MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C).

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.

Interrater reliability and aspects of validity of the myositis damage index.

OBJECTIVE: To test the interrater reliability, internal consistency and aspects of validity of the myositis damage index (MDI) in the assessment of damage in adult patients with idiopathic inflammatory myopathy (IIM). METHODS: 95 patients were assessed in six centres as part of this cross-sectional international study. Two parts of a MDI were used to assess disease damage, the MDI and the myositis damage score (MYODAM). The myositis disease activity assessment tool (MDAAT) was used to assess disease activity. Interrater reliability was assessed using intraclass correlation coefficient (ICC). Spearman's rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the two parts of the damage tool and to determine the correlation between the respective components of the damage and activity tools. RESULTS: In general, the damage index appears to have good interrater reliability for most of the systems with an ICC greater than 0.65. Convergent validity between the two parts of the damage tool showed good correlation for the individual organ systems (r>0.8). There were weak correlations between some parts of the MDI and corresponding components of the MDAAT. CONCLUSION: The MDI is a comprehensive tool to assess damage in patients with myositis. With physician education and emphasis to record items that have been diagnosed since the myositis diagnosis, the MDI will provide a valuable tool to assess damage in future clinical trials and longitudinal studies.

Reliability and validity of the myositis disease activity assessment tool.

OBJECTIVE: To test the interrater reliability and validity of the Myositis Disease Activity Assessment Tool, which consists of the Myositis Intention-to-Treat Activity Index and the Myositis Disease Activity Assessment Visual Analog Scales. METHODS: Two phases of the study were conducted to assess the reliability and validity of the tool, which was modified following the first phase. In the first phase of the reliability study, 123 adult myositis patients were evaluated in 7 centers, and in the second phase 40 patients were evaluated in 2 centers. The validity study included 294 patients in 5 centers in the first phase and 65 patients in 3 centers in the second phase. The interrater reliability was assessed using intraclass correlation coefficients. The criterion validity was calculated using sensitivity, specificity, and positive predictive value (PPV) of a grade of A in any system. Spearman's rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the 2 instruments. RESULTS: There was a 2:1 ratio of female to male patients. There was no significant difference in mean age at diagnosis (46.3 versus 46.8 years) and mean disease duration (7.7 versus 10 years) between the 2 groups recruited for the different phases of the study. There was an improvement in interrater reliability in the second phase of the study. There was a significant improvement in the validity of the assessment tool following modification of the tool. The sensitivity, specificity, and PPV of a grade of A in any system improved from 86%, 92%, and 67% in the first phase to 96%, 94%, and 83%, respectively, in the second phase. Convergent validity between the 2 activity tools showed good correlation, ranging from 0.8 to 0.94, for the individual organ systems. CONCLUSION: This is the first major attempt to assess the reliability and validity of a disease activity index in myositis. Our findings indicate that, following within-study modification, the tool appears to be a reliable and valid instrument to assess myositis disease activity.

The assessment and importance of disease activity versus disease damage in patients with inflammatory myopathy.

To capture the totality of the effect of a disease on a patient, three aspects of the disease need to be assessed: 1) the disease activity (which is potentially reversible with treatment); 2) damage (defined as irreversible changes in anatomy, physiology, or function) accumulated since the onset of the disease, albeit from the disease itself, comorbid conditions, or as a result of therapy; and 3) the patient's perception of the disease, because this is frequently different from the physician's perception. A fine line exists between under-treating a patient, which may lead to an increase in disease activity, and over- treating a patient, with the risk of serious morbidity from inappropriate therapy. Distinguishing between activity and damage can be difficult and measures to ascertain this are discussed. Further developments are underway to assess the measures that should be used for the assessment of disease activity and damage.