Immune mechanisms in fibrotic interstitial lung disease.

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

Short peripheral blood leukocyte telomere length in rheumatoid arthritis-interstitial lung disease.

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.

Therapeutic interception in individuals at risk of rheumatoid arthritis to prevent clinically impactful disease.

Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development.

Breakthrough COVID-19 After Tixagevimab/Cilgavimab Among Patients With Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: To determine the incidence and baseline factors associated with breakthrough coronavirus disease 2019 (COVID-19) after preexposure prophylaxis (PrEP) with tixagevimab/cilgavimab among patients with systemic autoimmune rheumatic diseases (SARDs). METHODS: We performed a retrospective cohort study among patients with SARDs who received tixagevimab/cilgavimab between January 2, 2022, and November 16, 2022. The primary outcome was breakthrough COVID-19 after tixagevimab/cilgavimab. We performed multivariable Cox regression models adjusted for baseline factors to identify risk factors for breakthrough COVID-19. RESULTS: We identified 444 patients with SARDs who received tixagevimab/cilgavimab (mean age 62.0 years, 78.2% female). There were 83 (18.7%) breakthrough COVID-19 cases (incidence rate 31.5/1000 person-months, 95% CI 24.70-38.24), 7 (1.6%) hospitalizations, and 1 (0.2%) death. Older age was inversely associated with breakthrough COVID-19 (adjusted hazard ratio [aHR] 0.86/10 years, 95% CI 0.75-0.99). Higher baseline spike antibody levels were associated with lower risk of breakthrough COVID-19 (aHR 0.42, 95% CI 0.18-0.99 for spike antibody levels > 200 vs < 0.4 units). CD20 inhibitor users had a similar risk of breakthrough COVID-19 (aHR 1.05, 95% CI 0.44-2.49) compared to conventional synthetic disease-modifying antirheumatic drug (DMARD) users. CONCLUSION: We found that patients with SARDs had frequent breakthrough COVID-19, but the proportion experiencing severe COVID-19 was low. DMARD type, including CD20 inhibitors, did not significantly affect risk of breakthrough COVID-19. Evidence of prior humoral immunity was protective against breakthrough infection, highlighting the continued need for a multimodal approach to prevent severe COVID-19 as novel PrEP therapies are being developed.

Factors Associated With an Electronic Health Record-Based Definition of Postacute Sequelae of COVID-19 in Patients With Systemic Autoimmune Rheumatic Disease.

OBJECTIVE: Many individuals with rheumatic disease are at higher risk for severe acute coronavirus disease 2019 (COVID-19). We aimed to evaluate risk factors for postacute sequelae of COVID-19 (PASC) using an electronic health record (EHR)-based definition. METHODS: We identified patients with prevalent rheumatic diseases and COVID-19 within the Mass General Brigham healthcare system. PASC was defined by the International Classification of Diseases, 10th revision (ICD-10) codes, relevant labs, vital signs, and medications at least 30 days following the first COVID-19 infection. Patients were followed until the earliest of incident PASC, repeat COVID-19 infection, 1 year of follow-up, death, or February 19, 2023. We used multivariable Cox regression to estimate the association of baseline characteristics with PASC risk. RESULTS: Among 2459 patients (76.37% female, mean age 57.4 years), the most common incident PASC manifestations were cough (14.56%), dyspnea (12.36%), constipation (11.39%), and fatigue (10.70%). Serious manifestations including acute coronary disease (4.43%), thromboembolism (3.09%), hypoxemia (3.09%), stroke (1.75%), and myocarditis (0.12%) were rare. The Delta wave (adjusted hazard ratio [aHR] 0.63, 95% CI 0.49-0.82) and Omicron era (aHR 0.50, 95% CI 0.41-0.62) were associated with lower risk of PASC than the early pandemic period (March 2020-June 2021). Age, obesity, comorbidity burden, race, and hospitalization for acute COVID-19 infection were associated with greater risk of PASC. Glucocorticoid (GC) use (aHR 1.19, 95% CI 1.05-1.34 compared to no use) was associated with greater risk of PASC. CONCLUSION: Among patients with rheumatic diseases, following their first COVID-19 infection, we found a decreased risk of PASC over calendar time using an EHR-based definition. Aside from GCs, no specific immunomodulatory medications were associated with increased risk, and risk factors were otherwise similar to those seen in the general population.

Air Pollution and Rheumatoid Arthritis Risk and Progression: Implications for the Mucosal Origins Hypothesis and Climate Change for RA Pathogenesis.

PURPOSE OF REVIEW: The goal of this review paper is to summarize the main research and findings regarding air pollution and its association with the risk and progression of rheumatoid arthritis (RA). RECENT FINDINGS: The most studied components of air pollution included particulate matter of ≤ 2.5 microns in diameter (PM2.5), PM10, carbon monoxide (CO), nitrogen dioxide (NO2), nitric oxide (NOx), sulfur dioxide (SO2), and ozone (O3). In addition, specific occupations and occupational inhalants have been investigated for RA risk. Several studies showed that increased exposure to air pollutants increased the risk of developing RA, particularly seropositive RA. There was evidence of gene-inhalant interactions for seropositive RA risk. Fewer studies have been conducted on RA disease activity and bone erosions. Some studies suggest that patients with RA-associated interstitial lung disease may have worse outcomes if exposed to air pollution. We summarized associations between air pollution and increased RA risk, including RA-associated interstitial lung disease. Relatively few studies investigated air pollution and RA disease activity or other outcomes. These results suggest an important role of air pollution for seropositive RA development and suggest that climate change could be a driver in increasing RA incidence as air pollution increases.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study.

BACKGROUND: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR). OBJECTIVE: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. DESIGN: Observational cohort study. SETTING: Multicenter health care system in Boston, Massachusetts. PARTICIPANTS: Ambulatory adults with acute COVID-19 with and without use of N-R. INTERVENTION: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. MEASUREMENTS: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. RESULTS: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. LIMITATIONS: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. CONCLUSION: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. PRIMARY FUNDING SOURCE: National Institutes of Health.

Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features. OBJECTIVE: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRSAsthma) and spirometry (FEV1 and FEV1/forced vital capacity; PRSspiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO). METHODS: We developed and tested 2 asthma PRSs and applied the higher performing PRSAsthma and a previously published PRSspiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry. RESULTS: In meta-analyses of 102,477 participants, the PRSAsthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRSspiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRSspiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRSspiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRSAsthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRSspiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRSAsthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRSspiro was associated with asthma exacerbations in White, LatinX, and East Asian participants. CONCLUSIONS: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.

Acute and postacute COVID-19 outcomes for patients with rheumatoid arthritis: lessons learned and emerging directions 3 years into the pandemic.

PURPOSE OF REVIEW: To summarize the findings of studies investigating patients with rheumatoid arthritis (RA) and risk of acute and postacute COVID-19 outcomes 3 years into the pandemic. RECENT FINDINGS: Most studies early in the pandemic included all patients with systemic autoimmune rheumatic diseases (SARDs), not only those with RA, due to limited sample size. Many of these studies found that patients with SARDs were at higher risk of COVID-19 infection and severe outcomes, including hospitalization, hyperinflammation, mechanical ventilation, and death. Studies performed later were able to focus on RA and found similar associations, while also identifying RA-specific factors such as immunosuppressive medications, disease activity/severity, and interstitial lung disease as risk factors for severe COVID-19. After COVID-19 vaccination, the risks for COVID-19 infection and severity were reduced for patients with RA, but a gap between the general population persisted, and some patients with RA are susceptible to breakthrough infection after vaccination. Preexposure prophylaxis, effective treatments, and changes in viral variants have also contributed to improved COVID-19 outcomes throughout the pandemic. Emerging data suggest that patients with RA may be at risk for postacute sequelae of COVID-19 (PASC). SUMMARY: Although COVID-19 outcomes have improved over the pandemic for patients with RA, some experience poor acute and postacute outcomes after COVID-19. Clinicians and patients should remain vigilant about risk mitigation for infection and consider early treatment for RA patients with COVID-19. Future studies are needed to investigate clinical outcomes and mechanisms of PASC among patients with RA.

Mogamulizumab-Associated Myositis With and Without Myasthenia Gravis and/or Myocarditis in Patients With T-Cell Lymphoma.

Mogamulizumab is being increasingly prescribed for the treatment of T-cell lymphomas (MF/SS/ATLL). We conducted a retrospective cohort study to identify muscular immune-related adverse events (irAEs) associated with mogamulizumab in patients with T-cell lymphoma followed at Dana-Farber Cancer Institute from January 2015 to June 2022. We identified 5 cases of mogamulizumab-associated myositis and/or myocarditis (MAM/Mc), 2 additionally affected by myasthenia gravis, among 42 patients with T-cell lymphoma. Three cases experienced -mogamulizumab-associated rash (MAR) prior to developing MAM/Mc. The incidence (n = 5/42, 11.9%) of muscular mogamulizumab-associated irAEs may be higher than has been previously reported in clinical trials and may be of late onset (a median of 5 cycles and as late as 100 days from the last infusion). We highlight the utility of IVIG, together with systemic corticosteroids, for the treatment of these potentially fatal side effects associated with mogamulizumab therapy.

Comparative effectiveness of BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19.

BACKGROUND: Both BNT162b2 (Pfizer-BioNTech) and ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines have shown high efficacy against COVID-19 in randomized controlled trials. However, their comparative effectiveness against COVID-19 is unclear in the real world. We evaluated the comparative effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against COVID-19 in the UK general population. METHODS: We emulated a target trial using IQVIA Medical Research Database (IMRD), an electronic primary care database from the UK (2021). We included 1,311,075 participants, consisting of 637,549 men and 673,526 women age≥18 years, who received vaccination with BNT162b2 or ChAdOx1 nCoV-19 between January 1 and August 31, 2021. The outcomes consisted of confirmed diagnosis of SARS-CoV-2 infection, hospitalisation for COVID-19 and death from COVID-19 in the IMRD. We performed a cox-proportional hazard model to compare the risk of each outcome variable between the two vaccines adjusting for potential confounders with time-stratified overlap weighting of propensity score (PS). RESULTS: During a mean of 6.7 months of follow-up, 20,070 confirmed SARS-CoV-2 infection occurred in individuals who received BNT162b2 vaccine (PS weighted incidence rate: 3.65 per 1000 person-months), and 31,611 SARS-CoV-2 infection occurred in those who received ChAdOx1 nCoV-19 vaccine (PS weighted incidence rate: 5.25 per 1000 person-months). The time-stratified PS weighted rate difference of SARS-CoV-2 infection for BNT162b2 group vs. ChAdOx1 nCoV-19 group was -1.60 per 1000 person-months (95% confidence interval [CI]: -1.76 to -1.43 per 1000 person-months), and the hazard ratio was 0.69 (95% CI: 0.68 to 0.71). The results were similar across the stratum of sex, age (<65 and ≥65 years), and study periods (i.e., alpha-variant predominance period and delta-variant predominance period). The PS weighted incidence of hospitalisation for COVID-19 was also lower in the BNT162b2 vaccine group than that in the ChAdOx1 vaccine group (RD: -0.09, 95%CI: -0.13 to -0.05 per 1000 person-months; HR: 0.65, 95%CI: 0.57 to 0.74). No significant difference in the risk of death from COVID-19 was observed between the two comparison groups. CONCLUSIONS: In this population-based study, the BNT162b2 vaccine appears to be more efficacious than the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2 infection and hospitalisation for COVID-19 but not death from COVID-19.

Impact of vaccination on postacute sequelae of SARS CoV-2 infection in patients with rheumatic diseases.

OBJECTIVE: Vaccination decreases the risk of severe COVID-19 but its impact on postacute sequelae of COVID-19 (PASC) is unclear among patients with systemic autoimmune rheumatic diseases (SARDs) who may have blunted vaccine immunogenicity and be vulnerable to PASC. METHODS: We prospectively enrolled patients with SARD from a large healthcare system who survived acute infection to complete surveys. The symptom-free duration and the odds of PASC (any symptom lasting ≥28 or 90 days) were evaluated using restricted mean survival time and multivariable logistic regression, respectively, among those with and without breakthrough infection (≥14 days after initial vaccine series). RESULTS: Among 280 patients (11% unvaccinated; 48% partially vaccinated; 41% fully vaccinated), the mean age was 53 years, 80% were female and 82% were white. The most common SARDs were inflammatory arthritis (59%) and connective tissue disease (24%). Those with breakthrough infection had more upper respiratory symptoms, and those with non-breakthrough infection had more anosmia, dysgeusia and joint pain. Compared with those with non-breakthrough COVID-19 infection (n=164), those with breakthrough infection (n=116) had significantly more symptom-free days over the follow-up period (+21.4 days, 95% CI 0.95 to 41.91; p=0.04) and lower odds of PASC at 28 and 90 days (adjusted OR, aOR 0.49, 95% CI 0.29 to 0.83 and aOR 0.10, 95% CI 0.04 to 0.22, respectively). CONCLUSION: Vaccinated patients with SARDs were less likely to experience PASC compared with those not fully vaccinated. While we cannot rule out the possibility that findings may be due to intrinsic differences in PASC risk from different SARS-CoV-2 variants, these findings support the benefits of vaccination for patients with SARDs and suggest that the immune response to acute infection is important in the pathogenesis of PASC in patients with SARDs.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Prevalence and mortality associations of interstitial lung abnormalities in rheumatoid arthritis within a multicentre prospective cohort of smokers.

OBJECTIVE: To investigate the prevalence and mortality impact of interstitial lung abnormalities (ILAs) in RA and non-RA comparators. METHODS: We analysed associations between ILAs, RA, and mortality in COPDGene, a multicentre prospective cohort study of current and past smokers, excluding known interstitial lung disease (ILD) or bronchiectasis. All participants had research chest high-resolution CT (HRCT) reviewed by a sequential reading method to classify ILA as present, indeterminate or absent. RA cases were identified by self-report RA and DMARD use; non-RA comparators had neither an RA diagnosis nor used DMARDs. We examined the association and mortality risk of RA and ILA using multivariable logistic regression and Cox regression. RESULTS: We identified 83 RA cases and 8725 non-RA comparators with HRCT performed for research purposes. ILA prevalence was 16.9% in RA cases and 5.0% in non-RA comparators. After adjusting for potential confounders, including genetics, current/past smoking and other lifestyle factors, ILAs were more common among those with RA compared with non-RA [odds ratio 4.76 (95% CI 2.54, 8.92)]. RA with ILAs or indeterminate for ILAs was associated with higher all-cause mortality compared with non-RA without ILAs [hazard ratio (HR) 3.16 (95% CI 2.11, 4.74)] and RA cases without ILA [HR 3.02 (95% CI 1.36, 6.75)]. CONCLUSIONS: In this cohort of smokers, RA was associated with ILAs and this persisted after adjustment for current/past smoking and genetic/lifestyle risk factors. RA with ILAs in smokers had a 3-fold increased all-cause mortality, emphasizing the importance of further screening and treatment strategies for preclinical ILD in RA.

Associations of DMARDs with post-acute sequelae of COVID-19 in patients with systemic autoimmune rheumatic diseases: a prospective study.

OBJECTIVE: We investigated the baseline disease-modifying antirheumatic drug (DMARD) use and post-acute sequelae of COVID-19 (PASC) risk among patients with systemic autoimmune rheumatic diseases (SARDs). METHODS: Patients with SARDs and confirmed COVID-19 infection at Mass General Brigham completed a survey ≥28 days after positive PCR/Antigen test to prospectively investigate their COVID-19 courses. We investigated DMARD use at COVID-19 onset and PASC risk. PASC was defined as any COVID-19 symptom that persisted for ≥28 days. We used logistic regression to estimate odds ratios (OR) for PASC by DMARD class. We also used restricted mean survival time to determine the difference in symptom-free days by DMARD class in the 28-day period after infection. RESULTS: We analyzed 510 patients with SARDs and COVID-19 from 11/Mar/2021-17/Jun/2023; 202 (40%) developed PASC. CD20 inhibitor (CD20i) users had significantly higher odds of developing PASC vs csDMARD users (adjusted OR 2.69, 95%CI 1.23-5.88). IL-12/23, IL-17A, or IL-23 inhibitor (IL-12/23i, IL-17Ai, IL-23i) users also had significantly higher odds of PASC (adjusted OR 3.03, 95%CI 1.08-8.49). CD20i users had significantly fewer symptom-free days vs csDMARD users (adjusted -4.12, 95%CI -7.29 to -0.94). CONCLUSION: CD20i users had significantly higher odds of PASC and fewer symptom-free days over the 28 days following COVID-19 diagnosis compared with csDMARD users. Further research is needed to investigate whether PASC risk in CD20i users may be due to prolonged infection or other immune mechanisms. The association of IL-12/23i, IL-17Ai, and IL-23i and PASC calls for additional study.

Rheumatoid arthritis, quantitative parenchymal lung features, and mortality among smokers.

OBJECTIVES: There have been limited investigations of the prevalence and mortality impact of quantitative computed tomography (QCT) parenchymal lung features in rheumatoid arthritis (RA). We examined the cross-sectional prevalence and mortality associations of QCT features, comparing RA and non-RA participants. METHODS: We identified participants with and without RA in COPDGene, a multicentre cohort study of current or former smokers. Using a k-nearest neighbor quantifier, high resolution CT chest scans were scored for percentage of normal lung, interstitial changes, and emphysema. We examined associations between QCT features and RA using multivariable linear regression. After dichotomizing participants at the 75th percentile for each QCT feature among non-RA participants, we investigated mortality associations by RA/non-RA status and quartile 4 vs quartiles 1-3 of QCT features using Cox regression. We assessed for statistical interactions between RA and QCT features. RESULTS: We identified 82 RA cases and 8820 non-RA comparators. In multivariable linear regression, RA was associated with higher percentage of interstitial changes (ß = 1.7 ± 0.5, p= 0.0008) but not emphysema (ß = 1.3 ± 1.7, p= 0.44). Participants with RA and >75th percentile of emphysema had significantly higher mortality than non-RA participants (HR 5.86, 95%CI 3.75-9.13) as well as RA participants (HR 5.56, 95%CI 2.71-11.38) with ≤75th percentile of emphysema. There were statistical interactions between RA and emphysema for mortality (multiplicative p= 0.014; attributable proportion 0.53, 95%CI 0.30-0.70). CONCLUSIONS: Using machine learning-derived QCT data in a cohort of smokers, RA was associated with higher percentage of interstitial changes. The combination of RA and emphysema conferred >5-fold higher mortality.

Considerations for Pharmacologic Management of Rheumatoid Arthritis in the COVID-19 Era: a Narrative Review.

PURPOSE OF REVIEW: To review the impact of disease-modifying antirheumatic drugs (DMARDs) on COVID-19 severity and vaccine immunogenicity and to discuss COVID-19 outcomes in patients with rheumatoid arthritis (RA). RECENT FINDINGS: Rituximab is associated with severe COVID-19 and impaired vaccine immunogenicity via its B cell-depleting mechanism. JAK inhibitors and glucocorticoids have been modestly associated with severe COVID-19 and impaired vaccine immunogenicity. TNF inhibitors may have a protective effect against severe COVID-19 and do not appear to affect vaccine immunogenicity. Clinical trials have shown improved seroconversion and antibody titers when methotrexate is held around vaccine doses, but this may yield increased risk of RA flare. Patients with RA are also impacted by DMARD disruption, RA flares, and post-acute sequelae of COVID-19 after COVID-19 infection. Given the risks of COVID-19, rituximab should be used with caution in RA. Holding methotrexate doses around COVID-19 vaccination improves immunogenicity but may increase RA flare risk.

Validation of serostatus of rheumatoid arthritis using ICD-10 codes in administrative claims data.

PURPOSE: To determine the accuracy of International Classification of Diseases- Tenth Revision (ICD-10) diagnosis codes for rheumatoid arthritis (RA) serostatus using a U.S. claims database (Optum Clinformatics Data Mart, Optum) and to compare the results to a previous validation study performed in IBM Marketscan Research Database (sensitivity 73%, positive predictive value, PPV, 84%). METHODS: In Optum (01/01/2016-03/31/2020) linked with laboratory results, we selected RA patients based on ≥2 ICD-10 diagnosis codes for RA (M05 or M06) and at least one dispensing of RA treatments. We included individuals with at least one laboratory result for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) performed 365 days prior to and including the cohort entry date. An individual was "seropositive" if at least one of the 2 diagnosis codes used to define RA status was M05. "Seronegative" patients were required to have only M06. Secondary analyses were performed using subsets of M05 and M06 diagnosis codes. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of M05 and M06 against the prespecified reference standard laboratory data. RESULTS: We identified 14 490 adult RA patients who had at least 1 RF or anti-CCP result. The number of patients identified for each reference standard definition ranged from 3315 (reference standard definition: high + anti-CCP) to 13 636 (any + RF). PPV for seropositive RA, M05, was 77.1%. The PPV of M06 for seronegative RA was 61.6%. When we applied more restricted definitions of M05 and M06, the PPV for seropositive RA increased to 79.2%. The PPV for seronegative RA also notably increased to 89.5%. CONCLUSION: ICD-10 codes (M05 and M06) can help identify RA serostatus in claims data, but their limitations should be acknowledged. The PPVs for seropositive and seronegative RA found in the Optum database were lower than those found in MarketScan, perhaps related to database variability or differing patient characteristics and clinical practice. When more restricted definitions of M05 and M06 were used, the PPVs for seropositive and seronegative RA improved to 79.2% and 89.5%, respectively.

Temporal trends in COVID-19 outcomes among patients with systemic autoimmune rheumatic diseases: from the first wave through the initial Omicron wave.

OBJECTIVES: To investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave. METHODS: We conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group). RESULTS: We identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 46% of cases were severe in the early COVID-19 period (1 March 2020-30 June 2020) vs 15% in the initial Omicron wave (17 December 2021-31 January 2022; adjusted OR 0.29, 95% CI 0.19 to 0.43). A higher proportion of those unvaccinated were severe compared with not severe cases (78% vs 60%). CONCLUSIONS: The proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.