Use of nonbiologic disease‐modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis

Objective

Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease‐modifying antirheumatic drugs (DMARDs) on infection risk in RA.

Methods

We performed a retrospective, longitudinal study of a population‐based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time‐dependent covariates (corticosteroids, comorbidity, prior infections).

Results

A total of 27,710 individuals with RA provided 162,710 person‐years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88–0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85–1.0). Use of corticosteroids increased the risk of mild and serious infections.

Conclusion

Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.     

Rheumatoid arthritis,its treatments,and the risk of tuberculosis in Quebec,Canada

Objective

To determine the risk of tuberculosis (TB) among a cohort of patients with rheumatoid arthritis (RA) in Quebec and assess whether this risk is associated with exposure to nonbiologic disease‐modifying antirheumatic drugs (DMARDs).

Methods

We studied a cohort of patients with RA identified from the Quebec provincial physician billing and hospitalization databases for 1980–2003. TB incidence rates were determined for the period 1992–2003 and compared with the general population, standardized for age and sex using the standardized incidence ratio (SIR). Conditional logistic regression was used in a nested case–control analysis to estimate the rate ratio (RR) of TB related to nonbiologic DMARD exposure during the year before the index date.

Results

Of the 24,282 patients with RA in the cohort, 50 cases of TB were identified. The standardized incidence rate was 45.8 cases per 100,000 person‐years compared with 4.2 cases per 100,000 person‐years in the general population of Quebec (SIR 10.9, 95% confidence interval [95% CI] 7.9–15.0). The adjusted RR of TB was 2.4 (95% CI 1.1–5.4) with corticosteroid use and 3.0 (95% CI 1.6–5.8) with nonbiologic DMARD use.

Conclusion

The age‐ and sex‐standardized incidence rate of TB in RA patients is 10 times that of the general population. At least some of this risk may be related to nonbiologic DMARD and corticosteroid therapies. Our data support the role of TB screening before initiation of any immunosuppressive therapy.     

Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis

OBJECTIVES: To assess the risk of severe infections associated with the use of traditional disease-modifying anti-rheumatic drugs (DMARDs) and glucocorticoid agents in rheumatoid arthritis (RA). METHODS: Our study was a case-control design nested within a cohort of 23 733 RA patients studied between 1 January 1980 and 31 December 2003. Matching on age and gender, and adjusting for comorbidity and physician use, conditional logistic regression was used to estimate the effect of specific drugs on the rate ratio (RR) for infections requiring hospitalization. RESULTS: The risk for all infections requiring hospitalization appeared to be most elevated with current exposures to cyclophosphamide [RR: 3.26, 95% confidence interval (CI): 2.28-4.67] and systemic glucocorticoid agents (RR: 2.56, 95% CI: 2.29-2.85); azathioprine was associated with a moderate increased risk (RR: 1.52, 95% CI: 1.18-1.97). There was a suggestion of increased risk of pneumonia due to methotrexate (RR: 1.16, 95% CI: 1.02-1.33). The results were similar for the period before and after the introduction of anti-tumour necrosis factor (TNF) agents. The RR point estimate for anti-TNF agents suggested about a 2-fold increased risk for all infections, but the estimate was imprecise. CONCLUSIONS: In this large cohort of RA patients, the most heightened risk of serious infections was seen with the use of glucocorticoid agents and immunosuppressive DMARDs. Assessments of infection risk related to newer and emerging therapies should carefully consider concomitant medication exposures, including traditional DMARDs and glucocorticoid therapy.     

Abatacept initiation in rheumatoid arthritis and the risk of serious infection: A population-based cohort study

ObjectiveTo assess whether abatacept as initial biologic disease-modifying antirheumatic drug (DMARD) in the treatment of rheumatoid arthritis is associated with an increased risk of serious infections, including bone and joint, gastrointestinal, respiratory tract, skin and soft tissue, and urinary tract, when compared with other biologic DMARDs.MethodsWe performed a population-based cohort study among patients newly-treated with biologic DMARDs within the US-based Truven MarketScan® population and Supplemental US Medicare from 2007 to 2014. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of serious infections requiring hospitalisation associated with initiation of abatacept, compared with initiation of other bDMARDs, after controlling for age and deciles of the propensity score.ResultsThe cohort included 5,752 patients who initiated abatacept and 78,556 who initiated another biologic DMARD, of whom 193 and 1531 had a serious infection during follow-up (crude incidence rate 4.45 per 100 person-years and 3.62 per 100 person-years, respectively). Compared with other biologic DMARDs, the use of abatacept was not associated with an increased incidence of serious infections overall (HR 1.04, 95% CI 0.89–1.21). The risk did not vary by duration of use (<1 year: HR 1.03, 95% CI 0.87–1.22; >1 year: HR 1.08, 95% CI 0.77–1.52). In addition, the risk was not increased for the site-specific infections.ConclusionThe use of abatacept as first biologic DMARD in the treatment of rheumatoid arthritis was not associated with different risks of serious infections compared with other biologic DMARDs.     

Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register

OBJECTIVE: To determine whether the rate of serious infection is higher in anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). METHODS: This was a national prospective observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis. RESULTS: Between December 2001 and September 2005, there were 525 serious infections in the anti-TNF-treated cohort and 56 in the comparison cohort (9,868 and 1,352 person-years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68-1.57). However, the frequency of serious skin and soft tissue infections was increased in anti-TNF-treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06-17.17). There was no difference in infection risk between the 3 main anti-TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti-TNF-treated cohort. CONCLUSION: In patients with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.     

Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis

OBJECTIVE: To assess the risk of hospitalization for congestive heart failure (CHF) associated with the use of disease-modifying anti-rheumatic drugs (DMARDs) and other medications used in RA. METHODS: We used a case-control design nested within an administrative database cohort of patients with rheumatoid arthritis (RA) who were dispensed a DMARD between September 1998 and December 2001. Subjects identified with a prior history of CHF were excluded. For each hospitalized case of CHF identified during follow-up, 10 controls matched on age and time were randomly selected from the cohort. Conditional logistic regression was used to estimate the rate ratio (RR) of hospitalizations for CHF associated with the current use of specific drugs, adjusted for sex and co-morbidity. RESULTS: The cohort included 41 885 patients; 75% were women, with an average age at cohort entry of 51 yr. During follow-up, 520 hospitalizations for CHF occurred, for a rate of 10.1 per 1000 per year. The adjusted RR of CHF for current use of any DMARD was 0.7 (95% CI 0.6-0.9) relative to no current use. By DMARD category, there was evidence of a beneficial effect for both tumour necrosis factor-alpha antagonists (RR 0.5, 95% CI 0.2-0.9) and methotrexate monotherapy (RR 0.8, 95% CI 0.6-1.0). For non-DMARD medications, the rate of CHF was not clearly increased or decreased, except for COX-2 inhibitors. The data suggested an increased risk of CHF with rofecoxib (RR 1.3, 95% CI 1.0-3.1) and a decreased risk of CHF with celecoxib (RR 0.6, 95% CI 0.4, 1.0). CONCLUSIONS: The use of DMARDs was associated with a reduction in the risk of hospitalizations for CHF in this RA cohort. The increased risk with rofecoxib alongside a decreased risk with celecoxib suggests the absence of a class effect with respect to COX-II inhibitors for some types of cardiovascular morbidity.     

Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis

OBJECTIVE: Spontaneous reports of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) treated with leflunomide, a disease-modifying antirheumatic drug (DMARD), have been appearing recently. To assess this risk, we conducted a population-based epidemiologic study. METHODS: A cohort of 62,734 patients with RA to whom a DMARD had been dispensed between September 1, 1998 and December 31, 2003 was formed using the PharMetrics claims database. A nested case-control design was used, in which each case of serious ILD requiring hospitalization was matched to 100 controls according to age (calendar time) and equal or greater duration of followup, to estimate adjusted rate ratios (RRs) of serious ILD associated with DMARD use. RESULTS: There were 74 cases of serious ILD, which corresponds to a rate of 8.1 per 10,000 patients per year. The risk of ILD was increased with the use of leflunomide (adjusted RR 1.9 [95% confidence interval (95% CI) 1.1-3.6]). Among subjects with no previous methotrexate use and no history of ILD, the risk associated with leflunomide treatment was not elevated (RR 1.2 [95% CI 0.4-3.1]), but it was elevated among the remaining subjects (RR 2.6 [95% CI 1.2-5.6]). Patients with a history of ILD were twice as likely to have been prescribed leflunomide as any other DMARD. CONCLUSION: The reports of ILD associated with leflunomide use are likely the result of channeling of high-risk patients to leflunomide treatment, particularly those with a history of methotrexate use or preexisting ILD. Patients with no history of ILD and no previous methotrexate use show no excess risk of developing ILD with leflunomide treatment.     

Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis

BACKGROUND: Spontaneous cases of hepatic adverse events have been reported in patients with rheumatoid arthritis who were being treated with leflunomide, one of the newer disease-modifying antirheumatic drugs (DMARDs). We assessed the risk of hepatic events associated with the use of leflunomide and other DMARDs. METHODS: Two cohorts comprising 41,885 patients with rheumatoid arthritis who had been dispensed a DMARD between September 1, 1998, and December 31, 2001, were formed using claims databases. Follow-up was from the first dispensing date to the occurrence of a serious or nonserious hepatic event. A nested case-control approach was used to estimate adjusted rate ratios of hepatic events associated with DMARDs dispensed during the prior year, as compared with methotrexate monotherapy. RESULTS: There were 25 cases of serious hepatic events (rate, 4.9 per 10,000 per year) and 411 nonserious hepatic events (rate, 80.0 per 10,000 per year). There was no increase in the rate of serious hepatic events with either leflunomide (rate ratio [RR] = 0.9; 95% confidence interval [CI]: 0.2 to 4.9) or traditional DMARDs (RR = 2.3; 95% CI: 0.8 to 6.5). However, the rate was increased with biologic DMARDs (RR = 5.5; 95% CI: 1.2 to 24.6). The rate of nonserious hepatic events was also increased with biologic DMARDs (RR = 1.5; 95% CI: 1.0 to 2.3), but not with leflunomide (RR = 0.9; 95% CI: 0.7 to 1.3) and traditional DMARDs (RR = 1.1; 95% CI: 0.8 to 1.4). CONCLUSIONS: We found no evidence of an excess risk of serious or nonserious hepatic events with the use of leflunomide as compared with methotrexate. Still, the increased risk observed with the new biologic DMARDs should be investigated further.     

Use of disease‐modifying antirheumatic drugs during pregnancy and risk of preeclampsia

Objective

To describe patterns of disease‐modifying antirheumatic drug (DMARD) use during pregnancy in a population‐based cohort, and to evaluate the association between autoimmune disease, DMARDs, corticosteroids, and nonsteroidal antiinflammatory drugs (NSAIDs) and preeclampsia.

Methods

Using health care utilization databases from British Columbia (1997–2006), we compared the risk for preeclampsia among 44,786 women with and without autoimmune disease with study drug dispensings before pregnancy (past users) and before and during the first 20 gestational weeks (continuous users). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated.

Results

Only 414 women (0.1%) had a DMARD dispensing during pregnancy. The incidence of preeclampsia was 2.3% for past DMARD users, 2.7% for past corticosteroid users, and 2.9% for past NSAID users. Compared to past users, the continuous DMARD user RR was 2.29 (95% CI 0.81–6.44), and was 0.89 (95% CI 0.51–1.56) for corticosteroid and 0.84 (95% CI 0.63–1.10) for NSAID users. Compared to women without autoimmune disease, the delivery year–adjusted RR was 2.02 (95% CI 1.11–3.64) for women with systemic lupus erythematosus (SLE). The DMARD results were attenuated when antimalarials were excluded, and the delivery year–adjusted RR was 0.95 (95% CI 0.25–3.55) when the DMARD analysis was restricted to women with autoimmune disease.

Conclusion

Few women were exposed to DMARDs during pregnancy. We observed a 2‐fold increased risk of preeclampsia among women with SLE and a nonsignificant increase in risk in DMARD users. The DMARD and preeclampsia association was attenuated when antimalarials were excluded and null when restricted to women with autoimmune disease, which suggests the association is likely due to greater autoimmune disease severity in DMARD users.     

The risk of hospitalized infection in patients with rheumatoid arthritis

OBJECTIVE: To determine whether patients with rheumatoid arthritis (RA) are at increased risk of hospitalized infection and whether the risk varies by RA treatment. METHODS: A retrospective cohort study was conducted using data from a medical and pharmacy claims managed-care database from 1999 to 2006. A total of 24,530 patients were included in the RA cohort; a random sample of non-RA patients served as a comparison cohort (n = 500,000). Rates of hospitalized infection were compared between the cohorts. A nested case-control analysis was performed within the RA cohort to assess the effect of current RA medication use on hospitalized infection risk. RESULTS: A total of 1,993 patients with RA and 11,977 non-RA patients experienced a hospitalized infection. The rate of first hospitalized infection was higher in the RA cohort [adjusted hazard ratio = 2.03; 95% confidence interval (CI) 1.93-2.13]. In the case-control analysis, the current use of biological disease modifying antirheumatic drugs (DMARD) was associated with slightly increased risk of hospitalized infection [rate ratio (RR) = 1.21; 95% CI 1.02-1.43]. Methotrexate and hydroxychloroquine were associated with decreased risk. Oral corticosteroid use increased risk (RR = 1.92; 95% CI 1.67-2.21), and there was a dose-related effect [< or = 5 mg/day: RR = 1.32 (95% CI 1.06-1.63), 6-10 mg/day: RR = 1.94 (95% CI 1.53-2.46), > 10 mg/day: RR = 2.98 (95% CI 2.41-3.69)]. CONCLUSION: These data confirm that individuals with RA are at increased risk of hospitalized infection compared to those without RA. Oral corticosteroid use was associated with a dose-related increase. Biological DMARD use was associated with slightly elevated risk; however, this may reflect confounding and channeling bias.     

Rates of serious infection,including site‐specific and bacterial intracellular infection,in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register

Objective

To determine whether the rate of serious infection is higher in anti–tumor necrosis factor (anti‐TNF)–treated rheumatoid arthritis (RA) patients compared with RA patients treated with traditional disease‐modifying antirheumatic drugs (DMARDs).

Methods

This was a national prospective observational study of 7,664 anti‐TNF–treated and 1,354 DMARD‐treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis.

Results

Between December 2001 and September 2005, there were 525 serious infections in the anti‐TNF–treated cohort and 56 in the comparison cohort (9,868 and 1,352 person‐years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the anti‐TNF–treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68–1.57). However, the frequency of serious skin and soft tissue infections was increased in anti‐TNF–treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06–17.17). There was no difference in infection risk between the 3 main anti‐TNF drugs. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the anti‐TNF–treated cohort.

Conclusion

In patients with active RA, anti‐TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.

     

The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis

OBJECTIVE: To evaluate the effect of disease-modifying antirheumatic drugs (DMARDs) on the likelihood of patients with rheumatoid arthritis (RA) developing septic arthritis (SA). METHODS: The United Kingdom General Practice Research Database (GPRD) was used to identify adults with RA, and age-, sex-, and practice-matched control subjects. Subjects were studied between 1987 and 2002. The risk of developing SA (excluding infected joint replacements) for individuals with RA was calculated and the effect of DMARD use determined. RESULTS: A total of 136,977 subjects (34,250 patients with RA, 102,747 controls) were identified. SA was identified in 345 subjects, of which 321 (236 in patients with RA, 85 in controls) cases occurred during the study period. The incidence rate of SA was 12.9 times higher in subjects with RA than in those without (95% confidence interval [95% CI] 10.1-16.5, P < 0.001). The incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications. Penicillamine (adjusted IRR 2.51, 95% CI 1.29-4.89, P = 0.004), sulfasalazine (adjusted IRR 1.74, 95% CI 1.04-2.91, P = 0.03), and prednisolone (adjusted IRR 2.94, 95% CI 1.93-4.46, P < 0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. The use of other DMARDs including methotrexate showed no such effect. CONCLUSION: Individuals with RA have an increased risk of developing SA. This increased risk can be attributed to both the disease process and the use of DMARDs.     

A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal

INTRODUCTION: Combinations of disease-modifying anti-rheumatic drugs (DMARDs) are increasingly used to treat rheumatoid arthritis (RA). Early trials showed their toxicity while recent trials suggest superior efficacy. Trials of DMARD combinations have enrolled different types of patient (early or established RA), used different designs (step-up, parallel or step-down) and utilized a range of outcome measures. We undertook a systematic review of combination DMARD therapy for RA and carried out a meta-analysis to evaluate the evidence for efficacy and toxicity. METHOD: Medline, PubMed and EmBase were searched using MESH headlines 'arthritis, rheumatoid', 'drug therapy, combination' and 'randomized controlled trial' (RCT) for papers published from 1975 to April 2004. References from published articles were also searched. Three independent assessors evaluated abstracts and selected trials for detailed examination. Trials were excluded if their quality was poor, were not published in English or studied DMARDs not licensed to treat RA. Two independent assessors extracted data. Efficacy was assessed by the numbers of patients withdrawn due to lack of efficacy. Toxicity was assessed by the numbers of patients withdrawn due to adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were calculated and meta-analysis was carried out based on a random effects model. Sensitivity analyses evaluated different treatment combinations, trial designs, study populations and outcome measures. RESULTS: Fifty-three potentially relevant RCTs were identified. Twelve were excluded due to: using unlicensed DMARDs (n = 3); reporting in journal supplements of RCTs already included (n = 2); follow-up of an earlier RCT, report of biological outcomes or pharmacokinetics (n = 5); and non-English language publications (n = 2). Forty-one RCTs were evaluated in detail and another five excluded (three open-labelled studies and two with high patient attrition); 36 studies were included in the meta-analysis. These comprised 13 step-up, 16 parallel and 7 step-down trials. Nine assessed early RA and 27 established RA. Seven added steroids to DMARD monotherapy and one study added steroids to DMARD combinations. Six assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors. Overall, combination DMARD therapy was more effective than monotherapy (RR 0.35; 95% CI 0.28, 0.45) although the risk of toxicity was also slightly higher (RR 1.37; 95% CI 1.16, 1.62). Combinations of MTX with TNF inhibitors and MTX with sulphasalazine or anti-malarials showed good efficacy/toxicity ratios. CONCLUSIONS: DMARD combinations vary in their efficacy/toxicity ratio. MTX plus sulphasalazine and/or anti-malarials and MTX plus TNF inhibitors have particularly favourable benefit/risk ratios.     

Rheumatoid arthritis pharmacotherapy and predictors of disease-modifying anti-rheumatic drug initiation in the early years of biologic use in Quebec, Canada

Disease-modifying anti-rheumatic drugs (DMARDs) are the cornerstone of rheumatoid arthritis (RA) pharmacotherapy and should be initiated promptly after RA diagnosis. We examined trends in use of traditional and biologic DMARDs, and non-DMARD treatments, among overall RA patients, and factors associated with DMARD initiation in the newly diagnosed RA. RA subjects identified with the Quebec administrative databases were followed between January 1, 2002, and December 31, 2008. DMARD use was characterized on November 1 of each year using cross-sectional analyses. For a subgroup of newly diagnosed subjects, we used multivariable logistic regressions to identify predictors of DMARD initiation within 12 months of diagnosis and survival analyses to appraise time to DMARD initiation. A total of 37,399 subjects were included (65.8 % ≥65 years; 70.5 % female). The percentage of subjects using any DMARDs increased over the study period from 41.4 % [95 % confidence interval (CI) 40.8–42.0] to 43.3 % (95 % CI 42.7–43.9). Among newly diagnosed RA, being followed by a rheumatologist was the strongest predictor of DMARD initiation (odds ratio 4.31; 95 % CI 3.73–4.97). Care by an internist, increasing calendar year, use of NSAIDs, corticosteroids, or opioids, and a history of hospitalization increased the likelihood of DMARD initiation. Older age, female, higher comorbidity score, number of medical visits pre-diagnosis, care by other specialists, and the use of acetaminophen were inversely associated with DMARD initiation. The probability of any DMARD initiation at 12 months was 38.5 %. Despite the clinical practice guideline recommendations for earlier aggressive RA management, DMARD use appears to be suboptimal in Quebec.     

Comparative cancer risk associated with methotrexate,other non-biologic and biologic disease-modifying anti-rheumatic drugs

Objective

There is little information comparing the potential risk of cancer across conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Methotrexate has not been the focus of most contemporary pharmacoepidemiologic studies of cancer.

Methods

We conducted a comparative effectiveness study with cancer as the outcome. A large observational cohort of RA was followed up from 2001 to 2010. Reports of any cancer prompted a confirmation process that included adjudication of the primary cancer records. We used a propensity score (PS) with relevant covariates and cohort trimming to improve the balance between DMARD cohorts. Cox proportional hazard regression models were constructed to estimate the risk of cancer with various DMARDs, all compared with methotrexate.

Results

We identified 6806 DMARD courses for analysis (1566 methotrexate; 904 nbDMARDs; 3761 TNF antagonists; 408 abatacept; and 167 rituximab). Non-biologic DMARDs (HR 0.17, 95% CI 0.05–0.65) and TNF antagonists (HR 0.29, 95% CI 0.05–0.65) were associated with a reduced adjusted risk of cancer compared with methotrexate. Abatacept (HR 1.55, 95% CI 0.40–5.97) and rituximab (HR 0.42, 95% CI 0.07–2.60) were similar in risk of cancer with methotrexate. These results were robust to sensitivity analyses. After controlling for DMARD exposures, risk factors for cancer included male gender, age, and alcohol consumption.

Conclusions

Cancer risk was elevated for methotrexate users compared with nbDMARDs and TNF antagonists.