Myositis-Specific and Associated Autoantibodies (MSA/MAA)

Immune-mediated muscle diseases are characterized by chronic muscle weakness and low muscle endurance and inflammation occurs due to the infiltration of inflammatory cells in muscle tissue. They are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses, and prognosis. Muscle weakness is usually the classical clinical manifestation, but other organs can also be affected, including the skin, joints, lungs, heart, and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that IIM is a systemic inflammatory disorder.

Reference:

• Lundberg IE, Miller FW, Tjärnlund A, Bottai M. Diagnosis and classification of idiopathic inflammatory myopathies. J Intern Med. 2016;280(1):39-51. doi:10.1111/joim.12524.
• Bonroy C, Piette Y, Allenbach Y, Bossuyt X, Damoiseaux J. Positioning of myositis-specific and associated autoantibody (MSA/MAA) testing in disease criteria and routine diagnostic workup. J Transl Autoimmun. 2022;5:100148.
• Lackner A, Tiefenthaler V, Mirzayeva J, et al. The use and diagnostic value of testing myositis-specific and myositis-associated autoantibodies by line immuno-assay: a retrospective study. Ther Adv Musculoskelet Dis. 2020;12:1759720X20975907.

MSAs are present in >50% of IIM associated with specific clinical features and not only help to identify subsets of patients with specific phenotypes of skin, muscle, lung disease, and malignancy but also explore disease-related potential environmental and genetic factors. 60–70% of children and adults with IIM carry an identifiable myositis-specific autoantibody. These findings have considerable implications for the diagnosis and management of myositis, especially should these findings lead to reduced delays in diagnosis, avoidance of unnecessary investigations, and a more personalized approach to management. MSAs are particularly useful in identifying those patients at risk of interstitial lung disease (ILD) associated with increased mortality and malignancy.

MAAs, on the other hand, are less illness-specific, as they are prevalent in various systemic autoimmune rheumatic disorders (SARD) and are closely associated with overlap disease.

Reference:

• Bonroy C, Piette Y, Allenbach Y, Bossuyt X, Damoiseaux J. Positioning of myositis-specific and associated autoantibody (MSA/MAA) testing in disease criteria and routine diagnostic workup. J Transl Autoimmun. 2022;5:100148.
• McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.

Anti-MDA5 autoantibody positivity correlated with a characteristic cutaneous phenotype with mucocutaneous ulcerations, arthritis, and mild muscle disease. Patients were found to have an increased risk of ILD and 22% of patients with anti-MDA5 autoantibodies developed rapidly progressive ILD with high mortality. The characteristic cutaneous disease can occur in the absence of clinical evidence of muscle involvement — so-called clinically amyopathic dermatomyositis (CADM) — although subclinical muscle disease can often be present.

Reference-

McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.

ASyS is associated with ILD (79-95%), arthritis (50-90%), Raynaud phenomenon (60%), fever (80%), and mechanic’s hands (dry cracking or fissuring along the sides of the fingers) (70%) with variable timing in presentation. Isolated arthritis, myositis, or ILD may occur in up to 50% of patients with ASyS. The ex-Novo appearance of further manifestations (ILD or myositis) during patient follow-up is common, emphasizing vigilance of disease evolution as a diagnostic factor in IIM-ILDs.

References:

• Bonroy C, Piette Y, Allenbach Y, Bossuyt X, Damoiseaux J. Positioning of myositis-specific and associated autoantibody (MSA/MAA) testing in disease criteria and routine diagnostic workup. J Transl Autoimmun. 2022;5:100148.
• Satoh M, Tanaka S, Ceribelli A, Calise SJ, Chan EK. A Comprehensive Overview on Myositis-Specific Antibodies: New and Old Biomarkers in Idiopathic Inflammatory Myopathy. Clin Rev Allergy Immunol. 2017;52(1):1-19.

Shappley C, Paik JJ, Saketkoo LA. Myositis-Related Interstitial Lung Diseases: Diagnostic Features, Treatment, and Complications. Curr Treatm Opt Rheumatol. 2019;5(1):56-83. doi:10.1007/s40674-018-0110-6

To date, antibodies specific for eight of the tRNA synthetases have been detected and reported in ILD- ASyS. They described having a heterogeneous presentation with arthritis presenting as the heralding symptom versus ILD being the predominant symptom. The most common anti-synthetase antibody is anti-Jo-1 and has a higher frequency of the classic triad of myositis, polyarthritis, and ILD. Though usually associated with non-erosive arthritis, ASyS may have a phenotype consistent with rheumatoid arthritis features (rheumatoid factor positivity and erosive disease on x-rays).

The less prevalent antisynthetases such as Anti-PL-7, anti-PL-12, anti-KS, and anti-OJ tend to present with ILD either in isolation or preceding the diagnosis of DM/PM.  The frequency of ILD in the absence of myositis was 33% for anti-PL 12 positive patients, 63% in anti-KS positive patients, and 77% in anti-OJ positive patients.

IIF reveals the intracellular location of the autoantigens recognized by MSAs, and some autoantigens are associated with characteristic staining patterns that provide an important clue to the presence of particular MSAs and MAAs. IIF staining performed on HEp-2 cells with diluted sera from patients with anti-MDA5 DM can give rise to characteristic cytoplasmic staining with a finely granular appearance, in rare, clustered cells. The other patterns like nuclear speckled patterns, associated with the typical cytoplasmic pattern, and isolated nuclear-speckled patterns can also be seen rarely.

Reference-

• McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.
• Nombel A, Fabien N, Coutant F. Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies. Front Immunol. 2021;12:773352. Published 2021 Oct 20. doi:10.3389/fimmu.2021.773352.

The lung is the most common extra-muscular organ in IIM with a spectrum ranging from mild to fatal ILD with or without muscle involvement.

The anti-synthetase antibodies (ASA) have the highest association with ILD with 75% being anti-Jo-1 antibodies. It was demonstrated that ILD was the most frequent new finding observed in the study, with 68% of forms without ILD at baseline developing ILD during follow-up. Interestingly, 50% of the patients who developed ILD during follow-up had only arthritis at disease onset, highlighting the importance of continued follow-up since ILD can develop in the follow-up period even in those patients who present only initially with arthritis.

Anti-MDA-antibodies patients had clinically amyopathic dermatomyositis with rapidly progressive ILD. These patients have a high risk for the development of ILD with some studies reporting MDA-5 presence representing an independent risk factor for death from ILD in DM patients. Furthermore, high titers of anti-MDA5 antibodies have been associated with a higher rate of respiratory failure and death.

Reference-

• Satoh M, Tanaka S, Ceribelli A, Calise SJ, Chan EK. A Comprehensive Overview on Myositis-Specific Antibodies: New and Old Biomarkers in Idiopathic Inflammatory Myopathy. Clin Rev Allergy Immunol. 2017;52(1):1-19.
• McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.
• Shappley C, Paik JJ, Saketkoo LA. Myositis-Related Interstitial Lung Diseases: Diagnostic Features, Treatment, and Complications. Curr Treatm Opt Rheumatol. 2019;5(1):56-83. doi:10.1007/s40674-018-0110-6

There are five dermatomyositis-specific autoantibodies, anti-Mi2, anti-Tif1-γ, anti-NXP2, anti-MDA5, and anti-SAE. Anti-Mi2 are associated with the "classical form" of DM with cutaneous and muscular involvement. Anti-Tif1γ and anti-NXP2 are found in juvenile and adult dermatomyositis and are associated with recurrent diseases with cutaneous involvement at the forefront. In adults, they are associated with cancer. Anti-MDA5 antibodies are associated with systemic involvement and interstitial lung disease. Finally, anti-SAE has been found only in adults, with a classic form. No known association of DM is found with Anti-cN1A till now.

Reference-

• McHugh NJ, Tansley SL. Autoantibodies in myositis. Nat Rev Rheumatol. 2018;14(5):290-302.

Dermatomyositis, new Antibody, new classification. Loïs Bolko ¹, Cyril Gitiaux ², Yves Allenbach- 2019 Nov;35 Hors série n° 2:18-23.