The objective of the study is to systematically review the malignancy risk of anti-tumor necrosis factor alpha (anti-TNFα) agents. Databases of PubMed Medline, OVID EMBASE, and Cochrane Library were searched to identify published systematic reviews and meta-analyses of randomized control trials, observational studies, and case series that evaluated malignancy risk of anti-TNFα blockers. Search time duration was restricted from January 1st, 2000 to July 16th, 2015. Overview Quality Assessment Questionnaires were used to assess the quality of included reviews. Two methodology trained reviewers separately and repeatedly screened searched studies according to study selection criteria, collected data, and assessed quality. Totally, 42 reviews proved eligible with only one Cochrane review. Anti-TNFα antagonists were extensively used to treat various diseases; nevertheless, malignancy risks were most commonly described in patients with rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In RA patients, no increased risks of breast cancer, lymphoma, and non-melanoma skin cancer were found, but if the use of anti-TNFα agents was associated with elevated risk of overall malignancy was still uncertainty. In IBD patients, the use of anti-TNFα inhibitors was not connected with enhanced risk of overall cancer. No increased cancer risk was found in other disease conditions. Twenty-nine reviews were rated as good quality, 12 as moderate, and one as poor. There are no sufficient evidences to draw the conclusion that anti-TNFα blockers have relationship with increased malignancy risk.
Tumor necrosis factor alpha (TNFα), a kind of pro-inflammatory cytokine, is generated by macrophage and monocyte and participates in normal inflammatory response and immune reaction. But, TNFα-mediated immune reaction plays a vital role in numerous auto-immune diseases (e.g., rheumatoid arthritis and inflammatory bowel disease). Correspondingly, anti-TNFα blockers (adalimumab, certolizumab pegol, etanercept, golilmumab, infliximab) are reckoned as the effective treatment agents [1, 2].
The use of anti-TNFα agents brings many benefits in the management of auto-immune diseases; however, potential harms have to be concerned due to the treatment-induced suppression of immune system . Previous studies have assessed the adverse effects of anti-TNFα agents in rheumatoid arthritis (RA) patients. The results showed that, one the one hand, anti-TNFα blockers seemed to slightly increase total cholesterol and high-density lipoprotein-cholesterol, but might decrease the first cardiovascular event by 50 % . On the other hand, anti-TNFα antagonists were identified as risk factors for serious infections and tuberculosis, and concomitant use of immunosuppressant (especially hormones) represented an additional risk factor for opportunistic infections [3, 5].
As for the malignancy risks of anti-TNFα blockers, abundant systematic reviews and meta-analyses have been conducted, but no consistent results were obtained [6–12]. In order to better understand the malignancy risk of anti-TNFα agents, we systematically performed this overview of systematic reviews and meta-analyses.
Definition of systematic review and meta-analysis
A systematic review, defined by Handbook, is tried to collect all the available evidences that meet prescribed eligibility criteria so as to answer a specific research question. It uses specific and systematic methods, aimed at minimizing bias, to provide more reliable findings, from which, conclusions can be drawn and decisions made. Many systematic reviews contain meta-analyses. Meta-analysis is a statistical method used to synthesize the results of several independent studies .
Study selection criteria
We included systematic reviews and meta-analyses of randomized control trials (RCTs), observational studies, and case series that assessed malignancy risk of anti-TNFα blockers used in any disease. Anti-TNFα agents included adalimumab (ADA), certolizumab pegol (CZP), etanercept (ETN), golimumab (GLM), and infliximab (IFX). Comparison interventions could be placebo (PBO), disease-modifying anti-rheumatic drugs (DMARDs), or any other effective drugs, if a study had a control group. The same concomitant therapy was allowed in both anti-TNFα agents group and control group. If a study met any one of the following statements, it would be excluded: (1) a non-human study, (2) a pooled analysis without using systematic methods, (3) an editorial, a comment, an erratum, a narrative review, or a letter, (4) a protocol, a structured (or provisional) abstract or an executive summary, (5) a non-English study, (6) a conference abstract, (7) a duplicate publication, and (8) anti-TNFα blockers as a baseline treatment.
According to our preset inclusion criteria, we systematically searched the electronic databases of PubMed Medline (Jan 1st, 2000 to July 16th, 2015), OVID EMBASE (Jan 1st, 2000 to July 15th, 2015) and Cochrane Library (Jan 1st, 2000 to July 16th, 2015), using a combination search of MeSH terms and keywords. Our search terms were “systematic review”, “meta-analysis”, “anti-tumor necrosis factor-alpha”, “adalimumab”, “certolizumab pegol”, “etanercept”, “golimumab”, “infliximab”, “malignancy”, “cancer”, “neoplasm,” and “carcinoma”. We limited search results to human and English language. Detailed search strategy could be found in appendix file (Appendix-Search Strategy).
Two methodology trained reviewers (Chen and Huang) independently and in duplicate screened the potential eligible studies through titles, abstracts, and full-texts, using predefined study screening forms and according to including and excluding criteria. Disagreements were solved by consensus. Study selection was conducted in Microsoft Office Access 2013.
Two authors (Chen and Sun) independently collected data from eligible systematic reviews and meta-analyses: family name of first author, year of publication, country of first author, treatment condition, review purpose, included studies, main results, and conclusion. We used Microsoft Office Access 2013 to manage data extraction.
We used the Overview Quality Assessment Questionnaires (OQAQ), totally, nine questions yielding the highest quality score 7 and the lowest quality score 0, to assess quality of included reviews. A score of 6–7 is deemed as “good” quality, 3–5 indicates “moderate” quality and 0–3 hints “poor’ quality” . Two reviewers (Chen and Yang) independently assessed quality.
In our overview, we systematically reviewed the results of included systematic reviews and meta-analyses instead of synthesizing extracted data. Data from eligible reviews were cited in the forms of, based on what the authors had reported, standardized incidence ratio (SIR), odds ratio (OR), relative risk (RR), or adjusted hazard ratio (aHR) with 95 % confidence interval (CI).
We identified 764 relevant records through searching electronic databases. After removing 152 duplications, 612 records went through title and abstract selection, then, 87 studies were read in full text. Finally, 42 eligible systematic reviews and meta-analyses were included in our overview. Study selection flow chart was listed in Fig. 1.
Table 1 showed the main findings of eligible systematic reviews and meta-analyses. Of the 42 included studies, only one study (2.4 %) was Cochrane review , other studies (97.6 %) were non-Cochrane reviews [6–12, 16–49]. Among the 42 reviews, 12 reviews (28.6 %) were performed in the USA, nine (21.4 %) in China, six (14.3 %) in France, four (9.5 %) in Canada, three (7.1 %) in UK, two (4.8 %) in the Netherlands, two (4.8 %) in Spain, one (2.4 %) in Italy, one (2.4 %) in Brazil, one (2.4 %) in Tunisia, and one (2.4 %) in Sweden. Of the 42 eligible reviews, 18 reviews (42.9 %) focused on RA, 12 reviews (28.6 %) focused on inflammatory bowel disease (IBD), four reviews (9.5 %) focused on several diseases (RA, PsA, AS or Crohn disease (CD), two reviews (4.8 %) focused on vasculitis, two reviews (4.8 %) focused on psoriatic arthritis (PsA) or plaque psoriasis (PsO) and the remaining four studies focused on other diseases (one hidradenitis suppurativa (HS), one ankylosing spondylitis (AS), one juvenile idiopathic arthritis (JIA), and one sarcoidosis). Twenty-three studies (54.8 %) chose malignancy risk as the primary review purpose while other 19 reviews (45.2 %) reported malignancy risk as the second study purpose. Twenty-seven reviews (64.3 %) merely included RCTs while other 15 reviews (35.7 %) included observational studies, case series, or/and RCTs. With respect to OQAQ quality of included reviews, 29 reviews (69.0 %) were rated as “good”, 12 (28.6 %) as “moderate” and one (2.4 %) as “poor”.
Malignancy risk of anti-TNFα blockers in RA patients
A total of 18 reviews [6–12, 15, 19, 28, 29, 36, 38, 39, 41–43, 49] assessed malignancy risk of anti-TNFα agents in RA patients (Table 1). Malignancy risk as the primary outcome was conducted in 14 studies while as the second outcome in four studies. Totally, 13 reviews only included RCTs and other five reviews included observational studies.
Four studies [19, 28, 39, 49] systemically reviewed cancer risk of anti-TNFα agents in RA patients without meta-analyses, the results suggested anti-TNFα blockers would not increase the risks of overall malignancies, lymphoma or non-melanoma skin cancer (NMSC), but might be related to mildly elevated risk of melanoma.
Fourteen studies [6–12, 15, 29, 36, 38, 41–43] performed meta-analyses to assess malignancy risk of anti-TNFα agents in RA patients. Results showed anti-TNFα agents used in RA patients would not increase the risks of breast cancer at proved dose (per protocol (PP) model OR = 0.65, 95 % CI 0.22–1.93; modified intention to treat (mITT) model OR = 0.75, 95 % CI 0.25–2.21) , lymphoma (OR = 1.26, 95 % CI 0.52–3.06; Peto OR = 2.14, 95 % CI 0.55–8.38) [9, 43] or NMSC (OR = 0.69, 95 % CI 0.23–2.11; OR = 0.79, 95 % CI 0.62–1.02; Peto OR = 1.37, 95 % CI 0.59–3.19; OR = 1.37, 95 % CI 0.71–2.66; OR = 1.27, 95 % CI 0.67–2.42) [8–11, 43] when compared to those who did not receive anti-TNFα agents treatment. However, as for total malignancy risk, there were no consistent results. Le Blay  meta-analyzed four registries (352 cases and 40,128 patient-years of follow-up (PYF) in anti-TNFα antagonists group versus 959 cases and 59,862 PYF in synthetic DMARDs group) and result showed anti-TNFα antagonists might decrease cancer risk (OR = 0.81, 95 % CI 0.71–0.94). Bongartz , pooled data from seven PBO-controlled RCTs (29 cases and 3192 study population number in anti-TNFα blockers versus 3/1428 in PBO group), reported anti-TNFα blockers would elevate malignancy risk (OR = 3.3, 95 % CI 1.2–9.1) and be dose-dependent risk, and the number needed to harm was 154, 95 % CI 91–500 for one additional malignancy. Nevertheless, several studies [6–11, 36, 38, 43] reported that anti-TNFα agents were not associated with increased cancer risk.
Several reviews [6, 7, 9, 15, 41–43] also assessed cancer risks of individual anti-TNFα blockers (including ADA, CZP, ETN, GLM, and IFX) in RA patients, but no statistical significance results were found.
In addition, two studies evaluated malignancy incidence rate of anti-TNFα blockers in RA patients. Wong  included 14 RCTs involving 5179 RA patients who received anti-TNFα blockers with 11 lymphoma cases and 4741 PYF, reported the adjusted overall rate of lymphomas was 1.65 per 1000 PYF. Bongartz  included nine RCT-enrolled 2244 RA patients who used ENT treatment with 26 cases and 2484 PYF, showed that incidence rate of malignancy was 10.47/1000 person-years.
Cancer risk of anti-TNFα blockers in IBD patients
A total of 12 reviews [16, 17, 21, 22, 26, 32–34, 40, 45, 46, 48] examined malignancy risk of anti-TNFα agents in IBD patients (Table 1). Of these studies, three focused on IBD, two focused on ulcerative colitis (UC), and seven focused on CD; nine reviews only included RCTs, three reviews included observational studies; malignancy risk as the primary study aims were performed in four reviews while as the second purpose in eight studies.
Four studies conducted meta-analysis, the results reported anti-TNFα blockers used in IBD patients would not increase malignancy risk as compared to control [22, 26, 33, 48] (RR = 0.77, 95 % CI 0.37–1.59; OR = 0.47, 95 % CI 0.19–1.16; OR = 0.57, 95 % CI 0.17–1.90; mean difference = −015 %, 95 % CI −0.45 to 0.18).
Two studies assessed the incidence rate of malignancy risk. Dulai  included five RCTs, seven case series, and 53 cohort studies to assess the incidence rate of serious infection, lymphoma, and death in pediatric patients with IBD who used anti-TNFα blockers, of the included studies, only two studies (one cohort study and one case series) reported two lymphomas, yielding an absolute lymphoma incidence rate 2.1 per 10,000 patient-years. Siegel  included 26 studies (nine RCTs, three cohort studies, and 14 case series) involving 8905 patients to assess non-Hodgkin lymphoma (NHL) rate in adult CD patients who received anti-TNFα blockers therapy. Totally, 13 lymphomas were observed in 21,178 PFY, yielding a rate of 6.1 NHLs per 10,000 patient-years.
Two reviews only systematically reviewed cancer risk of anti-TNFα agents in IBD patients without performing meta-analysis [34, 40]. The remaining four [16, 21, 32, 45] reviews mentioned malignancy but did not report detailed data.
Cancer risk of anti-TNFα blockers in patients with vasculitis
A total of two reviews evaluated cancer risk of anti-TNFα agents in vasculitis patients (Table 1). Osman  included 25 studies (three RCTs and 22 case series with ≥2 cases) to systematically review the effectiveness and safety of biological agents in patients with large vessel vasculitis (LVV). Of the included studies, only two cases series reported two malignancies (one breast cancer in ADA treatment group and one pancreatic cancer in IFX group). Silva-Fernández  included 80 studies (eight RCTs, 16 open-label studies, one case-control study, and 55 case series with >3 patients) to analyze the current evidence on the therapeutic use of biological agents for systemic vasculitis (SV). Of the included studies, seven studies regarding anti-TNFα agents reported cancer. A total of 17 cancer cases were reported; nevertheless, no meta-analysis was conducted.
Malignancy risk of anti-TNFα agents in PsA/PsO patients
Two reviews assessed cancer risk of anti-TNFα antagonists in psoriasis-related diseases (Table 1).
Dommasch  included 20 PBO-controlled RCTs with treatment duration at least 12 weeks to examine the risks of infection and malignancy in adult PsA and PsO patients with the use of anti-TNFα antagonists. Results showed that anti-TNFα agents would not elevate the risk of overall malignancy (28 cases and 4598 patients in anti-TNFα agents group versus 6/2313 in PBO group, OR = 1.48, 95 % CI 0.71–3.09) and NMSC (20/4598 vs. 4/2313, OR = 1.33, 95 % CI 0.58–3.04) as compared to PBO.
Brimhall  included 16 PBO-controlled studies involving 7931 patients with plaque psoriasis to evaluate and compare the efficacy and safety of biological agents. Totally, 10 cancer cases were reported in patients treated with ETN and 12 malignancies in patients using IFX.
Tumor risk of anti-TNFα agents in other treatment conditions
Of the 42 eligible reviews, in addition to treatment conditions reported above, the remaining eight studies focused on other diseases: one on HS, one on AS, one on JIA, one on sarcoidosis, and four reviews on multiple treatment condition (RA, PsA, AS or CD) (Table 1).
Blok  included 87 studies to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, but only one study reported one colon cancer occurred in 147 IFX treatment patients.
Li  included 14 PBO-controlled RCTs with 1570 participants to assess efficacy and safety of ETN in AS patients, but no malignancies were found during the therapy period in all studies.
Ungar  included 37 studies to systematically review the clinical efficacy and safety of biologics in the poly-articular category of JIA, but only two studies reported two cancer cases, one was thyroid cancer and the other was NHL.
Maneiro  included 69 studies to evaluate the safety and effectiveness of anti-TNFα antagonists in patients with sarcoidosis. Of these included studies, 14 studies (three clinical trials and 11 case series) reported six malignancies (four cases in IFX patients group (4/214), two cases in ETN patients group (2/26)).
Askling  included 74 RCTs involving 22,904 patients with RA, PsA, PsO, AS, or CD to assess the short-term risks of malignancies by using individual patient data from all corporate-sponsored RCTs of ADA, ETN, and IFX. Results showed anti-TNFα agents would not increase the risk of malignancy excluding NMSC (130/15,418 vs. 48/7486, RR = 0.99, 95 % CI 0.61–1.68), however, might elevate NMSC risk (53/8094 vs. 12/3613, RR = 2.02, 95 % CI 1.11–3.95) as compared to comparators by using Bayesian piecewise exponential models. Mariette  included 21 studies and eight abstracts to assess the risk of malignancy in patients (26 studies focused on RA, one study on RA and spondyloarthritis, one study on rheumatic disease, and one study on rheumatic disease plus CD) treated with anti-TNFα agents. The outcomes reported anti-TNFα agents were not related to increase risks of all-site malignancy (RR = 0.9, 95 % CI 0.85 to 1.05), lymphoma (RR = 1.11, 95 % CI 0.70 to 1.51), and melanoma (RR = 1.79, 95 % CI 0.92 to 2.67), but might elevate NMSC risk (RR = 1.45, 95 % CI 1.15 to 1.76). Zidi  and Nannini  included RCTs to assess the association of malignancies with anti-TNFα agents in RA, PsA or AS patients; however, no meta-analysis results were reported, qualitative review only.
This overview included 42 systematic reviews and meta-analyses with relatively high study quality to systematically display the malignancy risks of anti-TNFα agents. We could see that anti-TNFα agents were widely used in clinical therapy of multiple diseases, especially common in the treatment of RA patients and IBD patients. In RA patients, as compared to control, anti-TNFα agents would not increase the risks of lymphoma or NMSC; nevertheless, as for total malignancy risk, there was still no certain conclusion. In IBD patients, as compared control, anti-TNFα agents were not associated with elevated cancer risk.
Bongartz et al.  found a dose-dependent increased total malignancy risk from RCTs of ADA and IFX in RA patients as compared to placebo with or without concomitant methotrexate in both groups. However, the estimate of pooled OR decreased from 3.29 (95 % CI 1.19–9.08) to 2.02 (95 % CI 0.95–4.29) after adding malignancy results of PREMIER trial . It indicated that the result was influenced by relatively small sample size. The study was also limited by short duration of follow-up, imbalance dropout rate between the treatment group and control group and clinic heterogeneity of patients in included studies. Le Blay  reported a result of statistical significance that anti-TNFα blockers used in RA patients tended to decrease overall malignancy risk as compared to DMARDs. They speculated that the reduced malignancy risk might be realized through decreased disease activity by treatment of anti-TNFα blockers. But this study might be limited by the concomitant treatment of immunosuppressive and the missing information of previous therapy.
Lymphoma risks had been a major concern in patients who used anti-TNFα blockers, as it had been stated that the use of immunosuppressive was related to an elevated lymphoma risk . Several studies confirmed this statement that anti-TNFα blockers increased the risk of lymphoma (OR = 3.29, 95 % CI 1.19–9.08; SIR = 11.5, 95 % CI 3.7–26.9; SIR = 2.9, 95 % CI 1.7–4.9) in RA patients [12, 52, 53], but the results might be limited by short-term follow-up and underpowered sample size. Kaiser et al.  suggested that it was the disease itself with high disease activity rather than the use of anti-TNFα blockers that had relationship with the elevated lymphoma risk in RA patients. It was also reported that chronic inflammation might be a risk factor for lymphoma .
Skin cancers were also highly concerned in patients who received the therapy of anti-TNFα blockers, as the drugs suppressed the immune system and were used by subcutaneous injection or venous transfusion. Wolfe  reported, after adjusted age, sex, education, smoking history, baseline patient activity score, and baseline prednisone use, the use of IFX or ETN seemed to increase the risk of melanoma (OR = 2.6, 95% CI 1.0 to 6.7 and OR = 2.4, 95% CI 1.0 to 5.8, respectively) and NMSC (OR = 1.7, 95% CI 1.3 to 2.2 and OR = 1.2, 95% CI 1.0 to 1.5, respectively). Askling  and Mariette  reported a higher NMSC risk for anti-TNFα blockers as compared to control (RR = 2.02, 95 % CI 1.11–3.95 and RR = 1.45, 95 % CI 1.15–1.76, respectively). Although positive links of skin cancer with anti-TNFα blockers were reported, most studies did not affirm the results whether short-term exposure or a longer time therapy [8–11, 19, 31, 43], and anti-TNFα blockers were even recommended for those RA patients who had treatment history of solid malignancy and NMSC more than 5 years ago . Pierard-Franchimont et al. speculated anti-TNFα blockers might influence the progression of tumor rather than acted as an initiator or promoted the development of neoplasms .
Although the outcomes of overall malignancy, lymphoma, and skin cancer were reported having statistical significance in several studies, many other studies did not confirmed the results, which might be related to heterogeneity among the reviews, including the characteristics of study population (e.g., age, sex ratio, concomitant disease), study drug and drug doses, study designs, follow-up duration (especially to detect the disease needs long time to occurrence, e.g., tumor, maybe need 3 to 5 years), sample size (especially to detect sparse events), and concomitant drugs.
Malignancy incidence rates of anti-TNFα agents were also reported. In RA patients, the overall malignancy rate of anti-TNFα agents was 0.6 per 100 patient years , of IFX was 0.65 per 100 patient-years and of ADA was 0.7 per 100 patient-years , of ETN was 10.47 per 1000 person-years . Though ETN was reported with relatively higher malignancy risk, head to head evidences were lack and data were collected from different study population, so these results might be not comparable. In PsO patients who received ETN therapy, incidence rate of NMSC was 3.54 cases per 100 patient-years and of melanoma was 0.043 per 100 patient-years . Adjusted overall rate of lymphomas in RA patients who received anti-TNFα blockers was 1.65 per 1000 person-years . Incidence rate for lymphoma of IFX used in all indication was 0.11 cases per 100 patient-years . Incidence rate of NHLs was 6.1 per 10,000 patient-years in IBD patients .
There were several limitations originated from included reviews that we had to pay attention to. First of all, the primary purposes in the most of the included reviews were not directly related to malignancy risk and OQAQ quality was assessed but not aimed at malignancy risk, which might potentially affect the veracity of quality results. Secondly, the majority of eligible reviews only included RCTs to investigate the cancer risk of anti-TNFα blockers while few reviews focused on observational studies. As we all know, RCTs are the best study designs to survey effectiveness of drugs, but for drug safety, especially sparse adverse event, they may be limited by relatively short-term follow-up and small sample size, then observational studies (e.g., registries) may be the most trustworthy sources . Thirdly, the primary study aims of most reviews were not related to cancer risk so that some reviews did not fully report malignancy information. Finally, we did not pool the results of reviews, as there might have overlap data in the reviews; in addition, treatment contexts and outcomes were varied among the reviews.
To sum up, current available evidences are still not enough to support the consequences that anti-TNFα blockers have association with increased risk of overall malignancy, lymphoma, melanoma skin cancer, and NMSC although several studies have reported statistical meaning results; however, we should pay attention to the anti-TNFα blocker users about cancer risks. Whatever, accumulating evidences should keep updated during the clinical practice and cautions of cancer risk have to pay on patients who are using or have used anti-TNFα agents. In addition, further high-quality studies are still needed.
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Liu and Chen conceived the study and designed the study forms. Chen searched the literature; Chen and Huang screened the studies for inclusion; Chen and Sun extracted data; Chen and Yang assessed quality. All authors drafted and revised the manuscript.
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Chen, Y., Sun, J., Yang, Y. et al. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses. Clin Rheumatol 35, 1–18 (2016). https://doi.org/10.1007/s10067-015-3115-7
- Inflammatory bowel disease
- Malignancy risk
- Rheumatoid arthritis
- Systematic review
- Tumor necrosis factor α