Eosinophilic fasciitis remains one of the most poorly studied scleroderma-like diseases. Fifty years after its first description, we still do not know exactly what triggers it, how to treat it optimally in the second line, or which factors predict relapse after therapy is withdrawn. Each of these gaps in knowledge points to a concrete direction of current research.
Epidemiology — what we know
M35.4 is a rare disease. Precise epidemiological data are unavailable because there is no global M35.4 registry. Most figures come from single-centre case series:
- Reported cases: around 300 well-documented cases in the world literature since 1974 (the number is rising steadily with better detection)
- Incidence: unknown; estimates range from 0.1 to 1 case per 1 million people per year — which qualifies EF as a rare disease (the European Union defines “rare” as ≤ 1 in 2,000)
- Age: most often 40–60 years (the 4th and 5th decades of life); cases have, however, been reported from the 1st to the 9th decade
- Gender: a slight male predominance (about 55–60% of cases), although some series report the opposite
- Ethnicity: described in every ethnic group; no strong racial preference
- Geography: cases reported on every continent; no clear geographic distribution
The largest single retrospective series comes from the Mayo Clinic (Mango et al., 2020) — 89 patients followed for 20 years and described in a single paper. This is currently our best long-term dataset.
The peak of onset falls in the fourth and fifth decades of life. The disease has, however, been described in every decade — from childhood to the ninth decade.
The peak of onset falls between forty and sixty years of age, with the fourth and fifth decades alone accounting for over half of all diagnoses. The disease has been described in every decade — from childhood to the ninth — but the tails of the distribution are thin. The middle-aged peak shapes the practical picture of the condition: patients are most often still working when symptoms appear, and the disease lands squarely in the most professionally and socially active years. Paediatric cases exist and are described in the literature, but they remain exceptional.
Lakhanpal 1988 · Bischoff & Derk 2008 · Mango 2020
No registry = lost knowledge. In countries that have set up national rare-disease registries (France, the United Kingdom, parts of the United States), the number of diagnosed M35.4 cases has risen severalfold over a decade. These are not new patients — they are missed diagnoses that are only now being collected systematically.
Pathogenesis — what is still unknown
Despite half a century of research, the key questions about the mechanism of M35.4 remain open:
- What is the primary trigger? We know that eosinophil degranulation sets off a cascade of pro-fibrotic cytokines. We do not know what activates the eosinophils themselves. Hypotheses: a self-antigen from muscle or fascia, mechanical micro-injury, viral infection, autoimmune dysregulation.
- Why does the disease classically spare the fingers? The fascia of the hands and feet has a different architecture and vascular supply. Yet no one has mechanistically explained why the same autoimmune process “does not reach” there.
- Is there a genetic susceptibility? A few familial case reports exist, but no candidate gene has been identified.
- What is the role of T and B lymphocytes in the chronic phase? The efficacy of rituximab (anti-CD20, depleting B lymphocytes) suggests that, alongside eosinophils, B lymphocytes also play an important role — but the details of the mechanism are unknown.
Future treatment — what scientists are testing
Most research on new M35.4 treatments is not run as classical RCTs (too few patients), but as case-series reports and real-world protocols. The most interesting directions on the 2024–2026 horizon:
JAK inhibitors (Janus Kinase Inhibitors)
Tofacitinib, baricitinib and upadacitinib — drugs blocking the JAK-STAT signalling pathway, central to the action of many pro-inflammatory cytokines. Individual case reports show good effects in refractory M35.4. Larger prospective studies are not yet available.
Anti-IL-5 drugs
Mepolizumab, reslizumab and benralizumab — monoclonal antibodies neutralising interleukin 5 (IL-5), a key growth and activation factor for eosinophils. The mechanistic rationale is sound: if eosinophils are central to pathogenesis, switching them off selectively should work. The first reports (reslizumab, 2020) were promising. The limitation: in some patients, blood eosinophils are already low after steroids, which reduces the potential benefit.
Tocilizumab — IL-6 as a target
A more mature option than anti-IL-5. IL-6 is a pro-fibrotic cytokine strongly involved in the pathogenesis of M35.4. Tocilizumab (Actemra) has a growing number of case reports showing efficacy in refractory M35.4. It is increasingly being considered as an alternative to rituximab.
Sirolimus and mTOR inhibitors
Sirolimus (rapamycin) blocks the mTOR pathway, central to fibroblast proliferation and fibrosis. It has been used in individual M35.4 cases with good effect, but it remains an experimental therapy.
Four research directions for novel M35.4 treatment. The number of described patients is very low — no direction yet has a large prospective trial.
- Reported patients (approximate)
Four research directions cluster around the same central question: which cytokine or signalling pathway sits closest to the eosinophil–fibroblast loop? Tocilizumab (anti-IL-6) leads in reported patient numbers — thirty to fifty cases, which by rare-disease standards is the most mature evidence base. JAK inhibitors come second, followed by anti-IL-5 antibodies, with mTOR inhibition still at the case-report level. None of these directions has crossed into a prospective trial; the entire field is, for now, built on case series rather than controlled comparisons.
case-series reports 2018–2025
Open clinical questions
Questions every patient would like to ask — and to which today there are no unequivocal answers:
- How long should treatment continue after remission has been achieved? Clinical practice suggests at least 12–24 months, but this is based on consensus, not on data.
- Is there an “ideal” second-line treatment? Methotrexate dominates practice mainly because of availability and physician familiarity, not because of proven superiority over alternatives.
- What predicts relapse? Some series suggest: severe initial presentation, delay in starting treatment, presence of morphea. Prospective validation is lacking.
- Is there a biomarker to monitor disease activity? Peripheral eosinophilia correlates only partially with activity; ESR and CRP are less sensitive. Studies on collagen biomarkers (e.g. PIIINP), cytokine and transcriptomic signatures are underway.
- Are there clinical variants requiring different treatment? Is M35.4 one disease, or a spectrum of several entities with a similar clinical picture?
Timeline — milestones
- 1974 — Shulman LE: first description of a group of patients with “diffuse fasciitis with hypergammaglobulinaemia and eosinophilia”
- 1975 — Rodnan GP et al.: the name “eosinophilic fasciitis” is proposed
- 1981 — Spain: the toxic oil syndrome (TOS) epidemic — important as differential-diagnostic context
- 1988 — Lakhanpal S et al.: classic series of 52 patients from the Mayo Clinic, clinical characterisation and treatment responses
- 1989 — USA: the eosinophilia–myalgia syndrome (EMS) epidemic linked to contaminated L-tryptophan
- 2005 — Kransdorf MJ, Murphey MD: MRI established as the key imaging tool for the diagnosis of EF
- 2012 — Lebeaux D, Sène D: comprehensive clinical review, formulation of diagnostic criteria
- 2014 — Pinal-Fernandez I et al.: expanded diagnostic criteria
- 2016 — Wright NA et al.: analysis of 63 patients from 3 centres, outline of modern epidemiology
- 2018 — Japanese Dermatological Association (Jinnin et al.): the first formal treatment algorithm
- 2020 — Mango RL et al.: largest long-term series (89 patients, Mayo Clinic, 20 years of follow-up)
- 2022–2024 — first reports of effective treatment with tocilizumab, JAK inhibitors and anti-IL-5 drugs in refractory M35.4
- 2024 — Li Y et al.: description of an M35.4 case series following COVID-19, suggesting a viral trigger in some patients
Each marker is a publication that meaningfully changed our understanding of EF. The pace accelerates after 2010 — yet still no RCT.
Five decades of research compressed into ten markers — the publications that changed how clinicians actually approach M35.4. The pace is sparse until the early 2010s, then accelerates: MRI becomes the standard imaging tool in 2005, the Lebeaux–Sène criteria land in 2012, the first formal treatment algorithm appears in 2018, and the largest retrospective series (Mango, 89 patients) closes out the pre-COVID era in 2020. Two adjacent disease epidemics — toxic oil syndrome (1981) and eosinophilia–myalgia syndrome (1989) — sit on the same axis as differential-diagnosis context. Despite this density, no randomised controlled trial has ever been carried out.
Shulman 1975 → Wang 2025; full references in the bibliography
Research collaboration
This site is not a research project, but it would like to be a point of contact for those who want to genuinely increase the amount of data collected:
- Patients — can agree to an anonymous description of their disease course as part of the stories section. Over time we would like to collect a broader set of standardised course data (questionnaires).
- Doctors — we are happy to link Polish and international centres where M35.4 is diagnosed and treated. If you work in such a centre, please write.
- Researchers — we are looking for an academic partner for a potential collaboration on a patient registry in Poland and (one day) the EU. If you work on rare connective-tissue diseases, please get in touch.
References
- Shulman LE. Diffuse fasciitis with eosinophilia: a new syndrome? Trans Assoc Am Physicians 1975.
- Rodnan GP, et al.. Eosinophilic fasciitis Arthritis Rheum 1975.
- 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.
- Mazori DR, Femia AN, Vleugels RA. Eosinophilic Fasciitis: an Updated Review on Diagnosis and Treatment Curr Rheumatol Rep 2017.
- Wright NA, et al.. Epidemiology and Treatment of Eosinophilic Fasciitis: An Analysis of 63 Patients From 3 Tertiary Care Centers JAMA Dermatol 2016.
- Jinnin M, et al.. Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis J Dermatol 2018.
- Wang X, et al.. Clinicopathological profile of eosinophilic fasciitis: a retrospective cohort study from a neuromuscular disorder center in China Arthritis Res Ther 2025.
- Li Y, Kong HE, Cheeley J. Eosinophilic fasciitis following COVID-19: A case series of 3 patients JAAD Case Rep 2024.