Update on Outcome Assessment in Myositis

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Update on outcome assessment in myositis

Lisa G. Rider1*, Rohit Aggarwal2, Pedro M. Machado3, Jean-Yves Hogrel4, Ann M. Reed5, Lisa Christopher-Stine6 and Nicolino Ruperto7 Abstract | The adult and juvenile myositis syndromes, commonly referred to collectively as idiopathic inflammatory myopathies (IIMs), are systemic autoimmune diseases with the hallmarks of muscle weakness and inflammation. Validated, well-standardized measures to assess disease activity, known as core set measures, were developed by international networks of myositis researchers for use in clinical trials. Composite response criteria using weighted changes in the core set measures of disease activity were developed and validated for adult and juvenile patients with dermatomyositis and adult patients with polymyositis, with different thresholds for minimal, moderate and major improvement in adults and juveniles. Additional measures of muscle strength and function are being validated to improve content validity and sensitivity to change. A health-related quality of life measure, which incorporates patient input, is being developed for adult patients with IIM. Disease state criteria, including criteria for inactive disease and remission, are being used as secondary end points in clinical trials. MRI of muscle and immunological biomarkers are promising approaches to discriminate between disease activity and damage and might provide much-needed objective outcome measures. These advances in the assessment of outcomes for myositis treatment, along with collaborations between international networks, should facilitate further development of new therapies for patients with IIM.

Patient-reported outcome The idiopathic inflammatory myopathies (IIMs), comprising clinicians and researchers with a special measures also known as myositis, are a diverse group of auto interest in IIM, which include the International Myositis (PROMs). Measurements based immune diseases that are characterized by chronic Assessment and Clinical Studies Group (IMACS) and on information provided muscle inflammation and associated muscle weak the Paediatric Rheumatology International Trials directly by the patient (that is, ness. However, the IIMs are complex, systemic diseases Organisation (PRINTO)2, have developed standardized, the study subject) about the status of his or her health with skeletal muscle involvement and frequent mani well-validated assessment measures to evaluate these condition, without amendment festations in other organ systems, including the skin, constructs. In this Review, we discuss developments or interpretation of the patient’s joints and cardiopulmonary, gastrointestinal and con in the past few years in the assessment of IIM outcomes response by a clinician or stitutional systems. The most common forms of IIM and summarize the major tools available to clinicians and anyone else. are dermatomyositis, polymyositis and inclusion body researchers to evaluate the outcome of IIM treatment. Health-related quality of life myositis (IBM) in adults and dermatomyositis in chil (HRQoL). A multidimensional dren (juvenile dermatomyositis). To adequately evaluate Core set measures assessment of a subject’s health patients, assess their responses to therapies and track Core set measures (CSMs) are the minimum set of meas that includes domains related long-term outcomes, IIM researchers must assess the ures that are required to comprehensively assess disease to physical, mental, emotional and social functioning. HRQoL following constructs: disease activity, that is, the type, and that should be carried out and reported in all clinical goes beyond direct measures of extent and severity of reversible pathological manifes studies and therapeutic trials. International consortia of health, life expectancy and tations of IIM; disease damage, which includes persis collaborating IIM investigators have developed and val causes of death and focuses on tent changes from previously active disease (related to idated CSMs (TABLE 1) to assess disease activity in adult the effect that health status has on quality of life. scarring, atrophy or fibrosis), long-term complications patients with dermatomyositis or polymyositis (IMACS) of therapy or comorbid conditions; patient-reported and in children with juvenile dermatomyositis (IMACS outcome measures (PROMs), including patient reports and PRINTO)3. These measures are practical, well stand *e-mail: [email protected] about physical function and health-related quality of life ardized and reliable; they are easy to use in multicentre doi:10.1038/nrrheum.2018.33 (HRQoL); and objective measures, such as imaging international studies, they are applicable to all forms of Published online 12 Apr 2018 and biomarkers1. International collaborative groups IIMs, and they are well validated. The PRINTO CSMs

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Key points damage on growth and development, is also recom mended by the PRINTO for the assessment of damage • The primary assessment of myositis includes core set measures of disease activity and in patients with juvenile dermatomyositis4. disease damage and measures of patient-reported outcomes. The CSMs of disease activity and damage have been • A new composite myositis response criterion, which combines and differentially widely adopted not only by the IMACS and the PRINTO weights core set activity measures to determine minimal, moderate and major clinical but also by other groups12,13. Limitations of the CSMs response, has been developed and validated. include a lack of validation in patients with IBM and • Measures of muscle strength and function are being refined for myositis subgroups variations between specialists in assessments of strength and are being used as primary or secondary outcome measures in studies and clinical and function, as discussed below. trials in patients with myositis. • Disease-specific patient-reported outcomes, including health-related quality of life IIM response criteria measures that reflect patient perspectives, are being developed. Response criteria provide standardized measurements of • Imaging and immunological biomarkers provide objective measures that can changes in disease activity in response to a therapeutic discriminate disease activity from disease damage, but they still require validation in clinical trials. intervention and of the therapeutic efficacy of a treat ment14. The initial partially validated response criteria that were established for juvenile dermatomyositis and adult dermatomyositis or polymyositis included the pre Author addresses liminary definitions of improvement, which required 1Environmental Autoimmunity Group, National Institute of Environmental Health ≥20% improvement in a minimum of three of six CSMs Sciences, US National Institutes of Health, Bethesda, MD, USA. of disease activity to establish that patients showed a 2Department of Medicine, Division of Rheumatology and Clinical Immunology, minimal clinically meaningful improvement15,16. These University of Pittsburgh, Pittsburgh, PA, USA. preliminary response criteria were used successfully 3Centre for Rheumatology and MRC Centre for Neuromuscular Diseases, as primary end points in several therapeutic trials, University College London, London, UK. but they define only the minimal clinical improvement, 4 Institut de Myologie, GH Pitié-Salpêtrière, Paris, France. they were only partially validated, and they lacked 5Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA. 6 sufficient sensitivity and discriminatory validity in Division of Rheumatology, Department of Medicine, Johns Hopkins University School 6–10 of Medicine, Baltimore, MD, USA. randomized trials . 7Istituto Giannina Gaslini, Clinica Pediatria e Reumatologia, PRINTO, Genoa, Italy. The development of data-driven and consensus- driven conjoint analysis-based hybrid response criteria for adult patients with dermatomyositis or polymyositis of disease activity for juvenile dermatomyositis received and children with juvenile dermatomyositis, including provisional acceptance by both the ACR and EULAR3,4. quantitative assessment of improvement on a contin The IMACS CSMs have been recommended for use in uous scale and different thresholds for minimal, mod patients with IBM, although supporting validation stud erate and major improvement, marks a major advance ies are lacking, and therefore they are not universally in assessing the response to treatment in clinical trials 5 11 Biomarkers accepted for this subgroup . and studies of patients with IIMs . These composite Measurable indicators of The CSMs of disease activity are also responsive response criteria are based on weighted scores that are normal biological processes, to changes in disease activity, as demonstrated in sev applied to absolute percentage improvement in the six pathogenic processes or eral therapeutic trials in children with juvenile der CSMs (TABLE 2). The criteria were developed using data responses to an exposure or matomyositis and in adults with dermatomyositis or sets with many patients, novel conjoint analysis method intervention, including 6–10 17–21 therapeutic interventions. polymyositis . The minimal clinically meaningful ology , clinical trial validation and consensus among change in each disease activity measure has also been experts in adult and paediatric myositis who specialize in Core set measures established as ≥20% improvement for all IMACS or rheumatology, neurology or dermatology. These criteria (CSMs). The minimum set of PRINTO CSMs, except for ≥30% improvement in mus are now approved as the final IIM response criteria by validated assessments that are 22–25 recommended to be used in cle enzymes; moderate and major changes in CSMs of the ACR and the EULAR and are the same for adult 11 therapeutic trials and natural activity have also been defined . The relative importance and juvenile patients, although the criteria have different history studies. of each measure in assessing changes in disease activity thresholds to reflect the difference in responses between has been determined using conjoint analysis, which iden adults and children. Response criteria tified muscle strength as the most important measure, The 2016 ACR–EULAR IIM response criteria for A set of conditions, usually involving combinations of followed by physician global activity (PGA) and extra adult patients with polymyositis or dermatomyositis assessment tools, that define muscular activity for adult and juvenile patients with and children with juvenile dermatomyositis are hybrid clinically important dermatomyositis and adult patients with polymyositis11. criteria22–25, that is, the same criteria can be used either as improvement in disease One of the primary CSMs for disease damage, the a continuous outcome or as a categorical outcome. These symptoms and signs. These criteria allow investigators, Myositis Damage Index, has been validated for adult criteria generate a total improvement score (TIS; on a clinicians, regulators and dermatomyositis and polymyositis and for juvenile der scale of 0–100) that provides a quantitative measure of patients to determine the matomyositis and was used in several studies to assess improvement for each subject, which can be compared efficacy (or lack thereof) of a long-term outcomes and disease sequelae (reviewed between treatment arms using the mean or median therapeutic intervention, and elsewhere3). Other measures of disease damage include scores of all enrolled patients. The TIS is the sum of the they facilitate communication between these parties about physician global damage (on a 10 cm Likert scale), as well improvement in each of the six CSMs of disease activity, response to treatment by using as measures of physical function (TABLE 1). In addition, but the individual CSMs are weighted, such that CSMs the same metric. a measure of strength, as well as the effects of disease that are considered more important contribute more to

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Table 1 | Core set measures for disease activity and damage assessment for clinical studies and therapeutic trials in IIMs Domain Core set measures Included in the IMACSa core Included in the set measures for JDM and PRINTOa core set adult DM, PM and IBM4,126? measures for JDM1? Disease activity Physician global activity Physician global disease activity assessment by Likert or Yes b Yes b VAS Patient or parent global Patient or parent global disease activity assessment by Yes b Yes b activity Likert or VAS Muscle strength MMT on a scale of 0–10 points or on an expanded scale of Yes b Yes 0–5 points to include proximal, distal and axial muscles CMAS No Yes (preferred)b Physical function • Validated patient or parent questionnaire of activities of Yes b Yes b daily living (HAQ or CHAQ) • CMAS Laboratory assessment Elevated serum activity of at least two muscle-associated Yes b No enzymes among creatine kinase, aldolase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase Global disease activity, Myositis Disease Activity Assessment Tool to assess Yes b Yes including extramuscular extramuscular organs, including constitutional, disease activity cutaneous, skeletal, gastrointestinal, pulmonary and cardiac activity DAS No Yes (preferred) b Health-related quality of life CHQ–PF50 Physical Summary Score No Yes b Disease damage Physician global damage Physician global disease activity assessment by Likert or Yes Yes VAS Global damage tool Myositis Damage Index Yes Yes Physical function Validated patient or parent questionnaire of activities of Yes Yes daily living (HAQ or CHAQ) Muscle strength CMAS Yes Yes Growth and development Height and weight, menses and Tanner puberty stage Yes Yes Quality of life Health-related quality of life SF‑36 (adult) Yes No CHQ–PF50 Physical Summary Score Yes Yes CHAQ, Childhood Health Assessment Questionnaire; CHQ–PF50, Child Health Questionnaire–Parent Form 50; CMAS, Childhood Myositis Assessment Scale; DAS, Disease Activity Score; DM, dermatomyositis; HAQ, Health Assessment Questionnaire; IBM, inclusion body myositis; IMACS, International Myositis Assessment and Clinical Studies Group; IIM, idiopathic inflammatory myopathy; JDM, juvenile dermatomyositis; MMT, manual muscle testing; PM, polymyositis; PRINTO, Paediatric Rheumatology International Trials Organisation; SF‑36, Short Form‑36; VAS, visual analogue scale. See http://www.niehs.nih.gov/research/ resources/imacs/diseaseactivity/index.cfm for copies of the tools, glossaries, training materials and additional references. aIMACS criteria are recommended for adult and juvenile dermatomyositis, polymyositis and IBM, whereas PRINTO core set measures are recommended for juvenile dermatomyositis. bIncluded in the final core set activity measures used to develop the 2016 American College of Rheumatology and European League Against Rheumatism criteria for minimal, moderate and major improvement in adult dermatomyositis and polymyositis and juvenile dermatomyositis22,23. Modified from REF. 127, Elsevier.

the final score. For example, changes in the manual muscle Muscle strength and function measures testing (MMT) and PGA scores are weighted more heav Muscle weakness is the primary feature of the IIMs and ily than changes in the Health Assessment Questionnaire varies in location, severity and progression according (HAQ) or in the enzyme with the most abnormal to the phenotype and the patient27–31. Muscle weakness activity in serum. Continuous measures might allow results in functional limitations (disability) that can be for better statistical power (which is especially useful for assessed by standardized motor tasks or estimated by pilot studies) and have greater sensitivity to change26. questionnaires and scales. Although measures of muscle Manual muscle testing The criteria also provide categorical outcomes of min strength and function are part of the CSMs, additional (MMT). A method for assessing imal, moderate and major improvement, allowing the measures of strength and function have been examined the strength of individual proportion of patients who show a desired response to be to improve performance and measurement sensitivity, muscle groups on the basis of compared between treatment arms. However, these new cover aspects of disease that are not adequately assessed performing a movement in relation to the forces of gravity response criteria also have several limitations; most nota by CSMs and develop more appropriate measures that and manual resistance by the bly, they cannot be used for disease flare or remission are applicable to patients with IBM. The assessment of examiner. states (BOX 1). muscle strength and function requires adequate assessor

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Table 2 | 2016 ACR–EULAR criteria for minimal, moderate and major improvement in JDM and adult DM and PM Core set measurea Level of improvement (based on Improvement score absolute percentage change) Physician global activity Worsening to 5% improvement 0.0 >5–15% improvement 7.5 >15–25% improvement 15.0 >25–40% improvement 17.5 >40% improvement 20.0 Patient global activity or Parent global activity Worsening to 5% improvement 0.0 >5–15% improvement 2.5 >15–25% improvement 5.0 >25–40% improvement 7.5 >40% improvement 10.0 Manual muscle testing or Childhood Myositis Worsening to 5% improvement 0.0 Assessment Scale >2–10% improvement 10.0 >10–20% improvement 20.0 >20–30% improvement 27.5 >30% improvement 32.5 Health Assessment Questionnaire or Childhood Worsening to 5% improvement 0.0 Health Assessment Questionnaire >5–15% improvement 5.0 >15–25% improvement 7.5 >25–40% improvement 7.5 >40% improvement 10.0 Enzymeb or Child Health Questionnaire–Parent Worsening to 5% improvement 0.0 Form 50 Physical Summary Score >5–15% improvement 2.5 >15–25% improvement 5.0 >25–40% improvement 7.5 >40% improvement 7.5 Extramuscular activity or Disease Activity Score Worsening to 5% improvement 0.0 >5–15% improvement 7.5 >15–25% improvement 12.5 >25–40% improvement 15.0 >40% improvement 20.0 Improvement categories with total improvement scorec DM and PM improvement category thresholds Minimal ≥20.0 with total improvement scorec Moderate ≥40.0 Major ≥60.0 JDM mprovement category thresholds with total Minimal ≥30.0 improvement scorec Moderate ≥45.0 Major ≥70.0

DM, dermatomyositis; JDM, juvenile dermatomyositis; PM, polymyositis. aEither all the International Myositis Assessment and Clinical Studies Group (IMACS) or all the Paediatric Rheumatology International Trials Organisation (PRINTO) core set measures should be used. bThe muscle enzyme that has the most abnormal serum activity (among creatine kinase, aldolase, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase). cThe total improvement score is the sum of all six improvement scores associated with the change in each core set measure. Adapted with permission from REF. 22 and REF. 23, Wiley, and REF. 24 by permission from BMJ Publishing Group Limited [Aggarwal, R. et al., American College of Rheumatology/ European League Against Rheumatism criteria for minimal, moderate and major clinical response in adult dermatomyositis and polymyositis. Ann. Rheum. Dis. 76, 792–801, 2017] and REF. 25 [Rider, L. G. et al., American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in juvenile dermatomyositis. Ann. Rheum. Dis. 76, 782–791, 2017].

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Box 1 | Advantages and limitations of the 2016 ACR and EULAR response criteria for IIMs11,22–25 Advantages • Weighted measures are used, specifically, core set measures (CSMs) are scored according to their relative importance in defining disease activity • The use of continuous measures provides a total improvement score with a continuous degree of improvement • The response criteria provide categorical outcomes (minimal, moderate and major clinical response) • The criteria are hybrid in that the same criteria can be used either as a continuous outcome or as a categorical outcome • The response criteria do not require a minimal severity level at baseline for any CSM in a clinical trial of the idiopathic inflammatory myopathies (IIMs), and all levels of improvement in CSMs contribute to the response • The changes in response criteria are based on absolute percentage change rather than relative percentage change in CSMs, as the absolute percentage change might be more realistic and have better face validity • The same definition of improvement can be used for juvenile dermatomyositis and adult dermatomyositis and polymyositis, with different thresholds for minimal, moderate and major improvement, allowing therapeutic trials that include both children with juvenile dermatomyositis and adult patients with dermatomyositis or polymyositis • Either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) CSMs can be used to define improvement with the juvenile dermatomyositis response criteria Disadvantages • Some of the CSMs that the criteria are based on are subjective and evaluator dependent • Validation of the final criteria and thresholds for improvement was based on limited data • The threshold for a major response for adult dermatomyositis and polymyositis is preliminary: further data are needed to confirm the threshold • The criteria fail to differentiate between no change and a worsening of disease • The criteria cannot be used for disease flare or relapse • The criteria do not define remission • The criteria were developed for major clinical phenotypes (dermatomyositis, polymyositis and juvenile dermatomyositis); although there is no validation for other phenotypes (immune-mediated necrotizing myopathy or antisynthetase syndrome), the criteria are likely to work for these phenotypes as well • The criteria are difficult to use in everyday clinical practice without the use of a computer

training and patient participation to ensure optimal per is that scores from different muscle groups can be aggre formance. The choice of assessment tool should be based gated to generate composite scores that can be used to on the study population and on the goals of the study or gauge overall improvement or progression in both clin clinical trial. ical practice and therapeutic trials, which is not possi ble using absolute values of strength that are measured Muscle strength assessment measures. Muscle strength using dynamometers. can be measured by several techniques (TABLE 3), usually Muscle strength is increasingly being evaluated using in isometric conditions. MMT is the most commonly dynamometer-based methods, which are used primar used technique in the clinic, has been validated for ily in patients with IBM and other neuromuscular dis dermatomyositis, polymyositis and juvenile dermato eases and are rarely used in patients with polymyositis myositis3,27, is a CSM1,4 and has been used as a primary or dermatomyositis28,29. The clinometric properties of or secondary outcome measure in many therapeutic the measures depend on the metrological features of the trials in patients with IIM1,6–11. MMT has high practical dynamometer and on the operating procedures that ity and low time and equipment requirements, as well are utilized. One of the advantages of dynamometry is as adequate inter-rater and intra-rater reliability and that it is more objective and less examiner dependent validity when MMT is carried out by a trained exam than MMT. Combining the strength of different muscle iner32. The limitations of MMT include poor sensitivity groups is not consistent, however, owing to the diver to change as well as floor and ceiling effects in natural sity in their ranges. To calculate composite values, it is history studies3,27,33, although MMT has demonstrated necessary to express the primary data as a percentage good sensitivity to change in some clinical trials and of predicted values on the basis of patients’ age, weight, has also performed well in natural history studies1,6–8,10. height and/or sex (that is, normative data). Normative Furthermore, muscle strength assessed by MMT seems data exist for most of the muscle strength assessment to improve less than other CSMs in patients who are methods and for all age groups, including children, improving11. However, in two small therapeutic tri adolescents and adults (TABLE 3). Depending on the tech Dynamometers als of patients with dermatomyositis or polymyositis, nique, dynamometry might also have floor and ceiling Devices that measure muscle 29 strength during muscle MMT and fixed dynamometry (measured by maximal effects, although to a lesser extent than MMT . In IBM contraction, such as gripping, voluntary isometric contraction testing) had a similar trials, hand-held dynamometry and maximal voluntary pushing and pulling. responsiveness to change8,34. Another advantage of MMT isometric contraction testing (mostly using hand-held

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Table 3 | Methods of muscle strength assessment Manual muscle Hand-held Quantitative muscle Isokinetic Specific dynamometry testing dynamometry testing (fixed dynamometry dynamometry) Equipment

Practicality Very high High Moderate Moderate Moderate SpecificNature ReviewsNo | RheumatologyNature ReviewsYes | RheumatologyNature ReviewsYes | RheumatologyNature Reviews |Yes RheumatologyNature Reviews | YesRheumatology equipment and space required? Equipment cost None (as no Slightly expensive Moderately expensive Very expensive Slightly expensive specialized equipment required) Contraction Dynamic or static Isometric (make test) Isometric Isometric, isokinetic Isometric conditions (depends on patient’s or pseudo-isometric and isotonic abilities) (break test) Time to <1 <5 <5 5 5 administer (min per muscle function) Variable Ordinal score (grade) Best performance (kg) Best performance (kg) Best performance (Nm) Best performance (kg or Nm) Linearity? No Yes Yes Yes Yes Resolution Poor 0.1–1.0 kg 0.1–1.0 kg 0.5–1.0 Nm 0.001–0.100 kg Accuracy Limited 0.1–1.0% full scale 0.1–1.0% full scale 0.1–1.0% full scale 0.001–0.100% full scale Adapted to weak No No No Possibly Yes patients? Adapted to No No Yes Yes Yes strong patients? Normative data Not applicable Yes 128–130 Yes 131 Yes 132,133 Yes 134 exist?a Sensitivity to Poor in patients Moderate Moderate High High change with mild weakness; moderate in weaker patients Intra-rater Good Good to excellent Good to excellent Good to excellent Good to excellent reliability Inter-rater Moderate Moderate to Good to excellent Good to excellent Good to excellent reliability excellent Sensitivity to Yes Yes Yes No Depends on the device lever arm? Floor and/or Floor and ceiling Floor effect Floor effect Floor effect Limited ceiling effects effects Composite Yes No (except if No (except if No (except if expressed No (except if expressed scores? expressed as a expressed as a as a percentage of as a percentage of normal percentage of normal percentage of normal normal values) values) values) values) Use in IIM IMACS core set Adult PM and IBM35,39,138,139 Adult PM and DM or IBM28,29 subgroup measure; outcome DM135,136, JDM58 and JDM140 and IBM28,29,35 measure in DM, IBM137 PM, IBM and JDM therapeutic trials1,3,6–8,10 The table presents a comparison of the methodologies for muscle strength testing that are generally encountered in clinical protocols. The metrological properties of the equipment vary widely and depend on the devices that are used and on their calibration. The photographs show the example of ankle flexion assessment using each method. Note that the references cited are examples and are not an exhaustive list. DM, dermatomyositis; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathies; IMACS, International Myositis Assessment and Clinical Studies Group; JDM, juvenile dermatomyositis; PM, polymyositis. aNormative data are given as predictive equations using age, sex, weight and/or height. The image of quantitative muscle testing (fixed dynamometry) was obtained from REF. 134.

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or isokinetic dynamometers) have been used frequently, less onerous for patients48. To avoid patient fatigue, the but rheumatologists and neurologists have different pre number of observational functional tests must be lim ferred measures of strength. Quantitative strength test ited. The tests must be selected based on the patient’s ing of the quadriceps muscle using dynamometry seems characteristics and must be highly standardized. to be most relevant for patients with IBM, as effects on Normative data exist for most of the functional tests, the strength of the quadriceps muscle group correlate and results can be expressed as a percentage of predicted best with disease progression and functional decline, normal values. Validated functional measures can be a and quantitative strength testing was more sensitive to strong secondary end point in clinical trials or studies change (that is, more responsive) than MMT in assess of patients with IIM, especially in patients who have ing strength and changes in strength in a natural history baseline muscle weakness. study of patients with IBM5,28,29,35. By contrast, questionnaires and scales that evaluate a patient’s or parent’s self-report of performance of com Functional or disability measures. Physical impair mon functions of daily activities can be self-administered ments affect the day‑to‑day functioning of patients and or administered by an interviewer. Although functional can be assessed with task-oriented tests or functional questionnaires have the substantial advantages of fea assessment questionnaires (TABLE 4; Supplementary sibility and ease of administration, they have the limi Table S1). The generation of strength leads to the gen tation of not directly assessing physical activity. These eration of movements that are organized to accomplish questionnaires are discussed below (Supplementary adult-related or child-related motor tasks. The ability Table S1). to complete motor tasks can be evaluated by the time required to perform them (using timed tests) or the Physical activity monitoring. Habitual physical activ way that they are performed and/or the difficulty in ity can also be measured at home using accelerometers performing them (using scales and questionnaires). or other devices49. The use of accelerometry was pilot- The Childhood Myositis Assessment Scale (CMAS), tested in patients with IIM50. A full validation study which assesses muscle strength, observed function and of 50 consecutive patients with IIM is ongoing at two endurance, is the best-validated observational functional independent centres (R.A. and O. Benveniste, unpub test and has also been used in therapeutic trials and is lished observations). Numerous variables, such as aver a CSM for juvenile dermatomyositis3,4,7.The Functional age daily step count and acceleration vector magnitude, Index‑2 (FI‑2) is an observational measure of muscle can be used to describe the intensity, duration and types fatigue in which patients perform repetitive movements of activity. Although physical activity monitoring has in 11 proximal and distal muscle groups of the upper and good face validity, further studies are needed to estab lower extremities, and it has good construct and con lish its reliability and validity in patients with IIM. The tent validity and good rater reliability in adult patients major advantages of physical activity monitoring include with dermatomyositis or polymyositis3,36. The FI‑2 is practicality, objectivity, continuous longitudinal moni being used as a secondary end point in therapeutic tri toring and a lack of cognitive input from the patient or als in dermatomyositis and polymyositis9,10. The FI‑2 is the examiner. However, interpretation of the results is well tolerated by patients and does not require expen required, keeping in mind that the completion of phys sive equipment, and a unilateral FI‑2 test requires only ical activities depends mostly on behavioural factors 20 minutes to complete. A new hybrid measure of mus and not only on motor capacities. Interestingly, a study cle strength and function — a composite of the MMT showed poor agreement between actigraphy measure on a subset of eight muscles (MMT‑8) and three items ments and self-reported physical activity in patients with of the CMAS — was developed for patients with juvenile juvenile dermatomyositis33. Furthermore, patients must dermatomyositis and was validated in studies of three also be able to use the monitoring devices correctly. large multinational cohorts37. It is important that all tools that are specifically devel In neuromuscular disorders, several timed tests to oped for adult patients are also validated in paediatric assess muscle function, endurance and fatigability have patients to take into account the motor and developmen been used in therapeutic trials or observational studies. tal issues that are specific to growing children. Children In addition to the FI‑2 (REFS 3,38), these tests include the younger than 5 years of age often cannot cooperate in 2‑minute or 6‑minute walking distance test (2MWDT or strength and observational functional assessment, and 6MWDT)39, the timed 10 m walk or run test40, the timed different equipment sizes might be required for children up‑and‑go (TUG) test39,41,42, the 30‑second chair stand of different ages. test (30s‑CST)43,44 and the Short Physical Performance Battery45,46 (TABLE 4). Except for the 6MWDT, these tests Patient-reported outcomes have not been validated in adult or juvenile patients The value of incorporating the patient’s perspective on with IIM. The 6MWDT has been widely used to assess outcomes when conducting clinical research is increas gait performance and endurance capacity and was in ingly appreciated. Therapeutic trials and observational 2016 used as the primary end point in the bimagrumab studies should include PROMs, which are the outcomes therapeutic trial in patients with IBM, the largest IBM that matter most to patients. However, many clinical trial to date47. In patients with IBM, a moderate cor assessment tools that are used for rheumatic diseases relation between the 2MWDT and the 6MWDT was were developed with limited or no patient involvement, shown, although the 2MWDT was more feasible and and patients have mostly not evaluated existing PROMs

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Table 4 | Observational, functional and disability measures in IIMs Measure Assessment and Subgroups Completion Psychometric Advantages Limitations Refs description of IIM time (min) properties CMAS Muscle strength, JDM 15 Good reliability, Comprehensive; Longer time 3,4 function and construct validity examines muscle to administer; endurance in 14 and responsiveness strength, endurance substantial ceiling items and function effect FI‑2 Muscle endurance; PM and DM 30 Satisfactory No ceiling or floor Longer time to 3,38 assesses impairment construct validity effects and no administer of 11 muscle groups and inter-rater and redundant tasks; intra-rater reliability measures muscle endurance 2MWDT or Muscle strength and IBM 5 or 10 Valid and reliable in Simple, has been Floor effect present 39 6MWDT endurance patients with IBM; standardized in if weakness is too also used in patients other diseases and severe; requires with muscular is used to support indoor course of dystrophies regulatory approval of sufficient length neuromuscular drugs 10 m walk or Muscle power Populations <1 Unknown in IIM Test can be done Not evaluated in 40 run with using normal, IIM; variation in the neurological comfortable speed or guidance provided conditions maximum speed to perform this test; floor effect present if weakness is too severe TUG Ability to rise from IBM 5 Good construct A valid and reliable Assesses only lower 39, a chair and gait validity tool in frail and elderly extremities and 41,42 function (may require subjects; simple and recorded time, not the adaptation to allow quick patient’s movements; patients to use their the chair that is used arms to stand up) can affect the results 30s‑CST Lower limb function; PM and DM <1 Good test–retest Simple and quick Floor effect present 43,44 patients rise from reliability if weakness is too a standard-height severe; assesses only chair and sit down lower extremities; the as many times as test chair can affect possible in 30 s the results Short Lower limb function IBM <15 Excellent test– Provides useful Longer time to 45,46 Physical by using tests of retest reliability qualitative administer Performance gait speed, standing information on the Battery balance and the time nature of a patient’s taken to rise from a mobility limitation chair five times IBM Muscle strength and IBM <15 Not tested yet Developed Validated only for IBM 28, Weakness endurance specifically for IBM 29,141 Composite Index 2MWDT, 2‑minute walking distance test; 30s‑CST, 30 s chair stand test; 6MWDT, 6‑minute walking distance test; CMAS, Childhood Myositis Assessment Scale; DM, dermatomyositis; FI‑2, Functional Index 2; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; JDM, juvenile dermatomyositis; PM, polymyositis; TUG, timed up‑and‑go test.

for their relevance, feasibility and validity. Furthermore, eight functional domains, including dressing, rising, not all PROMs can be used for all patients with the same eating, walking, hygiene, reach, grip and social activi disease, given the heterogeneity in disease presentation ties, and have a total of 20 functional task items. Patients and the variable effects of disease on patients. Therefore, self-report their functional level on the basis of their disease-specific PROMs are vital to standardize clinical level of difficulty in performing the task. The HAQ and trial outcomes. the CHAQ have been well validated in adult and juvenile The available measurement tools for assessing patients with dermatomyositis and adult patients with PROMs in patients with IIM, including questionnaires polymyositis; they have been translated into multiple that evaluate functional status, pain, fatigue and HRQoL, languages; and they are one of the CSMs used in clinical are summarized in Supplementary Table S1. The HAQ trials of patients with polymyositis, dermatomyositis or (and the Childhood HAQ (CHAQ), which is completed juvenile dermatomyositis3,4,6,7,51. by parents on behalf of paediatric patients) is an example HRQoL is a multidimensional concept that includes of a questionnaire-based assessment of daily life activi physical, mental, emotional and social functioning ties that was not specifically developed for patients with domains and is focused on how health status affects qual IIM. The HAQ and the CHAQ are PROMs that have ity of life. HRQoL is particularly relevant in patients with

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IIMs because, despite their improved prognosis with Until the work of OMERACT concludes, the recom current treatment approaches, IIMs still have consider mendations from the European Neuromuscular Centre able effects on the HRQoL of patients52,53. PROMs have (ENMC) workshop on IIM outcome measures could added valuable data on both treatment efficacy and be utilized12, with consideration to include the SF‑36 quality of life, which are immediately relevant to the and/or Myositis Activities Profile as a PROM for adult management of disease activity54. A systematic review patients with dermatomyositis or polymyositis, and the of published studies on HRQoL in patients with IIM and CHQ–PF50, which has been validated by PRINTO, for a large North American registry study of adult patients patients with juvenile dermatomyositis53. For IBM, the with IIM demonstrated that overall HRQoL is lower in disease-specific Sporadic IBM Physical Functioning patients with any form of IIM (that is, dermatomyositis, Assessment63,64, which was developed with patient polymyositis or IBM) than in either healthy populations input, and the IBM functional rating scale (IBMFRS)35,65, or patients with rheumatoid arthritis; furthermore, active which was derived from the amyotrophic lateral sclerosis disease, higher damage scores and chronic illness are functional rating scale, are being used as end points in associated with a lower quality of life52,55. Patients with therapeutic trials66. Further work is needed to develop juvenile dermatomyositis have a substantially impaired PROMs for IBM. HRQoL compared with their healthy peers, particularly in the physical domain, with physical well-being primarily Other measures affected by the level of functional impairment53. Although individual CSMs and combinations of CSMs To assess HRQoL, the IMACS recommends the use have been well validated as composite response crite of the Short Form‑36 (SF‑36) for adult patients with IIM ria for clinical trials and studies in adult and juvenile and the Child Health Questionnaire–Parent Form 50 patients with dermatomyositis and adult patients with (CHQ–PF50) for patients with juvenile dermatomyositis, polymyositis and are most frequently used as outcome although the CHQ–PF50 is costly and the SF‑36 has not measures in therapeutic trials, the CSMs do not ade been fully validated in patients with IIM1,53,56. The CHQ– quately assess specific aspects of disease that might be PF50 physical summary score is one of the validated important in subgroups of patients. Additional clinical PRINTO CSMs for juvenile dermatomyositis that has measures to assess skin disease activity and damage for good responsiveness in clinical trials4,7. Strength corre adult and juvenile patients with dermatomyositis and lates with HRQoL in dermatomyositis, polymyositis57, to assess pulmonary disease for patients with interstitial juvenile dermatomyositis58 and IBM59. lung disease (ILD) have been developed and partially To date, no IIM-specific PROM has been developed, validated for adult and juvenile dermatomyositis and but efforts are ongoing through the Outcome Measures in polymyositis3,12. Consensus has been obtained by the Rheumatology Clinical Trials (OMERACT) consortium. ENMC outcome assessment working group to include OMERACT has brought health-care providers, patients the Cutaneous Dermatomyositis Disease Area and and other stakeholders together to evaluate, develop and Severity Index to assess skin activity and damage across validate PROMs for adult IIM under the Myositis Special multiple body regions in patients with dermatomyositis. Interest Group (SIG) framework60–62. The Myositis SIG In patients with dermatomyositis-associated ILD and has evaluated PROMs in studies and clinical trials of patients with polymyositis-associated ILD, consensus patients with IIM or neuromuscular disorders accord was reached to include the Myositis Disease Activity ing to the OMERACT filters of truth, discrimination Assessment Tool, as well as the OMERACT consensus and feasibility60 (Supplementary Table S1). A review measures for connective tissue-associated ILD, including of the Myositis Activities Profile for dermatomyosi pulmonary function testing (forced vital capacity and tis and polymyositis, one of the few IIM-specific, vali diffusion capacity of the lung for carbon monoxide), dated PROMs that was developed with the involvement supplemental oxygen requirement, dyspnoea scale of adult patients, indicated that, although the content ratings and 6MWDT12 as measures to evaluate ILD67. was deemed relevant and important to patients, there Progression-free survival or time to progression of ILD were several limitations, including the perception that is recommended for consideration as a composite end many questions were vague or ambiguous and that the point for clinical trials of connective tissue-associated dimensions of ‘difficulty’ and ‘importance’ were difficult ILD, with ≥10% decline in forced vital capacity asso to understand61. ciated with mortality in patients with IIM12,67. The To assess the impact of IIM on the daily lives of Swallowing Quality of Life questionnaire has been used patients, the OMERACT Myositis SIG conducted to assess dysphagia in patients with IBM68. semi-structured focus group interviews of patients with dermatomyositis and patients with polymyositis Disease state criteria from three countries. Five themes emerged as essen Disease state criteria are important as another type of tial elements to capture in a future IIM-specific PROM measure of clinical response14 (TABLE 5). The advent — symptoms, activity and/or participation, strategies, of new therapies and treatment strategies for juve knowledge of disease and self-management and emo nile dermatomyositis69 means that inactive disease tional factors61. From these focus group meetings, the top has become a realistic therapeutic target for patients five rated domains included muscle symptoms, fatigue, with juvenile dermatomyositis70,71. Using a data-driven interaction with health-care providers and authorities, approach in a large prospective cohort of patients with medication adverse effects and pain. juvenile dermatomyositis, the PRINTO group developed

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Table 5 | Disease state criteria end points for potential use in therapeutic trials and clinical studies End point Definition or description Applicable IIM Comments Refs subgroups Clinically inactive disease At least three of the following four criteria: JDM PRINTO criteria; no definition exists for 72 creatine kinase ≤150 U/l, CMAS score ≥48 of adult DM, PM or IBM 52, MMT‑8 score ≥78 of 80 and PGA ≤0.2 cm of 10 cm Clinically inactive disease PGA of ≤0.2 cm of 10 cm and at least two of the JDM Modified PRINTO criteria; no definition 73 (updated) following three criteria: creatine kinase ≤150 exists for adult DM, PM or IBM U/l, CMAS score ≥48 of 52 and MMT‑8 score ≥78 of 80 Complete clinical ≥6‑month continuous period with no evidence JDM, DM, PM and Consensus definition, not data-driven 74 response of disease activity while receiving IIM therapy IBM definition Remission ≥6‑month continuous period with no evidence JDM, DM, PM and Consensus definition, not data-driven 74 of disease activity while not receiving any IBM definition IIM therapy Clinical remission ≥6‑month continuous period of clinically JDM PRINTO trial of patients with new-onset 7 inactive disease (on or off therapy) JDM; utilized without validation Disease flare or Worsening of PGA by ≥2 cm on a 10 cm JDM, DM, PM and Consensus definition, not data-driven 74 worsening criteria VAS and worsening on MMT‑8 by ≥20%; IBM definition extramuscular organ disease activity worsening by ≥2 cm on a 10 cm VAS; or ≥30% worsening in any 3 of 6 IMACS CSMs Disease flare Worsening by ≥20% in any 2 of 6 CSMs, JDM PRINTO trial of patients with new-onset 7 with no more than one of the remaining JDM; utilized without validation variables improving by >30% (excluding muscle strength) Corticosteroid Cessation of oral prednisone therapy JDM PRINTO trial of patients with new-onset 7,8,142 discontinuation JDM; CARRA proposed a standardized corticosteroid dose-reduction regimen based on consensus; and etanercept trial for adult patients with DM also defines a standardized steroid-tapering regimen CARRA, Childhood Arthritis and Rheumatology Research Alliance; CMAS, Childhood Myositis Assessment Scale; CSMs, core set measures; DM, dermatomyositis; IBM, inclusion body myositis; IIM, idiopathic inflammatory myopathy; IMACS, International Myositis Assessment and Clinical Studies Group; JDM, juvenile dermatomyositis; MMT‑8, manual muscle testing on a subset of eight muscles; PGA, physician global acitivity; PM, polymyositis; PRINTO, Paediatric Rheumatology International Trials Organisation; VAS, visual analogue scale.

criteria for clinically inactive disease (a point in time be validated. The time to achieve clinical remission has with clinically and biologically quiescent disease, either been reported as a secondary end point in a therapeutic on or off therapy), which include three of the four CSMs trial of children with juvenile dermatomyositis but has returning to normal or near-normal values, including not been validated as an end point7. creatine kinase, CMAS, MMT and PGA72 (TABLE 5). The IMACS has also defined, via consensus, pre Because residual rashes and nailfold capillary changes liminary criteria for flare or worsening of disease, and frequently remain after the muscle criteria of clinically the PRINTO has defined flare criteria for children with inactive disease are met, requiring the PGA to return juvenile dermatomyositis for use as an end point in the to normal improves the positive predictive value of the new-onset juvenile dermatomyositis trial7,74 (TABLE 5). Not criteria for inactive disease73. Of note, criteria for inac only can these criteria be used as an outcome in therapeu tive disease are not yet available for adult patients with tic trials but they can also be used to determine whether a dermatomyositis, polymyositis or IBM. patient is not responding to an experimental therapy and The IMACS used consensus methodology to define should be withdrawn from a trial. The PRINTO trial used criteria for complete clinical response for dermatomyosi the time to prednisone discontinuation as an additional tis, polymyositis, juvenile dermatomyositis and IBM — secondary long-term outcome to take into account the that is, a ≥6‑month continuous period with no evidence fact that corticosteroids are still the mainstay treatment of disease activity while still receiving IIM therapy, as for juvenile dermatomyositis despite the known adverse compared with substantial disease activity in the past, effects of corticosteroids on growth and development7. whereas clinical remission is defined as a ≥6‑month con tinuous period of inactive disease while not receiving Imaging any IIM therapy74. These criteria are preliminary and Imaging modalities might be useful in IIM outcome were proposed for juvenile dermatomyositis and adult assessment as measures ancillary to the validated CSMs dermatomyositis, polymyositis and IBM and have yet to and response criteria, by providing measures that are

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82 Magnetic resonance potentially more objective than CSMs or response cri strength and function in patients with IBM . Semi- imaging teria, and by discriminating active disease from muscle quantitative and quantitative MRI scoring methods that (MRI). An imaging technique damage. Magnetic resonance imaging (MRI) is the pre are used to evaluate muscle involvement in patients with that uses a magnetic field and ferred muscle imaging modality and can be used as a IIM have been reviewed elsewhere79. radio waves to create detailed images of the organs and noninvasive tool to sensitively monitor disease activity Quantitative MRI scoring systems use continuous tissues within the body. and muscle damage in many muscle groups simulta scales of MRI parameters that reflect muscle compo neously without exposing the patient to ionizing radi sition and/or haemodynamic properties. The most ation75,76. The ability to differentiate between acute and frequently used quantitative muscle imaging methods chronic muscle pathology makes MRI particularly are fat fraction (which quantifies tissue fat content useful. However, there is still no standardized and uni on a 0–100% fat-fraction scale), transverse relaxation versally accepted MRI protocol or quantitative or qual time (T2) and magnetization transfer ratio. T2 and itative scoring of MRI assessment in IIMs. In routine magnetization transfer ratio are sensitive to changes care, T2‑weighted sequences with fat suppression, such in the water distribution and lipid content in muscle. as the short tau inversion recovery (STIR) sequence, are In a prospective quantitative MRI study in patients used to detect water deposition or muscle oedema as with IBM, the fat fraction of whole calf muscles and part of muscle inflammation, regeneration and necro thigh muscles (measured using MRI Dixon fat water sis, whereas T1‑weighted sequences are usually used to imaging) increased significantly after 1 year and corre detect muscle atrophy and intramuscular fat accumu lated with the lower limb components of the IBMFRS83 lation or fibrosis as part of chronic changes77. MRI has (FIG. 1). This study demonstrated the validity and also been used to clarify whether a patient is flaring and responsiveness of MRI outcome measures, particularly requires additional treatment or whether the muscle fat fraction, in patients with IBM, suggesting that MRI inflammation has resolved and therefore a reduction in biomarkers will be valuable in therapeutic trials and therapy is supported78. have the potential to decrease sample size if used as Semi-quantitative and quantitative assessments the primary end point in early-phase clinical trials83. of muscle oedema and damage by MRI have poten Another study of MRI quantification in adult and juve tial as outcome measures in patients with IIM. Semi- nile patients with dermatomyositis and adult patients quantitative MRI scoring systems use ordinal scales of with polymyositis showed good construct validity of varying range to assess fatty infiltration of muscle and semi-quantitative STIR and T1 scores, as well as quan muscle oedema, and less frequently muscle atrophy, titative maps of T2, fat-corrected T2 and fat fraction of as well as perifascicular, subcutaneous, soft-tissue and thigh muscles, with measures of clinical disease activ fascial oedema, but these scoring systems have not ity and damage. The MRI scores were responsive to been standardized79. In studies using semi-quantitative change in a subgroup of patients from the Rituximab scoring systems, total oedema and damage scores in in Myositis trial, but changes in these MRI measures the muscle and fascia correlated with MMT and func did not agree well with the clinical response criteria, tional testing measures in patients with antisynthetase perhaps because only changes in muscle oedema are syndrome80, whereas muscle oedema correlated with quantified by MRI84. PGA, muscle strength by MMT and creatine kinase lev Whole-body MRI is used at some centres and can els in patients with polymyositis or dermatomyositis81, provide a comprehensive picture of the distribution pat and fatty infiltration of muscle correlated with muscle terns of affected muscles and reveal clinically unsus pected involvement of distal or axial muscle groups, thereby offering advantages over regional imaging85. Baseline: 18.8% fat 1 year: 25.0% fat Whole-body MRI can also detect associated cardio pulmonary disease, avascular necrosis and malig nancies86, although it is still not widely available and is prone to fat-suppression artefacts. Other emerging, but still exploratory, imaging modalities include func tional MRI, magnetic resonance spectroscopy and magnetic resonance or ultrasound elastography, which are being evaluated in patients with some subtypes of IIM75,76. Real-time MRI has shown potential for eval uating dysphagia in patients with IBM68. Finally, total lean body mass and appendicular lean body mass meas ured by dual-energy X‑ray absorptiometry have been Figure 1 | MRI of inclusion body myositis. A fat-fraction Nature Reviews | Rheumatology used as outcome measures in clinical trials of patients T1 MRI map of the right thigh in a patient with inclusion 47,66 body myositis, at baseline (left panel) and at 1‑year with IBM . follow‑up (right panel), is shown. In this instance, an absolute percentage increase of 6.2% in fat fraction was Biomarkers observed, as indicated by the increased area of fatty Traditional biomarkers of disease activity in patients infiltration in the thigh muscle tissue (arrows). Images with IIMs include serum levels of creatine kinase and provided by Jasper Morrow, University College London, other muscle-related enzymes, which are part of the London, UK. IMACS and PRINTO CSMs. However, the relationship

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of serum muscle enzyme activity to disease activity is changes in global activity scores in adult patients with variable, especially in adult and juvenile patients with ILD (including those with anti-melanoma differen dermatomyositis and patients with IBM, and therefore, tiation-associated protein 5 (MDA5) autoantibody- a great need exists for the development of more specific associated ILD)90,92,96,106. A novel disease marker that and sensitive biomarkers. At present, it is established was described in patients with juvenile dermato that innate and adaptive immunity, as well as non- myositis, galectin 9, correlates strongly with other immune muscle-related mechanisms, are involved in biomarkers, such as TNF receptor 2 (TNFR2; also the pathogenesis of IIMs87,88. Genes and proteins related known as TNFRSF1B) and CXCL10, as well as with to immune activation are some of the many poten measures of disease activity and the need for ongoing tial new biomarkers for IIMs. However, many stud treatment108. Mucin 1 is expressed in the lung and is ies often examine only a single biomarker of disease, elevated in the serum of patients with dermatomyositis- and most biomarkers have not been validated in lon related ILD110. Serum ferritin is also elevated in patients gitudinal or multisite studies and thus require confir with dermatomyositis or polymyositis and ILD and is a mation. Immune activation results in the secretion predictor of survival112. A subgroup of IIM, immune-

of cytokines, chemokines and other proteins into the mediated necrotizing myopathy, has a strong TH1 cell serum or plasma when there is active disease (TABLE 6). response in the muscle tissue, which might inform the The potential of these immune molecules as biomark identification of future biomarkers and aid in diagnostic ers was first proposed when gene expression and pro decisions113. tein assays were developed and they demonstrated Myositis-specific autoantibodies (MSAs) are increas how complex and entwined the immune system is ingly recognized in patients with any form of IIM. The with IIMs. detection of specific autoantibodies might identify the Cytokine levels and expression, particularly IL‑6, subtype of IIM and suggests the development of distinct are dysregulated in IIMs. Studies showed that IL‑6 is clinical features and outcomes114,115,116 (see the Review on expressed by both immune cells and muscle cells in myositis autoantibodies in this Focus Issue117) (TABLE 6). muscle tissue88–92. Serum IL‑6 levels are significantly MSA titres have been shown to be associated with dis elevated in adult and juvenile patients with dermato ease activity, and in many cases, the serum levels of myositis and correlate with disease activity at diagnosis, MSAs decrease after therapy116,118,119. Similarly, decreases ongoing disease changes after varying treatments and in anti‑MDA5 autoantibody levels have been associated the presence of ILD. with longer remission, whereas increased levels have been T cell-derived biomarkers include those produced by associated with relapses120,121. Elevated MSA titres have

T helper 17 (TH17) cells, such as IL‑17 and IL‑23, which also been associated with poorer outcomes, such as the are detected in the muscle and serum of patients with association of high titres of anti‑MDA5 autoantibodies dermatomyositis or juvenile dermatomyositis early in with rapidly progressive ILD122. the disease course and correlate with active disease88–91,93 Many of these biomarkers have been studied in (TABLE 6). The levels of some biomarkers are elevated clinical trials, including in the Rituximab in Myositis in subgroups of patients, such as the cytokine B cell- trial6. In this trial, correlations were found between activating factor (BAFF; also known as TNFSF13B), improvement in the interferon chemokine score and which is dysregulated at both the protein level (in improvement in global and specific measures of dis serum) and the gene expression level in patients with ease activity, as well in the levels of some MSAs90,99. dermatomyositis, polymyositis or juvenile dermato MSA titres also declined after rituximab therapy and myositis, especially those patients with ILD, anti- correlated with changes in disease activity measures116. histidyl-tRNA synthetase (Jo1) autoantibodies or active In particular, the serum levels of autoantibodies to Jo1, disease91,94,95. transcription intermediary factor 1γ (TIF1γ) and Mi2 In both adult and juvenile dermatomyositis, type I decreased after rituximab treatment and showed mod interferon-related cytokines and chemokines are upreg erate to strong correlation with most disease activity ulated in the muscle and blood of patients who have measures. A reduction in the interferon gene score in the active disease88–92,96–100. In the IIMs, type I interferon- blood and muscle correlated with clinical improvement regulated proteins are some of the most studied bio in muscle strength in a trial of a monoclonal anti-IFNα markers that are related to disease activity and outcome. antibody, as well as in the rituximab trial123,124. In particular, CXC-chemokine ligand 10 (CXCL10), Serial muscle biopsies have sometimes been used to CXCL11, CC‑chemokine ligand 2 (CCL2) and IL‑6 assess treatment effects in patients with IIMs, particu are highly expressed in muscle, the skin and periph larly to examine specific biomarkers9,10,123,124. A score eral blood, and CXCL10 is highly expressed in blood tool for assessing the histological severity of inflamma vessel endothelial cells. Furthermore, the levels of these tion, vasculopathy and myopathic and connective tissue immune molecules correlate with measures of IIM fibrotic changes in affected muscle has been validated disease activity, including cutaneous disease101–104. in patients with juvenile dermatomyositis but not in Other proposed biomarkers, such as myeloid cell- patients with other IIMs125. However, the utility of out derived molecules, adipokines and innate immune come assessment using histological biomarkers is lim receptors, are elevated in children and adults with ited by the invasiveness of the biopsy procedure and the active dermatomyositis90,96,105–111. The level of the macro lack of validation of the score tool in patients with IIMs phage and endothelial cell cytokine IL‑8 correlates with aside from juvenile dermatomyositis.

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Table 6 | Biomarkers related to disease activity in the idiopathic inflammatory myopathies Biomarker JDM DM PM IMNM ILD Source Detection method Refs IL‑6 ++++ ++ + NI + DNA, serum, Gene expression, protein 88–91 muscle or whole multiplex assay or blood immunohistochemistry T cell-related markers

88–91 IL‑17 and IL‑23 (TH17 +++ ++ NI NI NI DNA, serum, Gene expression, protein cells) muscle or whole multiplex assay or blood immunohistochemistry

88,89 IL‑4, IL‑5 and IL‑10 (TH2 NI ++ + NI NI DNA, serum or Gene expression or protein cells) muscle multiplex assay

88–91 TNF, IL‑2 and IFNγ (TH1 NI NI + + (IFNγ, + DNA, serum or Gene expression or protein cells) TNF, IL‑12 whole blood multiplex assay and STAT1) IL‑35 NI NI NI NI ++ (DM and PM) Serum ELISA 143 Myeloid cell markers and other related markers IL‑8 NI NI NI NI ++ (DM and Serum, muscle or Gene expression, ELISA or 90, MDA5‑positive whole blood protein multiplex assay 96,106 individuals) IL‑33 and sST2 NI ++ NI NI NI Serum ELISA 107 Galectin 9 +++ NI NI NI NI Plasma Protein multiplex assay 108 Adipokines ++ ++ NI NI NI Muscle or whole Gene expression 109 blood Mucin 1 NI NI NI NI ++ Serum Immunohistochemistry 110 MRP8 and MRP14 + NI NI NI NI Serum or muscle Immunohistochemistry or 105 protein multiplex assay BAFF ++ ++ + – – Serum or whole Gene expression or ELISA 91,94,95 blood Eotaxin + – NI NI NI Serum Protein multiplex assay 111,144 Other Type I interferon- +++ ++ + NI + (DM) Serum, muscle or Gene expression, 88–91, related markers (CCL2, whole blood protein multiplex 96–100 CCL3, CCL4, CCL8, assay, immunoblot or CXCL9, CXCL10, immunohistochemistry CXCL11 and MX1) Gene regulators + + NI NI NI Serum or muscle Gene expression 93 (GATA3, STAT6 and (RORC) (STAT3 STAT4) and BCL‑6) Myositis-specific ++ ++ ++ ++ ++ Serum ELISA or 114–121, autoantibodies (TIF1a, (TIF1γa, (TIF1γa, (SRP and (Jo1, MDA5 and immunoprecipitation 145 (autoantibodies with NXP2, Jo1a, Jo1a, SRP, HMGCR) PL12) >5% prevalence MDA5, Mi2a, HMGCR noted) Mi2a and SAE, and NXP2) PM–Scl) MDA5 and NXP2) Biomarkers in clinical IL‑8, CCL2, IL‑8, IL‑8, NI NI Serum, muscle or ELISA, gene expression or 99, trials IL‑6, IL‑1β, CCL2, CCL2, whole blood protein multiplex assay 122–124 IL‑13, IL‑6, IL‑6, IL‑1β, IL‑10, IL‑2 IL‑1β, IL‑13, and IFNγ IL‑13, IL‑10, IL‑2 IL‑10, and IFNγ IL‑2 and IFNγ Scale for level of evidence supporting biomarker: +, 1–2 references; ++, 2–5 references; +++, >5 references; –, little or no evidence; NI, no information available. BAFF, B cell-activating factor; BCL‑6, B cell lymphoma 6 protein; CCL, CC‑chemokine ligand; CXCL, CXC-chemokine ligand; DM, dermatomyositis; ELISA, enzyme-linked immunosorbent assay; GATA3, GATA-binding protein 3; HMGCR, 3‑hydroxy‑3‑methylglutaryl-CoA reductase; ILD, interstitial lung disease; Jo1, histidyl-tRNA synthetase; MDA5, melanoma differentiation-associated protein 5; MRP, migration inhibitory factor-related protein; MX1, interferon-induced GTP-binding protein MX1; NXP2, nuclear matrix protein 2; PL12, alanyl-tRNA synthetase; PM, polymyositis; PM–Scl, polymyositis–scleroderma autoantigen; RORC, RAR-related orphan receptor C; SAE, small ubiquitin-like modifier activating enzyme small ubiquitin-like modifier activating enzyme; SRP, signal recognition particle; sST2, soluble a suppression of tumorigenicity protein T2; STAT, signal transducer and activator of transcription; TH, T helper; TIF1, transcriptional intermediary factor 1. Changes with disease activity.

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Conclusions that can discriminate disease activity from damage, but The development and dissemination of many validated they require standardization and further evaluation of outcome assessment measures for IIM disease activity their capacity to discern the effects of therapies and their and damage have brought standardization to the field, sensitivity to change. We regard the use of the CSMs and which has aided in our understanding of the long-term the response criteria as central to outcome assessment in outcomes of these diseases and in developing and eval all IIM therapeutic trials, which will facilitate interna uating new therapies. The new IIM response criteria for tional use, standardization of end points and compar dermatomyositis, polymyositis and juvenile dermato isons between studies, therapies and patient subgroups myositis should provide a more robust and sensitive and might be applied in the clinic to guide therapeutic composite end point to detect clinical responses of decisions. Further development of additional outcome different magnitudes. Additional measures of muscle measures might result in a targeted assessment of spe strength and function, as well as the assessment of other cific disease features to augment the CSMs. We envision target organs and HRQoL, require further development future development of additional measures and indi and validation but show promise in advancing new tools ces that are more sensitive and objective than current with good content and construct validity. These meas measures. Furthermore, obtaining real-time, real-life ures might also be used as end points in trials, including data from patients through the use of smart-phone potentially as part of future composite response criteria, applications and actigraphy might augment our current in studies of specific organ manifestations (such as for targeted clinical assessments. Finally, although the vari skin or pulmonary disease) or for a specific subgroup of ous outcome measures are often presented as competing, patients. Imaging and biomarkers are objective measures they should be considered as complementary.

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