HLA class II and serological profiles of UK Caucasian patients with myositis overlapping with connective tissue disease

Background: The study objective was to characterise the serological and HLA class II genetic profiles of UK Caucasian patients with myositis overlapping with other connective tissue diseases (myositis/CTD-overlap). Methods: Seventy four Caucasians with myositis/CTD-overlap disease (16 males, 46.5 10 years) defined according to Bohan and Peter (Bohan and Peter, 1975), were compared to 537 randomly selected UK Caucasian controls. Patients and controls were genotyped at HLA-DRB1 and DQB1 using commercial kits, and DQA1 results then derived. The type of detectable circulating MSA (anti-Jo-1, PL-7, PL-12, EJ, OJ, KS, Mi-2, SRP) and MAA (U1/U3-RNP, Ku, PM-Scl) was established. Results: Patients were identified with the following primary diagnoses: 48 systemic sclerosis (SSc), 10 mixed connective tissue disease (MCTD), 7 Sjogren s syndrome, 7 systemic lupus erythematosus and 2 rheumatoid arthritis (RA). Seventy-one percent of the cohort had a defined MSA/MAA. The predominant Abs observed were anti-U1-RNP and anti-PM-Scl (see table). Eight of nine patients with anti-synthetase Abs possessed anti-Jo-1, most frequently found in the SSc group. Anti-PM-Scl, Ku and U3-RNP Abs were exclusively found in SSc. No cases with anti-SRP or Mi-2 Abs were observed. Both anti-Jo-1 and U1-RNP Abs were found in a patient with Sjogren s syndrome, but MSA/MAAs were otherwise absent in Sjogren s and RA patients. HLA-DRB1*03 was a strong risk factor for myositis/CTD-overlap disease (odds ratio [OR] 6.2, 95% confidence interval 3.5-11.2), SSc (OR 7.5, 3.6-16.2), anti-PM-Scl Abs (OR 46, 7.1-1922) and anti-synthetases (OR 8.9, 1.7-88.8). The other members of the 8.1 common ancestral haplotype (AH), DQA1*05 and DQB1*02, showed similar strength of association to DRB1*03. After allowing for the presence of anti-PM-Scl and the anti-synthetases, HLA-DRB1*03 was no longer a significant risk factor for SSc, but remained significant for myositis/CTD-overlap overall (OR 3.7, 1.9-7.4). Conclusions: MSA/MAAs are frequently found in myositis/CTD-overlap. HLA alleles comprising the 8.1 AH are significant risk factor in myositis/CTD-overlap. In SSc/myositis overlap, these associations are explained by the presence of anti-synthetase and anti-PM-Scl Abs, reinforcing the known strong link between HLA class II and MSA/MAAs, and that associations are stronger for defined serological subtypes than clinically defined myositis/CTD-overlap disease subtypes. Serological frequencies (n (%)) in myositis/CTD-overlap subgroups AutoAbs SSc MCTD SLE Sjogren s RA Total (n=45) (n=9) (n=7) (n=7) (n=2) (n=70) Jo-1 7 (15.6) 0 1 (14.3) 0 0 8 (11.4) OJ 0 0 1 (14.3) 0 0 1 (1.4) RNP 8 (17.8) 9 (100) 3 (42.9) 1 (14.3) 0 21 (30.0) Ku 3 (6.7) 0 0 0 0 3 (4.2) PM-Scl 19 (42.2) 0 0 0 0 19 (27.1) No detectable Abs 10 (22.2) 0 2 (28.6) 6 (85.7) 2 (100) 20 (28.6) Serology tested in 70 patients. Columns do not add up to totals due to presence of patients with multiple autoantibodies