International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis activity and damage indices in patients with adult onset disease

D. A. Isenberg1, E. Allen2, V. Farewell6, M. R. Ehrenstein1, M. G. Hanna3, I. E. Lundberg8, C. Oddis9, C. Pilkington4, P. Plotz10, D. Scott5, J. Vencovsky12, R. Cooper7, L. Rider11 and F. Miller11 for the International Myositis and Clinical Studies Group (IMACS){dagger}

1Centre for Rheumatology, Department of Medicine, The Middlesex Hospital, 2Department of Statistical Science, 3Institute of Neurology, 4Department of Paediatric and Adolescent Rheumatology, University College London, 5King's College Hospital, London, 6MRC Biostatistics Unit, Institute of Public Health, University of Cambridge, 7Rheumatic Diseases Centre, Hope Hospital, Salford, UK, 8Rheumatology Unit, Department of Medicine, Karolinski Hospital, Karlolinska Institutet, Stockholm, Sweden, 9Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 10Arthritis and Rheumatism Branch, NIAMS, 11Environmental Autoimmunity Group, Office of Clinical Research, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA and 12Institute of Rheumatology, Prague, Czech Republic.

Correspondence to: D. A. Isenberg, Centre for Rheumatology, Department of Medicine, The Middlesex Hospital, University College London, 4th Floor, Arthur Stanley House, 40–50 Tottenham Street, London W1T 4NJ, UK. E-mail: d.isenberg{at}ucl.ac.uk

Abstract

Objective. To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM).

Methods. An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis.

Results. The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training.

Conclusions. The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.

KEY WORDS: myositis, disease activity assessment, damage assessment

In the past 15 yr there have been several international attempts to define validated disease activity and damage indices to assess patients with systemic lupus erythematosus [reviewed in 1]. These have been welcome developments following several decades during which some 60 disease activity indices, neither validated nor compared, had been described [2]. These attempts brought considerable order to what had become an increasingly chaotic situation. We now describe an attempt to extend many of the concepts used in the assessment of patients with lupus to those with myositis.

Idiopathic inflammatory myopathies are usually regarded as a heterogeneous group of autoimmune rheumatic diseases defined by criteria which incorporate clinical features, serological abnormalities, electromyographic changes and typical histological appearances [3]. Dermatomyositis and polymyositis may affect children and adults and, although rare, are now widely recognized as a major cause of disability which, thanks to the introduction of immunosuppressive drugs, is often treatable, at least to some extent [reviewed in 4]. The first attempt to collect patients with myositis that was published suggested that myositis was frequently associated with premature mortality [5]. Although there has never been an adequate double-blind controlled trial of corticosteroids, it seems certain that these drugs, in spite of all their many side-effects, have substantially improved the outcome of patients with inflammatory muscle disease. Nevertheless, neither steroids on their own nor steroids in conjunction with a variety of other immunosuppressive drugs, including azathioprine, methotrexate, cyclosporin, cyclophosphamide and mycophenolate, have the capacity to induce full remission in every case. Likewise, other modalities, including intravenous immunoglobulin, total body irradiation and thoracic drainage, have either not been adequately assessed in double-blind controlled trials or have been shown to be of limited benefit in trials of modest duration [4]. The many side-effects associated with immunosuppressive drugs remind the physician of the fine line that exists between undertreating the disease, leading to increasing muscle weakness, and overtreating it, which often results in serious morbidity. Furthermore, in our experience disease activity is not always reflected by the level of serum creatinine kinase (or other muscle enzymes). In order to assess more accurately the potential advantages and disadvantages of both conventional therapy and newer therapies as they are introduced (e.g. anti-tumour necrosis factor {alpha} drugs), there is an urgent need to have available validated and reliable tools which assess disease activity (meaning clinical features which have the capacity to be substantially improved or to return to normal) and damage (implying permanent change). There would clearly be a major advantage if clinical research groups were all using the same indices.

The initial meeting to begin a serious international dialogue about these issues in patients with myositis took place during the European Union League Against Rheumatism (EULAR) meeting in Glasgow in June 1999. Subsequently, following internet exchanges, a group of adult and paediatric specialists and patient support group leaders with expertise in the myopathies met in Oxford, UK in March 2000 to develop a core set of measures for assessing myositis outcomes for clinical trials. Development and consensus on the tools described here was achieved via Delphi methods by a multidisciplinary group of over 70 rheumatologists, neurologists, rehabilitation specialists and others, who constitute the International Myositis Outcome Assessment Collaborative Study Group (IMACS). Further meetings have taken place in San Francisco at the American College of Rheumatology meeting in November 2001, and two ‘real patient’ exercises have been conducted at the Centre for Rheumatology, Middlesex Hospital, University College London, in March 2001 and May 2002. We now describe sets of activity and damage indices which we believe have been at least partially validated (though ongoing studies remain to be completed) and can now be recommended for use in clinical trials. A more detailed review of the concepts that underpin our efforts to develop these indices has already been published [6].

Though muscle weakness is clearly the principle clinical feature evident in patients with myositis, other organs or systems which may be involved include articular, cardiac, pulmonary, gastrointestinal and cutaneous. The numbers of patients with these extramuscular features varies considerably, from <10% with major gastrointestinal involvement to 100% with dermatological disease (in patients with dermatomyositis). However, in some patients the extramuscular features may be the predominant clinical feature. Thus, we have attempted to capture both activity and damage in each of these organs or systems.

As indicated above, we have sought to define ‘disease activity’ essentially as a reversible process due to inflammatory change, whereas ‘damage’ implies persistent/permanent change in anatomy, physiology, pathology or function which is considered to be present if it occurs after the diagnosis of the disease. In the tools we now describe, as in the damage index introduced for patients with lupus, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index [7], no attempt is made to ascribe the damage to a particular cause. This decision was made deliberately as permanent change may be due solely to prior disease activity, the complications of therapy, or other concomitant conditions. However, very frequently it is difficult to be certain what was the primary or sole cause of the damage. The utility of a relatively simple damage index which merely records the items of damage has been amply demonstrated in three recent studies of patients with lupus, in whom the early acquisition of damage in the first 1 or 2 yr following diagnosis is a very powerful prognostic marker [810].

The criteria we have used for selecting the particular items to be included in the indices we now describe have been discussed in detail at the meetings described previously and also by internet exchanges of the IMACS.

Methods

Assessment of myositis disease activity
Myositis disease activity was measured by two somewhat overlapping tools, the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scales (MYOACT). Both indices take a comprehensive approach to information capture and evaluate the presence and extent of involvement in the constitutional, articular, cardiac, pulmonary, gastrointestinal, cutaneous and skeletal muscle organ/systems. These two indices may be considered to be complementary or stand-alone.

MITAX
This index is, in essence, a modification of the British Isles Lupus Assessment Group (BILAG) tool for assessing the disease activity of patients with lupus [11]. It is based on the principle of the physician's intention to treat. Each of the items included in this index has been carefully considered by the group. Individual clinical features, or combinations of features, which the group anticipate would lead to the prescription of large doses of corticosteroids and/or immunosuppressive drugs, define grade A, the most active score in each organ or system. For those patients with known disease activity which is evident but requires somewhat lower doses of immunosuppression and/or drugs such as antimalarials or topical steroids, sets of criteria were used to define a B grade. The C grade in each organ or system defines patients with mild, persistent activity. The D grade implies that the organ or system was once active but is no longer active, and the E grade indicates that the organ or system has never been active. The MITAX index provides a testable hypothesis and an ongoing study is collecting data to determine whether patients meeting the clinical criteria for grades A, B and C really do receive the treatment envisaged. The MITAX index, as used in the second patient exercise, is shown in Supplementary Material (available at Rheumatology Online). The physicians were asked to score MITAX on the basis of activity in the preceding 2 weeks.

MYOACT
The MYOACT consists of a series of 10 cm visual analogue scales (the higher the number the more active the disease) completed by the physician assessing the patients. The scales refer to disease activity in the constitutional, articular, cardiac, pulmonary, gastrointestinal, cutaneous and muscle organs or systems. The scales have been modified from those proposed for use in assessing vasculitis activity [12].

Assessment of myositis damage
The myositis damage index (MDI) is a comprehensive tool to assess the extent and severity of damage developing in different organs and systems. The MDI is composed of two portions. One portion counts the items of damage developing in different organs or systems. This portion is in essence a modification of the SLICC/ACR damage index [7]. The other portion, the myositis damage score (MYODAM), consists of a series of 10 cm visual analogue scales to quantitate the severity of damage in the same organ/systems. The MDI used in the second study is shown in Supplementary Material.

Real patient exercises
In both real patient exercises, the order of assessment was randomized according to a 7 x 7 Latin square design. For this design, the appropriate statistical model is additive, and any interaction between order, physicians or patients is identified with error.

During each of the patient exercises, the assessors (six out of seven of whom were the same in both exercises), who were provided with a one-page synopsis of the patient's history, were asked to complete both of the activity and both of the damage scores. During the first exercise the assessors were also asked to complete a formal assessment of muscle strength in the neck flexors, deltoid, biceps, wrist extensors, gluteus maximus, gluteus medius, quadriceps and ankle dorsiflexors. Prior to the first exercise, one of us (FM) demonstrated the preferred method of assessing these muscle groups on a patient with active myositis, using a scale of 0–10. Prior to the second exercise, two of us (DAI and FM) went through the activity and damage assessments on three myositis patients. The patients used in these teaching exercises were not included in the ensuing real patient studies.

The first exercise took place in March 2001, when seven adult patients with myositis (four females and three males; four with polymyositis and three with dermatomyositis) were assessed by seven physicians (six rheumatologists and one neurologist). Each consultation took up to 1 h.

Further discussion about the proposed activity and damage indices took place between the two real patient exercises. A number of minor changes were agreed and the versions used in the second exercise are shown in Supplementary Material. For example, the cardiac and pulmonary systems were considered together in the original MITAX tool but were separated for the second exercise.

During the second real patient exercise in May 2002, six adult patients (three males and three females, three each with polymyositis and dermatomyositis) were assessed by seven physicians (six rheumatologists and one neurologist). Two patients participated in both exercises. The consultations again lasted up to 1 h. Prior to attending the second exercise, the physician-assessors reviewed training materials, including paper patient profiles and real patient example cases of scoring global assessments, and MITAX, MYOACT and MDI; a cutaneous slide collection covering examples was also used. The patients who participated all gave their informed consent.

One patient failed to turn up for the second real patient exercise, which introduced some correlation between order and physician. However, given that in both the first and the second exercise variation due to order was very small, this correlation had minimal impact on the results.

Statistical considerations
In both real patient exercises a large number of outcomes were examined. Given that there is debate as to the suitability of measures of agreement, the choice of any one measure for all outcomes is problematic. However, for presentation purposes, a commonality in analysis may be useful. We have chosen to focus on the same two summary measures for all outcomes: an intraclass correlation coefficient (ICC) and the ratio of the estimates of the standard error attributable to the physicians to the standard error attributable to the patients themselves ({sigma}phys/{sigma}pat). Both are well defined for all outcomes, but the distributional properties are best understood for the more continuous measures. Although the numerical values must therefore be interpreted with some caution, they should provide qualitative guidance for the comparison of the behaviour of the different tools.

A three-way model appropriate for the Latin square design was used, and, following the approach of Shrout and Fleiss [13], an appropriate ICC with a 95% confidence interval was defined on the basis of physician, patient and error variation. The model used is equivalent to ICC as given by Shrout and Fleiss [13]. Although order was adjusted for in the analysis, it can be considered to be an artefact of the design and has not been incorporated into the ICC.

A 95% confidence interval was similarly defined for {sigma}phys/{sigma}pat, but no confidence interval is given in the results when the estimated value of {sigma}phys/{sigma}pat is 0.

Analysis of variance was used to estimate the variance components, under the assumption that patients and physicians were chosen randomly from larger populations. This assumption allows the results to be generalized beyond the physicians who took part in the real patient exercises.

For each tool, both summary measures are presented together, as it was felt that to assess the performance of a tool it is necessary to consider both its reliability and the level of physician agreement. Reliability, as measured here by the ICC, refers to the ability of a tool to differentiate between patients, whereas agreement, assessed here by the examination of the standard errors of measurement, refers to the level of agreement between the physicians. It is possible for a tool to have a high ICC, indicating that it differentiates well between patients, together with a high standard error of measurement attributable to the physicians, indicating poor agreement. Given a homogeneous population, it is also possible for a tool to have a low ICC, indicating poor ability to differentiate between patients, but a low standard error attributable to the physicians, indicating good agreement.

Both measures have been used to classify the results from both real patient exercises into three categories. For the purpose of this classification, we have considered an ICC > 0.65 as high, indicating that a tool differentiates well between the patients, and we have considered agreement among physicians to be high if {sigma}phys/{sigma}pat < 0.40. (These boundaries are arbitrary and have been based on an evaluation of the results of the experiments. They have been defined to ease classification of the results.)

The first category consists of those tools for which both the ICC is high and {sigma}phys/{sigma}pat is low, indicating that the tool is differentiating well between patients with a high level of physician agreement. These results have been categorized as GOOD.

The second category consists of those tools that demonstrate a good performance in only one of the two measures. These results have been categorized as GOOD*. Among these, when {sigma}phys/{sigma}pat is low, indicating a high level of agreement among the physicians, it appears that the low ICC is generally due to little or no variation among the patients, and these tools can be considered to be performing reasonably well. However, in this category, when the ICC is high, indicating an ability to differentiate between the patients, the high value of {sigma}phys/{sigma}pat indicates that there remained some variability among the physicians.

The third group consists of those tools for which both the ICC is low and {sigma}phys/{sigma}pat is high, indicating that the tool is not differentiating well between patients and there is a poor level of physician agreement. These tools have been classified as POOR.

Results

The results of the first and second London exercises are shown in Tables 1 and 2 respectively. It was not possible to estimate variance components for elements of tools for which there was little or no variability among the patients. No results are given for these.


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TABLE 1. Intraclass correlation coefficients and values of {sigma}phys/{sigma}pat with 95% confidence intervals from the first real patient exercise

 

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TABLE 2. Intraclass correlation coefficients and values of {sigma}phys/{sigma}pat with 95% confidence intervals from the second real patient exercise

 
In the first exercise with respect to disease activity assessment, the MITAX system seemed to work well with, perhaps paradoxically, only the assessment of disease activity in the muscle system exhibiting poor reliability and a low level of agreement among the physicians. The MYOACT assessments exhibited both poor reliability and a low level of agreement among the physicians in the global and skeletal assessments.

With respect to damage in the first real patient exercise, the total MDI performed poorly with respect to both reliability and agreement. The MYODAM index performed poorly with respect to reliability and agreement in the gastrointestinal, skeletal, muscle and global elements.

In the second real patient exercise, the MITAX system appeared in the main to lead to a high level of agreement between the physicians. However, both agreement and reliability were poor with respect to the constitutional element. The MYOACT assessments all appeared to exhibit a high level of agreement among the physicians. Overall, the results of the second exercise were generally better for both the MITAX and the MYOACT.

In the second real patient exercise, there was generally a high level of agreement among the physicians for the different components of the MDI. Only the skeletal and pulmonary MDI elements performed poorly with respect to both reliability and agreement. Skeletal assessment in the MYODAM index also performed poorly with respect to both reliability and agreement.

Discussion

With the improved overall outlook for patients with myositis and the prospect of new therapies being prescribed for these patients, there is an urgent need to achieve internationally accepted methods of disease assessment. Taking a lead from investigators interested in the outcome of patients with systemic lupus erythematosus [1, 2], we propose that, in order to assess the totality of the effect of a disease like myositis upon a patient, there is a requirement to develop disease activity, disease damage and patient perception measures. Although we did not focus on patient perception in this study, the use of Short-Form 36 (SF36) in a group of patients with myositis has been reported [14]. Given the wide use of SF36 in a variety of diseases (with readily available translations in many languages), it seems likely that this will prove to be the current gold standard for this measure.

In contrast, there are no agreed measures for assessing disease activity and damage. The work we now describe represents a concerted effort over a 3-yr period to establish a choice of measures to assess both disease activity and damage. The MITAX index, which is derived in concept from the BILAG lupus disease activity index, has been developed on the basis of the physician's intention to treat. It therefore provides a testable hypothesis, and an ongoing study involving centres in several countries is seeking to validate its use. However, the visual analogue scales which constitute the MYOACT index are more conventional and dependent upon the physician's grading of activity in the various organs and systems known to be involved in patients with myositis.

The MDI is, in essence, a modification of the SLICC/ACR damage index for lupus and its use will also need to be formally validated in future studies. The MYODAM index again relies upon a visual analogue assessment by a physician.

As described in this report, two real patient exercises involving patients selected to have a range of activity and damage were assessed by a group of interested rheumatologists and a neurologist. Following a training session prior to the first real patient exercise (using a separate patient), the manual muscle tests exhibited, in general, reasonable reliability and levels of physician agreement. The main areas of concern were the neck and wrist elements, where in particular physician agreement seemed poor. However, it was felt that the results for the manual muscle tests were generally satisfactory and the assessments were not repeated in the second exercise.

In general, the results of the second exercise did appear to have improved and showed that most of the tools appeared to be performing well. For example, the MYOACT showed POOR results for global and musculoskeletal in the first exercise but GOOD/GOOD* results in the second exercise. Lower ICCs generally occurred when there was little or no variation among patients, and in these cases the level of physician agreement was usually high, the standard areas of measurement attributable to the physicians being close to 0. With respect to activity, as already discussed, only the constitutional element of the MITAX performed poorly. However, it is likely that physicians using this system will need to consider carefully whether the muscle weakness they observe represents activity or damage or some element of both.

The major area of concern with respect to damage was in the skeletal system as measured by both MDI and MYODAM. This outcome was a little surprising, given the clear-cut nature of the clinical features required to be scored or assessed as damage in the system.

We are aware that the number of patients we have studied is relatively small. With additional patients, we would have obtained more precise estimates with smaller confidence intervals of the measures we now describe. However, as this was a preliminary study limited by practical considerations, we felt that that numbers were sufficient to indicate adequate agreement.

We do not imagine that we have created the perfect tools to assess patients with inflammatory muscle disease. We do, however, hope that our current proposals will provide a useful start for investigators interested in myositis. Equally clearly, training will be required in the use of these instruments and this necessity should be anticipated by investigators wishing to use them in clinical trials or long-term observational studies.

In conclusion, we believe that much progress has been made in a short time in developing activity and damage tools for assessing patients with myositis. We propose that those interested in assessing patients, either as part of long-term outcome studies or in a drug trial, should use one or both of the activity and damage measures we now describe. These tools, which are now undergoing further validation testing, should enhance the consistency and reliability of assessment in patients with myositis.

Appendix A

Members of the International Myositis Assessment and Clinical Studies Group (IMACS) who participated in the development of these assessment tools include:

Elizabeth Adams, Bethesda, MD; Helene Alexanderson, Stockholm, Sweden; Nancy Armentrout, Harrisonburg, VA; Zohar Argov, Jerusalem Israel; Richard Barohn, Dallas, TX; Suzanne Bowyer, Indianapolis, IN; Hermine Brunner, Cincinnati, OH; Ruben Burgos-Vargas, Mexico City, Mexico; Jeffrey Callen, Louisville KY; Gail Cawkwell, New York, NY; Patrick Cherin, Paris, France; Yuen-Li Chung, London, UK; Hanna Chwalinska-Sadowska, Warsaw, Poland; Robert Cooper, Manchester, UK; Mary Cronin, Milwaukee, WI; Katarina Danko, Debrecen, Hungary; Joyce Davidson, Liverpool, UK; Peter Dent, Montreal, Canada; Elizabeth Dugan, Washington, DC; Brian Feldman, Toronto, Canada; Richard Finkel, Philadelphia, PA; Ignacio Garcia de la Torre, Guadalajara, Mexico; Ekkehard Genth, Aachen, Germany; Edward Giannini, Cincinnati, OH; Gerald Hengstman, Nijmegen, The Netherlands; Jeanne Hicks, Bethesda, MD; Adam Huber, Halifax, Canada; Hans-Iko Huppertz, Bremen, Germany; Lisa Imundo, New York, NY; Kent Johnson, Rockville, MD; Joseph Jorizzo, Winston-Salem, NC; Lawrence Kagen, New York, NY; John Kissel, Columbus, OH; Marisa Klein-Gitelman, Chicago, IL; Abraham Garcia Kutzbach, Guatemala City, Guatemala; Bianca Lang, Halifax, Canada; Marissa Lassere, Kogarah Australia; Carol Lindsley, Kansas City, KS; Daniel Lovell, Cincinnati, OH; Sue Maillard, London, UK; Peter Malleson, Vancouver, Canada; Alberto Martini, Genoa, IT; Thomas Medsger, Pittsburgh, PA; Kevin Murray, London, UK; Chester Oddis, Pittsburgh PA; Lauren Pachman, Chicago, IL; Amy Paller, Chicago, IL; Maria Perez, Houston, TX; Paul Plotz, Bethesda, MD; Dieter Pongratz, Munchen, Germany; Angelo Ravelli, Genoa, IT; Ann Reed, Rochester, MN; Robert Rennebohm, Columbus, OH; Nicolino Ruperto, Genoa, IT; Seward Rutkove, Boston, MA; Clyde Ryder, Birmingham, UK; Jean-Luc Senecal, Montreal, Canada; Georges Serratrice, Marseille, France; Jacques Serratrice, Marseille, France; David Sherry, Philadelphia, PA; Kumaraswamy Sivakumar, Phoenix, AZ; Yeong Song, Seoul, Korea; Richard Sontheimer, Iowa City IA; Ira Targoff, Oklahoma City, OK; Maria Turner, Bethesda, MD; Basiel van Engelen, Nijmegen, The Netherlands; Maria Villalba, Rockville MD; Kelly Vincent, London, UK; Victoria Werth, Philadelphia, PA; Patience White, Washington, DC; James Witter, Rockville, MD; Robert Wortmann, Tulsa, OK; Steven Ytterberg, Rochester, MN

Acknowledgments

We are grateful to the UK Myositis Support Group, whose support made the two workshops possible. JV was supported by the Czech Ministry of Health (No. 02378) and IEL was supported by Vardalstiftelsen and Swedish Rheumatism Association. We thank Drs Judy Beeler, Karen Farizo, Rachel Gafni, Ronald Gibson, Kristina Rother, Pamela Stratton and Glen Tamura for valuable input in defining the grading and glossary, and for assistance with specific items of the instruments within their areas of subspeciality expertise. We thank Drs Joan Mican and Robert Oglesby for critical reading of the manuscript.

Notes

{dagger}For a full list of contributing members see Appendix A. Back

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Submitted 12 December 2002; Accepted 2 May 2003