Eosinophilic fasciitis

INTRODUCTION — Eosinophilic fasciitis (EF) is an uncommon disorder of unknown etiology and poorly understood pathogenesis [1]. EF is characterized in its early phase by limb or trunk erythema and nonpitting edema and later by collagenous thickening of the subcutaneous fascia. Eosinophilia is a prominent laboratory finding in the early phase, although not always present in active early cases and less prominent in later stages [2].

This topic will review the clinical manifestations, pathology, diagnosis, differential diagnosis, and treatment of EF. The approach to the patient with eosinophilia, and other major causes of eosinophilia are discussed separately. (See "Approach to the patient with unexplained eosinophilia" and "Eosinophil biology and causes of eosinophilia".)

ETIOLOGY — The etiology of eosinophilic fasciitis (EF) is unknown. The following have been suggested as possible triggers or factors associated with EF [3]:

●Strenuous exercise [1]

●Initiation of hemodialysis [4]

●Infection with Borrelia burgdorferi [5-7]

●Physical factors such as radiation therapy and burns

●Chronic graft-versus-host disease (GVHD)

●Exposure to certain medications including statins, phenytoin, ramipril, subcutaneous heparin, and immune checkpoint inhibitor therapy (eg, nivolumab and pembrolizumab) [8-10]

●Autoimmune diseases including thyroid disease [11-15], primary biliary cirrhosis, systemic lupus erythematosus, and Sjögren's disease

●Hematologic disorders (see 'Association with hematologic disorders' below)

However, most cases of EF are not associated with these factors and are considered idiopathic.

CLINICAL FEATURES — Eosinophilic fasciitis (EF) is characterized by symmetrical bilateral induration of the skin and deeper perimuscular fascial planes [16,17]. The onset is typically acute, when findings include erythema, swelling, and induration of the extremities that is accompanied by peripheral blood eosinophilia [18]. A subacute course may also occur. The thickening and hide-bound quality of the affected skin is similar to that seen with the scleroderma-spectrum disorders.

Symptoms and signs — The following features can be observed in patients with EF:

●Skin involvement – Nearly all patients with EF have clinically apparent symmetrical bilateral skin involvement, although unilateral skin disease can occur. There is a temporal evolution of skin findings. Initially, there may be marked, non-pitting edema of the skin. With progression of the disease, the swelling resolves and is replaced by symmetrical induration with puckering that gives the skin the texture of orange peel (peau d'orange). Following onset of symptoms, there may be involvement of additional areas over the course of weeks. While the initial edematous phase may be indistinguishable from early sclerodermatous skin changes, the irregular, woody, peau d'orange texture of established EF is distinct from the smooth, shiny skin surface seen in patients with systemic sclerosis (picture 1). Skin involvement most commonly occurs on the extremities, neck, and trunk. Scleroderma of the fingers (sclerodactyly), the hallmark of systemic sclerosis, is absent in EF. Moreover, the skin of the hands and feet is generally spared.

Elevation of an affected limb, which reduces the distending venous pressure, causes visible indentation along the course of the superficial veins (picture 2). This physical finding, referred to as the "groove sign," is probably due to the relative sparing of the epidermis and superficial dermis by the fibrotic process coupled with the relative immobility of the connective tissue around the remainder of the veins. Thus, the superficial layers of skin can bow inward as the peripheral venous pressure falls.

●Arthritis – Inflammatory arthritis occurs in a substantial minority of patients with EF. In one study of 52 patients with EF, 40 percent had arthritis [19]. The arthritis tends to involve joints in the areas adjacent to fasciitis. Limited joint mobility may be the result of thickening and loss of pliability of overlying skin and fascia. Joint contractures may develop, sometimes occurring in the absence of typical skin involvement [20]. In the series of 52 patients cited earlier [19], 56 percent had flexion contractures of the joints.

●Myalgias and myositis – Muscle pain and muscle weakness are common symptoms in EF [21]. Deep skin and fascial involvement merging into perimyositis may occur. However, inflammatory myositis is uncommon.

●Neuropathies – Cranial and peripheral neuropathies occur more often than would be expected by chance. Carpal tunnel syndrome has been a commonly described peripheral neuropathy in association with EF [19,22], occurring in 12 of 52 patients (23 percent) in one series [19]. In one case, electromyography (EMG) and nerve conduction studies of the lower extremities attributed a peripheral neuropathy to mononeuritis multiplex [23].

●Visceral involvement – Visceral involvement is rarely present in patients with EF [19]. Occasional cases of pleural effusions [24], pericarditis [25], and renal involvement [26] have been described.

Laboratory findings — The majority of patients with EF have a peripheral blood eosinophilia early in the disease [19]. Peripheral eosinophilia is transient and does not correlate with disease severity. Over 50 percent of patients have elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as a polyclonal hypergammaglobulinemia [19,27]. Serum antinuclear antibodies have not been reported to be present in EF with any consistency [17]. Serum levels of creatine kinase (CK) are typically normal, even in patients with myalgia.

Association with hematologic disorders — Hematologic disorders can be seen associated with EF in up to 10 percent of patients and can be the presenting manifestation [19]. Hematologic abnormalities that have been described in association with EF include [19,28-38]:

●Aplastic anemia

●Acquired amegakaryocytic thrombocytopenia

●Myeloproliferative disorders

●Myelodysplastic syndromes

●Lymphoma

●Lymphocytic and eosinophilic leukemia

●Multiple myeloma

●Paroxysmal nocturnal hemoglobinuria

DIAGNOSIS

Overall approach — The diagnosis of eosinophilic fasciitis (EF) is suspected in patients presenting with erythema, swelling, and induration of the extremities that is accompanied by peripheral eosinophilia. Skin changes typically spare the fingers, hands, and feet, and evidence of systemic involvement is usually absent. The absence of a history of Raynaud phenomenon helps distinguish EF from systemic sclerosis. In most cases, the diagnosis of EF is confirmed with a full thickness skin-to-muscle biopsy. We obtain magnetic resonance imaging (MRI) of the affected area when the biopsy is nondiagnostic or cannot be obtained. In atypical cases (eg, fasciitis without clinically evident skin changes), MRI may also be useful for guiding the location of a biopsy. In light of the association of EF with hematologic disorders, we also carefully review the complete blood count to determine whether further hematologic investigations are warranted.

Biopsy — Skin biopsy for EF requires an elliptical full thickness incisional biopsy of skin and subcutaneous tissues down to the muscle surface. Although there is no pathognomonic finding of EF on biopsy, the finding of compatible pathologic changes in the deep dermis and fascia at any point in the disease course is helpful in ruling out systemic sclerosis and other scleroderma-like disorders.

Early in the course of the disease, the deep fascia and lower subcutis are edematous and infiltrated with lymphocytes, plasma cells, histiocytes, and eosinophils; these features are generally associated with peripheral eosinophilia. Eosinophil infiltrates are present in the majority of patients but may also be absent [8]. The fascia becomes thickened and sclerotic as EF progresses, with disappearance of inflammatory cell infiltrates (picture 3) [39].

Infiltrating eosinophils in the fascia degranulate locally, resulting in release and tissue accumulation of cellular proteins such as cationic granule proteins that have toxic and potentially fibrogenic properties (picture 4) [40]. Mast cells and their degranulation product, histamine, have been found in affected tissue as well, and elevated circulating levels of histamine have been noted in some patients with EF [41].

Histologic abnormalities are also frequently found in the subjacent muscle. Thickening and inflammation of varying severity occurs in the epimysium, in the perimysium, in the endomysium, and, to a lesser degree, even within muscle fibers. This was illustrated in a study of 15 patients with EF who had muscle biopsies that were compared with biopsies from 94 postmortem controls [42]. All 15 EF muscle biopsies showed some degree of inflammation of the epi-, peri-, or endomysium or of muscle fibers. With routine histologic studies, the inflammation in EF in or around muscles could not be distinguished from that seen in other idiopathic inflammatory myopathies, such as polymyositis or dermatomyositis.

Magnetic resonance imaging — Findings on MRI are helpful to confirm fascial inflammation [43-45]. Increased T2 signal in the subcutaneous and deep fascia and enhancement of these structures on fat-suppressed T1 images after gadolinium administration have been noted [20,43-48]. If performing MRI is not possible or is contraindicated, other imaging modalities can be used. These include ultrasound and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) [49,50]. We prefer ultrasound because of its ease of administration and lower cost compared with nuclear medicine testing.

DIFFERENTIAL DIAGNOSIS — A variety of other disorders including localized and systemic sclerosis as well as exposures to certain chemicals (tryptophan- or 5-hydroxytryptophan-containing products) should be considered in the differential diagnosis of eosinophilic fasciitis (EF).

●Localized scleroderma – Localized forms of scleroderma include morphea, linear, and diffuse or pansclerotic scleroderma. Unlike EF, localized forms of scleroderma generally have a slowly progressive course and are not associated with significant eosinophilia. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

●Systemic sclerosis – Skin changes associated with systemic sclerosis may be difficult to distinguish from those of EF. The absence of the Raynaud phenomenon favors a diagnosis of EF, since the overwhelming majority of patients with limited and diffuse cutaneous forms of systemic sclerosis have or develop Raynaud phenomenon at or near the time of the earliest skin changes. Nailfold capillaries are typically normal in EF, while dilated capillary loops, microhemorrhages, and avascular areas observed by capillaroscopy are seen in systemic sclerosis [51]. Unlike systemic sclerosis, digital tip pitting is absent and the fingers, feet, and face are spared in EF. Internal organ involvement (eg, pulmonary fibrosis, pulmonary hypertension, renal crisis) is frequent in systemic sclerosis but typically absent in EF. In contrast to systemic sclerosis, EF is only rarely associated with serum antinuclear antibodies or systemic sclerosis-specific autoantibodies. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●Scleroderma-like disorders – Skin thickening and decreased pliability similar to that seen with scleroderma and EF may occur in the following scleroderma-like disorders. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Causes of scleroderma-like skin changes'.):

•Nephrogenic systemic fibrosis – Among patients with advanced renal failure (dialysis-dependent or estimated glomerular filtration rate less than 15 mL/min), the administration of gadolinium may be associated with nephrogenic systemic fibrosis (previously called nephrogenic fibrosing dermopathy). The clinical manifestations of this novel syndrome resemble EF but are distinguished by frequent involvement of the hands and feet and the absence of eosinophilia and eosinophilic tissue infiltration. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

•Scleromyxedema – Scleromyxedema is an idiopathic disorder that may occur alone or in association with malignancies. Skin thickening is due to the deposition of an amorphous mucinous material in the dermis [52]. The presence of waxy, yellow-red papules and a serum monoclonal gammopathy are characteristic features. (See "Cutaneous manifestations of internal malignancy", section on 'Scleromyxedema'.)

•Scleredema – Diffuse skin induration without serum autoantibodies or evidence of inflammation on skin biopsy is typical of scleredema. These skin changes may occur in patients with diabetes, typically those with longstanding insulin-treated disease. Scleredema may also occur in the absence of associated diabetes mellitus. Associated plasma cell disorder and a monoclonal gammopathy have been described. (See "Scleredema".)

●Eosinophilia and skin thickening – When significant peripheral blood eosinophilia and skin or fascial thickening are both present, the differential diagnosis is more limited; among the diseases to be considered are the following:

•Eosinophilia myalgia syndrome – The pathology of skin and subcutaneous tissue in eosinophilia-myalgia syndrome (EMS), a condition associated with use of L-tryptophan supplements, cannot be differentiated from EF. Most cases of EMS resulted from exposure to a contaminant of the dietary supplement L-tryptophan used most commonly to treat insomnia. The illness occurred in the United States and other countries in an epidemic form in 1989, and subsequent sporadic cases have been rare [53]. A related supplement, 5-hydroxytryptophan, has also been suggested as a cause. Myalgia, often severe, is seen in EMS and is one of the classification criteria, whereas myalgia is infrequent and mild in patients with EF. Nonpitting edema of the extremities that evolves into induration with a peau d'orange appearance in EMS is similar to that seen with EF [18]. Visceral involvement, such as pneumonitis and neuropathy, may occur in patients with EMS, whereas these are uncommon in EF. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'L-tryptophan'.)

•Toxic oil syndrome – Adulterated rapeseed oil was associated with an epidemic outbreak in the 1980s in Spain. The illness was characterized by symptoms of dyspnea, myalgia, and arthralgia; physical findings of limb edema, chronic scleroderma-like skin changes, livedo reticularis, neuropathy, and joint contractures [54-56]. Other clinical features included pulmonary infiltrates, prominent eosinophilia, and elevation of serum creatine kinase (CK) [54-56].

●Graft-versus-host disease – Skin induration and fibrosis are common manifestations of chronic graft-versus-host disease (GVHD). Both morphea-like, localized induration and eosinophilic fasciitis have been described [57]. (See "Cutaneous manifestations of graft-versus-host disease (GVHD)", section on 'Sclerotic manifestations'.)

TREATMENT — Systemic glucocorticoids are the mainstay of treatment of eosinophilic fasciitis (EF). Patients who do not respond to initial therapy with glucocorticoids or who have relapses of skin involvement require additional therapy. Patients with an associated hematologic disorder should be evaluated and treated for the underlying disease.

Initial therapy — No randomized trials have evaluated therapies for EF, and the best approach to treatment remains unclear. Our approach is to treat initially with systemic glucocorticoids, usually starting at doses equivalent to prednisone 1 mg/kg per day [19,58,59]. There is often a rapid resolution of the peripheral blood eosinophilia and normalization of the erythrocyte sedimentation rate (ESR). Doses are slowly reduced as the affected skin softens, which can take from weeks to months, and generally lags behind the resolution of eosinophilia. If symptoms and signs of EF do not improve and/or eosinophilia persists, higher doses of glucocorticoids may be necessary.

All patients treated with high-dose glucocorticoids are at risk for glucocorticoid-induced osteoporosis. Thus, patients initiating treatment courses of EF are potential candidates for antiresorptive therapy to prevent bone loss. The prevention and treatment of glucocorticoid-induced osteoporosis are discussed separately (see "Prevention and treatment of glucocorticoid-induced osteoporosis"). Also, patients on high-dose glucocorticoid therapy are at increased risk for opportunistic infection. Prophylaxis against Pneumocystic jirovecii is thus often indicated for patients treated with high-dose glucocorticoids and/or other immunosuppressive agents. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Treatment of relapsed or refractory disease — Relapses of EF may occur, and many patients do not respond to glucocorticoids [19,58,60]; thus, other immunosuppressive or immunomodulatory agents are required to obtain a therapeutic response and/or as glucocorticoid-sparing agents.

Superior response rates were reported in combining a glucocorticoid medication with methotrexate 15 to 25 mg/week [61]. In a retrospective review of 89 patients with EF from a single institution, from 1997 to 2016, prednisone treatment was supplemented with methotrexate in 79 percent of cases, with hydroxychloroquine in 45 percent of cases, mycophenolate mofetil in 18 percent, and azathioprine in 8 percent. No single immunosuppressant agent was associated with a superior response during treatment. Complete response rate was 60 percent at three years.

In patients with no evidence of a satisfactory response to prednisone at doses of up to 1.5 mg/kg/day given for three months, we use low-dose methotrexate (15 to 25 mg once weekly), following the dosing regimen employed in rheumatoid arthritis. The usual duration of therapy once remission is achieved is four to six months, depending upon the clinical response. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)

Alternatives to methotrexate include mycophenolate or hydroxychloroquine, although there are limited data supporting the use of either agent [19,62]. A two- to four-month trial of one or the other of these agents should be sufficient to assess the clinical response.

Other interventions — The successful use of other therapies is largely based on anecdotal reports and case series. These interventions include tocilizumab [63], baricitinib [64], sulfasalazine, azathioprine, infliximab, rituximab, intravenous immune globulin, dapsone, cyclosporine A, ultraviolet A (UVA) 1 phototherapy, psoralen plus UVA (PUVA) photochemotherapy, and antithymocyte globulin [19,27,59,65-71]. Some patients with refractory disease have been reported to respond to treatment with anti-interleukin (IL) 5 antibody reslizumab [72]. Consideration for these agents should be reserved for patients with refractory disease that is unresponsive to more traditional second- and third-line therapies. Physical therapy is generally useful for preventing the development of joint contractures.

Surgical release of joint contractures in combination with glucocorticoid therapy has been used [73]. Others have resorted to surgical fasciectomy in patients resistant to glucocorticoids [74]. Surgical release may also be necessary for some patients with chronic carpal tunnel syndrome that does not respond to glucocorticoids [22].

PROGNOSIS — The majority of patients (75 percent) respond to glucocorticoid therapy, and approximately half of all patients can achieve remission with glucocorticoid therapy. Patients seen in the edematous phase generally demonstrate a prompt resolution of the edema with glucocorticoid treatment. The presence of peau d'orange is associated with an incomplete response to therapy [75].

Skin disease affecting the trunk is also associated with treatment resistance (hazard ratio 1.87, 95% CI 1.06-3.31) [75]. Patients with an incomplete response to therapy may develop chronic skin thickening and localized soft tissue contractures.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Eosinophilic fasciitis".)

SUMMARY AND RECOMMENDATIONS

●Definition – Eosinophilic fasciitis (EF) is an uncommon disorder of unknown etiology and poorly understood pathogenesis. Exposure to certain medications, including immune checkpoint inhibitors, has been associated with EF onset. The onset is typically acute, and findings include erythema, swelling, and induration of the extremities that is accompanied by a peripheral blood eosinophilia. (See 'Clinical features' above.)

●Symptoms and signs – The thickening and hide-bound quality of the affected skin is somewhat similar to that seen with the scleroderma-spectrum disorders; however, sclerodactyly, the hallmark of systemic sclerosis, is absent in EF. Moreover, the skin of the hands and feet is generally spared. Elevation of an affected limb, which reduces the distending venous pressure, causes visible indentation (the groove sign) along the course of the superficial veins (picture 2). (See 'Symptoms and signs' above.)

●Laboratory findings – The majority of EF patients have a peripheral blood eosinophilia. Peripheral eosinophilia is transient and does not correlate with disease severity. Over 50 percent of patients have an elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as a polyclonal hypergammaglobulinemia. (See 'Laboratory findings' above.)

●Association with hematologic disorders – Hematologic disorders can be associated with EF in up to 10 percent of patients and can be the presenting manifestation. (See 'Association with hematologic disorders' above.)

●Diagnosis – The diagnosis of EF is suspected in patients presenting with erythema, swelling, and induration of the extremities that is accompanied by peripheral eosinophilia. Skin changes typically spare the hands and feet, and evidence of systemic involvement is usually absent. In most cases, the diagnosis of EF is confirmed with a full skin-to-muscle biopsy. We obtain MRI of the affected area when the biopsy is nondiagnostic or cannot be obtained. In atypical cases (eg, fasciitis without skin changes), MRI may also be useful for guiding the location of a biopsy. (See 'Overall approach' above.)

●Differential diagnosis – The differential diagnosis includes localized and systemic sclerosis; scleroderma-like disorders such as nephrogenic systemic fibrosis, scleromyxedema, and scleredema; eosinophilia myalgia syndrome (EMS), toxic oil syndrome; and graft-versus-host disease (GVHD). (See 'Differential diagnosis' above.)

●Treatment

•Initial therapy – For all patients with EF, we suggest initial management with systemic glucocorticoids, usually starting at doses equivalent to prednisone 1 mg/kg per day (Grade 2C). Doses are reduced as the affected skin softens, which can take from weeks to months. If symptoms and signs of EF do not improve and eosinophilia persists, higher doses of glucocorticoids may be necessary. Patients with an associated hematologic disorder should be treated for the underlying disease. (See 'Initial therapy' above.)

•Subsequent therapy – In patients with no evidence of a response to prednisone at doses of up to 1.5 mg/kg/day given for three months, we suggest treatment with low-dose methotrexate (15 to 25 mg once weekly) (Grade 2C). The usual duration of therapy once remission is achieved is four to six months, depending upon the clinical response. (See 'Treatment of relapsed or refractory disease' above.)

Alternatives to methotrexate include mycophenolate or hydroxychloroquine, although there are limited data supporting the use of either agent. A two- to four-month trial of one or the other of these agents should be sufficient to assess the clinical response. (See 'Treatment of relapsed or refractory disease' above.)

•Other interventions – The successful use of other therapies is largely based on anecdotal reports and case series. Some of these interventions include tocilizumab, baricitinib, sulfasalazine, azathioprine, infliximab, rituximab, intravenous immune globulin, dapsone, cyclosporine A, ultraviolet A (UVA) 1 phototherapy, psoralen plus UVA (PUVA) photochemotherapy, antithymocyte globulin, and reslizumab. Consideration for these agents should be reserved for patients with refractory disease that is unresponsive to more traditional second- and third-line therapies. Rarely, surgical interventions have been used in patients resistant to glucocorticoids. (See 'Other interventions' above.)