Long-Term Mortality Following SARS-CoV-2 Infection in Rural Versus Urban Dwellers with Autoimmune or Inflammatory Rheumatic Disease (AIRD): A Retrospective Cohort Analysis from the National COVID Cohort Collaborative (N3C).

OBJECTIVE: Autoimmune or inflammatory rheumatic diseases (AIRD) increase the risk for poor COVID-19 outcomes. While rurality is associated with higher post-COVID-19 mortality in the general population, whether rurality elevates this risk among people with AIRD is unknown. We assessed associations between rurality and post-COVID-19 all-cause mortality, up to 2 years post-infection, among people with AIRD using a large, nationally sampled U.S. METHODS: This retrospective study utilized the National COVID Cohort Collaborative, a medical-records repository containing COVID-19 patient data. We included adults with ≥2 AIRD diagnostic codes and a COVID-19 diagnosis documented between April 2020 and March 2023. Rural residency was categorized using patient residential ZIP Codes. We adjusted for AIRD medications and glucocorticoid usage, age, sex, race and ethnicity, tobacco/substance usage, comorbid burden, and SARS-CoV-2 variant-dominant periods. Multivariable Cox Proportional Hazards with inverse probability treatment weighting assessed associations between rurality and 2-year, all-cause mortality. RESULTS: Among the 86,467 SARS-CoV-2-infected persons with AIRD, we observed a higher risk for 2-year post-COVID-19 mortality in rural versus urban dwellers. Rural-residing persons with AIRD had higher 2-year, all-cause mortality risk (aHR 1.24, 95% CI 1.19-1.29). Use of glucocorticoids, immunosuppressives, and rituximab was associated with a higher risk for 2-year post-COVID-19 mortality, while risk with non-biologic or biologic DMARDs was lower. CONCLUSION: Rural residence in people with AIRD was independently associated with higher post-COVID-19 2-year mortality in a large U.S. cohort after adjusting for background risk factors. Policymakers and healthcare providers should consider these findings when designing interventions to improve outcomes in people with AIRD following SARS-CoV-2 infection, especially among higher-risk rural residents.

Cardiovascular disease in spondyloarthritis: a narrative review of risk factors and the effect of treatments.

PURPOSE OF REVIEW: This review summarizes the recent evidence available regarding the epidemiology of cardiovascular disease in spondyloarthritis (SpA), including the effect of disease modifying drugs on cardiovascular risk. RECENT FINDINGS: People with SpA suffer from an increased risk of cardiovascular disease compared to the general population. This elevated risk is explained by the high prevalence of traditional cardiovascular risk factors and inflammation from disease activity leading to endothelial dysfunction and accelerated atherosclerosis. Consequently, the American College of Cardiology/American Heart Association and the European League Against Rheumatism recommend enhanced cardiovascular risk screening in SpA patients. There is evidence from observational studies that methotrexate and tumor necrosis factor inhibitors reduce the risk of cardiovascular events in SpA. Unlike what is observed in the general population, the use of nonsteroidal anti-inflammatory drugs does not appear to increase cardiovascular disease risk in SpA. SUMMARY: Cardiovascular diseases are increasingly recognized in patients suffering from SpA, especially axial SpA and psoriatic arthritis. Cardiovascular diseases can cause significant morbidity, mortality, and add to the overall disease burden. Disease modifying drugs may mitigate some of the cardiovascular risk; however, a multidisciplinary team is needed to monitor patients and improve cardiovascular health status.

Concerns, Healthcare Use, and Treatment Interruptions in Patients With Common Autoimmune Rheumatic Diseases During the COVID-19 Pandemic.

OBJECTIVE: To assess concerns and healthcare-related behaviors of patients with autoimmune rheumatic diseases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Adults from the United States with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) from the ArthritisPower Patient-Powered Research Network and CreakyJoints patient community completed surveys. Concerns and behaviors were compared among patients with different autoimmune conditions, disease-modifying antirheumatic drug (DMARD) use, and geographic measures of urban status, income, education, and COVID-19 activity. RESULTS: Among 1517 participants (925 RA, 299 PsA, 185 AS, 108 SLE), mean age was 55.1 years, 88.3% were female, and 89.5% were White. COVID-19 concerns were similar across the country and were higher in biologic users (P < 0.001). Avoidance of doctor's office visits (56.6%) or laboratory testing (42.3%) and use of telehealth (29.5%) were more common in urban areas. Among participants receiving a DMARD without COVID-19 or other respiratory illness, 14.9% stopped a DMARD, with 78.7% of DMARD interruptions not recommended by a physician. DMARD stopping was more common in participants with lower socioeconomic status (SES) and in participants who avoided an office visit (OR 1.46, 95% CI 1.04-2.04) or reported lack of telehealth availability OR 2.26 (95% CI 1.25-4.08). CONCLUSION: In the early months of the COVID-19 pandemic, patients with RA, PsA, AS, and SLE frequently avoided office visits and laboratory testing. DMARD interruptions commonly occurred without the advice of a physician and were associated with SES, office visits, and telehealth availability, highlighting the need for adequate healthcare access and attention to vulnerable populations during the pandemic.

Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: COVID-19 outcomes in people with rheumatic diseases remain poorly understood. The aim was to examine demographic and clinical factors associated with COVID-19 hospitalisation status in people with rheumatic disease. METHODS: Case series of individuals with rheumatic disease and COVID-19 from the COVID-19 Global Rheumatology Alliance registry: 24 March 2020 to 20 April 2020. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Age, sex, smoking status, rheumatic disease diagnosis, comorbidities and rheumatic disease medications taken immediately prior to infection were analysed. RESULTS: A total of 600 cases from 40 countries were included. Nearly half of the cases were hospitalised (277, 46%) and 55 (9%) died. In multivariable-adjusted models, prednisone dose ≥10 mg/day was associated with higher odds of hospitalisation (OR 2.05, 95% CI 1.06 to 3.96). Use of conventional disease-modifying antirheumatic drug (DMARD) alone or in combination with biologics/Janus Kinase inhibitors was not associated with hospitalisation (OR 1.23, 95% CI 0.70 to 2.17 and OR 0.74, 95% CI 0.37 to 1.46, respectively). Non-steroidal anti-inflammatory drug (NSAID) use was not associated with hospitalisation status (OR 0.64, 95% CI 0.39 to 1.06). Tumour necrosis factor inhibitor (anti-TNF) use was associated with a reduced odds of hospitalisation (OR 0.40, 95% CI 0.19 to 0.81), while no association with antimalarial use (OR 0.94, 95% CI 0.57 to 1.57) was observed. CONCLUSIONS: We found that glucocorticoid exposure of ≥10 mg/day is associated with a higher odds of hospitalisation and anti-TNF with a decreased odds of hospitalisation in patients with rheumatic disease. Neither exposure to DMARDs nor NSAIDs were associated with increased odds of hospitalisation.

IFNγ induces epigenetic programming of human T-bethi B cells and promotes TLR7/8 and IL-21 induced differentiation.

Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgDnegCD27negCD11c+CXCR5neg (DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bethi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.

Routine Use of Quantitative Disease Activity Measurements among US Rheumatologists: Implications for Treat-to-target Management Strategies in Rheumatoid Arthritis.

OBJECTIVE: The aim of our study was to examine why real-world practices and attitudes regarding quantitative measurements of rheumatoid arthritis (RA) have received limited attention. METHODS: An e-mail survey asked US rheumatologists to self-report on their use of quantitative measurements (metric). RESULTS: Among 439 respondents, metric rheumatologists (58%) were more likely to be in group practice and to use tumor necrosis factor inhibitors. The quantitative tools most commonly used were the Health Assessment Questionnaire (35.5%) and the Routine Assessment of Patient Index Data 3 (27.1%). Reasons for not measuring included time needed and electronic availability. Based on simulated case scenarios, providing more quantitative information increased the likelihood that a patient would change to a different disease-modifying antirheumatic drug or biologic. CONCLUSION: Routine use of quantitative measurement for patients in the United States with RA is increasing over time but remains low.

Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk and Damage in African Americans.

Over 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody positive RA and 933 African American controls on the ImmunoChip (iChip) array. Using multivariable regression we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (OR = 1.97, p = 1.28 × 10-15) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11, and TNFSF18 loci were suggestively associated (10-4 < p < 3.1 × 10-6). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants including rs9653442, rs7608424, and rs6712515 as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1, and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1, and IL2RA.

Increased pretreatment serum IFN-ß/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis.

OBJECTIVE: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement. METHODS: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-ß activity were measured using a functional reporter cell assay. RESULTS: In the test set, an increased ratio of IFN-ß to IFN-α (IFN-ß/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-ß/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-ß/α activity ratio (p=0.005). CONCLUSIONS: Increased pretreatment serum IFN-ß/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

Pharmacogenetics of etanercept in rheumatoid arthritis.

Etanercept is one of several TNF inhibitors approved for rheumatoid arthritis (RA) and a variety of other immune-mediated inflammatory conditions. Given the plethora of drugs approved for RA, and the wide variations in cost and treatment response, markers of efficacy would be very useful. Several candidate genes, including HLA-DRB1 alleles and those encoding TNF, TNF receptors and Fc receptors, have been examined for a role in the response to treatment with etanercept. In this review, we discuss pharmacogenetic studies of etanercept in RA and other diseases, and comment on the future of such analyses to advance the goal of personalized medicine in RA.

Biologics and heart failure in rheumatoid arthritis: are we any wiser?

PURPOSE OF REVIEW: To summarize the recent literature concerning the role of TNF-alpha in heart failure, epidemiology of heart failure in rheumatoid arthritis and risk of heart failure associated with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. RECENT FINDINGS: TNF-alpha has been implicated in the pathogenesis of heart failure. It has direct deleterious effects on the myocardium in the setting of acute injury or chronic heart failure. In animal models, TNF-alpha is important in cardiac remodeling, leading to cardiac dysfunction following acute injury. Both incident and worsening heart failure have been reported in patients with rheumatoid arthritis who are treated with anti-TNF-alpha therapy. Recent cohort studies, however, have shown no increased risk and, in some, a protective effect on the risk of heart failure. Certain traditional cardiovascular risk factors have a relatively lesser contribution to cardiovascular morbidity and mortality in patients with rheumatoid arthritis, suggesting that disease-related perturbations of the cytokine network may contribute to the excess risk of heart failure in these patients. SUMMARY: Overall mortality in rheumatoid arthritis has remained stagnant despite advances in rheumatoid arthritis and heart failure management and improved cardiovascular mortality in the general population. Heart failure prevalence is increased in patients with rheumatoid arthritis and leads to greater mortality. Despite current expert consensus contraindicating the use of anti-TNF-alpha agents in patients with moderate to severe heart failure, epidemiological studies in rheumatoid arthritis have not consistently substantiated this association.