders with persistent marked peripheral eosinophilia and
    multi-organ eosinophilic infiltration; shares eosinophilia with EF but
    differs in systemic organ involvement and lack of the fascial fibrosis
    pattern.
  distinguishing_features:
  - Hypereosinophilic syndrome features sustained marked eosinophilia with end-organ eosinophilic damage across multiple organs.
  - EF eosinophilia is often transient and the disease is anatomically restricted to the deep fascia.
  evidence:
  - reference: PMID:23040360
    reference_title: "Eosinophilic fasciitis (Shulman disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Differential diagnoses should be ruled out, including eosinophilia-myalgia
      syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes
      (HES), systemic sclerosis
    explanation: >-
      Lists hypereosinophilic syndromes among the differentials to exclude in
      suspected EF.
- name: eosinophilic granulomatosis with polyangiitis
  disease_term:
    preferred_term: eosinophilic granulomatosis with polyangiitis
    term:
      id: MONDO:0015943
      label: eosinophilic granulomatosis with polyangiitis
  description: >-
    An eosinophilic ANCA-associated vasculitis (Churg-Strauss syndrome) with
    asthma, eosinophilia, and multi-organ vasculitic involvement; shares
    eosinophilia with EF but is a systemic vasculitis rather than a
    fascia-restricted fibrosing disorder.
  distinguishing_features:
  - EGPA is a systemic eosinophilic vasculitis with asthma and frequent pulmonary, cardiac, neurologic, and ANCA-associated features.
  - EF is anatomically restricted to the deep fascia with fibrosis and lacks vasculitis and asthma.
  evidence:
  - reference: PMID:23040360
    reference_title: "Eosinophilic fasciitis (Shulman disease)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Differential diagnoses should be ruled out, including eosinophilia-myalgia
      syndrome (EMS) after L-tryprophane ingestion, hypereosinophilic syndromes
      (HES), systemic sclerosis, Churg-Strauss syndrome
    explanation: >-
      Lists Churg-Strauss syndrome (eosinophilic granulomatosis with
      polyangiitis) among the differentials to exclude in suspected EF.
discussions:
- discussion_id: ef-hematologic-association
  kind: INTERPRETATION
  prompt: >-
    Eosinophilic fasciitis is associated with hematologic disorders, especially
    aplastic anemia; how should this paraneoplastic/associated marrow disease be
    represented and surveilled?
  rationale: >-
    A minority of EF patients have an associated hematologic disorder (aplastic
    anemia, myelodysplastic syndrome, lymphoma, monoclonal gammopathy). This
    association carries prognostic weight and warrants surveillance for
    cytopenias, but EF itself is not caused by these clonal diseases. Modeled as
    a discussion because dismech has no top-level comorbidity slot on the Disease
    class.
  evidence:
  - reference: PMID:9283913
    reference_title: "Aplastic anemia in eosinophilic fasciitis: responses to immunosuppression and marrow transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eosinophilic fasciitis (EF) is a rare connective tissue disorder which is
      frequently associated with hematologic disorders, especially aplastic
      anemia
    explanation: >-
      Establishes the recognized association between EF and hematologic
      disorders, especially aplastic anemia.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0009175
      label: eosinophilic fasciitis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease identifier for eosinophilic fasciitis (Shulman
      syndrome). MONDO records the Orphanet:3165 and OMIM:226350 cross-references;
      the schema mappings block has no dedicated Orphanet slot, so the
      Orphanet:3165 equivalence is captured here as provenance.
  ncit_mappings:
  - term:
      id: NCIT:C112116
      label: Eosinophilic Fasciitis
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: >-
      NCI Thesaurus concept for Eosinophilic Fasciitis (Shulman syndrome),
      cross-referenced by the MONDO term.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
references:
- reference: PMID:36768300
  title: "Eosinophilic Fasciitis: Current and Remaining Challenges."
  findings: []
- reference: PMID:36130069
  title: "Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms."
  findings: []
- reference: PMID:23040360
  title: "Eosinophilic fasciitis (Shulman disease)."
  findings: []
- reference: PMID:29235676
  title: "Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis."
  findings: []

📚

References & Deep Research

References

4

PMID:36768300

Eosinophilic Fasciitis: Current and Remaining Challenges.

No top-level findings curated for this source.

PMID:36130069

Eosinophilic fasciitis (Shulman syndrome)-recognition of the histological spectrum allows for new insights into possible pathomechanisms.

No top-level findings curated for this source.

PMID:23040360

Eosinophilic fasciitis (Shulman disease).

No top-level findings curated for this source.

PMID:29235676

Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-4-8[1m] 13 citations 2026-06-30T08:15:53.260495

1. Disease Information

Overview. Eosinophilic fasciitis (EF) is a rare, acquired, sclerosing/fibrosing connective-tissue disorder marked by acute-to-subacute inflammation and progressive thickening (fibrosis) of the deep muscular fascia and overlying subcutis, classically of the limbs. It presents with symmetric edema, erythema and induration of the extremities, evolving into a woody "peau d'orange" (orange-peel) skin texture and a pathognomonic "groove sign" (linear depressions along the course of superficial veins, accentuated by limb elevation). It is accompanied in most patients by peripheral blood eosinophilia, polyclonal hypergammaglobulinemia, and elevated inflammatory markers (ESR/CRP). EF is widely regarded as a scleroderma-like / scleroderma-spectrum disease, but is distinguished from systemic sclerosis by sparing of the fingers and face, absence of Raynaud phenomenon, absence of nailfold capillary changes, and lack of visceral organ involvement (Mazilu et al. 2023, Int J Mol Sci, PMID:36768300; original description Shulman 1974).

Key identifiers. - MONDO: MONDO:0009175 (eosinophilic fasciitis) — verified against the local MONDO adapter. - Orphanet: ORPHA:3165 (flag for verification; Orphanet page was behind a bot-check at fetch time). - ICD-10: M35.4 (Diffuse [eosinophilic] fasciitis). - ICD-11: 4A43.0 (Eosinophilic fasciitis), under "Diseases of the immune system with predominant connective-tissue involvement." - MeSH: D005159 "Fasciitis" / EF appears as "Eosinophilic Fasciitis" (Shulman syndrome). - OMIM: None — EF has no OMIM Mendelian entry (not a single-gene disorder).

Synonyms / alternative names: Shulman syndrome; Shulman disease; diffuse fasciitis with eosinophilia; diffuse eosinophilic fasciitis; eosinophilic fasciitis with eosinophilia.

Data provenance. Knowledge is derived almost entirely from aggregated disease-level resources and case series/case reports (EF is too rare for large registries). There is no large EHR cohort; the literature is dominated by single-center series (e.g., a 52-patient Mayo Clinic cohort) and systematic reviews of pooled case reports.

2. Etiology

Causal factors. EF is idiopathic in the majority of cases. It is best understood as an immune-mediated fibrosing reaction to a triggering insult in a susceptible host, not a genetic disease. Recognized/proposed triggers (each from case reports/series; association ≠ proven causation):

Strenuous/unaccustomed physical exertion or trauma — the single most frequently cited antecedent; reported in ~30–50% of cases preceding onset (Mazilu et al. 2023, PMID:36768300: "Sustained intense physical exercise" is the most prominent trigger).
Drugs: statins (notably simvastatin/atorvastatin), phenytoin, ramipril, subcutaneous heparin, and — increasingly important — immune checkpoint inhibitors (ICIs) (anti–PD-1/PD-L1 pembrolizumab, nivolumab; anti–CTLA-4 ipilimumab) (PMID:40399177, 2025 review of 30 ICI-EF cases; PMID:32127188 nivolumab-triggered EF).
Infections / immune triggers: Borrelia burgdorferi (controversial), and recently SARS-CoV-2 (COVID-19) and COVID vaccination (PMID:38292575, EF following COVID-19 case series).
Toxic exposures: historically L-tryptophan (eosinophilia–myalgia syndrome) and toxic-oil syndrome are EF-like but are distinct toxic entities; trichloroethylene and other organic solvents have been implicated.
Hematologic / neoplastic association: EF can be paraneoplastic, associated with hematologic disorders (see §9).

Genetic risk factors. No established Mendelian gene, GWAS locus, or validated susceptibility allele. Rare familial clustering and isolated HLA associations have been suggested but are not established. No ClinVar/ClinGen/GWAS-Catalog entries are applicable.

Environmental risk factors. Vigorous exercise/trauma, the drug exposures above, and (debated) infectious triggers. Age (peak 30–60 y) and possibly male sex in ICI-related disease are demographic risk modifiers.

Protective factors. None established (no genetic protective variant or dietary/lifestyle protective factor is documented for this rare disease).

Gene–environment interactions. Not characterized. The plausible model is that an environmental/immune trigger (exercise, drug, checkpoint blockade) drives a Th2/eosinophil-skewed, profibrotic fascial response in a host of undefined predisposition; no specific GxE data exist (CTD/PheGenI have no EF-specific entries).

3. Phenotypes

Suggested HPO terms in brackets; frequencies are qualitative pooled estimates from case series — treat frequency bands as needing their own evidence per the dismech frequency SOP.

Cutaneous / fascial (the core phenotype): - Symmetric skin induration / "woody" thickening of extremities — near-universal; forearms and lower legs most affected, typically sparing hands/feet and face. [HP:0007543 "Subcutaneous tissue induration"? or HP:0100679 "Localized skin lesion"; best fit HP:0100683 not ideal — consider HP:0001075 "Abnormal skin morphology" plus a descriptive preferred_term; HP:0011924 "Abnormal skin morphology" family]. Onset: adult; course: progressive. - "Peau d'orange" / orange-peel skin texture — characteristic; FREQUENT. - "Groove sign" (depression along superficial veins on limb elevation) — fairly specific, OCCASIONAL–FREQUENT. - Erythema and edema of limbs (early, inflammatory phase) — FREQUENT. [HP:0000964 "Eczema"? no — use HP:0100749 "Chest pain"? no; for edema HP:0000969 "Edema"]. - Pruritus — OCCASIONAL. [HP:0000989 "Pruritus"]. - Morphea-like plaques / overlap with morphea — ~29–40% of EF patients have concurrent morphea (PMID:36768300). [HP:0100698 "Morphea"? use HP:0100699 "Scleroderma" family].

Musculoskeletal: - Joint contractures (especially elbows, wrists, knees, ankles) — common and a major cause of disability; can require surgery. [HP:0001371 "Flexion contracture"]. Course: progressive. - Arthritis / inflammatory arthritis — "present in less than half the patients" (PMID:36768300). [HP:0001369 "Arthritis"]. - Myalgia — present but "much less common and much milder" than in eosinophilia–myalgia syndrome (PMID:36768300). [HP:0003326 "Myalgia"]. - Carpal tunnel syndrome — from fascial compression at the wrist; OCCASIONAL. [HP:0012185 "Carpal tunnel syndrome"]. - Limited joint mobility / reduced range of motion — FREQUENT. [HP:0001376 "Limitation of joint mobility"].

Laboratory abnormalities: - Peripheral blood eosinophilia — present in ~60–90% (transient, often early, and not correlated with disease severity; PMID:36768300). [HP:0001880 "Eosinophilia"]. - Polyclonal hypergammaglobulinemia — FREQUENT. [HP:0003237 "Increased circulating IgG level" / HP:0010701 "Abnormal immunoglobulin level"]. - Elevated ESR / CRP — FREQUENT. [HP:0003565 "Elevated erythrocyte sedimentation rate"; HP:0011227 "Elevated C-reactive protein level"]. - Elevated serum aldolase (with often-normal CK) — a useful marker of fascial/muscle inflammation; OCCASIONAL–FREQUENT. [HP:0008331 "Elevated aldolase"? → use HP:0003236 "Elevated circulating creatine kinase" family / aldolase has no precise HP]. - TARC/CCL17 elevation, IL-5 elevation — research biomarkers (see §6).

Systemic / general: constitutional symptoms (fatigue, low-grade fever, weight loss) are usually mild; visceral organ involvement is characteristically ABSENT, which is a key diagnostic discriminator from systemic sclerosis.

Quality-of-life impact. Driven mainly by joint contractures and limb stiffness → impaired hand function, gait, dressing, and activities of daily living; chronic refractory disease and contractures are the principal QoL detractors. No EF-specific EQ-5D/SF-36 dataset exists; impact is inferred from functional-outcome reporting in case series.

4. Genetic / Molecular Information

Causal genes: None. EF is a non-Mendelian, acquired immune-fibrotic disease; there is no causal gene, pathogenic variant, modifier gene, founder mutation, or chromosomal abnormality established as a cause. ClinVar/HGMD/OMIM contain no EF gene entries.
Pathogenic variants / allele frequencies / somatic vs germline: Not applicable.
Epigenetics: Not specifically characterized in EF (no methylome/ChIP studies dedicated to EF fascia in the literature surveyed).
Clonal/somatic context: The relevant "molecular genetics" of EF is in its paraneoplastic associations — clonal hematologic disorders (aplastic anemia/PNH, MDS, T-cell and other lymphomas, myeloproliferative neoplasms) co-occur in up to ~10% of patients (PMID:9283913; PMC4553982). These are clonal diseases associated with EF, not the genetic cause of EF.

Bottom line for KB: populate genetics sections as "not applicable / acquired immune-mediated disease"; do not invent HGNC gene annotations. The gene-relevant content lives in the immunology/cytokine layer (§6), not in a causal-variant layer.

5. Environmental Information

Environmental/occupational factors: strenuous physical activity and trauma; organic solvents (trichloroethylene), historically adulterated L-tryptophan and toxic rapeseed oil (distinct toxic syndromes that mimic EF).
Drug exposures (iatrogenic environment): statins, phenytoin, heparin, ramipril, and immune checkpoint inhibitors (the most clinically important contemporary drug trigger; PMID:40399177, PMID:32127188).
Lifestyle factors: intense/unaccustomed exercise is the dominant lifestyle association; no robust smoking/alcohol/diet links.
Infectious agents (triggers, not pathogens of a primary infection): Borrelia burgdorferi (debated; [NCBITaxon:139], SARS-CoV-2 ([NCBITaxon:2697049]; PMID:38292575), Mycoplasma. EF is not an infectious disease; these are putative immune triggers.

6. Mechanism / Pathophysiology

EF is a Th2-skewed, eosinophil-and-TGF-β-driven fibrosing inflammation centered on the deep fascia, progressing from an inflammatory phase to fibrosis. Current understanding (idiopathic and ICI-related forms appear to converge mechanistically):

Causal chain (proposed): 1. Trigger (mechanical/exertional injury, drug/checkpoint blockade, infection) → release of fascial antigens / danger signals. 2. Type 2 immune activation: recruitment and degranulation of eosinophils in the fascia and elevation of interleukin-5 (IL-5) (eosinophil growth/survival factor) and IL-4 (Th2). The 2023 histological-spectrum study found upregulation of Th2–M2 markers STAT6 and IL-4 alongside Th1–M1 markers STAT1 and IFN-γ, with CD206⁺ (M2) macrophages predominating at the muscle–fascia interface (Pehl, Preuße, Allenbach et al. 2023, Rheumatology, PMID:36130069). 3. Eosinophil effector molecules (major basic protein, eosinophil cationic protein) and cytokines activate fascial fibroblasts. 4. Profibrotic signaling: TGF-β1 upregulation drives fibroblast → myofibroblast activation and excess extracellular-matrix/collagen deposition; tissue inhibitors of metalloproteinases (TIMPs) are elevated, shifting the MMP/TIMP balance toward matrix accumulation (PMID:36768300: "Elevated levels of TIMPs… reported in patients with EF"; "increase in the expression of transforming growth factor-β1"). 5. Fibrosis of deep fascia and septa → fascial thickening, skin induration, and joint contractures (the clinical end-state).

Distinctive immunopathology. EF shows perifascicular pathology with MHC class I and II upregulation (dermatomyositis-like) but, importantly, NO type I interferon signature, no hypoxia-mediated process, and no perifascicular fiber atrophy — distinguishing it mechanistically from idiopathic inflammatory myopathies (PMID:36130069). The eosinophil chemoattractants themselves were not significantly upregulated in that study, suggesting eosinophils are recruited/retained by mechanisms beyond classic chemokine gradients.

ICI-related mechanism. Checkpoint blockade (loss of PD-1/CTLA-4 restraint) is thought to unleash autoreactive T cells and a Th2/eosinophil response in fascia; notably, sirolimus (mTOR inhibitor) produced remarkable efficacy in a nivolumab-triggered case, implicating mTOR/T-cell metabolic signaling (PMID:32127188).

Molecular pathways / GO suggestions: - TGF-β receptor signaling — GO:0007179 (transforming growth factor beta receptor signaling pathway), modifier INCREASED. - IL-5 / type 2 cytokine signaling — GO:0038043 (interleukin-5–mediated signaling pathway). - Eosinophil degranulation — GO:0043308. - Extracellular matrix organization / collagen fibril deposition — GO:0030198 (ECM organization), GO:0030199 (collagen fibril organization). - Fibroblast→myofibroblast activation / chronic inflammation — GO:0006954 (inflammatory response), GO:0072537 (fibroblast activation).

Cell types (CL suggestions): - Eosinophil — CL:0000771. - Fibroblast / fascial fibroblast → myofibroblast — CL:0000057 (fibroblast); myofibroblast CL:0000186. - M2 / CD206⁺ macrophage — CL:0000890 (alternatively activated macrophage). - CD4⁺ T helper (Th2) cell — CL:0000546 (Th2 cell) / CL:0000492 (CD4⁺ T cell). - Plasma cell (hypergammaglobulinemia) — CL:0000786.

Chemical entities (CHEBI): TGF-β1 (protein), IL-5 (protein); small-molecule/marker context — collagen; eosinophil cationic protein (protein). For treatment chemicals see §12.

Molecular profiling. No large transcriptomic/proteomic/metabolomic datasets specific to EF were identified (GEO/PRIDE coverage is minimal). The 2023 Rheumatology paper (PMID:36130069) is the most granular immunophenotyping to date (immunohistochemistry/transcript markers, not omics-scale). Serum TARC/CCL17 and IL-5 are the most cited candidate activity biomarkers. This is a genuine knowledge gap worth flagging in the entry (discussions: kind: KNOWLEDGE_GAP).

7. Anatomical Structures Affected

Primary structure: deep (muscular) fascia — the defining target. [UBERON:0007825 "deep fascia" / UBERON:0011892 "fascia of muscle"; general fascia UBERON:0007798 "vasculature"? no — UBERON:0002384 "connective tissue", UBERON:0001134 "skeletal muscle tissue" at interface].
Subcutaneous tissue / septa — UBERON:0002072 (skin of body)/ UBERON:0001013 "adipose tissue" septa; subcutis UBERON:0002072.
Skin (dermis, overlying) — UBERON:0002067 "dermis", UBERON:0002097 "skin of body".
Skeletal muscle (perifascial/superficial myositis at the muscle–fascia interface) — UBERON:0001134 "skeletal muscle tissue".
Joints (secondary — contractures) — UBERON:0000982 "skeletal joint".
Peripheral nerve at fascial entrapment sites (e.g., median nerve → carpal tunnel) — UBERON:0001021 "nerve".

Body systems: musculoskeletal/connective-tissue (primary), integumentary (skin), immune/hematologic (eosinophilia, paraneoplastic marrow disease). Internal viscera (heart, lung, GI, kidney) are characteristically spared.

Lateralization: typically symmetric and bilateral, limb-predominant (forearms, lower legs > thighs, upper arms, trunk); hands, feet, and face usually spared — a key clinical discriminator.

Subcellular: extracellular (ECM/collagen deposition in fascia); no specific organelle pathology. GO cellular component — GO:0062023 "collagen-containing extracellular matrix".

8. Temporal Development

Onset: Adult-predominant (peak ~30–60 years); juvenile EF exists and may be more systemic/disabling (PMID:36768300). Onset is often acute/subacute — "In 50% of cases, the onset of the disease is sudden" (PMID:36768300) — frequently following an exertional or other trigger.
Phases: (1) early inflammatory/edematous phase (painful swelling, erythema, eosinophilia) → (2) indurative/fibrotic phase (woody induration, peau d'orange, groove sign) → (3) fibrotic/contracture end-stage.
Course: can be self-limited in a minority, but is frequently chronic and relapsing; a substantial fraction become corticosteroid-refractory and develop persistent contractures.
Critical window: early treatment matters — combination corticosteroid + methotrexate started early "significantly improves" outcomes and reduces residual fibrosis/contractures (multiple series; PMC12309119 early-EF case report; PMID:36768300). Delay → irreversible fibrosis.
Remission: treatment-induced remission is achievable in most steroid-responsive patients; spontaneous remission occurs but is less common.

9. Inheritance and Population

Epidemiology: Rare. No precise incidence/prevalence figures exist; ~>300 cases described historically and fewer than ~3,000 reported worldwide. Largest single cohort is a Mayo Clinic series of 52 patients. No reliable per-100,000 incidence is published — record as "unknown/rare" in the KB rather than fabricating a rate.
Inheritance: Not heritable — sporadic/acquired. No AD/AR/X-linked pattern, penetrance, expressivity, anticipation, founder effect, consanguinity, or carrier-frequency data apply.
Sex ratio: Most series show a slight male predominance or roughly equal distribution (varies by series; ICI-related EF showed M:F ≈ 1.3 with median age 57, PMID:40399177).
Ethnicity/geography: No strong ethnic or geographic predilection established; reported worldwide.
Key disease associations (not inheritance, but population-level comorbidity):
Hematologic disorders in up to ~10% — aplastic anemia / AA-PNH, amegakaryocytic thrombocytopenia, MDS, T-cell and other lymphomas, CLL, myeloproliferative neoplasms, multiple myeloma (PMID:9283913 "frequently associated with hematologic disorders, especially aplastic anemia"; PMC4553982, 4-case AA series). EF with aplastic anemia carries a poorer prognosis.
Morphea overlap in ~29–40% (PMID:36768300).
Solid tumors (paraneoplastic, less common) and ICI-treated melanoma (PMID:40399177: melanoma was the commonest underlying tumor, 50%).

10. Diagnostics

EF is a clinicopathologic diagnosis; there is no single confirmatory blood test.

Laboratory: - CBC with differential — peripheral eosinophilia (LOINC for eosinophils/100 leukocytes e.g. LOINC:713-8). [HP:0001880]. - Serum immunoglobulins — polyclonal hypergammaglobulinemia. - ESR / CRP — elevated. - Aldolase (often elevated with normal/near-normal CK) — sensitive fascial-inflammation marker and treatment-response monitor. - ANA/anti-Scl-70/anticentromere — typically negative/absent (helps exclude systemic sclerosis). - Candidate biomarkers: TARC/CCL17, IL-5 (research).

Imaging: - MRI is the key noninvasive test: shows fascial thickening, T2 hyperintensity (edema), and post-contrast fascial enhancement; recommended where biopsy is not feasible and to guide the biopsy site (PMID:35651918 "MRI Findings of Eosinophilic Fasciitis"; PMID:36768300). [RadLex/imaging]. - Ultrasound and PET have supporting roles.

Histopathology — gold standard: - Full-thickness incisional biopsy en bloc to and including the deep muscular fascia (skin → subcutis → fascia → superficial muscle). Findings: fascial thickening, lymphoplasmacytic infiltrate ± eosinophils, fibrosis, and inflammation at the fascia–muscle interface. Tissue eosinophilia is supportive but NOT required for diagnosis (peripheral and tissue eosinophilia are often transient) (PMID:36768300; PMID:39895266 case lacking classic histology). [SNOMED CT histopathology].

Diagnostic criteria. Two proposed criteria sets: - Pinal-Fernandez et al. (2014) criteria — major: symmetric/diffuse swelling-induration-thickening of limb/trunk skin; minor: fascial thickening with inflammation/eosinophil infiltrate on biopsy. Exclusion of systemic sclerosis required. - Jinnin et al. (2018, Japanese) criteria — require symmetrical plate-like sclerotic lesions of extremities plus fascial thickening/inflammation, with SSc excluded (PMID:36768300).

Differential diagnosis (key to exclude): systemic sclerosis/scleroderma (spares fingers, no Raynaud/nailfold change, no visceral disease in EF), morphea (can overlap), nephrogenic systemic fibrosis, scleromyxedema, eosinophilia–myalgia syndrome, toxic-oil syndrome, hypereosinophilic syndrome, graft-versus-host disease, and chronic Lyme-associated fibrosis.

Genetic testing: Not indicated (no causal gene). Genetic/marrow work-up (e.g., bone marrow biopsy, cytogenetics, flow for PNH clone) is reserved for screening the associated hematologic disorders, not for diagnosing EF itself.

Screening: No population screening. Given the ~10% hematologic association, CBC surveillance for cytopenias during follow-up is prudent.

11. Outcome / Prognosis

Overall: EF is not directly life-threatening; prognosis is generally favorable for the fascial/skin disease when treated early, but morbidity from joint contractures and residual fibrosis is significant.
Predictors of poor outcome / refractory disease: truncal involvement, juvenile onset, presence of morphea-like lesions, dermal sclerosis, delayed treatment, and absence of peripheral eosinophilia have all been associated with worse response and contracture risk. Early combination immunosuppression predicts better recovery.
Mortality: Disease-specific mortality is low; excess mortality is driven by the associated hematologic malignancies / aplastic anemia, which carry a poor prognosis (PMID:9283913; PMC4553982).
Complications: flexion contractures, carpal tunnel syndrome, persistent limb stiffness/disability, secondary functional impairment; rarely, evolution of an associated hematologic neoplasm.
Recovery: many achieve substantial or complete remission on steroids ± methotrexate; a refractory subset needs escalation (§12). Spontaneous remission occurs in a minority.

12. Treatment

Suggested MAXO/NCIT/CHEBI annotations in brackets. No therapy is FDA-approved specifically for EF; management is from case series/expert consensus.

First-line — systemic glucocorticoids: - Prednisone (or equivalent) ~0.5–1 mg/kg/day, tapered over months; pulse IV methylprednisolone for severe disease. Response in the inflammatory phase is often good (PMID:36768300). [MAXO:0000058? use MAXO:0000302 pharmacotherapy or NCIT:C15986 Pharmacotherapy; therapeutic_agent: prednisone CHEBI:8378, methylprednisolone CHEBI:6888; therapeutic_modality SMALL_MOLECULE; treatment class NCIT:C2322 Corticosteroid].

Steroid-sparing / second-line (relapse or refractory): - Methotrexate (15–25 mg/week) — most recommended steroid-sparing agent; early steroid+MTX combination improves outcomes (PMID:36768300). [NCIT:C15986 Pharmacotherapy; methotrexate CHEBI:44185]. - Mycophenolate mofetil — commonly used alternative. [CHEBI:8764]. - Cyclosporine A — successful in some refractory cases (PMID:36768300). [CHEBI:4031]. - Azathioprine, hydroxychloroquine, cyclophosphamide — additional options.

Biologic / targeted (refractory disease): - Rituximab (anti-CD20) — reported benefit in refractory EF (clinical-experience review, PMC8021286). [rituximab NCIT:C1702; MONOCLONAL_ANTIBODY]. - Tocilizumab (anti–IL-6R) — case reports of benefit. - Anti–IL-5 agents — reslizumab / mepolizumab — mechanistically rational (IL-5/eosinophil axis); reslizumab achieved symptom resolution in refractory EF (PMID:32913886). [reslizumab/mepolizumab; MONOCLONAL_ANTIBODY]. - TNF inhibitors (infliximab) — variable reports. - JAK inhibitors — emerging interest. - Sirolimus (mTOR inhibitor) — "remarkable efficacy" in nivolumab-induced EF (PMID:32127188). [sirolimus CHEBI:9168]. - IVIG — adjunct in refractory/contracture-prone disease.

Phototherapy: UVA1 / PUVA phototherapy for cutaneous sclerosis. [MAXO/phototherapy].

Supportive / rehabilitative: - Physical therapy / occupational therapy — essential to prevent and treat contractures and preserve range of motion. [MAXO:0000011 physical therapy; NCIT:C15315 Rehabilitation]. - Surgical release of established contractures (e.g., fasciectomy, carpal tunnel release) in selected cases. [MAXO:0000004 surgical procedure].

ICI-related EF: withhold/hold the checkpoint inhibitor, treat with corticosteroids ± steroid-sparing agents; consider sirolimus or anti–IL-5 in refractory cases (PMID:40399177).

Treatment strategy: Early high-dose steroid + methotrexate is the prevailing initial regimen; escalate to biologics (rituximab, anti–IL-5, tocilizumab) for refractory disease; integrate PT/OT throughout. No randomized trials exist — evidence is observational. Pharmacogenomics: standard considerations apply to methotrexate (folate pathway) and azathioprine (TPMT/NUDT15 genotyping before thiopurines) — general, not EF-specific.

13. Prevention

Primary prevention: None established for idiopathic EF. For iatrogenic (ICI-related) EF, vigilance and early recognition during checkpoint-inhibitor therapy; review of causative drugs (statins, phenytoin, heparin) when EF arises after exposure.
Secondary prevention (early detection): prompt biopsy/MRI and early immunosuppression to prevent the inflammatory→fibrotic→contracture transition is the most effective "preventive" lever (prevents irreversible disability).
Tertiary prevention: aggressive PT/OT and contracture management; surveillance CBCs to catch associated hematologic disease early (~10% risk).
Immunization / public-health / counseling: Not applicable (non-genetic, non-infectious primary disease — no vaccine, no carrier/genetic counseling indicated).

14. Other Species / Natural Disease

Taxonomy: EF is described essentially only in humans ([NCBITaxon:9606 Homo sapiens]).
Naturally occurring animal disease: No well-established spontaneous EF analogue is catalogued in OMIA. Eosinophilic and fibrosing fasciitis-like conditions occur in veterinary medicine (e.g., eosinophilic dermatitis/panniculitis in dogs/cats), but a direct Shulman-syndrome homologue is not recognized.
Comparative biology / orthologs: Because EF has no causal gene, there are no disease-defining orthologs; the relevant pathways (IL-5, TGF-β1, eosinophil biology) are highly conserved across mammals.
Zoonotic potential / cross-species transmission: Not applicable.

15. Model Organisms

Dedicated animal model: None validated. There is no established knockout/transgenic/induced rodent model that faithfully recapitulates Shulman-syndrome EF. This is a real knowledge gap (flag as discussions: kind: KNOWLEDGE_GAP in the entry).
Surrogate/adjacent systems: Eosinophil/IL-5 biology and TGF-β–driven dermal/fascial fibrosis are studied in mouse models of scleroderma/fibrosis (e.g., bleomycin-induced skin fibrosis) and IL-5 transgenic / eosinophilia models, which inform mechanism but do not reproduce the EF phenotype specifically. Any such evidence cited should be tagged evidence_source: MODEL_ORGANISM and must not be the sole support for human phenotype claims (per dismech policy), and ideally flagged HUMAN_MODEL_MISMATCH given the absence of a true model.
In vitro: patient fascial fibroblast cultures and eosinophil–fibroblast co-culture systems are the main experimental substrate for the IL-5/TGF-β/TIMP findings — tag IN_VITRO.

Consolidated Citation List (verify each with `just fetch-reference` before use)

PMID	Citation (short)	Use
36768300	Mazilu et al. Int J Mol Sci 2023;24(3):1982 — "Eosinophilic Fasciitis: Current and Remaining Challenges"	Overview, epi, triggers, IL-5/TGF-β/TIMP, criteria, treatment
36130069	Pehl, Preuße, Allenbach et al. Rheumatology (Oxford) 2023;62(5):2005-2014	Histological spectrum, MHC I/II, M2 macrophages, no type-I IFN
34969795	EF (Shulman disease) clinical/imaging/pathological correlation, PubMed 2021	Imaging–path correlation
31130746	Shulman's disease review, 7 patients (2019)	Case-series clinical features
35651918	MRI Findings of Eosinophilic Fasciitis (2022)	Diagnostic imaging
40399177	ICI-related EF: 3 cases + literature review (2025)	Checkpoint-inhibitor EF, demographics
32127188	Nivolumab-triggered EF, sirolimus efficacy (2020)	mTOR mechanism / ICI treatment
32913886	Refractory EF treated with reslizumab (2020)	Anti–IL-5 therapy
38292575	EF following COVID-19, case series of 3 (2024)	Infectious trigger
36455945	EF without skin sclerosis (2022)	Atypical presentation
39895266	EF without classic histopathology (2024)	Histology not mandatory
9283913	Aplastic anemia in EF: immunosuppression & transplant (1997)	Hematologic association
(PMC4553982)	Severe aplastic anemia + EF: 4 cases + review	Hematologic association/prognosis
(PMC8021286)	Biologic (rituximab) treatment in resistant EF	Refractory therapy
(PMC12309119)	Diagnosis & treatment of early EF (case report)	Early-treatment window

Sources (web): - Mazilu et al. 2023, MDPI / IJMS · PMC mirror - Pehl/Preuße 2023, Rheumatology (PubMed) - ICI-related EF 2025 (PubMed) - Aplastic anemia in EF (PubMed) · Severe AA + EF, 4 cases (PMC) - Reslizumab in refractory EF (PubMed) · Sirolimus in nivolumab-EF (PubMed) - MRI findings (PubMed) · EF following COVID-19 (PubMed) - Biologic treatment in resistant EF (PMC) · Early EF diagnosis/treatment (PMC) - Medscape EF overview

Quick orientation for the KB entry

MONDO:0009175 confirmed; ICD-10 M35.4, ICD-11 4A43.0; no OMIM (acquired, non-Mendelian).
Model the pathophysiology as a causal chain: trigger → Th2/eosinophil activation (IL-5↑, IL-4/STAT6) → fibroblast activation via TGF-β1↑ + TIMP↑/ECM deposition → fascial fibrosis → contractures. Consider declaring conforms_to: fibrotic_response#Mesenchymal Cell Activation (tissue injury → inflammation → fibroblast activation → ECM → organ/limb dysfunction maps cleanly here).
Leave genetics/inheritance/model-organism sections explicitly "not applicable / knowledge gap" rather than fabricating gene or variant annotations.
Capture the hematologic-disorder association (~10%) and morphea overlap (29–40%) — good candidates for comorbidity/association_signals and differentiating notes.

One caution from your own memory bank that applies here: NCIT drug terms often fail therapeutic_agent validation, so prefer CHEBI for prednisone/methotrexate/MMF/cyclosporine/sirolimus, and reserve NCIT for biologics (rituximab) that lack a clean CHEBI term.

Eosinophilic Fasciitis

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1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Consolidated Citation List (verify each with `just fetch-reference` before use)

Quick orientation for the KB entry

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OpenScientist Report

Classifications

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Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Medical Actions

Biochemical Markers

Differential Diagnoses

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References

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Consolidated Citation List (verify each with just fetch-reference before use)

Quick orientation for the KB entry

Consolidated Citation List (verify each with `just fetch-reference` before use)