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Eosinophilic fasciitis
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Eosinophilic fasciitis (EF), also known as Shulman syndrome , is a rare fibrosing disorder characterized by the rapid onset of symmetric induration of the extremities. The trunk and neck are affected less commonly; the distal digits and face are typically spared. The condition overlaps with plaque morphea in 35% of patients. Clinically, EF is marked by an early, edematous phase with erythema, followed by progressive sclerosis and a peau d’orange appearance. Depressions over superficial veins produce the characteristic ‘groove’ sign. Ultimately, woody induration and stiffness of the limbs develop, leading to decreased range of motion. Joint contractures are a major cause of morbidity and occur in 50%–56% of patients.
Laboratory investigations may reveal peripheral blood eosinophilia, present in 58% of patients, and an elevated erythrocyte sedimentation rate, but these are not essential in securing a diagnosis. EF has been reported in association with hematologic disorders, including monoclonal gammopathy, aplastic anemia, hemolytic anemia, thrombocytopenia, leukemias, and lymphomas; as such, abnormalities in complete blood count and immunofixation and/or protein electrophoresis may be seen. Histologically, EF presents with fascial thickening associated with a mixed inflammatory infiltrate composed of lymphocytes, plasma cells, histiocytes, and occasionally eosinophils. Dermal sclerosis can be seen in more advanced disease. Although the etiology remains unknown, vigorous physical activity and infection have been reported prior to EF onset in select cases, presumably triggering an aberrant immune response; however, these factors may be present in a minority of patients, with preceding trauma or intense exercise reported in only 28% of cases.
EF is differentiated from systemic sclerosis by the relative absence of sclerodactyly, Raynaud disease, nailfold capillary changes, and serologic markers. In addition, patients with EF traditionally lack visceral involvement. This clinical distinction is critical given that data supports avoiding systemic corticosteroids, a first-line agent for EF, in systemic sclerosis. EF must also be distinguished from the eosinophilia–myalgia syndrome, which is characterized by diffuse muscle pain and weakness, polyneuropathy, respiratory and pulmonary involvement, and most notably a history of contaminated l -tryptophan ingestion.
Management Strategy
The constellation of clinical, laboratory, imaging, and histologic findings establish the diagnosis of EF. Histopathologic examination from a full-thickness skin-to-muscle biopsy has been considered the gold standard for diagnosis. Diagnostic biopsy can be challenging to obtain due to feasibility issues, concerns regarding healing, and sampling error. Magnetic resonance imaging ( MRI ) is increasingly used by experts as a non-invasive modality to establish the diagnosis and monitor the effectiveness of treatment. On MRI, findings typically show high signal intensity of the deep and superficial fasciae on T 1 , T 2 , and short tau inversion recovery imaging with enhancement after intravenous contrast administration. Ultrasound and positron emission tomography/computed tomography (PET/CT) are additional non-invasive tools to aid in diagnosis, but are utilized less frequently. Serum aldolase levels have also been proposed as a useful indicator of disease activity.
Though spontaneous remission of EF has rarely been reported, treatment is crucial to help prevent the progression of sclerosis and development of contractures and limited mobility. Although a validated skin index does not exist, clinical response is usually defined as resolution of erythema and edema with improvement in skin thickening. As fibrosed tissue becomes softer and looser, it allows for increased range of motion. The primary goal of EF management is to halt disease progression. Softening of recently involved areas of sclerosis is possible with appropriate early treatment. Complete resolution of induration is rare and not routinely expected, particularly in patients with longstanding disease. Importantly, when patients are appropriately diagnosed and treated during the early, edematous phase, avoidance of induration and joint contractures is often possible, underscoring the need for prompt diagnosis and management.
Although responsive to oral steroids , EF will typically flare upon taper of steroids, and thus EF requires long-term treatment with a steroid-sparing immunosuppressive agent for durable clinical response and to avoid sequalae of prolonged steroid use. The combination of systemic corticosteroids and either methotrexate or mycophenolate mofetil should be considered first line for EF, initiated simultaneously at the time of diagnosis. This regimen consists of high-dose oral corticosteroids ( prednisone 1 mg/kg/day, slowly tapered over 3–6 months depending on disease severity) or pulse methylprednisolone (1000 mg/day for 3 days, followed by prednisone taper). The authors utilize pulse methylprednisolone in moderate-to-severe cases as there are data to support this results in improved outcomes. Simultaneously, therapy with methotrexate (target dose 25 mg weekly) or mycophenolate mofetil (target dose 2–3 g daily, often 3 g in moderate-to-severe cases) is initiated. Pulse methotrexate has also been efficacious (4 mg/kg/month with 25 mg/day folinic acid 24 hours after administration) with or without systemic corticosteroids for five treatment months. The addition of hydroxychloroquine (200–400 mg/day) to this regimen can also be considered.
Although methotrexate has traditionally been considered the steroid-sparing agent of choice for EF, novel data reveals that mycophenolate mofetil (2–3 g/day) is efficacious both first line and in cases where methotrexate fails or is contraindicated. Intravenous immunoglobulin (2 g/kg over 2 days, monthly) may also be considered in refractory cases as an adjuvant to corticosteroids and/or methotrexate, or as monotherapy in patients with contraindications to methotrexate or mycophenolate mofetil . Use of ciclosporin monotherapy (3.7–5 mg/kg/day) is supported by several case reports. Ultraviolet A1 (UVA1) at cumulative doses of 1750–1930 J/cm 2 was efficacious in one case as monotherapy and in a second case with concomitant methylprednisolone.
Infliximab, sirolimus, d -penicillamine, ketotifen, chloroquine, psoralen and ultraviolet light (PUVA), azathioprine, griseofulvin, dapsone, rituximab, tocilizumab, tofacitinib, and sulfasalazine have all been reported to have beneficial effects in case reports or series. Mepolizumab, an antiinterleukin-5 antibody, is being evaluated in a clinical trial (NCT04305678) given the role of IL-5 in hypereosinophilia. Additionally, physical therapy should be routinely recommended to prevent and/or improve joint contractures and related functional morbidity.
Specific Investigations
Epidemiology and treatment of eosinophilic fasciitis: an analysis of 63 patients from 3 tertiary care centers
Wright NA, Mazori DR, Patel M, et al. JAMA Dermatol 2016; 152: 97–9.
In this large cohort of EF patients, peripheral eosinophilia was present in 58% of cases. Seventy-nine percent of patients were initially misdiagnosed, most frequently with systemic sclerosis. Although 50% of patients had joint contractures, only 37% were referred for physical therapy.
The use of an elevated aldolase in diagnosing and managing eosinophilic fasciitis
Nashel J, Steen V. Clin Rheumatol 2015; 34: 1481–4.
In this retrospective review of 15 patients, the aldolase level was the last parameter to normalize and the first to rise during a flare compared with eosinophilia and inflammatory markers.
Eosinophilic fasciitis: spectrum of MRI findings
Moulton SJ, Kransdorf MJ, Ginsburg WW, et al. Am J Roentgenol 2005; 184: 975–8.
In this case series of six patients with histologically proven EF, MRI revealed characteristic findings, including thickening, signal abnormalities, and contrast enhancement of the superficial and, to a lesser extent, deep muscle fasciae.
Eosinophilic fasciitis: typical abnormalities, variants and differential diagnosis of fasciae abnormalities using MR imaging
Kirchgesner T, Dallaudiere B, Omoumi P, et al. Diagn Interv Imaging 2015; 96: 341–8.
This review summarizes the MRI findings in EF and other subcutaneous conditions on the differential diagnosis of entities that produce abnormal fascial signal intensities.
Ultrasound assessment of subcutaneous compressibility: a potential adjunctive diagnostic tool in eosinophilic fasciitis
Kissin EY, Garg A, Grayson PC, et al. J Clin Rheumatol 2013; 19: 382–5.
A cross-sectional study of 12 patients with EF revealed a significant reduction in subcutaneous compressibility quantified by ultrasound.
Usefulness of FDG PET/CT in the diagnosis of eosinophilic fasciitis
Kim HJ, Lee SW, Kim GJ, et al. Clin Nucl Med 2014; 39: 801–2.
In one case report, increased uptake of FDG on PET/CT along the superficial and deep fasciae suggested FDG PET/CT may be a non-invasive tool to illustrate more detailed anatomic involvement of the disease, especially if MRI is contraindicated.
Eosinophilic fasciitis. A pathologic study of twenty cases
Barnes L, Rodnan GP, Medsger TA, et al. Am J Pathol 1979; 96: 493–517.
Deep fascia and subcutaneous tissue are infiltrated with lymphocytes, plasma cells, histiocytes, and eosinophils early in the course of the disease. Sclerosis of the dermis with increased collagen occurs later in the course of the disease.
Clinicopathologic and immunophenotypic features of eosinophilic fasciitis and morphea profunda: a comparative study of 27 cases
Onajin O, Wieland CN, Peters MS, et al. J Am Acad Dermatol 2018; 78: 121–8.
While EF and morphea profunda share clinical and pathologic features, EF patients are more likely to have forearm involvement and peripheral eosinophilia. Histopathologically, fascia in patients with EF is more likely to reveal eosinophils and focal loss of CD34 staining.
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