Clinical and human leucocyte antigen class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis- specific autoantigen target, in UK Caucasian adult- onset myositis Z E Betteridge, 1 H Gunawardena, 1,2 H Chinoy, 3,4 J North, 1 W E R Ollier, 4 R G Cooper, 3 N J McHugh, 1,2 for the UK Adult Onset Myositis Immunogenetic Collaboration 1 School for Health, The University of Bath, Bath, UK; 2 Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK; 3 The University of Manchester Rheumatic Diseases Centre, Salford Royal NHS Foundation Trust, Salford, UK; 4 Centre for Integrated Genomic Medical Research, The University of Manchester, Manchester, UK Correspondence to: Professor N J McHugh, Royal National Hospital for Rheumatic Diseases, Upper Borough Walls, Bath, BA1 1RL, UK; neil.mchugh@rnhrd.nhs.uk ZEB and HG contributed equally to this work and are joint first authors. Accepted 30 September 2008 Published Online First 17 October 2008 ABSTRACT Objectives: Autoantibodies to a novel autoantigen small ubiquitin-like modifier activating enzyme (SAE) associated with dermatomyositis (DM) have previously been identified. The aim of this study was to establish the frequency of anti-SAE autoantibodies in a UK myositis cohort and investigate clinicoimmunogenetic associations. Methods: Clinical data and sera were studied from 266 patients recruited to the Adult Onset Myositis Immunogenetic Collaboration. Myositis sera, control sera including 250 patients with other connective tissue diseases and 50 healthy participants were screened using radio-immunoprecipitation. Immunodepletion was per- formed on all sera immunoprecipitating 40 and 90 kDa bands to confirm the presence of anti-SAE. DNA from 202 patients with myositis was genotyped for human leucocyte antigen (HLA)-DRB1 and DQB1; DQA1 data were inferred. Results: Out of 266 patients with myositis, 11 (4%) were positive for anti-SAE, which was found exclusively in DM with a frequency of 8%. Patients with anti-SAE had a high frequency of cutaneous lesions including heliotrope (82%) and Gottron rash (82%). Of the 11, 9 (82%) had systemic features and 7 of 9 (78%) developed dysphagia. Of those nine, seven (78%) presented with skin disease before myositis onset. All patients with anti-SAE possessed at least one copy of HLA-DQB1*03. HLA-DRB1*04- DQA1*03-DQB1*03 was a significant risk factor in anti- SAE positive versus patients who were anti-SAE negative (haplotype frequency 18% vs 6%, p,0.001, OR 5.7, 95% CI 1.9 to 17.3). Conclusions: Anti-SAE is a myositis-specific autoanti- body that identifies a subset of patients with adult DM. The majority of patients with anti-SAE presented with cutaneous disease and progressed to myositis with systemic features including dysphagia. This novel auto- antibody has a strong association with the HLA-DRB1*04- DQA1*03-DQB1*03 haplotype. There is increasing evidence that myositis-specific autoantibodies (MSAs) are associated with specific clinical phenotypes within the idiopathic inflam- matory myopathy (IIM) spectrum. MSAs directed against components found in the nucleus and the cytoplasm with specific cellular functions, are being detected with increasing frequency. To date, several MSAs have been described including the anti-aminoacyl tRNA synthetases (anti-synthetase autoantibodies (ASAs)), anti-signal recognition particle (SRP), anti-Mi-2 and most recently anti- p155(/p140). 1 The association of ASAs with anti- synthetase syndrome (ASS), including a high frequency of interstitial pneumonia, is well recog- nised. 2 Anti-SRP autoantibodies have been detected in patients with severe necrotising myositis which may be refractory to treatment. 3 Anti-Mi-2 and anti-p155(/p140) autoantibodies have both been found in dermatomyositis (DM) in patients with hallmark cutaneous disease and anti-p155(/p140) is associated with cancer in adult DM. 4–8 Furthermore, the type of MSA appears to be associated with distinct human leucocyte antigen (HLA) class II haplotypes. 9 This highlights the importance of the association between genotype, serotype and clinical phenotypes in IIM. Classifying patients into syndromes based on immunogenetic and serological profiles may lead to a more targeted clinical approach and therefore has prognostic implications. The formation of the Adult Onset Myositis Immunogenetic Collaboration (AOMIC) (for details see Chinoy et al 9 ) has facilitated the collection of clinical data and biological samples from a large UK Caucasian cohort of patients with IIM to further investigate genetic and serological markers in IIM. Our group has recently described a novel MSA that targets small ubiquitin-like modi- fier activating enzyme (SAE). 10 The target auto- antigen SAE is involved in post-translational modification of various proteins by a process termed sumoylation. In this study, we report the prevalence, clinical and immunogenetic associa- tions of patients with IIM with anti-SAE. PATIENTS, MATERIALS AND METHODS Patients and sera The AOMIC registry has recruited UK Caucasian patients with adult-onset myositis, 18 years or over at disease onset, from hospitals around the UK. All patients had probable or definite myositis accord- ing to the Bohan and Peter diagnostic criteria. 11 12 A standardised proforma, including demographic and clinical data, was used throughout. Cancer-asso- ciated myositis (CAM), defined as cancer occurring within 3 years of diagnosing myositis (as per the modified Bohan and Peter classification used in a previous study) 6 was confirmed by the local Extended report Ann Rheum Dis 2009;68:1621–1625. doi:10.1136/ard.2008.097162 1621