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Concurrence of Celiac Disease and Juvenile Dermatomyositis: Result of a Specific Immunogenetic Susceptibility?

1997; Lippincott Williams & Wilkins; Volume: 25; Issue: 1 Linguagem: Inglês

10.1097/00005176-199707000-00018

1536-4801

Stephan Buderus, Norbert Wagner, M. J. Lentze,

Immunodeficiency and Autoimmune Disorders

Molecular genetic techniques permit identification of major histocompatibility complex (MHC) alleles and thus play a role in elucidating disease associations and possible factors related to etiology or pathogenesis. Recently, an association between two immunemediated diseases, celiac disease and juvenile dermatomyositis (JDM), has been reported, with DR3 or DR5/DR7 for the first and DR3 for the latter (1-3). Most importantly, a high prevalence of the DQA1*0501 allele has been documented in both diseases due to a linkage disequilibrium of this allele with either DR3 or heterozygosity for DR5/DR7 (1,2,4). These studies demonstrate that most individuals suffering from celiac disease or JDM are positive for either DR3 or DR5, both of which are associated with the DQA1*0501 allele. One hypothesis about the significance of this observation is that the DQA1*0501 allele leads to activation of CD4-positive T cells by presentation of a yet unidentified peptide that may induce celiac disease or JDM. Herein we report the first case known to us that was diagnosed with both diseases, celiac disease and JDM. The patient was found to be positive for the heterozygous state of DR5/DR7. This might indicate a specific susceptibility for the concurrence of both diseases. CASE REPORT An 8-year-old girl was admitted to the hospital suffering from increasing muscle weakness and pain in the upper arms and thighs. She developed malaise and dyspnea on exertion. Associated with her symptoms was an undulant fever with temperatures up to 38.5°C. At the age of 18 months, the patient had presented with chronic diarrhea. The diagnosis of celiac disease had been established by testing for antibodies against gliadin and typical histopathological findings in the duodenal suction-biopsy. On a gluten-free diet, the patient gained weight properly and showed normal physical and mental development. She adhered strictly to the diet and no relapse of celiac disease occurred. On physical examination the skin was pale and there was marked muscular weakness of the proximal limbs (grade 3) as well as tenderness on pressure. The laboratory investigations showed a marked elevation of creatine kinase (CK; Fig. 1). The C-reactive protein (CRP) was 1.4 mg/dl and the erythrocyte sedimentation rate (ESR) was 30 mm in the first hour. No antibodies against gliadin and endomysium were found. In addition, none of the following autoantibodies (rheumatoid factor, antinuclear antibodies, antimitochondrial antibodies, anti-DNA antibodies, cardiolipin antibodies, antibodies against smooth muscle cells, reticulin, and myofibrils) was detectable. Microbiological testing for borreliosis, enterovirus, parvovirus, cytomegalovirus, toxoplasma, and mycoplasma were negative. Serological human leukocyte antigen (HLA) typing gave the following result: A2/A10, B13/B44, Cw5/Cw6, DR5/DR7, DQ2/DQ7. An electromyogram (EMG) showed typical signs of acute myopathy. A muscle biopsy was performed and the histopathological diagnosis was necrotizing myopathy. Magnetic resonance imaging (MRI) of gluteal and femoral muscles showed a marked elevation of signal intensity of T2-weighed images (5). Thus by signs and symptoms of muscle pain and weakness, elevation of CPK, and diagnostic EMG and biopsy findings, the patient met the criteria (6) for the diagnosis of polymyositis. The clinical course was initially characterized by a brief spontaneous improvement with respect to the muscular weakness and the CK level without specific treatment (Fig. 1). This was followed by a deterioration of the clinical situation within 4 days in which the patient developed a violacious rash of the face crossing the nasal bridge and of the dorsal hands, which, in addition, exhibited a marked edema. The diagnosis of juvenile dermatomyositis was established. Treatment with oral ibuprofen [days 10-17 after admission to the hospital; 24 mg/kg/day (7)] did not improve the child's status. Prednisone therapy [1.2 mg/kg/day (8-10)] was initiated, leading to a rapid clinical improvement of muscular and cutaneous symptoms with a concomitant decline in the serum concentration of CPK levels (Fig. 1). After 4 weeks the dosage of prednisone was tapered stepwise over a 12-month period without any relapse of the disease. Currently the patient is not on medication and has been asymptomatic for 18 months. DISCUSSION Both diseases, JDMS and celiac disease seem to be immunogenetically determined. Ninety-five percent of Northern Europe patients with celiac disease possess HLA class II antigens DR3 and DQ2 with the alleles DQA1*0501 DQB1*0201 (11). In Southern Europe there is an association of celiac disease with DR3 or the heterozygous state of DR5/DR7. Those individuals who have DR5 together with DR7 show a combination of the DQ alleles (DQA1*0501 DQB1*0201) identical to that of Northern European patients who are DR3 positive (2,11). Ninetytwo percent of patients from Southern Europe are either DR3 or DR5/DR7 heterozygotes. The only difference with respect to the DQ alleles is that in DR3-positive patients, the alleles (DQA1*0501 DQB1*0201) are located on one chromosome (cis configuration), while in the DR5/DR7-positive patients these alleles (DQA1*0501 DQB1*0201) lie on different chromosomes (trans configuration). It has been shown that functional MHC molecules are synthesized regardless of whether the alleles are in the cis or in trans configuration (12). In JDMS there is no comparable close association between immunogenetic background and disease, although the frequency of B8 and DR3 is increased (3,13). Most important, a molecular genetic study (4) revealed an increased association of the DQA1*0501 allele with JDMS (80, vs. 28% in normal individuals). Therefore, the DQA1*0501 allele might play a role in both diseases, celiac disease and JDMA. This immunogenetic overlap leads to the question of a common genetic susceptibility factor and of common aspects in the pathogenesis of these two immunemediated diseases. For this reason, patients with JDMS should be screened for celiac disease by antibody testing (anti-gliadin and antiendomysial) to determine the prevalence of latent celiac disease in JDMS. If this is significant, then further work could elucidate the nature of this association in terms of either immunogenetic background or pathogenesis.FIG. 1: . Time course of CK levels after the onset of dermatomyositis in an 8-year-old girl.