Tumor Necrosis Factor Therapy and the Risk of Serious Infection and Malignancy in Patients With Early Rheumatoid Arthritis

ARTHRITIS & RHEUMATISM Vol. 63, No. 6, June 2011, pp 1479 1485 DOI 10.1002/art.30310 2011, American College of Rheumatology Tumor Necrosis Factor Therapy and the Risk of Serious Infection and Malignancy in Patients With Early Rheumatoid Arthritis A Meta-Analysis of Randomized Controlled Trials Andrew E. Thompson, 1 Scott W. Rieder, 2 and Janet E. Pope 1 Mr. Rieder is recipient of a summer research grant from Roche Canada. 1 Andrew E. Thompson, MD, MHPE, FRCPC, Janet E. Pope, MD, FRCPC: University of Western Ontario and St. Joseph s Health Care, London, Ontario, Canada; 2 Scott W. Rieder, BSc: University of Western Ontario, London, Ontario, Canada. Address correspondence to Andrew E. Thompson, MD, MHPE, FRCPC, Rheumatology Centre, St. Joseph s Health Care, 268 Grosvenor Street, PO Box 5777, London, Ontario N6A 4V2, Canada. E-mail: andy.thompson@sjhc.london.on.ca. Submitted for publication May 4, 2010; accepted in revised form February 10, 2011. Objective. To conduct a meta-analysis of the rates of serious infection and malignancy in patients with early rheumatoid arthritis (RA) who have started anti tumor necrosis factor (anti-tnf) therapy and had not received treatment with disease-modifying antirheumatic drugs (DMARDs) or methotrexate (MTX). Methods. A systematic literature search was conducted through the summer of 2009. All studies included were randomized, double-blind, placebocontrolled trials involving patients with early RA who were started on anti-tnf therapy without prior DMARD/MTX use. Six trials met the inclusion criteria for the meta-analysis, comprising a total of 2,183 patients receiving biologic therapy and 1,236 patients receiving MTX. The data extracted were from published trials. Results. A pooled odds ratio (OR) (determined using Mantel-Haenszel methods, with a continuity correction designed for sparse data) was calculated for serious infections (requiring hospitalization) and malignancies, comparing anti-tnf therapy to MTX control. The pooled OR for serious infections was 1.28 (95% confidence interval [95% CI] 0.82 2.00) and that for malignancies was 1.08 (95% CI 0.50 2.32). There was no significant difference in either the rate of serious infections or the rate of malignancies between the anti-tnf therapy group and the control group. Conclusion. Whereas other meta-analyses have shown an increased risk of serious infection and malignancy in patients receiving anti-tnf therapy, the results of the present meta-analysis show that there is not an increased risk when the patients have early disease and have not previously been treated with DMARDs and/or MTX. The efficacy of tumor necrosis factor (TNF) inhibition has been shown in numerous trials, both in patients with early rheumatoid arthritis (RA) and in those with established RA (1). As a result, TNF inhibition has significantly improved the signs and symptoms, function, radiographic progression, and quality of life for patients with RA. The most important side effects of TNF inhibition are the risks of serious infection and the potential for malignancy. Although product monographs include warnings and precautions about these side effects, they do not provide an estimate of risk. The risk of serious infections is likely increased in the first 6 12 months of therapy (2). A meta-analysis of randomized controlled trials of patients starting TNF monoclonal antibody therapy showed that these patients have an increased risk of serious infection (3). This early increased risk of infection was also observed in an inception cohort of RA patients starting anti-tnf treatment, and was also confirmed in a meta-analysis of patients treated with etanercept (a TNF inhibitor) (4,5). The risk of solid and hematopoietic malignancies with TNF inhibition is much less clear. Meta-analyses of clinical trial data have revealed conflicting results (3,5). An increased risk of malignancy has not been observed in the majority of 1479

1480 THOMPSON ET AL patients in registry databases, with the exception of a risk of lymphoma and melanoma found in some registries (2). The challenge with regard to current metaanalysis data and on-going registry data is that the information has been obtained from heterogeneous populations of patients with varying degrees of comorbidity. This heterogeneity makes it very difficult to understand and communicate the risk in individual patients. It is important to know whether early RA has the same risk of serious infection or risk of malignancy as that in older patients with longstanding RA and multiple comorbidities. The goal of this study was to estimate the risk of serious infection and risk of malignancy through a meta-analysis of randomized controlled trials of anti- TNF therapy in patients with early RA. PATIENTS AND METHODS Information sources and search strategy. The data from all of the selected studies were extracted and analyzed using a predefined, peer-reviewed assessment written by the Cochrane Collaboration. The present analysis was conducted by adhering to the QUOROM statement on quality of reports on meta-analyses of randomized controlled trials (6). Using the NCBI database, we extracted data from the inception of the analysis until August 2009, searching for the terms early rheumatoid arthritis, biologics, anti-tnf therapy, adalimumab, infliximab, etanercept, golimumab, certolizumab, and randomized controlled trials. We also cross-referenced the citations from all of the articles selected and from current meta-analyses on this subject. Study selection and outcomes. All studies were scored by 2 independent reviewers (AET and SWR). A study was included if it met the eligibility criteria and received a Jadad quality score of 3 (7). The Jadad score is a procedure to independently assess the methodologic quality of a clinical trial and is the most widely used meta-analysis assessment tool (8). We included randomized controlled trials that involved treatment with any of the currently licensed anti-tnf biologic agents (adalimumab, etanercept, golimumab, certolizumab, and infliximab). In addition, patients with RA were required to have a disease duration of 3 years since diagnosis, and were currently not being treated with a disease-modifying antirheumatic drug (DMARD) or biologic agent. All patients had to be allocated to receive either a biologic monotherapy versus placebo or biologic therapy plus DMARD therapy versus placebo, for at least 6 months. Table 1. Characteristics of the trials of anti-tnf therapy included in the meta-analysis* Adalimumab in ERA ASPIRE COMET ERAS PREMIER SWEFOT Trial sites United Kingdom Europe, North Australia, Europe, North America Australia, Europe, Sweden America North America North America Trial size, no. of 148 1,040 542 632 799 258 patients Treatment arm Experimental ADA MTX Inflix. MTX Etan. MTX Etan. ADA MTX or Inflix. MTX ADA mono Control MTX MTX MTX MTX MTX MTX SSZ HCQ No. of study arms 2 3 2 2 3 2 Age, mean years 47 50 51 50 52 52 Female, % 56 72 74 75 75 77 Duration of 9 11 10 12 9 6 disease, mean months RF positive, % 95 72 70 (CCP) 88 100 67 Taking steroids, % NA 38 50 40 36 7 SJC, mean 10 22 17 24 22 NA CRP, mean mg/dl 2.9 3.8 2.6 3.0 3.6 3.7 3.3 4.4 3.9 4.1 NA DAS, mean NA NA NA NA NA 4.8 HAQ score, mean 1.3 1.5 1.6 NA 1.5 1.3 * Full descriptions of the anti tumor necrosis factor (anti-tnf) trials are provided in refs. 14 19. ERA Early Rheumatoid Arthritis; ASPIRE Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; COMET Comparison of Methotrexate Monotherapy With a Combination of Methotrexate and Etanercept in Active, Early, Moderate to Severe Rheumatoid Arthritis; ERAS Early Rheumatoid Arthritis Study; PREMIER Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With Adalimumab Plus Methotrexate versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis who had not had Previous Methotrexate Treatment; SWEFOT Addition of Infliximab Compared With Addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in Patients With Early Rheumatoid Arthritis; ADA adalimumab; MTX methotrexate; Inflix. infliximab; Etan. etanercept; mono monotherapy; SSZ sulfasalazine; HCQ hydroxychloroquine; RF rheumatoid factor; CCP cyclic citrullinated peptide; NA not available; SJC swollen joint count; CRP C-reactive protein; DAS Disease Activity Score; HAQ Health Assessment Questionnaire.

ANTI-TNF THERAPY AND SERIOUS INFECTION/MALIGNANCY RISK IN EARLY RA 1481 Table 2. Summary of serious infections* No. of patients with serious infections Trial, randomization Adalimumab in ERA Adalimumab MTX 3/75 MTX 2/73 ASPIRE Infliximab MTX 40/749 MTX 6/291 COMET Etanercept MTX 5/274 MTX 8/268 Description of infections No opportunistic infections reported Tuberculosis (n 4) and sepsis (n 3) in infliximab group No opportunistic infections; 1 case of disseminated herpes zoster in MTX group ERAS No opportunistic infections Etanercept MTX 12/415 and no deaths from MTX 6/217 infection in either group PREMIER Pleural tuberculosis (n 1) Adalimumab MTX 12/542 in adalimumab group; MTX 7/257 death due to infection (n 1) in MTX group SWEFOT Infliximab MTX 1/128 MTX sulfasalazine 1/130 plaquenil * See Table 1 for definitions. No opportunistic infections or deaths reported The 2 primary outcomes examined were serious infection (requiring hospitalization) and malignancy. Our primary data sources were from the published data. Serious infection was defined according to the definition given within each trial protocol. Statistical analysis. We used a fixed-effects metaanalysis to assess the pooled data, because of the rareness of outcomes in the trials. Results are expressed as the odds ratio (OR) with 95% confidence interval (95% CI). Using the ORs from each trial, we constructed a pooled data table using Mantel-Haenszel methods. Inconsistency across the trials was measured by calculating the I 2 statistic. All statistical tests and creation of forest plots were carried out with Review Manager version 5 software (9). RESULTS Included studies. Of the 548 published reports retrieved on the initial search, 503 were initially excluded on the basis of the title and abstract (exclusions for lack of control groups, no anti-tnf therapy, patients without RA, or no randomization). Of the remaining 45 studies, 39 were not eligible because the patients with RA had a disease duration of 3 years (in trials of golimumab, etanercept, or certolizumab therapy [10 13]), patients had been previously treated unsuccessfully with DMARDs, or the Jadad quality score for the study (7) was below the cutoff level of 3. Thus, 6 trials were considered eligible for inclusion in our meta-analysis (14 19). The included trials were fairly homogeneous in terms of patient characteristics (Table 1). Among the 6 trials, the mean age ranged from 47 years to 52 years, 56 77% of the patients were female, the disease duration ranged from 6 months to 12 months, and at least two-thirds of the patients in each trial were rheumatoid factor positive. The mean swollen joint count was substantial in all 6 trials, ranging from 10 to 24, and the scores for disability were high in all 6 trials, with a Figure 1. Effect of anti tumor necrosis factor antibody therapy (experimental group), compared with control therapy, on the occurrence of serious infections in patients with rheumatoid arthritis. Results are shown as forest plots, with values expressed as the pooled odds ratio with 95% confidence interval (95% CI), determined using the Mantel-Haenszel (M-H) test. ERA Early Rheumatoid Arthritis; ASPIRE Active- Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset; COMET Comparison of Methotrexate Monotherapy With a Combination of Methotrexate and Etanercept in Active, Early, Moderate to Severe Rheumatoid Arthritis; ERAS Early Rheumatoid Arthritis Study; PREMIER Multicenter, Randomized, Double-Blind Clinical Trial of Combination Therapy With Adalimumab Plus Methotrexate versus Methotrexate Alone or Adalimumab Alone in Patients With Early, Aggressive Rheumatoid Arthritis who had not had Previous Methotrexate Treatment; SWEFOT Addition of Infliximab Compared With Addition of Sulfasalazine and Hydroxychloroquine to Methotrexate in Patients With Early Rheumatoid Arthritis.

1482 THOMPSON ET AL Table 3. Summary of malignancies* No. of patients with malignancies Trial, randomization Adalimumab in ERA Adalimumab MTX 0/75 MTX 0/73 ASPIRE Infliximab MTX 4/749 MTX 0/291 Description of malignancies No reported malignancies Endometrial cancer, pancreatic cancer, colon cancer, acute myeloid leukemia COMET Breast cancer (n 3), Etanercept MTX 4/274 prostate cancer (in MTX 4/268 etanercept group); chronic lymphocytic leukemia, epidermoid cancer of the tongue, basal cell carcinoma, Bowen s disease (in MTX group) ERAS Etanercept MTX 5/415 MTX 2/217 PREMIER Adalimumab MTX 6/542 MTX 4/257 SWEFOT Infliximab MTX 0/128 MTX sulfasalazine 0/130 plaquenil * See Table 1 for definitions. Breast cancer, lung cancer, carcinoid lung cancer, Hodgkin s lymphoma, prostate cancer (in etanercept group); colon cancer, bladder cancer (in MTX group) Ovarian cancer, prostate cancer, breast cancer, multiple myeloma, colon cancer, metastatic cancer with unknown primary (in adalimumab group); lymphoma, melanoma, prostate cancer, breast cancer (in MTX group) No reported malignancies reported mean Health Assessment Questionnaire score ranging from 1.3 to 1.6. Overall, 3,419 patients with RA were randomized to receive either a TNF inhibitor or MTX treatment. Risk of serious infection. Review of the published data from the 6 randomized controlled trials revealed that a serious infection occurred in 73 (3.3%) of 2,183 patients with RA who had received at least one dose of a TNF inhibitor, compared with 30 (2.4%) of 1,236 patients in the control treatment groups (Table 2). Statistical heterogeneity was low (I 2 11%) and not beyond variations that could be due to chance (P 0.27). The risk of serious infection in patients treated with a TNF inhibitor was not statistically significantly different than that in MTX-treated controls, and numerically was only slightly increased in the TNF inhibitor group compared with MTX controls (OR 1.28, 95% CI 0.82 2.00) (Figure 1). For this meta-analysis of the risk of serious infections, we calculated the power to detect an increased risk in patients treated with a TNF inhibitor. Using a post hoc procedure, the effect size for the estimate of risk of serious infections in the studies was calculated to be 0.19. Given the large sample size, the power of the meta-analysis was found to be sufficient (99% power to detect a significant difference in the rate of serious infections between the groups), given the small effect size. Risk of malignancy. Review of the published data from the 6 randomized controlled trials revealed that malignancies occurred in 19 (0.87%) of 2,183 patients with RA who had received at least one dose of a TNF inhibitor, and in 10 (0.81%) of 1,236 control patients (Table 3). Statistical heterogeneity was low (I 2 0%) Figure 2. Effect of anti tumor necrosis factor antibody therapy (experimental group), compared with control therapy, on the occurrence of malignancy in patients with rheumatoid arthritis. Results are shown as forest plots, with values expressed as the pooled odds ratio with 95% confidence interval, determined using the Mantel-Haenszel test. See Figure 1 for definitions.

ANTI-TNF THERAPY AND SERIOUS INFECTION/MALIGNANCY RISK IN EARLY RA 1483 and was not beyond variations that could be due to chance (P 0.77). The risk of malignancy was not increased in patients treated with a TNF inhibitor compared with control patients treated with MTX (OR 1.08, 95% CI 0.50 2.32) (Figure 2). For this meta-analysis of the risk of malignancy, we calculated the power to detect an increased risk in patients treated with a TNF inhibitor. Using a post hoc procedure, the effect size for the estimate of risk of malignancies in the studies was calculated to be 0.11. Given the large sample size, the power of the metaanalysis was deemed sufficient to detect a significant difference between groups (89%), making the possibility of a Type II error highly unlikely. DISCUSSION This meta-analysis did not show any significant differences in the risk of infection or risk of malignancy between patients with early RA treated with anti-tnf therapy and those treated with MTX. With regard to the risk of malignancy, prior meta-analyses have shown similar rates of malignancy in the anti-tnf treatment arm of the selected studies (3,5) (Table 4). The only meta-analysis to show a statistically significant increase in the risk of malignancy included trials involving monoclonal antibody therapy (3). In that analysis, the rate of malignancy in the control arm was much lower than the rate reported in our analysis or in the meta-analysis of trials of etanercept. This finding is not explained. The results of the present meta-analysis provide continued support to the existing observational data showing that a globally increased risk of malignancy has not been found with anti-tnf therapy (20 25). Although these observations are reassuring, caution must be exercised when interpreting these results, since the duration of the trials included in this metaanalysis ranged from 6 months to 12 months. No assurances regarding the long-term risk of malignancy are provided. Moreover, it would be inappropriate to generalize the results of this meta-analysis to a pediatric population. With regard to the risk of serious infection, this meta-analysis did not find an increased risk of infection in patients with newly diagnosed RA treated with anti- TNF therapy. The mean age of the patients with newly diagnosed RA in the anti-tnf trials included in this analysis ranged from 47 years to 52 years, as compared to a mean age of 53 57 years in those with established RA (26 28). This finding may be explained by the fact that younger patients with recent-onset RA may have fewer infectious complications, attributable to a lower Table 4. Risk of malignancy among studies from prior meta-analyses and the ERAS trial* Study, Treatment arm year (ref.) Anti-TNF Control Odds ratio (95% CI) Bongartz et al, 0.8 0.2 3.3 (1.2 9.1) 2006 (3) Bongartz et al, 1.1 0.7 1.84 (0.79 4.28) 2009 (5) ERAS, 2000 (16) 0.9 0.8 1.08 (0.50 2.32) * Values for each treatment arm are the rate of malignancy, expressed as a percentage. The odds ratio with 95% confidence interval (95% CI) shows the likelihood of the occurrence of malignancy in anti-tnf treated patients compared with control patients. See Table 1 for other definitions. rate of associated comorbidities. A review of observational research designs has shown a higher risk of infections in patients with RA in the first few months following anti-tnf initiation, followed by a reduction in risk with increasing duration of use (2). The findings in the patients with newly diagnosed RA starting anti-tnf therapy in our analysis are not consistent with these observational database results. Although our findings are promising, screening of participants prior to entry into a randomized controlled trial would likely reduce the risk of infection. There are several limitations to our metaanalysis. Our search of publications on Medline and the references of the key articles may not reveal all of the relevant published articles. Our only source of data was from published results of randomized controlled trials, and access to raw data would result in a more rigorous analysis. However, we believe that this would be unlikely to significantly change the results. A potential source of bias in the included trials was the higher number of withdrawals in the control group, due to treatment inefficacy, which hinders subsequent ascertainment of events in the control group. This occurred in 4 of the 6 included trials. Any bias associated with loss of safety data as a result of these withdrawals would lead to a smaller difference in the rate of serious adverse events between treatment and control groups. This meta-analysis has not shown an increased risk of malignancy or serious infections in patients with newly diagnosed RA treated with anti-tnf therapy. However, further review of this population of patients in an observational inception cohort would be important to confirm and strengthen these findings. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved

1484 THOMPSON ET AL the final version to be published. Dr. Thompson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Thompson, Pope. Acquisition of data. Thompson, Rieder. Analysis and interpretation of data. Thompson, Rieder, Pope. REFERENCES 1. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59: 762 84. 2. Askling J, Dixon W. The safety of anti-tumour necrosis factor therapy in rheumatoid arthritis. Curr Opin Rheumatol 2008;20: 138 44. 3. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. 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