Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers

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Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers Maïté de La Forest Divonne a,b , Jacques Eric Gottenberg c,d , Carine Salliot a,b,∗ a

Rheumatology Department and IPROS, Orleans Hospital, 14, avenue de l’Hôpital, CS 86706, 45067 Orleans cedex 2, France EA4708 Orleans University, 45067 Orleans cedex 2, France Rheumatology Department, National Center for Rare Systemic Autoimmune Diseases, hôpital de Hautepierre, hôpitaux universitaires de Strasbourg, avenue Molière, BP 49, 67098 Strasbourg cedex, France d CNRS, Institut de biologie moléculaire et cellulaire, immunopathologie et chimie thérapeutique/Laboratory of Excellence Medalis, université de Strasbourg, 67098 Strasbourg, France b c

a r t i c l e

i n f o

Article history: Accepted 3 February 2016 Available online xxx Keywords: Rheumatoid arthritis Biotherapies Registers Meta-analyses Safety

a b s t r a c t Objectives: In daily practice, safety in rheumatoid arthritis (RA) patients receiving biological treatment is an important issue. Unlike randomized controlled trials, biologic registers provide long-term real life safety data. To identify all biologic registers worldwide, to extract and analyze data regarding safety in RA patients under biologics. Method: Systematic review was performed independently by 2 rheumatologists using PUBMED, COCHRANE Library and EMBASE databases, up to December 2014. Worldwide biologic registers and related publications were identified. Data on safety issues in RA patients were extracted for metaanalyses. Random-effect meta-analyses were performed to estimate risk ratios (RRs) of mortality, cardiovascular events, cancer, including lymphoma and melanoma and serious infections between (1) biological and non-biological DMARD (cDMARD), (2) between biologics when data were available. Results: Forty-three biological registers were identified worldwide and 27 publications were included for safety meta-analyses on anti-TNFs. Compared to cDMARD, mortality and cardiovascular events were significantly decreased in patients treated with anti-TNFs: RR = 0.60 [95% CI 0.38–0.94] and RR = 0.62 [0.44–0.88], respectively. Anti-TNFs did not increase the risk of solid cancer in patients without or with prior malignancy (RR = 0.84 [0.60–1.18] and RR = 0.77 [0.29–2.03], respectively), lymphoma (RR = 0.90 [0.62–1.31]) and melanoma (RR = 1.17 [0.86–1.59]). As expected, serious infections were significantly increased during anti-TNF treatment (RR = 1.48 [1.18–1.85]) compared to cDMARD. No significant difference was found between soluble receptor to TNF and monoclonal antibodies (RR = 0.55 [0.22–1.35]). Conclusions: By reducing dramatically chronic inflammation in RA patients, anti-TNFs decrease mortality, cardiovascular events without increase significantly the risk of cancer, compared to cDMARDs. ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. © 2016 Societ

1. Introduction Anti-TNFs and other biologic agents (bDMARD for biologic disease modifying anti-rheumatic drug) are major therapeutic advances in the management of rheumatoid arthritis (RA). Although they are efficacious, there still are concerns about longterm safety. Randomised controlled trials (RCTs) are not capable to detect rare or delayed-onset events, such as infections, solid cancers and lymphoma. Moreover, results from RCTs may not be

transposable to “real life” because patients eligible for RCTs may have less comorbidities than those from our daily practice. Since the approval of anti-TNFs in 2000, many countries have set up national and local biologics registers, which are longitudinal observational prospective cohort studies, to evaluate long-term outcomes (safety and efficacy) in clinical practice. Our objectives were first to identify and describe worldwide registries on RA patients under biological agents, and then to perform meta-analyses of safety issues. 2. Methods

∗ Corresponding author. Rheumatology Department, Orleans Hospital, 14, avenue de l’Hôpital, CS 86706, 45067 Orleans cedex 2, France. E-mail address: [email protected] (C. Salliot).

A systematic literature review was performed independently by 2 rheumatologists (MDLFD, CS) according to the

http://dx.doi.org/10.1016/j.jbspin.2016.02.028 ´ e´ franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. 1297-319X/© 2016 Societ

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Cochrane Collaboration Guidelines (http://www.handbook. cochrane.org/ version 5.1.0 updated March 2011) and PRISMA statement (Preferred reporting Items for Systematic reviews and Meta-analyses) [1]. 2.1. Data sources and searches With the help of 2 librarians, a systematic review search was performed in PUBMED, EMBASE and Cochrane Library databases until the end of December 2014 with no limitation of time and journal. The first search (search 1) identified registries using the following combination of keywords in MeSh terms (PUBMED): “Arthritis, Rheumatoid” “AND” “Registries”. After identification of all registries, a second search (search 2) was performed to identify, all publications related to registries. The following combination of keywords was used in PUBMED: “Arthritis, Rheumatoid” “AND” the name of the registry. In EMBASE, we used “Rheumatoid arthritis” and “Disease registry” (non-human and pediatric studies were excluded). We completed the review by hand search using reviews previously published. 2.2. Study selection The selection was performed independently by 2 rheumatologists (MLFD and CS) as well. Published data were selected by screening the titles and abstracts, and then by reading the complete paper of potentially relevant studies. We included all registries and related publications with data on RA adult (> 18 years) under biological agents. Only articles in English, French and Spanish were included. 2.3. Data extraction and synthesis for meta-analyses From complete reading of selected publications, we extracted the following data: • baseline registries’ characteristics: country or area, year of start, inclusion criteria, population(s), effectives, treatments, biological agent(s), duration of follow-up, number of publications, comparator groups (general population and/or non biological DMARD group); • data on safety regarding cancer (including lymphoma and melanoma), serious infections, cardiovascular events and mortality: number of events, risk factors in biological and non biological (control) groups of patients. 2.4. Quality assessment Studies selected for safety meta-analyses were assessed for quality using Newcastle-Ottawa Scale [NOS, ref: Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The NewcastleOttawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analyses (Ottawa: Department of Epidemiology and Community Medicine, University of Ottawa; 2009, accessed at www.ohri.ca/programs/clinical epidemiology/oxford.htm)]. This scale is validated to assess the quality of non-randomised studies such as cohorts and case-control studies. It allocated points in three domains: participant selection (0–4 points), comparability (0–2 points) and exposure or outcome (0–3 points). 2.5. Statistical analysis for meta-analyses Extracted data were combined for meta-analyses. For all outcomes, Mantel–Haenszel random-effects method was applied. This

assumes that studies were estimating different intervention effects and partly explains the heterogeneity between studies. Forest plots were created to summarize risk ratios (RR) estimates and their 95% confidence intervals (95% CI). These figures present measures of heterogeneity across observational studies (Cochrane Q statistic noted as Chi2 and the I2 statistic) and a test for overall effect (Z). Funnel plots were also produced to help to detect publication bias. We used RevMan version 5.3 (Review Manager, Copenhagen, The Nordic Cochrane Centre, 2003) statistical software.

3. Results The literature search is summarized in the flowchart (Fig. 1). From 813 abstracts, we selected 309 publications from 36 registers. Sixteen published reviews allowed us to identify 7 other registries with no publication identified in databases (hand search) [2–17]. Thus, 43 worldwide registers were identified. Their main characteristics are summarized in the supplemental file (Table S1; See the supplementary material associated with this article online). Briefly, 23 registries biologic registers are European, 9 from North America, 4 from South America, 4 from Asia, 1 from The Emirates and 1 from Australia. Thirty-seven registers were national and 6 were regional. Twenty-one registers included exclusively RA patients, the others included patients with other chronic inflammatory disorders (such as spondyloarthritis, psoriatic arthritis. . .). Inclusion criteria were mainly RA patients who start their first or a new biological or non-biological DMARD, excepted in RATIO and AERS. In these 2 registers, patients with inflammatory diseases (such as Crohn disease, ankylosing spondylitis, rheumatoid arthritis or psoriatic arthritis) were included when they developed a serious safety event under anti-TNF (serious infection or lymphoma). Some registers are limited to one biologic, such as ORA for abatacept, AIR-PR and MIRA for rituximab, REGATE for tocilizumab. Baseline collected data were age, gender, RA characteristics (duration, seropositivity, diseases activity measures, previous biologic and non-biologic DMARDs), concomitant treatments (cDMARDS, oral steroids) and important comorbidities. During the follow-up, data were collected at regular time intervals either by patients, physicians or nurses reported outcomes. Recorded outcomes were adverse events, changes of treatments and disease activity. Published results were mainly about the first 3 licensed antiTNFs (infliximab, adalimumab and etanercept) for 128 publications from 39 registers. Other biologics were less represented: rituximab (4 registers and 5 publications), anakinra (2 registers and 2 publications), tocilizumab (6 publications from 3 registers) and abatacept (2 registers and 2 publications). Thirteen registers collected also data on comparison cohorts of patients with RA being treated with cDMARD. Three used general population as comparator (i.e. BIOBADASER, RATIO, and LORHEN). From these 43 registers, we identified 324 publications on RA: 25 assessed epidemiology/register description, 139 assessed biologic efficacy, 124 safety, 24 were about drug survival and 12 on cost effectiveness of biological agents.

3.1. Safety of biological agents in RA patients From 124 publications on safety, we included 27 from 13 registers in the meta-analyses [18–45,51]. These publications were included because they provided data on safety issues (mortality, cardiovascular events, serious infections, cancer included melanoma and lymphoma) in biological and non-biological RA patients.

Please cite this article in press as: de La Forest Divonne M, et al. Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.02.028

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Idenficaon

S1: 442 records idenfied through database searching

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S2: 514 records idenfied through database searching and hand search

813 records aer duplicates removed

78 records excluded

Screening

402 records screened

411 records excluded

Included

Eligibility

324 arcles related to 43 worldwide registers

Registers descripon =25 Efficacy=139 Drug survival=24 Cost effecveness=12

124 Studies included in qualitave synthesis on safety

27 Studies included in safety meta-analyses

Fig. 1. Systematic literature search selection process to identify biologics registers and related publications (flowchart).

Briefly, 9 registers were European: BIOBADASER from Spain, BSRBR-RA from UK, RABBIT from Germany, ARTIS, SSATG from Sweden, DANBIO from Denmark, GISEA, LORHEN from Italy and DREAM from The Netherlands. Three registers included patients from US (CORRONA, NDB and RADIUS) and 1 from Japan (REAL). Table S2 showed the baseline characteristics in biological (bDMARD) and non-biological agent (cDMARD) groups. Meta analyses compared pooled data on anti-TNFs versus cDMARDs because few data were available on non anti-TNF biologics. 3.1.1. Mortality and cardiovascular events (Fig. 2) 3.1.1.1. Mortality (Fig. 2A). Five studies were included in metaanalyses because they compared mortality rates between anti-TNF and cDMARD RA groups [18–22]. Pooled results showed a decrease of mortality in patients receiving anti-TNFs compared to cDMARD: RR = 0.60 (95% CI 0.38–0.94). Regarding non anti-TNF biologic, Listing et al. showed significantly lower mortality in patients treated with rituximab [adjusted hazard ratio = 0.57 (95% CI 0.39–0.84)], or non-anti-TNF non rituximab biologics [adjusted hazard ratio = 0.64 (95% CI 0.42–0.99)], compared to those receiving methotrexate [21]. 3.1.1.2. Cardiovascular events. Cardiovascular events (Fig. 2 B) were defined as all events reported as acute myocardial infarction, cardiac failure and stroke. To estimate RR, we pooled data from 7 publications [18,19,22–26]. As for mortality, pooled data suggested that anti-TNFs might reduce the risk of incident cardiovascular events compared to cDMARD (RR = 0.62 [95% CI 0.44–0.88]). 3.1.2. Solid cancers (Fig. 3C1 and C2) Because TNF has a complex effect of carcinogenesis, inhibition of TNF could enhance or inhibit cancer development. In registers, solid cancers comprised all cancers, except lymphoproliferative,

myeloproliferative malignancies and melanoma skin cancers. Using data from 9 studies, our result suggested that anti-TNFs did not increase the risk of solid cancer compared to biologic naïve-RA (RR = 0.84 [95%CI 0.60–1.18]) (C2) [24,29–35,37]. According to the Swedish Biologics Register (ARTIS), no major differences in cancer stage at diagnosis or in post-cancer survival were observed as compared to biologics-naive RA patients with cancer [34]. Only 2 studies from RABBIT and CORRONA registers reported data on cancer under non anti-TNFs treatment: no increased risk of cancer was detected with anakinra comparing to cDMARD (adjusted hazard ratio = 1.4 [0.6–3.5]) [13], with abatacept (HR = 1.55 [0.40–5.97]) and rituximab (HR = 0.42 [0.07–2.60]) comparing to methotrexate [35]. Interestingly, 3 studies evaluated the risk of recurrent cancer in RA patients with a history of malignancy: pooled RR did not demonstrate a significant increase risk of recurrence in these patients (RR = 0.77 [95% CI 0.29–2.03]) (C1) [27–29]. Median times from prior malignancy to anti-TNF initiation were between 5 and 13 years. 3.1.3. Other cancers (Fig. 3D and E) 3.1.3.1. Lymphoma (Fig. 3D). Pooled results from 6 registers did not show an increased risk of lymphoma versus cDMARD group: RR = 0.90 (95% CI 0.62–1.31) [22,31,35–38]. 3.1.3.2. Melanoma (Fig. 3E). Three studies evaluate the risk of melanoma with anti-TNF [31,35,39]. Pooled data did not show an increase risk of melanoma (all stages) in biologic group: RR = 1.17 (95% CI 0.86–1.59). Nevertheless, ARTIS register found a 50% increase in relative risk of invasive melanoma in RA patients treated with anti-TNF compared with non-biological drug treated patients (hazard ratio: 1.5 [1.0–2.2]) after stratification for sex and adjustment for age [39]. The risk of a second primary melanoma was

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Fig. 2. Effects of anti-TNFs on mortality (A) and cardiovascular events (B) versus cDMARDs (forest plots).

non-significantly increased (hazard ratio = 3.2 [0.8–13.1]) in RA patients treated with TNF inhibitors. 3.1.4. Serious infections Ten publications were included for meta-analyses on serious infections [18,22,24,40–45,51]. For all studies, serious infections were defined as those requiring intravenous antibiotics or hospitalization, or those resulting in death. As expected, serious infections were significantly increased during anti-TNF treatment (RR = 1.48 [1.18–1.85]) compared to cDMARD [18,22,24,42,44,45,51]. When we compared soluble receptor to TNF (etanercept) to monoclonal antibodies (adalimumab and infliximab), we did not found a significant difference (RR = 0.55 [0.22–1.35]) (Fig. 4) [40–43]. 4. Discussion To our knowledge, this is the first overview and description of worldwide biologic registers, including updated meta-analyses on major long-term safety issues during anti-TNFs treatments. Our updated findings regarding serious infections, cancers and cardiovascular events confirm some previous individual studies and meta-analyses results. Anti-TNFs are safe in RA patients with cautions for serious infections. Moreover, this is the first metaanalyses on the risks of lymphoma, solid cancers in case of previous malignancy, melanoma and mortality under anti-TNFs. Our results suggest no increased risks in RA patients receiving anti-TNF compared to cDMARD. Sparse data are available on safety of non anti-TNF biologics. Du to chronic systemic inflammation, RA confers a substantially increased risk of cardiovascular morbidity and mortality compared to the general population. Control chronic systemic inflammation may reduce cardiovascular morbidity and then mortality as showed in our results [14]. No statistically significant difference in

mortality rates between the 3 anti-TNFs (infliximab, etanercept and adalimumab) was found in ARTIS study group data [46]. On cardiovascular events, our results confirm those from the meta-analyses by Barnabe et al. on observational cohorts and RCTs: anti-TNF would not increase the risk of cardiovascular events (pool adjusted RR = 0.16 [0.28–0.77]) [47]. Some studies reported an association between RA and nonHodgkin’s lymphoma. Data from ARTIS and RATIO suggested an increased risk of lymphoma in RA patients receiving anti-TNF versus general population: adjusted hazard ratio = 2.7 (1.8–4.1) and 2.3 (1.6–3.3), respectively [36,48]. This appears to be related both to disease activity and immunosuppressive therapy. Since anti-TNFs were approved, 27 cases of lymphoma in RA patients were reported by RATIO in France and 26 cases by the FDA [48,49]. According to RATIO data (2004–2006), patients with rheumatic diseases receiving adalimumab or infliximab had a higher risk of lymphoma than those treated with etanercept: odds ratios were 4.7 (1.3–17.7) and 4.1 (1.4–12.5), respectively [48]. Because TNF plays a role in the defence against infections and in the formation and maintenance of granulomas, numerous cases of serious infections have been described since the first anti-TNFs were approved. Published data showed that RA patients treated with anti-TNF had a 1.5–2.5-fold greater risk of serious infection than those receiving cDMARD. This excess of risk is accentuated in the first 6 to 12 months of treatment with anti-TNF [50,51]. Compared to general population and RA treated by cDMARD, anti-TNF have been recognised as a risk factor for reactivation of latent tuberculosis (TB) and other non-tuberculosis opportunistic infections, such as listeriosis, non-typhoid salmonellosis, histoplasmosis, legionella pneumophila pneumonia [52–54]. Rates of others serious infections are increased as well: septic arthritis, skin and soft tissue infections, such as herpes zoster [42,55]. In a previous meta-analysis, the relative risk of herpes zoster was 1.6 (95% CI 1.16–2.23) [15].

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Fig. 3. Effects of anti-TNFs on solid cancers in RA patients with (C1) and without (C2) previous malignancy, lymphoma (D) and melanoma (E) versus cDMARDs (forest plots).

Soluble receptor against TNF would lead to less serious infections than monoclonal antibodies. This was suggested by data on active TB, non-tuberculosis opportunistic infection and herpes zoster [53–55]. Regarding non anti-TNFs biologics, in BSRBR, there was a tendency towards increased infection rates during anakinra

regimen, although this was no significant [hazard ratio 1.58 (95% CI 0.92–2.74)] after adjusting for confounders [42]. In BIOBADASER, the incident rate of serious infections was higher during rituximab (IR = 11 [6.7–11.9] per 100 patient-years) comparing to anti-TNF group (IR = 3.1 [2.8–3.4]) [56].

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Fig. 4. Effect on serious infections of anti-TNF monoclonal antibodies (i.e. adalimimab and infliximab) versus anti-TNF soluble receptor (i.e. etanercept) (forest plot).

Fig. 5. Funnel plots for (A) mortality, (B) cardiovascular events, (C1) solid cancers in patients with previous malignancy, (C2) solid cancers, (D) lymphoma, (E) melanoma, (F) serious infections (soluble receptor versus monoclonal antibodies).

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Others factors have been identified as risk factors for serious infections in RA patients under biologics, such as comorbidities (chronic lung disease, smoking, diabetes, previous severe infection. . .), concomitant use of steroid, advanced age, presence of extra-articular manifestations and RA activity [57–59]. Low immunoglobulin G level before rituximab treatment is also a risk factor [58]. Our review of the literature was performed according to Cochrane and PRISMA recommendations. We included exclusively publications from biologics registers with comparable inclusion criteria and definitions of safety outcomes. Our results concern almost exclusively long-term safety under anti-TNF because few published data were available on non-anti-TNF biologic DMARDs. The strengths of registers include their ability – to recruit a large representative sample of patients with the same inflammatory condition, the same biological treatment and a long follow-up, – to provide real life data on long-term safety and efficacy. Their weaknesses include missing data, loss of follow-up and confounding factors. One of them is the confounding factors by indication. For example, the interpretation of the risk of lymphoma during anti-TNF is challenging because anti-TNFs are prescribed to active and severe RA patients at risk of lymphoma. On the other hand, by controlling RA activity, anti-TNF may reduce the risk of lymphoma. The beneficial effect of anti-TNF on cardiovascular events may be due to the “selection” of healthy young RA patients for the initiation of anti-TNF treatment. But the association between anti-TNFs and fewer cardiovascular events is consistent across registers, time of publication, ages and socioeconomic groups [13,47,60]. Regarding solid cancers, we did not found excess risk under anti-TNF. This result is consistent with data previously published. The interpretation of data on serious infections is also challenging because of potential confounders, such as co-morbidities and concomitant treatment by steroids. Information on these variables for statistical adjustment are important but not always available. Nevertheless, our results regarding serious infections are comparable with previous publications (individual studies and reviews). Analyse for publication bias was performed using funnel plots for all outcomes (Fig. 5). Subjective visual inspection did not suggest publication bias, excepted for solid cancers in patients with previous malignancy. When we combine data from worldwide registers, we have to discuss the extent of heterogeneity. In present meta-analyses, I2 values show substantial heterogeneity for mortality, cardiovascular events, cancers and serious infections. For lymphoma, melanoma and cancers in patients with previous malignancy, heterogeneity is low to moderate. Such heterogeneity can be explained by the differences in the use of bDMARD in RA patients across the world due to accessibility, availability, prescribing guidelines and local practice differences. Thus, RA patients who start a bDMARD may have differences in terms of RA duration, activity, severity and number of previous cDMARDs. Heterogeneity may also influence data during the prospective recruitment and follow-up because clinical practices change over time. Thus, in the same register a RA patient included in 2002 may not be comparable to another who start a bDMARD in 2012. Moreover registries differ for instance in their design (some are population-based and have access to other registries through linkage, while others are clinical-based and rely on data collection by the physician, which is more prone to missing events). While combined approach to understand the risk of rare outcomes is necessary, the simple pooling of data from registers is problematic. Nevertheless, to date, there is no consensual method to combine data from observational studies. To avoid such heterogeneity, the EULAR study group for Registers and Observational Drug Studies is working on the

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harmonization of inclusion criteria and data collection of future European RA cohort studies and on the most effective way to combine these data despite heterogeneity [17]. Disclosure of interest The authors declare that they have no competing interest. Acknowledgements We thank Julie Brugneaux and Guillemette Utard who both contributed to the systematic literature search. Appendix A. Supplementary data Supplementary data (Table S1 and S2) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/ j.jbspin.2016.02.028. References [1] Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006–12. [2] de la Vega M, da Silveira de Carvalho HM, Ventura Ríos L, et al. The importance of rheumatology biologic registries in Latin America. Rheumatol Int 2013;33:827–35. [3] Arora A, Mahajan A, Spurden D, et al. Long-term drug survival of TNF inhibitor therapy in ra patients: a systematic review of European National Drug Registers. Int J Rheumatol 2013:30. [4] van Vollenhoven RF, Askling J. Rheumatoid arthritis registries in Sweden. Clin Exp Rheumatol 2005;23:S195–200. [5] Mariette X, Gottenberg JE, Ravaud P, et al. Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries. Rheumatology (Oxford) 2011;50:222–9. [6] Hjardem E, Hetland ML, Østergaard M, et al. Prescription practice of biological drugs in rheumatoid arthritis during the first 3 years of post-marketing use in Denmark and Norway: criteria are becoming less stringent. Ann Rheum Dis 2005;64:1220–3. [7] Ruderman EM. Overview of safety of non-biologic and biologic DMARDs. Rheumatology (Oxford) 2012;51:vi37–43. [8] Strangfeld A, Hyrich K, Askling J, et al. Detection and evaluation of a drug safety signal concerning pancreatic cancer: lessons from a joint approach of three European biologics registers. Rheumatology (Oxford) 2011;50:146–51. [9] Pease C, Pope JE, Truong D, et al. Comparison of anti-TNF treatment initiation in rheumatoid arthritis databases demonstrates wide country variability in patient parameters at initiation of anti-TNF therapy. Semin Arthritis Rheum 2011;41:81–9. [10] Pease C, Pope JE, Thorne C, et al. Canadian variation by province in rheumatoid arthritis initiating anti-tumor necrosis factor therapy: results from the optimization of adalimumab trial. J Rheumatol 2010;37:2469–74. [11] 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;40:2–14. [12] Cho SK, Sakai R, Nanki T, et al. A comparison of incidence and risk factors for serious adverse events in rheumatoid arthritis patients with etanercept or adalimumab in Korea and Japan. Mod Rheumatol 2014;24:572–9. [13] Greenberg JD, Furer V, Farkouh ME. Cardiovascular safety of biologic therapies for the treatment of RA. Nat Rev Rheumatol 2012;8:13–21. [14] Che H, Lukas C, Morel J, et al. Risk of herpes/herpes zoster during anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Systematic review and meta-analysis. Joint Bone Spine 2014;81:215–21. [15] Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis 2014;73:529–35. [16] Le Blay P, Mouterde G, Barnetche T, et al. Risk of malignancy including non-melanoma skin cancers with anti-tumor necrosis factor therapy in patients with rheumatoid arthritis: meta-analysis of registries and systematic review of long-term extension studies. Clin Exp Rheumatol 2012;30:756–64. [17] Kearsley-Fleet L, Závada J, Hetland ML, et al. The EULAR Study Group for Registers and Observational Drug Studies: comparability of the patient case mix in the European biologic disease modifying anti-rheumatic drug registers. Rheumatol (Oxford) 2015;54:1074–9. [18] Carmona L, Descalzo MA, Perez-Pampin E, et al. All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007;66:880–5.

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Please cite this article in press as: de La Forest Divonne M, et al. Safety of biologic DMARDs in RA patients in real life: A systematic literature review and meta-analyses of biologic registers. Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2016.02.028