Eosinophilic Fasciitis (Shulman's Syndrome)
This 55-year-old man has a four-month history of progressive muscle stiffness, aching discomfort and weakness in his proximal and distal limbs that subsequently spread to involve his trunk. In addition, he develops limb edema with marked weight gain one month prior to his initial clinic evaluation. He has no bulbar or extraocular muscle involvement. He did not participate in unusual excessive physical activity, have toxic exposure, or travel to areas where Lyme disease is endemic. The progressive limb swelling prompted him to seek medical evaluation and he was initially diagnosed with an inflammatory myositis based on abnormalities on his EMG.
This patient's examination reveals prominent symmetric non-pitting edema in the distal limbs up to the forearms and calves. The cranial nerves are all normal. He has normal bulk and mild to moderate proximal limb weakness with the legs more affected than the arms. His serum CPK values are normal and his complete blood count differential shows eosinophilia of 20%. A muscle and fascial biopsy performed shows markedly thickened fascia containing large collections of inflammatory cells of mixed type including eosinophils, with extension into the perimysial and rarely, endomysial areas consistent with fasciitis.
Eosinophilic fasciitis can sometimes be unrecognized and misdiagnosed as inflammatory myopathy. Eosinophilic perimyositis has many similar clinical features including myalgia, muscle stiffness, and eosinophilic. However, the skin changes, relatively mild muscle weakness, prominent pain symptoms and normal serum CPK levels should aid in differentiating these entities. A skin-fascia-muscle biopsy is ultimately necessary to confirm this diagnosis.
After the biopsy, this patient was treated with pulse intravenous steroid. He then had intermittent boosters weekly over the next month with good resolution of the limb edema, myalgia and weakness.
Eosinophilic fasciitis (EF) is an uncommon idiopathic fibrosing disorder with generalized edema, pain and symmetric induration of skin. The clinical presentation is one of acute painful, swollen extremities progressing to disabling cutaneous fibrosis.[1] A predominance of eosinophilic cells in association with a generalized fasciitis is seen in this rare disorder.
The etiology and pathogenesis of EF, while poorly understood, has been a subject of investigation since its identification in 1974 by Shulman, who described two patients with diffuse fasciitis, hypergammaglobulinemia, elevated sedimentation rate, eosinophilia, and skin changes similar to that of scleroderma.[2] Patients typically have an acute onset of erythema, swelling, and pain.[1] Some experience arthralgias, fatigue, low-grade fever, and muscle ache.[3] Skin findings may initially begin as non-pitting edema of the extremities and progress to a more thickened appearance (peau d'orange). Extremities, and to a lesser degree, the neck and trunk, are the most common sites of involvement generally sparing the face and skin of the hands and feet. A subacute process soon leads to chronic fibrotic skin changes, similar to that seen in various collagen vascular diseases. A small percentage of patients may also develop an arthritis or myositis in conjunction with a fasciitis due to the nearby inflammatory process.[1] Visceral involvement and Raynaud's phenomenon are rare. Patients may go on to have generalized joint contractures.
EF has been weakly associated with strenuous exercise, initiation of hemodialysis and infections with Borrelia burgdorferi, the causative organism in Lyme disease.[4] Most cases, however, are idiopathic. Patients are between 30 to 60 years of age, although rare cases are seen in children. There appears to be an increased incidence of hematological disorders associated with this condition including aplastic anemia, myeloproliferative disorders, myelodysplastic syndromes, lymphoma, leukemia and multiple myeloma (up to 10% in one case series).[5]
The pathogenesis of EF involves infiltration of the deep fascia and lower subcutaneous tissues with inflammatory cells (lymphocytes, plasma cells, histiocytes and eosinophils) with a significant peripheral eosinophilia.[5] Interestingly eosinophilic fasciitis refers to eosinophilia of the blood and not tissue eosinophilia. In the early stages of EF, fibrinoid necrosis or myxoid degeneration may be seen.[6] As the inflammation progresses with the release of various inflammatory mediators, there is increase in tissue fibrosis and thickening of the dermis. The fibrosis can be seen in the septae of the subcutaneous fat, and may also extend into the lower dermis and the underlying fascial and muscular tissue. The muscle may have evidence of focal necrosis, degeneration, and regeneration.[6] In vitro experiments have demonstrated increased levels of collagen III, IV, and I mRNA production in fibroblasts from tissues of involved fascia. Fascial fibroblasts in EF express transforming growth factor-beta I and connective-tissue growth factor mRNA, which may account for the fibrosis seen in this condition. In addition, eosinophil degranulation may lead to fibroblast activation.[5]
The diagnosis of EF is based on a history of skin changes in the setting of an elevated peripheral eosinophilia. In one report, peripheral eosinophilia was present in 33 of 52 patients.[5] Other laboratory abnormalities found include elevated sedimentation rate and polygammaglobulinemia.[5] Serum creatine kinase values are typically normal despite pathological evidence of muscle involvement. Electromyography may show short duration motor unit potentials suggestive of a myopathy.[6]
Imaging is a tool increasing used in the diagnosis of EF. MRI demonstrates increased T2 signal in the subcutaneous tissues and deep fascia. There may also be fascial enhancement in fat suppressed post gadolinium T1 weighted images.[7]
Confirmatory diagnosis is based on a full-thickness incisional biopsy that includes the dermis, subcutaneous fat, and the deep fascia to look for evidence of generalized inflammation of the fascia. Although there are no pathognomonic findings on the biopsy, it is valuable to exclude other processes including collagen vascular disorders, which may have a similar clinical appearance without the association fascial alterations.[6]
The constellation of eosinophilia and skin changes can also be seen in eosinophia-myalgia syndrome (EMS), which has peripheral eosinophil count of greater than or equal to 1000 cells/mm3 and severe myalgia that interferes with daily activities in the absence of other conditions that account for these abnormal findings.[6] Patients with EMS have more acute, severe symptoms, and a higher frequency of rash and systemic involvement than patients with EF. Pulmonary, cardiac, gastrointestinal, neurologic, myopathic and thyroid abnormalities are detected.[8] Outbreaks of EMS have been reported in association with ingestion of contaminated L-tryptophan supplement.[8]
Another condition that produces a similar clinical syndrome involves the ingestion of adulterated rapeseed oil leading to a syndrome of eosinophilia, myalgia, and arthralgia associated with chronic scleroderma-like skin changes.[9] Eosinophilic perimyositis is another rare syndrome with symptoms of myalgia on exertion and muscle stiffness without skin or fascial involvement. Pathological findings include perimysial infiltration by macrophages and CD4 positive lymphocytes without endomysial invasion or myonecrosis. A recent study shows T-cell clonality in muscle, blood, and bone marrow from a patient with this syndrome and it is suggested that the monoclonal expansion is responsible for the muscle involvement.[10]
Although there is limited data regarding optimal treatment of EF, steroids are the mainstay of treatment. Most cases respond to corticosteroids, with 25% achieving complete recovery. Spontaneous remissions are common. Typically doses equivalent to prednisone 1mg/kg per day are given for several months with a steroid taper based on improvement of the skin changes.[11] Continuous steroid treatment for 2-5 years may be needed in some individuals. If the symptoms are persistent, high dose steroids may be employed. Hydroxychloroquine has been shown to be equally efficacious as prednisone in one series. Other effective agents include cyclosporine A, methotrexate, sulfasalazine, D-penicillamine, antithymocyte globulin and psoralen UVA photochemotherapy. There are reports of success with allogeneic bone marrow transplants.[12]
Muscle cramps and pain may respond to quinine, methocarbamol, dantrolene, cyclobenzaprine or non-steroidal medications. Physical therapy may be beneficial for patients with contractures and to improve mobility. Evaluation of psychological factors in individuals with chronic disease and appropriate counseling may further contribute to improvement in the quality of life of these patients. Although the course of Shulman's syndrome is difficult to predict, most individuals improve, often with stigmata of residual skin changes.[6]
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