Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis.

OBJECTIVE: To examine interrelationships among myositis subsets, autoantibodies, and major histocompatibility complex (MHC) class II alleles across ethnic lines, and to localize genetic susceptibility (presence of HLA-DR versus DQ) to myositis within the MHC class II region. METHODS: MHC class II alleles (HLA-DRB1, DQA1, and DQB1, detected by DNA oligotyping) and myositis-specific autoantibodies (MSA) were determined in 224 patients with various myositis syndromes, including 89 whites, 89 African-Americans, 25 Mexican-Americans, and 21 Japanese. RESULTS: Anti-Jo-1 (histidyl-transfer RNA [tRNA] synthetase) and other MSAs (anti-PL-12, anti-PL-7, anti-OJ, anti-EJ, anti-KJ, anti-tRNA, and anti-signal recognition particle) were equally distributed among the races, but occurred more often in patients with polymyositis (PM) than in those with dermatomyositis (DM) or other myositis syndromes. MSA frequencies were significantly positively associated with anti-Ro (SS-A) (P = 0.002), and significantly negatively associated with anti-U1 RNP (P = 0.003). Frequencies of the HLA-DRB1*0301 (DR3), DQA1*0501, and DQB1*0201 (DQ2) alleles (and haplotype) were each increased in white patients with myositis, especially those with PM, but most strikingly in those with MSAs. However, in the other ethnic groups, except the Japanese group, only frequencies of HLA-DQA1*0501 and the structurally similar DQA1*0401 alleles were significantly increased. The presence of HLA-DQA1*0501 or *0401 was most significantly associated with anti-Jo-1, anti-PL-12, and other MSAs, compared with myositis patients without MSAs (P = 0.0008, Pcorr = 0.01, odds ratio [OR] = 3.7), and with normal, ethnically matched controls (P = 3 x 10(-7), Pcorr = 1 x 10(-6), OR = 6.5). Among MSA-positive patients who were negative for HLA-DQA1*0501 and *0401, including Japanese patients, the HLA-DQA1*0102 and *0103 alleles predominated. In addition, there appeared to be a negative association of the HLA-DR2 alleles (DRB1*1501 and *1503) with PM (P = 0.007, Pcorr not significant, OR = 0.39), but not with DM or myositis overall. CONCLUSION: By transracial gene mapping, genetic susceptibility to anti-Jo-1 and other MSAs in patients with myositis can be localized within the MHC region to the HLA-DQA1 locus.

Pustular psoriasis induced by hydroxychloroquine: a case report and review of the literature.

A variety of pharmacologic agents have been known to induce pustular psoriasis. We describe a patient with a positive personal and family history of psoriasis who developed an extensive annular pustular eruption 3 weeks after starting hydroxychloroquine (Plaquenil) for arthritis. The drug was discontinued, and she received 3 weeks of systemic and topical corticosteroids; in spite of the therapeutic intervention, showers of new lesions appeared daily, and progressed to involve 75% of the body. The development of new lesions stopped, and the older lesions began to clear after one dose of 7.5 mg of methotrexate. Subsequently, methotrexate therapy was stopped because of mild transaminase elevation; the pustular lesions then flared. New lesions stopped appearing after four doses of weekly methotrexate. The patient remains clear of lesions 6 months later.

Serologic tests for connective tissue diseases and the primary vasculitides.

This article provides a brief historical perspective on the development of tests for antiphospholipid antibodies, antinuclear antibodies, myositis-specific antibodies, and antineutrophil cytoplasmic antibodies in the clinical laboratory. Tests presently available in most clinical laboratories that are used in the diagnosis and treatment of the connective tissue diseases and the vasculitides are discussed. Mention is made of antibodies under study in the research laboratories.

Complement component C4A and C4B levels in systemic lupus erythematosus: quantitation in relation to C4 null status and disease activity.

Immunoassays using C4 monoclonal antibodies were developed to quantitate C4A, C4B and total C4 in the serum of healthy controls and patients with systemic lupus erythematosus (SLE). Mean C4A or C4B levels were reduced when a single C4A*Q0 or C4B*Q0 gene was present; however, total C4 levels showed considerable overlap with and did not differ significantly from the non-C4 null groups in either patients or controls. Black patients with SLE without active disease, as well as black controls, had higher levels of C4B and consequently total C4 than whites. Ten patients with SLE studied serially showed that C4A and C4B levels changed proportionally during changes in disease activity. Thus, it may be more important to consider race and disease activity rather than C4 null gene status when assessing C4 levels in patients with lupus.

Autoantibodies and rheumatic disorders in a neurology inpatient population: a prospective study.

PURPOSE: To determine the prevalence and spectrum of underlying rheumatic diseases, especially Sjögren's syndrome (SS) and the antiphospholipid syndrome, and the prevalence of the lupus anticoagulant, antinuclear antibody (ANA), and rheumatoid factor (RF) within a neurologic patient population. PATIENTS AND METHODS: The study design entailed a prospective, consecutive sample of patients admitted to a university-affiliated neurology service for 72 hours or more. Study patients were obtained from a sequential evaluation of 100 inpatients with a wide spectrum of neurologic diseases. Another 31 eligible patients were not included due to refusal (n = 4), inability to give consent (n = 12), or an incomplete database (n = 15). All patients underwent a physical examination and responded to a rheumatic disease questionnaire (administered by one rheumatologist) assessing signs and symptoms relevant to rheumatic disease. All had lupus anticoagulant, ANA, and RF determinations. An independent patient evaluation was done by the attending neurologist. RESULTS: Eleven patients had a rheumatic or autoimmune disorder directly related to their neurologic admission: three patients with SS (one each with embolic stroke, dementia, and hemiparetic somatization); three patients with lupus anticoagulant syndrome (all with stroke, recurrent in two); one patient with systemic lupus erythematosus accompanied by migraine headache and the lupus anticoagulant; and one patient each with isolated central nervous system (CNS) angiitis, neuro-Behçet's disease, CNS Whipple's disease, and HLA-B27-associated spondyloarthropathy. Nineteen patients had one or more autoantibodies: ANA greater than or equal to 1:80 (n = 10); RF greater than or equal to 1:80 (n = 6); and positive lupus anticoagulant (n = 7). The seroreactivity of 10 of these patients remained unexplained. CONCLUSIONS: This neurologic population demonstrated significant seroreactivity and rheumatic disease associations, with SS and lupus anticoagulant-related neurologic disease the most common. Since SS and the antiphospholipid syndrome can be overlooked, it is recommended that a formal evaluation for SS and a direct lupus anticoagulant assay should be considered in the examination of patients with neuropsychiatric symptoms.

Quantitative and antigenic differences in complement component C4 between American blacks and whites.

A population of 98 healthy Black Americans was studied in order to determine normal ranges for total C4, C4A and C4B. Mean total C4 in Blacks measured by an enzymelinked immunoassay (EIA) was 44 +/- 12.8 mg/dl which was significantly different (p less than 0.001) from Caucasian levels of 31.7 +/- 11.5 mg/dl. The difference in total C4 was due to increased levels of C4B in Blacks (means = 24.4 mg/dl) as compared to Whites (means = 15.7 mg/dl; p less than 0.001). These results remained significantly different even when 8 samples having the C4A 91 phenotype were excluded. Since EIAs using monoclonal antibodies with Ch 1 specificity may yield false results, C4 allotyping is recommended when quantitating C4A and C4B levels in Blacks.

Association of labial salivary gland histopathology with clinical and serologic features of connective tissue diseases.

Focal sialadenitis is now widely accepted as an objective criterion for the oral component of Sjögren's syndrome (xerostomia). We investigated the association between labial salivary gland histopathologic changes and the clinical and serologic features of 192 patients with suspected connective tissue disorders. A retrospective review of the medical records of all patients was performed, and historical, physical, laboratory, histologic, and roentgenographic data were abstracted. Each patient had undergone labial salivary gland biopsy as part of a rheumatologic evaluation. There were significant associations between positive findings on lip biopsy and the presence of keratoconjunctivitis sicca (P = 0.013), positive antinuclear antibodies (titer greater than or equal to 1:80) (P = 2 x 10(-8)), and positive Ro antibodies (P = 1 x 10(-8)). However, sicca symptoms and glandular enlargement were not statistically associated with positive findings on lip biopsy. Features predictive of a positive lip biopsy included Ro antibodies (P = 0.914), keratoconjunctivitis sicca (P = 0.700), and positive antinuclear antibodies (P = 0.590).

HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis.

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.

C4 null genes in American whites and blacks with myositis.

The frequencies of C4A and C4B alleles were determined in 66 adults with myositis in relation to HLA class I and II. In whites with myositis, the C4A*Q0 allele occurred in 13/31 (47%) as compared to 25/101 (25%) normal controls (p = 0.08, relative risk = 2.7). Only 11/35 (31%) of black patients with myositis had a C4A*Q0 allele compared to 11/55 (20%) of controls (p = NS, RR = 1.8). Thus, the MHC class III genes do not appear to be the primary genetic risk factors for myositis in adults.

Sjögren's syndrome and other rheumatic disorders presenting to a neurology service.

A prospective study of 100 consecutive admissions to a university neurology inpatient service was done to assess the prevalence and spectrum of autoimmune rheumatic disorders, most specifically Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and lupus anticoagulant (LA)-associated disorders. All patients underwent a physical exam (PE), a rheumatic disease questionnaire, and serologic testing (ANA, RF, and LA). The 100 patients consisted of 36 men and 64 women, aged 17 to 98 (mean 60) years and included 47 white, 45 black and eight other. Definite rheumatic diseases were found in 11%. These included three with previously undiagnosed SS and neurologic symptoms of seizures and dementia, psychiatric disease, and embolic cerebrovascular accident (CVA). Also present were three CVA patients with LA; one migraine patient with known SLE and LA; and one each with CNS Whipples disease, Behcet's disease, isolated CNS angiitis, and B27+ spondyloarthritis. With respect to SS questions and PE findings, three groups of patients were identified: --Questionnaire; +PE 14 patients, aged 33-81 (mean 73) years; 13 F, 1 M who were not further evaluated although significant seroreactivity was present in three (RF 2, LA 1). --Questionnaire; -PE 16 patients, aged 32-98 (mean 56) years; 13 F, 3 M. Four patients had further evaluation, diagnostic for SS in three of them (3/3 abnormal lip biopsies, 2/3 KCS, 2/3 anti-Ro). Another four had unexplained seroreactivity (ANA 2, RF 1, LA 1). --Questionnaire; +PE 12 patients, aged 24-77 (mean 54) years; 10 F, 2 M, not further evaluated although four had seroreactivity in the setting of idiopathic neurologic disorders.(ABSTRACT TRUNCATED AT 250 WORDS)