Anna Tjärnlund

2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups

Objective To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. Methods Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. Results Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) ‘probable IIM’, had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to ‘definite IIM’. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50 to <55% as ‘possible IIM’. Conclusions The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of ‘definite’, ‘probable’ and ‘possible’ IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Diagnosis and classification of idiopathic inflammatory myopathies

The idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of diseases, collectively termed myositis, sharing symptoms of muscle weakness, fatigue and inflammation. Other organs are frequently involved, supporting the notion that these are systemic inflammatory diseases. The IIMs can be subgrouped into dermatomyositis, polymyositis and inclusion body myositis. The myositis‐specific autoantibodies (MSAs) identify other and often more distinct clinical phenotypes, such as the antisynthetase syndrome with antisynthetase autoantibodies and frequent interstitial lung disease and anti‐SRP and anti‐HMGCR autoantibodies that identify necrotizing myopathy. The MSAs are important both to support myositis diagnosis and to identify subgroups with different patterns of extramuscular organ involvement such as interstitial lung disease. Another cornerstone in the diagnostic procedure is muscle biopsy to identify inflammation and to exclude noninflammatory myopathies. Treatment effect and prognosis vary by subgroup. To develop new and better therapies, validated classification criteria that identify distinct subgroups of myositis are critical. The lack of such criteria was the main rationale for the development of new classification criteria for IIMs, which are summarized in this review; the historical background regarding previous diagnostic and classification criteria is also reviewed. As the IIMs are rare diseases with a prevalence of 10 in 100 000 individuals, an international collaboration was essential, as was the interdisciplinary effort including experts in adult and paediatric rheumatology, neurology, dermatology and epidemiology. The new criteria have been developed based on data from more than 1500 patients from 47 centres worldwide and are based on clinically easily available variables.

Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies

Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.

Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial

Objectives To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM). Methods Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines. Results 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies. Conclusions In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.

2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Adult and Juvenile Idiopathic Inflammatory Myopathies and Their Major Subgroups

To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups.

Autoantibody Specificities and Type I Interferon Pathway Activation in Idiopathic Inflammatory Myopathies.

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN‐inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti‐IFNAR or anti‐IFN‐α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA‐binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti‐IFNAR or anti‐IFN‐α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA‐binding proteins and with autoantibody multispecificity. These studies identify IFN‐α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN‐α as a possible target for therapy in these patients.

Progress report on development of classification criteria for adult and juvenile idiopathic inflammatory myopathies

Classification criteria are needed to aid recruitment of appropriate patients into research studies. The International Myositis Classification Criteria Project (IMCCP) was set up with support from ACR and EULAR.

SAT0436 Abatacept in the Treatment of Adult Dermatomyositis and Polymyositis: Artemis, a Randomized, Treatment Delayed-Start Trial

Background Polymyositis (PM) and dermatomyositis (DM) are chronic inflammatory diseases primarily affecting skeletal muscle leading to muscle weakness. T cells are likely to have a role in the disease process indicated by the predominance of T cells in the inflammatory infiltrates found in affected muscle, and further supported by the associations with certain HLA class II alleles. The role of T cells may be direct as mediators of muscle fiber necrosis and as producers of inflammatory molecules that may have a negative effect on muscle fiber contractility. Objectives To assess the clinical efficacy of Abatacept, an agent blocking T cell co-stimulation, on disease activity in adult DM and PM patients in a trial with randomized treatment delayed-start design. Methods DM and PM patients with persisting signs of inflammatory active disease after treatment with glucocorticoids and ≥1 immunomodulating drug for ≥3 months were randomized to receive either immediate active treatment with Abatacept intravenous (10 mg/kg) infusions or a delayed start after 3 months. The primary endpoint was the number of responders, defined as improved according to the International Myositis Assessment and Clinical Studies (IMACS) Group definition of improvement (DOI), after treatment for 6 months. The secondary endpoint included the number of responders in the delayed onset arm compared to the active treatment arm at 3 months, and the efficacy after 6 months treatment on the individual components of the IMACS core set measures for the disease activity, and health-related quality of life assessed by SF-36. Results Among 20 randomized patients (9 DM, 11 PM; 13 female, 7 male), 17 were included in the analyses and 8 (47%) achieved the DOI after 6 months of active treatment. No differences between DM and PM, or female and male patients could be seen. At 3 months after study start, 5 of the 10 (50%) patients in the active treatment arm were responders achieving the DOI compared to only 1 of the 7 (14%) patients in the delayed onset arm. After active treatment for 6 months (n=17), significant improvement was seen in muscle strength, assessed by the manual muscle test (MMT)-8, from (median) 70 to 73 (p=0.0082), in gastrointestinal disease activity from 3 to 0 (p=0.0156), and in muscle disease activity from 18 to 10 (p=0.0133). SF-36 physical was significantly improved from median 31 at start to 36 at end of treatment (p=0.0054). There were 36 adverse events (AE) reported. Eight AE were judged as related to the drug, of which 4 were mild and 4 were moderate. These included infections, flank pain and dizziness. There were 3 serious AE, none of which was related to the drug. These included hospitalization due to fracture, worsening in muscle weakness and reconstructive surgery. Conclusions In this pilot study, treatment of PM and DM patients with Abatacept resulted in improved muscle performance and health-related quality of life in half of the patients, and warrants further investigation. Acknowledgements This research received funding support from Bristol-Myers Squibb. Disclosure of Interest A. Tjärnlund: None declared, M. Dastmalchi: None declared, H. Mann: None declared, J. Tomasová Studýnková: None declared, R. Chura: None declared, N. Gullick: None declared, R. Salerno: None declared, P. Gordon Paid instructor for: Bristol-Myers Squibb, J. Vencovský Consultant for: Medimmune, Servier, Novartis, I. Lundberg Consultant for: Novartis, Servier, Astra-Zeneca och Bristol-Myers Squibb

EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a methodology report

Objective To describe the methodology used to develop new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIMs) and their major subgroups. Methods An international, multidisciplinary group of myositis experts produced a set of 93 potentially relevant variables to be tested for inclusion in the criteria. Rheumatology, dermatology, neurology and paediatric clinics worldwide collected data on 976 IIM cases (74% adults, 26% children) and 624 non-IIM comparator cases with mimicking conditions (82% adults, 18% children). The participating clinicians classified each case as IIM or non-IIM. Generally, the classification of any given patient was based on few variables, leaving remaining variables unmeasured. We investigated the strength of the association between all variables and between these and the disease status as determined by the physician. We considered three approaches: (1) a probability-score approach, (2) a sum-of-items approach criteria and (3) a classification-tree approach. Results The approaches yielded several candidate models that were scrutinised with respect to statistical performance and clinical relevance. The probability-score approach showed superior statistical performance and clinical practicability and was therefore preferred over the others. We developed a classification tree for subclassification of patients with IIM. A calculator for electronic devices, such as computers and smartphones, facilitates the use of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria. Conclusions The new EULAR/ACR classification criteria provide a patient’s probability of having IIM for use in clinical and research settings. The probability is based on a score obtained by summing the weights associated with a set of criteria items.

Response to: '2017 EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: little emphasis on autoantibodies, why?' by Malaviya

We are grateful for the insightful and highly relevant question raised by Dr Malaviya1 concerning the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. The question concerns autoantibodies, and in particular myositis-specific autoantibodies (MSAs), and why only the anti-Jo-1 autoantibody is included in the new classification criteria. We understand the concern that was raised and we have discussed the limitation of having limited data on MSAs in our publication.2 This letter gives us a possibility to expand on this limitation and include some more explanations. Our study was initiated more than 10 years ago, and during the last decade we have seen a great advancement in the knowledge of autoantibodies specific for and associated with idiopathic inflammatory myopathies (IIM). This includes identification of several new MSAs, as well as advancement in methods used to detect MSAs that have made it possible to …