Dermatologic Manifestations of Eosinophilic Fasciitis 

Updated: Jan 31, 2017
Author: Brad S Graham, MD; Chief Editor: William D James, MD 

Overview

Background

Eosinophilic fasciitis is an idiopathic, fibrotic disorder with the histopathologic hallmark of fascial fibrosis. The presentation of eosinophilic fasciitis is acute with painful, swollen extremities progressing to disabling cutaneous fibrosis. Joint contractures, arthritis, neuropathy, and myositis may be associated with eosinophilic fasciitis. Many authors consider eosinophilic fasciitis to be a variant of morphea; others consider it a distinct entity.

Pathophysiology

 

The etiology of eosinophilic fasciitis is unknown, but aberrant immune responses may play a role because hypergammaglobulinemia and antinuclear antibodies are associated. In addition, toxic, environmental, or drug exposures have been implicated in causing eosinophilic fasciitis. A 2006 case report implicated atorvastatin in a temporal relationship as the cause of a patient's eosinophilic fasciitis.[1] Simvastatin has also been reported temporally to the onset of eosinophilic fasciitis.[2]

Reports indicate that Borrelia burgdorferi may be a possible etiologic agent in some cases of eosinophilic fasciitis. However, one report of a patient with eosinophilic fasciitis and a review of the literature of cases in which Borrelia species were implicated in the pathogenesis failed to show a relationship between eosinophilic fasciitis and Borrelia infection. Borrelia species were not identified by direct microscopic examination of tissue samples or by polymerase chain reaction amplification of tissue samples in any of these reported cases of eosinophilic fasciitis. The conclusion was that positive serology alone for Borrelia does not implicate Borrelia infection in the pathogenesis of eosinophilic fasciitis in the absence of the positive demonstration of Borrelia by histochemical stains, immunohistochemical stains, or polymerase chain reaction amplification in tissue samples.[3]

In vitro fibroblasts from involved fascia produce increased levels of mRNA for collagen types I, III, and IV compared with adjacent dermal fibroblasts. In addition, fascial fibroblasts express transforming growth factor-beta I and connective-tissue growth factor mRNA, which may account for the clinical fibrosis. Eosinophil degranulation may lead to fibroblast activation.

Further research into eosinophilic fasciitis has shown elevations of transforming growth factor-beta and interleukin 5, which normalize with corticosteroid therapy. Another study has show that the fascial inflammatory infiltrate is predominately composed of CD8+ T lymphocytes, macrophages, and fewer eosinophils, suggesting a possible cytotoxic immune reaction in response to possible infectious or environmental agents. Other studies have shown elevated serum levels of manganese superoxide dismutase and tissue inhibitor of metalloproteinase (TIMP-1). Serum TIMP-1 may also serve as a marker of disease severity.[4, 5]

One report describe of diffuse eosinophilic fasciitis developing after local radiation therapy for breast cancer, implicating radiation injury as a possible traumatic trigger for the development of eosinophilic fasciitis.[6]

An additional case report in 2010 identified a patient with a temporal and anatomic relationship with the development of localized eosinophilic fasciitis after intravenous iron infusions for correction of anemia.[7]

A 2012 case report describes of a young male with eosinophilic fasciitis, recurrent fever, a sclerotic prepuce, and urethritis. Urethral and blood cultures were positive for Mycoplasma arginini. In addition, M arginini DNA was isolated in skin biopsy specimens of sclerotic skin by polymerase chain reaction (PCR). The authors suggested that the Mycoplasma infection may have contributed to the development of the sclerotic process.[8]

A case report in 2016 discussed a male patient with the development of eosinophilic fasciitis following an intestinal parasitic infection. Treatment with antiparasitic drugs, however, did not lead to resolution of symptoms.[9]

 

Epidemiology

Frequency

Eosinophilic fasciitis is uncommon.

Race

Whites are primarily affected by eosinophilic fasciitis.

Sex

Eosinophilic fasciitis occurs equally in males and females.

Age

Most eosinophilic fasciitis patients are in their third to sixth decades of life; however, cases in children have been reported.

Prognosis

The prognosis for eosinophilic fasciitis is good. Most patients experience partial or complete recovery.

The end stage of the fibrotic process leads to substantial morbidity due to skin sclerosis and joint contractures. In addition, arthritis, neuropathies, and myositis may be present. Ten percent of cases may result in myelodysplasia, such as aplastic anemia, which portends a poor prognosis. Spontaneous resolution is possible, and treatment with corticosteroids usually results in recovery; however, skin sclerosis and joint contractures may persist.

A 2007 study reported that the risk of residual fibrosis/contractures after therapy was much higher with an age younger than 12 years at presentation, trunk involvement, associated morphealike, and dermal fibrosis in addition to the subcutaneous fat/fascial fibrosis.[10]

 

Presentation

History

Eosinophilic fasciitis patients present with the sudden onset of painful, tender, edematous, and erythematous extremities. The disorder progresses rapidly; within weeks to months, patients develop stiffness and sclerodermatous induration, resulting in characteristic flexion contractures and impaired mobility. The forearms, the upper arms, the lower legs, the thighs, and the trunk are involved (in order of decreasing frequency).

As many as 50% of patients report an episode of strenuous physical exercise or activity immediately preceding the onset of the illness.

Malaise, weakness, and fever are frequently present. A study in 2008 addressing the physical burden noted that fatigue was the most common symptom. Pain and itch were also frequent complaints. Of all patients, 62% noted fatigue, pain, and itch.[11]

Overt arthritis occurs in as many as 40% of patients. Symptoms of carpal tunnel syndrome have been reported. Visceral involvement and Raynaud phenomenon are rare.

Physical Examination

The clinical presentation of eosinophilic fasciitis evolves through 3 stages; the various stages present simultaneously in different areas of the body. The first stage presents with symmetric, diffuse, erythematous tenderness of the extremities, followed by an edematous phase that produces a coarsely dimpled appearance (cobblestoning) or a finely dimpled appearance (peau d'orange). The last phase involves rippling of the skin with areas of hypopigmentation, induration, and skin tightness.

Lower back part of the legs shows hypopigmentation Lower back part of the legs shows hypopigmentation, induration, biopsy site, and asymmetric involvement.
Posterior thigh shows woody induration, sclerosis, Posterior thigh shows woody induration, sclerosis, and hypopigmentation.
Close-up view of left posterior thigh 2 weeks late Close-up view of left posterior thigh 2 weeks later shows erythema, scaling, alopecia, and rippled induration.
Posterior part of the calf in the first week of il Posterior part of the calf in the first week of illness shows erythema, edema, alopecia, scaling, and early induration. The right calf is relatively uninvolved with patchy erythema only.
Photograph of the posterior part of the calf at 3 Photograph of the posterior part of the calf at 3 weeks shows complete sclerosis and induration with patchy erythema.

In severely affected areas, both the skin and the subcutaneous tissues are bound-down and inseparable from the underlying muscle, and they have a woody-type appearance. With elevation of the involved extremities, furrows along the course of the superficial veins may be present; this finding is referred to as the groove sign. Although the extremities are preferentially involved (88%), the trunk may be involved. The hands, the feet, and the face are spared.

Joint contractures of the elbows, wrists, ankles, knees, and shoulders may be found in 55-75% of patients. Unilateral involvement has been reported.[12]  Carpal tunnel syndrome is present in 20% of patients. Inflammatory arthritis is present in as many as 40% of patients.

Subclinical myositis is present in a minority of patients.

A concurrent localized lesion of morphea may be seen in 25% of patients.

In contrast to scleroderma, Raynaud phenomenon, abnormal nail fold capillaries, and sclerodactyly are not present. Visceral involvement is rare, with few reports of involvement of the lungs, the esophagus, and the myocardium.

Primary presentation as angioedema was also reported in a patient.[13]

Causes

See Pathophysiology.

Complications

Aplastic anemia and other forms of myelodysplasia may complicate eosinophilic fasciitis in as many as 10% of patients. Some authors advocate a bone marrow examination in all eosinophilic fasciitis patients. More recent case reports have shown associations of eosinophilic fasciitis with multiple myeloma, polycythemia vera, peripheral T-cell lymphoma, immunoglobulin A nephropathy, and idiopathic hypercalcemia.

An additional report in 2103 documented a patient with eosinophilic fasciitis who developed moderate aplastic pancytopenia during treatment. Late sequela 2 years later included onset of paroxysmal nocturnal hemoglobinuria and persistent stable pancytopenia.[14]

Associations have also been noted with systemic lupus erythematosus,[15] hyperthyroidism with thyroid adenoma,[16] and primary biliary cirrhosis.[17]

A case report in 2012 describes a 30-year-old woman with eosinophilic fasciitis who also presented with a painful sensory neuropathy in her legs, with resultant functional incapacity. It was thought the multiple mononeuritis was related to neurotoxicity from secreted eosinophil products. Treatment with corticosteroids and gabapentin improved the neuropathic symptoms.[18]

 

DDx

Diagnostic Considerations

Consider the following:

Differential Diagnoses

 

Workup

Laboratory Studies

CBC count shows eosinophilia (10-40%) in as many as 80-90% of patients. In addition, pancytopenia, anemia, or thrombocytopenia may be encountered in eosinophilic fasciitis.

The erythrocyte sedimentation rate (ESR) is elevated in as many as 60-80% of eosinophilic fasciitis patients.

Immunoglobulin levels show hypergammaglobulinemia, usually polyclonal immunoglobulin G.

Muscle enzyme levels are sometimes elevated, especially aldolase.

The antinuclear antibody result is occasionally positive.

The rheumatoid factor result is occasionally positive.

A 2015 study showed elevated serum aldolase levels in 11 of 12 patients with eosinophilic fasciitis. Aldolase was more frequently abnormal than peripheral eosinophilia, hypergammaglobulinemia, and elevated ESR. They recommended serum aldolase be measured in all patients with suspected eosinophilic fasciitis and suggested aldolase values may play a role in disease monitoring.[22]

Imaging Studies

If clinically indicated, MRI of the involved areas shows a high-intensity signal in the fascia. A 2005 study demonstrated that MRI shows characteristic findings of fascial thickening, abnormal signal intensity, and contrast enhancement. According to the authors, these findings are useful to make the diagnosis, to guide the location for biopsy, and to monitor the response to therapy.[23]

Other Tests

If clinically indicated, electromyograms may show slow motor unit potentials with reduced duration and amplitude consistent with a myositis.

Pulmonary function test results may show a restrictive pattern with severe truncal involvement.

Procedures

If abnormal values other than eosinophilia are found on the CBC count, a bone marrow examination may be necessary.

A full-thickness incisional biopsy that includes the dermis, the subcutaneous fat, and the fascia is necessary to confirm a diagnosis of eosinophilic fasciitis.

Histologic Findings

The most profound changes associated with eosinophilic fasciitis occur in the superficial fascia, which is markedly thickened, fibrosed, and sclerotic. In the early stages, fibrinoid necrosis or myxoid degeneration may be seen. The fibrosis extends into the septae of the subcutaneous fat, which entrap the fat within intersecting bands of fibrosis. The fibrotic process also extends into the lower dermis and the underlying musculature. The muscle may show focal necrosis, degeneration, and regeneration.

The inflammatory infiltrate is usually mild to moderate and consists of lymphocytes, histiocytes, plasma cells, and variable numbers of eosinophils. Eosinophils are not required to make the diagnosis; the term eosinophilic fasciitis refers to peripheral eosinophilia not tissue eosinophilia. The inflammatory infiltrate, including lymphoid follicles, involves the lower dermis, the septae, the fascia, and the muscle. The epidermis, the papillary dermis, and the adnexa are usually spared. On direct immunofluorescence, immunoglobulin M is found at the dermal-epidermal junction, and immunoglobulin G and C3 are found around blood vessels in the lower dermis, the fascia, and the skeletal muscle.

Note the marked thickening and replacement of the Note the marked thickening and replacement of the entire dermis with sclerotic collagen on this incisional biopsy sample from the left posterior part of the thigh.
Photomicrograph of subcutaneous fat-fascia junctio Photomicrograph of subcutaneous fat-fascia junction shows entrapment of subcutaneous fat by intersecting thick bands of fibrosis. Thickening and fibrosis of fascia and lymphoid aggregates are seen.
Photomicrograph of fascia-skeletal muscle junction Photomicrograph of fascia-skeletal muscle junction shows markedly thickened fascia with heavy inflammatory infiltration.
High-power photomicrograph of fascia shows heavy i High-power photomicrograph of fascia shows heavy inflammatory infiltration with numerous eosinophils, lymphocytes, and occasional plasma cells.
 

Treatment

Medical Care

Many eosinophilic fasciitis cases respond to corticosteroids (88%, with 25% obtaining complete recovery), although spontaneous resolution is possible. Complete recovery may take up to 1-3 years. No consensus on the treatment of eosinophilic fasciitis exists, but most studies indicate that the best response is with moderate-to-high doses of corticosteroids, especially if started early in the disease course. No set dosing schedule is available, but most studies advocate doses of 0.5-1 mg/kg/d until response, with rapid tapering to alternate day therapy.

Several eosinophilic fasciitis cases exist in the literature of recalcitrant disease to corticosteroids in which adjunctive therapy may be required.

Adjunctive medications for eosinophilic fasciitis include hydroxychloroquine, colchicine, cimetidine, cyclosporin,[24] azathioprine, and methotrexate. A more recent study looked at extracorporal photochemotherapy in the treatment of corticosteroid-resistant cases. After 1 year of therapy, 2 of 3 patients showed considerable improvement when combined with low-dose corticosteroids.[25]

Newer therapies that have been used as corticosteroid adjuncts or as monotherapy for eosinophilic fasciitis include infliximab,[26] cyclophosphamide,[27] dapsone,[28] retinoid-UVA1,[29] and oral psoralen plus UVA (PUVA).[30]

In a promising follow-up report on three cases of steroid-resistant eosinophilic fasciitis, all patients showed improvement in skin induration and joint contractures with infliximab at 3 mg/kg every 8 weeks. All patients were in remission in 1-3 years.[31]

A case report in 2016 ironically noted the onset of eosinophilic fasciitis during infliximab therapy for psoriatic arthritis.[32]

A single case report in 2009 reported the use of intravenous immunoglobulin to treat eosinophilic fasciitis.[33]

In a large series of 34 patients with eosinophilic fasciitis, corticosteroids was the standard first-line therapy. In this series, 44% of patients received a second-line therapy adjunctive immunosuppressant, usually methotrexate. The highest chance of complete remission was in patients treated with pulse methylprednisolone at the earliest onset of diagnosis. This also minimized the need for additional immunosuppressive drugs.[34]

A case report in 2102 documented 2 patients with corticosteroid-refractory eosinophilic fasciitis who were successfully treated with D-penicillamine.[35]

A case report in 2015 described a relapse post corticosteroid treatment, which became steroid-resistant and refractory to methotrexate and antitumor necrosis factor agent treatment. This patient had a rapid response with sustained remission to the anti-interleukin 6 agent, tocilizumab.[36]

A study in 2016 of 12 patients with eosinophilic fasciitis refractory to corticosteroids and weekly methotrexate were treated with high-dose intravenous pulse methotrexate. Methotrexate was dosed at 4 mg/kg monthly (followed by folinic rescue) for 5 months. Skin scores and range of motion improved significantly.[37]

A 2016 case report discussed successful treatment of a patient with refractory eosinophilic fasciitis with sirolimus at 2 mg/d. After 9 months, the patient had a significant reduction in skin thickening. Therapy also allowed for a reduction of the prednisone dose.[38]

 

Surgical Care

Surgical decompression of carpal tunnel syndrome may be required for eosinophilic fasciitis.

Consultations

A physical therapist may be consulted. Active and passive range of motion therapy of the involved extremities and joints is crucial along with medical therapy to prevent and to treat joint contractures.

 

Medication

Medication Summary

The mainstay of therapy for eosinophilic fasciitis is anti-inflammatory agents.

Corticosteroids

Class Summary

These agents halt active inflammatory process, ensuing fibrosis, and restriction of mobility.

Prednisone (Deltasone, Orasone)

Prednisone is a synthetic adrenocortical steroid drug with predominantly glucocorticoid properties. Its anti-inflammatory effects include depressed production of eosinophils and lymphocytes. Anti-inflammatory processes (eg, edema, fibrin deposition, capillary dilatation, migration of leukocytes, phagocytosis) and the later stages of wound healing (eg, capillary proliferation, deposition of collagen, cicatrization) are inhibited.