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ObjectiveGrowing evidence suggests that patients with rheumatoid arthritis (RA) have increased risk for dementia. We assessed risk factors for incident dementia in an inception cohort of patients with RA.MethodsThis retrospective population-based cohort study included residents of 8 counties in Minnesota who were ≥ 50 years of age when they met 1987 American College of Rheumatology criteria for incident RA between 1980 and 2014 and were followed until death/migration or December 31, 2019. Patients with dementia before RA incidence were excluded. Incident dementia was defined as 2 relevant International Classification of Diseases, 9th or 10th revision codes at least 30 days apart. Data on sociodemographics, disease characteristics, cardiovascular/cerebrovascular disease (CVD) risk factors, and comorbidities were abstracted from medical records.ResultsThe study included 886 patients with RA (mean age 65.1 yrs, 65.2% female). During the follow-up period (median 8.5 yrs), 103 patients developed dementia. After adjusting for age, sex, and calendar year of RA incidence, older age at RA incidence (HR 1.14 per 1 year increase, 95% CI 1.12-1.17), rheumatoid nodules (HR 1.76, 95% CI 1.05-2.95), hypertension (HR 1.84, 95% CI 1.19-2.85), presence of large joint swelling (HR 2.03, 95% CI 1.14-3.60), any CVD (HR 2.25, 95% CI 1.38-3.66), particularly ischemic stroke (HR 3.16, 95% CI 1.84-5.43) and heart failure (HR 1.82, 95% CI 1.10-3.00), anxiety (HR 1.86, 95% CI 1.16-2.97), and depression (HR 2.63, 95% CI 1.76-3.93) were associated with increased risk of dementia. After adjusting for CVD risk factors and any CVD, all covariates listed above were still significantly associated with risk of dementia.ConclusionApart from age, hypertension, depression, and anxiety, all of which are universally recognized risk factors for dementia, clinically active RA and presence of CVD were associated with an elevated risk of dementia incidence among patients with RA.

Aims To assess differences in estimated cardiovascular disease (CVD) risk among rheumatoid arthritis (RA) patients from different world regions and to evaluate the management and goal attainment of lipids and blood pressure (BP). Methods and results The survey of CVD risk factors in patients with RA was conducted in 14 503 patients from 19 countries during 2014–19. The treatment goal for BP was Conclusion We revealed considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for LLT was observed, and only half the patients obtained BP goal. Despite a high focus on the increased CVD risk in RA patients over the last decade, there is still substantial potential for improvement in CVD preventive measures.

OBJECTIVE Treat-to-target (T2T) and shared decision-making are valued features of current guidelines for rheumatoid arthritis (RA) management. Although T2T has demonstrated value for improving RA outcomes, implementation remains inconsistent and lacks standardization and procedures for including patient input. We sought to better understand the impact of shared decisions on T2T and how treatment goal discussions between patients and providers impact RA treatment improvement and satisfaction. METHODS An anonymous, web-based questionnaire was presented to United States residents aged 18 years or older with a self-reported diagnosis of RA by a medical professional with 28 questions regarding socio-demographics, RA disease activity (DA), diagnosis, treatments, outcomes, and goals. Analyses included descriptive statistics with χ2 and rank sum tests for comparisons. RESULTS The questionnaire was completed by 907 people (mean age of 58 years; mean 11 years since diagnosis; 90% female). The majority (571; 63%) did not discuss RA treatment goals with providers. Patients engaging in treatment goal discussions with their providers were three times more likely to be satisfied with their treatment plans. Patients discussing treatment goals with their providers were more likely to have improved DA levels and 68% more likely to reach remission. CONCLUSION A majority of patients with RA report having no treatment goal discussion with their providers; however, these discussions are associated with greater DA improvement and treatment satisfaction. Further research should seek understanding of how shared treatment goal discussions relate to successful RA management and explore the development of practical tools to implement them in regular clinic practice as part of a T2T regimen.

To characterize and compare trends in body mass index (BMI) and variability in BMI between subjects with rheumatoid arthritis (RA) and matched non-RA subjects and to determine predictors of BMI trends and variability within RA subjects. This retrospective population-based cohort study included 1114 Olmsted County, Minnesota residents, 558 with incident RA (age $$\ge$$ 18 years, 1987 ACR criteria met in 1995–2009) and 556 non-RA subjects from the same underlying population with similar age, sex, and index calendar year. All subjects were followed until death, migration, or 12/31/2018. Generalized linear models with smoothing splines and random effects to account for multiple measurements per subject were used to examine trends in BMI measurements over time. Mean BMI of patients with incident RA (28.8 kg/m2) was not significantly different from that of non-RA subjects (28.9 kg/m2). There was no significant difference in BMI trends over time between RA and non-RA cohorts, or between seropositive for rheumatoid factor (RF) and/or citrullinated antibody (CCP-antibody) and seronegative RA patients, or between male and female subjects. RA subjects were noted to have significantly higher BMI variability following diagnosis compared to non-RA subjects [difference in standard deviation between RA and non-RA subjects prior to index (p = 0.12), 0–5 years after index (p = 0.044), and 5–15 years after index (p = 0.013)]. The BMI trajectory of the RA population is not significantly different compared to that of the non-RA population, but patients with RA demonstrate higher variability in BMI following diagnosis compared to the non-RA population.

To identify differences in multimorbidity and individual comorbidities among individuals with rheumatoid arthritis (RA), separated by race and ethnicity.This case-control study within OptumLabs Data Warehouse from 2010 to 2019 matched RA cases (defined by 2 codes plus prescription of an RA drug) to non-RA controls 1:1 on age, sex, race and ethnicity, region, index date of RA, and insurance coverage duration. We defined multimorbidity as the presence of ≥2 or ≥5 validated comorbidities. Logistic regression models calculated adjusted odds of multimorbidity with 95% confidence intervals (95% CIs) within each race and ethnicity.We identified 154,391 RA cases and 154,391 controls (mean age 59.6, 76% female). Black enrollees had the most multimorbidity ≥2/≥5 (73.1%, 34.3%); Asian enrollees had the least (52.4%, 17.3%). Adjusted odds of multimorbidity ≥2 and ≥5 in RA cases versus controls was 2.19 (95% CI 2.16-2.23) and 2.06 (95% CI 2.02-2.09), respectively. This increase was similar across race and ethnicity. However, we observed elevated occurrence of certain comorbidities by race and ethnicity versus controls (P 0.001), including renal disease in White enrollees (4.7% versus 3.2%) and valvular heart disease in Black and White enrollees (3.2% and 2.8% versus 2.6% and 2.2%).Multimorbidity is a problem for all RA patients. Targeted identification of certain comorbidities by race and ethnicity may be a helpful approach to mitigate multimorbidity.

Background: Observational studies suggested that dementia risk in patients with rheumatoid arthritis (RA) is higher than in the general population. Objective: To examine the associations of RA with cognitive decline and dementia, and neuroimaging biomarkers of aging, Alzheimer’s disease, and vascular pathology in adult participants in the Mayo Clinic Study of Aging (MCSA). Methods: Participants with RA were matched 1:3 on age, sex, education, and baseline cognitive diagnosis to participants without RA. RA cases with MRI were also matched with non-cases with available MRI. All available imaging studies (i.e., amyloid and FDG PET, sMRI, and FLAIR) were included. The study included 104 participants with RA and 312 without RA (mean age (standard deviation, SD) 75.0 (10.4) years, 33% male and average follow-up (SD) 4.2 (3.8) years). Results: Groups were similar in cognitive decline and risk of incident dementia. Among participants with neuroimaging, participants with RA (n = 33) and without RA (n = 98) had similar amyloid burden and neurodegeneration measures, including regions sensitive to aging and dementia, but greater mean white matter hyperintensity volume relative to the total intracranial volume (mean (SD)% : 1.12 (0.57)% versus 0.76 (0.69)% of TIV, p = 0.01), and had higher mean (SD) number of cortical infarctions (0.24 (0.44) versus 0.05 (0.33), p = 0.02). Conclusion: Although cognitive decline and dementia risk were similar in participants with and without RA, participants with RA had more abnormal cerebrovascular pathology on neuroimaging. Future studies should examine the mechanisms underlying these changes and potential implications for prognostication and prevention of cognitive decline in RA.

For his Second Labor, Heracles was tasked with slaying the Hydra, a serpentine monster from ancient Greek mythology who possessed many heads. When Heracles attempted to decapitate the monster, two new heads grew in place of each severed head, an expression of hopelessness of such struggle for anyone but the hero. The invulnerability of the Hydra was because of its one immortal head. Once the immortal head was cut off, the monster was defeated, and Heracles' second task was completed.

ObjectiveTo assess trends in incidence of cardiovascular disease (CVD) and mortality following incident CVD events in patients with rheumatoid arthritis (RA) onset in 1980–2009 vs non-RA subjects.MethodsWe studied Olmsted County, Minnesota residents with incident RA (aged > 18 yrs, 1987 American College of Rheumatology criteria met in 1980–2009) and non-RA subjects from the same source population with similar age, sex, and calendar year of index. All subjects were followed until death, migration, or December 31, 2016. Incident CVD events included myocardial infarction and stroke. Patients with CVD before RA incidence/index date were excluded. Cox models were used to compare incident CVD events by decade, adjusting for age, sex, and CVD risk factors.ResultsThe study included 905 patients with RA and 904 non-RA subjects. Cumulative incidence of any CVD event was lower in patients with incident RA in the 2000s vs the 1980s. The HR for any incident CVD in the 2000s vs 1980s was 0.53 (95% CI 0.31–0.93). The strength of association attenuated after adjustment for anti-rheumatic medication use (HR 0.64, 95% CI 0.34–1.22). Patients with RA in the 2000s had no excess in CVD over non-RA subjects (HR 0.71, 95% CI 0.42–1.19). Risk of death after a CVD event was somewhat lower in patients with RA after the 1980s with an HR of 0.54 (95% CI 0.33–0.90) in the 1990s vs 1980s and 0.68 (95% CI 0.33–1.41) in the 2000s vs 1980s.ConclusionThe incidence of major CVD events in RA has declined in recent decades. The gap in CVD occurrence between patients with RA and the general population is closing. Mortality after CVD events in RA may be improving.

OBJECTIVE Since comorbidities such as autoimmune diseases may be associated with rheumatoid arthritis (RA) risk, we hypothesized that a family history of these other conditions might also predict RA. Therefore, we aimed to determine the association between family history of 79 comorbidities and RA. METHODS This case-control study identified 821 cases of RA in the Mayo Clinic Biobank (positive predictive value 95%) and matched 3 controls to each case based on age, sex, recruitment year, and location. Patients self reported family history and characteristics (adjusted). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for RA risk according to the presence of family history for each comorbidity, adjusted for body mass index, race, and smoking. RESULTS Family history of several conditions was associated with developing RA, including rheumatic autoimmune diseases (ORadj 1.89 [95% CI 1.41-2.52]), pulmonary fibrosis (ORadj 2.12 [95% CI 1.16-3.80]), inflammatory bowel disease (ORadj 1.45 [95% CI 1.05-1.98]), hyper/hypothyroidism (ORadj 1.34 [95% CI 1.10-1.63]), and obstructive sleep apnea (ORadj 1.28 [95% CI 1.05-1.55]). Parkinson's disease and type 2 diabetes mellitus were associated with a statistically decreased risk of RA that did not reach the prespecified significance threshold of P < 0.01 (ORadj 0.70 [95% CI 0.49-0.98] and ORadj 0.81 [95% CI 0.67-0.97], respectively). Analyses among 143 cases of incident RA were similar and also suggested an association with a family history of autism (OR 10.5 [95% CI 2.51-71.3]). CONCLUSION Family history of several autoimmune and nonautoimmune comorbidities was associated with increased risk of RA, providing an opportunity to identify novel populations at risk for RA.

We aimed to determine the association of physical activity and dietary factors on RA risk.This case-control study within the Mayo Clinic Biobank matched incident RA cases (two codes plus disease-modifying anti-rheumatic drug, PPV 95%) to controls 1:3 on age, sex, and recruitment year/location. A baseline questionnaire assessed activity and dietary exposures. Logistic regression models calculated adjusted odds ratios (aOR) with 95% confidence intervals (CI) of RA for each of 45 activity/dietary exposures.We identified 212 incident RA cases and 636 controls (mean age 64, 70% female). Active work physical activity was associated with elevated risk of RA (aOR 3.00, 95% CI 1.58-5.69 vs. sedentary); leisure activity was not (aOR 0.96, 95% CI 0.64-1.42 sedentary vs. active). Three or more servings high-fat food and 5+ servings fruits/vegetables daily showed non-significant associations with RA (aOR 1.22, 95% CI 0.74-2.00 vs. 0-1 time; aOR 0.75, 95% CI 0.51-1.11 vs. 0-3 times), especially in sensitivity analyses with at least five years between questionnaire and RA (aOR 1.80, 95% CI 0.69-4.71; aOR 0.54, 95% CI 0.27-1.08). Alcohol binging was not associated with RA risk (aOR 1.28, 95% CI 0.56-2.96). Finally, sensitivity (versus primary) analyses showed a nonsignificant increase in RA risk for most vitamins and supplements.Active work physical activity and some nutritional profiles (increased high-fat, reduced fruit/vegetable consumption) may be associated with increased risk of RA. Confirmatory studies are needed.

To identify clusters of comorbidities in patients with rheumatoid arthritis (RA) using 4 methods and to compare to patients without RA.In this retrospective, population-based study, residents of 8 Minnesota counties with prevalent RA as of January 1, 2015 were identified. Age-, sex-, and county-matched non-RA comparators were selected from the same underlying population. Diagnostic codes were retrieved for 5 years before January 1, 2015. Using 2 codes ≥30 days apart, 44 previously defined morbidities and 11 nonoverlapping chronic disease categories based on Clinical Classifications Software were defined. Unsupervised machine learning methods of interest included hierarchical clustering, factor analysis, K-means clustering, and network analysis.Two groups of 1,643 patients with and without RA (72% female; mean age 63.1 years in both groups) were studied. Clustering of comorbidities revealed strong associations among mental/behavioral comorbidities and among cardiovascular risk factors and diseases. The clusters were associated with age and sex. Differences between the 4 clustering methods were driven by comorbidities that are rare and those that were weakly associated with other comorbidities. Common comorbidities tended to group together consistently across approaches. The instability of clusters when using different random seeds or bootstrap sampling impugns the usefulness and reliability of these methods. Clusters of common comorbidities between RA and non-RA cohorts were similar.Despite the higher comorbidity burden in patients with RA compared to the general population, clustering comorbidities did not identify substantial differences in comorbidity patterns between the RA and non-RA cohorts. The instability of clustering methods suggests caution when interpreting clustering using 1 method.

Objective.Both erectile dysfunction (ED) and rheumatoid arthritis (RA) are associated with increased cardiovascular (CV) risk. It is unknown if these diagnoses are associated or if their combination confers additional CV risk. We aimed to define the incidence of ED in RA, and to determine if ED correlates with increased CV risk in RA.Methods.Medical information concerning RA, ED, and CV diagnoses for men with RA (n = 260) diagnosed in Olmsted County, Minnesota, and age-matched male comparators was extracted from a comprehensive medical record system.Results.ED incidence was similar between the RA cohort and comparators (HR 0.80, 95% CI 0.55–1.16). In men with RA, ED diagnosis was associated with a trend toward an increase in peripheral arterial disease (HR 2.22, 95% CI 0.98–5.03) and a significantly decreased rate of myocardial infarction (HR 0.26, 95% CI 0.07–0.90), heart failure (HR 0.49, 95% CI 0.25–0.94), and death (HR 0.56; 95% CI 0.36–0.87). In men with RA and ED, phosphodiesterase-5 inhibitor use was associated with a decreased risk of death (HR 0.35, 95% CI 0.16–0.79), with a trending decreased risk of some CV diagnoses.Conclusion.Incidence of ED was not statistically increased in RA. Although patients with both RA and ED had a similar overall CV risk to those with RA alone, men with both RA and ED had decreased risk of heart failure, myocardial infarction, and death, as well as an increased risk of peripheral arterial disease. Further studies are needed to clarify these associations and their implications for pathogenesis and therapeutics.

Background Case reports and referral-based studies suggest spontaneous coronary artery dissection (SCAD) is associated with autoimmune diseases and causes 2% to 4% of acute coronary syndromes. Objectives This study determined the association of SCAD with autoimmune diseases, together with incidence and recurrence, in a population-based study. Methods This case–control study took place from 1995 to 2018 within the Rochester Epidemiology Project. The study identified cases with SCAD from diagnosis codes and verified them using coronary angiography images, matching each case to 3 control subjects on age, sex, county, and years of medical history. Autoimmune disease history came from a validated, code-based definition. A multivariable logistic regression model calculated the odds ratio (OR) for SCAD among patients with a history of autoimmune disease, adjusting for race and body mass index. Results The study identified 114 cases with SCAD (mean age 51 years and 90% women) and 342 matched control subjects. Autoimmune disease occurred in 13 (11%) cases with SCAD and 40 (12%) control subjects (p = 0.93). Even after adjustment, autoimmune diseases were not associated with SCAD (OR: 0.81; 95% confidence interval [CI]: 0.40 to 1.66). SCAD incidence between 2010 and 2018 (2.7 per 100,000; 95% CI: 1.7 to 3.7) was 10-fold higher than the incidence between 1995 and 2009 (0.3 per 100,000; 95% CI: 0.0 to 0.6). SCAD recurrence was 10% (95% CI: 3% to 16%) at 5 years. Conclusions These findings suggested SCAD pathogenesis is noninflammatory and screening for autoimmune diseases based on SCAD alone is not warranted. The code-based incidence of SCAD has increased over time, highlighting the importance of considering SCAD among patients with acute coronary syndromes.

Introduction The objective was to evaluate the relationships between multimorbidity and overall fatigue as well as fatigue subdomains in patients with rheumatoid arthritis (RA). Methods A cross-sectional study of a population-based cohort of patients with RA was performed. Fatigue was assessed using the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ). Patients’ medical records were reviewed for 25 chronic comorbidities prior to the BRAF-MDQ. Linear and logistic regression models were used to estimate the differences in BRAF-MDQ total and subdomain (physical, living, cognitive, and emotional) scores associated with multimorbidity, adjusting for age, sex, disease duration, obesity, smoking, C-reactive protein, and RA autoantibodies. Higher BRAF-MDQ scores indicate greater fatigue severity. Results The cohort included 192 patients, median age 62 years, and median RA duration 13 years. Multimorbidity was common with 93 (48%) having ≥ 2 comorbidities, and 27 (14%) having ≥ 4 comorbidities. The median BRAF-MDQ total score was 9 (interquartile range 3–18), with higher scores indicating greater fatigue. Patients with ≥ 4 comorbidities had higher total BRAF-MDQ scores (median 16.5, interquartile range: 6.8–24.8) than patients with

ObjectivesTo examine trends in the incidence of rheumatoid arthritis (RA) from 2005 to 2014 overall and by serological status as compared with 1995–2004 and 1985–1994.MethodsWe evaluated RA incidence trends in a population-based inception cohort of individuals aged ≥18 years who first fulfilled the 1987 American College of Rheumatology (ACR) criteria for RA between 1 January 1985 and 31 December 2014. Incidence rates were estimated and were age-adjusted and sex-adjusted to the white population in the USA in 2010. Trends in incidence were examined using Poisson regression methods.ResultsThe 2005–2014 incidence cohort comprised 427 patients: mean age 55.4 years, 68% female, 51% rheumatoid factor (RF) positive and 50% anti-cyclic citrullinated peptide antibody positive. The overall age-adjusted and sex-adjusted annual RA incidence in 2005–2014 was 41/100 000 population (age-adjusted incidence: 53/100 000 in women and 29/100 000 in men). While these estimates were similar to the 1995–2004 decade, there was a decline in the incidence of RF-positive RA in 2005–2014 compared with the previous two decades (p=0.004), with a corresponding increase in RF-negative cases (pConclusionsSignificant increase in incidence of RF-negative RA and decrease in RF-positive RA in 2005–2014 compared with previous decades was found using 1987 ACR criteria. The incidence of RA overall during this period remained similar to the previous decade. The changing prevalence of environmental factors, such as smoking, obesity and others, may have contributed to these trends. Whether these trends represent a changing serological profile of RA requires further investigation.

ObjectiveTo assess trends in the incidence of heart failure (HF) in patients with incident rheumatoid arthritis (RA) from 1980 to 2009 and to compare different HF definitions in RA.MethodsThe study population comprised Olmsted County, Minnesota residents with incident RA (age ≥ 18 yrs, 1987 American College of Rheumatology criteria met in 1980-2009). All subjects were followed until death, migration, or April 30, 2019. Incident HF events were defined as follows: (1) meeting the Framingham criteria for HF, (2) diagnosis of HF (outpatient or inpatient) by a physician, or (3) International Classification of Diseases, 9th revision (ICD-9), or ICD, 10th revision (ICD-10), codes for HF. Patients with HF prior to the RA incidence/index date were excluded. Cox proportional hazards models were used to compare incident HF events by decade, adjusting for age, sex, and cardiovascular risk factors. HF definitions 2 and 3 were compared to the Framingham criteria.ResultsThe study included 905 patients with RA (mean age 55.9 years; 68.6% female; median follow-up 13.4 years). The 10-year cumulative incidence of HF events by any chart-reviewed method in the RA cohort in the 1980s was 11.66% (95% CI 7.86-17.29), in the 1990s it was 12.64% (95% CI 9.31-17.17), and in the 2000s it was 7.67% (95% CI 5.36-10.97). The incidence of HF did not change across the decades of RA incidence using any of the HF definitions. Physician diagnosis of HF and ICD-9/10 code-based definitions of HF performed well compared to the Framingham criteria, showing moderate to high sensitivity and specificity.ConclusionThe incidence of HF in patients with incident RA in the 2000s vs the 1980s was not statistically significantly different. Physician diagnosis of HF and ICD-9/10 codes for HF performed well against the Framingham criteria.

To identify the incidence, risk factors, and outcomes of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to assess time trends in the incidence and mortality in RA-ILD.We included adult residents of Olmsted County, Minnesota with incident RA between 1999 and 2014. Subjects were followed until death, emigration, or April 30, 2019. ILD was defined as the presence of a radiologist-defined pattern consistent with ILD on chest computed tomography (CT). When chest CT was absent, the combination of chest radiograph abnormalities compatible with ILD and restrictive pattern on pulmonary function testing was considered consistent with ILD. Potential risk factors included age, sex, smoking, obesity, seropositivity, extraarticular manifestations (EAMs), and medications. For survival analysis, we matched RA-ILD patients to RA-non-ILD comparators. The frequency and mortality from clinician-diagnosed RA-ILD from 1999 to 2014 was compared against a cohort from 1955 to 1994.During the 1999-2014 time period, 645 individuals (70% women) had incident RA, were a median age of 55.3 years, and 53% never smoked. Twenty-two patients had ILD before RA, and 51 (67% women) developed ILD during follow-up. The 20-year cumulative incidence of RA-ILD was 15.3%. Ever-smoking (hazard ratio [HR] 1.92), age at RA onset (HR 1.89 per 10-year increase), and severe EAMs (HR 2.29) were associated with incident RA-ILD. The RA-ILD cases had higher mortality than their matched RA comparators (HR 2.42). Incidence of RA-ILD was non-significantly lower from 1999 to 2014 than from 1955 to1994, but mortality was improved.RA-ILD occurs in nearly 1 in 6 patients with RA within 20 years and is associated with shorter survival. Lack of significant change in RA-ILD incidence over 6 decades deserves further investigation.

ObjectiveTo comprehensively assess multimorbidity burden in patients with rheumatoid arthritis (RA) in order to unify the multimorbidity definition for RA research and clinical practice.MethodsIn this population-based study, residents of eight Minnesota counties with prevalent RA on 1 January 2015 were identified. Age, sex and county-matched non-RA comparators were selected from the same population. Diagnostic codes were retrieved for 5 years before 1 January 2015. Using two codes ≥30 days apart, 44 previously defined morbidities and 78 non-overlapping chronic disease categories based on Clinical Classification Software were defined. Prevalence of each morbidity in the RA versus non-RA cohorts was compared using false discovery rate to adjust for multiple comparisons. Morbidities more common in RA than non-RA and those with prevalence ≥5% were retained.Results1643 patients with RA and 1643 non-RA subjects (72% women; mean age 63.1 years) were studied. Using the 44 morbidities, multimorbidity (defined as 2+ morbidities) was present in 1411 (86%) of RA and 1164 (71%) of non-RA subjects (pConclusionPatients with RA have a higher prevalence of multimorbidity compared with non-RA subjects. These results confirm the list of 44 morbidities and add several other morbidities of interest in RA.

To determine the prevalence of comorbidities in rheumatoid arthritis (RA), discover which comorbidities might predispose to developing RA, and identify which comorbidities are more likely to develop after RA.We performed a case-control study using a single-center biobank, identifying 821 cases of RA (143 incident RA) between January 1, 2009, and February 28, 2018, defined as 2 diagnosis codes plus a disease-modifying antirheumatic drug. We matched each case to 3 controls based on age and sex. Participants self-reported the presence and onset of 74 comorbidities. Logistic regression models adjusted for race, body mass index, education, smoking, and Charlson comorbidity index.After adjustment for confounders and multiple comparisons, 11 comorbidities were associated with RA, including epilepsy (odds ratio [OR], 2.13; P=.009), obstructive sleep apnea (OR, 1.49; P=.001), and pulmonary fibrosis (OR, 4.63; P.001), but cancer was not. Inflammatory bowel disease (OR, 3.82; P.001), type 1 diabetes (OR, 3.07; P=.01), and venous thromboembolism (VTE; OR, 1.80; P.001) occurred more often before RA diagnosis compared with controls. In contrast, myocardial infarction (OR, 3.09; P.001) and VTE (OR, 1.84; P.001) occurred more often after RA diagnosis compared with controls. Analyses restricted to incident RA cases and their matched controls mirrored these results.Inflammatory bowel disease, type 1 diabetes, and VTE might predispose to RA development, whereas cardiovascular disease, VTE, and obstructive sleep apnea can result from RA. These findings have important implications for RA pathogenesis, early detection, and recommended screening.

To compare the time from first joint swelling to fulfillment of the American College of Rheumatology/European League Against Rheumatism classification criteria between patients with seropositive and seronegative rheumatoid arthritis (RA) and to assess the impact of seronegative status on the time from first joint swelling to initiation of disease-modifying antirheumatic drug (DMARD) therapy and achievement of remission.Times from first provider-documented joint swelling to fulfillment of the 1987 and 2010 American College of Rheumatology/European League Against Rheumatism criteria and to the clinical diagnosis of RA were measured in a population-based cohort of adults with incident RA between January 1, 2009, and December 31, 2014. Disease characteristics and achievement of remission were compared between seropositive (rheumatoid factor positive and/or anti-citrullinated peptide antibody positive) and seronegative (rheumatoid factor negative/anti-citrullinated peptide antibody negative) patients.The median time from first joint swelling to fulfillment of the 1987 (48 [interquartile range (IQR), 0-300] days vs 2 [IQR, 0-45] days; P=.001) and 2010 (14 [IQR, 0-196] days vs 0 [IQR, 0-29] days; P=.004) classification criteria and the median time from first joint swelling to the clinical diagnosis of RA (187 [IQR, 13-503] days vs 11 [IQR, 0-76] days; P.001) were significantly longer in seronegative patients than in seropositive patients. The median time from first joint swelling to first prescribed DMARD therapy was significantly longer in seronegative patients (40 [IQR, 5-199] days vs 14 [IQR, 0-73] days; P=.01). Patients with seronegative RA were less likely to achieve remission (28% vs 50% at 5 years after fulfillment of the 2010 criteria; P=.007), but there was no difference when the patient global score was removed from the remission definition.Patients with seronegative RA experienced a delay in diagnosis, according to both the 1987 and 2010 classification criteria, as well as a delay in the initiation of DMARD therapy. Patients with seronegative RA were also less likely to attain remission, suggesting that the window of opportunity for intervention may be more frequently missed in this group.

The objective of the study was to assess trends in functional disability (FD) in patients with rheumatoid arthritis (RA) vs individuals without RA. This retrospective population-based study included 586 patients with RA and 531 individuals without RA. Information on activities of daily living was obtained from self-report questionnaires. The prevalence of FD was higher in those with RA (586 [26%]) vs those without RA (531 [11%]) at RA incidence/index date (P.001), with persistent excess over the follow-up and calendar time. Patients with RA had a 15% or higher prevalence of FD than individuals without RA in most age groups. Patients with RA have a higher prevalence of FD across RA duration, age, and calendar time than those without RA.

OBJECTIVE. To assess transition probability between different levels of functional disability (FD) and time spent with FD in patients with versus without rheumatoid arthritis (RA) after RA incidence/index date. METHODS. This retrospective population-based cohort study included Olmsted County, Minnesota residents (1987 ACR criteria met in 1999–2013) and comparators without RA from the same area with similar age, sex and RA incidence/index date. Activities of Daily Living (ADL) were obtained by self-report questionnaires annually since 1999. FD was defined as having difficulty with ≥1 ADL. Multistate modeling was used to estimate the probability of transitioning between FD states. RESULTS. Five hundred fifty-eight patients with RA and 457 comparators completed ≥2 questionnaires and were included. Patients with RA had increased risk of transitioning from no FD to FD: Hazard Ratio (HR) 2.4; 95%CI:1.9–3.0. Each additional FD at RA onset reduced the probability of returning to no FD by 14%. However, the probability of having ≥1 FD was stable between RA incidence and 10-year follow-up. In the first 15 years of disease, patients with RA spent on average 10.1 years without FD and 3.4 years with ≥1 FD versus 11.6 years and 2.0 years (p

Objective We aimed to assess the incidence of dementia over time in patients with incident rheumatoid arthritis (RA) as compared to non-RA referents. Methods This population-based, retrospective cohort study included Olmsted County, Minnesota residents with incident RA by ACR 1987 criteria, diagnosed between 1980 and 2009. We matched non-RA referents 1:1 on age, sex, and calendar year and followed all individuals until 12/31/2019. Incident dementia was defined as two codes for Alzheimer's disease and related dementias (ADRD) at least 30 days apart. Cumulative incidence of ADRD was assessed, adjusting for the competing risk of death. Cox proportional hazards models calculated hazard ratios (HR) with 95% confidence intervals (CI) for incident ADRD by decade. Results After excluding individuals with prior dementia, we included 897 persons with incident RA (mean age 56 years; 69% female) and 885 referents. The 10-year cumulative incidence of ADRD in individuals diagnosed with RA during the 1980s was 12.7% (95%CI:7.9–15.7%), 1990s was 7.2% (95%CI:3.7–9.4%), and 2000s was 6.2% (95%CI:3.6–7.8%). Individuals with RA diagnosed in 2000s had insignificantly lower cumulative incidence of ADRD than those in the 1980s (HR 0.66; 95%CI:0.38–1.16). The overall HR of ADRD in individuals with RA was 1.37 (vs. referents; 95%CI:1.04–1.81). When subdivided by decade, however, the risk of ADRD in individuals diagnosed with RA was higher than referents in the 1990s (HR 1.72, 95%CI:1.09–2.70) but not 2000s (HR 0.86, 95%CI:0.51–1.45). Conclusions The risk of dementia in individuals with RA appears to be declining over time, including when compared to general population referents.

To characterize and compare trends in body mass index (BMI) and variability in BMI between subjects with rheumatoid arthritis (RA) and matched non-RA subjects and to determine predictors of BMI trends and variability within RA subjects.This retrospective population-based cohort study included 1114 Olmsted County, Minnesota residents, 558 with incident RA (age ≥ 18 years, 1987 ACR criteria met in 1995-2009) and 556 non-RA subjects from the same underlying population with similar age, sex, and index calendar year. All subjects were followed until death, migration, or 12/31/2018. Generalized linear models with smoothing splines and random effects to account for multiple measurements per subject were used to examine trends in BMI measurements over time.Mean BMI of patients with incident RA (28.8 kg/mThe BMI trajectory of the RA population is not significantly different compared to that of the non-RA population, but patients with RA demonstrate higher variability in BMI following diagnosis compared to the non-RA population. Key Points • This study uniquely characterizes longitudinal trajectory in BMI measures and their variability in the RA population versus the non-RA population • This study suggests that RA patients have greater BMI variability compared to the non-RA population, which is highly relevant as BMI variability is increasingly understood as a cardiovascular risk factor.

ObjectiveTo estimate the prevalence and incidence of multimorbidity (MM) in a population-based cohort of patients with rheumatoid arthritis (RA) compared to subjects without RA.MethodsBetween 1999–2013, residents of Olmsted County, Minnesota with incident RA who met the 1987 American College of Rheumatology criteria were compared to age- and sex-matched non-RA subjects from the same population. Twenty-five chronic comorbidities from a combination of the Charlson, Elixhauser, and Rheumatic Disease Comorbidity Indices were included, excluding rheumatic comorbidities. The Aalen-Johansen method was used to estimate the cumulative incidence of MM (MM2+; ≥ 2 chronic comorbidities) or substantial MM (MM5+; ≥ 5), adjusting for the competing risk of death.ResultsThe study included 597 patients with RA and 594 non-RA subjects (70% female, 90% White, mean age 55.5 yrs). At incidence/index date, the prevalence of MM2+ was higher in RA than non-RA subjects (38% RA vs 32% non-RA, P = 0.02), whereas prevalence of MM5+ was similar (5% RA vs. 4% non-RA, P = 0.68). During follow-up (median 11.6 yrs RA, 11.3 yrs non-RA), more patients with RA developed MM2+ (214 RA vs 188 non-RA; adjusted HR 1.39, 95% CI 1.14–1.69). By 10 years after RA incidence/index, the cumulative incidence of MM2+ was 56.5% among the patients with RA (95% CI 56.5–62.3%) compared with 47.9% among the non-RA (95% CI 42.8–53.7%). Patients with RA showed no evidence of increase in incidence of MM5+ (adjusted HR 1.17, 95% CI 0.93–1.47).ConclusionPatients with RA have both a higher prevalence of MM at the time of RA incidence as well as increased incidence thereafter.

Objective.To examine the relationship between the use of hydroxychloroquine (HCQ) and risk of developing heart failure (HF) in rheumatoid arthritis (RA).Methods.In this nested case-control study, cases were Olmsted County, Minnesota residents with incident RA (based on 1987 American College of Rheumatology criteria) from 1980 to 2013 who developed HF after RA incidence. Each case was matched on year of birth, sex, and year of RA incidence with an RA control who did not develop HF. Data on HCQ use including start and stop dates, as well as dose changes, were reviewed and used to calculate HCQ duration and cumulative dose. Age-adjusted logistic regression models were used to examine the association between HCQ and HF.Results.The study identified 143 RA cases diagnosed with HF (mean age 65.8 yrs, 62% females) and 143 non-HF RA controls (mean age 64.5, 62% female). HCQ cumulative dose was not associated with HF (OR 0.96 per 100-g increase in cumulative dose, 95% CI 0.90–1.03). Likewise, no association was found for patients with a cumulative dose ≥ 300 g (OR 0.92, 95% CI 0.41–2.08). The HCQ duration of intake in years prior to index was not associated with HF (OR 0.98, 95% CI 0.91–1.05).Conclusion.Use of HCQ was not associated with development of HF in patients with RA in this study. Further studies are needed to understand the effect of higher doses of HCQ on the development of HF in RA.

BackgroundRapid advances in the past decade have shown that dysbiosis of the gut microbiome is a key hallmark of rheumatoid arthritis (RA). Yet, the relationship between gut microbiome and clinical improvement in RA disease activity remains unclear. In this study, we explored the gut microbiome of patients with RA to identify features that are associated with, as well as predictive of, minimum clinically important improvement (MCII) in disease activity.MethodsWhole metagenome shotgun sequencing was performed on 64 stool samples, which were collected from 32 patients with RA at two separate time-points. The Clinical Disease Activity Index (CDAI) of each patient was measured at both time-points to assess achievement of MCII; depending on this clinical status, patients were distinguished into two groups. Multiple linear regression models were used to identify microbial taxa and biochemical pathways associated with MCII while controlling for potentially confounding factors. Lastly, a deep-learning neural network was trained upon gut microbiome, clinical, and demographic data at baseline to classify patients according to MCII status, thereby enabling the prediction of whether a patient will achieve MCII at follow-up.ResultsWe determined that MCII status can explain a significant proportion of the overall compositional variance in the gut microbiome (R2 = 3.8%, P = 0.005, PERMANOVA). Additionally, by looking at patients’ baseline gut microbiome profiles, we observed significantly different microbiome traits between patients who eventually showed MCII and those who did not. Taxonomic features include alpha- and beta-diversity measures, as well as several microbial taxa, such as Coprococcus, Bilophila sp. 4_1_30, and Ruminococcus sp. Functional profiling identified thirteen biochemical pathways, most of which were involved in the biosynthesis of L-arginine and L-methionine, to be differentially abundant between the MCII patient groups. In addition to these observations at baseline, we found microbiome features that vary differently in fold-change (from baseline to follow-up) between the two patient groups. These results could suggest that, depending on the clinical course, gut microbiomes not only start at different ecological states, but also are on separate trajectories. Finally, the neural network proved to be highly effective in predicting which patient will achieve MCII (balanced accuracy = 90.0%), demonstrating potential clinical utility of gut microbiome profiles.ConclusionsOur findings confirm the presence of taxonomic and functional signatures of the gut microbiome associated with MCII in RA patients. Ultimately, the gut microbiome may aid in the development of non-invasive tools for predicting future prognosis in RA.Trial registrationN/A

Objective: To test the ability of machine learning (ML) approaches with clinical and genomic biomarkers to predict methotrexate treatment response in patients with early rheumatoid arthritis (RA). Methods: Demographic, clinical, and genomic data from 643 patients of European ancestry with early RA (mean age 54 years; 70% female) subdivided into a training (n = 336) and validation cohort (n = 307) were used. The genomic data comprised 160 single-nucleotide polymorphisms (SNPs) previously associated with RA or methotrexate metabolism. Response to methotrexate monotherapy was defined as good or moderate by the European Alliance of Associations for Rheumatology (EULAR) response criteria at the 3-month follow-up. Supervised ML methods were trained with 5 repeats and 10-fold cross-validation using the training cohort. Prediction performance was validated in the independent validation cohort. Results: Supervised ML methods combining age, sex, smoking, rheumatoid factor, baseline Disease Activity Score in 28 joints (DAS28) scores and 160 SNPs predicted EULAR response at 3 months with the area under the receiver operating curve of 0.84 (P = 0.05) in the training cohort and achieved a prediction accuracy of 76% (P = 0.05) in the validation cohort (sensitivity 72%, specificity 77%). Intergenic SNPs rs12446816, rs13385025, rs113798271, and ATIC (rs2372536) had variable importance above 60.0 and along with baseline DAS28 scores were among the top predictors of methotrexate response. Conclusion: Pharmacogenomic biomarkers combined with baseline DAS28 scores can be useful in predicting response to methotrexate in patients with early RA. Applying ML to predict treatment response holds promise for guiding effective RA treatment choices, including timely escalation of RA therapies.

Objective Omega-3 fatty acids may decrease systemic lupus erythematosus (SLE) disease activity, however randomized controlled trials (RCT) have been small with conflicting findings. We conducted a systematic review and meta-analysis to estimate the effect of omega-3 fatty acids on SLE disease activity in adults. Methods A literature search was conducted from database inception to January 2020. RCTs of adults with SLE comparing omega-3 fatty acids supplementation to placebo or standard of care that evaluated SLE disease activity were included. Abstracts, full text reviews, data abstraction and statistical analysis were evaluated independently by two investigators. Study-specific standardized mean differences (SMD) were estimated and combined using random-effects model. Results Five RCTs with 136 patients in the comparison groups and 138 in the treatment groups, were included. All the studies used ≤3 g of omega-3 fatty acids. The trial follow-up time ranged from 12 to 52 weeks. The mean age of the patients was 43 years and 80% or more were female. Omega-3 fatty acids reduced SLE activity [SMD -0.33 (95CI: −0.57, −0.09), low certainty evidence, moderate effect size]. Transforming the SMD to the SLE Disease Activity Index (SLEDAI) scale, omega-3 fatty acids reduced disease activity by 0.9 (95CI: −1.6, −0.3, I2 = 0%) SLEDAI points compared to placebo. Conclusion This meta-analysis suggests that omega-3 fatty acids could provide therapeutic benefit in addition to immunosuppressive regimens used for SLE.