Lymphoma Risk in Rheumatoid Arthritis in the US

Lymphoma Risk in Rheumatoid Arthritis in the US: No Association with Anti-TNF Therapy Frederick & Kaleb 1National Data Bank for Rheumatic Diseases, Wichita, KS 2Stanford University, Stanford, CA Background. It is generally acknowledged that the risk of lymphoma is increased in persons with RA, and population based studies from Sweden and other European countries suggest that the risk is increased by approximately 1.9 times (Askling, 2005). Although no lymphoma increase was found in patients treated with anti-TNF therapy in the Askling study and other studies (Baecklund, 2004), treatment risk remains a major concern of regulatory authorities throughout the world and is the subject of warnings by regulators, pharmaceutical companies and physicians. 1 Wolfe 1,2 Michaud Methods (continued). Lymphomas were categorized as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Current SEER analyses do not include CLL as a part of NHL and we did not analyze CLL cases unless the CLL case also was diagnosed separately as NHL. We used life table methods, Cox regression and conditional logistic regression (CLR) to compare groups and categorize patients and groups. CLR, conditioning on semiannual entry and exit periods, was employed to control for unobserved heterogeneity. The standardized incidence ratios (SIR) were based on age and sex adjusted comparisons to the SEER data bank. Exposure time for biologic treatments was calculated as time on treatment during study observation. Results. There were 22,151 RA patients and 6,302 MSD patients. Biologic therapy was used by 51.3% of patients (Table 1). Infliximab was used by 36.7%. This large number is found because the NDB is the site of an infliximab safety registry. At the time of first assessment methotrexate (MTX) was used by 56.4% of patients. Variable Table 4. Lymphoma Risk and Biologic Therapy in RA Odds ratio P-value 95% C.I. Lymphoma & Biologics: Model I First Age (years) Sex (male=1) Biologic (ever) Lymphoma & Biologics: Model II First Age (years) Sex (male=1) Biologic (ever) First Prednisone First Patient activity score (0-10) Objectives. To determine the risk of lymphoma in a large RA population in which treatment with anti-TNF therapy was common, and to determine whether anti-TNF therapy was associated with increased risk. 122 lymphomas occurred during 112,543 patient years of followup, including 104 in RA (89,659 patient-years) and 18 (22,860 patient-years) in MSD (Table 2). The incidence rate for lymphoma in RA was 116 (95% C.I. 95 to 141) per 100,000 patient years of observation. Compared with MSD, the hazard ratio (HR) for RA was 1.9 (95% C.I. 1.1 to 3.1) (Table 3). Using the SEER database for comparison, the SIR for lymphoma in RA patients was 2.0 (95% C.I. 1.7 to 2.5). We examined the association of biologic therapy and lymphoma in RA in Table 4 using conditional logistic regression. Model I shows no association between biologic therapy and lymphoma (p = 0.38). When use of prednisone at first assessment and the patient activity score (PAS) were added as severity covariates, there was almost no change in the odds ratio or p-value. Analysis specific to biologics in Model I and Model II showed no significant association between any biologic and lymphoma. We tested whether the odds ratio of infliximab and etanercept differed in Model II. The chi2 was 0.85 and the p value for the difference was 0.356. In data not shown we also tested whether duration of exposure for each biologic was associated with the risk of lymphoma. No significant association was found. 1.04 2.04 1.25 0.00 0.00 0.38 [1.02,1.06] [1.37,3.06] [0.76,2.07] 1.04 1.88 1.27 1.41 0.88 0.00 0.00 0.36 0.10 0.01 [1.02,1.06] [1.25,2.82] [0.76,2.12] [0.94,2.13] [0.80,0.97] Table 1. Characteristics of 22,151 RA Patients Methods. Participants were members of the U.S National Data Bank for Rheumatic Diseases longitudinal study of rheumatic disease outcomes. Between 1998 and June 2005, we followed 22,151 RA patients and 6,302 patients with non-inflammatory musculoskeletal disorders (MSD) with semiannual questionnaire assessments. All lymphoma reports were followed up on by contact with the patients for specific details, and then followed up by a request for hospital records or physician confirmation. We also searched the National Death Index annually and received reports of deaths from family and friends. To determine expected rates of lymphoma, we used the MSD group and the U.S. SEER data bank as comparison populations. The MSD group was assessed by the same methods used to assess RA and therefore may be considered an ideal comparison group. The SEER (Surveillance, Epidemiology, and End Results) Program of the National Cancer Institute (NCI) is an authoritative source of information on cancer incidence and survival in the United States. SEER currently collects and publishes cancer incidence and survival data from populationbased cancer registries covering approximately 26 percent of the US population. We used age and sex categories from the SEER database to estimate the Standardized Incidence Ratio (SIR) for lymphoma in the RA study population compared with the US population. Variable First Age (years) Sex (% male) Biologic (ever) Infliximab (ever) Etanercept (ever) Adalimumab (ever) First Prednisone (%) First MTX (%) First HAQ (0-3) Patient activity score (0-10) Mean or % 59.3 23.1 51.3 36.7 18.1 6.6 45.5 56.4 1.1 3.9 SD 13.3 Lymphoma & Specific Biologics: Model I First Age (years) 1.04 Sex (male=1) 2.05 Infliximab (ever) 1.45 Etanercept (ever) 0.97 Adalimumab (ever) 0.90 0.00 0.00 0.22 0.92 0.89 [1.02,1.06] [1.37,3.07] [0.81,2.62] [0.51,1.82] [0.21,3.93] 0.7 2.2 Lymphoma & Specific Biologics: Model II First Age (years) 1.04 Sex (male=1) 1.88 Infliximab (ever) 1.46 Etanercept (ever) 0.97 Adalimumab (ever) 0.88 First MTX 1.16 First Prednisone 1.39 First Patient activity score (0-10) 0.88 0.00 0.00 0.22 0.93 0.87 0.48 0.12 0.01 [1.02,1.06] [1.25,2.82] [0.80,2.67] [0.51,1.83] [0.20,3.84] [0.77,1.76] [0.92,2.10] [0.80,0.97] Table 2.The Rate of Lymphoma Among RA and MSD Patients Group MSD RA All Lymphomas 18 104 122 Exposure (Pt-years) 22,860 89,659 112,543 Rate per 100,000 Pt-years 79 116 108 95% C.I. [47,124] [95,141 [90,129] Discussion. The results of this study, using two control populations, show the risk of lymphoma is increased by approximately two times in RA. There were no statistically significant increases in the risk of lymphoma associated with specific RA treatments, including treatment with biologics. These data are in accord with the results of other long-term registries (Askling, 2005) and do not suggest that anti-TNF therapy is a risk factor for lymphoma development. References: 1) Askling, J, et al.: Ann.Rheum.Dis 64(10):14141420, 2005. 2) Baecklund, E, et al. Current Opinion in Rheumatology. 16(3):254-261, 2004 Table 3. The Risk of Lymphoma Among Patient with RA Data Comparison Source Method Risk: RA vs. non RA S.I.R. 2.0 [1.7-2.5] US SEER Database O.R. 1.9 [1.1-3.1] MSD internal controls The NDB has received research grant support from the following companies: Centocor, Bristol-Meyers-Squibb, Amgen, Abbott, Sanofi, Merck and Pfizer. Observational studies can provide useful “real-life” experience of treatment risk. However such studies can be biased by nonrandom selection and unobservable differences between patients prescribed various treatments (heterogeneity). In addition, the risk of treatment and the severity of patients receiving treatment changes with time. In these analyses we used conditional logistic regression to assess risk. In the CLR model, patients are compared within groups, entry and exit time forming the 139 groups of this study. This method controls not only for entry time, but for study drop-out as well as severity of patients entering at different times. Although we also controlled for disease severity using the prednisone prescription at entry and the combined HAQ, pain and patient global (PAS score) (Table 4), these measures had no effect on risk estimates. In summary, although lymphoma is increased in RA, this very large study found no association with biologic therapy.