119th ENMC international workshop: Trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands

Article Outline

• 1. Introduction
• 2. Difficulties in the design of trials for polymyositis and dermatomyositis
  • 2.1. Classification criteria
  • 2.2. Measuring outcome
• 3. Proposals for improving trial design for polymyositis and dermatomyositis
  • 3.1. Classification criteria
  • 3.2. Measuring outcome
• 4. New treatments, ongoing randomised controlled trials, international collaboration
• 5. Conclusions
• Acknowledgements
• appendix a. List of participants
• References
• Copyright

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1. 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.

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2. Difficulties in the design of trials for polymyositis and dermatomyositis 

2.1. 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) muscle-biopsy evidence of necrosis, phagocytosis, regeneration, perifascicular atrophy, inflammatory exudate, often perivascular; (3) elevation of skeletal-muscle enzymes in serum; (4) electromyography (EMG): short, small, polyphasic motor units, fibrillations, positive sharp waves, insertional irritability, high-frequency repetitive discharges. DM was differentiated from PM only by the presence of typical dermatologic features. Exclusion criteria were a slowly progressive course and various neuromuscular disorders, which nowadays would also comprise inclusion body myositis (IBM). Patients were classified as either PM, DM, DM/PM associated with neoplasms, childhood DM/PM, or DM/PM associated with collagen-vascular disease. The Bohan and Peter criteria and classifications were important improvements at the time and have served clinicians and researchers very well for many years.

Subsequently, studies performed with detailed immunopathology have led to better histopathologic characterisation of DM and PM and more importantly have provided evidence for distinct pathogenic bases of these disorders [2], [8], [9], [10], [11], [12], [13], [14]. First in patients with DM skin abnormalities, muscle biopsies demonstrated inflammatory infiltrates, mainly CD4+ T-cells, macrophages and B-cells, which were confined to the perimysium, often around blood vessels, and perifascicular muscle fibre atrophy.

The earliest demonstrable histologic abnormality in DM is deposition of the C5b-9 complement membrane attack complex (MAC) on small blood vessels [9], [10], [11]. MAC precedes inflammation and other structural abnormalities in the muscle on light microscopy and is specific for DM. Other complement components (C3 and C9), IgM, and less often IgG are also deposited within the walls of intramuscular blood vessels. The subsequent necrosis of vessels results in a reduction in the capillary density (number of capillaries per area of muscle). These immunopathological studies have led to the current assumption that DM is a complement-mediated microangiopathy [2].

In contrast, in patients without a rash typical of DM (i.e. PM), muscle biopsies demonstrate mononuclear inflammatory cell infiltrates in the endomysium [2], [8], [12], [13], [14]. The inflammatory cells are composed predominantly of CD8+ T-cells and macrophages and are seen to invade non-necrotic muscle fibres that expressed major histocompatibility antigen type I (MHC I) on the sarcolemma. Thus, PM appears to be the result of a MHC I-restricted cytotoxic T-cell response against an (auto-) antigen expressed by muscle fibres [2].

The immunohistopathological abnormalities described above for DM and PM were proposed to be included in diagnostic criteria for PM and DM [2], [15], and have been utilized for the inclusion of patients in various studies trying to further elucidate the pathogenesis of the inflammatory myopathies [16], [17], [18], [19], [20], [21].

In a recent retrospective follow-up study into the applicability of clinical, laboratory, and histopathological features to diagnose patients with an idiopathic inflammatory myopathy excluding IBM, only nine of 165 patients (5%) showed the histopathological features of PM [22]. At follow-up examination, five of them had developed features indicative of IBM. DM was diagnosed in 59 patients (36%). In 97 patients (58%), a diagnosis of neither PM nor DM could be made: in 39% of the patients, the muscle biopsy showed a non-specific perimysial/perivascular localisation of the cell infiltrates, but no endomysial inflammatory cells surrounding and invading muscle fibres which would have allowed a diagnosis of PM, and no skin changes or perifascicular muscle fibre atrophy which would have allowed a diagnosis of DM. One quarter of these patients was diagnosed with a connective tissue disease (CTD) after onset of myositis. Nineteen percent of the patients had a prednisone-responsive necrotising myopathy, without inflammatory infiltrates in their muscle biopsy and without DM skin abnormalities.

These findings have several implications for the design of clinical trials. First, the majority of patients in this study would have been diagnosed as PM according to the Bohan and Peter criteria (because of the absence of skin features). In view of the differences in histopathology within this group it is conceivable that this group comprises patients with different immunopathogenesis [23]. This is important if drugs with more specific immunological actions are to be investigated in future RCTs. Secondly, applying Bohan and Peter's classification to newly diagnosed patients would be hampered by the fact that a considerable proportion of patients are diagnosed with a CTD or cancer sometime after onset of myositis. Thirdly, any attempt to perform a RCT in PM exclusively has to be regarded as unrealistic in view of the extreme rarity of these patients if PM is diagnosed based on the histopathological features. It was concluded that RCTs for myositis would benefit importantly from adjustments of the diagnostic criteria acknowledging new insights in immunopathogenesis.

2.2. Measuring outcome 

Ernest Choy presented the results of a review being prepared for the Cochrane library on immunosuppressant and immunomodulatory treatment for DM and PM. Only seven RCTs have been concluded and reported thus far [24], [25], [26], [27], [28], [29], [30]. All studies were small. Two RCTs were done in newly diagnosed patients. In one, no significant difference in muscle strength was detected comparing prednisone only with prednisone plus azathioprine [24], but non-blinded observations showed less disability in the latter group after 3 years [25]. In the other study, published in abstract form, methotrexate and azathioprine, both in addition to prednisone, had an equal effect on muscle strength, but methotrexate had a better side effect profile [26]. Four trials were done in treatment-resistant patients. Only one gave positive results showing that intravenously administered immunoglobulin had a better effect on muscle strength and function than placebo after 3 months [27].

The design of these RCTs differed considerably (Table 1). Four trials included both PM and DM patients, one trial was done in DM patients only, and the other in PM patients. Duration of treatment until final outcome assessment ranged from 1 to 3 years. Muscle strength was an outcome measure in five of the seven studies. In four, weakness was expressed as a summation of scores according to modifications of the Medical Research Council (MRC) grading system [31], but the selection and number of muscles tested was comparable in only two investigations [28], [29]. Outcome measures to assess disability or handicap were even more diverse and included a disability grading system designed by Rose and Walton [32], a modified Convery assessment scale [28], [33], the neuromuscular symptom scale [27], the Barthel index [34], a 0–10 rating scale for the global assessment by the patient, and timed walking tests. Their validity, sensitivity, and reliability for myositis have not been established, which hampers the interpretation of results. The large variation in outcome measures used makes it impossible to compare trial results and perform meta-analyses, which are important particularly in rare diseases such as PM and DM. It was concluded that there is a pressing need for consensus on the outcome measures to be used in trials.

Table 1. Aspects of design of published randomised controlled drug trials for the idiopathic inflammatory myopathies (except IBM)

MMT, manual muscle testing using MRC grading [25]; CK, serum creatine kinase level; MRI, magnetic resonance imaging.

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3. Proposals for improving trial design for polymyositis and dermatomyositis 

3.1. 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 myositis and immune-mediated necrotizing myopathy may occur as isolated conditions, or in association with a CTD or with cancer. The classification criteria are intended to allow a diagnosis based on pathogenesis, and so require histopathological investigation in all cases.

The muscle-biopsy criteria were the main subject of in-depth discussions focussing on the applicability in clinical trials. Some workshop participants feared that it would not be feasible to perform highly specialized histopathological tests in all centres interested to participate in clinical trials, which could lead to the unwanted exclusion of many eligible patients. They also felt that this approach could decrease the external validity of clinical trials, since patients included in trials diagnosed using the proposed criteria might not be comparable to patients diagnosed in routine clinical practice. Other participants argued that a diagnosis based on pathogenesis is mandatory because different pathogeneses could underlie differences in prognosis and response to targeted drugs. ‘Non-specific myositis’ and ‘immune-mediated necrotizing myopathy’ should therefore be diagnosed separately as long as their pathogenesis has not been clarified. They also stressed that ancillary investigations of the muscle biopsy are indispensable to accurately differentiate between myositis and other myopathies, notably certain muscular dystrophies and IBM. Obviously, a misdiagnosis of myositis in patients with a myopathy that will not respond to immuno-therapy would be particularly harmful for clinical trials.

As a result of these discussions, it was agreed that the improvement of classification criteria (allowing the accurate exclusion of other diseases, and based on the underlying pathogenesis) should not be entirely controlled by practical considerations. At the same time, however, new criteria should be broadly applicable in pragmatic clinical trials. Therefore, certain histopathological investigations with an as yet unlikely or uncertain added diagnostic value in every patient, notably immunophenotyping of lymphocytes and MHC-I staining, should not be required routinely for eligibility in trials.

Other aspects of the proposed criteria that were discussed concerned the distribution of weakness, serum CK elevation, EMG, and so-called ‘myositis-specific autoantibodies’ (MSAs). Some participants worried that not requiring proximal leg muscles to be more severely affected than the arms would lead to the erroneous inclusion of patients with other diseases, notably facioscapulohumeral muscular dystrophy, which may show large inflammatory infiltrates in the muscle biopsy. Others, however, mentioned that in myositis, especially if associated with a CTD, weakness may be most pronounced in the arms (always with neck flexor weakness).

Normal values for serum CK levels or activity were not defined, since these depend on the techniques used. It was noted, however, that normal values differ between the sexes (higher in men), and between ethnic groups (higher in blacks). With respect to EMG, it was noted that reliability has not been established, and that the interpretation depends on the skills of the electromyographer and the number of muscles tested. On the other hand, whereas this may hold true for myopathic muscle action potentials, spontaneous muscle fibre activity is an all-or-nothing phenomenon, easily detectable and interpretable in proximal (including paraspinal) muscles. With respect to MSAs, it was emphasized that their presence virtually excludes IBM and muscular dystrophies, but that sensitivity is only 20–25% [35]. Further, these antibodies are not specific for myositis, as they can be seen in patients without an inflammatory myopathy. Also, they have not as yet been demonstrated to be specific in regards to the subtype of inflammatory myopathy (e.g. DM, PM, non-specific myositis, or necrotizing myositis) defined by more up-to-date immunopathology. Determining MSAs may be useful for patient management, however, because of their association with lung involvement (e.g. Jo-1 antibodies) and other signs of systemic disease.

Finally, it was agreed that the diagnostic features and proposed classification criteria as shown in Table 2, Table 3 will be applicable in therapeutic trials and do justice to progress that has been made in understanding disease mechanisms in these disorders. It was stressed strongly that these criteria should be validated and tested for reliability in prospective studies in order to allow further improvements in the future. ENMC workshop participants expressed their interest in collaborating in such investigations.

Table 2. Components of classification criteria for the idiopathic inflammatory myopathies (except IBM), proposed by Anthony A. Amato, and approved by the MSG and this ENMC workshop

Table 3. Classification criteria for the idiopathic inflammatory myopathies, proposed by Anthony A. Amato, and approved by the MSG and this ENMC workshop

3.2. Measuring outcome 

Ingrid Lundberg presented ongoing research on behalf of the International Myositis Assessment and Clinical Studies (IMACS) Group. During the past few years, this group has been engaged in defining valid, sensitive, reliable, and feasible consensus outcome measures applicable in RCTs for PM/DM, following a highly structured procedure [36], [37], [38]. The first result was the development of a core set of measures determining disease activity covering the following six domains: (1) global disease activity by physician's assessment; (2) global disease activity by patient's/parent's assessment; (3) muscle strength; (4) physical function; (5) serum activity of muscle enzymes; and (6) extra-skeletal muscle disease activity. Currently, outcome measures to capture each of these domains have been specified or are under investigation. Manual muscle testing graded according to Kendall's 10-point scale [39], [40] (Table 4) was proposed for measuring muscle strength, and the Stanford Health Assessment Questionnaire (HAQ) [41] for measuring disability and handicap (physical function).

Table 4. Kendall's grading for manual muscle testing [39], [40]

Subsequently, IMACS researchers defined the minimal degree of change in each core set domain that is clinically meaningful. This has led to a proposed definition for minimal meaningful improvement [38]. For the assessment of disease damage, IMACS is currently investigating two tools: the Myositis Damage Index (MDI) and the MyoDam [37]. Disease activity and damage together result in health-related quality of life, which in adults, following IMACS' proposal, could best be measured through the Short-form 36 Health Status Questionnaire (SF36) [42]. Ingrid Lundberg [43] finally discussed the Myositis Activities Profile, a promising disease-specific tool capturing activity limitations of daily life, which has been developed by her group.

ENMC workshop participants welcomed IMACS' achievements with general approval, and further results are awaited with great interest. A few comments were made. Firstly, it was noted that any definition of improvement should equal the definition of responder. Likewise, absence of improvement should be considered as treatment failure (other definitions of treatment failure were not discussed). Secondly, the muscles proposed by IMACS to be tested in future RCTs do not include the iliopsoas muscle. This was generally felt undesirable by ENMC workshop participants, since this muscle sometimes is the only weakened muscle, and amongst the most severely affected. Ten muscles and muscle groups (Table 5) were then agreed on to be probable, most suitable for standard testing in future RCTs, adding up to a maximum score of 100 (normal strength) if tested on one (the dominant) side.

Table 5. Minimum muscle groups to be tested in RCTs for the idiopathic inflammatory myopathies (except IBM)

In the next session, Bryan Lecky lead a discussion concerning several other items that should be standardized if future RCTs are to be comparable, notably indications for initiating treatment, the duration of observation until final assessment, and the definition of relapse. It was decided that patients must have at least some degree of muscle weakness (as established by the physician), and disability/handicap to be eligible for a clinical trial.

It was proposed that an observation-time of 6 months is probably adequate to investigate treatment efficacy using improvement (responder) as primary outcome measure. Eventually, however, patients will be more interested in returning to normal muscle strength and resuming daily life activities than in achieving a certain minimal degree of improvement. (This holds especially true for newly diagnosed patients, since the effect size of the standard first-line treatment with prednisone is usually much larger than the IMACS definition of minimal clinically meaningful improvement). In RCTs aiming at investigating the eventual effect on muscle strength and disability/handicap, occurrence of relapses, and side effects, observation-time should probably be at least 12 months.

Dr Lecky proposed defining a relapse as a worsening of muscle strength following improvement (at least two Kendall points in at least two muscle groups), worsening of functional scale scores (HAQ, SF36), and increase of CK levels, to such degree that an increase in prednisone dose or change of medication is felt to be needed by the treating physician. All agreed in general with these criteria, but not all details were discussed.

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4. 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 have been reported in two newly diagnosed patients [45]. Tacrolimus, an inhibitor of CD4 T helper cell activation, was reported to be effective in eight patients with Jo-1 positive, refractory myositis with interstitial lung disease [46]. In IBM, anti-T-lymphocyte globulin (ATG) was found to have a possible favourable effect on muscle strength [47], but this treatment has not been investigated in the other IIMs. B-cell depletion can be induced by anti-CD20 antibody treatment with rituximab. A non-selective new drug is mycophenolate mofetil, a blocker of purine synthesis like azathioprine, found to be effective in uncontrolled observations in DM [48]. Other treatments that could be considered to be investigated in future are physical exercise (studied earlier in small numbers of patients [49], [50]), creatine supplementation, and anabolic steroids.

Michael Rose and Richard Hughes described how the ENMC Clinical Trial Network wishes to support international multicentre trials. Its programme is advertised on the ENMC website at www.enmc.org. The initial phase involves the completion of Cochrane systematic reviews, which are necessary before undertaking a randomised trial. The ENMC is willing to support clinical trial workshops, which will facilitate the preparation of trial grant applications. It will use its network to introduce principal investigators to potential collaborators. They suggested that future RCTs for rare diseases like myositis should preferably be designed for international conduct from the start.

Finally, all RCTs that are currently about to start, or are being conducted by ENMC workshop participants were listed (Table 6). Two of these appeared to be open to international collaboration: the SELAM trial and the PROMETHEUS trial. Those who are interested to participate are invited to contact the principal investigators of these studies. Dr Van Engelen will welcome participation in his uncontrolled pilot study on the effect of infliximab plus methotrexate.

Table 6. Ongoing and about-to-start RCTs for the idiopathic inflammatory myopathies (except IBM)

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5. 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. Workshop participants applauded the important results of IMACS on the development of valid, sensitive, and reliable outcome measures for RCTs in myositis, and had a chance to discuss several aspects with representatives of this group.

This was an enjoyable and fruitful workshop that will lead to new collaborations and will contribute significantly to the improvement of therapeutic RCTs for myositis in both Europe and North America.

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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 (Austria), Vereniging Spierziekten Nederland (The Netherlands), and ENMC associate member: Muscular Dystrophy Association of Finland.

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appendix a. List of participants 

Anthony Amato (Boston, MA, USA)

Enrico Bertini (Rome, Italy)

Jan De Bleecker (Gent, Belgium)

Patrick Cherin (Paris, France)

Ernest Choy (London, UK)

Baziel van Engelen (Nijmegen, The Netherlands)

Jessica Hoogendijk (Utrecht, The Netherlands)

Richard Hughes, ENMC Clinical trial Network Mediator (London, UK)

Isabel Illa (Barcelona, Spain)

Bryan Lecky (Liverpool, UK)

Ingrid Lundberg (Stockholm, Sweden)

Renato Mantegazza (Milan, Italy)

Isabelle Marie (Rouen, France)

Wolfgang Müller-Felber (Munich, Germany)

Carl-Detlev Reimers (Arnsdorf, Germany)

Michael Rose (London, UK)

Anthony Swan (London, UK)

Jiri Vencovsky (Prague, Czech Republic)

Marianne de Visser (Amsterdam, The Netherlands)

Gerrit Jan Weverling (Amsterdam, The Netherlands)

John Winer (Birmingham, UK).

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