I54. CLINICAL AND ACADEMIC IMPERATIVES FOR SERVICE DEVELOPMENTS AND MECHANICS OF HOW

Abstract

Treatments for the idiopathic inflammatory myopathies (IIM) are borrowed from other rheumatology conditions, and not surprisingly are frequently ineffective. Some patients thus die prematurely, while survivors often suffer persistent weakness and disability. Such failure reflects that IIM disease mechanisms remain elusive. However, due to the rarity of IIM, mechanistic research had proven difficult, e.g. prior to 2000 the largest candidate gene study comprised only ∼150 IIM cases, which were ethnically and phenotypically diverse. More meaningful IIM research thus required the generation of larger and homogeneous patient cohorts. To enable large-scale, UK-wide case recruitment this prompted initiation of the UK Adult Onset Myositis Immunogenetic Collaboration (AOMIC), later renamed UKMYONET. A European myositis collaboration (EUMYONET), and a collaboration with the USA (MYOGEN), followed. These international interactions permitted the first ever genome-wide association scans in polymyositis (PM) and dermatomyositis (DM). UKMYONET has correlated myositis phenotypes with myositis genotypes and serotypes, the latter made possible by the immunoprecipitation technique, used in collaborations with the Universities of Pittsburgh (Prof Chet Oddis) and Bath (Prof Neil McHugh). The results demonstrate a remarkable ability of such serology to predict an individual adult myositis patient's clinical phenotype, including the likelihood of extra-muscular complications and treatment responses. Anti-synthetases thus predict increased risk for interstitial lung disease but reduced risk for associated malignancies, anti-TIF1g and anti-NXP2 in adult DM cases predict increased risk for cancerassociated myositis, possession of anti-Mi-2 predicts hallmark DM which will be treatment responsive etc. In translational terms, knowledge of an individual patient's antibody status provides obvious clinical utility (e.g. guiding cancer screens, awareness of ILD, dysphagia risks, etc.). Many of the more common myositis-specific antibodies also have specific genetic associations with the Major Histocompatibility Complex. For instance, anti-Jo-1 associates with HLA-DR1∗03, anti-Mi-2 with HLA-DR1∗07, anti-MDA5 with HLADR1 ∗15, etc. As these antibodies are gene products, such associations have potential mechanistic implications, although yet to be elucidated. An immune-mediated necrotizing myopathy is a rare complication of statin use, and statistically associated with HLADR1 ∗11. HLA-1 molecules are manufactured on the inside of the endoplasmic reticulum (ER), and take protein waste to the cell surface, and HLA up-regulation is a recognized feature of myositis, including with statin use. Interestingly, the target of statin therapy, HMG-CoA reductase, also sits on the inside of the ER, alongside cytochrome P450. These enzymes will both be under polymorphic genetic control, so it is intriguing to speculate that interactions of their phenotypes and with HLA molecules and statins within the ER could cause problems. The many novel findings made by the collaborations listed emphasize their importance, and pose important mechanistic questions which, when answered, could facilitate the development of more effective novel therapies.