Risk factors and outcomes in inflammatory myopathies

Abstract

Idiopathic inflammatory myopathies (IIM) are complex autoimmune diseases associated with high morbidity and mortality. Although knowledge about the pathogenic mechanisms underlying IIM is improving, limited data are available to inform clinical decision-making contributing to overall poor clinical outcomes in that population. The different projects in this thesis aimed to generate knowledge to help improve clinical outcomes in IIM and covered a wide range of topics related to outcome research namely risk factors, drug effectiveness, morbidity, mortality, and healthcare costs.

In study I, genetic predisposition to autoantibody development in IIM was studied using a large international cross-sectional study. Based on an unsupervised cluster analysis, eight autoantibody-defined IIM subgroups were identified, and associated with distinct HLA class II and I, supporting the incorporation of autoantibody profiles in future IIM classification projects.

In study II, based on a single center experience, significant improvement in physical function was found in anti-aminoacyl tRNA synthetase (ARS) positive patients but not in anti-ARS negative patients after exposure to one cycle of rituximab. Moreover, 78% of anti-ARS positive and 50% of anti-ARS negative patients achieved moderate/major ACR/EULAR improvement, supporting the effectiveness of rituximab in IIM.

In study III, using Swedish administrative databases, a 2.4-fold higher risk of acute coronary syndrome (ACS) was found in patients with IIM compared to the general population. When accounting for the competing risk of death, the cumulative incidence of ACS at 5 years was estimated at 7% in IIM compared to 3% in the general population, confirming the substantial cardiovascular burden in IIM.

In study IV, a modification effect of cancer on the association between dysphagia in early disease and mortality was demonstrated using an international IIM cohort. While dysphagia exposure in the absence of cancer was not associated with higher mortality risk, exposure to dysphagia in the presence of cancer was associated with a 5-fold higher mortality risk when compared to patients with IIM unexposed to dysphagia and cancer. This finding highlights the importance of stratification on cancer status when studying mortality in IIM.

In study V, annual healthcare costs in IIM were estimated using Swedish administrative databases and found to be 3 to 5-fold higher than the general population in the 5-year period following diagnosis. In addition to providing the first Swedish estimates of IIM healthcare costs, this study emphasized the significant contribution of indirect costs that accounted for 40 to 60% of the overall annual costs over the five-year period after IIM diagnosis.

Thus, the results generated by these studies demonstrate novel HLA associations with autoantibody-defined subgroups in IIM while supporting the effectiveness of B-cell depletion, confirming the increased cardiovascular risk, and shedding light on the relationship between dysphagia and mortality in IIM. These results, along with the comprehensive estimates of IIM healthcare costs, are valuable to define the orientation of future studies that will help bridge the therapeutic gap, reduce the cardiovascular burden, and improve cancer-associated management in IIM.