SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

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, placebo-controlled 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 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 meta-analysis 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

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

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.

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 meta-analysis 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 I2 statistic. All statistical tests and creation of forest plots were carried out with Review Manager version 5 software (9).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

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 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.

Table 1. Characteristics of the trials of anti-TNF therapy included in the meta-analysis*
 Adalimumab in ERAASPIRECOMETERASPREMIERSWEFOT
  • *

    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.

Trial sitesUnited KingdomEurope, North  AmericaAustralia, Europe, North AmericaNorth AmericaAustralia, Europe, North AmericaSweden
Trial size, no. of patients1481,040542632799258
Treatment arm      
 ExperimentalADA + MTXInflix. + MTXEtan. + MTXEtan.ADA + MTX or ADA monoInflix. + MTX
 ControlMTXMTXMTXMTXMTXMTX + SSZ + HCQ
No. of study arms232232
Age, mean years475051505252
Female, %567274757577
Duration of disease, mean months911101296
RF positive, %957270 (CCP)8810067
Taking steroids, %NA385040367
SJC, mean1022172422NA
CRP, mean mg/dl2.9–3.82.6–3.03.6–3.73.3–4.43.9–4.1NA
DAS, meanNANANANANA4.8
HAQ score, mean1.31.51.6NA1.51.3

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 (I2 = 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.

Table 2. Summary of serious infections*
Trial, randomizationNo. of patients with serious infectionsDescription of infections
  • *

    See Table 1 for definitions.

Adalimumab in ERA No opportunistic infections reported
 Adalimumab + MTX3/75
 MTX2/73
ASPIRE Tuberculosis (n = 4) and sepsis (n = 3) in infliximab group
 Infliximab + MTX40/749
 MTX6/291
COMET No opportunistic infections; 1 case of disseminated herpes zoster in MTX group
 Etanercept + MTX5/274
 MTX8/268
ERAS No opportunistic infections and no deaths from infection in either group
 Etanercept + MTX12/415
 MTX6/217
PREMIER Pleural tuberculosis (n = 1) in adalimumab group; death due to infection (n = 1) in MTX group
 Adalimumab + MTX12/542
 MTX7/257
SWEFOT No opportunistic infections or deaths reported
 Infliximab + MTX1/128
 MTX + sulfasalazine + plaquenil1/130
thumbnail image

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.

Download figure to PowerPoint

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 (I2 = 0%) 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).

Table 3. Summary of malignancies*
Trial, randomizationNo. of patients with malignanciesDescription of malignancies
  • *

    See Table 1 for definitions.

Adalimumab in ERA No reported malignancies
 Adalimumab + MTX0/75
 MTX0/73
ASPIRE Endometrial cancer, pancreatic cancer, colon cancer, acute myeloid leukemia
 Infliximab + MTX4/749
 MTX0/291
COMET Breast cancer (n = 3), prostate cancer (in etanercept group); chronic lymphocytic leukemia, epidermoid cancer of the tongue, basal cell carcinoma, Bowen's disease (in MTX group)
 Etanercept + MTX4/274
 MTX4/268
ERAS Breast cancer, lung cancer, carcinoid lung cancer, Hodgkin's lymphoma, prostate cancer (in etanercept group); colon cancer, bladder cancer (in MTX group)
 Etanercept + MTX5/415
 MTX2/217
PREMIER 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)
 Adalimumab + MTX6/542
 MTX4/257
SWEFOT No reported malignancies
 Infliximab + MTX0/128
 MTX + sulfasalazine + plaquenil0/130
thumbnail image

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.

Download figure to PowerPoint

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 meta-analysis was deemed sufficient to detect a significant difference between groups (89%), making the possibility of a Type II error highly unlikely.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

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).

Table 4. Risk of malignancy among studies from prior meta-analyses and the ERAS trial*
Study, year (ref.)Treatment armOdds ratio (95% CI)
Anti-TNFControl
  • *

    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.

Bongartz et al, 2006 (3)0.80.23.3 (1.2–9.1)
Bongartz et al, 2009 (5)1.10.71.84 (0.79–4.28)
ERAS, 2000 (16)0.90.81.08 (0.50–2.32)

Although these observations are reassuring, caution must be exercised when interpreting these results, since the duration of the trials included in this meta-analysis 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 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 meta-analysis. 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

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved 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. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. 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: 76284.
  • 2
    Askling J, Dixon W. The safety of anti-tumour necrosis factor therapy in rheumatoid arthritis. Curr Opin Rheumatol 2008; 20: 13844.
  • 3
    Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials [published erratum appears in JAMA 2006;295:2482]. JAMA 2006; 295: 227585.
  • 4
    Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists [published erratum appears in Ann Rheum Dis 2007;66:1548]. Ann Rheum Dis 2007; 66: 133944.
  • 5
    Bongartz T, Warren FC, Mines D, Matteson EL, Abrams KR, Sutton AJ. 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: 117783.
  • 6
    Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Onkologie 2000; 23: 597602.
  • 7
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 112.
  • 8
    Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ. Scales to assess the quality of randomized controlled trials: a systematic review. Phys Ther 2008; 88: 15675.
  • 9
    Review Manager (RevMan) software for preparing and maintaining Cochrane Reviews: version 5.0. Copenhagen (Denmark): Cochrane Collaboration; 2009.
  • 10
    Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, et al. Golimumab, a human anti–tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four–week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis [published erratum appears in Arthritis Rheum 2010;62:3005]. Arthritis Rheum 2009; 60: 227283.
  • 11
    Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, et al, TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) Study Investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 67581.
  • 12
    Smolen J, Landewe RB, Mease P, Brzezicki J, Mason D, Luijtens K, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009; 68: 797804.
  • 13
    Keystone E, van der Heijde D, Mason D Jr, Landewe R, van Vollenhoven R, Combe B, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two–week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study [published erratum appears in Arthritis Rheum 2009;60:1249]. Arthritis Rheum 2008; 58: 331929.
  • 14
    Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet 2008; 372: 37582.
  • 15
    Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, et al, for the PREMIER Investigators. The PREMIER study: a 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. Arthritis Rheum 2006; 54: 2637.
  • 16
    Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis [published erratum appears in N Engl J Med 2001;344:76 and N Engl J Med 2001;344:240]. N Engl J Med 2000; 343: 158693.
  • 17
    St.Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, et al, for the 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: a randomized, controlled trial. Arthritis Rheum 2004; 50: 343243.
  • 18
    Bejarano V, Quinn M, Conaghan PG, Reece R, Keenan AM, Walker D, et al, and the 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: 146774.
  • 19
    Van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Coster L, Waltbrand E, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (SWEFOT trial): 1-year results of a randomised trial. Lancet 2009; 374: 45966.
  • 20
    Okada SK, Siegel JN. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis [letter]. JAMA 2006; 296: 22012.
  • 21
    Setoguchi S, Solomon DH, Weinblatt ME, Katz JN, Avorn J, Glynn RJ, et al. Tumor necrosis factor α antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54: 275764.
  • 22
    Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti–tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum 2004; 50: 174051.
  • 23
    Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 2007; 56: 288695.
  • 24
    Askling J, Fored CM, Baecklund E, Brandt L, Backlin C, Ekbom A, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 2005; 64: 141420.
  • 25
    Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 2005; 64: 14216.
  • 26
    Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, 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: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004; 50: 140011.
  • 27
    Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 47886.
  • 28
    Lipsky PE, van der Heijde DM, St.Clair EW, Furst DE, Breedveld FC, Kalden JR, et al, for the 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: 1594602.