Assessment, Therapy and Prevention Of Autoimmune Disease

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

We are focusing on the idiopathic inflammatory myopathies (IIM), or the myositis syndromes, as prototypic autoimmune diseases from which principles may be applied generally to other autoimmune diseases. Myositis is associated with substantial lifelong morbidity and mortality. Their treatment is unsatisfactory in many cases and drug efficacy evaluation is hampered by the lack of reliable and standardized measures of disease outcome. Few therapies have been studied in randomized controlled clinical trials. Because of the lack of consensus on how to best assess disease in myositis, new disease assessment tools are being developed and validated to apply to both children and adults with myositis. We have led a multidisciplinary collaborative group of >600 adult and pediatric specialists with interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS), to assist in this project. IMACS aims standardize the conduct and reporting of clinical studies in the IIM. Achieving these goals should enhance the consistency by which clinical trials are performed, improve the capacity to compare different treatments, and encourage development of promising novel therapeutic agents. Therapeutic studies of novel biologic agents are in progress and others are being planned to utilize these outcome measures in prospective trials. Together, and with input from the FDA and the European regulatory bodies, and with collaboration with Pediatric Rheumatology International Trials Organization (PRINTO), IMACS has: 1) developed and validated new tools to assess myositis disease activity and damage; 2) achieved consensus on core set outcome measures to comprehensively assess disease activity; 3) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM; 4) developed a clinical trial and outcomes data repository to allow us to reassess and revise IMACS tools; 5) developed new ACR-EULAR approved response criteria for polymyositis (PM) and dermatomyositis (DM) in adults and children that should result in more sensitive endpoints and fewer subjects needed for future clinical trials; and 6) in collaboration with other myositis researchers and consortia, have defined new classification criteria for adult and juvenile myositis which are provisionally approved by EULAR-ACR and should result in broader agreement on the inclusion of subjects in future clinical studies and trials. We have created a website to consolidate all IMACS activities, member lists, educational materials, presentations, assessment tools, and ongoing collaborative initiatives and studies (https://www.niehs.nih.gov/research/resources/imacs/index.cfm). We developed response criteria for juvenile and adult DM and PM, using candidate response criteria derived from natural history data and a conjoint analysis survey. These were further validated using data from the PRINTO trial of prednisone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis trial. Consensus was reached for a conjoint analysis-based continuous model, using absolute per cent change in core set measures to determine minimal, moderate, and major improvement. The same criteria were chosen for adult DM/PM and JDM, with differing thresholds for improvement. These new response criteria had excellent performance characteristics in existing datasets and should be sensitive criteria that will provide a uniform approach for assessing treatment responses in future therapeutic and preventive clinical trials. These criteria are now approved by the American College of Rheumatology and European League Against Rheumatism. Work to validate these criteria demonstrates they perform consistently across multiple studies, supporting its use as an efficacy endpoint in future IIM therapeutic trials. The number of improving CSM and absolute percentage change in all CSM increased by improvement category. Almost all patients with at least minimal improvement by the response criteria had improvement in muscle-related measures and a majority had improvement in patient-reported outcomes. Patients with minimal improvement had worsening in a median of 0-1 measure, and most patients with moderate-major improvement had no worsening measures. Physician assessment of change agreed moderately to substantially with MRC improvement categories. Growing differences among specialties in how the IIM and their major subgroups are defined has led to difficulties in comparing findings from multiple research studies. New classification criteria for IIM with readily assessable measurements and symptoms have been developed that generally show superior performance compared with existing criteria. These criteria use a model system with differential weights for the clinical and laboratory variables, and a classification tree approach to the sub-classification of clinical subgroups of myositis. These criteria have been accepted by the American College of Rheumatology-European League Against Rheumatism, and have been endorsed by international specialty groups. They employ easily accessible and operationally defined elements, and enable classification of "definite," "probable," and "possible" IIM, in addition to the major subgroups of IIM. These new classification criteria had excellent performance characteristics and should be sensitive criteria that will provide a uniform approach for assessing IIM patients in future clinical studies. The therapy of myositis is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. Given the poor outcomes of myositis patients with standard therapy, novel biologic anti-inflammatory agents, which have been shown to be safe and effective for other immune-mediated diseases and have rationale for use in myositis, are reasonable candidates for study and may represent important advances in the treatment of myositis. As part of the rituximab in myositis trial, we have identified changes in gene expression patterns in muscle and peripheral blood before (week 0) and after (week 16) therapy. We hypothesized that IFN and B cell signaling would be downregulated in muscle tissue in patients responding to therapy. Estrogen Receptor 1 (ESR1) gene expression was found to be differentially upregulated in responders and was also a miRNA target. Myotubes and DM muscle cells treated with rituximab in vitro also showed an increase in ESR1 gene expression and downregulation of sphingomyelinase-like phosphodiesterase 3b (SMPDL3B), which is upstream of ESR1 signaling and appears to be an alternative target for rituximab binding in muscle. An increase in ESR1 signaling is hypothesized to lead to decrease in NF-KB activation and inflammation and decrease in muscle damage. We are currently evaluating treatment responses for sodium thiosulfate as a novel therapy for moderate to severe calcinosis. In the first study to develop novel measures to assess calcinosis, we evaluated 31 DM/JDM patients with calcinosis using whole-body CT imaging. Using whole body CT imaging at low radiation doses, we identified five patterns of calcinosis, some of which were not detectable by traditional x-ray imaging. We collaborated with investigators in NIAMS and George Washington Univ. on treatment responses of JAK kinase inhibitors and abatacept therapy in patients with JDM. We have observed dramatic clinical improvement in treatment-refractory JDM patients following therapy with baricitinib (compassionate use pilot study) and abatacept, including documented improvement in muscle inflammation. With abatacept, 9 of 10 patients achieved the the IMACS response criteria, most with major response. Clinical improvement correlated with change in IFN genes and IFN-related chemokines.