0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

Risk of Malignancies in Patients With Rheumatoid Arthritis Treated With Biologic Therapy:  A Meta-analysis FREE

Maria A. Lopez-Olivo, MD, PhD; Jean H. Tayar, MD; Juan A. Martinez-Lopez, MD; Eduardo N. Pollono, MD; Jose Polo Cueto, MD; M. Rosa Gonzales-Crespo, MD; Stephanie Fulton, MSIS; Maria E. Suarez-Almazor, MD, PhD
[+] Author Affiliations

Author Affiliations: The University of Texas MD Anderson Cancer Center, Houston (Drs Lopez-Olivo, Tayar, and Suarez-Almazor and Ms Fulton); Spanish Society of Rheumatology (Dr Martinez-Lopez) and Hospital 12 de Octubre (Dr Gonzalez-Crespo), Madrid, Spain; Texas Tech University Health Science Center–Paul Foster School of Medicine, El Paso (Dr Pollono); and Manati Medical Center, Manati, Puerto Rico (Dr Cueto).


JAMA. 2012;308(9):898-908. doi:10.1001/2012.jama.10857.
Text Size: A A A
Published online

Context Concerns exist regarding the potential development of malignancies in patients with rheumatoid arthritis (RA) who are receiving biologic response modifiers (BRMs).

Objective To assess the risk of malignancy in patients with RA enrolled in randomized controlled trials (RCTs) of BRMs.

Data Sources Electronic databases, conference proceedings, and websites of regulatory agencies were searched for RCTs evaluating abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab in RA from inception through July 9, 2012.

Study Selection Independent selection of studies included RCTs that compared the safety of any BRMs used in RA patients with placebo and/or any traditional disease-modifying antirheumatic drugs with a minimum of 24 weeks of follow-up.

Data Extraction Independent reviewers selected studies and extracted data on quality and outcomes. Pooled estimates and 95% confidence intervals were calculated for each BRM.

Results Sixty-three RCTs with 29 423 patients were analyzed. No statistically significant increased risk of developing malignancy was observed. Of the 29 423 patients, 211 developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, and 26 not specified). The incidence rate for any malignancy during the first year of therapy was very low in the BRM plus methotrexate group (0.77%; 95% CI, 0.65%-0.92%), the BRM monotherapy group (0.64%; 95% CI, 0.42%-0.95%), and the controls (0.66%; 95% CI, 0.52%-0.84%). Anakinra plus methotrexate showed lower odds compared with methotrexate alone (Peto odds ratio, 0.11; 95% CI, 0.03-0.45). No statistically significant risk was observed for specific cancer sites, although the Peto odds ratio for lymphoma was 2.1 (95% CI, 0.55-8.4) in patients receiving tumor necrosis factor inhibitors compared with controls.

Conclusion The use of BRMs among patients with RA included in RCTs of at least 6 months' duration was not significantly associated with an increased risk of malignancy compared with other disease-modifying antirheumatic drugs or with placebo.

Figures in this Article

Rheumatoid arthritis (RA) is a systemic inflammatory polyarthritis that can lead to significant morbidity, joint deformity, and impaired quality of life1 and affects approximately 1% of the general population. Treatment with traditional disease-modifying antirheumatic drugs (DMARDs) reduces disease activity, retards joint destruction, and improves patients' quality of life. However, in many patients with active disease, traditional DMARDs fail or are not tolerated.2

Biologic response modifiers (BRMs) provide clinically important improvement in patients not responding to traditional DMARDs by targeting specific immune pathways, reducing inflammation, and leading to better control of symptoms and structural damage.2 In 2010, published data from European and US registries reported that 25% to 56% of patients with RA used BRMs.3 Available BRMs include tumor necrosis factor (TNF) inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab), an interleukin 1 receptor antagonist (anakinra), B-cell–depleting anti-CD20 antibodies (rituximab), a selective costimulation modulator inhibiting T-cell activation by binding to CD80 and CD86 (abatacept), and an interleukin 6 inhibitor (tocilizumab).

Because these biologic agents interfere with the immune system, concerns exist regarding their safety, specifically with respect to infections and malignancies. The US Food and Drug Administration (FDA) has recommended adding a warning label concerning risk of malignancy to all TNF inhibitors because of the increase in cases of spontaneous lymphoma in children and adolescents in the Adverse Event Reporting System database.4

Since 2005, conflicting data have existed associating TNF inhibitors with an increased risk of developing certain types of malignancies. Most observational studies have found increased risk of malignancies ranging across studies, with relative risks (RRs) of 0.7 to 2.7 for all types of malignancies, 1.1 to 5.0 for lymphoma, and 1.1 to 1.5 for nonmelanoma skin cancer. Eleven meta-analyses of randomized controlled trials (RCTs) have been performed evaluating the risk of malignancy in patients with RA undergoing treatment with TNF inhibitors.515 This is the first systematic review, to our knowledge, evaluating the risk of developing any type of malignancy in patients with RA only and providing data on all 9 approved BRMs .

For this systematic review, we followed Cochrane Collaboration methods.16

Data Sources and Searches

A comprehensive search of the literature was performed by an experienced medical librarian and information specialist (S.F.) with input from the study team, using the following databases: MEDLINE, Cochrane Library, EMBASE (through SCOPUS), Web of Science, and electronic abstract databases of the annual scientific meetings of both the American College of Rheumatology and the European League Against Rheumatism. We searched all databases from inception to June 6, 2011. Ovid Auto Alerts were set up to provide weekly updates of new literature until July 09, 2012. Limits included human subjects and English, French, and Spanish languages. The search strategies for each electronic database are reported in eAppendix 1, eAppendix 2, and eAppendix 3). Websites and reference lists from systematic reviews and RCTs were hand-searched for additional citations not retrieved through electronic databases.

Study Selection

Study selection was performed by 4 pairs of independent reviewers (M.A.L.-O. and J.P.C., J.A.M.-L. and M.R.G.-C., E.N.P. and M.E.S.-A., and M.A.L.-O. and J.H.T.). Disagreements were clarified by consensus and, when needed, an external reviewer acted as an adjudicator. κ Agreement scores were calculated for each pair of reviewers.

To be eligible for inclusion, trials had to (1) compare the safety of any of the BRMs (abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and/or tocilizumab) against placebo and/or any DMARD; (2) include only patients with RA; and (3) report a minimum of 24 weeks of follow-up. We excluded studies with no descriptions of adverse events and follow-up reports of original publications (parent studies) that were open labeled without a control group.

Data Extraction and Quality Assessment

Data extraction was done independently by 2 reviewers (M.A.L.-O. and E.N.P.) and cross-checked by 2 additional reviewers (J.P.C. and J.H.T.). Discrepancies were solved by consensus, and there was an adjudicator (M.E.S.-A.) in case of persistent disagreement. From each selected trial, we collected general information, study, population, and intervention characteristics. Primary outcome data included number and type of malignancies. We contacted all corresponding authors and pharmaceutical companies to obtain data for trials that did not include number of malignancies observed.

Risk of bias of included studies was assessed by 2 reviewers (M.A.L.-O. and E.N.P.). Trials were appraised on sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other biases (baseline imbalance, carryover, funding).16 Each criterion was judged using the categories of yes (low risk of bias), no (high risk of bias), and unclear (lack of information or uncertainty about the potential for bias). A summary score was then derived whereby low risk of bias was given to studies with bias unlikely altering the results; unclear risk of bias was given to studies raising doubt about the results; and high risk of bias was given to studies that weakened confidence in the results.

Data Synthesis and Analysis

Our meta-analysis was performed using RevMan version 5.0.21 (Cochrane IMS) and Comprehensive Meta-analysis version 2.2.055. Data were combined and expressed as both Peto odds ratios (ORs) and RRs with their associated 95% confidence intervals. Although we show both measures of association, the Peto OR is preferred for uncommon events, and corrections for 0 cell counts in a single group are not necessary.16,17 Our numerators were the number of patients with malignancy reported in each trial. For the denominator, we considered all patients reported for safety in the original trial; for some trials, this represented the intention-to-treat population, but for most trials, it was patients exposed to at least 1 dose of the study drug as proposed by Bongartz et al.5

For the Peto ORs and RRs, 0-total-event trials (no events in either the intervention or control group) are automatically excluded because the studies do not provide any indication of either the direction or the magnitude of the relative treatment.16 We analyzed the data adding 0-total-event trials with a continuity correction estimate of the OR. Trials that did not report malignancies were included in the meta-analysis with a 0 in the numerator. For correction, a constant value of 0.5 was added to all cells of the 2 × 2 contingency table to provide a more conservative estimate of effect size.18

Heterogeneity of the data was formally tested. We used random-effects models to calculate a more conservative combined estimate of RR. Subgroup analyses were performed to check whether BRM monotherapy or combination therapy with traditional DMARDs or based on follow-up (24, 52, 104, and 156 weeks) would substantially change the findings. Sensitivity analyses were performed for intention-to-treat vs completer samples, quality of the trials, drug dosages, duration of the exposure (<1 year or ≥1 year), and excluding trials that did not report malignancies or that used rescue alternatives (before 24 weeks) and placebo-controlled trials with no concomitant treatment. Publication bias was assessed and quantified using funnel plots, the Orwin fail-safe N, the Duval and Tweedie trim and fill, and the Egger test. Results were analyzed both at a 2-sided α level of significance of .05 and with a Bonferroni correction to control for multiple testing of various BRMs (significance was set at α/κ).

Study Selection

We identified 16 587 unique citations located through databases, hand-searching, and conference proceedings. Our first selection round resulted in 2114 records potentially relevant to our topic. Of those, 395 were retrieved in full article form for further reading. Of the 395 articles, 71 publications1989 reporting on 63 distinct trials met inclusion for our systematic review (eFigure 1). κ Coefficients for selection ranged between 0.96 and 0.99. Also, no evidence of publication bias was observed. eFigure 2 shows the funnel plots. Additionally, the Orwin fail-safe N and the Duval and Tweedie trim and fill were performed with no changes in the effect sizes. The Egger test indicated no publication bias in all studies for all comparisons.

Study Characteristics

eTable 1 shows the characteristics of included studies. Most trials were randomized, double-blind, and placebo-controlled. Randomization ratios ranged from 1:1 to 3:2.

Thirty-six trials had more than 1 treatment group and 1 placebo group. Follow-up ranged from 24 to 156 weeks (eTable 2 and eTable 3). There were multiple dosages for each BRM. Dosages for abatacept were 2 to 10 mg/kg every 4 weeks; adalimumab, 20, 40, or 80 mg every other week and 20 or 40 mg every week; anakinra, 30 to 150 mg or 0.04 to 1 mg/kg daily; certolizumab, 200 or 400 mg every 2 or 4 weeks; etanercept, 10 or 25 mg twice weekly; golimumab, 50 or 100 mg every 2 or 4 weeks or 2 or 4 mg/kg every 12 weeks; infliximab, 1, 3, 5, 6, or 10 mg/kg every 4 or 8 weeks; rituximab, 500 or 1000 mg at day 0 and 15 mg every 6 or 12 months; and tocilizumab, 2, 4, or 8 mg/kg every 4 weeks. Thirty-four studies included a rescue regimen for nonresponders in the control group by increasing control dosages, changing to other traditional DMARDs, withdrawing from the study, or administering the study BRMs.

Sample sizes ranged from 2019 to 1399.20eTable 4 describes the characteristics of patients included in each trial. All trials were reported as multicenter trials without further specific information regarding the setting. Sixty-six percent (42/63) were reported as multinational studies.

Sixty-three trials with 29 423 patients were included in this analysis. A total of 15 989 were assigned to BRMs plus methotrexate (and/or other DMARDs), 3615 to BRMs alone, and 9819 to control groups. Four trials had comparisons between BRMs: Genovese et al21 compared anakinra plus etanercept vs etanercept; Weinblatt et al22 compared abatacept plus etanercept vs etanercept; Greenwald et al23 compared rituximab plus etanercept or adalimumab vs etanercept or adalimumab; and van Vollenhoven et al24 compared atacicept vs adalimumab. Furthermore, the ATTEST trial25 was a head-to-head trial comparing infliximab vs abatacept vs control, and we only analyzed each group vs control. For 50 trials, to be eligible participants had to have active disease and failure of traditional DMARDs (15 trials also required a previous failure of TNF inhibitors), and 13 trials included patients naïve to methotrexate and/or other DMARDs. The majority of patients were white (79%) and women (76%). The mean age ranged from 44.8 to 56.5 years. Mean disease duration ranged from 0.35 to 13 years.

Eleven trials did not mention malignancies in their reported adverse events, and the corresponding authors and sponsors were contacted to retrieve the data.19,2635 Listed primary end points were efficacy, safety, and radiographic outcomes in 6 trials; efficacy and safety in 23 trials; efficacy and radiographic outcomes in 7 trials; efficacy and job loss in 1 trial; efficacy alone in 16 trials; safety alone in 7 trials; radiographic outcomes alone in 2 trials; and work disability in 1 trial.

Risk of Bias in Included Studies

Only 19 trials clearly reported adequate sequence generation and allocation concealment by assigning each patient a unique sequential number using a central (interactive voice) randomization system, and the randomization schedules were generated and kept sealed until the unblinding of the study. Forty-three trials did not mention allocation concealment in the published article. One study reported adequate allocation concealment, but no information was provided on how randomization was performed. Five trials were unblinded.26,3640 Nishimoto et al41 conducted a reader-blinded study and van Vollenhoven et al24 included an open-label adalimumab group.

The completion rates ranged from 49% to 94% in the BRM-monotherapy groups, from 58% to 99% in the BRM combination therapy groups, and from 5% to 100% in the control groups; adverse events were cause for discontinuation in 23%, 33%, and 18%, respectively; and lack of efficacy was reported for 37%, 29%, and 50%, respectively. There was little risk of bias due to selective reporting. Fifty-six trials were sponsored by a pharmaceutical company and 3 trials did not disclose the source of funding. The remaining 4 were funded by the French Society of Rheumatology,36 the Dutch College of Health Insurances,37,38 the Swedish Rheumatism Association,40 or the National Center for Research Resources30; however, drugs were provided free of charge by industry.

Malignancies

We obtained additional information on malignancies from the authors/sponsors for 9 trials.2632,34,35 An additional 2 trials did not report malignancies, but the authors did not provide additional data.19,33 Of the 29 423 patients, 211 developed a malignancy during the trial (0.72%; 95% CI, 0.63%-0.82%): 23 of 3615 patients in the BRM monotherapy group (0.64%; 95% CI, 0.42%-0.95%), 123 of 15 989 patients in the BRM combination therapy group (0.77%; 95% CI, 0.65%-0.92%), and 65 of 9819 patients in the control group (0.66%; 95% CI, 0.52%-0.84%). eTable 2 and eTable 3 show the malignancies reported in each trial for TNF inhibitors and other BRMs, respectively.

Of the 211 malignancies, 118 were solid tumors (ie, adrenal, bladder, breast, cholangiocarcinoma, fibrosarcoma, gastrointestinal, hepatic, leiomyosarcoma, liposarcoma, lung, ovarian, pancreatic, prostate, renal, testicular, thyroid, tongue, uterine), 48 were skin cancer (ie, basal cell, squamous cell, and 4 melanomas), 14 were lymphomas, 26 were not specified, and 5 were hematologic nonlymphoma (ie, multiple myeloma, leukemia). Table 1 and Table 2 show the risk of malignancy for TNF inhibitors and other BRMs. We show all 3 risk estimates: Peto OR, RR, and continuity correction for 0-total-event trials, but focus on the Peto ORs because they are the most appropriate for events occurring with low frequency. For each individual BRM, Peto ORs ranged from 0.11 to 7.4. The only statistically significant increase in risk of malignancy we observed was for the combined TNF inhibitor plus methotrexate group vs controls (Peto OR, 2.1; 95% CI, 1.1-3.9) at 52 weeks (Table 1); with an attributable risk percentage of 52% (95% CI, 9%-74%; P = .005). However, with random effects, the model was not significant (RR, 1.8; 95% CI, 0.82-3.8). No differences were observed when TNF inhibitors alone were compared with controls (methotrexate or DMARDs alone) (Peto OR, 0.98; 95% CI, 0.51-1.9). Individually, none of the TNF inhibitors showed a statistically significant risk. For the non-TNF inhibitors, non–statistically significant differences were observed in most instances. Anakinra plus methotrexate had statistically significantly lower odds of malignancy compared with methotrexate alone (Peto OR, 0.11 [95% CI, 0.03-0.45]; prevented risk percentage, 89% [95% CI, 55%-97%]; and absolute risk reduction, 9 [95% CI, 2-21] per 1000 patients) at 24 weeks (Table 2).

Table Graphic Jump LocationTable 1. Risk of Malignancy (All Types Combined) in Patients Treated With TNF Inhibitors
Table Graphic Jump LocationTable 2. Risk of Malignancy (All Types Combined) in Patients Treated With Non–TNF Inhibitor BRMs

The Figure shows the occurrence of melanoma and nonmelanoma skin cancer, lymphoma, solid tumors combined, other hematologic, and unspecified malignancies in patients with RA treated with BRMs. Peto ORs ranged between 0.01 (95% CI, 0.00-0.94) for developing lymphoma with anakinra therapy to 5.7 (95% CI, 0.31-104.9) for other hematological malignancies with infliximab therapy (eTable 5). Patients treated with anakinra had lower odds of developing nonmelanoma skin cancer (Peto OR, 0.06; 95% CI, 0.00-0.94). No other pooled results were statistically significant. The risk of lymphoma with TNF inhibitors was doubled but did not reach statistical significance (Peto OR, 2.1; 95% CI, 0.55-8.4).

Place holder to copy figure label and caption
Figure. Effect of BRMs on Occurrence of Specific Types of Cancer in Patients With Rheumatoid Arthritis
Graphic Jump Location

BRM indicates biologic response modifier; OR, odds ratio; TNF, tumor necrosis factor. Numbers of patients included in each comparison are reported in eTable 5. Diamonds represent pooled effect estimates with 95% CIs for all TNF inhibitors. aFor infliximab, 1 patient reported both squamous cell carcinoma and melanoma. bAdrenal, bladder, breast, cholangiocarcinoma, fibrosarcoma, gastrointestinal, hepatic, leiomyosarcoma, liposarcoma, lung, ovarian, pancreatic, prostate, renal, testicular, thyroid, tongue, and uterine. cMultiple myeloma and leukemia.

Sensitivity Analysis

Using the continuity correction, results were similar to the Mantel-Haenszel RR. Analyzing by intention to treat, quality of the trials, dosage, drug exposure (≤1 year or >1 year), no rescue therapy (before 24 weeks), or excluding placebo-controlled trials with no concomitant treatment had no effect on our results (eTable 6 and eTable 7). When analyzing the data excluding trials with no report of malignancy using the continuity correction, the only significant increase, in risk of malignancy observed for the combined TNF inhibitor plus methotrexate group vs controls, remained significant (Peto OR, 2.0; 95% CI, 1.1-3.8 at 52 weeks) but with no increased risk at other time points. There were no statistically significant differences for any of the analyses when applying Bonferroni correction.

To our knowledge, this is the largest systematic review and meta-analysis examining the risk of malignancy in patients with RA receiving BRMs in RCTs. We pooled results from 63 RCTs including 29 423 patients, followed up for at least 24 weeks, to estimate the risk of developing cancer among users of BRMs compared with controls (ie, traditional DMARDs, placebo, or a BRM). There was no statistically significant increased risk of any type of cancer with use of BRMs vs controls. The only increased risk of malignancy we observed was in patients with RA treated with TNF inhibitors plus methotrexate at 52 weeks, for all cancers combined, with patients receiving these agents having twice the risk of malignancy than controls. However, this increase was not observed at other time points (24, 104, or 156 weeks) or with monotherapy.

There are various published reports reviewing the risk of malignancy in patients with RA treated with TNF inhibitors.5,6,9093 Ours are in contrast with the findings published by Bongartz et al,5 who reported a dose-dependent increased risk of malignancies in patients with RA treated with a TNF inhibitor. In a follow-up analysis of etanercept RCTs, an increased risk of 1.8 was observed but did not reach statistical significance. In a more recent meta-analysis by Askling et al94 including RCTs of TNF inhibitors, using patient-level data and Bayesian methods, no increased short-term risk of cancer other than nonmelanoma skin cancer was found. This analysis, however, included patients with any condition, not just RA, and did not categorize the analyses with respect to addition of other DMARDs (eg, methotrexate) in the treatment or control groups.

In observational studies, the association between malignancies and BRMs has varied. Wolfe and Michaud95 examined the incidence of cancer among 13 001 patients with RA, about 50% of them treated with BRMs, during 49 000 patient-years of observation, observing a small but significant increase in the risk of both nonmelanoma and melanoma skin cancers (ORs, 1. 5 and 2.3, respectively). Wolfe and Michaud96 and Geborek et al97 also documented increased risk of lymphoma in patients with RA compared with the general population, with greater risk in patients treated with TNF inhibitors. Others have not found significant increases in the risk of hematologic malignancies and common solid tumors in BRM users.8,98,99 The reason for the observed discrepancies are somewhat unclear but could be attributed to some degree to the selection of the control population in these observational studies. Unlike clinical trials, cohort studies may be subject to confounding by indication, and the controls, patients with RA not receiving BRMs, might be very different with respect to relevant factors compared with those receiving therapy. Conceivably, patients with a personal or family history of cancer or other important risk factors might be less likely to receive BRMs and could have a higher incidence of cancer than the population with RA at large, therefore decreasing the risk that could be attributable to the intervention when included as controls. Of interest, Carmona et al100 found no increase in the overall risk of malignancy in patients exposed to TNF inhibitors compared with controls. However, when examining the risk factors for cancer in these patients, age, treatment with methotrexate, treatment with steroids, and chronic obstructive pulmonary disease were significantly associated with developing a malignancy. Despite being subject to bias, cohort studies are needed to evaluate long-term exposures and cumulative effects.

The available data appear to suggest that there is no cumulative risk over time, but these data are also subject to attrition bias. Clinical trials, however, are less subject to bias and, in the context of malignancies, are appropriate to evaluate rapid development of cancer and possibly increased risk of progression of existing occult disease. While trials in RA are relatively short and cannot evaluate risk over long-term exposure, as observational studies do, we thought there was a need to conduct an updated meta-analysis of RCTs because of the older reports of the possible increase in malignancies5 and the more recent FDA advisory for TNF inhibitors, mostly based on studies in children.4 Furthermore, Brown et al101 reviewed MedWatch reports of 26 cases of lymphoproliferative disorders that occurred following treatment with either etanercept or infliximab and found that more than half of the patients who developed lymphoma did so within 8 weeks after initiation of TNF inhibitors. In addition, the concerns in patients receiving BRMs are not only for de novo development of cancer but also for potential acceleration of progression of an occult, not yet diagnosed malignancy. Nannini et al8 conducted a qualitative systematic review of RCTs in patients with RA, psoriatic arthritis, and ankylosing spondylitis and found that 26% of cancers occurred within 12 weeks of onset of therapy, suggesting that these were preexisting occult malignancies.

Overall, our results show no increased risk of malignancy in RCTs of at least 24 weeks' duration. There was only a small increase in risk at 52 weeks for patients receiving TNF inhibitors in combination with methotrexate, but this effect was not consistent throughout all 3 analytic approaches, in patients receiving TNF inhibitors as monotherapy, or at other time points. Furthermore, the incidence rate for any malignancy was very low in both the TNF inhibitor plus methotrexate group and in controls (1.1% vs 0.5%, respectively). The absolute risk was therefore quite small at 6 per 1000 patients with a number needed to harm of 159.

Other biologic agents did not show clear trends of an increase in malignancy. In fact, anakinra showed a statistically significant decrease in risk. Interestingly, laboratory data suggest that interleukin 1 may have carcinogenetic effects that could be exerted through their inflammatory properties or through direct stimulus of tumor growth.102104 Anakinra has been shown to inhibit tumor growth in mouse models.102 Furthermore, preliminary epidemiologic data show an association between interleukin 1 expression and cancer progression.105 We cannot discard the possibility that the protective effect of anakinra could be partially due to a higher-than-usual malignancy rate in controls. However, our data are based on a pooled estimate of 63 RCTs, with an expectation that baseline expected rates for malignancy before intervention were similar for active and control groups.

Our study has several limitations related to the quality of data in the original sources. First, in this review we could not adequately assess risk of bias in some instances because the publications did not provide enough details in their reports. Data necessary for further analysis and information on type of malignancy, time point of occurrence, and history of cancer were sometimes lacking; however, we successfully contacted corresponding authors and sponsors to retrieve data on most studies (61/63).

Second, owing to the unavailability of translators, we included only trials published in English, French, or Spanish. There is a concern that articles reporting positive results are more likely to be published in English, which may have led to underestimation in our results. However, our analysis did not find evidence of publication bias.

Third. our data abstraction was not blinded, and failure to blind could lead to a bias. While there is some limited evidence that blinding in data abstraction may not alter the results of a meta-analysis, this methodological issue has not been entirely resolved.106108 One of the data extractors was not familiar with the study area and, in addition, data extraction was cross-checked independently by 2 investigators to decrease potential biases related to lack of blinding.

Fourth, most of the studies were funded by pharmaceutical companies, which can also affect outcomes. There is evidence that industry-sponsored trials may overestimate the treatment effect and could possibly also overestimate safety.109 The effect of funding bias could not be explored because the 4 trials for which funding was not reported evaluated 3 different drugs (adalimumab, infliximab, and abatacept). To minimize the limited statistical power to detect differences between treatments for rare events, we combined different agents with a similar mode of action (all TNF inhibitors), and the validity of pooling did not appear to be compromised because studies were homogeneous (I2 = 0%).

Fifth, data from RCTs are not always generalizable; the superior internal validity can be good to establish causality, but their strict selection criteria can compromise generalizability.110 Registry data can overcome this problem with results more applicable to the “real world.” However, community-based observational data are generally very complex and can be subject to confounding bias.

Overall, our findings do not support an increased risk of malignancy for patients with RA receiving BRMs in RCTs of at least 24 weeks' duration. Additional systematic reviews of observational studies are needed to establish risk in the longer term. Although the findings suggest that BRMs may be generally safe with respect to risk of malignancy in the short term, the risk of recurrence in patients with RA with history of cancer or cancer risk factors remains unknown.

Corresponding Author: Maria E. Suarez-Almazor, MD, PhD, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1465, Houston, TX 77030 (msalmazor@mdanderson.org).

Author Contributions: Dr Suarez-Almazor 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 concept and design: Lopez-Olivo, Martinez-Lopez, Suarez-Almazor.

Acquisition of data: Lopez-Olivo, Tayar, Martinez-Lopez, Pollono, Cueto, Gonzales-Crespo, Fulton.

Analysis and interpretation of data: Lopez-Olivo, Tayar, Martinez-Lopez, Gonzales-Crespo, Suarez-Almazor.

Drafting of the manuscript: Lopez-Olivo, Tayar, Cueto, Gonzales-Crespo.

Critical revision of the manuscript for important intellectual content: Lopez-Olivo, Tayar, Martinez-Lopez, Pollono, Cueto, Gonzales-Crespo, Fulton, Suarez-Almazor.

Statistical analysis: Lopez-Olivo, Martinez-Lopez.

Obtained funding: Cueto, Suarez-Almazor.

Administrative, technical, or material support: Martinez-Lopez, Pollono, Cueto, Fulton.

Study supervision: Lopez-Olivo, Tayar, Suarez-Almazor.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was not funded or supported by any organization. Dr Suarez-Almazor has a K24 career award from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant AR053593).

Role of the Sponsor: No sponsors were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Online-Only Material: The Author Audio Interview is available here.

Additional Contributions: We are grateful to Hong Zhang, PhD, statistician at the Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, for her assistance with deduplication of the data, κ calculation, and invaluable feedback on the meta-analytic techniques used for the analysis. Dr Zhang did not receive any compensation for her contributions.

Badley EM, Lee J, Wood PH. Impairment, disability, and the ICIDH (International Classification of Impairments, Disabilities, and Handicaps) model, II.  Int Rehabil Med. 1987;8(3):118-124
PubMed
Cohen SB, Cohen MD, Cush JJ,  et al.  Unresolved issues in identifying and overcoming inadequate response in rheumatoid arthritis.  J Rheumatol Suppl. 2008;81:4-30
PubMed
Curtis JR, Jain A, Askling J,  et al.  A comparison of patient characteristics and outcomes in selected European and US rheumatoid arthritis registries.  Semin Arthritis Rheum. 2010;40(1):2-14
PubMed   |  Link to Article
Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy.  Eur J Gastroenterol Hepatol. 2011;23(12):1150-1156
PubMed   |  Link to Article
Bongartz T, Sutton AJ, Sweeting MJ,  et al.  Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies.  JAMA. 2006;295(19):2275-2285
PubMed   |  Link to Article
Kaiser R. Incidence of lymphoma in patients with rheumatoid arthritis.  Clin Lymphoma Myeloma. 2008;8(2):87-93
PubMed   |  Link to Article
Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis.  Ann Rheum Dis. 2009;68(7):1136-1145
PubMed   |  Link to Article
Nannini C, Cantini F, Niccoli L,  et al.  Single-center series and systematic review of randomized controlled trials of malignancies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis receiving anti-tumor necrosis factor α therapy.  Arthritis Rheum. 2009;61(6):801-812
PubMed   |  Link to Article
Singh JA, Wells GA, Christensen R,  et al.  Adverse effects of biologics.  Cochrane Database Syst Rev. 2011;(2):CD008794
PubMed
Wiens A, Correr CJ, Pontarolo R,  et al.  A systematic review and meta-analysis of the efficacy and safety of etanercept for treating rheumatoid arthritis.  Scand J Immunol. 2009;70(4):337-344
PubMed   |  Link to Article
Wiens A, Correr CJ, Venson R,  et al.  A meta-analysis of the efficacy and safety of using infliximab for the treatment of rheumatoid arthritis.  Clin Rheumatol. 2009;28(12):1365-1373
PubMed   |  Link to Article
Wiens A, Correr CJ, Venson R,  et al.  A systematic review and meta-analysis of the efficacy and safety of adalimumab for treating rheumatoid arthritis.  Rheumatol Int. 2010;30(8):1063-1070
PubMed   |  Link to Article
Wiens A, Venson R, Correr CJ,  et al.  Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis.  Pharmacotherapy. 2010;30(4):339-353
PubMed   |  Link to Article
Le Blay P, Mouterde G, Barnetche T,  et al.  Short-term risk of total malignancy and nonmelanoma skin cancers with certolizumab and golimumab in patients with rheumatoid arthritis.  J Rheumatol. 2012;39(4):712-715
PubMed   |  Link to Article
Wong AK, Kerkoutian S, Said J,  et al.  Risk of lymphoma in patients receiving antitumor necrosis factor therapy.  Clin Rheumatol. 2012;31(4):631-636
PubMed   |  Link to Article
Higgins JPT, ed, Green S, edCochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. www.cochrane-handbook.org. Accessed August 2, 2012
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events.  Stat Med. 2007;26(1):53-77
PubMed   |  Link to Article
Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.  Ann Intern Med. 2007;147(8):578-581
PubMed   |  Link to Article
Quinn MA, Conaghan PG, O’Connor PJ,  et al.  Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal.  Arthritis Rheum. 2005;52(1):27-35
PubMed   |  Link to Article
Weinblatt M, Combe B, Covucci A,  et al.  Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs.  Arthritis Rheum. 2006;54(9):2807-2816
PubMed   |  Link to Article
Genovese MC, Cohen S, Moreland L,  et al; 20000223 Study Group.  Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate.  Arthritis Rheum. 2004;50(5):1412-1419
PubMed   |  Link to Article
Weinblatt M, Schiff M, Goldman A,  et al.  Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept.  Ann Rheum Dis. 2007;66(2):228-234
PubMed   |  Link to Article
Greenwald MW, Shergy WJ, Kaine JL,  et al.  Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis.  Arthritis Rheum. 2011;63(3):622-632
PubMed   |  Link to Article
van Vollenhoven RF, Kinnman N, Vincent E,  et al.  Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate.  Arthritis Rheum. 2011;63(7):1782-1792
PubMed   |  Link to Article
Schiff M, Keiserman M, Codding C,  et al.  Efficacy and safety of abatacept or infliximab vs placebo in ATTEST.  Ann Rheum Dis. 2008;67(8):1096-1103
PubMed   |  Link to Article
Bingham CO III, Looney RJ, Deodhar A,  et al.  Immunization responses in rheumatoid arthritis patients treated with rituximab.  Arthritis Rheum. 2010;62(1):64-74
PubMed   |  Link to Article
Edwards JCW, Szczepanski L, Szechinski J,  et al.  Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.  N Engl J Med. 2004;350(25):2572-2581
PubMed   |  Link to Article
Emery P, Fleischmann R, Filipowicz-Sosnowska A,  et al; DANCER Study Group.  The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment.  Arthritis Rheum. 2006;54(5):1390-1400
PubMed   |  Link to Article
Emery P, Keystone E, Tony HP,  et al.  IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals.  Ann Rheum Dis. 2008;67(11):1516-1523
PubMed   |  Link to Article
Genovese MC, Becker J-C, Schiff M,  et al.  Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition.  N Engl J Med. 2005;353(11):1114-1123
PubMed   |  Link to Article
Genovese MC, McKay JD, Nasonov EL,  et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs.  Arthritis Rheum. 2008;58(10):2968-2980
PubMed   |  Link to Article
Mease PJ, Cohen S, Gaylis NB,  et al.  Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors.  J Rheumatol. 2010;37(5):917-927
PubMed   |  Link to Article
Moreland LW, Schiff MH, Baumgartner SW,  et al.  Etanercept therapy in rheumatoid arthritis.  Ann Intern Med. 1999;130(6):478-486
PubMed   |  Link to Article
Nishimoto N, Miyasaka N, Yamamoto K,  et al.  Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI).  Mod Rheumatol. 2009;19(1):12-19
PubMed   |  Link to Article
Weinblatt ME, Kremer JM, Bankhurst AD,  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.  N Engl J Med. 1999;340(4):253-259
PubMed   |  Link to Article
Soubrier M, Puéchal X, Sibilia J,  et al.  Evaluation of 2 strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis.  Rheumatology (Oxford). 2009;48(11):1429-1434
PubMed   |  Link to Article
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF,  et al.  Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial.  Ann Intern Med. 2007;146(6):406-415
PubMed   |  Link to Article
Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF,  et al.  Clinical and radiographic outcomes of 4 different treatment strategies in patients with early rheumatoid arthritis (the BEST study).  Arthritis Rheum. 2005;52(11):3381-3390
PubMed   |  Link to Article
Durez P, Malghem J, Nzeusseu Toukap A,  et al.  Treatment of early rheumatoid arthritis.  Arthritis Rheum. 2007;56(12):3919-3927
PubMed   |  Link to Article
van Vollenhoven RF, Ernestam S, Geborek P,  et al.  Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial).  Lancet. 2009;374(9688):459-466
PubMed   |  Link to Article
Nishimoto N, Hashimoto J, Miyasaka N,  et al.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI).  Ann Rheum Dis. 2007;66(9):1162-1167
PubMed   |  Link to Article
Miyasaka N.CHANGE Study Investigators.  Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation.  Mod Rheumatol. 2008;18(3):252-262
PubMed   |  Link to Article
van de Putte LBA, Atkins C, Malaise M,  et al.  Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.  Ann Rheum Dis. 2004;63(5):508-516
PubMed   |  Link to Article
Breedveld FC, Weisman MH, Kavanaugh AF,  et al.  The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate vs methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.  Arthritis Rheum. 2006;54(1):26-37
PubMed   |  Link to Article
Furst DE, Schiff MH, Fleischmann RM,  et al.  Adalimumab, a fully human anti tumor necrosis factor-α monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis.  J Rheumatol. 2003;30(12):2563-2571
PubMed
Kim HY, Lee SK, Song YW,  et al.  A randomized, double-blind, placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate.  APLAR J Rheumatol. 2007;10(1):9-16
Link to Article
Weinblatt ME, Keystone EC, Furst DE,  et al.  Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate.  Arthritis Rheum. 2003;48(1):35-45
PubMed   |  Link to Article
Bejarano V, Quinn M, Conaghan PG,  et al; Yorkshire Early Arthritis Register Consortium.  Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis.  Arthritis Rheum. 2008;59(10):1467-1474
PubMed   |  Link to Article
Keystone EC, Kavanaugh AF, Sharp JT,  et al.  Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy.  Arthritis Rheum. 2004;50(5):1400-1411
PubMed   |  Link to Article
Fleischmann R, Vencovsky J, van Vollenhoven RF,  et al.  Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy.  Ann Rheum Dis. 2009;68(6):805-811
PubMed   |  Link to Article
Smolen J, Landewé RB, Mease P,  et al.  Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study.  Ann Rheum Dis. 2009;68(6):797-804
PubMed   |  Link to Article
Choy E, McKenna F, Vencovsky J,  et al.  Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX.  Rheumatology (Oxford). 2012;51(7):1226-1234
PubMed   |  Link to Article
Keystone E, Heijde D, Mason D Jr,  et al.  Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis.  Arthritis Rheum. 2008;58(11):3319-3329
PubMed   |  Link to Article
Hu D, Bao C, Chen S,  et al.  A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) and methotrexate in treatment of patients with active rheumatoid arthritis in China.  Rheumatol Int. 2009;29(3):297-303
PubMed   |  Link to Article
Bathon JM, Martin RW, Fleischmann RM,  et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.  N Engl J Med. 2000;343(22):1586-1593
PubMed   |  Link to Article
Combe B, Codreanu C, Fiocco U,  et al; Etanercept European Investigators Network.  Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine vs etanercept alone in patients with rheumatoid arthritis.  Ann Rheum Dis. 2009;68(7):1146-1152
PubMed   |  Link to Article
Combe B, Codreanu C, Fiocco U,  et al; Etanercept European Investigators Network.  Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine.  Ann Rheum Dis. 2006;65(10):1357-1362
PubMed   |  Link to Article
Klareskog L, van der Heijde D, de Jager JP,  et al; TEMPO Study Investigators.  Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis.  Lancet. 2004;363(9410):675-681
PubMed   |  Link to Article
Emery P, Breedveld FC, Hall S,  et al.  Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET).  Lancet. 2008;372(9636):375-382
PubMed   |  Link to Article
van der Heijde D, Klareskog L, Landewé R,  et al.  Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis.  Arthritis Rheum. 2007;56(12):3928-3939
PubMed   |  Link to Article
van der Heijde D, Klareskog L, Rodriguez-Valverde V,  et al; TEMPO Study Investigators.  Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis.  Arthritis Rheum. 2006;54(4):1063-1074
PubMed   |  Link to Article
Emery P, Fleischmann RM, Moreland LW,  et al.  Golimumab, a human anti-tumor necrosis factor α monoclonal antibody, injected subcutaneously every 4 weeks in methotrexate-naive patients with active rheumatoid arthritis.  Arthritis Rheum. 2009;60(8):2272-2283
PubMed   |  Link to Article
Kay J, Matteson EL, Dasgupta B,  et al.  Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate.  Arthritis Rheum. 2008;58(4):964-975
PubMed   |  Link to Article
Kremer J, Ritchlin C, Mendelsohn A,  et al.  Golimumab, a new human anti-tumor necrosis factor α antibody, administered intravenously in patients with active rheumatoid arthritis.  Arthritis Rheum. 2010;62(4):917-928
PubMed   |  Link to Article
Smolen JS, Kay J, Doyle MK,  et al; GO-AFTER Study Investigators.  Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study).  Lancet. 2009;374(9685):210-221
PubMed   |  Link to Article
Keystone EC, Genovese MC, Klareskog L,  et al; GO-FORWARD Study.  Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy.  Ann Rheum Dis. 2009;68(6):789-796
PubMed   |  Link to Article
Maini RN, Breedveld FC, Kalden JR,  et al.  Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.  Arthritis Rheum. 1998;41(9):1552-1563
PubMed   |  Link to Article
Westhovens R, Yocum D, Han J,  et al; START Study Group.  The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities [published correction appears in Arthritis Rheum. 2007;56(5):1675].  Arthritis Rheum. 2006;54(4):1075-1086
PubMed   |  Link to Article
St Clair EW, van der Heijde DMFM, Smolen JS,  et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group.  Combination of infliximab and methotrexate therapy for early rheumatoid arthritis.  Arthritis Rheum. 2004;50(11):3432-3443
PubMed   |  Link to Article
Maini R, St Clair EW, Breedveld F,  et al;  ATTRACT Study Group.  Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) vs placebo in rheumatoid arthritis patients receiving concomitant methotrexate.  Lancet. 1999;354(9194):1932-1939
PubMed   |  Link to Article
Lipsky PE, van der Heijde DM, St Clair EW,  et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Infliximab and methotrexate in the treatment of rheumatoid arthritis.  N Engl J Med. 2000;343(22):1594-1602
PubMed   |  Link to Article
Maini RN, Breedveld FC, Kalden JR,  et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Sustained improvement over 2 years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate.  Arthritis Rheum. 2004;50(4):1051-1065
PubMed   |  Link to Article
van Vollenhoven RF, Geborek P, Forslind K,  et al; Swefot Study Group.  Conventional combination treatment vs biological treatment in methotrexate-refractory early rheumatoid arthritis.  Lancet. 2012;379(9827):1712-1720
PubMed   |  Link to Article
Emery P, Durez P, Dougados M,  et al.  Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis.  Ann Rheum Dis. 2010;69(3):510-516
PubMed   |  Link to Article
Kremer JM, Westhovens R, Leon M,  et al.  Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig.  N Engl J Med. 2003;349(20):1907-1915
PubMed   |  Link to Article
Kremer JM, Genant HK, Moreland LW,  et al.  Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis.  Ann Intern Med. 2006;144(12):865-876
PubMed   |  Link to Article
Westhovens R, Robles M, Ximenes AC,  et al.  Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors.  Ann Rheum Dis. 2009;68(12):1870-1877
PubMed   |  Link to Article
Bresnihan B, Alvaro-Gracia JM, Cobby M,  et al.  Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.  Arthritis Rheum. 1998;41(12):2196-2204
PubMed   |  Link to Article
Cohen S, Hurd E, Cush J,  et al.  Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate.  Arthritis Rheum. 2002;46(3):614-624
PubMed   |  Link to Article
Fleischmann RM, Schechtman J, Bennett R,  et al.  Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis.  Arthritis Rheum. 2003;48(4):927-934
PubMed   |  Link to Article
Cohen SB, Moreland LW, Cush JJ,  et al; 990145 Study Group.  A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.  Ann Rheum Dis. 2004;63(9):1062-1068
PubMed   |  Link to Article
Cohen SB, Emery P, Greenwald MW,  et al; REFLEX Trial Group.  Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy.  Arthritis Rheum. 2006;54(9):2793-2806
PubMed   |  Link to Article
Emery P, Deodhar A, Rigby WF,  et al.  Efficacy and safety of different doses and retreatment of rituximab.  Ann Rheum Dis. 2010;69(9):1629-1635
PubMed   |  Link to Article
Tak PP, Rigby WF, Rubbert-Roth A,  et al; IMAGE Investigators.  Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis.  Ann Rheum Dis. 2011;70(1):39-46
PubMed   |  Link to Article
Tak PP, Rigby W, Rubbert-Roth A,  et al.  Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis.  Ann Rheum Dis. 2012;71(3):351-357
PubMed   |  Link to Article
Jones G, Sebba A, Gu J,  et al.  Comparison of tocilizumab monotherapy vs methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis.  Ann Rheum Dis. 2010;69(1):88-96
PubMed   |  Link to Article
Smolen JS, Beaulieu A, Rubbert-Roth A,  et al; OPTION Investigators.  Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study).  Lancet. 2008;371(9617):987-997
PubMed   |  Link to Article
Yazici Y, Curtis JR, Ince A,  et al.  Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs.  Ann Rheum Dis. 2012;71(2):198-205
PubMed   |  Link to Article
Kremer JM, Blanco R, Brzosko M,  et al.  Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate.  Arthritis Rheum. 2011;63(3):609-621
PubMed   |  Link to Article
Askling J, Bongartz T. Malignancy and biologic therapy in rheumatoid arthritis.  Curr Opin Rheumatol. 2008;20(3):334-339
PubMed   |  Link to Article
Bongartz T, Warren FC, Mines D,  et al.  Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials.  Ann Rheum Dis. 2009;68(7):1177-1183
PubMed   |  Link to Article
Chakravarty EF, Farmer ER. Risk of skin cancer in the drug treatment of rheumatoid arthritis.  Expert Opin Drug Saf. 2008;7(5):539-546
PubMed   |  Link to Article
Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis.  Arthritis Res Ther. 2008;10(2):R45
PubMed   |  Link to Article
Askling J, Fahrbach K, Nordstrom B,  et al.  Cancer risk with tumor necrosis factor α (TNF) inhibitors.  Pharmacoepidemiol Drug Saf. 2011;20(2):119-130
PubMed   |  Link to Article
Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis.  Arthritis Rheum. 2004;50(6):1740-1751
PubMed   |  Link to Article
Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy.  Arthritis Rheum. 2007;56(9):2886-2895
PubMed   |  Link to Article
Geborek P, Bladström A, Turesson C,  et al.  Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas.  Ann Rheum Dis. 2005;64(5):699-703
PubMed   |  Link to Article
Setoguchi S, Solomon DH, Weinblatt ME,  et al.  Tumor necrosis factor α antagonist use and cancer in patients with rheumatoid arthritis.  Arthritis Rheum. 2006;54(9):2757-2764
PubMed   |  Link to Article
Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor α (TNF) inhibitors.  Pharmacoepidemiol Drug Saf. 2011;20(2):119-130
PubMed   |  Link to Article
Carmona L, Abasolo L, Descalzo MA,  et al;  BIOBADASER Study Group; EMECAR Study Group.  Cancer in patients with rheumatic diseases exposed to TNF antagonists.  Semin Arthritis Rheum. 2011;41(1):71-80
PubMed   |  Link to Article
Brown SL, Greene MH, Gershon SK,  et al.  Tumor necrosis factor antagonist therapy and lymphoma development.  Arthritis Rheum. 2002;46(12):3151-3158
PubMed   |  Link to Article
Harnack U, Johnen H, Pecher G. IL-1 receptor antagonist anakinra enhances tumour growth inhibition in mice receiving peptide vaccination and β-(1-3),(1-6)-D-glucan.  Anticancer Res. 2010;30(10):3959-3965
PubMed
Dinarello CA. Why not treat human cancer with interleukin-1 blockade?  Cancer Metastasis Rev. 2010;29(2):317-329
PubMed   |  Link to Article
Chen MF, Lu MS, Chen PT, Chen WC, Lin PY, Lee KD. Role of interleukin 1 beta in esophageal squamous cell carcinoma.  J Mol Med (Berl). 2012;90(1):89-100
PubMed   |  Link to Article
Heikkilä K, Harris R, Lowe G,  et al.  Associations of circulating C-reactive protein and interleukin-6 with cancer risk.  Cancer Causes Control. 2009;20(1):15-26
PubMed   |  Link to Article
Berlin JA.University of Pennsylvania Meta-analysis Blinding Study Group.  Does blinding of readers affect the results of meta-analyses?  Lancet. 1997;350(9072):185-186
PubMed   |  Link to Article
Buscemi N, Hartling L, Vandermeer B,  et al.  Single data extraction generated more errors than double data extraction in systematic reviews.  J Clin Epidemiol. 2006;59(7):697-703
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials.  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Bhandari M, Busse JW, Jackowski D,  et al.  Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials.  CMAJ. 2004;170(4):477-480
PubMed
Weisberg HI, Hayden VC, Pontes VP. Selection criteria and generalizability within the counterfactual framework.  Clin Trials. 2009;6(2):109-118
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Effect of BRMs on Occurrence of Specific Types of Cancer in Patients With Rheumatoid Arthritis
Graphic Jump Location

BRM indicates biologic response modifier; OR, odds ratio; TNF, tumor necrosis factor. Numbers of patients included in each comparison are reported in eTable 5. Diamonds represent pooled effect estimates with 95% CIs for all TNF inhibitors. aFor infliximab, 1 patient reported both squamous cell carcinoma and melanoma. bAdrenal, bladder, breast, cholangiocarcinoma, fibrosarcoma, gastrointestinal, hepatic, leiomyosarcoma, liposarcoma, lung, ovarian, pancreatic, prostate, renal, testicular, thyroid, tongue, and uterine. cMultiple myeloma and leukemia.

Tables

Table Graphic Jump LocationTable 1. Risk of Malignancy (All Types Combined) in Patients Treated With TNF Inhibitors
Table Graphic Jump LocationTable 2. Risk of Malignancy (All Types Combined) in Patients Treated With Non–TNF Inhibitor BRMs

References

Badley EM, Lee J, Wood PH. Impairment, disability, and the ICIDH (International Classification of Impairments, Disabilities, and Handicaps) model, II.  Int Rehabil Med. 1987;8(3):118-124
PubMed
Cohen SB, Cohen MD, Cush JJ,  et al.  Unresolved issues in identifying and overcoming inadequate response in rheumatoid arthritis.  J Rheumatol Suppl. 2008;81:4-30
PubMed
Curtis JR, Jain A, Askling J,  et al.  A comparison of patient characteristics and outcomes in selected European and US rheumatoid arthritis registries.  Semin Arthritis Rheum. 2010;40(1):2-14
PubMed   |  Link to Article
Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED. Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy.  Eur J Gastroenterol Hepatol. 2011;23(12):1150-1156
PubMed   |  Link to Article
Bongartz T, Sutton AJ, Sweeting MJ,  et al.  Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies.  JAMA. 2006;295(19):2275-2285
PubMed   |  Link to Article
Kaiser R. Incidence of lymphoma in patients with rheumatoid arthritis.  Clin Lymphoma Myeloma. 2008;8(2):87-93
PubMed   |  Link to Article
Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis.  Ann Rheum Dis. 2009;68(7):1136-1145
PubMed   |  Link to Article
Nannini C, Cantini F, Niccoli L,  et al.  Single-center series and systematic review of randomized controlled trials of malignancies in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis receiving anti-tumor necrosis factor α therapy.  Arthritis Rheum. 2009;61(6):801-812
PubMed   |  Link to Article
Singh JA, Wells GA, Christensen R,  et al.  Adverse effects of biologics.  Cochrane Database Syst Rev. 2011;(2):CD008794
PubMed
Wiens A, Correr CJ, Pontarolo R,  et al.  A systematic review and meta-analysis of the efficacy and safety of etanercept for treating rheumatoid arthritis.  Scand J Immunol. 2009;70(4):337-344
PubMed   |  Link to Article
Wiens A, Correr CJ, Venson R,  et al.  A meta-analysis of the efficacy and safety of using infliximab for the treatment of rheumatoid arthritis.  Clin Rheumatol. 2009;28(12):1365-1373
PubMed   |  Link to Article
Wiens A, Correr CJ, Venson R,  et al.  A systematic review and meta-analysis of the efficacy and safety of adalimumab for treating rheumatoid arthritis.  Rheumatol Int. 2010;30(8):1063-1070
PubMed   |  Link to Article
Wiens A, Venson R, Correr CJ,  et al.  Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis.  Pharmacotherapy. 2010;30(4):339-353
PubMed   |  Link to Article
Le Blay P, Mouterde G, Barnetche T,  et al.  Short-term risk of total malignancy and nonmelanoma skin cancers with certolizumab and golimumab in patients with rheumatoid arthritis.  J Rheumatol. 2012;39(4):712-715
PubMed   |  Link to Article
Wong AK, Kerkoutian S, Said J,  et al.  Risk of lymphoma in patients receiving antitumor necrosis factor therapy.  Clin Rheumatol. 2012;31(4):631-636
PubMed   |  Link to Article
Higgins JPT, ed, Green S, edCochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. www.cochrane-handbook.org. Accessed August 2, 2012
Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events.  Stat Med. 2007;26(1):53-77
PubMed   |  Link to Article
Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death.  Ann Intern Med. 2007;147(8):578-581
PubMed   |  Link to Article
Quinn MA, Conaghan PG, O’Connor PJ,  et al.  Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal.  Arthritis Rheum. 2005;52(1):27-35
PubMed   |  Link to Article
Weinblatt M, Combe B, Covucci A,  et al.  Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs.  Arthritis Rheum. 2006;54(9):2807-2816
PubMed   |  Link to Article
Genovese MC, Cohen S, Moreland L,  et al; 20000223 Study Group.  Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate.  Arthritis Rheum. 2004;50(5):1412-1419
PubMed   |  Link to Article
Weinblatt M, Schiff M, Goldman A,  et al.  Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept.  Ann Rheum Dis. 2007;66(2):228-234
PubMed   |  Link to Article
Greenwald MW, Shergy WJ, Kaine JL,  et al.  Evaluation of the safety of rituximab in combination with a tumor necrosis factor inhibitor and methotrexate in patients with active rheumatoid arthritis.  Arthritis Rheum. 2011;63(3):622-632
PubMed   |  Link to Article
van Vollenhoven RF, Kinnman N, Vincent E,  et al.  Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate.  Arthritis Rheum. 2011;63(7):1782-1792
PubMed   |  Link to Article
Schiff M, Keiserman M, Codding C,  et al.  Efficacy and safety of abatacept or infliximab vs placebo in ATTEST.  Ann Rheum Dis. 2008;67(8):1096-1103
PubMed   |  Link to Article
Bingham CO III, Looney RJ, Deodhar A,  et al.  Immunization responses in rheumatoid arthritis patients treated with rituximab.  Arthritis Rheum. 2010;62(1):64-74
PubMed   |  Link to Article
Edwards JCW, Szczepanski L, Szechinski J,  et al.  Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.  N Engl J Med. 2004;350(25):2572-2581
PubMed   |  Link to Article
Emery P, Fleischmann R, Filipowicz-Sosnowska A,  et al; DANCER Study Group.  The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment.  Arthritis Rheum. 2006;54(5):1390-1400
PubMed   |  Link to Article
Emery P, Keystone E, Tony HP,  et al.  IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals.  Ann Rheum Dis. 2008;67(11):1516-1523
PubMed   |  Link to Article
Genovese MC, Becker J-C, Schiff M,  et al.  Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition.  N Engl J Med. 2005;353(11):1114-1123
PubMed   |  Link to Article
Genovese MC, McKay JD, Nasonov EL,  et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs.  Arthritis Rheum. 2008;58(10):2968-2980
PubMed   |  Link to Article
Mease PJ, Cohen S, Gaylis NB,  et al.  Efficacy and safety of retreatment in patients with rheumatoid arthritis with previous inadequate response to tumor necrosis factor inhibitors.  J Rheumatol. 2010;37(5):917-927
PubMed   |  Link to Article
Moreland LW, Schiff MH, Baumgartner SW,  et al.  Etanercept therapy in rheumatoid arthritis.  Ann Intern Med. 1999;130(6):478-486
PubMed   |  Link to Article
Nishimoto N, Miyasaka N, Yamamoto K,  et al.  Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI).  Mod Rheumatol. 2009;19(1):12-19
PubMed   |  Link to Article
Weinblatt ME, Kremer JM, Bankhurst AD,  et al.  A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.  N Engl J Med. 1999;340(4):253-259
PubMed   |  Link to Article
Soubrier M, Puéchal X, Sibilia J,  et al.  Evaluation of 2 strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis.  Rheumatology (Oxford). 2009;48(11):1429-1434
PubMed   |  Link to Article
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF,  et al.  Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial.  Ann Intern Med. 2007;146(6):406-415
PubMed   |  Link to Article
Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF,  et al.  Clinical and radiographic outcomes of 4 different treatment strategies in patients with early rheumatoid arthritis (the BEST study).  Arthritis Rheum. 2005;52(11):3381-3390
PubMed   |  Link to Article
Durez P, Malghem J, Nzeusseu Toukap A,  et al.  Treatment of early rheumatoid arthritis.  Arthritis Rheum. 2007;56(12):3919-3927
PubMed   |  Link to Article
van Vollenhoven RF, Ernestam S, Geborek P,  et al.  Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial).  Lancet. 2009;374(9688):459-466
PubMed   |  Link to Article
Nishimoto N, Hashimoto J, Miyasaka N,  et al.  Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI).  Ann Rheum Dis. 2007;66(9):1162-1167
PubMed   |  Link to Article
Miyasaka N.CHANGE Study Investigators.  Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation.  Mod Rheumatol. 2008;18(3):252-262
PubMed   |  Link to Article
van de Putte LBA, Atkins C, Malaise M,  et al.  Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.  Ann Rheum Dis. 2004;63(5):508-516
PubMed   |  Link to Article
Breedveld FC, Weisman MH, Kavanaugh AF,  et al.  The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate vs methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.  Arthritis Rheum. 2006;54(1):26-37
PubMed   |  Link to Article
Furst DE, Schiff MH, Fleischmann RM,  et al.  Adalimumab, a fully human anti tumor necrosis factor-α monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis.  J Rheumatol. 2003;30(12):2563-2571
PubMed
Kim HY, Lee SK, Song YW,  et al.  A randomized, double-blind, placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate.  APLAR J Rheumatol. 2007;10(1):9-16
Link to Article
Weinblatt ME, Keystone EC, Furst DE,  et al.  Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate.  Arthritis Rheum. 2003;48(1):35-45
PubMed   |  Link to Article
Bejarano V, Quinn M, Conaghan PG,  et al; Yorkshire Early Arthritis Register Consortium.  Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis.  Arthritis Rheum. 2008;59(10):1467-1474
PubMed   |  Link to Article
Keystone EC, Kavanaugh AF, Sharp JT,  et al.  Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy.  Arthritis Rheum. 2004;50(5):1400-1411
PubMed   |  Link to Article
Fleischmann R, Vencovsky J, van Vollenhoven RF,  et al.  Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy.  Ann Rheum Dis. 2009;68(6):805-811
PubMed   |  Link to Article
Smolen J, Landewé RB, Mease P,  et al.  Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study.  Ann Rheum Dis. 2009;68(6):797-804
PubMed   |  Link to Article
Choy E, McKenna F, Vencovsky J,  et al.  Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX.  Rheumatology (Oxford). 2012;51(7):1226-1234
PubMed   |  Link to Article
Keystone E, Heijde D, Mason D Jr,  et al.  Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis.  Arthritis Rheum. 2008;58(11):3319-3329
PubMed   |  Link to Article
Hu D, Bao C, Chen S,  et al.  A comparison study of a recombinant tumor necrosis factor receptor:Fc fusion protein (rhTNFR:Fc) and methotrexate in treatment of patients with active rheumatoid arthritis in China.  Rheumatol Int. 2009;29(3):297-303
PubMed   |  Link to Article
Bathon JM, Martin RW, Fleischmann RM,  et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.  N Engl J Med. 2000;343(22):1586-1593
PubMed   |  Link to Article
Combe B, Codreanu C, Fiocco U,  et al; Etanercept European Investigators Network.  Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine vs etanercept alone in patients with rheumatoid arthritis.  Ann Rheum Dis. 2009;68(7):1146-1152
PubMed   |  Link to Article
Combe B, Codreanu C, Fiocco U,  et al; Etanercept European Investigators Network.  Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine.  Ann Rheum Dis. 2006;65(10):1357-1362
PubMed   |  Link to Article
Klareskog L, van der Heijde D, de Jager JP,  et al; TEMPO Study Investigators.  Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis.  Lancet. 2004;363(9410):675-681
PubMed   |  Link to Article
Emery P, Breedveld FC, Hall S,  et al.  Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET).  Lancet. 2008;372(9636):375-382
PubMed   |  Link to Article
van der Heijde D, Klareskog L, Landewé R,  et al.  Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis.  Arthritis Rheum. 2007;56(12):3928-3939
PubMed   |  Link to Article
van der Heijde D, Klareskog L, Rodriguez-Valverde V,  et al; TEMPO Study Investigators.  Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis.  Arthritis Rheum. 2006;54(4):1063-1074
PubMed   |  Link to Article
Emery P, Fleischmann RM, Moreland LW,  et al.  Golimumab, a human anti-tumor necrosis factor α monoclonal antibody, injected subcutaneously every 4 weeks in methotrexate-naive patients with active rheumatoid arthritis.  Arthritis Rheum. 2009;60(8):2272-2283
PubMed   |  Link to Article
Kay J, Matteson EL, Dasgupta B,  et al.  Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate.  Arthritis Rheum. 2008;58(4):964-975
PubMed   |  Link to Article
Kremer J, Ritchlin C, Mendelsohn A,  et al.  Golimumab, a new human anti-tumor necrosis factor α antibody, administered intravenously in patients with active rheumatoid arthritis.  Arthritis Rheum. 2010;62(4):917-928
PubMed   |  Link to Article
Smolen JS, Kay J, Doyle MK,  et al; GO-AFTER Study Investigators.  Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study).  Lancet. 2009;374(9685):210-221
PubMed   |  Link to Article
Keystone EC, Genovese MC, Klareskog L,  et al; GO-FORWARD Study.  Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy.  Ann Rheum Dis. 2009;68(6):789-796
PubMed   |  Link to Article
Maini RN, Breedveld FC, Kalden JR,  et al.  Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis.  Arthritis Rheum. 1998;41(9):1552-1563
PubMed   |  Link to Article
Westhovens R, Yocum D, Han J,  et al; START Study Group.  The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities [published correction appears in Arthritis Rheum. 2007;56(5):1675].  Arthritis Rheum. 2006;54(4):1075-1086
PubMed   |  Link to Article
St Clair EW, van der Heijde DMFM, Smolen JS,  et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group.  Combination of infliximab and methotrexate therapy for early rheumatoid arthritis.  Arthritis Rheum. 2004;50(11):3432-3443
PubMed   |  Link to Article
Maini R, St Clair EW, Breedveld F,  et al;  ATTRACT Study Group.  Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) vs placebo in rheumatoid arthritis patients receiving concomitant methotrexate.  Lancet. 1999;354(9194):1932-1939
PubMed   |  Link to Article
Lipsky PE, van der Heijde DM, St Clair EW,  et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Infliximab and methotrexate in the treatment of rheumatoid arthritis.  N Engl J Med. 2000;343(22):1594-1602
PubMed   |  Link to Article
Maini RN, Breedveld FC, Kalden JR,  et al; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group.  Sustained improvement over 2 years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate.  Arthritis Rheum. 2004;50(4):1051-1065
PubMed   |  Link to Article
van Vollenhoven RF, Geborek P, Forslind K,  et al; Swefot Study Group.  Conventional combination treatment vs biological treatment in methotrexate-refractory early rheumatoid arthritis.  Lancet. 2012;379(9827):1712-1720
PubMed   |  Link to Article
Emery P, Durez P, Dougados M,  et al.  Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis.  Ann Rheum Dis. 2010;69(3):510-516
PubMed   |  Link to Article
Kremer JM, Westhovens R, Leon M,  et al.  Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig.  N Engl J Med. 2003;349(20):1907-1915
PubMed   |  Link to Article
Kremer JM, Genant HK, Moreland LW,  et al.  Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis.  Ann Intern Med. 2006;144(12):865-876
PubMed   |  Link to Article
Westhovens R, Robles M, Ximenes AC,  et al.  Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors.  Ann Rheum Dis. 2009;68(12):1870-1877
PubMed   |  Link to Article
Bresnihan B, Alvaro-Gracia JM, Cobby M,  et al.  Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist.  Arthritis Rheum. 1998;41(12):2196-2204
PubMed   |  Link to Article
Cohen S, Hurd E, Cush J,  et al.  Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate.  Arthritis Rheum. 2002;46(3):614-624
PubMed   |  Link to Article
Fleischmann RM, Schechtman J, Bennett R,  et al.  Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis.  Arthritis Rheum. 2003;48(4):927-934
PubMed   |  Link to Article
Cohen SB, Moreland LW, Cush JJ,  et al; 990145 Study Group.  A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.  Ann Rheum Dis. 2004;63(9):1062-1068
PubMed   |  Link to Article
Cohen SB, Emery P, Greenwald MW,  et al; REFLEX Trial Group.  Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy.  Arthritis Rheum. 2006;54(9):2793-2806
PubMed   |  Link to Article
Emery P, Deodhar A, Rigby WF,  et al.  Efficacy and safety of different doses and retreatment of rituximab.  Ann Rheum Dis. 2010;69(9):1629-1635
PubMed   |  Link to Article
Tak PP, Rigby WF, Rubbert-Roth A,  et al; IMAGE Investigators.  Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis.  Ann Rheum Dis. 2011;70(1):39-46
PubMed   |  Link to Article
Tak PP, Rigby W, Rubbert-Roth A,  et al.  Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis.  Ann Rheum Dis. 2012;71(3):351-357
PubMed   |  Link to Article
Jones G, Sebba A, Gu J,  et al.  Comparison of tocilizumab monotherapy vs methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis.  Ann Rheum Dis. 2010;69(1):88-96
PubMed   |  Link to Article
Smolen JS, Beaulieu A, Rubbert-Roth A,  et al; OPTION Investigators.  Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study).  Lancet. 2008;371(9617):987-997
PubMed   |  Link to Article
Yazici Y, Curtis JR, Ince A,  et al.  Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs.  Ann Rheum Dis. 2012;71(2):198-205
PubMed   |  Link to Article
Kremer JM, Blanco R, Brzosko M,  et al.  Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate.  Arthritis Rheum. 2011;63(3):609-621
PubMed   |  Link to Article
Askling J, Bongartz T. Malignancy and biologic therapy in rheumatoid arthritis.  Curr Opin Rheumatol. 2008;20(3):334-339
PubMed   |  Link to Article
Bongartz T, Warren FC, Mines D,  et al.  Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials.  Ann Rheum Dis. 2009;68(7):1177-1183
PubMed   |  Link to Article
Chakravarty EF, Farmer ER. Risk of skin cancer in the drug treatment of rheumatoid arthritis.  Expert Opin Drug Saf. 2008;7(5):539-546
PubMed   |  Link to Article
Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis.  Arthritis Res Ther. 2008;10(2):R45
PubMed   |  Link to Article
Askling J, Fahrbach K, Nordstrom B,  et al.  Cancer risk with tumor necrosis factor α (TNF) inhibitors.  Pharmacoepidemiol Drug Saf. 2011;20(2):119-130
PubMed   |  Link to Article
Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis.  Arthritis Rheum. 2004;50(6):1740-1751
PubMed   |  Link to Article
Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy.  Arthritis Rheum. 2007;56(9):2886-2895
PubMed   |  Link to Article
Geborek P, Bladström A, Turesson C,  et al.  Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas.  Ann Rheum Dis. 2005;64(5):699-703
PubMed   |  Link to Article
Setoguchi S, Solomon DH, Weinblatt ME,  et al.  Tumor necrosis factor α antagonist use and cancer in patients with rheumatoid arthritis.  Arthritis Rheum. 2006;54(9):2757-2764
PubMed   |  Link to Article
Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor α (TNF) inhibitors.  Pharmacoepidemiol Drug Saf. 2011;20(2):119-130
PubMed   |  Link to Article
Carmona L, Abasolo L, Descalzo MA,  et al;  BIOBADASER Study Group; EMECAR Study Group.  Cancer in patients with rheumatic diseases exposed to TNF antagonists.  Semin Arthritis Rheum. 2011;41(1):71-80
PubMed   |  Link to Article
Brown SL, Greene MH, Gershon SK,  et al.  Tumor necrosis factor antagonist therapy and lymphoma development.  Arthritis Rheum. 2002;46(12):3151-3158
PubMed   |  Link to Article
Harnack U, Johnen H, Pecher G. IL-1 receptor antagonist anakinra enhances tumour growth inhibition in mice receiving peptide vaccination and β-(1-3),(1-6)-D-glucan.  Anticancer Res. 2010;30(10):3959-3965
PubMed
Dinarello CA. Why not treat human cancer with interleukin-1 blockade?  Cancer Metastasis Rev. 2010;29(2):317-329
PubMed   |  Link to Article
Chen MF, Lu MS, Chen PT, Chen WC, Lin PY, Lee KD. Role of interleukin 1 beta in esophageal squamous cell carcinoma.  J Mol Med (Berl). 2012;90(1):89-100
PubMed   |  Link to Article
Heikkilä K, Harris R, Lowe G,  et al.  Associations of circulating C-reactive protein and interleukin-6 with cancer risk.  Cancer Causes Control. 2009;20(1):15-26
PubMed   |  Link to Article
Berlin JA.University of Pennsylvania Meta-analysis Blinding Study Group.  Does blinding of readers affect the results of meta-analyses?  Lancet. 1997;350(9072):185-186
PubMed   |  Link to Article
Buscemi N, Hartling L, Vandermeer B,  et al.  Single data extraction generated more errors than double data extraction in systematic reviews.  J Clin Epidemiol. 2006;59(7):697-703
PubMed   |  Link to Article
Jadad AR, Moore RA, Carroll D,  et al.  Assessing the quality of reports of randomized clinical trials.  Control Clin Trials. 1996;17(1):1-12
PubMed   |  Link to Article
Bhandari M, Busse JW, Jackowski D,  et al.  Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials.  CMAJ. 2004;170(4):477-480
PubMed
Weisberg HI, Hayden VC, Pontes VP. Selection criteria and generalizability within the counterfactual framework.  Clin Trials. 2009;6(2):109-118
PubMed   |  Link to Article

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Supplemental Content

Maria A. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308(9):898-908.

eAppendix 1. Ovid MEDLINE Search Strategy

eAppendix 2. Scopus Search Strategy

eAppendix 3. Web of Science Strategy

eFigure 1. Diagram of Study Selection

eFigure 2a. Funnel Plot of Comparison TNF-a Inhibitors Combined With MTX (or Any Other DMARD) Versus Placebo Plus MTX (or Any Other DMARD)

eFigure 2b. Funnel Plot of BRM Combined With MTX (or Any Other DMARD) Versus Placebo Plus MTX (or Any Other DMARD)

eTable 1. Characteristics of Included Studies

eTable 2. Malignancies Reported In each Trial a TNF- Inhibitors

eTable 3. Malignancies Reported in Each Trial a Biologics Non TNF- Inhibitors

eTable 4. Participants Characteristics

eTable 5. Effect of BRMs on Occurrence of Specific Type of Cancer in Patients With RA

eTable 6. Sensitivity Analyses

eTable 7. Sensitivity Analyses - Results According to Summary of Risk of Bias

Assessment and Excluding Any Trials Where the Control Group Received Only Placebo

Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 43

Related Content

Customize your page view by dragging & repositioning the boxes below.

Related Multimedia

Author Interview

Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
For example, the American College of Rheumatology developed the 7-item core set of disease...

The Rational Clinical Examination
Clinical Scenario