An unusual case of eosinophilia, myalgia and skin contractures: Shulman's disease revisited

Abstract

Shulman's disease (eosinophilic fasciitis) is a very rare autoimmune disorder with an unknown etiopathogenesis. During the initial period of disease, it usually causes limb and trunk edema followed by collagenous thickening of the subcutaneous fascia. Eosinophilia is a predominant laboratory finding during the initial phase of the disease and less prominent in the later phases. Patients may also present with arthritis, myositis, peripheral neuropathy, and rarely pleuropericarditis. Here, we are reporting a case of eosinophilic fasciitis presenting with vague constitutional symptoms, fever, and peripheral blood eosinophilia followed by rapidly evolving skin tightening with joint contractures and muscle stiffness, which misled the treating team toward Scleroderma and its overlap syndromes. The diagnosis was finally clinched by a full-thickness skin biopsy along with underlying fascia and muscle tissue from an effected area, with a gratifying treatment response to standard immune suppression.

Introduction

Most cases of eosinophilic fasciitis (EF) are idiopathic.¹ However, some triggering factors are found to be associated with this disease. These are strenuous exercise, infection with Borrelia Burgdorferi, drugs such as ramipril, simvastatin, and atorvastatin.² Clinically, skin involvement is seen in the form of swelling, indurations, and skin thickening in the extremities. Subsequently, during the course of the disease, edema in the extremities evolves into woody indurations characterized by orange-colored hyperpigmentation and skin thickening.³ Characteristic “groove sign” is seen in the periphery. Few patients also develop muscle weakness, pain, synovitis, contracture, and features of local inflammation in the form of panniculitis. Here, we aim to present a case of EF with characteristic clinical and histologic findings.

Case Report

A 47-year-old male patient, was diagnosed as a case of primary hypertension and was on regular medication with tablet telmisartan since 2010. He first reported to a private hospital on 05 Feb 2018, with the chief complaints of easy fatigability of two months duration and fever of one-week duration. He was regularly running 4–5 km daily as part of fitness and training, but at presentation, he could only run 2–3 km with difficulty. This was also associated with anorexia, night sweats, and significant weight loss (5 kg in 2 months). During initial evaluation at private hospital, his investigation revealed mild anemia (Hb, 12.2 gm/dl), eosinophilia (20%), thrombocytosis (Plt, 813000/mm³⁾ and transaminitis (SGOT/SGPT-42/68 U/L). There was no growth in his blood or urine culture. His initial imaging studies (CXR, USG Abdomen) were normal and serology for malaria, dengue, human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) was negative. He was managed as a case of probable enteric fever, with empirical oral antibiotic (tab cefixime 200-mg BD for 5 days). He became afebrile after three days of treatment, however his complaints of easy fatigability and malaise persisted. Two weeks after discharge from the private hospital, the patient again developed fever which was associated with worsening of fatigability, severe body ache, and muscle stiffness in both arms and thigh region. He also experienced intermittent severe cramp-like pain, predominantly involving the thighs and calves. He gradually started having difficulty in getting up from squatting and sitting position and lifting objects overhead. He also noticed feeling of tightness of skin around bilateral upper limb which gradually progressed to involve the upper chest and neck. During this period, the patient also noticed restriction of full range of movement at various joints starting initially at right elbow followed by involvement of left elbow, both hip and knee joints and difficulty in neck extension. At presentation to our hospital, he needed assistance for most of his activities of daily living, and he was unable to walk without support of another person. On musculoskeletal examination, he had induration and thickening of skin over bilateral upper arms, thighs, and chest. The skin in these areas had a peau d’ orange appearance. Groove sign was visible on the leg (Fig. 1) and also in the thigh region. He had fixed flexion deformities of 10⁰-30⁰, involving bilateral elbow, knee, and neck with mild tenderness of muscle in these same areas. His CNS examination revealed normal higher mental functions, speech, and cranial nerves. In motor system examination, mild atrophy with a “woody” induration of both arms, forearms, and thigh muscles was noted. Muscle power was 4+/5 in both proximal and distal muscles with pain and contractures interfering with power testing. Sensory examination revealed preserved spinothalamic and posterior column sensations. No abnormality was detected during the examination of cardiovascular, respiratory and gastrointestinal system.

Fig. 1.

Groove sign in the leg area (red arrow).

The patient was again extensively evaluated at our center. He was again noted to have mild anemia (Hb, 11.9 gm%), eosinophilia (12%), thrombocytosis (Plt, 851000/mm³) and transaminitis (SGOT/SGPT-62/121 IU/dl). His peripheral blood smear showed microcytic hypochromic anemia with eosinophilia and thrombocytosis. His absolute eosinophil count was elevated at 850/cmm. His blood sugars, renal functions, serum proteins, and electrolytes were all within normal limits. His viral markers for HBsAG, anti-HCV, and HIV were all negative. Imaging studies with chest radiograph and ultrasound abdomen were also normal. Evaluation for connective tissue disorder revealed an elevated erythrocyte sedimentation rate (ESR) of 24 mm after 1 h and CRP of 99.8 mg/L. His anti-cyclic citrullinated peptide (CCP) and anti nuclear antibody (ANA) by immunofluorescence were negative. His creatine phosphokinase (CPK) was normal (68U/L) and myositis antibody profile (Mi2,Ku,PM-SCL 100/75, Jo 1,SRP, PL-7/12 EJ, OJ, RO 52) was also negative. Both c-ANCA and p-ANCA were negative and nailfold capillaroscopy (NFC) was normal. His whole body positron emission tomography-CT (PET-CT) showed mildly increased symmetrical uptake in all muscle groups of limbs with no evidence of occult malignancy. Subsequently, his magnetic resonance imaging (MRI) of both thighs and arms showed short tau inversion recovery (STIR) hyperintensities involving deep fascia, with normal signal intensity in the muscles. There was no evidence of edema or fatty infiltration in the muscular plane (Fig. 2 and Fig. 3). electro myography (EMG) of arm and forearm muscles showed marked skin induration at needle entry but normal insertional activity with normal recruitment and interference patterns of motor unit potentials. Finally, a confirmatory test was performed with full-thickness skin (Fig. 4), muscle (Fig. 5), and facia (Fig. 6) biopsy from right arm region (biceps). His biopsy showed perivascular inflammation in the subcutaneous tissue and facia, with predominantly lymphocytic infiltration and perimysial inflammation in the intermuscular plane. On the basis of his clinical profile, laboratory evaluation, imaging and tissue biopsy, he was diagnosed as a case of EF. Patient consent for inclusion in study was also obtained.

Fig. 2.

MRI thigh (STIR coronal view) – showing hyperintense areas suggestive of edema in the intermuscular fascial planes (thin arrows) with characteristic sparing of the muscles (thick arrows). STIR, short tau inversion recovery.

Fig. 3.

MRI thigh (STIR axial view) – again showing hyperintensities of fascia (thin arrow) with sparing of muscles (thick arrow). STIR, short tau inversion recovery.

Fig. 4.

Skin histology (Hematoxylin & Eosin (H & E) × 100) showing perivascular inflammation in the epidermis and upper dermis with predominantly lymphocytes.

Fig. 5.

Muscle biopsy ( Hematoxylin & Eosin H & E × 200) microphotograph showing focal perimysial inflammation (arrow).

Fig. 6.

Skin with facia (Hematoxylin & Eosin H & E × 200) microphotograph showing perivascular inflammation (arrow) in the fascia. The inflammatory cells include lymphocytes, plasma cells, and a few histiocytes.

Discussion

Eosinophilic fasciitis (EF) presenting as a scleroderma-like disorder, was first described by Shulman in 1974.¹ These patients showed typical dermal involvement, peripheral blood eosinophilia, and ESR. It is usually seen equally in both sexes.⁴ Age at onset of the disease usually ranges from childhood to advanced age with mean age ranging from 40 to 50 years.⁵ Pathogenesis of the disease involves degranulation of the infiltrating eosinophils in the fascia, resulting in abnormal accumulation of cationic granule proteins, which posses toxic fibrogenic properties. Other factors involved in the pathogenesis are tissue inhibitor of metalloproteinase 1, IL-5, and CD8 + T lymphocytes–mediated cytotoxicity.⁶

This patient initially presented with nonspecific symptoms of easy fatigue and malaise. Except for history of indulging in strenuous physical activity (4–5 km running daily), no other triggering factors were noted in his case. Though ACE inhibitor ramipril⁷ is shown to be associated with EF but our patient was on telmisartan for his blood pressure control. During the subsequent course of his illness, he developed the characteristic features of indurated skin with Peau d'orange appearance, groove sign (along fascial planes), and contractures of joints. Rarely, patient also presents with pleural effusions, pericarditis, and renal involvement, but our patient did not have any of these features. Clinically EF does mimic systemic sclerosis (considering the involvement of skin and muscle), however, systemic sclerosis typically manifest with Raynaud's phenomenon and most patients have abnormal NFC findings, both of which are conspicuously absent in EF.

Peripheral eosinophilia or tissue eosinophilia is not a consistent finding in all case of EF.⁸ It is present in 60%–80% of patients in various reports but not mandatory for its diagnosis.⁹ It does not correlate with disease severity and is not a useful marker for follow-up of disease activity.¹⁰

Magnetic resonance imaging of both thigh and arms showed evidence of intermuscular facial plane involvement in the form of STIR hyperintensities along the fascia, with sparing of the muscles per se. Subsequently, he was evaluated with a full-thickness skin and muscle biopsy, taken from the right biceps region. It showed reactive changes in epidermis and upper dermis with perivascular inflammation in the deep dermis and facia, along with focal perimysial inflammation in the intermuscular planes. On the basis of his clinical profile, investigations and imaging study, he was diagnosed as a case of EF.

He was started on intravenous immunoglobulin (IVIG) at a dose of 2 gm/kg, given over a period of 5 days, followed by tab prednisolone 60-mg OD for six weeks, with a very gradual tapering of 10 mg per month. Patient showed dramatic improvement after therapy with settling of pain and stiffness along with regression of acute phase reactants. Later on, he was started on long-term immune suppression with tab azathioprine (150 mg/day) along with a low-dose maintenance steroid regimen (tab prednisolone 15 mg alternate day). In addition, he was also given supportive treatment with proton pump inhibitors, calcium, vitamin D, and baclofen. Presently, he is stable and under regular monthly follow up. He has mild residual flexion contractures persisting at the elbow joints. He has joined back duties and is independent for all activities of daily living.

Conclusion

EF is a rare autoimmune disorder and usually presents with nonspecific constitutional symptoms and peripheral eosinophilia, followed by early appearance of skin and joint contractures. It is distinct from scleroderma, with selective involvement of facial planes and relative sparing of muscles and soft tissue. The presence of typical “Groove sign” along the intermuscular planes and sparing of nail folds on NFC are useful clinical clues to the diagnosis. A full-thickness skin, fascia, and underlying muscle biopsy is needed to confirm the diagnosis which is usually well supported by STIR MR images of the effected areas. Once confirmed, the disease responds well to standard pulse therapy with steroids/IVIG followed by transition to long-term immune suppression. It is important to distinguish EF from other connective tissue disorders with similar phenotype (scleroderma and dermatomyositis), as it has a much better response to therapy and long-term remission, if treated early before the appearance of permanent skin contractures.

Disclosure of competing interest

The authors have none to declare.