Immune mechanisms in chronic rheumatic muscle inflammation, myositis

The idiopathic inflammatory myopathies (IIM), shortly named myositis, is a group of heterogeneous and rare autoimmune diseases with the target tissue of skeletal muscle. It is not curable and affects the daily life of patients. The treatment of myositis is mainly glucocorticoids in combination with immunosuppressive agents. The incomplete response and common side effects of conventional treatment requires new therapies. The pathological mechanisms of myositis are still not known, however, it is widely accepted that both innate immunity and adaptive immunity contribute to the pathogenesis of myositis. T cells play an important role in the pathogenesis of myositis, which is also a promising target to develop novel treatment. The main aim of Project 1 and 2 was to investigate the effects of abatacept (CTLA4-Ig), a costimulatory modulator of T cells, on disease activity, expression of different molecules in muscle biopsies, and phenotypes of T and B cells in blood samples of adult patients with refractory dermatomyositis (DM) or polymyositis (PM). In this pilot study, we found that almost half of the DM and PM patients obtained improvement of disease activity after abatacept treatment and few side effects. The elevated number of FOXP3 Tregs in repeated muscle biopsies indicates a positive effect of treatment in muscle tissue. CyTOF technology requires a larger patient cohort for discovery research and for immune-monitoring if the patients are clinically heterogeneous. Furthermore, CD4/CD8 ratio in circulation at time of active disease may be a predictor of response to abatacept treatment in patients with DM and PM. Type І IFN is also thought to be an important pathway involved in the pathogenesis of patients with DM and PM. In Project 3, we found evidence to support our hypothesis that CD66b neutrophils express LL-37, which may stimulate BDCA2 pDCs to produce type I IFN (MxA) in muscle and skin samples of patients with DM and PM, regardless of short or long disease duration. The higher number of CD66b neutrophils and the association between neutrophils and MxA in patients negative for autoantibodies targeting RNA-binding proteins may suggest that our hypothesis is a potential alternative pathway to induce the elevated type І IFN in myositis patients without these autoantibodies. In project 4, we aimed to identify biomarkers in repeated muscle biopsies or blood samples, taken before and after conventional immunosuppressive therapy, to predict therapeutic response in patients with myositis. In this pilot study, we conclude that baseline biopsy, or monocyte profile did not predict long-term treatment response, but in the repeated biopsy taken within 1 year of immunosuppressive treatment, the lower number of macrophages (CD68) seemed to predict a more favorable long-term response with regard to improved muscle strength. Furthermore, T cells in muscle biopsies were not affected by the conventional immunosuppressive therapy. This may indicate that repeated muscle biopsies provide additional information to guide immunosuppressive treatment. In conclusion, our findings provide more information about effects of treatment and pathologic immune mechanisms of myositis and strengthen the critical role of innate and adaptive immune response in the pathogenesis of myositis by investigation from different perspectives, which may provide basis to develop novel and effective therapies for patients with myositis. LIST OF SCIENTIFIC PAPERS I. Tjärnlund A*, Tang Q*, Wick C, Dastmalchi M, Mann H, Tomasová Studýnková J, Chura R, Gullick NJ, Salerno R, Rönnelid J, Alexanderson H, Lindroos E, Aggarwal R, Gordon P, Vencovsky J, Lundberg IE. Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis. 2018;77(1):55-62. II. Quan Tang, Daniel Ramsköld, Olga Krystufkova, Herman F Mann, Cecilia Wick, Maryam Dastmalchi, Tadepally Lakshmikanth, Yang Chen, Jaromir Mikes, Helene Alexanderson, Adnane Achour, Petter Brodin, Jiri Vencovsky, Ingrid E. Lundberg, Vivianne Malmström. Effect of CTLA4-Ig (abatacept) Treatment on T cells and B cells in Peripheral Blood and Muscle Tissue of Patients with Polymyositis and Dermatomyositis. (Submitted manuscript) III. Lu X*, Tang Q*, Lindh M, Dastmalchi M, Alexanderson H, Popovic Silwerfeldt K, Agerberth B, Lundberg IE, Wick C. The host defense peptide LL-37 a possible inducer of the type I interferon system in patients with polymyositis and dermatomyositis. J Autoimmun. 2017;78:46-56. IV. Quan Tang, Karina R. Gheorghe, Xing-Mei Zhang, Eva Lindroos, Helene Alexanderson, Cecilia Wick, Mei Bruton, Cátia Fernandes-Cerqueira, Robert A. Harris, Inger Nennesmo, Ingrid E. Lundberg. Muscle biopsy features in repeated biopsies and response to treatment in patients with idiopathic inflammatory myopathy – a pilot study. (Manuscript) * Contributed equally