Introduction

In 1974 Shulman [1] described a rare scleroderma-like syndrome designated as eosinophilic fasciitis (EF). Eosinophilic fasciitis is rare disease characterized by subacute onset of erythema, edema, and induration of the skin and soft tissues of the limbs and trunk [2]. These manifestations are replaced by fascial fibrosis, leading to a cobblestone appearance or peau d’orange, as well as the “groove sign,” a linear depression along the course of veins, accentuated by limb elevation, due to inward tethering of the skin. Concurrent plaque morphea can be present in 29–41% of cases. Extracutaneous involvement includes muscle pain and weakness [3], neuropathies such as carpal tunnel syndrome (23%) [4], articular symptoms like joint contractures (50–56%) [5], and arthritis (40%) [6], with a high impact of morbidity related to EF. Visceral involvement is rare, but some cases have been reported as pericarditis [7], pleural effusions [8], and renal involvement.

Laboratory evaluation often reveals peripheral eosinophilia (58–85%) [9], hypergammaglobulinemia (36–46%) [7] monoclonal gammopathy (16%) [8], and an elevated erythrocyte sedimentation rate (ESR), although it is not mandatory for the diagnosis.

The incidence of EF is uncertain. It occurs most commonly in middle-aged individuals, with peak incidence between 40 and 50 years of age.

The pathogenesis of EF is not well understood. Eosinophils degranulate and induce tissue damage, which results in fibrosis via accumulation of extracellular matrix. Various studies have indicated that eosinophils interact with fibroblasts and express fibrogenic cytokines including tumor growth factor (TGF) α, TGF-β, interleukin (IL) 1, and IL-6 [10].

There are some possible triggering factors or factors associated with EF, such as infections [11], initiation of hemodialysis [12], radiotherapy, graft-versus-host disease, hematological disorders, as well as autoimmune diseases [13] (primary biliary cirrhosis, systemic lupus erythematosus, Sjögren’s syndrome). Other reasons for EF are also taken into account, such us: exposure to certain medications [14] (ramipril, phenytoin, subcutaneous heparin, statins), strenuous exercise, or trauma. However, most cases are considered as idiopathic. Rarely, EF can be associated with solid or hematological neoplasms [15]. Hematological abnormalities associated with EF include the following: multiple myeloma, lymphoma, myelodysplastic syndromes, myeloproliferative disorders, acquired amegakaryocytic thrombocytopenia, aplastic anemia, and paroxysmal nocturnal hemoglobinuria.

The diagnosis of EF is based on clinical features complemented by laboratory findings; however, universally accepted international diagnostic criteria are lacking. A full-thickness skin biopsy including the fascia usually confirms the diagnosis by demonstrating characteristic lymphocytic and eosinophilic infiltrate with thickened collagen bundles in the fascia. Magnetic resonance imaging (MRI) should be performed when the biopsy is non-diagnostic or cannot be obtained. Findings on MRI show an increased T2 signal in subcutaneous and deep fascia and enhancement of these structures on fat-suppressed T1 images after gadolinium administration. If MRI cannot be performed, 18-F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PT/CT) [16] or ultrasound should be performed [17].

There are a variety of other disorders that should be considered in the differential diagnosis of EF. Systemic sclerosis (SSc) is the main differential diagnosis of EF. Sometimes EF can be misdiagnosed and there are some features that can help clinicians distinguish these two entities. In EF there is no skin tightening of distal digits, nailfold capillary changes, digital ulcers, or Raynaud’s phenomenon. Histopathology in EF universally involves fascia and involvement of the dermis, subcutaneous fat, and muscle may occur, whereas in SSc only dermis and subcutaneous fat are involved [18].

Localized scleroderma includes morphea and linear scleroderma. These entities have a slowly progressive course and are not associated with significant eosinophilia.

In scleroderma-like disorders we can find skin thickening and decreased pliability. Scleromyxedema can occur alone or in association with malignancies. Scleroderma is associated with diabetes, plasma cell disorder, and monoclonal gammopathy. In the skin biopsy of scleroderma there is no evidence of inflammation.

Early treatment of patients with EF showed better outcomes in some studies, but these findings were not statically significant [19].

Currently, systemic corticosteroids (SCS) are the cornerstone of treatment. In those patients who develop a steroid-resistant disease the introduction of an immunosuppressive drug is essential. The most common agent used is methotrexate (MTX), especially in patients with morphea-like skin lesions. Other treatment options include hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, or an anti-TNF agent (etanercept). There are some recent studies showing the efficacy of a therapy targeting IL-6 cytokine, tocilizumab (TCZ), in EF refractory to steroids and other immunosuppressive drugs [20].

Material and methods

This was an observational, retrospective, and descriptive study based on the population of Clinical Immunology Unit (CIU) in a single central hospital between January 1, 2005, and April 30, 2018.

Results

Discussion

Shulman’s disease is rare, and high clinical suspicion is needed for the diagnosis, which can be difficult because of the differential diagnoses that should be considered.

Typical clinical manifestations include edema and skin thickening, with orange peel skin texture, and groove sign, with more common involvement in the extremities, neck, and trunk. Complaints of myalgias and muscle weakness are common. Inflammatory arthritis is only present in a minority of patients. In these patients, sclerodactyly and Raynaud’s syndrome are absent, as well as visceral involvement, and hence they are compatible with this study [21].

Rarely, some conditions can accompany the disease like compartment syndrome [22], esophageal dysmotility [23], reactive hepatitis [24], contractures in the joints due to edema [25], and peripheral polyneuropathy [26]. Contractures in the joints were found in 57% of patients, which can be very disabling and drastically reduce the quality of life.

Frequent analytical findings include peripheral eosinophilia, which may be transient, increased ESR, and polyclonal hypergammaglobulinemia. The laboratory abnormalities can be transitory and are not mandatory for the diagnosis. In this study, peripheral eosinophilia was present in all patients.

In most cases, the diagnosis is confirmed by skin biopsy (thickening of the fascia with accumulation of lymphocytes and macrophages with or without eosinophilic infiltrate) [18], and in this study the result of the biopsy was consistent with the suspected disease. Magnetic resonance imaging may be performed in atypical cases or if the biopsy does not confirm the diagnosis.

The differential diagnoses include neoplasia, infections, systemic sclerosis and other scleroderma subsets such as morphea, and epidemic fasciitis syndromes caused by toxic agents such as myalgia-eosinophilia syndrome and toxic oil syndrome [27]. Neoplasia should be suspected when corticosteroid therapy is refractory. In our study, none of the patients had an underlying disease diagnosed.

The standard treatment is systemic corticosteroid therapy [28]. Recent studies show a more favorable response of the combination of PDN and MTX than of PDN alone [29].

Currently there are new therapies that can improve the outcome of these patients, and it is fundamental to establish effective therapy as early as possible, to obtain a better prognosis. The introduction of a therapy targeting IL-6 cytokine in the case of EF refractory to steroids and other immunosuppressive drugs has been described [30]. In this study, TCZ at 162 mg for three months showed softening of the skin with a significant reduction of skin hardness.

Limitations of our study include its retrospective design and small study size.

Conclusions

Eosinophilic fasciitis is a rare disease that may present a variable spectrum of clinical manifestations.

The variability of the age, presentation form, and laboratory changes make the EF challenging from the point of view of the possible differential diagnoses, as well as the therapeutic management.

Considering the rarity of the disease, more long-term studies are needed regarding the etiopathogenesis, progression, recurrence of EF, and new effective therapies.