Antibody predictors of mortality and lung function trends in myositis spectrum interstitial lung disease.

OBJECTIVES: The impact of autoantibody profiles on prognosis of idiopathic inflammatory myositis associated interstitial lung disease (IIM-ILD) and myositis spectrum ILD with Myositis Specific Antibodies (MSA) remains unclear. This retrospective cohort study examines whether serological profiles are associated with mortality and longitudinal lung function change. METHODS: Baseline clinical/demographic characteristics and follow-up lung function of consecutive adult patients with IIM-ILD or Interstitial Pneumonia with Autoimmune Features (IPAF) positive for MSAs were extracted from three hospitals. Univariate and multi-variate Cox-Proportional Hazards analyses were used to compare mortality between autoantibodies. Regression models were used to analyse lung function trends. RESULTS: Of 430 included patients, 81% met IIM criteria, 19% were IPAF-MSA. On univariate analysis, risk factors associated with mortality included higher age, Charlson Co-morbidity Index and CRP; and lower BMI, baseline TLCO% and FEV1%. Compared to anti-MDA5-negativity, anti-MDA5-positivity (MDA5+) was associated with high mortality in the first 3 months (HR 65.2. 95%CI 14.1, 302.0), while no significant difference was seen thereafter (HR 0.55, 95%CI 0.14, 2.28). On multi-variate analysis, combined anti-synthetase antibodies carried a reduced risk of mortality (HR 0.63), although individually, mortality was reduced in anti-Jo1 + (HR 0.61, 95%CI 0.4-0.87) and increased in anti-PL7+ patients (HR 2.07, 95%CI 1.44-2.99). Anti-MDA5+ was associated with slow improvement in %FVC over the first 3 years, while anti-PL7+ was linked with a slow decline from 12 months onwards. CONCLUSIONS: Among autoantibody profiles in myositis spectrum disorders, anti-MDA5+ and anti-PL7+ confer higher mortality risks. Survivors of an early peak of mortality in anti-MDA5+ disease appear to have a favourable prognosis.

A Systematic Review and Metaanalysis of Predictors of Mortality in Idiopathic Inflammatory Myopathy-Associated Interstitial Lung Disease.

OBJECTIVE: Idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD) can range from rapidly progressive disease with high mortality to indolent disease with minimal morbidity. This systematic review and metaanalysis describe immunological, clinical, and radiographical predictors of mortality in IIM-ILD. METHODS: MEDLINE and Embase database searches were completed on October 18, 2021, to identify articles providing survival data according to baseline characteristics in patients with concurrent IIM and ILD. Prognostic factors common to more than 5 papers were included in the metaanalysis using a random-effects model to report odds ratios (ORs) for binary variables and Hedges g for continuous variables. Risk of bias was assessed using the Newcastle-Ottawa Scale score and the Egger test for publication bias. RESULTS: From 4433 articles, 62 papers were suitable for inclusion; among these studies, 38 different variables were considered. The OR for risk of death regarding the presence of anti-melanoma differentiation-associated protein 5 (MDA5) antibodies was 6.20 (95% CI 3.58-10.71), and anti-tRNA synthetase antibodies were found to be protective (OR 0.24, 95% CI 0.14-0.41). Neither antinuclear antibodies, anti-52-kDa Ro antigen antibodies, nor SSA significantly altered mortality, nor was MDA5 titer predictive. Examples of prognostic factors that are significantly associated with mortality in this study include the following: age; male sex; acute/subacute onset; clinically amyopathic dermatomyositis; dyspnea; ulceration; fever; raised C-reactive protein, ferritin, lactate dehydrogenase, alveolar to arterial O2 (A-aO2) gradient, ground-glass opacity on high-resolution computed tomography (HRCT), and overall HRCT score; and reduced albumin, lymphocytes, ratio of partial pressure of oxygen in the arterial blood to fraction of inspired oxygen (PF ratio), percentage predicted transfer factor for carbon monoxide, and percentage predicted forced vital capacity. Baseline surfactant protein-D and Krebs von den Lungen-6 levels were not predictors of mortality. CONCLUSION: Many mortality risk factors were identified, though heterogeneity was high, with a low quality of evidence and a risk of publication bias. Studies regarding anti-MDA5 antibody-positive disease and and those from East Asia predominate, which could mask risk factors relevant to other IIM subgroups or populations.

Validation of methods to identify people with idiopathic inflammatory myopathies using hospital episode statistics.

Objective: Hospital episode statistics (HES) are routinely recorded at every hospital admission within the National Health Service (NHS) in England. This study validates diagnostic ICD-10 codes within HES as a method of identifying cases of idiopathic inflammatory myopathies (IIMs). Methods: All inpatient admissions at one NHS Trust between 2010 and 2020 with relevant diagnostic ICD-10 codes were extracted from HES. Hospital databases were used to identify all outpatients with IIM, and electronic care records were reviewed to confirm coding accuracy. Total hospital admissions were calculated from NHS Digital reports. The sensitivity and specificity of each code and code combinations were calculated to develop an optimal algorithm. The optimal algorithm was tested in a sample of admissions at another NHS Trust. Results: Of the 672 individuals identified by HES, 510 were confirmed to have IIM. Overall, the positive predictive value (PPV) was 76% and sensitivity 89%. Combination algorithms achieved PPVs between 89 and 94%. HES can also predict the presence of IIM-associated interstitial lung disease (ILD) with a PPV of 79% and sensitivity of 71%. The optimal algorithm excluded children (except JDM code M33.0), combined M33.0, M33.1, M33.9, M36.0, G72.4, M60.8 and M33.2, and included M60.9 only if it occurred alongside an ILD code (J84.1, J84.9 or J99.1). This produced a PPV of 88.9% and sensitivity of 84.2%. Retesting this algorithm at another NHS Trust confirmed a high PPV (94.4%). Conclusion: IIM ICD-10 code combinations in HES have high PPVs and sensitivities. Algorithms tested in this study could be applied across all NHS Trusts to enable robust and cost-effective whole-population research into the epidemiology of IIM.

Skeletal muscles and Covid-19: a systematic review of rhabdomyolysis and myositis in SARS-CoV-2 infection.

OBJECTIVES: Myalgia is a widely publicised feature of Covid-19, but severe muscle injury can occur. This systematic review summarises relevant evidence for skeletal muscle involvement in Covid-19. METHODS: A systematic search of OVID and Medline databases was conducted on 16/3/2021 and updated on 28/10/2021 to identify case reports or observational studies relating to skeletal muscle manifestations of Covid-19 (PROSPERO: CRD42020198637). Data from rhabdomyolysis case reports were combined and summary descriptive statistics calculated. Data relating to other manifestations were analysed for narrative review. RESULTS: 1920 articles were identified. From these, 61 case reports/series met inclusion criteria, covering 86 rhabdomyolysis cases. Median age of rhabdomyolysis patients was 50 years, (range 6-89). 49% had either hypertension, diabetes mellitus or obesity. 77% were male. Symptoms included myalgia (74%), fever (69%), cough (59%), dyspnoea (68%). Median peak CK was 15,783U/L. 28% required intravenous haemofiltration and 36% underwent mechanical ventilation. 62% recovered to discharge and 30% died. Dyspnoea, elevated CRP and need for intravenous haemofiltration increased risk of fatal outcome. Additional articles relating to skeletal muscular pathologies include 6 possible concomitant diagnoses or relapses of idiopathic inflammatory myopathies and 10 reports of viral-induced muscle injuries without rhabdomyolysis. Localised myositis and rhabdomyolysis with SARS-CoV-2 vaccination have been reported. CONCLUSIONS: Rhabdomyolysis is an infrequent but important complication of Covid-19. Increased mortality was associated with a high CRP, renal replacement therapy and dyspnoea. The idiopathic inflammatory myopathies (IIM) may have viral environmental triggers. However, to date the limited number of case reports do not confirm an association with Covid-19.

IL-6 inhibition in the treatment of COVID-19: A meta-analysis and meta-regression.

OBJECTIVES: Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. METHODS: Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. RESULTS: Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. CONCLUSIONS: IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Pulmonary Complications of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease characterized by the production of pathogenic autoantibodies and immune complexes and is responsible for significant morbidity and mortality through a wide range of clinical manifestations which can affect almost any organ. Pulmonary involvement is prevalent and seen in 50 to 70% of SLE patients and may even be the presenting feature in 4 to 5% of patients. By 10 years postdiagnosis, 12% will have accumulated an element of permanent lung damage. Pulmonary complications are broad and include pleural disease, interstitial lung disease (ILD), vasculitis, pulmonary embolism, pulmonary hypertension, large airway disease, shrinking lung syndrome, and infection. Conditions can range mostly from asymptomatic, for example, in mild cases of pleural effusion or obstructive airway disease, to life-threatening disease, for example, in acute lupus pneumonitis or diffuse alveolar hemorrhage. ILD and pulmonary hypertension are both frequently seen in other autoimmune rheumatic diseases such as systemic sclerosis; however, in SLE, they tend to be milder and have a comparatively favorable prognosis. Although collectively pulmonary involvement in SLE is common, the heterogeneity of SLE and rareness of individual complications make clinical trials difficult and treatment is usually based on case series reports and anecdotal experience with various immunosuppressive agents. Some of these immunosuppressive agents such as azathioprine, methotrexate, and cyclophosphamide have also been linked with drug-induced lung injury.