Abstract
Background
With the widespread use of immune checkpoint inhibitors (ICI), rare cutaneous immune‐related adverse events (cirAEs), including ICI‐induced eosinophilic fasciitis (ICI‐EF), are increasingly encountered. However, data on its clinical presentation and optimal therapeutic approaches remain sparse.
Objectives
This study aimed to further characterize the clinical features and outcomes of ICI‐EF.
Methods
This retrospective observational study analysed clinical features, treatment strategies and outcomes of ICI‐EF cases from EADV Task Force‐affiliated dermatology departments, complemented by cases from the current available literature and two international pharmacovigilance databases. Patient demographics, clinical characteristics, diagnostics, treatment and follow‐up data were extracted from the medical records and databases.
Results
We present 121 ICI‐EF cases from the EADV Task Force (n = 15), FPVD (n = 21), VigiBase® (n = 45) and the literature (n = 40). The most prevalent underlying malignancy in all groups was melanoma (50%), with PD‐1 inhibitor monotherapy (81%) being the predominant offending drug class. The median time to ICI‐EF onset was 10 months (IQR 6.8–16.3; range < 1–36). Detailed clinical information was available for 76 of the 121 cases (63%), revealing a highly variable clinical presentation. Treatment primarily involved ICI discontinuation (83%) and systemic corticosteroids (80%), followed by methotrexate (41%), intravenous immunoglobulins (12%) and mycophenolate mofetil (13%), resulting in the partial or complete resolution of ICI‐EF symptoms (66%).
Conclusions
ICI‐EF is a rare heterogeneous cirAE with varying clinical features and significant morbidity. Early recognition and timely treatment are key to ensuring ICI continuation and preserve oncologic outcomes.
Keywords: anti‐CTLA‐4, anti‐PD‐1, cancer, drug eruption, eosinophilic fasciitis, immune checkpoint inhibitor, immune‐related adverse event, melanoma
Plain Language Summary
What Is the Disease?
Immune checkpoint inhibitors (ICIs) are widely used cancer treatments that help the immune system fight tumours. In some patients, these drugs can cause side effects involving the skin and connective tissues. One rare but potentially serious side effect is immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF), a condition that causes inflammation and thickening of the tissue beneath the skin, leading to pain, swelling and stiffness of the limbs.
Location of the Study
This study included patients from dermatology departments specializing in supportive oncodermatology and affiliated with the European Academy of Dermatology and Venereology (EADV) Task Force, as well as cases reported worldwide through published medical literature and two international pharmacovigilance databases.
Aim of the Study
The aim was to better describe how ICI‐EF presents in clinical practice and how it is diagnosed and treated.
Methodology
We performed a retrospective observational study including 121 patients with ICI‐EF. Data were collected from hospital records, published case reports and international safety databases. We analysed patient characteristics, symptoms, diagnostic findings, treatments and outcomes.
Key Findings
ICI‐EF most often occurred in patients treated for melanoma and was mainly associated with PD‐1 inhibitor therapy. Symptoms usually developed several months after starting immunotherapy and varied widely between patients. Most patients were treated with stopping the ICI and using systemic corticosteroids, often combined with other immune‐suppressing treatments. About two thirds of patients showed partial or complete improvement.
Conclusions and Practical Implications
ICI‐EF is rare but can cause significant symptoms. Early recognition and timely treatment are important to reduce long‐term complications and, where possible, allow continuation of cancer therapy while maintaining good cancer outcomes.
A comprehensive retrospective analysis of 121 immune checkpoint inhibitor‐induced eosinophilic fasciitis cases, including clinical presentation, diagnostic features and treatment outcomes using data from the EADV Task Force ‘Dermatology for Cancer Patients’, two international pharmacovigilance databases and the current literature.
Why was the study undertaken?
This study was conducted to systematically characterize immune checkpoint inhibitor (ICI)‐induced eosinophilic fasciitis (EF), a rare scleroderma‐like dermatological adverse event following ICI therapy. Prior to this work, published evidence was limited to isolated case reports and small case series, leaving the clinical spectrum, frequency and outcomes of this toxicity poorly defined.
What does this study add?
By combining an international case series with data from two international pharmacovigilance databases and a comprehensive literature review, this study aggregates 121 unique cases—the largest compilation to date. It delineates patterns of presentation, time to onset and treatment responses, providing a more robust understanding of this adverse event.
What are the implications of this study for disease understanding and/or clinical care?
These findings expand knowledge of the clinical manifestations and natural history of ICI‐EF. They offer clinicians a clearer framework for early recognition and diagnosis, and may inform management, monitoring strategies and future research.
BACKGROUND
By blocking inhibitory self‐tolerance pathways, immune checkpoint inhibitors (ICIs) enhance T cell‐mediated antitumor immunity yet can simultaneously result in the development of cutaneous immune‐related adverse events (cirAEs). 1 , 2 , 3 These cirAEs present with diverse phenotypes, many of which resemble ‘classic’ dermatoses. 4 Furthermore, the expanding use of ICIs has been accompanied by a rising incidence of rarer cirAEs, including sclerodermoid forms. 5 These scleroderma‐like disorders, such as ICI‐induced eosinophilic fasciitis (ICI‐EF), show a more severe or refractory presentation, resulting in a higher patient symptom burden and possible discontinuation of immunotherapy, potentially compromising oncological outcomes. 6
Classic eosinophilic fasciitis (EF), also known as Shulman syndrome, is a rare fibrosing connective tissue disease commonly presenting with symmetrical and painful oedema, erythema and progressive skin induration of the extremities, often leading to functional impairment and typically occurring in the absence of Raynaud's phenomenon. While peripheral eosinophilia is frequently observed, it is not a mandatory diagnostic criterion. Diagnosis requires concordant clinical features, exclusion of systemic sclerosis and confirmation by MRI demonstrating fascial inflammation and/or a full‐thickness biopsy showing inflammatory infiltration of lymphocytes and eosinophils, along with thickening and fibrosis of the skin and fascia. 7
Although EF aetiology and pathogenesis remain unclear, recent heightened physical activity, repetitive trauma or drug exposures (e.g. statins, ramipril or heparin) are recognized triggers. 8 , 9 Among anticancer treatments, radiotherapy and ICIs have been shown to sporadically induce EF. 9 , 10 Given the limited characterization of ICI‐EF, its management relies largely on expert experience. This study's aim was to characterize the clinical features, diagnostic profile, as well as treatment and clinical outcomes of ICI‐EF patients.
MATERIALS AND METHODS
Study design and data sources
The European Academy of Dermatology and Venereology (EADV) Task Force ‘Dermatology for Cancer Patients’ conducted an international multicentre retrospective observational study combined with a literature review and analysis of two pharmacovigilance databases: the French Pharmacovigilance Database (FPVD) and VigiBase® of the World Health Organization (WHO). A duplicate check was performed in all cases to prevent analysis of identical cases.
EADV Task Force data collection
The EADV Task Force ‘Dermatology for Cancer Patients’ is an international network of dermatologists, specializing in supportive oncodermatology. Each participating dermatologist identified cases that qualified for inclusion in their institution's database between 2014 and 2025. Inclusion criteria included patients with cancer, age ≥ 18 years, histopathologically or radiologically confirmed diagnosis of EF, and ICI (either monotherapy or combination) as a suspected drug. The electronic medical records of the patients were reviewed and data were extracted, including patient demographics, clinical characteristics, diagnostics (histopathology, radiology and laboratory analysis), treatment and clinical outcomes. Grading was performed according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). 11
Literature review
A narrative literature review with a systematic search was performed using the PubMed, Embase and Scopus databases to identify cases of ICI‐EF in adult (≥ 18 years) patients receiving ICIs up to 1 December 2026, with no restrictions on language or article type. Database searches were carried out by a clinical librarian. The search strategy involved the use of the following key terms: ‘eosinophilic fasciitis’, ‘immune checkpoint inhibitors’ and their respective variations. The line‐by‐line search strategy and detailed results are provided in the Supplementary Materials. Articles were screened by two independent screeners in two rounds using the ‘Rayyan’ Q online reviewing system and included only when they fulfilled the inclusion criteria and sufficient clinical information was available. 12 Inclusion criteria and patient data extraction were performed using the same approach as in the retrospective study, ensuring consistency.
Pharmacovigilance databases
French pharmacovigilance database (FPVD)
The French Pharmacovigilance System, established in 1973, operates through a network of 30 Regional Pharmacovigilance Centers (CRPVs). Since 1985, the FPVD has systematically documented all adverse drug reactions (ADRs) submitted by healthcare professionals and patients. 13 Recorded data includes patient demographics (e.g. age, sex and medical history), details of the ADRs (e.g. date of onset and outcome) and drug exposure (e.g. date of introduction and withdrawal). Each case report concludes with a detailed clinical summary. ADRs are encoded using the Medical Dictionary for Drug Regulatory Activities (MedDRA®), whereas drug classifications adhere to the Anatomical Therapeutic Chemical (ATC) system. 14 To ensure robust scientific assessment, additional case‐specific details are actively gathered, as necessary.
VigiBase®
The Uppsala Monitoring Center (UMC) oversees the WHO Safety Database, also known as VigiBase®. 15 Since 1967, VigiBase® has been collecting individual case safety reports from national pharmacovigilance networks in over 172 countries. Post‐marketing reports are issued by healthcare professionals, patients and pharmaceutical companies. The anonymity of both patients and reporters is preserved. Each report includes demographic details such as the country of origin, qualifications of the reporter, patient characteristics, information about the drugs involved (indication, start and stop dates, dosage, any other concomitant or suspect medications taken simultaneously) and information about ADR (effects, seriousness, onset and outcome).
Query
De‐duplicated datasets of VigiBase® and FPVD were queried for all reports of MedDRA (version 27.0) Preferred Term ‘Eosinophilic fasciitis’ involving atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab or tremelimumab. In MedDRA, a preferred term is defined as a distinct descriptor of a single medical concept. 14
Data analysis
Absolute and relative frequencies were described for all study variables. As Vigibase provided less comprehensive clinical data, Vigibase cases were analysed separately. The remaining cases were pooled for collective analysis.
Disproportionality analysis
Disproportionality analysis is a statistical technique used in pharmacovigilance to identify the potential safety signals. This consisted of comparing the proportion of reports with a specific ADR and a given drug (cases) to the proportion of reports with the same ADR and other drugs (non‐cases). If the proportion of cases is higher than that of non‐cases, this suggests a possible association between the drug and an ADR. Disproportionality was assessed using the Information Component (IC) (95% confidence interval [CI]). The IC was derived from a Bayesian confidence propagation neural network. It compares the observed and expected number of reports for a specific ADR‐drug combination. The positive lower end of the 95% confidence interval of the IC is commonly used as the threshold for identifying potential safety signals. 16 Hence, we calculated the IC to assess whether ICI‐EF was disproportionately reported in association with ICIs. Specifically, we calculated the IC for the association between each class of ICIs (CTLA‐4, PD‐1 or PD‐L1 inhibitors) and the occurrence of ICI‐EF. 17
RESULTS
Baseline characteristics of the study population
In total, 121 patients with ICI‐EF were included in this study. Fifteen patients were identified by the EADV Task Force members (France, n = 4; Greece, n = 3; the United Kingdom, n = 4; the Netherlands, n = 2; Spain, n = 1; and the United States of America, n = 1). An additional 66 ICI‐EF cases were identified from the VigiBase® (n = 45) and FPVD (n = 21) databases. Finally, the literature review yielded 36 articles with a total of 40 ICI‐EF cases, categorized as follows: 29 case reports, two case series, four retrospective studies and one prospective observational study. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 Details of the literature review's selection process can be found in Figure 1. Baseline patient characteristics are shown in Table 1. Anti‐PD‐1 monotherapy was most frequently associated with ICI‐EF across all groups (n = 98, 81%). In a small proportion of cases (n = 22; 18%), ICIs were combined with other cancer treatments (e.g. chemotherapy, radiotherapy or targeted therapy). The most common malignancies were melanoma (n = 60; 50%) and non‐small‐cell lung cancer (NSCLC) (n = 29; 24%). Overall, the majority (n = 53/76; 70%) of patients had stage IV disease, although stage data were unavailable for Vigibase® cases. For the melanoma subgroup, around half (n = 29/60; 48%) had stage IV disease.
FIGURE 1.
Flow chart of literature review screening process.
TABLE 1.
Patient characteristics of included immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) patients.
| Clinical characteristics n (%) | Total (n = 121) |
|---|---|
| Age (years) Mean/median (range) | 61 a /61 (25–89) |
| Sex | |
| Female | 64 (52.9) |
| Male | 54 (44.6) |
| Unknown | 3 (2.5) |
| Immune checkpoint target | |
| PD‐1 b | 98 (81.0) |
| PD‐L1 c | 13 (10.7) |
| CTLA‐4 d | 1 (0.8) |
| CTLA‐4/PD‐1 e | 9 (7.5) |
| Concurrent cancer therapies | |
| Chemotherapy | 13 (10.7) |
| Radiotherapy | 5 (4.1) |
| Tyrosine kinase inhibitors | 4 (3.3) |
| Primary cancer | |
| Melanoma | 60 (49.6) |
| NSCLC | 29 (24.0) |
| Urothelial cell carcinoma | 8 (6.6) |
| Renal cell carcinoma | 4 (3.3) |
| HNSCC | 5 (4.1) |
| Breast cancer | 2 (1.7) |
| Other f | 10 (8.3) |
| Unknown | 3 (2.5) |
| Cancer stages | |
| Stage I–II | 1 (0.8) |
| Stage III | 9 (7.4) |
| Stage IV | 53 (43.8) |
| Unknown | 58 (47.9) |
Abbreviations: CTLA‐4, cytotoxic T‐lymphocyte‐associated protein 4; HNSCC, head and neck squamous cell carcinoma; ICI, icmmune checkpoint inhibitor; NSCLC, non–small cell lung carcinoma; PD‐1, programmed cell death protein 1; PD‐L1, programmed cell death ligand 1.
Weighted mean.
Nivolumab (n = 48; 39.7%), pembrolizumab (n = 45; 37.2%), cemiplimab (n = 4; 3.3%), camrelizumab (n = 1; 0.8%).
Atezolizumab (n = 8; 6.6%), avelumab (n = 2; 1.7%), durvalumab (n = 3; 2.5%).
Ipilimumab (n = 1; 0.8%).
Ipilimumab/nivolumab (n = 7; 5.8%), ipilimumab/pembrolizumab (n = 2; 1.7%).
Classical hodgkin lymphoma (n = 1; 0.8%), cervical cancer (n = 2; 1.7%), colorectal cancer (n = 1; 0.8%), neuroendocrine carcinoma (n = 2; 1.7%), non‐melanoma skin cancer (n = 3; 2.5%) and angioimmunoblastic T‐cell lymphoma (n = 1; 0.8%).
Descriptive analysis based on EADV Task Force, FPVD and literature review cases
Clinical data and outcomes of the pooled ICI‐EF cohort (n = 76) are shown in Table 2. Detailed information stratified by database is provided in Tables S1–, S3. No history of EF or other autoimmune diseases was reported, and only two cases (2.6%) reported a recent history of increased physical activity. The median time (IQR; range) to onset was 10.0 months (7–16; < 1–36). Marked differences in CTCEA grading were observed across sources: grade III toxicity occurred in 73% of EADV cases, compared with 38% in FPVD and 15% in literature cases, the latter frequently lacking severity data. The arms (n = 52; 68%) and legs (n = 59; 78%) were most frequently affected. Acral involvement, which is rare in classical EF, was reported in approximately one third of the cases. Oedema (n = 51; 67%) was the predominant symptom, while classical EF manifestations such as peau d'orange (n = 15; 20%) and the Groove sign (n = 20; 26%) were less commonly reported. Histology (n = 53; 70%) and MRI (n = 50; 69%) were primarily performed to support the diagnosis (Figures 2, 3; Figure S3). Peripheral eosinophilia was detected in 50 (66%) patients at the time of diagnosis. Most patients received systemic corticosteroids (n = 61; 80%), followed by methotrexate (MTX) (n = 31; 41%), mycophenolate mofetil (MMF) (n = 10; 13%) and intravenous immunoglobulins (IVIg) (n = 9; 12%). First‐line treatment predominantly consisted of systemic corticosteroid ((methyl‐)prednisolone) monotherapy (n = 38; 50%), typically at a dose of 1 mg/kg/day (n = 21/38; 55%) or a median starting dose of 40 mg/day (IQR: 30–60, range 10–170), and occasionally combined with MTX (n = 15; 20%), MMF (n = 3; 4%) or other therapies (n = 3; 4%). In steroid‐refractory or progressive cases, MTX (n = 14), MMF (n = 7) and IVIg (n = 6) were the most frequently prescribed second‐line therapies. Among patients receiving (methyl‐)prednisolone as monotherapy (n = 19; 25%), ICI‐EF stabilized (n = 2/19; 11%) or regressed (n = 16/19; 84%) in all evaluable cases, with no cases of progression. In addition to immunosuppressive treatment, ICIs were discontinued in most patients (n = 63; 83%) with missing data in six cases. Nevertheless, ICI‐EF progression still occurred despite ICI cessation (n = 7/63; 11%). Notably, among the patients who continued ICI therapy (n = 7; 9%), only one showed ICI‐EF progression. Conversely, complete radiological response of malignancy was observed in 34 patients (45%), including 23 in the melanoma subgroup, and occurred despite early ICI discontinuation in 26 of 34 cases (81%). Malignancy progression (n = 9; 12%) and malignancy‐related death (n = 4; 5%) were observed only in patients who temporarily or permanently discontinued ICI therapy.
TABLE 2.
Clinical characteristics and outcomes of immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) patients from the EADV Task Force, the French pharmacovigilance database (FPVD) and the literature review.
| Characteristics n (%) | Total (n = 76) |
|---|---|
| Time to first symptoms (months); median (IQR) | 10.0 (6.8–16.3) |
| Time to diagnosis (months); median (IQR) | 14.0 (11.0–20.0) |
| Grading CTCAE | |
| Grade 1 | 4 (5.3) |
| Grade 2 | 13 (17.1) |
| Grade 3 | 25 (32.9) |
| Unknown | 34 (44.7) |
| Clinical distribution | |
| Bilateral distribution | 66 (86.8) |
| Face | 13 (17.1) |
| Neck | 13 (17.1) |
| Trunk | 29 (38.2) |
| Arms | 52 (68.4) |
| Hands | 24 (31.6) |
| Legs | 59 (77.6) |
| Feet | 23 (30.3) |
| Clinical features | |
| Oedema | 51 (67.1) |
| Erythema | 24 (31.6) |
| Peau d'orange | 15 (19.7) |
| Groove sign | 20 (26.3) |
| Raynaud | 5 (6.6) |
| Localized scleroderma | 32 (42.1) |
| Morphea‐like | 25 (32.9) |
| LS‐like | 1 (1.3) |
| Undefined | 6 (7.9) |
| Inflammatory arthritis | 7 (9.2) |
| Dysphagia | 8 (10.5) |
| Dyspnoea | 13 (17.1) |
| Histology performed | 59 (77.6) |
| Supportive of ICI‐EF | 53 (89.8) |
| Histologic presence of | |
| Thickened fascia | 22 (37.3) |
| Cellular infiltrate | 42 (72.2) |
| Eosinophils infiltrate | 26 (44.1) |
| Fibrosis | 25 (42.4) |
| Laboratory analysis | |
| Peripheral eosinophilia | 50 (65.8) |
| Hypergammaglobulinaemia | 3 (3.9) |
| Increased levels of | |
| Rheumatoid factor | 3 (3.9) |
| aCCP antibodies | 0 (0) |
| Creatine kinase | 5 (6.6) |
| ESR | 8 (10.5) |
| LDH level | 8 (10.5) |
| MRI of the limbs performed | 52 (68.4) |
| Signs of ICI‐EF | 50 (96.2) |
| Myositis‐specific immunoblot | |
| Negative | 14 (18.4) |
| Positive | 0 (0) |
| Topical steroid response | 6 (7.9) |
| Systemic treatments | |
| None | 9 (11.8) |
| Corticosteroids | 61 (80.3) |
| Methotrexate | 31 (40.8) |
| Mycophenolate mofetil | 10 (13.2) |
| Intravenous immunoglobulins | 9 (11.8) |
| Cyclosporine | 3 (3.9) |
| Sirolimus | 2 (2.6) |
| Infliximab | 2 (2.6) |
| Tocilizumab | 3 (3.9) |
| Doxycycline | 2 (2.6) |
| Alendronic acid | 2 (2.6) |
| Hydroxychloroquine | 2 (2.6) |
| Omalizumab | 1 (1.3) |
| Rituximab | 1 (1.3) |
| Dupilumab | 1 (1.3) |
| Psoralen plus ultraviolet‐A radiation (PUVA) | 1 (1.3) |
| Sulfasalazine | 1 (1.3) |
| Baricitinib | 1 (1.3) |
| Benralizumab | 1 (1.3) |
| Dapsone | 1 (1.3) |
| Plasma exchange | 1 (1.3) |
| Discontinuation of ICI | |
| No | 7 (9.2) |
| Yes, temporary | 7 (9.2) |
| Yes, permanent | 56 (73.7) |
| Unknown | 6 (7.9) |
| Dermatological outcome | |
| Regression | 50 (65.8) |
| Stable disease | 15 (19.7) |
| Progression | 8 (10.5) |
| Unknown | 3 (3.9) |
| Oncologic outcome | |
| Complete response | 34 (44.7) |
| Partial response | 5 (6.6) |
| Stable disease | 8 (10.5) |
| Progression | 9 (11.8) |
| Unknown | 20 (26.3) |
| Death | 4 (5.3) |
| Other immune‐related adverse events | |
| Cutaneous | 18 (23.7) |
| Non‐cutaneous | 16 (21.1) |
Abbreviations: aCCP, anti‐cyclic citrullinated peptide; CTCAE, Common Terminology Criteria for Adverse Events; ESR, erythrocyte sedimentation rate; LDH, lactate dehydrogenase; LS, lichen sclerosis; MRI, magnetic resonance imaging.
FIGURE 2.
Fascia biopsy from a 73‐year‐old female treated with durvalumab (anti‐PD‐L1 immune checkpoint inhibitor) for non–small cell lung carcinoma (NSCLC): Microscopical and immunohistochemical analysis of the inflammatory infiltrate. (a) Haematoxylin and eosin (H&E) staining of the thickened fascia showing scattered foci of lymphocytic inflammatory infiltrates, consistent with fasciitis; a single eosinophil is shown in the inset. (b) CD3 immunostaining demonstrating T lymphocytes within the fascia, predominantly clustering around blood vessels. (c, d) CD68 immunostaining highlighting macrophages. (e) CD20 immunostaining showing B lymphocytes distributed around blood vessels. (f) CD138 immunostaining revealing only a few plasma cells. Scale bar = 50 μm.
FIGURE 3.
MRI findings of eosinophilic fasciitis in the lower extremities, with bilaterally mild muscle oedema and more prominent oedema along the fascial planes, more pronounced on the left side.
Descriptive analysis based on VigiBase®
Forty‐five ICI‐EF reports were identified (2017–2025). Most reports involved anti‐PD‐1 monotherapy (n = 42; 93.3%). Anti‐CTLA‐4 (n = 6; 13.3%) were always administered in combination with anti‐PD‐1. The only concomitantly reported drugs in ≥2 reports were prednisone (n = 3; 6.7%) and esomeprazole (n = 2; 4.4%). The median (IQR; range) time to onset was 13 months (9–17; 6 days to 3 years). Eosinophilia was the only co‐reported symptom (n = 2; 4.4%). Partial or full regression of ICI‐EF was observed in most cases (n = 23; 51.1%), while five patients (11.1%) showed no symptom improvement. A fatal outcome coinciding with cancer progression was noted in two reports (4.4%). Cessation of ICI therapy was reported in 29 (64.4%) cases, with a favourable outcome observed in 18 (62.1%) of these cases, whereas ICI‐EF persisted in six (20.7%) cases. ICI re‐challenge was described in two reports, with one recurrence of ICI‐EF.
Disproportionality analysis of VigiBase® reports
ICIs were significantly associated with ICI‐EF, with an IC of 5.0 [4.7;5.4], with 66 reports observed as compared to the two expected. Specifically, PD‐1 inhibitors exhibited an IC of 5.3 [4.9;5.6], with 63 reports observed compared to one expected. CTLA‐4 inhibitors showed an IC of 3.1 [1.7;4.0], with six reports observed as compared to none expected, and the IC of PD‐L1 inhibitors was 2.1 [0.1;3.3], with three reports observed as compared to none expected. The combination of nivolumab and ipilimumab yielded an IC of 2.7 [1.0;3.8].
DISCUSSION
This international multicentre retrospective study and pharmacovigilance‐based analysis, complemented by a narrative literature review, represents the largest compilation of ICI‐EF cases to date, combining data from different sources from a heterogeneous population of unselected patients. In line with prior research, ICIs are a leading trigger for EF alongside drugs such as statins, proton‐pump inhibitors, and anti‐tumour necrosis factor agents (anti‐TNF‐α). 9 , 10 The exact pathogenesis of ICI‐EF remains unclear. Classic EF is proposed to involve a pro‐inflammatory immune reaction, with an inflammatory infiltrate predominantly composed of CD8+ lymphocytes, macrophages and eosinophils, with subsequent fibrosis in the deep fascia. 54 , 55 One proposed mechanism regarding the effect of PD‐1 blockade in ICI‐EF is T‐cell activation, particularly CD8+ and Th17 subsets, potentially leading to an aberrant cytotoxic immune response resulting in a pro‐inflammatory cytokine cellular environment (IL‐5, IL‐6, IL‐10, TGF‐β), followed by eosinophil and macrophage infiltration and subsequent fibroblast activation in the fascia. 56 , 57 , 58 Nevertheless, direct translation to ICI‐EF must be performed with caution, as ICIs can introduce considerable pathological heterogeneity despite their phenotypic similarities to classical patterns.
Beyond ICIs, an inflammatory aetiology has been suggested for various classical EF triggers, including infections (e.g. Borrelia burgdorferi, Ascaris lumbricoides, Mycoplasma), autoimmune diseases (e.g. vitiligo, rheumatoid arthritis and systemic lupus erythematosus) and preceding physical exertion, burns or trauma. 7 , 8 , 54 Although intense physical activity before disease onset is the most reported classical EF trigger (30%–45%), only two patients reported such a history, suggesting a reduced role in cancer patients or reflecting missing data due to the study's retrospective design. 55 , 59 Furthermore, clinicians should consider EF as a potential paraneoplastic syndrome, as it has been sporadically described in both solid and hematological malignancies, warranting careful evaluation of underlying malignancy progression. 10 , 60
Similar to classical EF, ICI‐EF exhibits a pattern of bilateral involvement and a distribution that predominantly affects the extremities, followed by the trunk and neck. In contrast, acral involvement is rare in classical EF, yet it was involved in one third of the study cohort. 54 , 55 , 59 Oedema (66%) is commonly present in both classical and ICI‐EF. Hallmark symptoms, such as peau d'orange (21%) and Groove sign (26%), were less frequently reported in this study. This could be attributed either to their lower prevalence in ICI‐EF or to clinicians' reduced familiarity with recognizing and documenting them. However, some studies have proposed a temporal progression of cutaneous features, starting with oedema and later progressing to peau d'orange and Groove signs. 61 , 62 Similarly, peripheral blood eosinophilia (66%) was often present, while other hallmark laboratory findings such as hypergammaglobulinaemia (4%) and an elevated erythrocyte sedimentation rate (ESR) (8%) were not frequently reported. The median time to onset of 10.5 months after ICI initiation was notably shorter than previously reported by Teboul et al., where drug‐induced EF had a mean onset of 24 months (range 8–36 months). 9
Currently, systemic corticosteroids remain the established first‐line therapy for EF, as supported by their frequent use in this study (80%) and in the literature. 54 , 63 , 64 Unfortunately, relapses and refractory or steroid‐dependent forms often occur, and long‐term use of high‐dose corticosteroids may negatively impact oncological outcomes. 65 Methotrexate serves as a second‐line option, either alone or in combination with corticosteroids, in various dosing schedules, including high‐dose intravenous administration, with response rates of up to 80% in classical EF cases with steroid refractoriness or prolonged steroid dependency. 64 , 66 Other immunosuppressants such as MMF, azathioprine, cyclosporine, cyclophosphamide and sulfasalazine have been used with variable success. 64 Nevertheless, the immunosuppressive effects of these drugs may diminish the efficacy of ICIs and negatively affect overall survival, as is the case with TNF‐α inhibitors. 65 Therefore, these treatments for ICI‐EF should be used with caution and a more targeted steroid‐sparing approach may be appropriate. Alternative treatments such as IL‐6 inhibitors (tocilizumab; n = 4/4; CR 25%; PR 75%), immunoglobulins (IVIg and ATG; n = 8/12; CR 33.3%; PR 33.3%) and anti‐CD20 monoclonal antibodies (rituximab; 4/6; CR 33.3%; PR 33.3%) have shown promising response rates in very small classical EF cohorts. 67 Additionally, anti‐eosinophilic (anti‐IL‐5) therapies (mepolizumab, benralizumab and reslizumab), which target eosinophil growth and migration via IL‐5 or its receptor, have been suggested as attractive alternative treatments, although this has not yet been attempted in ICI‐EF patients. 61 A range of other steroid‐sparing therapies (e.g. IL‐4 inhibitors, tyrosine kinase inhibitors and sirolimus) have been explored in case reports and case series. 54 , 67 In conclusion, due to the absence of randomized studies, evidence guiding therapeutic choice is limited. For classical EF, current evidence supports systemic corticosteroids as first‐line treatment, with methotrexate as the steroid‐sparing agent. Finally, the efficacy of IL‐6 inhibitors, which has recently been reported in a wide range of refractory and severe irAEs (e.g. cytokine release syndrome, encephalitis, arthritis), should be prospectively evaluated in ICI‐EF. 68 , 69
Despite current recommendations advocating immunosuppressive therapy for ICI‐EF, such treatment and subsequent ICI discontinuation may increase the risk of oncological disease progression. However, this risk may vary considerably depending on the type and biological behaviour of the underlying malignancy. 70 Furthermore, concomitant corticosteroid use makes it difficult to determine its potential negative effects on oncological outcomes. In the study cohort, partial or complete oncological response was observed in over half (n = 37/73; 51%) of the patients. This could suggest either the early effectiveness of ICIs following a few cycles, a reduced risk of immunosuppressive agents on oncological progression or that ICI‐EF development may reflect an improved ICI response. 71 However, the (complete) radiological response could not be consistently verified using standardized criteria because staging data were missing for part of the cohort. Therefore, it cannot be reliably concluded that the absence of detectable disease reflects true treatment response, and any link between ICI‐EF occurrence and improved oncological outcomes should be interpreted with caution. Remarkably, ongoing ICI treatment did not correlate with ICI‐EF symptom progression (n = 1/8; 14%), suggesting that continuing treatment may be optional.
LIMITATIONS
Limitations include the retrospective design of this study with missing data and possible underestimation of cases suitable for inclusion owing to memory bias or non‐exhaustive databases of ADRs in the participating centres. Additionally, while we performed a systematic search, we primarily included case reports, which may introduce bias and heterogeneity. Lastly, ICI‐EF is difficult to accurately assess in real‐life clinical practice, and although some assessment tools exist, none were available for use in our cohort. While partial or complete regression of ICI‐EF was observed in most cases, no predefined criteria were used, limiting the assessment of treatment response.
CONCLUSIONS
ICI‐EF is a rare scleroderma‐like cirAE that can cause significant morbidity and limit the ability to continue effective ICI therapy. Continuous patient monitoring is necessary because symptoms may appear late in the treatment process or even after ICI therapy has been concluded. Given the rarity of this condition, further research should focus on optimizing and validating treatment schedules.
AUTHOR CONTRIBUTIONS
Tristan V.M. Bruijn: Conceptualization, methodology, data curation, analysis, writing (original draft preparation and editing) and visualization (tables, figures, graphical abstract). Alexandre O. Gérard: Conceptualization, data curation (Vigibase) and writing (review and editing). Maëlys Labat: Data curation (FPVD) and writing (review and editing). Zoe Apalla: case contribution and writing (review). Wouter van Binsbergen: Case contribution, writing (review). Dimitra Koumaki: Case contribution and writing (review). Valerian Rivet: Case contribution and writing (review). Frederic Dezoteux: Case contribution, visualization (figure) and writing (review). Damien Giacchero: Case contribution and writing (review). Michael R. Ardern‐Jones: Case contribution, visualization (figure) and writing (review). Kara Heelan: Case contribution and writing (review). Jesse Hirner: Case contribution and writing (review). Ander Mayor: Case contribution and writing (review). Mariette Labots: Writing (review and editing). Markus V. Starink: Case contribution and writing (review). Conny J. van der Laken: Writing (review and editing). Vincent Sibaud: Writing (review and editing). Yannick S. Elshot: Conceptualization, data curation, writing (review and editing) and supervision.
FUNDING INFORMATION
The authors have nothing to report.
CONFLICT OF INTEREST STATEMENT
Tristan V.M. Bruijn, Alexandre O. Gérard, Maëlys Labat, Zoe Apalla, Jesse P. Hirner, Kara Heelan, Wouter van Binsbergen, Michael R. Ardern‐Jones, Valerian Rivet, Frederic Dezoteux, Dimitra Koumaki, Damien Giacchero, Ander Mayor and Markus V. Starink declares that they have no conflicting financial or personal interests. Yannick S. Elshot: speaker for AbbVie, Bristol‐Myers Squibb, MSD, Novartis and Johnson & Johnson; all outside the submitted work. Vincent Sibaud: speaker or advisory role for Novartis, Bayer, BMS, Immunocore, Regeneron, MSD, Astellas, Janssen, L'Oréal, Pierre Fabre and Astra Zeneca. Conny J. van der Laken: speaker or advisory role for GSK, Lilly, UCB Pharma, Novartis, AbbVie and Johnson & Johnson; all not related to this manuscript. Mariette Labots: advisory role for Bristol‐Myers Squibb, fee paid to institution outside the submitted work.
ETHICAL APPROVAL
Reviewed and approved by the non‐WMO Committee of the Medical Ethics Review Committee of Amsterdam University Medical Centers; approval #2025.0476.
ETHICS STATEMENT
The patients in this manuscript provided written informed consent for publication of their case details.
Supporting information
DATA S1. Line‐by‐line search strategy and detailed results of the performed literature review.
FIGURE S1. Fascia biopsy from a 45‐year‐old female treated with pembrolizumab (anti‐PD‐1 immune checkpoint inhibitor) for metastasized melanoma: microscopical and immunohistochemical analysis of the inflammatory infiltrate: Histological sections demonstrate extensive thickening of the septa within the subcutaneous tissue, caused by dense hyalinized fibrous tissue. This is accompanied by mild to moderate chronic inflammation involving primarily the septa and, focally, the adjacent subcutaneous fat. The inflammatory infiltrate consists predominantly of small lymphocytes. The overlying skin shows a normal epidermis and dermis.
FIGURE S2. Higher magnification view of the areas shown in Figure S1, highlighting the inflammatory component. The image demonstrates mild to moderate chronic inflammatory infiltrates, composed predominantly of small lymphocytes, within the thickened septa and extending focally into the surrounding subcutaneous fat.
FIGURE S3. MRI findings of eosinophilic fasciitis in the lower extremities, with bilaterally mild muscle oedema and more prominent oedema along the fascial planes, more pronounced on the left side.
TABLE S1. Patient characteristics of included immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) patients grouped by source.
TABLE S2. Clinical and diagnostic characteristics of immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) grouped by source.
TABLE S3. Treatment and clinical outcomes of immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) grouped by source.
Bruijn TVM, Gérard AO, Labat M, Apalla Z, Binsbergen Wv, Koumaki D, et al. Immune checkpoint inhibitor‐induced eosinophilic fasciitis: A pharmacovigilance and EADV Task force study. J Eur Acad Dermatol Venereol. 2026;40:1702–1712. 10.1111/jdv.70512
Alexandre O. Gérard and Maëlys Labat shared as second author.
Linked Article: A. Pugliesi. J Eur Acad Dermatol Venereol 2026;40:1587–1588. https://doi.org/10.1111/jdv.70650.
DATA AVAILABILITY STATEMENT
The data supporting the findings of this study are available from the corresponding author upon reasonable request. Access to VigiBase® is available without fees to Dr. Fanny Rocher and the pharmacovigilance centre of Nice. The views expressed in this article are the authors' personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EADV, ANSM, EMA, WHO or one of their committees or working parties.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
DATA S1. Line‐by‐line search strategy and detailed results of the performed literature review.
FIGURE S1. Fascia biopsy from a 45‐year‐old female treated with pembrolizumab (anti‐PD‐1 immune checkpoint inhibitor) for metastasized melanoma: microscopical and immunohistochemical analysis of the inflammatory infiltrate: Histological sections demonstrate extensive thickening of the septa within the subcutaneous tissue, caused by dense hyalinized fibrous tissue. This is accompanied by mild to moderate chronic inflammation involving primarily the septa and, focally, the adjacent subcutaneous fat. The inflammatory infiltrate consists predominantly of small lymphocytes. The overlying skin shows a normal epidermis and dermis.
FIGURE S2. Higher magnification view of the areas shown in Figure S1, highlighting the inflammatory component. The image demonstrates mild to moderate chronic inflammatory infiltrates, composed predominantly of small lymphocytes, within the thickened septa and extending focally into the surrounding subcutaneous fat.
FIGURE S3. MRI findings of eosinophilic fasciitis in the lower extremities, with bilaterally mild muscle oedema and more prominent oedema along the fascial planes, more pronounced on the left side.
TABLE S1. Patient characteristics of included immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) patients grouped by source.
TABLE S2. Clinical and diagnostic characteristics of immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) grouped by source.
TABLE S3. Treatment and clinical outcomes of immune checkpoint inhibitor‐induced eosinophilic fasciitis (ICI‐EF) grouped by source.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request. Access to VigiBase® is available without fees to Dr. Fanny Rocher and the pharmacovigilance centre of Nice. The views expressed in this article are the authors' personal views and may not be understood or quoted as being made on behalf of or reflecting the position of the EADV, ANSM, EMA, WHO or one of their committees or working parties.