Incident RA Research Articles

Comparing Glucagon-like peptide-1 receptor agonists versus metformin in drug-naive patients: A nationwide cohort study.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly being prescribed in drug-naive patients. We aimed to contrast add-on therapy, adherence, and changes in biomarkers, 1 year after treatment initiation with GLP-1 RA or metformin. Using Danish nationwide registers, we included incident GLP-1 RA or metformin users from 2018 to 2021 with glycated hemoglobin (HbA1c) ≥ 42 mmol/mol. GLP-1 RA initiators were matched to metformin initiators in a ratio of 1:1 to assess outcomes in prediabetes and diabetes. Main outcomes analyzed were 1-year risk of add-on glucose-lowering medication and 1-year risk of nonadherence. One-year risks were estimated with multiple logistic regression and standardized. Multiple linear regression was used to estimate the average differences in biomarker changes. In total, 1778 individuals initiating GLP-1 RA and metformin were included. After standardizing for various factors, GLP-1 RA compared with metformin was associated with reduced 1-year risk of add-on glucose-lowering treatment in patients with prediabetes (1-year risk ratio [RR]: 0.27, 95% confidence interval [CI]: 0.10-0.44) and diabetes (RR: 0.67, 95% CI: 0.37-0.98). GLP-1 RA was associated with higher 1-year risk of nonadherence among patients with prediabetes (RR: 1.60, 95% CI: 1.45-1.75), but no difference in patients with diabetes (RR: 0.88, 95% CI: 0.70-1.06). Compared to metformin, GLP-1 RA was associated with greater HbA1c reduction (prediabetes: -2.59 mmol/mol 95% CI: -3.10 to -2.09, diabetes: -3.79 mmol/mol, 95% CI: -5.28 to -2.30). GLP-1 RA was associated with a reduced risk of additional glucose-lowering medication, achieving better glycated hemoglobin control overall. However, among patients with prediabetes, metformin was associated with better adherence.

Gene-respiratory disease interactions for rheumatoid arthritis risk

ObjectiveWe aimed to identify gene by respiratory tract disease interactions that increase RA risk. MethodsIn this case-control study using the Mass General Brigham Biobank, we matched incident RA cases, confirmed by ACR/EULAR criteria, to four controls on age, sex, and electronic health record history. Genetic exposures included a validated overall genetic risk score (GRS) for RA, a Human Leukocyte Antigen (HLA) GRS for RA, and the MUC5B promoter variant, an established risk factor for RA-associated interstitial lung disease (ILD). Preceding respiratory tract diseases came from diagnosis codes (positive predictive value 86%). We estimated attributable proportions (AP) and multiplicative odds ratios (OR) with 95% confidence intervals (CI) for RA for each genetic and respiratory exposure using conditional logistic regression models, adjusting for potential confounders. ResultsWe identified 653 incident RA cases and 2,607 matched controls (mean 54 years, 76% female). The highest tertile of the overall GRS and the HLA GRS were both associated with increased RA risk (OR 2.28, 95% CI 1.89,2.74; OR 2.02, 95% CI 1.67–2.45). ILD and the HLA GRS exhibited a synergistic relationship for RA risk (OR for both exposures 4.30, 95% CI 1.28,14.38; AP 0.51, 95% CI-0.16,1.18). Asthma and the MUC5B promoter variant also exhibited a synergistic interaction for seropositive RA (OR for both exposures 2.58, 95% CI 1.10,6.07; AP 0.62, 95% CI 0.24,1.00). ConclusionILD-HLA GRS and asthma-MUC5B promoter variant showed synergistic interactions for RA risk. Such interactions may prove useful for RA prevention and screening.

Mortality in patients with incident rheumatoid arthritis and depression: a Danish cohort study of 11 071 patients and 55 355 comparators.

In patients with RA, the association between mortality and depression has been investigated only in patients with prevalent RA. In this study, we estimated the mortality risk associated with depression, defined as the first filling of a prescription for antidepressants, in patients with incident RA and background population comparators. From 2008 to 2018, we identified patients with incident RA in the nationwide Danish rheumatologic database, DANBIO. For each patient, we randomly selected five comparators. Participants were not treated with antidepressants or diagnosed with depression 3 years prior to the index date. From other registers we collected data on socioeconomic status, mortality and cause of death using unique personal identifiers. Using Cox models, we calculated hazard rate ratios (HRR) with 95% CI. In depressed patients with RA vs patients without depression, adjusted HRR for all-cause mortality was 5.34 (95% CI 3.02, 9.45) during 0-2 years and 3.15 (95% CI 2.62, 3.79) during the total follow-up period, and highest in patients <55 years with HRR 8.13 (95% CI 3.89, 17.02). In comparators with depression vs comparators without depression, the association with mortality was similar to that in patients with RA. There were no unnatural causes of death among depressed patients with RA. The most frequent natural causes of death were cancer, cardiovascular disease, stroke and pneumonia. In patients with RA, depression was a predictor of death but with a strength similar to that in matched comparators.

Risk of severe infections after the introduction of biologic DMARDs in people with newly diagnosed rheumatoid arthritis: a population-based interrupted time-series analysis.

To determine the impact of the introduction of biologic DMARDs (bDMARDs) on severe infections among people newly diagnosed with RA compared with non-RA individuals. In this population-based retrospective cohort study using administrative data (from 1990-2015) for British Columbia, Canada, all incident RA patients diagnosed between 1995 and 2007 were identified. General population controls with no inflammatory arthritis were matched to RA patients based on age and gender, and were assigned the diagnosis date (i.e. index date) of the RA patients they were matched with. RA/controls were then divided into quarterly cohorts according to their index dates. The outcome of interest was all severe infections necessitating hospitalization or occurring during hospitalization after the index date. We calculated 8-year severe infection rates for each cohort and conducted interrupted time-series analyses to compare severe infection trends in RA/controls with index date during pre-bDMARDs (1995-2001) and post-bDMARDs (2003-2007) periods. A total of 60 226 and 588 499 incident RA/controls were identified. We identified 14 245 severe infections in RA, and 79 819 severe infections in controls. The 8-year severe infection rates decreased among RA/controls with increasing calendar year of index date in the pre-bDMARDs period, but increased over time only among RA, not controls, with index date in the post-bDMARDs period. The adjusted difference between the pre- and post-bDMARDs secular trends in 8-year severe infection rates was 1.85 (P = 0.001) in RA and 0.12 (P = 0.29) in non-RA. RA onset after bDMARDs introduction was associated with an elevated severe infection risk in RA patients compared with matched non-RA individuals.

Lifetime female hormonal exposure and risk of rheumatoid arthritis in postmenopausal women: Results from the French E3N cohort.

To assess the relationships between lifetime female hormonal exposures and the risk of incident RA in postmenopausal women. E3N is an ongoing French prospective cohort of 98,995 women since 1990 aged 40-65 years at enrolment. Data on reproductive/hormonal factors and treatments were regularly recorded. Exposures were defined as follows:-reproductive span (in years)=duration from menarche to menopause;-total ovulatory years=reproductive span-(number of full-term pregnancies×0.75+number of miscarriages×0.25+total duration of breast feeding+total duration of oral contraception);-lifetime duration of hormonal exposure (in years)=reproductive span+total duration of menopausal hormonal therapy;-composite estrogen score (CES, range=0-6): 1 point for each item: early menarche, high parity, history of hysterectomy, use of oral contraception, use of menopausal hormonal therapy and late menopause. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of incident RA were estimated using Cox proportional hazards regression models with age as the time scale. Among the 78,391 postmenopausal cohort women, 637 validated incident RA cases occurred. Lifetime durations of hormonal exposures were not associated with incident RA in postmenopausal women. High (CES=4-6) versus low (CES=0-1) estrogen exposure was inversely associated with the risk of RA: HR 0.37; 95% CI 0.2-0.8. In the E3N cohort, high lifetime estrogen exposure, that summarizes cumulative endogenous and exogenous exposures, was associated with a decreased risk of RA in postmenopausal women.

Association between beverage consumption and risk of rheumatoid arthritis: a prospective study from the French E3N Cohort.

To assess the relationship between consumption of largely consumed beverages (coffee, tea, alcohol and soft drinks) and the risk of RA. The E3N Study (Étude Épidémiologique auprès des femmes de la Mutuelle Générale de l'Éducation Nationale) is a French prospective cohort including 98 995 women since 1990. Food and beverage consumption was assessed using a validated food-frequency questionnaire. Hazard ratios (HR) and their 95% CI for incident RA were estimated by Cox proportional hazards model. Among 62 631 women, 481 incident RA cases were identified. Consumptions of tea, alcohol and sugar-sweetened soft drinks were not associated with RA risk. We observed a linear association between coffee consumption and RA risk [≥4 cups/day vs ≤1cup/day, HR = 1.24; 95% CI (0.94, 1.64), Ptrend = 0.04], and a higher risk of RA with artificially sweetened soft drinks consumption [consumers vs not, HR = 1.66; 95% CI (1.12, 2.45)], particularly in never-smokers. Among ever-smokers, moderate liquor intake was associated with a reduced risk of RA [1-3 glasses/week vs non-consumers, HR = 0.63; 95% CI (0.43, 0.91)] and moderate wine consumption with a reduced risk of seropositive RA. In a large cohort of women, tea, alcohol and sugar-sweetened soft drinks consumption was not associated with RA risk, whereas consumption of coffee (especially caffeinated coffee), and artificially sweetened soft drinks was associated with higher RA risk, particularly among never-smokers. If further confirmed, these results could lead to novel mechanistic hypotheses and to simple prevention measures.

Association between work physical activity, dietary factors, and risk of rheumatoid arthritis

ObjectiveWe aimed to determine the association of physical activity and dietary factors on RA risk. MethodsThis 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. ResultsWe 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. ConclusionActive 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.

Long-term weight changes and risk of rheumatoid arthritis among women in a prospective cohort: a marginal structural model approach.

To examine the association of long-term weight change with RA risk in a large prospective cohort study. The Nurses' Health Study II started in 1989 (baseline); after exclusions, we studied 108 505 women 25-42 years old without RA. Incident RA was reported by participants and confirmed by medical record review. Body weight was reported biennially through 2015. We investigated two time-varying exposures: weight changes from baseline and from age 18; change was divided into five categories. We used a marginal structural model approach to account for time-varying weight change and covariates. Over 2 583 266 person-years, with a median follow-up time of 25.3 years, 541 women developed RA. Compared with women with stable weight from baseline, weight change was significantly associated with increased RA risk [weight gain 2-<10 kg: RR = 1.98 (95% CI 1.38, 2.85); 10-<20 kg: RR = 3.28 (95% CI 2.20, 4.89); ≥20 kg: RR = 3.81 (95% CI 2.39, 6.07); and weight loss >2 kg: RR = 2.05 (95% CI 1.28, 3.28)]. Weight gain of 10 kg or more from age 18 compared with stable weight was also associated with increased RA risk [10-< 20 kg: RR = 2.12 (95% CI 1.37, 3.27), ≥20 kg: RR = 2.31 (95% CI 1.50, 3.56)]. Consistent findings were observed for seropositive and seronegative RA. Long-term weight gain was strongly associated with increased RA risk in women, with weight gain of ≥20 kg associated with more than a three-fold increased RA risk. Maintenance of healthy weight may be a strategy to prevent or delay RA.

Female hormonal exposures and risk of rheumatoid arthritis in the French E3N-EPIC cohort study.

To assess the relationships between female hormonal exposures and risk of RA in a prospective cohort of French women. E3N (Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale) is an on-going French prospective cohort that included 98995 women aged 40-65 years in 1990. Every 2-3 years, women completed mailed questionnaires on their lifestyles, reproductive factors and health conditions. Cox proportional hazards regression models were used to determine factors associated with risk of incident RA, with age as the time scale, adjusted for known risk factors of RA, and considering endogenous and exogenous hormonal factors. Hazard ratios (HRs) and 95% CIs were estimated. Effect modification by smoking history was investigated. A total of 698 incident cases of RA were ascertained among 78452 women. In multivariable-adjusted Cox regression models, risk of RA was increased with early age at first pregnancy (<22 vs ≥27 years; HR = 1.34; 95% CI 1.0, 1.7) and menopause (≤45 vs ≥53 years; HR = 1.40; 95% CI 1.0, 1.9). For early menopause, the association was of similar magnitude in ever and never smokers, although the association was statistically significant only in ever smokers (HR = 1.54; 95% CI 1.0, 2.3). We found a decreased risk in nulliparous women never exposed to smoking (HR = 0.44; 95% CI 0.2, 0.8). Risk of RA was inversely associated with exposure to progestogen only in perimenopause (>24 vs 0 months; multi-adjusted HR = 0.77; 95% CI 0.6, 0.9). These results suggest an effect of both endogenous and exogenous hormonal exposures on RA risk and phenotype that deserves further investigation.

Rheumatoid factor and anti-citrullinated peptide antibodies in the general population: hepatitis B and C virus association and 15-year-risk of rheumatoid arthritis.

The study aimed to determine the prevalence of rheumatoid factor (RF) and anti-citrullinated peptides (ACPA), to estimate the association with hepatitis B (HBV) or C (HCV) virus infections and the 15-year risk of developing RA in a large cohort from a Northern Italian region. In 1998, 15,907 subjects between the ages of 18 and 75 were randomly selected 1:4 for HBV and HCV testing; more recently, we tested a subgroup of sera for RF (n=2196) and ACPA (n=2525). Administrative databases were searched after 15 years for incident RA diagnoses occurring between 1998 and 2013. RF was positive in 8.1% of cases with 10% of RF-positive subjects having HBsAg (p=0.004) and 9% anti-HCV. ACPA were detected in 4.8% of subjects with 5% of the ACPA-positive subjects having HBsAg and 5.9% anti-HCV. Older subjects had higher positivity rates for both RF and ACPA. HBsAg and anti-HCV were detected in 5.5% and 4.3% of sera, respectively. Over 15 years, 10 RA cases were recorded (9 women, median age at diagnosis 52 years) with RF previously positive in 2/10 and ACPA in 5/10 cases. RF and ACPA were associated with relative risks for developing RA of 5.7 (adjusted for HBsAg status; 95% CI 1.2-26.3) and 13.2 (95% CI 3.8-46.3), respectively. Our data in a large cohort from an unselected general population confirm a higher risk of RA development associated with ACPA compared to RF. HBV exposure correlates with RF but not with ACPA positivity.

Ten-year risk of cerebrovascular accidents in incident rheumatoid arthritis: a population-based study of trends over time.

To evaluate secular trends in 10-year risk of incident cerebrovascular accidents (CVA), in incident RA relative to the general population. We conducted a retrospective study of a population-based incident cohort with RA onset from 1997 to 2004 in British Columbia, Canada, with matched general population controls (2:1), using administrative health data. RA and general population cohorts were divided according to year of RA onset, defined according to the first RA visit of the case definition. Incident CVA was defined as the first CVA occurring within 10 years from the first RA visit. Secular trend was assessed using delayed-entry Cox models with a two-way interaction term between the year of RA onset and indicator of RA vs general population. Linear, quadratic and spline functions of year of RA onset were compared with assess non-linear effects. The model with the lowest Akaike Information Criterion was selected. Overall, 23545 RA and 47090 general population experienced 658 and 1220 incident CVAs, respectively. A spline Cox model with a knot at year of onset 1999 was selected. A significant decline in risk of CVA was observed in individuals with RA onset after 1999 [0.90 (0.86, 0.95); P = 0.0001]. The change in CVA risk over time differed significantly in RA with onset from 1999 onwards compared with the general population (P-value of interaction term = 0.03), but not before 1999 (P = 0.06). Our findings suggest that people with RA onset from 1999 onwards, had a significantly greater decline in 10-year risk of CVA compared with the general population.

Cardiovascular risk and mortality in rheumatoid arthritis compared with diabetes mellitus and the general population

To compare risk of cardiovascular disease and mortality in patients with incident RA, diabetes mellitus (DM) and the general population (GP). Patients diagnosed with incident RA were matched 1:5 by age, sex and year of RA diagnosis with the GP. In the same period, patients with incident DM were included. Outcomes were heart failure (HF), myocardial infarction (MI), coronary revascularization, stroke, major adverse cardiovascular events (MACE) and death up to 10 years after diagnosis. We included 15032 patients with incident RA, 301246 patients with DM and 75160 persons from the GP. RA patients had an increased risk of HF [hazard ratio (HR) 1.51, 95% CI: 1.38, 1.64], MI (HR 1.58, 95% CI: 1.43, 1.74), percutaneous coronary intervention (PCI; HR 1.44, 95% CI: 1.27, 1.62), coronary artery bypass grafting (CABG; HR 1.30, 95% CI: 1.05, 1.62) and stroke (HR 1.22, 95% CI: 1.12-1.33) compared with the GP. However, the 10-year all-cause mortality was at the same level as observed in the GP. Cardiac death and MACE were increased in RA compared with the GP. When compared with patients with DM, RA patients had a lower adjusted risk of HF (HR 0.79, 95% CI: 0.73, 0.85), CABG (HR 0.62, 95% CI: 0.51, 0.76) and stroke (HR 0.82, 95% CI: 0.76, 0.89), and similar risk of MI and PCI. DM patients had the highest risk of 10-year mortality, cardiac death and MACE. This study demonstrates that RA is associated with an increased risk of HF, MI, stroke and coronary revascularization than found in the GP but without reaching the risk levels observed in DM patients.

The risk and trend of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a general population-based study.

To estimate the overall risk of venous thromboembolism (VTE), pulmonary embolism (PE) and deep vein thrombosis (DVT) among patients newly diagnosed with RA compared with the general population without RA; and to estimate the risk trends of VTE, PE and DVT after RA diagnosis up to 5 years compared with the general population. Using previously validated RA case definition, we conducted a matched cohort study using the population-based administrative health database from the province of British Columbia, Canada. We calculated incidence rates (IRs) and fully adjusted hazard ratios (HRs) for the risk of VTE, DVT and PE after RA index date. Among 39 142 incident RA patients (66% female, mean age 60), 1432, 543 and 1068 developed VTE, PE and DVT, respectively. IRs for the RA cohort were 3.79, 1.43 and 2.82 per 1000 person-years vs 2.70, 1.03 and 1.94 per 1000 person-years for the non-RA cohort. After adjusting for VTE risk factors, the HRs (95% CI) were 1.28 (1.20, 1.36), 1.25 (1.13, 1.39) and 1.30 (1.21, 1.40) for VTE, PE and DVT, respectively. The fully adjusted HRs for VTE during the first five years after RA diagnosis were 1.60, 1.47, 1.40, 1.30 and 1.28, respectively. A similar trend was shown in PE. This population-based study demonstrates that RA patients have an increased risk of VTE, PE and DVT after diagnosis compared with the general population. This risk is independent of traditional VTE risk factors and is highest during the first year after RA diagnosis, then progressively declined.

Glucocorticoid use is associated with an increased risk of hypertension.

ObjectivesPatients with RA are frequently treated with glucocorticoids (GCs), but evidence is conflicting about whether GCs are associated with hypertension. The aim of this study was to determine whether GCs are associated with incident hypertension in patients with RA.MethodsA retrospective cohort of patients with incident RA and without hypertension was identified from UK primary care electronic medical records (Clinical Practice Research Datalink). GC prescriptions were used to determine time-varying GC use, dose and cumulative dose, with a 3 month attribution window. Hypertension was identified through either: blood pressure measurements >140/90 mmHg, or antihypertensive prescriptions and a Read code for hypertension. Unadjusted and adjusted Cox proportional hazards regression models were fitted to determine whether there was an association between GC use and incident hypertension.ResultsThere were 17 760 patients in the cohort. A total of 7421 (42%) were prescribed GCs during follow-up. The incident rate of hypertension was 64.1 per 1000 person years (95% CI: 62.5, 65.7). The Cox proportional hazards model indicated that recent GC use was associated with a 17% increased hazard of hypertension (hazard ratio 1.17; 95% CI: 1.10, 1.24). When categorized by dose, only doses above 7.5 mg were significantly associated with hypertension. Cumulative dose did not indicate a clear pattern.ConclusionRecent GC use was associated with incident hypertension in patients with RA, in particular doses ≥7.5 mg were associated with hypertension. Clinicians need to consider cardiovascular risk when prescribing GCs, and ensure blood pressure is regularly monitored and treated where necessary.

THU0133 DIAGNOSES AND COMORBIDITIES IN PRE-RHEUMATOID ARTHRITIS: COMPARISON BETWEEN SEROPOSITIVE AND SERONEGATIVE PATIENTS AND MATCHED NON-RA SUBJECTS

Background:Previous studies have suggested that comorbidities accumulate before the clinical diagnosis of RA, i.e., ‘pre-RA’ (1). Understanding patterns of diagnoses and comorbidities during the pre-RA period may provide new insights into pathogenesis.Objectives:To elucidate diagnoses and comorbidities before the onset of clinically apparent RA compared to non-RA subjects, and for seropositive (RF and/or CCP positive) compared to seronegative (RF and CCP negative) patients with RA.Methods:Adult residents of Olmsted County, Minnesota, with incident RA in 1999-2013 fulfilling the 1987 ACR classification criteria were identified by medical record review. Patients were age- and sex-matched 1:1 to non-RA controls from the same underlying population. The index date for each control corresponded to the incidence date of the matched RA patient. ICD9/10 diagnosis codes (≥2 codes ≥30 days apart prior to index date) were categorized using 161 chronic conditions identified by Clinical Classification Software. Logistic regression models adjusted for age and sex were used to estimate odds ratios (OR) and 95% confidence intervals (CI).Results:The study included 597 RA patients (388 seropositive, 209 seronegative) and 594 controls. The median (range) age was 55 (19-91) years and 70% were female. The median (IQR) of total comorbidities at index was higher among RA patients at 3 (1-6) than controls at 2 (1-5) (p&lt;.001). The median (IQR) of total comorbidities at index was higher in seronegative RA at 4 (2-7) compared to seropositive RA at 3 (1-5) (p=.001); the proportion with six or more was 37% vs. 24% respectively (p&lt;.001). The Table shows the ORs (95% CI) for comorbidities with statistically significant associations with RA overall. The magnitude of the association between total comorbidities and RA peaked at 5+ comorbidities (OR 1.84; 95% CI 1.4-2.43). Spondylosis, intervertebral disc disorders, and back problems (OR 2.38; 95% CI 1.31-4.34); polymyalgia (OR 3.84; 95% CI 1.71-9.16); and systemic lupus erythematosus or other connective tissue disorders (OR 5.3; 95% CI 1.78-19.4) were more prevalent than among seronegative than seropositive patients.Table.Statistically significant associations between comorbidity categories and RA, adjusting for age and sex.Comorbidity Category DescriptionNon-RAN (%)RAN (%)Odds Ratio(95% CI)Polymyalgia1 (0.2%)30 (5%)35.8 (7.51-643)Systemic lupus erythematosus and connective tissue disorders0 (0%)15 (2.5%)31.7 (4.25-4051)Other respiratory disease1 (0.2%)6 (1.0%)6.17 (1.03-118)Hypertension with complications and secondary hypertension2 (0.3%)9 (1.5%)4.57 (1.16-30.2)Anemia (including pregnancy)3 (0.5%)11 (1.8%)3.7 (1.15-16.4)Other circulatory disease4 (0.7%)12 (2.0%)3.03 (1.05-10.9)Osteoarthritis67 (11.3%)138 (23.1%)2.6 (1.87-3.67)Other connective tissue disease17 (2.9%)35 (5.9%)2.19 (1.21-4.12)Fibromyalgia16 (2.7%)34 (5.7%)2.19 (1.21-4.11)Other nervous system disorders43 (7.2%)82 (13.7%)2.04 (1.39-3.04)Other upper respiratory disease23 (3.9%)41 (6.9%)1.83 (1.09-3.14)Asthma37 (6.2%)63 (10.6%)1.78 (1.17-2.74)Coronary atherosclerosis and other heart disease44 (7.4%)63 (10.6%)1.56 (1.01-2.43)Thyroid disorders78 (13.1%)107 (17.9%)1.46 (1.06-2.02)Conclusion:The findings provide new insights about diagnoses and comorbidities preceding clinically apparent RA. Future studies of retrospective medical records for patients with particular comorbidities may provide new insights into the pathogenesis and clinical features of the transition from pre-RA to clinically overt RA, especially for seronegative disease.

Chronic diarrhoea and risk of rheumatoid arthritis: findings from the French E3N-EPIC Cohort Study.

To assess the relationship between gastrointestinal disorders and the risk of further development of RA. The Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition Study is a French prospective cohort including 98 995 healthy women since 1990. Participants completed mailed questionnaires on their lifestyles and health-related information. Gastrointestinal disorders were assessed in the third questionnaire (sent in 1993). Hazard ratios and 95% CIs for incident RA were estimated using Cox proportional hazards regression models with age as the time scale. Models were age adjusted, and then additionally adjusted for known risk factors of RA such as smoking, and for potential cofounders. Among 65 424 women, 530 validated incident RA cases were diagnosed after a mean (s.d.) of 11.7 (5.9) years after study baseline. In comparison with no gastrointestinal disorder, chronic diarrhoea was associated with an increased risk of developing RA during follow-up (hazard ratio = 1.70, 95% CI 1.13, 2.58), independently of dysthyroidism or dietary habits. The association was stronger among ever-smokers (hazard ratio = 2.21, 95% CI 1.32, 3.70). There was no association between RA risk and constipation or alternating diarrhoea/constipation. Chronic diarrhoea was associated with an increased risk of subsequent RA development, particularly among ever-smokers. These data fit with the mucosal origin hypothesis of RA, where interaction between intestinal dysbiosis and smoking could occur at an early stage to promote emergence of autoimmunity, followed years later by clinical disease.

Circulating plasma metabolites and risk of rheumatoid arthritis in the Nurses' Health Study.

RA develops slowly over years. We tested for metabolic changes prior to RA onset using a large non-targeted metabolomics platform to identify novel pathways and advance understanding of RA development. Two hundred and fifty-four incident RA cases with plasma samples drawn pre-RA onset in the Nurses' Health Study (NHS) cohorts were matched 1:2 to 501 controls on age, race, menopause/post-menopausal hormone use and blood collection features. Relative abundances of 360 unique, known metabolites were measured. Conditional logistic regression analyses assessed associations between metabolites and incidence of RA, adjusted for age, smoking and BMI, accounting for multiple comparisons. Subgroup analyses investigated seropositive (sero+) RA and RA within 5 years of sample collection. Significant metabolites were then tested in a female military pre-RA case-control study (n = 290). In the NHS, metabolites associated with RA and sero+RA in multivariable models included 4-acetamidobutanoate (odds ratio (OR) = 0.80/S.d., 95% CI: 0.66, 0.95), N-acetylputrescine (OR = 0.82, 95% CI: 0.69, 0.96), C5 carnitine (OR = 0.84, 95% CI: 0.71, 0.99) and C5:1 carnitine (OR = 0.81, 95% CI: 0.68, 0.95). These were involved primarily in polyamine and leucine, isoleucine and valine metabolism. Several metabolites associated with sero+RA within 5 years of diagnosis were replicated in the independent military cohort: C5 carnitine (OR = 0.55, 95% CI: 0.33, 0.92), C5:1 carnitine (OR = 0.62, 95% CI: 0.39, 0.99) and C3 carnitine (OR = 0.57, 95% CI: 0.36, 0.91). Several metabolites were inversely associated with incidence of RA among women. Three short-chain acylcarnitines replicated in a smaller dataset and may reflect inflammation in the 5-year period prior to sero+RA diagnosis.

The risk of deliberate self-harm following a diagnosis of rheumatoid arthritis or ankylosing spondylitis: A population-based cohort study.

ObjectiveRheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with mental illness. The risk of serious mental illness, including deliberate self-harm (DSH), in these conditions is not well known. We aimed to determine if RA or AS independently increases the risk for DSH.MethodsWe conducted retrospective, population-based cohort studies using administrative health data for the province of Ontario, Canada between April 1, 2002 and March 31, 2014. Individuals with incident RA (N = 53,240) or AS (N = 13,964) were separately matched 1:4 by age, sex, and year with comparators without RA or AS. The outcome was a first DSH attempt identified using emergency department data. We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for risk of DSH in RA and AS versus comparators, adjusting for demographic, clinical and health service utilization variables.ResultsSubjects with AS were significantly more likely to self-harm (crude incidence rate [IR] of 0.68/1,000 person years [PY] versus 0.32/1,000 PY in comparators), with an adjusted HR of 1.59 (95% CI 1.15 to 2.21). DSH was increased for RA subjects (IR 0.35/1,000 PY) versus comparators (IR 0.24/1,000 PY) only before (HR 1.43, 95% CI 1.16 to 1.74), but not after covariate adjustment (HR 1.07, 95% CI 0.86 to 1.33).ConclusionsAS carries an increased risk for DSH but no such risk was observed in RA. Further evaluation of at-risk AS subjects is needed, including the longitudinal effects of disease and arthritis therapies on self-harm behaviour. This will inform whether specific risk-reduction strategies for DSH in inflammatory arthritis are needed.

Opioid Use among Patients with Early Inflammatory Arthritides Compared to the General Population.

To assess to what extent the worldwide opioid epidemic affects Finnish patients with early inflammatory arthritis (IA). From the nationwide register maintained by the Social Insurance Institution of Finland, we collected all incident adult patients with newly onset seropositive and seronegative rheumatoid arthritis (RA+ and RA-) and undifferentiated arthritis (UA) between 2010 and 2014. For each case, 3 general population (GP) controls were matched according to age, sex, and place of residence. Drug purchases between 2009 and 2015 were evaluated 1 year before and after the index date (date of IA diagnosis), further dividing this time into 3-month periods. A total of 12,115 patients (66% women) were identified. At least 1 opioid purchase was done by 23-27% of the patients 1 year before and 15-20% one year after the index date. Relative risk (RR) of opioid purchases compared to GP was highest during the last 3-month time period before the index date [RR 2.81 (95% CI 2.55-3.09), 3.06 (2.68-3.49), and 4.04 (3.51-4.65) for RA+, RA-, and UA, respectively] but decreased after the index date [RR 1.38 (1.23-1.58), 1.91 (1.63-2.24), and 2.51 (2.15-2.93)]. Up to 4% of the patients were longterm users both before and after the diagnosis. During 2009-15 in Finland, opioid use peaked just before the diagnosis of IA but decreased rapidly after that, suggesting effective disease control, especially in seropositive RA. Further, opioids were used to treat arthritis pain of patients with incident RA and UA less often than previously reported from other countries.

Prognostic value of comorbidity indices and lung diseases in early rheumatoid arthritis: a UK population-based study.

ObjectivesWe assessed comorbidity burden in people with RA at diagnosis and early disease (3 years) and its association with early mortality and joint destruction. The association between lung disease and mortality in RA is not well studied; we also explored this relationship.MethodsFrom a contemporary UK-based population (n = 1, 475 762) we identified a cohort with incident RA (n = 6591). The prevalence of comorbidities at diagnosis of RA and at 3 years was compared with age- and gender-matched controls (n = 6591). In individuals with RA we assessed the prognostic value of the Charlson Comorbidity Index and Rheumatic Disease Comorbidity Index calculated at diagnosis for all-cause mortality and joint destruction (with joint surgery as a surrogate marker). We separately evaluated the association between individual lung diseases [chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease] and mortality.ResultsRespiratory disease, cardiovascular disease, stroke, diabetes, previous fracture and depression were more common (P < 0.05) in patients with RA at diagnosis than controls. Comorbidity (assessed using RDCI) was associated with all-cause mortality in RA [adjusted hazard ratio (HR) 1.26, 95% CI 1.00–1.60]. There was no association with joint destruction. COPD, but not asthma, was associated with mortality (COPD HR 2.84, 95% CI 1.13–7.12).ConclusionThere is an excess burden of comorbidity at diagnosis of RA including COPD, asthma and interstitial lung disease. COPD is a major predictor of early mortality in early RA. Early assessment of comorbidity including lung disease should form part of the routine management of RA patients.