Davis, John M

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.

Objective Individuals with serum elevations of anti–cyclic citrullinated peptide (anti‐CCP) antibodies are at increased risk for future rheumatoid arthritis (RA). No pharmacologic interventions have been approved for the prevention of RA in such at‐risk individuals. However, hydroxychloroquine (HCQ) is used without supporting clinical trial evidence. Methods In this phase 2 randomized trial, individuals at risk for RA with anti‐CCP3 ≥2 times the upper limit of normal (ULN) were assigned to receive HCQ or placebo for 12 months, with up to 24 months of postdrug follow‐up. The primary outcome was the development of clinical RA, as defined in the protocol, at 36 months. Secondary outcomes included safety, development of inflammatory arthritis (IA), and participant‐reported joint symptoms. Results Of 144 randomized participants, 71 were assigned to HCQ and 73 to placebo. In the modified intent‐to‐treat population, clinical RA occurred in 21 of 69 (30.4%) participants in the HCQ group and 24 of 73 (32.9%) in the placebo group. The risk of clinical RA at 36 months was 0.336 with HCQ and 0.394 with placebo (difference −0.058; 95% confidence interval −0.336 to 0.220; P = 0.52). Results for IA were similar. The occurrence and severity of joint symptoms were not observed to differ between groups. Adverse event incidence was similar between groups. Conclusion In this trial involving individuals with anti‐CCP3 levels ≥2 times the ULN, 12 months of HCQ did not prevent the development of clinical RA at 36 months. image

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 aim of this study was to determine whether pollutants such as fire smoke–related particulate matter <2.5 μm (PM 2.5 ) are associated with incident rheumatoid arthritis (RA) and RA‐associated interstitial lung disease (RA‐ILD). Methods This patient–control study used Veterans Affairs (VA) data from October 1, 2009, to December 31, 2018. We identified patients with incident RA and RA‐ILD using validated algorithms, matching each patient to ≤10 controls on age, sex, and VA enrollment year. We obtained pollutants including fire smoke PM 2.5 , carbon monoxide, nitrogen oxides (NOx), ozone, overall PM 2.5 , PM 10 , and sulfur dioxide (SO 2 ) at least one year before the index date. We fit conditional logistic regression models to estimate adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for incident RA and RA‐ILD, adjusted for confounders. Results We identified 9,701 patients with incident RA (mean age 65 years, 86% male), including 531 patients with RA‐ILD (mean age 69 years, 91% male), and 68,852 matched controls. Fire smoke PM 2.5 was not associated with RA (aOR 1.07, 95% CI 0.92–1.23) but was associated with RA‐ILD (aOR 1.98, 95% CI 1.08–3.62, per 1 μg/m 3 ). Increased levels of NOx were associated with RA (aOR 1.16, 95% CI 1.06–1.27, highest vs lowest quartile). The highest quartiles of ozone (aOR 1.19, 95% CI 1.06–1.34) and PM 10 (aOR 1.25, 95% CI 1.10–1.43) were associated with seronegative RA. Carbon monoxide, overall PM 2.5 , and SO 2 were not, or negatively, associated with RA and RA‐ILD. Conclusion Increased fire smoke PM 2.5 was associated with RA‐ILD, whereas NOx, ozone, and PM 10 were associated with RA risk. Thus, air pollution may increase the risk of RA and RA‐ILD. image

INTRODUCTION: Spondyloarthritis (SpA), the most common extraintestinal manifestation of inflammatory bowel disease (IBD), is reported in up to 39% of patients with IBD. Despite this high prevalence, risk factors of developing SpA in patients with IBD are not well described. In this study, we aimed to determine the factors associated with SpA symptoms and their prevalence in an IBD cohort. METHODS: Two validated screening questionnaires for the detection of SpA in IBD (DETAIL = DETection of Arthritis in Inflammatory boweL diseases, IBIS-Q = IBD Identification of Spondyloarthritis Questionnaire) were administered to patients with IBD without a prior diagnosis of SpA in 6 US academic medical centers. Demographic data, IBD characteristics, and medication history were recorded. RESULTS: Screening questionnaires were completed by 588 patients (220 ulcerative colitis, 349 Crohn's disease, and 19 IBD-unclassified), with a median age of 40 years (interquartile range 30–53) and median disease duration of 12 years (interquartile range 6–22). The number of positive screens was 130 (22%) for DETAIL, 196 (33%) for IBIS-Q, and 204 (35%) for either DETAIL or IBIS-Q. Age, female sex, history of smoking, prior bowel surgery, and history of any biologic or targeted small molecule exposure were associated with a positive screen on univariate analysis. After multivariate analysis, female sex (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.41–2.93), older age (OR 1.02, 95% CI 1.01–1.04), history of smoking (OR 1.67, 95% CI 1.04–2.69), and history of any biologic or targeted small molecule exposure (OR 2.27, 95% CI 1.34–3.84) were independently associated with positive screens. Higher number of biologic exposures was associated with higher risk of positive screens, with the highest risk seen with 3 or more exposures (OR 3.25, 95% CI 1.75–6.03). DISCUSSION: A substantial number of patients with IBD screen positive for SpA symptoms, indicating a potentially high burden of undiagnosed illness. Factors associated with SpA symptoms include older age, female sex, and more severe disease (based on increased number of advanced therapies or prior surgery), whereas IBD phenotype does not independently increase the risk of a positive SpA screen. Further studies are needed to confirm these findings and better characterize SpA in IBD.

ObjectiveSpondyloarthritis (SpA) is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). The application of screening tools to detect SpA in patients with IBD may lead to earlier recognition of SpA and affect treatment decisions.MethodsA combination of two previously described SpA screening questionnaires, the Detection of Arthritis in Inflammatory Bowel Disease (DETAIL) and IBD Identification of Spondyloarthritis Questionnaire (IBIS‐Q), was administered to consecutive patients with IBD attending IBD specialty clinics in six US academic medical centers. Demographic data, IBD, and rheumatology history were extracted by chart review.ResultsA total of 669 patients were analyzed. The median age was 40 years (interquartile range [IQR] 30–54) with a median disease duration of 12 years (IQR 6–22) and moderate to severe IBD based on medication exposure and history of bowel surgery. A total of 81 patients (12%) carried a diagnosis of an inflammatory rheumatic disease, whereas 75 (11%) had consulted a rheumatologist during the previous year. Using published cutoffs, 180 out of 669 patients (27%) screened positive with DETAIL, 266 (40%) with IBIS‐Q, and 275 (41%) with either questionnaire. Axial symptoms were more frequently reported than peripheral musculoskeletal complaints. Notably, 189 out of 275 (69%) screen‐positive patients had neither a documented inflammatory rheumatic disease diagnosis nor a visit with a rheumatologist within the past year.ConclusionA substantial proportion of patients with IBD have symptoms suggestive of SpA, and many of these may have undiagnosed SpA. The IBIS‐Q questionnaire appears to identify more potential SpA cases than DETAIL. Strategies are needed to prioritize rheumatology consultations for those patients with IBD who are most likely to benefit.

ObjectiveThe focus of this study was to assess changes in the cumulative incidence of extra‐articular manifestations of rheumatoid arthritis (ExRAs) and associated mortality risk.MethodsThis study evaluated trends in occurrence of ExRAs using a population‐based inception cohort that included all adult patients with incident rheumatoid arthritis (RA) from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985 to 1999 and 2000 to 2014. The occurrence of ExRAs was determined by manual chart review, and the 10‐year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRAs and between ExRAs and mortality.ResultsThere were 907 patients included, 296 in the 1985 to 1999 cohort and 611 in the 2000 to 2014 cohort. The 10‐year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, P < 0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, P < 0.001) and nonsevere ExRAs (41.4% vs 28.8%, P = 0.001). Identified risk factors for the development of any ExRAs include rheumatoid factor positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43–2.86) and current smoking (HR 1.61, 95% CI 1.10–2.34). Mortality was increased in patients with either nonsevere (HR 1.83, 95% CI 1.18–2.85) or severe ExRAs (HR 3.05, 95% CI 1.44–6.49).ConclusionsThe incidence of ExRAs has decreased over time. Mortality remains increased in patients with ExRAs.