Immune checkpoint inhibitors enhance the immune response against tumours but may also trigger immune-related adverse events (IRAEs). Myositis is a rare IRAE. For example, creatine kinase (CK) elevations occurred in just 0.3% of those treated with avelumab, an antiprogrammed death-ligand 1 antibody.1
Thymomas are the most common anterior mediastinal masses in adults. Since effective systemic therapies for thymic epithelial tumours are lacking, we included seven patients with recurrent thymoma and one patient with recurrent thymic carcinoma in a phase I trial of avelumab (NCT01772004). Details regarding this trial have been published separately.2
Myasthenia gravis and myositis occur in up to 30% and 5% of patients with thymoma, respectively.3 Although no patient had a history of autoimmunity or weakness and each had normal baseline CK levels, four patients developed weakness and elevated CK levels, ranging from 762 IU/L to 16 037 IU/L, within 5 weeks of avelumab administration (see online supplementary text and table 1). CK levels normalised in patients within weeks of stopping avelumab and starting immunosuppressive therapy. Of note, …
To determine the safety of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in patients with statin-associated anti-3-hydroxy-3-methlyglutaryl coenzyme A reductase (anti-HMGCR)-positive immune-mediated necrotizing myopathy (IMNM).Muscle strength was assessed in anti-HMGCR-positive patients at each visit before and after initiation of PCSK9 inhibitors. The trends in creatine kinase (CK) levels and serum anti-HMGCR antibody titers were monitored over time.Among 122 anti-HMGCR-positive patients, we identified 8 patients who were receiving PCSK9 inhibitors for hyperlipidemia. Patients were followed up for an average of 1.5 years (range 3-37 months), and none exhibited reduction in muscle strength. The mean ± SD CK level prior to the initiation of PCSK9 inhibitors was 956 ± 1,137 IU/liter, which was reduced to 419 ± 393 IU/liter at their last visit. Anti-HMGCR antibody titers followed a similar trend. Notably, in 2 patients, the initiation of the lipid-lowering medication was followed by unanticipated spontaneous clinical improvement and reduction in immunosuppression.PCSK9 inhibitors are safe for long-term use as a cholesterol-lowering agent in patients with statin-associated IMNM.
Abstract Objectives Four-and-a-half LIM domains 1 (FHL1) is a muscle-specific protein. Autoantibodies against FHL1 were recently discovered in adults with idiopathic inflammatory myopathies (IIMs) and were found to be associated with clinical features and outcomes indicative of increased disease severity. Anti-FHL1 autoantibodies have not been described in children. Here, the prevalence and clinical features associated with anti-FHL1 autoantibodies were examined in a large North American cohort of juvenile patients with IIM. Methods Sera from 338 juvenile IIM patients and 91 juvenile healthy controls were screened for anti-FHL1 autoantibodies by ELISA. Clinical characteristics and HLA alleles of those with and without anti-FHL1 autoantibodies were compared among those with juvenile IIM. Results Anti-FHL1 autoantibodies were present in 10.9% of juvenile IIM patients and 1.1% of controls. The frequency of anti-FHL1 autoantibodies among clinical and serologic subgroups did not differ. A higher percentage of Asian patients had anti-FHL1 autoantibodies (11% vs 0.7%; P = 0.002). Myositis-associated autoantibodies (MAAs) [odds ratio (OR) 2.09 (CI 1.03, 4.32)], anti-Ro52 autoantibodies specifically [OR 4.17 (CI 1.83, 9.37)] and V-sign rash [OR 2.59 (CI 1.22, 5.40)] were associated with anti-FHL1 autoantibodies. There were no differences in other features or markers of disease severity. No HLA associations with anti-FHL1 autoantibodies in Caucasian myositis patients were identified. Conclusion Anti-FHL1 autoantibodies are present in ∼11% of juvenile IIM patients and commonly co-occur with MAAs, including anti-Ro52 autoantibodies. In contrast to adult IIM, anti-FHL1 autoantibodies in juvenile myositis are associated with V-sign rash but not with other distinctive clinical features or worse outcomes.
Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.
Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body’s natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.
"Human Leukocyte Antigen Alleles Associated with Interstitial Lung Disease in North Americans with Idiopathic Inflammatory Myopathy." American Journal of Respiratory and Critical Care Medicine, 207(5), pp. 619–622
An 18 year old woman presented with a year of progressive proximal limb weakness. Serum creatine kinase (CK) was elevated and electromyography suggested an irritable myopathy. Muscle biopsy revealed severe, chronic, active, necrotizing myopathy. Myositis-specific autoantibodies were initially negative; however, an immune-mediated necrotizing myopathy was suspected. She had only minimal response to variable immunomodulatory therapies over 17 years, with progression of weakness. Subsequent repeat testing confirmed positive anti-Signal Recognition Particle (SRP) autoantibodies. A thigh MRI, 17 years after symptom onset, showed extensive fatty replacement and significant muscle atrophy, suggesting a low likelihood of response to further immunosuppression. Nonetheless, motor function significantly improved after initiation of subcutaneous methotrexate (MTX). She has been stable off immunosuppressive therapy for 4.5 years. This report exemplifies that a protracted clinical course, extensive fatty replacement and atrophy on muscle MRI and normal CK levels do not preclude a late response to immunomodulatory therapy in anti-SRP myopathy.
To inform guidance for cancer detection in patients with idiopathic inflammatory myopathy (IIM), we evaluated the diagnostic yield of computed tomography (CT) imaging for cancer screening/surveillance within distinct IIM subtypes and myositis-specific autoantibody strata.
Myositis-specific autoantibodies (MSAs) are typically considered mutually exclusive, and multiple positivities using the reference standard, Immunoprecipitation, are increasingly rare. However, other techniques, such as Enzyme-Linked Immunosorbent Assay (ELISA) and Line Blot Immunoassay (LIA), are commonly employed in clinical practice. These assays are cheaper, faster and require less clinical expertise to perform; however, they are associated with rates of multiple positivity and an increased probability of false positivity.
Objectives:
This study aims to evaluate the real-life prevalence and the clinical meaning of multiple seropositivity for MSA and Myositis Associated Antibodies (MAAs) in the Classification Criteria of Anti-Synthetase Syndrome (CLASS) cohort.
Methods:
The CLASS Project represents a collaborative, multi-center initiative to develop and validate classification criteria for Anti-synthetase Syndrome (ASSD). This retrospective and prospective study involved 101 centers globally, enrolling 2003 ASSD patients and 2175 controls (ASSD mimickers) from June 2020 to March 2022. Data for the study were collected and managed using Research Electronic Data Capture. From our database, we extracted clinical features and Antinuclear Antibody (ANA) patterns in patients exhibiting positivity for MSA and/or Myositis Associated Antibodies (MAA), excluding anti-Ro52kD (Figure 1).
Results:
Seropositivity for MSA/MAA was confirmed in 2832 patients (67.8%). Multiple positivities for MSA/MAAs (excluding anti-Ro52kD) were identified in 305/2589 cases (11.8%). Notably, 176/2589 patients (6.8%) exhibited positivity for at least two MSAs. Multiple seropositivity was reported by 69/101 centres, with a single centre contributing to 25.2% of total positive results. ELISA confirmed multiple seropositivity in 134/585 subjects (33.7%), IP in 99/412 (24%), and LIA in 720/1646 (43.7%, p=<0.0001). Unknown or other methods were recorded in 377 seropositive patients, of which 119 (31.6%) had multiple positivity. Anti-PmScl and anti-Mi2 exhibited significantly less association with the expected ANA pattern when present in combination than alone (p=0.005 and 0.001, respectively). No differences were noted for the other autoantibodies. We stratified multiple seropositive patients according to the reported autoantibodies, obtaining seven groups (Figure 1). Interstitial Lung Disease (ILD) and arthritis were more common in combinations including ASA, whereas myositis was more prevalent in combinations including NA-MSA (Figure 2). Beyond the triad of ASSD, combinations including ASA showed the highest proportion of Mechanic's Hands (MH) (MH, p=0.007 vs. MAA+NA-ASA), and those with NA-MSA exhibited the highest proportion of Gottron's Papules (GP) or Heliotropic Rash (HR) (GP or HR, p=0.0004 vs. MAA+ASA). Associations including MAA had the highest proportion of scleroderma skin involvement and Raynaud's Phenomenon (RP) (RP, p=0.0002 and 0.04, respectively, vs. multiple ASA positivity). We defined the presence of Scleroderma features by the presence of RP and skin fibrosis or puffy fingers; ASSD features by the presence of ILD, MH, arthritis, or myositis and Dermatomyositis as myositis and GP or HR. With this strict definition, 11.8% of the 305 multiple seropositive patients, specifically 7.9% of those with multiple MSAs, exhibit a clinical picture coherent with the reported autoantibodies.
Conclusion:
The utilization of LIA exposes individuals to a recognized risk of false positivity. However, in the CLASS cohort, a substantial contribution of patients was from a single centre. It was noted that there was an absence of an association between anti-PmScl and anti-Mi2 with the anticipated ANA pattern, whether present individually or in combination. Our study demonstrates that MSAs correlated with known clinical associations even in instances of combined positivity. Notably, 7.9% of cases with multiple MSAs exhibited a clinical presentation coherent with all the seropositivity. Our analysis demonstrates the potential existence of overlap syndromes that may be under-recognized in clinical practice.
REFERENCES:
NIL.
Acknowledgements:
We are grateful to all members of the CLASS project
Disclosure of Interests:
Aravinthan Loganathan: None declared, Gianluca Sambataro Boheringer Ingelheim, Akira Yoshida: None declared, Eduardo Dourado: None declared, Giovanni Zanframundo: None declared, Francisca Bozan: None declared, Daphne Rivero Gallegos: None declared, Iazsmin Bauer-Ventura: None declared, Yasuhiko Yamano: None declared, Sangmee Bae: None declared, Darosa Lim: None declared, Sara Faghihi-Kashani: None declared, Francesco Bonella: None declared, Tamera J. Corte: None declared, Tracy Doyle Bayer, David Fiorentino: None declared, Miguel Ángel González-Gay: None declared, Marie Hudson: None declared, Masataka Kuwana Asahi Kasei Parma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, Kissei, Mochida, Nippon Shinyaku, and Ono Pharmaceuticals, AstraZeneca, Boehringer-Ingelheim, Chugai, GSK, Kissei, and Mochida; Research grants: Boehringer-Ingelheim, MBL, and Ono Pharmaceuticals, Ingrid E. Lundberg: None declared, Andrew Mammen: None declared, Neil McHugh: None declared, Fredrick Miller: None declared, Carlomaurizio Montecucco: None declared, Chester V Oddis: None declared, Jorge Rojas-Serrano: None declared, Jens Schmidt: None declared, Carlo Alberto Scirè: None declared, Albert Selva-O'Callaghan: None declared, Victoria Werth: None declared, Rohit Aggarwal Actigraph, Alexion, ANI Pharmaceuticals, Argenx, AstraZeneca, Boehringer-Ingelheim, Bristol Myers-Squibb, CabalettaBio, Capella Bioscience, Corbus, CSL Behring, EMD Serono, Galapagos, Horizon Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Novartis, Nuvig Therapeutics, Octapharma, Pfizer, Regeneron, Roivant, Sanofi, Teva, Artsome, Capstanx, Manta, Boehringer Ingelheim, Bristol Myers-Squibb, EMD Serono, Janssen, Mallinckrodt, Pfizer, Q32, Lorenzo Cavagna Boheringer Ingelheim.
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