Risk of malignant melanoma and non-melanoma skin cancer in rheumatoid arthritis patients initiating methotrexate versus hydroxychloroquine: a cohort study.

OBJECTIVES: To characterise the incidence rate of skin cancer associated with methotrexate and hydroxychloroquine in older adults with rheumatoid arthritis (RA). METHODS: RA patients aged ≥65 years who initiated methotrexate or hydroxychloroquine as their first disease modifying antirheumatic drugs (DMARDs). The primary outcome was new occurrence of any skin cancer (i.e. malignant melanoma or non-melanoma skin cancer; NMSC) based on validated algorithms (positive predictive value >83%). Secondary outcomes were malignant melanoma, NMSC, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). We estimated the incidence rates (IRs) and hazard ratios (HRs) for each outcome in the 1:1 propensity score (PS)-matched methotrexate and hydroxychloroquine groups. RESULTS: We included 24,577 PS-matched pairs of methotrexate and hydroxychloroquine initiators. Compared with hydroxychloroquine (IR 25.20/1,000 person-years), methotrexate initiators (IR 26.21/1,000 person-years) had a similar risk of any skin cancer [HR 1.03 -(95%CI 0.92, 1.14)] over a mean follow-up of 388 days. The HR (95%CI) associated with methotrexate was 1.39 (0.87, 2.21) for malignant melanoma, 1.01(0.90, 1.12) for NMSC, 1.37 (1.13, 1.66) for BCC, and 0.79 (0.63, 0.99) for SCC compared with hydroxychloroquine. CONCLUSIONS: In this large cohort of older RA patients initiating methotrexate or hydroxychloroquine as their first DMARD, we found no difference in the risk of skin cancer including malignant melanoma and NMSC. However, for specific components of NMSC, methotrexate initiators had higher risk of BCC but lower risk of SCC compared with hydroxychloroquine initiators.

Comparative Risk of Nonvertebral Fractures Among Patients With Rheumatoid Arthritis Treated With Biologic or Targeted Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: The objective of this study was to compare the incidence rate of nonvertebral osteoporotic fractures (NVFs) in patients with rheumatoid arthritis (RA) initiating one of the nine biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS: We analyzed claims data from Optum (2008 to March 2019), Medicare, and MarketScan (2008-2017) to identify adults with RA who newly initiated b/tsDMARDs. Adalimumab was the most frequently used and was thus selected as a reference. The primary outcome was a composite of incident NVFs, including hip, humerus, pelvis, and wrist fractures, based on validated algorithms. We adjusted for greater than 70 potential confounders in each database through propensity score-based inverse probability treatment weighting. Follow-up time started the day after cohort entry until the first occurrence of one of the following: outcome, treatment discontinuation, switching, nursing home admission, death, disenrollment, or end of study period. For each drug comparison, weighted Cox proportional hazards models estimated the hazard ratios (HRs) and 95% confidence intervals (CIs). Secondary analyses were conducted in patients switching from a tumor necrosis factor inhibitor to a different b/tsDMARD. RESULTS: A total of 134,693 b/tsDMARD initiators were identified across three databases. The adjusted HRs showed similar risk of composite NVFs in all b/tsDMARD exposures compared with adalimumab: abatacept, HR 1.03 (95% CI 0.82-1.30); certolizumab, HR 1.08 (95% CI 0.79-1.49); etanercept, HR 1.12 (95% CI 0.89-1.40); golimumab, HR 0.91 (95% CI 0.59-1.39); infliximab, HR 1.03 (95% CI 0.84-1.28); rituximab, HR 1.07 (95% CI 0.74-1.55); tocilizumab, HR 1.24 (95% CI 0.71-2.17); and tofacitinib, HR 1.07 (95% CI 0.69-1.64). Secondary analyses showed similar results. CONCLUSION: This multidatabase cohort study found no differences in the risk of NVFs across individual b/tsDMARDs for RA, which provides reassurance to physicians prescribing b/tsDMARDs, especially to patients at high risk of developing NVFs.

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

INTRODUCTION: Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. OBJECTIVE: We aimed to assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10 g/dL. METHODS: Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10 g/dL in the prior month) between the periods. RESULTS: In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level 0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74, slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42], slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. CONCLUSION: REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

Glucose-lowering medications and the risk of cancer: A methodological review of studies based on real-world data.

AIM: To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias. METHODS: We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time. RESULTS: Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time. CONCLUSIONS: The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.