Definition
Eosinophilic fasciitis (EF; also known as Shulman’s disease or diffuse fasciitis with eosinophilia) is a rare, fibrosing disease of the connective tissue. Its ICD-10 code is M35.4 — within the group “Other systemic involvement of connective tissue”.
The core of the disease is inflammation and progressive fibrosis of the deep fascia — the thin, elastic membrane that surrounds and separates the muscles. As the fascia thickens and loses elasticity under the inflammation, the skin above it “adheres” to the muscle. Hence the two most characteristic signs: peau d’orange (a skin appearance resembling an orange peel) and the “groove sign” (a linear depression along the course of superficial veins, visible when the limb is raised).
In short: M35.4 is a rare autoimmune disease of the deep tissues of the limbs (sometimes the trunk), in which the fascia undergoes inflammation and fibrosis. It most often affects people between 40 and 60 years of age, with a slight male predominance. It responds well to corticosteroids, but requires careful workup — it is easily mistaken for scleroderma or other scleroderma-like diseases.
History of the discovery
The disease was first described in 1974 by the American rheumatologist Lawrence Shulman at Johns Hopkins School of Medicine. Shulman noted a group of patients whose clinical picture resembled systemic sclerosis, but — unlike it — the disease spared the fingers, was not accompanied by Raynaud’s phenomenon or organ involvement, and the blood tests showed a marked peripheral eosinophilia.
A year later, in 1975, Gerald Rodnan et al. proposed the name “eosinophilic fasciitis” — which became the standard. Shulman himself, in 1984, described the disease more broadly as “diffuse fasciitis with hypergammaglobulinaemia and eosinophilia — a new syndrome?” — signalling that even ten years after the first observation it was not clear whether it was a distinct entity or a variant of another condition.
To this day, just over 300 well-documented cases have been described in the literature. There are no randomised controlled trials. Most of the knowledge about treatment comes from case series, retrospective analyses from single centres and case reports.
The disease has barely five decades of history and still no single randomised controlled trial to its name.
The timeline collapses fifty years of clinical progress into a handful of papers — each marker is a publication that meaningfully shifted what we know about M35.4. The early decades are markedly sparse: the disease was first observed in 1974 and named in 1975, but the next solid case series did not appear until 1988. Half a century in, the field has accumulated barely a few hundred documented cases and not a single randomised controlled trial. The pace is typical of rare diseases — and explains why current treatment guidance still leans heavily on retrospective case series rather than prospective evidence.
Shulman 1975 · Rodnan 1975 · Lakhanpal 1988 · Lebeaux & Sène 2012 · Mango 2020
Pathogenesis — what happens in the body
The exact cause remains unknown. The best-accepted hypothesis is that some — still unidentified — trigger leads to the activation and degranulation of eosinophils (a type of white blood cell). Eosinophils, interacting with fibroblasts in the fascia, induce the release of profibrotic cytokines:
- TGF-β (transforming growth factor beta) — a key regulator of fibrosis
- IL-1, IL-5, IL-6 — pro-inflammatory interleukins
- TGF-α, TIMP-1 — modulators of extracellular matrix metabolism
The result is overproduction of collagen and other extracellular matrix proteins in the fascia. The fascia thickens 2–5 times, loses its elasticity, and mechanically restricts the mobility of the limbs.
Possible triggers
In about 30–50% of patients the onset can be temporally linked to a specific event. The most commonly described are:
- Intense physical effort — especially unfamiliar, untrained (the classic description: someone returning to running after a long break, or doing a major home renovation)
- Mechanical trauma, including work with vibrating machinery
- Infections — including described cases after COVID-19 (2024)
- Some drugs — in isolated reports, statins, immune-checkpoint inhibitors and others
- Lyme disease — an association was hypothesised in the older literature
- Allogeneic haematopoietic stem-cell transplantation — very rarely, as a manifestation of chronic GVHD
It should be stressed: in a significant proportion of patients no specific trigger is identified. The disease appears “out of nowhere”, without a clear cause.
In roughly half of patients no specific trigger can be pinned down. The rest splits between a handful of recurring scenarios.
In roughly half of patients no specific trigger is ever pinned down — the disease simply appears. Among the cases where a trigger is recognised, two scenarios dominate: an episode of unaccustomed physical exertion and a blunt mechanical injury, together accounting for about a third of all onsets. Infections — including post-COVID-19 cases reported from 2020 onward — sit below ten per cent. Drug- and vaccine-linked onsets remain anecdotal and should not drive routine clinical reasoning.
Lebeaux & Sène 2012 · Mango 2020
What distinguishes M35.4 from systemic sclerosis
Eosinophilic fasciitis has historically been confused with systemic sclerosis (SSc) and for years was regarded as one of its variants. Today we know it is a distinct entity. Key differences:
EF spares the fingers and toes. Scleroderma almost always begins with acrosclerosis — hardening of the fingers. That is the first thing a rheumatologist distinguishing the two diseases looks for.
- Acrosclerosis: present in scleroderma, absent in EF
- Raynaud’s phenomenon: characteristic of scleroderma, absent in EF
- Nailfold capillary changes: typical of scleroderma, absent in EF
- Organ involvement (lungs, kidneys, oesophagus): scleroderma causes it, EF does not
- Peripheral eosinophilia: present in EF in about 50–80% of patients, absent in scleroderma
- Depth of changes: scleroderma starts in the dermis; EF starts in the fascia and subcutaneous tissue
- Response to steroids: EF responds excellently; scleroderma — poorly
Classification and place in nosology
In ICD-10, M35.4 sits in block M30–M36 (“Systemic connective-tissue disorders”) as “Other systemic involvement of connective tissue”. In ICD-11 it is classified as 4A43 (“Eosinophilic fasciitis”) in the systemic connective-tissue diseases group.
In rheumatology practice, EF is grouped with the scleroderma-like disorders, alongside localised scleroderma (morphea), nephrogenic systemic fibrosis, the eosinophilia-myalgia syndrome (historically linked with L-tryptophan) and the toxic oil syndrome (Spanish 1981 epidemic).
Prognosis
The prognosis is generally good, but it needs nuance. Depending on the centre and the case series:
- Complete remission is achieved in 50–70% of patients within the first 2–3 years of treatment
- Partial remission with persistent chronic skin changes — in about 20–30% of patients
- Relapses after stopping treatment: about 30–70% (depending on source and regimen), usually responding well to re-initiation of therapy
- Spontaneous remissions without treatment — described, but rare
- Long-term complications: restricted mobility, joint contractures, occasionally permanent skin fibrosis
Mortality directly related to M35.4 is low. The few reported deaths involved complications of coexisting haematological conditions — mainly aplastic anaemia (the rare association of EF with bone-marrow aplasia is a known if uncommon clinical entity). Patients with EF should have their blood counts monitored in long-term follow-up.
Three percentages worth holding together: the chance of full remission, the risk of persistent skin changes, and the risk of relapse once treatment is stopped.
Most patients achieve full remission within two to three years of starting treatment — the strongest piece of good news in M35.4. At the same time, one in four to one in three is left with partial skin changes, and 30–70% relapse after steroids are withdrawn; the wide range reflects differences in tapering protocols between centres. Spontaneous remission without treatment is described but rare. The strongest predictor of a good response remains a short interval between symptom onset and the start of corticosteroids.
Lakhanpal 1988 · Mango 2020 · Wright 2016
The earlier, the better. The strongest predictor of a good response to treatment is a short time from symptom onset to the introduction of corticosteroids. Unfortunately, given the rarity of the disease, time to diagnosis is often measured in months, sometimes years. Hence the mission of this site — so that the next patient finds an answer faster.
Sources
Full bibliography with DOI/PubMed references will be added in the final version. In the mockup we list the main works on which the text above is based:
- Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians 1975; 88: 70-86.
- Lebeaux D, Sène D. Eosinophilic fasciitis (Shulman disease). Best Pract Res Clin Rheumatol 2012; 26: 449-458.
- Pinal-Fernandez I, et al. Diagnosis and classification of eosinophilic fasciitis. Autoimmun Rev 2014; 13: 379-382.
- Mango RL, et al. Baseline characteristics and long-term outcomes of eosinophilic fasciitis in 89 patients seen at a single center over 20 years. Int J Rheum Dis 2020; 23: 233-239.
- Mazori DR, Femia AN, Vleugels RA. Eosinophilic Fasciitis: an Updated Review on Diagnosis and Treatment. Curr Rheumatol Rep 2017; 19: 74.
- Onajin O, et al. Clinical guide to eosinophilic fasciitis: straddling dermatology and rheumatology. Expert Rev Clin Immunol 2022; 18: 707-718.