LOCALIZED SCLERODERMA PROGRESSING TO SYSTEMIC DISEASE

Size: px

Start display at page:

Download "LOCALIZED SCLERODERMA PROGRESSING TO SYSTEMIC DISEASE"

Jonathan Blankenship
5 years ago
Views:

410 LOCALIZED SCLERODERMA PROGRESSING TO SYSTEMIC DISEASE Case Report and Review of the Literature NINA BIRDI, RONALD M. LAXER, PAUL THORNER, MARVIN J. FRITZLER, and EARL D.

1 410 LOCALIZED SCLERODERMA PROGRESSING TO SYSTEMIC DISEASE Case Report and Review of the Literature NINA BIRDI, RONALD M. LAXER, PAUL THORNER, MARVIN J. FRITZLER, and EARL D. SILVERMAN We describe a 15-year-old girl with biopsyproven morphea who developed progression to systemic disease 2 years after initial presentation. In contrast to other reported patients with localized scleroderma, some of whom have had mild, nonprogressive systemic involvement, this patient developed severe, debilitating disease, with skin tightness, sclerodactyly, esophageal involvement, restrictive pulmonary disease, and myopathy. From the time of her initial evaluation, the patient was positive for antinuclear antibodies (ANA), which were shown to be primarily directed against the Ku antigens. This observation suggests that ANA may be a prognostic indicator for progression to systemic disease. Localized scleroderma is a relatively rare condition in children. However, it does occur more com- - From the Division of Rheumatology and the Department of Pathology, The Hospital for Sick Children, Toronto, Ontario, and the Division of Rheumatology, Clinical Immunology and Dermatology, University of Calgary, Calgary, Alberta, Canada. Dr. Birdi is a Fellow of the Arthritis Society. Drs. Laxer and Silverman are Associates of the Arthritis Society. Nina Birdi, MD, FRCPC: Division of Rheumatology, The Hospital for Sick Children, and Assistant Professor of Pediatrics, Staff Rheumatologist, The Children s Hospital of Eastern Ontario, Ottawa, Ontario, Canada; Ronald M. Laxer, MD, FRCPC: Associate Professor of Pediatrics, Head, Division of Rheumatology, The Hospital for Sick Children; Paul Thorner, MD, PhD, FRCPC: Associate Professor of Pathology, Staff Pathologist, Department of Pathology, The Hospital for Sick Children; Marvin J. Fritzler, MD, PhD, FRCPC: Professor and Head, Division of Rheumatology, Clinical Immunology, and Dermatology, University of Calgary; Earl D. Silverman, MD, FRCPC: Associate Professor of Pediatrics and Immunology, Division of Rheumatology, The Hospital for Sick Children. Address reprint requests to Ronald M. Laxer, MD, FRCPC, Division of Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario MSG 1x8, Canada. Submitted for publication March 19, 1992; accepted in revised form November 3, monly in the pediatric population than does systemic sclerosis (SSc). Localized scleroderma may be classified into 3 forms: morphea, generalized morphea, and linear scleroderma. The course of localized scleroderma is usually benign, with slow resolution of the skin lesions; progression to the systemic form of the disease is extremely rare. Localized scleroderma and SSc have a number of features in common, such as the pathologic findings in the skin and the presence of autoantibodies, and they may represent two ends of a spectrum of disease. The patient described herein had well-documented progression of her disease during a period of close observation. CASE REPORT Clinical course. The patient, a 12-year-old girl, presented to the division of dermatology at our institution in October 1987, with a 2-month history of rash on her face and upper arm. The lesions were not pruritic, tender, or photosensitive. She was otherwise asymptomatic. There was no history of Raynaud s phenomenon, dysphagia, gastroesophageal reflux, sicca symptoms, skin tightness, alopecia, photosensitivity, fatigue, weight loss, or fevers. She reported having infrequent retrosternal chest pains. Other than having mild asthma, she had previously been well. The family history was positive for systemic lupus erythematosus in the paternal grandmother, and arthritis in a maternal aunt. On examination, she had 4 erythematous nodules involving the right nasolabial fold and the right upper arm. The remainder of her physical examination findings were normal. The results of laboratory inves- Arthritis and Rheumatism, Vol. 36, No. 3 (March 1993)

SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA 41 1 Table 1. Results of laboratory studies and other tests at presentation and at followup* Oct. 1987 Feb. 1988 Nov.

2 SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA 41 1 Table 1. Results of laboratory studies and other tests at presentation and at followup* Oct Feb Nov CBC Normal Normal Normal Eosinophil count Normal Normal Normal ESR (mdhour; normal 20) AST (unitsfliter; normal 45) ALT (units/liter; normal <45) Not done CPK (unitsfliter; normal <180) Not done Not done 1,850-5,628 LE cell preparation 1: 1,280 1: 1,280 1 : 1,280 ANA Anti-dsDNA Anticentromere Anti-Ku Positive Positive Positive RF 1:20 (80 IU) 1:lO (40 IU) 1:20 (80 IU) Urinalysis BUNkreatinine Normal Normal Normal Complement C3, C4 Normal Normal Normal Chest radiography Not done Not done Normal PFT Not done Not done Restrictive defect Chest CT Not done Not done Normal Gallium scan Not done Not done Uptake lower lobes, both lungs Electrocardiography Not done Not done Occasional PVC 2D echocardiography, stress Not done Not done Normal thallium Upper GI series, Not done Not done Severe reflux, jejunal dilatation, esophagoscop y esophageal ulceration Electromyography Not done Not done Myopathic Nerve conduction Not done Not done Normal Triceps muscle biopsy Not done Not done No inflammation, few regenerating fibers, vessels normal, no eosinophils Nailfold microscopy Not done Not done Dropout, dilatation * CBC = complete blood cell count; ESR = erythrocyte sedimentation rate; AST = aspartate transaminase; ALT = alanine transaminase; CPK = creatine phosphokinase; LE = lupus erythematosus; ANA = antinuclear antibodies; anti-dsdna = antiaouble-stranded DNA; RF = rheumatoid factor; BUN = blood urea nitrogen; PIT = pulmonary function testing; CT = computed tomography; PVC = premature ventricular contraction; 2D = 2-dimensional; GI = gastrointestinal. tigations are shown in Table 1. Punch biopsy of a lesion on the upper arm revealed prominent acellular collagenous fibrosis involving the full thickness of the dermis to the level of the subcutaneous tissue, with loss of skin adnexa (Figure 1). Immunofluorescence staining was negative for immunoglobulin and complement. The biopsy findings were consistent with morphea. Four months later (February 88) she developed pain in the right wrist, right hip, and lower back. She took tiaprofenic acid 300 mg twice daily, prescribed by her family doctor, with no improvement. She had also developed new skin lesions. Physical examination revealed a well-looking, normotensive girl. Hyperpigmented, indurated lesions were noted on the right shoulder, extending anteriorly over the clavicle (Figure 2)* She had pain the right wrist, Figure 1. photomicrograph of &in biopsy specimen from the pa- with range Of motion and n and low lack Pain On full flexion. Radiography revealed spinal dysraphism. She was followed up in the dermatology tient s upper arm, showing fibrosis of the dermis with loss of skin adnexa, consistent with morphea (hematoxylin and eosin stained, original magnification x 80).

In February 1989 (1 year later), she presented with anorexia, fatigue, fever, and tender inguinal adenopathy.

3 412 BIRD1 ET AL Figure 2. Photograph of the patient s shoulder, showing a slightly raised, ill-defined, hyperpigmented lesion. clinic. Her facial lesion resolved, and the shoulder lesion remained stable with topical betamethasone treatment. In February 1989 (1 year later), she presented with anorexia, fatigue, fever, and tender inguinal adenopathy. Lymph node biopsy revealed perinodal fibrosis and obliterative changes in the blood vessels. The adenopathy resolved without treatment. In November 1989, she developed a new plaque involving the left side of the neck, left arm, and posterior aspect of the right shoulder. In addition, she now had arthralgias involving the fingers, wrists, and knees, early morning stiffness lasting 2 hours, fatigue, myalgias, and muscle weakness. She had triphasic Raynaud s phenomenon and reported dry mouth and tightness of the skin around her mouth and fingers. She had sharp, retrosternal chest pain that radiated to the left shoulder and was associated with palpitations. She also reported heartburn, reflux, and bloating after meals. Physical examination revealed new skin lesions involving the left side of the neck and both arms symmetrically, and sclerodactyly. The skin over the arms, chest, abdomen, and thighs was tight. There was proximal muscle weakness with no distal weakness and no deficit in sensation or reflexes. There was no Gottron s sign or heliotrope rash. Biopsy of the skin of the upper arm revealed changes similar to those noted previously. Immunofluorescence results were again negative. Results of laboratory investigations performed at this time are shown in Table 1. A diagnosis of SSc was made based on the sclerodactyly, Raynaud s phenomenon, dysphagia, esophageal dysmotility, restrictive pulmonary defect, arthralgias, and myopathy. Her subsequent course has been characterized by persistent proximal muscle weakness with serum creatine phosphokinase levels ranging from 2,000 units/liter to 3,000 unitsfliter. She also has had shortness of breath, episodic chest pain, and worsening dysphagia, and decreased lung volumes demonstrated on chest radiography. Response to treatment with high-dose prednisone (60 mglday), penicillamine, and nifedipine has been minimal. The myopathy responded transiently to intravenous pulse methylprednisone (1 gm daily for 3 days). A 6-month course of cyclosporin A resulted in softening of her skin, but no improvement in the muscle weakness. ANA studies. Antinuclear antibody specificity was characterized on the basis of indirect immunofluorescence (IIF), double-immunodiffusion, and Western immunoblotting, using control samples of known specificity (Sm, UI RNP, Ro, La, double-stranded DNA [dsdna]), as described previously (1,2). A prototype anti-ku serum (a gift from Dr. Eng Tan, Scripps Clinic and Research Foundation, La Jolla, CA) was used. The ANA titer as determined by IIF on HEp-2 substrate (Immuno Concepts, Sacramento, CA) was 21: 1,280 in all samples tested. No anticentromere antibodies were seen. No antibodies against dsdna, histone, Sm, U1 RNP, SS-AIRo, SS-B/La, or Scl-70 were detected. However, double-immunodiffusion studies suggested the presence of anti-ku antibodies (results not shown). This was confirmed by Western immunoblotting using MOLT-4 whole cell extract separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The 2 protein bands reactive with the patient s serum were identical to the 80-kd and 70-kd Ku antigens bound by the prototype serum (Figure 3). All samples demonstrated the same pattern of reactivity although there was variability between samples in the titer of anti-ku, as implied by the intensity of the reaction. DISCUSSION Localized scleroderma can be classified into 3 forms: morphea, generalized morphea, and linear scleroderma. Although localized scleroderma is not considered to be a systemic disease, arthralgias, arthritis (3,4), and myopathic changes similar pathologically to those seen underlying an involved area of skin in juvenile dermatomyositis (5) can occur. Raynaud s phenomenon is rare. An increased incidence of spinal dysraphism has been reported (4). Laboratory abnor-

Lane 1, Prototype anti-ku serum. Lanes 2-6, Sequential samples from the patient, showing reactivity with the 80-kd and 70-kd Ku proteins. Lane 7, Normal human serum (NHS).

4 SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA 413 Figure 3. Immunoblotting profile of the patient. MOLT4 whole cell extract was separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred to nitrocellulose, and probed with patient serum diluted 1:lOO. Lane 1, Prototype anti-ku serum. Lanes 2-6, Sequential samples from the patient, showing reactivity with the 80-kd and 70-kd Ku proteins. Lane 7, Normal human serum (NHS). Molecular mass markers are indicated on the left. malities may include eosinophilia, elevated erythrocyte sedimentation rate (ESR), hypergammaglobulinemia, positive ANA, double-stranded and singlestranded DNA antibodies, positive lupus erythematosus cell preparation, rheumatoid factor (RF), and positive Borrelia burgdorferi serology (6-9), but all of these may also be normal in localized scleroderma. Pathologically, the skin lesions of localized scleroderma are indistinguishable from those of systemic sclerosis. The course of localized scleroderma is generally benign, with spontaneous resolution of the skin lesions over several years. Progression to the systemic form of the disease is considered to be extremely rare (6). Our patient presented with biopsy-proven morphea and had positive ANA and RF, mild hypergammaglobulinemia, and transiently elevated ESR. Other than mild arthralgias, she had no evidence of systemic disease until 2 years after her initial presentation. In retrospect, the retrosternal chest pain and lymphadenopathy may have indicated a systemic disease process. Progression of localized scleroderma to SSc has been reported, albeit infrequently. Christianson et a1 (4) reported that 2 of 235 patients with generalized morphea developed SSc. Curtis and Jansen (10) noted progression in 6 of 106 patients with localized scleroderma. Some investigators have documented the presence of abnormal esophageal peristalsis and decreased carbon monoxide diffusing capacity in patients with localized scleroderma (1 1-13). These patients do not fulfill criteria for a diagnosis of SSc (14), and the systemic involvement appears to have a mild and nonprogressive course. Falanga and colleagues (15) reported 53 patients with linear scleroderma, none of whom had signs of systemic progression after a mean followup time of 10 years. The issue of whether patients with localized scleroderma are at increased risk of systemic progression remains unresolved. It has been suggested that the presence of generalized morphea, symmetric skin involvement, or Raynaud s phenomenon may represent a transitional form of the disease. The difficulty in determining the incidence of systemic progression stems from a number of factors: Not all patients have had clear documentation of the presence of sclerodactyly, Raynaud s phenomenon, or dysphagia at the onset of their localized scleroderma. Systemic involvement, if present, may be asymptomatic. Localized scleroderma itself may have some mild systemic features in addition to the occasional elevated ESR, hypergammaglobulinemia, and positive results on serologic immunologic tests that are not considered to denote a more serious systemic disease. It is impossible to distinguish the conditions based on skin pathology. Localized scleroderma and systemic sclerosis likely represent two ends of a continuous spectrum of disease. Our patient represents a well-documented case of progression along this spectrum. In contrast to most other reported patients with localized scleroderma and mild systemic features that have generally remained mild

5 414 BIRD1 ET AL on followup, this patient s course evolved to severe, debilitating systemic disease. Of interest, early in the patient s clinical course, she had autoantibodies directed against the 80-kd and 70-kd Ku antigens. The presence of this antibody has remained constant throughout her clinical course, with apparent changes in titer as estimated by the intensity of the immunoblotting reaction. Anti-Ku antibodies were originally detected in patients with polymyositislscleroderma overlap (16), but more recent studies have identified these antibodies in a wide variety of connective tissue diseases including systemic lupus erythematosus, scleroderma, myositis, Sjogren s syndrome, and mixed connective tissue disease (17). They have not been described in patients with localized scleroderma (18,19). The importance of the observation that this patient had anti-ku antibodies when she presented with localized scleroderma is twofold. First, similar to reports of anticentromere antibodies in the CREST (calcinosis, Raynaud s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) variant of scleroderma (20,21), the presence of anti-ku may be a marker for morphea patients whose disease will progress to a systemic form. Second, it is possible that the presence of these markers early in the disease process was an indication of much more widespread systemic involvement than was recognized. We suggest that all patients with localized scleroderma be carefully evaluated for the presence of systemic involvement. Patients with evidence of systemic involvement may be at risk for progressive, severe disease. With thorough clinical and laboratory monitoring, a better understanding of the eventual disease course and outcome of localized scleroderma may be achieved. ACKNOWLEDGMENTS The authors thank Dr. Bernice Krafchik for referring the patient, Edda Laxer for editorial assistance, and Joanne Blagdon for preparation of the manuscript. REFERENCES 1. Fritzler MJ, Tan EM: Antinuclear antibodies and the connective tissue diseases, Laboratory Diagnostic Procedures in the Rheumatic Diseases. Edited by AS Cohen. New York, Grune and Stratton, Chan EKL, Pollard KM: Autoantibodies to ribonucleoprotein particles by immunoblotting, Manual of Clinical Laboratory Immunology. Edited by NR Rose, ED de Macario, JL Fahey, H Friedman, GM Penn. Washington, DC, American Society for Microbiology, Bourgeois-Drouin C, Touraine R: Sclerodermie en plaques: perturbations imunologiques et viscerales. Ann Med Interne (Paris) 129: , Christianson HB, Dorsey CS, O Leary PA, Kierland RR: Localized scleroderma: a clinical study of two hundred and thirty-five cases. Arch Dermatol 74: , Hiike T, Ontani Y, Hattori S, Ono T, Kageshita T, Matsuda I: Childhood type myositis and linear scleroderma. Neurology 33: , Falanga V: Localized scleroderma. Med Clin North Am 73: , Falanga V, Medsger TA: Frequency, levels and significance of blood eosinophilia in systemic sclerosis, localized scleroderma, and eosinophilic fasciitis. J Am Acad Dermatol 17: , Falanga V, Medsger TA, Reichlin M: Antinuclear and anti-single stranded DNA antibodies in morphea and generalized morphea. Arch Dermatol 123: , Hoesly JM, Mertz E, Winkelmann RK: Localized scleroderma and antibody to Borrelia burgdorferi. J Am Acad Dermatol 17:455458, Curtis AC, Jansen TG: The prognosis of localized scleroderma. Arch Dermatol 78:74%756, Kornreich HK, King KK, Bernstein BH, Singsen BH, Hanson V: Scleroderma in childhood. Arthritis Rheum 20 (suppl 2): , Person JR, Su WPD: Subcutaneous morphea: a clinical study of sixteen cases. Br J Dermatol 100: , Diaz-Perez L, Connolly SM, Winkelmann RK: Disabling pansclerotic morphea of childhood. Arch Dermato1 116: , Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum , Falanga V, Medsger TA, Reichlin M, Rodnan P: Linear scleroderma: clinical spectrum, prognosis and laboratory abnormalities. Ann Intern Med 104: , Mimori T, Akizki M, Yamagata H, Inada S, Yoshida S, Homma M: Characterization of a high molecular weight acidic nuclear protein recognized by autoantibodies in sera from patients with polymyositis-scleroderma overlap. J Clin Invest 68: , Reeves WH: Use of monoclonal antibodies for the characterization of novel DNA-binding proteins recognized by human autoimmune sera. J Exp Med 161:18-39, 1985

SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA 415 18. Yaneva M, Arnett FC: Antibodies against Ku protein in sera from patients with autoimmune diseases. Clin Exp Immunol76:366372, 1989 1987 19.

6 SYSTEMIC PROGRESSION OF LOCALIZED SCLERODERMA Yaneva M, Arnett FC: Antibodies against Ku protein in sera from patients with autoimmune diseases. Clin Exp Immunol76:366372, Takehara K, Moroi Y, Nakabayashi Y, Ishibashi Y: Antinuclear antibodies in localized scleroderma. Arthritis Rheum 26: , Sarkozi J, Bookman AAM, Lee P, Keystone EC, Frit- zler MJ: The significance of anticentromere antibody in idiopathic Raynaud's syndrome. Am J Med , 21. Kallenberg CGM, Pastoor GW, Wouda AA, The TH: Antinuclear antibodies in patients with Raynaud's phenomenon: clinical significance of anticentromere antibodies. Ann Rheum Dis 41: , 1982

2/23/18. Disclosures. Rheumatic Diseases of Childhood. Making Room for Rheumatology. I have nothing to disclose. James J.

2/23/18. Disclosures. Rheumatic Diseases of Childhood. Making Room for Rheumatology. I have nothing to disclose. James J. Making Room for Rheumatology James J. Nocton, MD Disclosures I have nothing to disclose Rheumatic Diseases of Childhood Juvenile Idiopathic Arthritis (JIA) Systemic Lupus Erythematosus (SLE) Juvenile Dermatomyositis