A three-way interplay of DR4, autoantibodies and synovitis in biopsy-proven idiopathic inflammatory myositis

Abstract

The aim of this study was to determine the HLA and autoantibody associations of patients with histologically confirmed idiopathic inflammatory myositis (IIM). Serum and DNA were archived from South Australian patients with biopsy-proven dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). HLA typing for Class I and II alleles was performed by serology and DNA-based technology, respectively, for 133 myositis patients and 166 Caucasian population-based controls. Myositis-specific and myositis-associated autoantibodies were detected by line immunoblot. All alleles of the 8.1AH were associated with myositis susceptibility. The B8-DR3 haplotype fragment conferred the strongest susceptibility (OR 2.9, 95% CI 1.8-4.6), and the B-DR region of other ancestral haplotypes was associated with myositis subgroups. Autoantibodies were present in 42/130 (32%) IIM patients and were more frequent in DM (11/17, 65%) than PM (23/70, 33%) or IBM (8/43, 19%), P = 0.002. Autoantibodies were associated with DRB1 03 (P = 0.0005) but also with DRB1 04 (P = 0.004). The frequency of autoantibodies in the three myositis subgroups mirrored the frequency of DR4. Polyarthralgia (±synovitis) was more common in DM/PM (30/76, 39%) than IBM (3/32, 9%), P = 0.004, and there was a strong ordinal association between the prevalence of autoantibodies and polyarthralgia ± synovitis (proportional OR = 5.5, 95% CI 2.3-13.7, P = 0.0004). The central MHC region confers the strongest susceptibility for IIM and also modulates disease phenotype. Our findings reveal a novel association of autoantibodies with DR4 and with arthralgia/synovitis in IIM and raise the possibility of a genetically (DR4) determined citrullination of myositis autoantigens expressed in muscle and synovium.

Autoantibodies against a 43 KDa Muscle Protein in Inclusion Body Myositis

“…While previous studies have reported an association between IBM and the presence of various autoantibodies, thus suggesting an autoimmune process in IBM, none have been identified as disease specific [13] and their prevalence is less than that seen with DM and PM [3] [14] [15] [16] [17]. In a review of 99 patients with sporadic IBM, 43 (44%) had elevated titers of one or more of nine different non disease-specific autoantibodies [13].…”

Frequency of autoantibodies and correlation with HLA-DRB1 genotype in sporadic inclusion body myositis (s-IBM): A population control study

“…The HLA-DRB1*0301 allele is strongly associated with the risk of developing autoimmune inflammatory myopathies in Caucasians (Arnett et al, 1996;Rider et al, 1998;O'Hanlon et al, 2005) and with autoantibodies, particularly the antisynthetases (Hausmanowa-Petrusewicz et al, 1997;Chinoy et al, 2006;Selva-O'Callaghan et al, 2006;Limaye et al, 2012) but previous studies have included few patients with s-IBM. We have previously reported a strong association with HLA-DRB1*03 in an Australian s-IBM cohort, as well as a correlation with age at onset and disease severity (Needham et al, 2008;Mastaglia, 2009).…”

“…Our findings confirm that there is a higher than expected incidence of nonspecific AAb such as ANA and antibodies to the nuclear antigens Ro-52, Ro-60, La and RNP, but not of organ-specific AAbs such as anti-TPO or anti-tTg or of the MSAs. Previous studies in American, Dutch and South Australian s-IBM cohorts have reported frequencies of MAAs of up to 43% of cases but the significance of these findings is uncertain as none of these studies included a population control group (Love et al, 1991;Koffman et al, 1998;Brouwer et al, 2001;O'Hanlon et al, 2006;Limaye et al, 2012). In other AAb studies, selected healthy individuals or patients with other neurological disorders were used as controls and patient and control sera were assayed in different laboratories.…”

“…Previous studies have reported nonspecific myositis-associated antibodies (MAA) in 17-43% of cases of s-IBM (Love et al, 1991;Koffman et al, 1998;Brouwer et al, 2001;O'Hanlon et al, 2005;Limaye et al, 2012) and low frequencies of myositis-specific antibodies (MSA) (Love et al, 1991;Hengstman et al, 2002;O'Hanlon et al, 2006). However, these studies did not compare the frequencies of AAb with population control frequencies and did not investigate organ-specific AAb such as anti-thyroid peroxidase (anti-TPO) and coeliac antibodies (e.g.…”

Levels of soluble adhesion molecules and their associations in inflammatory myositis

“…We have previously reported the diagnostic criteria employed to diagnose IIM. 6 The histological features recorded were the presence of polyphasic polyfocal muscle fibre necrosis with lymphocytic and macrophage myoinvasion, lymphocytic invasion of non-necrotic fibres, perivascular and interstitial lymphocytic infiltrates, up-regulation of major histocompatability complex (MHC)1 and 2, immune-staining for CD45 (lymphocytes) and CD68 (macrophages), vacuoles (rimmed and non-rimmed), perifascicular atrophy and basophilic fibre regeneration. Serum has been stored from a large number of patients.…”