Clinico-Sero-Morphological Classification of the Antisynthetase Syndrome (ASyS) – Associated Myositis

273^rd ENMC International Workshop:

Location: Hoofddorp, The Netherlands

Title: Clinico-Sero-Morphological Classification of the Antisynthetase Syndrome (ASyS) – Associated Myositis

Date: 27.-29. October 2023

Organisers: Prof. A. Mammen (USA), Prof. O. Benveniste (France), Prof. W. Stenzel (Germany), Prof. Y. Allenbach (France)

Translations of this report by:
Danish by L. Diederichsen
Dutch by L. Kolsters
German by M.-T. Holzer and F. Kleefeld
Greek by I. Minopoulou
French by L. Gallay
Italian by M. Giannini
Swedish by I. Lundberg
Thai by J. Tanboon

Participants: J. Tanboon (Thailand), D. Fiorentino (USA), A. Meyer (France), S.K. Danoff (USA), L. Diederichsen (Denmark), Y. Uzunhan (France), C. Preusse (Germany), T. Ruck (Germany), L. Kolsters (patient representative, The Netherlands), S. Tansley (UK), J. Damoiseaux (The Netherlands), I. Lundberg (Sweden, online), I. Minopoulou (Germany), M. Giannini (France), F. Kleefeld (Germany, Early-Career Researcher), M.-T. Holzer (Germany, Early-Career Researcher), L. Gallay (France), L. De Ceuninck (argenx, Belgium).

The 273^rd ENMC workshop was held on 27^th to 29^th of October 2023. 22 participants including one patient representative and one industry representative attended the workshop with the aim to define clinical, serological, and morphological aspects of the Antisynthetase Syndrome (ASyS). Antisynthetase Syndrome has previously not been defined as a distinct entity in the 2016 ACR/EULAR classification criteria for idiopathic inflammatory myopathies (IIM). In recent years, new scientific evidence on ASyS has emerged that is not yet reflected in current classifications of myositis.

In the opening session of the workshop, unmet needs and open questions in the context of ASyS were presented and discussed: the problems of autoantibody testing with different techniques and newly identified antibodies, the definition of ASyS as “disease” or “syndrome”, clinical aspects and the identification of new treatment options and specific outcome measures.

This was followed by a talk on different clinical presentations, and it was emphasized that ASyS can present sometimes only with few symptoms, such as myositis or interstitial lung disease or arthritis. The clinical presentation is variable and, in many cases, linked to specific ASyS antibodies. Specific histopathological findings in the muscle biopsies of ASyS patients were highlighted in the following talks. It was emphasized that muscle biopsies should be, if possible, interpreted by someone with experience, as some findings can easily be overlooked or reported as unspecific. The next talk focused on regional differences regarding the frequency of autoantibodies detected in the blood of ASyS patients in Europe and Asia. Furthermore, an overview on the presentation of arthritis in ASyS patients was presented, and it was highlighted that some patients show a characteristic pattern of symptoms (as calcinosis of the joint capsules in distal joints or subluxations). Regarding the skin manifestations, some common skin symptoms of ASyS were identified. However, many of these features may also be seen in dermatomyositis, such as Gottron signs and papules, heliotrope rash, but also vasculopathic lesions and mechanic’s hands.

On Saturday, aspects of cardiac manifestations including myocarditis but also pulmonary hypertension in ASyS were discussed. Larger analysis regarding prevalence and optimal treatment are needed to draw definite conclusions. It was pointed out that lung involvement was higher in non-Jo-1 patients. The outcome of interstitial lung disease (ILD) in ASyS patients is usually better than in other myositis patients, but the concomitant detection of Ro-52 antibodies seems to be a risk factor for progressive ILD. Disease activity should be monitored on a regular basis (e.g. with pulmonary function tests and patient reported outcomes) to detect progression and adjust treatment. Furthermore, latest research suggests that the lung and a combination of hereditary and environmental factors may play a crucial role in disease development. Future perspectives were illustrated by the presentation of data on the importance of B- and plasma cells and the role of animal models to understand the underpinnings of the disease.

Regarding the laboratory detection of ASyS-antibodies it was stated, that depending on the method, the results can vary and especially in rare antibodies, false positive results or negative results might be problematic.

The patient representative shared her long diagnostic journey with the other participants. She expressed the patients’ unmet needs, including the delay from symptom onset to diagnosis, the need for more reliable information, for information on patient-support-groups, and psychological support. She emphasized the need for support with all aspects of the disease, including exercise and diet recommendations as well as for a standard follow-up one week after diagnosis and for an easier access to follow-up meetings with the treating physician.

The closing talks on Saturday were focused on treatment and disease monitoring of the different aspects of ASyS, as well as on the opportunities of new experimental treatment approaches like CAR-T cell-therapies.

On Sunday, the participants discussed how ASyS can be defined in a clinical, serological and morphological way. It was concluded that a highly positive antibody and a typical symptom of the disease, such as ILD or myositis, is diagnostic of ASyS. Afterwards, there was an intense discussion on the best treatment options for the organ manifestations in ASyS, and for mild to moderate and severe cases. As the evidence regarding specific therapies in ASyS is limited to mostly case series and expert opinions or data from myositis basket trials, more research is warranted on this topic. The group reached consensus that ASyS patients have a high risk for relapse and therefore a long-term remission should be achieved before thinking about tapering the therapy.

Defining ASyS as separate disease entity within the spectrum of idiopathic inflammatory myopathies will help to improve patient care as well as future research in the context of ASyS.

A full report on definitive diagnostic guidelines as well as therapeutic recommendations will be published in the medical journal Neuromuscular Disorders (pdf).