The assessment and therapy of autoimmune diseases are poorly studied. This is in part due to the rarity and heterogeneity of many of these disorders as well as the uncertainty of their pathogeneses. For this project, we are now focusing on the idiopathic inflammatory myopathies (IIM), also known as the myositis syndromes, as prototypic autoimmune diseases from which we hope that principles learned in these disorders may be applied generally to other diseases. The IIM are 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. Consequently, drug safety and efficacy data tend to be from small-uncontrolled, non-comparable clinical trials. No agents are currently licensed for the treatment of the IIM and few have been studied in randomized controlled clinical trials.
The aims of this project are to standardize the conduct and reporting of clinical studies of autoimmune diseases and to coordinate international efforts in this area in order to develop improved therapies. Because of the lack of consensus on how to best measure disease in the myositis syndromes, and to enhance recruitment of patients for other studies, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children. We have organized a collaborative group of over 100 adult and pediatric specialists with special interest in myositis, known as the International Myositis Assessment and Clinical Studies Group (IMACS) to assist in this project. The goals of IMACS are to develop and validate sensitive and efficient disease activity and damage measurement tools, define improvement criteria for use in clinical trials, develop consensus on a number of clinical trial design parameters and to assist in the conduct of multicenter clinical trials. 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 Rheumatology Working Group, 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 describe disease activity; 3) delineated preliminary definitions of improvement for use as clinical trial outcomes, which provide clinically meaningful change in combinations of the core set measures in a composite endpoint; and 4) developed international consensus guidelines on details of the conduct of multi-center therapeutic trials for adult and juvenile IIM. In terms of the development of definitions of improvement, the data sets used from therapeutic trials and natural history studies were the largest available in the world to derive these composite trial endpoints. These studies also used a combination of approaches, including traditional rules based on fixed per cent improvement in each measure, as well as classification and regression trees and logistic regression analyses. We have created a website to consolidate all IMACS activities, including member lists and contacts, educational materials, meeting presentations, references, assessment tools and ongoing and future collaborative initiatives and studies (https://dir-apps.niehs.nih.gov/imacs/). The therapy of the IIM is focused on immunosuppression to minimize effects from immune activation and rehabilitation to improve remaining muscle function. While most patients respond at least initially to corticosteroids, many have inadequate responses, and many more experience varying toxicities from the drug, which preclude its use. Although most studies have involved single referral centers reporting on small numbers of patients followed for relatively brief periods of time, we and others have attempted to define the safety and efficacy of a number of these forms of therapy in larger, prospective, randomized clinical studies. 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 IIM in the future. Our experience is that conducting therapeutic trials also greatly enhances recruitment to our other epidemiologic investigations. Infliximab is one of several anti-TNFa agents shown to be safe and effective for a number of immune-mediated diseases. It is a chimeric IgG1 kappa monoclonal antibody that neutralizes TNFa by binding with high affinity to the soluble and transmembrane forms of TNFa and inhibits binding of TNFa with its receptors. In collaboration with Paul Plotz, we have initiated a Phase 1-2 randomized, double-blind, placebo-controlled trial of infliximab in 28 patients with PM and DM. The goals of this study are to: 1) assess the safety and efficacy of intravenous infliximab in refractory patients receiving corticosteroids and another immunosuppressive agent; 2) determine the effective dose of infliximab in the therapy of PM/DM patients; and 3) perform gene expression profiling in muscle before and after therapy to help define pathophysiological cascades involved in the progression of these diseases and molecular signatures of responses to anti-TNFa therapy. Participants who have failed corticosteroids, and continue to have active disease on another immunosuppressive agent, are randomly assigned to receive either 3 mg/kg body weight of infliximab or a placebo. Four infusions are given prior to week 16, the primary outcome assessment time point, when muscle strength and other IMACS core outcome measures are assessed. Patients who improve with treatment will continue with the same dose for four additional infusions. Those who do not improve will be randomized to receive either 5 mg/kg or 10/mg/kg of infliximab for four more infusions. At 38 weeks, treatment with the experimental agent will be discontinued but prednisone and the other immunosuppressive agent will be continued at the same dose, and patients will be observed for an additional 30 weeks after the last infusion. Outcome assessments will be performed at weeks 0, 6, 16 and 40. Additional therapeutic studies are under consideration. The identification of environmental risk factors for autoimmune diseases offers the hope of preventing some of these disorders by exposure avoidance in genetically susceptible individuals. Investigations underway in our companion study - ES101074-04 DIR, Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease ? are focused on identifying environmental risk factors for autoimmune conditions and may offer such approaches to disease prevention. On example is our recent finding that ultraviolet radiation plays an important role in the development of dermatomyositis and related autoantibodies, as well as inducing flares in established disease. Therefore, studies to assess the efficacy of ultraviolet radiation avoidance in reducing dermatomyositis disease flares are now under consideration.
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| Abramowitz, Joel; Grenet, Dagoberto; Birnbaumer, Mariel et al. (2004) XLalphas, the extra-long form of the alpha-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex. Proc Natl Acad Sci U S A 101:8366-71 |
