Crowson, CS

Objective The aim of this study was to compare infection‐related hospitalization risk among patients with nonrenal systemic lupus erythematosus initiating commonly used immunosuppressants. Methods We emulated a target trial using Optum Labs Data Warehouse claims to compare the risk of infection‐related hospitalization among patients initiating azathioprine, belimumab, methotrexate, or mycophenolic acid analogues (MPAAs) between March 2011 and September 2023. We excluded patients with prior lupus nephritis, solid‐organ or bone marrow transplantation, or rituximab/cyclophosphamide exposure. The primary outcome was time to first infection‐related hospitalization using intention‐to‐treat (ITT) and per‐protocol (PP) analyses. We applied inverse probability of treatment weighting to account for baseline covariates and fitted marginal structural Cox models incorporating time‐varying monthly glucocorticoid dose during follow‐up. Results Among 6,168 patients, 24‐month cumulative incidence of infection‐related hospitalization was 10% (95% confidence interval [CI] 8–12) for azathioprine, 8% (95% CI 5–10) for belimumab, 10% (95% CI 8–11) for methotrexate, and 13% (95% CI 10–15) for MPAAs. In ITT analyses, MPAAs had higher risk than belimumab (hazard ratio [HR] 1.55, 95% CI 1.07–2.25) and methotrexate (HR 1.32, 95% CI 1.04–1.68). In PP analyses, azathioprine (HR 2.04, 95% CI 1.01–4.16) and MPAAs (HR 2.27, 95% CI 1.11–4.62) had higher risk compared with belimumab. After accounting for time‐varying monthly glucocorticoid dose, between‐treatment differences were no longer significant. Conclusion Initial differences in the infection‐related hospitalization risk were attenuated after accounting for time‐varying glucocorticoid exposure. These findings highlight glucocorticoid exposure as an important factor associated with serious infection risk while recognizing that postbaseline glucocorticoid use may reflect both evolving disease activity and a pathway through which therapies influence infection risk. image

The underlying immunopathogenesis of inflammatory arthritis (IA) immune-related adverse event (irAE) remains obscure. Unlike rheumatoid arthritis (RA), where autoantibodies and B cell dysfunction are central features, the contribution of humoral immunity to IA-irAE is unclear. Here, we performed immunophenotyping of peripheral blood from patients with IA-irAE and compared them with patients with seronegative RA, immune checkpoint inhibition–treated patients without irAE, and healthy controls. IA-irAE was marked with increased cytotoxic gene expression and metabolic activation in T cells and reduced CXCR3 and CCR6 expression in CD4 + T cells. Contrary to seronegative RA, patients with IA-irAE displayed no substantial elevation in autoantibody levels or atypical CD11c + CD21 − B cells. IA-irAE was further characterized by elevated levels of interleukin-6 (IL-6), IL-12, and type I interferon, which correlated with the T cell activation phenotypes. Together, our findings define IA-irAE as a disease with certain immunological features distinctive from RA, representing a potentially T cell–driven, autoantibody-independent autoimmunity. These results offer insights into immune tolerance breakdown and therapeutic targeting in irAEs.

Objective The objective of this study was to investigate the association between dual seropositive, single seropositive, and seronegative rheumatoid arthritis (RA) with radiographic erosions, disease flares, and death. Methods We performed a retrospective, population‐based study of residents in Southern Minnesota with incident RA who fulfilled criteria for RA in 2003 to 2019. Radiographic erosions and flares were evaluated within one year of incident RA. All‐cause mortality was obtained from medical records and death certificates. Cox models adjusted for age, sex, smoking status, year of incident RA, and comorbidities were used. Results The study included 1,373 patients with RA. At RA incidence, 37% were dual seropositive, 13% seropositive for anti–cyclic citrullinated protein (anti‐CCP) only, 12% seropositive for rheumatoid factor (RF) only, and 38% seronegative. The highest proportion of radiographic erosions before or within one year of RA incidence was in the dual seropositive (31%) and lowest in those seropositive for anti‐CCP only (13%). Flares occurred in 69% of the dual seropositive and 51% of the seropositive for anti‐CCP only within the first year of RA incidence. Those seropositive for RF only had over a two‐fold increase in mortality rates compared with the seronegatives (adjusted hazard ratio [aHR] 2.18, 95% confidence interval [CI] 1.47–3.24). In contrast, the dual seropositives had only a >50% increase in mortality rates (aHR 1.66, 95% CI 1.21–2.28), and those seropositive only for anti‐CCP had a >30% increase in mortality rates (aHR 1.32, 95% CI 0.83–2.11). Conclusion Patients with RA seropositive for RF only have an increase in mortality rates compared with patients who are dual seronegative. RF positivity could be an indicator of inflammation that requires pharmacologic treatment to decrease mortality rates.

Objective The purpose of this study was to determine the cumulative incidence of diagnosis switching, drug‐free remission, and initiation of a biologic or targeted synthetic disease‐modifying antirheumatic drug (b/tsDMARD) in individuals with seronegative rheumatoid arthritis (RA). Methods Adult residents of Olmsted County, Minnesota, with incident seronegative (rheumatoid factor negative/anti–cyclic citrullinated peptide antibody negative) RA meeting the 1987 and/or 2010 American College of Rheumatology classification criteria were included. Data were collected from January 1, 2005, to December 31, 2023, through manual chart review. Drug‐free remission was defined as a period of at least six months where the individual was no longer taking treatment for RA and did not have evidence of active inflammatory arthritis upon evaluation by a rheumatologist. We calculated the 10‐year cumulative incidence of a change in diagnosis, adjusting for the competing risk of death, and of drug‐free remission and initiation of a b/tsDMARD, adjusting for the competing risks of death or change in diagnosis. Results A total of 176 individuals with seronegative RA (68% women) were included. The 10‐year cumulative incidence of a change in diagnosis was 12.8% (95% confidence interval [CI] 8.7%–18.9%). The most common change in diagnosis was to spondyloarthritis (4%). The 10‐year cumulative incidence of drug‐free remission and initiation of a b/tsDMARD was 26.6% (95% CI 20.7%–34.2%) and 19.9% (95% CI 14.7%–26.9%), respectively. Over a median follow‐up of 11.8 years, 49 individuals entered drug‐free remission. Conclusion After initial diagnosis of seronegative RA, about 13% of individuals had a change in diagnosis and a quarter experienced drug‐free remission within 10 years.

Objectives To examine associations between multimorbidity, the social determinants of health (SDoHs) and rheumatoid arthritis (RA) flare and remission. Methods All patients aged ≥18 years in Olmsted County, Minnesota, with incident RA in 1999–2014 were identified. Using a list of 55 chronic medical conditions, multimorbidity was defined as the presence of ≥2 conditions and substantial multimorbidity as ≥5 conditions. The Area Deprivation Index and Social Vulnerability Index (SVI) were used as proxies for adverse SDoH burden. Flare and remission were defined using Outcome Measures in Rheumatoid Arthritis Clinical Trials definitions. Mixed effects models were used to assess associations between flare/remission and multimorbidity, adverse SDoH burden and other patient characteristics. Results This study included 659 patients with incident RA. Multimorbidity and substantial multimorbidity predicted 29% (OR:1.29, 95% CI:1.04 to 1.59) and 26% (OR:1.26, 95% CI:1.03 to 1.53) higher odds of flare, respectively. Both were associated with 34% (OR:0.66, 95% CI:0.49 to 0.90) and 33% (OR:0.67, 95% CI:0.51 to 0.90) lower odds of remission, respectively. SVI predicted 8% lower odds of remission for every 0.1 increase above 0.3 (OR:0.92, 95% CI:0.85 to 0.99). Flare was also associated with female sex, smoking, younger age and shorter disease duration, but not seropositivity. Remission was also associated with male sex, never smoking, older age and longer disease duration, but not seropositivity. Conclusions Multimorbidity predicts higher odds of RA flare and lower odds of remission. Adverse SDoH burden predicts lower odds of remission. These findings have the potential to inform disease prognostication and clinician interventions.

Objective We aimed to assess the occurrence of carpal tunnel syndrome (CTS) before and after rheumatoid arthritis (RA) incidence and by serologic status. Methods This population‐based study included residents of a geographically defined area meeting the 1987 American College of Rheumatology classification criteria for RA in 1980 to 2019 matched 1:1 with individuals without RA. At least two diagnosis codes ≥30 days apart were used to identify CTS. Cumulative incidence of CTS adjusting for competing risk of death was assessed. Logistic regression and Cox proportional hazard models were used, adjusting for age, sex, calendar year, smoking, obesity, diabetes mellitus, and hypothyroidism. Results We included 1,335 patients with RA and 1,331 individuals without RA. The overall prevalence of CTS before or on RA incidence or index was 179 patients with RA (13%) and 85 individuals without RA (6%), respectively (odds ratio [OR] 2.23; 95% confidence interval [CI] 1.69–2.94). Most previous incidences of CTS occurred ≥2 years before the index date (112 events in patients with RA and 75 events in individuals without RA, respectively). Following RA incidence or index, individuals with RA (vs those without RA) had ~80%‐higher risk of CTS (hazard ratio [HR] 1.78; 95% CI 1.38–2.30). The risk estimates of CTS in patients with seronegative (vs seropositive) RA were OR 1.33 (95% CI 0.96–1.84) before RA incidence and HR 1.37 (95% CI 0.99–1.88) after RA incidence. In RA, obesity (HR 1.42, 95% CI 1.02–1.99) and seronegative cyclic citrullinated peptide antibody status (HR 1.79, 95% CI 1.07–2.99), but not other risk factors, were associated with increased CTS risk. Conclusion We found a more than two‐fold increase in risk of CTS in the years preceding RA and a 1.8‐fold increased risk of incident CTS following RA onset. image

Objective The 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria score (≥20 points) has been associated with poor outcomes. We aimed to evaluate its utility as a predictor for mortality and hospitalisation and to derive and validate an ominosity score based on the SLE classification criteria set. Methods Incident patients with SLE in a population-based cohort were included. The association between the 2019 EULAR/ACR SLE score and mortality and hospitalisation was assessed using Cox regression adjusted for age, sex and calendar year. An ominosity score for mortality was developed based on the SLE criteria set. The least absolute shrinkage and selection operator method was used to estimate model coefficients. Concordance and calibration were assessed by cross-validation and by plotting the observed event rates against the deciles of predicted probabilities. Results Among 374 patients with incident SLE, a EULAR/ACR score ≥20 points was not associated with an increased risk of mortality (HR 1.17, 95% CI 0.67 to 2.03) or first hospitalisation (HR 1.14, 95% CI 0.79 to 1.64) compared with a score ≤19 points. The derived ominosity score for mortality included age, sex, thrombocytopaenia, neuropsychiatric manifestations, subacute cutaneous or discoid lupus, non-scarring alopecia, inflammatory arthritis, renal involvement, antiphospholipid antibodies and hypocomplementaemia. This model demonstrated a concordance=0.76 with adequate calibration. Age and sex were the main predictors, as seen in the model including just age, sex and year (concordance=0.77). Conclusion The 2019 EULAR/ACR SLE criteria score was not associated with mortality and hospitalisation. The derived ominosity score for mortality presented good prediction for mortality but was not better than age and sex alone.

ObjectiveWe aimed to characterize presentation and care pathways of patients with systemic lupus erythematosus (SLE), and delays in access to SLE‐specialized care.MethodsWe included patients with incident SLE from the Lupus Midwest Network registry. Time from the first medical encounter for SLE clinical manifestation to access to SLE‐specialized care, physician diagnosis, and treatment was estimated. Delays were defined as ≥6 months to access specialized care. We compared SLE manifestations, disease activity, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage indexes (SDI) between patients with and without delays. Logistic regression models assessed associations with delays.ResultsThe study included 373 patients with SLE. The median time to access SLE‐specialized care was 1.1 (95% confidence interval [CI] 0.9–1.5) months, time to diagnosis was 30.6 (95% CI 18.9–48.1) months, and time to treatment initiation was 4.7 (95% CI 3.9–8.4) months. Approximately 25% of patients (93 out of 373) experienced delays accessing specialized care, which were associated with fewer SLE manifestations at first SLE‐related encounter (fewer than two SLE domains; 92% vs 72%, P < 0.001). Patients with mucocutaneous or musculoskeletal manifestations were less likely to experience delays, whereas hematologic (odds ratio [OR] 1.71, 95% CI 1.03–2.84) or antiphospholipid antibodies domains (OR 6.05, 95% CI 2.46–14.88) were associated with delays. Delays were associated with damage at first access to SLE‐specialized care (SDI ≥1; 30% vs 7%, P < 0.001).ConclusionPatients follow a heterogeneous pathway to receive care. One‐fourth of patients experienced delays accessing SLE‐specialized care, which was associated with disease‐related damage. Fewer manifestations, hematologic manifestations, or antiphospholipid antibodies were associated with delays.image