Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjögren’s syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient’s management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs.

The classification of idiopathic inflammatory myopathies (IIM) is based on clinical, serological and histological criteria. The identification of myositis‐specific antibodies has helped to define more homogeneous groups of myositis into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), sporadic inclusion body myositis (sIBM) and immune‐mediated necrotising myopathy (IMNM). sIBM and IMNM patients present predominantly with muscle involvement, whereas DM and ASyS patients present additionally with other extramuscular features, such as skin, lung and joints manifestations. Moreover, the pathophysiological mechanisms are distinct between each myositis subsets. Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In DM, the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in muscle, blood and skin of DM patients. In addition, DM‐specific antibodies are targeting antigens involved in the IFN signalling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signalling pathways induces systemic manifestations such as interstitial lung disease, myositis and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signalling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in ASyS, available data suggest a role of type II IFN in blood, muscle and lung. Indeed, transcriptomic analyses highlighted a type II IFN gene expression in ASyS muscle tissue. In sIBM, type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to myodegenerative features. For IMNM, currently published data are scarce, suggesting a minor implication of type II IFN. This review highlights the involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset.

Objective: The objective of this study was to evaluate the presence of different types of interferon in idiopathic inflammatory myopathies (IIM) and their subgroups using ultrasensitive cytokine detection techniques (SIMOA) and to assess their potential as activity biomarkers.Methods: Disease activity was measured at the time of serum collection and assessed by manual muscle testing eight (MMT8 score 0-150), muscle enzymes to calculate the Physician Global Assessment (PGA) (0-10). Patients were classified as active if PGA>5.Serum IFN-α and IFN-γ levels was measured using the single molecule array (SIMOA) technique. Serum IFN-β level was measured by Elisa. Correlation between IFN levels and disease activity were performed.Results: We included 242 IIM patients and found a good correlation between type I Interferon (IFN) and dermatomyositis disease activity. IFN-α and IFN-β was highly correlated with disease activity (r=0.76 and r=0,58). To evaluate whether the different types of Interferons could serve as biomarkers of activity, we generated ROC curves. Patients with active DM had a higher median IFN-α level (0.49 pg/ml [0.1-3.7]) compared with non-active patients (0.03 pg/ml [0.01-0.07] p<0.05). The area under the curve was 0.90 IC95 (0.76-0.97) p<0.05. Furthermore, Myositis-specific antibodies appear to be associated with a different secretion profile; patients with anti-MDA 5 antibodies had higher level of IFN-α than most other antibodies (6.58 vs 0.14 p<0.005). NXP2 had higher IFN-β level than patients with Tif1γ antibodies.Conclusion: Serum IFN-α level measured by SIMOA is a reliable biomarker of DM activity. Myositis-specific antibodies appear to be associated with a different secretion profile. This data needs to be confirmed in order to select the good therapeutics strategies in DM.

Objectives: To assess factors associated with rapidly progressive interstitial lung disease (ILD) (RP‐ILD) at time of ILD diagnosis in a multicentric retrospective cohort study of antisynthetase syndrome (ASyS). We used a complementary unsupervised approach, hierarchical clustering, to delineate distinct phenotypes among ASyS patients with ILD. Methods: A total of 132 patients with ASyS, defined according to the 2024 ACR/European Alliance of Associations for Rheumatology (EULAR) ASyS classification criteria, and ILD, diagnosed by CT scan, were included. RP‐ILD was defined by the presence of respiratory failure at ILD diagnosis or rapid ILD progression during the first 3 months. Results: In our study, 39% of patients had RP‐ILD at ILD diagnosis. Multivariate logistic regression analysis with cluster‐robust SE identified the factors associated with RP‐ILD at ILD diagnosis as male sex (aOR = 9.7 [1.6–59.5], p = 0.006), fever (aOR = 128 [12.6–1300], p < 0.001), organizing pneumonia (OP) pattern (aOR = 66.8 [3.4–1316], p = 0.006), and pleural effusion (aOR = 20.2 [1.1–373], p = 0.04), whereas RP‐ILD was associated with lower likelihood of severe muscle disease (aOR = 0.004 [0.0001–0.13], p = 0.002). Clustering analysis identified four distinct groups: Cluster 1 ( n = 62) included patients with systemic presentation, non‐RP‐ILD at ILD diagnosis, and anti‐Jo‐1 antibodies with good prognosis; Cluster 2 ( n = 40) included older age patients with more RP‐ILD at ILD diagnosis, pleuropericarditis, and a higher mortality rate. Conclusion: Fever, pleural effusion, and OP pattern were independently associated with RP‐ILD in ASyS patients. Unsupervised cluster analysis identified a severe inflammatory phenotype in ASyS patients with ILD.