Workshop report119th ENMC international workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands
Introduction
Polymyositis (PM) and dermatomyositis (DM) are idiopathic inflammatory myopathies (IIMs) with an autoimmune pathogenesis. Typical features are subacute-onset, proximal, symmetric muscle weakness, elevated serum creatine kinase (CK) activity, and mononuclear cell infiltrates in the muscle biopsy [1], [2]. In addition, patients with DM have characteristic skin abnormalities. PM and DM occur isolated or in connection with a connective tissue disease (CTD) or with cancer [1], [2]. High-dose prednisone is the treatment of first choice on an empirical basis; its effect has not been investigated in a randomised controlled trial (RCT) [2], [3], [4]. If this treatment fails (because of too small an effect, repeated relapses, or unacceptable side effects) various second line treatments are in use, but most of these have not been appropriately investigated [2], [3], [4]. Despite current therapies, outcome is poor in many patients [5], [6]. New drugs are emerging, but improvements in treatment are hampered by difficulties in the design of trials and the low incidence and prevalence of patients. Therefore, the need for consensus on trial design and for conditions allowing the enrolment of patients in trials in a timely manner is urgent.
Twenty-one neurologists, rheumatologists, and statisticians from Belgium, Czech Republic, France, Germany, Italy, The Netherlands, Spain, Sweden, UK, and USA assembled in Naarden, the Netherlands, aiming at two goals. The first was to make progress towards reaching consensus on main issues in the design of RCTs for PM and DM, notably classification criteria and outcome measures. This was addressed by first reviewing and discussing the design and conduct of past RCTs, and pinpointing specific difficulties. Subsequently, we discussed proposals concerning each of these issues. The second aim was to explore the possibilities of international RCTs.
Section snippets
Classification criteria
In almost all past RCTs, the Bohan and Peter diagnostic criteria were used for the inclusion of patients. Marianne de Visser explained how these criteria conflict with more recent insights in the pathogeneses of PM and DM.
In 1975, Bohan and Peter formulated the following elements for the diagnosis of PM and DM [7]: (1) symmetrical weakness of limb-girdle muscles and anterior neck flexors, progressing over weeks to months, with or without dysphagia or respiratory muscle involvement; (2)
Classification criteria
Tony Amato proposed new classification criteria for the IIMs, which he designed on behalf of the Muscle Study Group (MSG). These criteria distinguish the following categories: (1) inclusion body myositis; (2) polymyositis; (3) dermatomyositis; (4) non-specific myositis (in patients with non-specific perimysial/perivascular infiltrates, but without features diagnostic of PM or DM); and (5) immune-mediated necrotizing myopathy (if there is no inflammatory infiltrate). PM, DM, non-specific
New treatments, ongoing randomised controlled trials, international collaboration
Ingrid Lundberg gave an overview of treatments of interest to be investigated in future RCTs. She illustrated how current insights in the immunopathogenetic pathways (see for reviews Refs. [2], [44]) can form a rationale for more targeted treatment. For instance, overexpression of tumor necrosis factor α (TNF-α) can be blocked by the TNF-α antagonists infliximab and etanercept, and overexpressed interleukin-1 can be blocked by an interleukin-receptor antagonist. Promising effects of infliximab
Conclusions
Animated discussions during this workshop clarified different points of view, and constructively resulted in a proposal for improved classification criteria designed by Tony Amato, and adjusted to the consent of all participants. These classification criteria will allow the accurate exclusion of other diseases and the differentiation of myositis types with anticipated different pathogenesis, while at the same time these criteria are considered to be broadly applicable in clinical trials.
Acknowledgements
This workshop was made possible by the financial support from the European Neuromuscular Centre (ENMC) and its main sponsors and associated members: Association Française contre les Myopathies (France), Deutsche Gesellschaft für Muskelkranke (Germany), Telethon Foundation (Italy), Muscular Dystrophy Campaign (UK), Muskelsvindfonden (Denmark), Prinses Beatrix Fonds (The Netherlands), Schweizerische Stiftung für die Erforschung der Muskelkrankheiten (Switzerland), Österreichische Muskelforschung
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Mediator of the European Neuromuscular Centre (ENMC) Clinical Trial Network.