Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis... Abstract Background and Aims The association between anti-tumour necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumour necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. Methods MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Results Twelve studies comprising 285,811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumour necrosis factor alpha agents exposed and anti-tumour necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR] = 1.43, 95% CI, 0.91–2.25; P = 0.116; random effects: risk ratio [RR] = 0.83, 95% CI, 0.47–1.48; P = 0.534). However, monotherapy of anti-tumour necrosis factor alpha agents [random effects: IRR = 1.65, 95% CI, 1.16–2.35; P = 0.006; random effects: RR = 1.00, 95% CI, 0.39–2.59; P = 0.996] or combination therapy [random effects: IRR = 3.36, 95% CI, 2.23–5.05; P < 0.001; random effects: RR = 1.90, 95% CI, 0.66–5.44; P = 0.233] can significantly increase the risk of lymphoma. Conclusions Exposition of anti-tumour necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumour necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease. Inflammatory bowel disease, anti-tumour necrosis factor alpha agents 1. Introduction Conventional therapies of inflammatory bowel disease [IBD] include 5-aminosalicylic acid [5-ASA] agents, corticosteroids, thiopurines, and other biologic agents. Responding to the urgency of developing a kind of treatment that allows long-term efficiency in moderate-to-severe IBD patients, the first of anti-tumour necrosis factor alpha agents [ATAs], infliximab [IFX], was approved for Crohn’s disease [CD] in 1998 and for ulcerative colitis [UC] in 2006, followed by the approval of adalimumab [ADA] and other ATAs.1 They not only prolong the maintenance of clinical remission and long-term mucosal healing, but also reduce surgery risks.2–4 Despite the well-acknowledged benefits of ATAs, their risk of developing cancer on account of the treatment-induced suppression of the immune system has always been a confusing factor in clinical decisions. Lymphoma is one of the reported haematological cancers in IBD patients. As time goes by, the need for reliable and definite risk evaluations on lymphoma has been urgently growing. However, obstacles have been encountered when accessing lymphoma risk with ATAs therapy. In clinical practice, IBD patients are often treated with combination therapy of immunosuppressives [IMM] and ATAs, and the majority of ATAs-treated IBD patients have been treated with IMM previously.5 Therefore, the safety of IMM or when combined with ATAs should be considered in the lymphoma risk evaluation of ATAs monotherapy. Plenty of studies have reported increased risk of lymphoma with monotherapy of thiopurines in IBD patients,6–9 though no consensus has been reached, with several studies showing conflicting results.10,11 Also, evidence consistently indicates that treatment with thiopurines [azathioprine and 6-mercaptopurine] combined with ATAs significantly increases lymphoma risk in IBD.12–14 The risk of ATAs monotherapy therefore has been difficult to evaluate, given that it is hard to fully quantify the risk of lymphoma among patients on ATAs therapy in the absence of concurrent thiopurine therapy. The number of studies investigating the relation between ATAs and lymphoma is abundant but their conclusions remain controversial. A couple of studies demonstrated that using ATAs alone did not reveal an increased risk of lymphoma in IBD,15–18 whereas a systematic review and meta-analysis published in 2006 reported a higher incidence of lymphoma among patients treated with infliximab or adalimumab.19 A certain number of studies reported a numerically, but not statistically, higher odds of lymphoma with ATAs monotherapy compared with IMM monotherapy.1,20 In a nutshell, previous evaluations of the risk of lymphoma associated with ATAs therapy have reached equivocal conclusions. With some but not all studies illustrating that ATAs therapy may increase the risk of lymphoma, the balance of risks and benefits when making prescriptions may consistently baffle physicians. Accordingly, we conducted this meta-analysis to systematically evaluate lymphoma risk in IBD patients with ATAs, aiming at a definite conclusion. 2. Methods 2.1. Data sources The search was conducted using MEDLINE [1966April 2018], EMBASE [1985April 2018], and the Cochrane Central Register of Controlled Trials. The following terms were used in search: [‘Inflammatory Bowel Diseases’ OR ‘Crohn Disease’ OR ‘Ulcerative Colitis’] AND [‘lymphoma*’ OR ‘malignancy’ OR ‘malignancies’] AND [‘anti-TNFα therapy’ OR ‘anti-tumor necrosis factor-α therapy’ OR ‘anti-TNFα agents’ OR ‘infliximab’ OR ‘adalimumab’ OR ‘certolizumab’ OR ‘golimumab’ OR ‘natalizumab’ OR ‘vedolizumab’ OR ‘etanercept’]. No language or publication type was restricted. The reference lists of all studies were also scanned in order to identify additional literature on this topic. The selection process of the studies is shown in Figure 1. Figure 1. View largeDownload slide Flow diagram of literature screening. Figure 1. View largeDownload slide Flow diagram of literature screening. 2.2. Study selection Studies included in this meta-analysis were cohort studies and randomised controlled trials [RCTs] which met the following inclusion criteria: [1] diagnosed IBD according to definite criteria; [2 no previous exposure to ATAs; [3] provision of specific information about the treatment; and [4] reported incidence rate ratios [IRRs] with corresponding 95% confidence interval [CIs] or underlying data enabling calculation of effect measures [including the incident cases of lymphoma and the total number of patient-years of the comparison groups]. Studies lacking necessary data were excluded. Letters, conference abstracts, review articles, case reports, expert opinions, and posters were also excluded. In studies with multiple publications from the same population, only data from the most recent publication were included. All articles were assessed independently by two investigators, and any questions were resolved by discussion. 2.3. Data extraction and quality assessment Data were extracted independently by two investigators onto an Excel database. The following items recorded for each study were extracted: first author, year of publication, mean/median age, geographical distribution, study design, number of cases and controls, treatment strategy, follow-up time, treatment duration, lymphoma type, subtype of IBD (ulcerative colitis [UC] and/or Crohn’s disease [CD]), total number of patient-years, and incident cases of lymphoma. For cohort studies we used the Newcastle–Ottawa scale [NOS] to assess the quality.21 In brief, a maximum of nine points was assigned to each study: four for selection, two for comparability, and three for outcomes. The overall quality of a study was considered ‘poor’ if the total NOS score was lower than four. Studies with a NOS score between four and six were considered to be ‘moderate’, and those with a NOS score between seven and nine were considered to be of high quality. For the randomised controlled trials we used the Cochrane collaboration risk of bias [ROB] tool to examine study validity.22 The overall risk of bias of a study was considered ‘low’ if more than four items in the Cochrane collaboration ROB tool were rated as ‘low risk’. The overall risk of bias of a study was considered ‘moderate’ if two or three items in the Cochrane collaboration ROB tool were rated as ‘low risk’. The overall risk of bias of a study was considered ‘high’ if fewer than two items in the Cochrane collaboration ROB tool were rated as ‘low risk’ or if more than one item was rated as ‘high risk’. 2.4. Data synthesis and analysis The study population was divided into the following six groups to make comparisons: [1] ATAs exposed [exposure to any ATAs, including infliximab, adalimumab, and certolizumab pegol, in the presence or absence of exposure to other agents]; [2] ATAs unexposed [exposure to any agents excluding ATAs]; [3] ATAs monotherapy [exposure to ATAs only, in the absence of other agents]; [4] unexposed to IMM or ATAs [exposure to non-biologics excluding IMM and biologics excluding ATAs]; [5] IMM monotherapy [exposure to IMM only, in the absence of other agents]; and [6] combination therapy [exposure to IMM and ATAs, in the absence of other agents]. Incidence rates [IRs] per patient-year were computed by dividing the incident cases of lymphoma by the number of patient-years of follow-up [the total numbers of patient-years were either calculated or extracted from the included studies]. The RRs and IRRs which represent the risk ratios and incidence rate ratios were used to express the pooled results. RRs and 95% CIs were computed by comparing the lymphoma risk between two groups. IRRs and 95% CIs were used to compare the lymphoma incidence rates per patient-year between two groups. Cochran’s Q test and I2 were used to evaluate the heterogeneity of pooled outcomes. Cochran’s Q < 0.10 or I2 > 50% represented significant heterogeneity among included studies.23,24 Random-effects modelling [DerSimonian–Laird method] was applied to calculate pooled RR and IRR.25 To explore the underlying source of heterogeneity, subgroup analysis was conducted according to geographical distribution, sample size, follow-up period, IBD duration, IBD type, age, lymphoma type, and study design. Egger’s linear regression test and the rank correlation test [Begg’s test] were used to evaluate publication bias. All statistical analyses were performed by STATA statistical software V.13.0 [StataCorp. LP]. All statistical tests used in this study were two-sided and P < 0.05, except for testing for heterogeneity, was considered statistically significant. 3. Results 3.1. Search results The search strategy found 10,744 citations: MEDLINE [n = 4190], EMBASE [n = 6073], Cochrane [n = 481]; 1829 duplicate articles were excluded, and 2995 articles were left for screening. After examining titles and abstracts, 5920 were excluded. Subsequently, 33 potentially relevant articles were retrieved for detailed evaluation. After reading the full text, 21 articles were excluded because of insufficient data of control groups [n = 10], lack of necessary data [n = 10], or duplicate datasets [n = 1]. Eventually, 12 studies were included in this meta-analysis. 3.2. Description of included studies The main characteristics of the 12 studies included are displayed in Supplementary Table 1 [available as Supplementary data at ECCO-JCC online], and in Table 1 and Table 2. Of the 12 study entries, two studies were RCTs, three studies were retrospective cohort studies, and the remaining seven studies were prospective cohort studies. Overall, 285,811 participants were involved. Five studies were conducted in the EU, three studies in the USA, and the remaining four studies were multinational. Patients in five studies had an IBD duration of over 5 years. The numbers of patients with different therapies and the number of lymphoma cases can be extracted from 10 studies [Table 2]. The total numbers of patients involved in the combination therapy group, IMM monotherapy group, ATAs monotherapy group, and non-exposure to IMM or ATAs therapy group, were 20,917, 64,246, 32,074, and 168,574, respectively. The total number of lymphoma cases in patients involved in the combination therapy group, IMM monotherapy group, ATAs monotherapy group and non-exposure to IMM or ATAs therapy group, were 37, 150, 34, and 380, respectively. Detailed information on medication in each group is presented in Supplementary Table 2, available as Supplementary data at ECCO-JCC online. Table 1. General characteristics of the eligible studies Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Data are recorded as mean standard deviation: SD], median [minimum-maximum], median [interquatile range: IQR]. Cases: number of lymphoma cases. Controls: number of patients in unexposed to anti-tumour necrosis factor alpha agents group. Y, years; EU. European Union; RCT, randomised controlled trial; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; CI, confidence interval; RR, risk ratio; NA, not available; BL: B-cell lymphoma; HL: Hodgkin lymphoma; NL: nonfollicular lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ML: metastatic lymphoma; NHL: non-Hodgkin lymphoma; TCL: T cell lymphoma; EMP: extra-medullary plasmacytoma; LL: lymphoblastic lymphoma; FBCL: follicular B cell lymphoma; PBLD*: plasmacytic B lymphoproliferative disorder; PBLD: polymorphic B lymphoproliferative disorder; ILBCL: immunoblastic large B-cell lymphoma; EPMBLD: early post-MINI B-lymphoproliferative disorder; ALCLD: anaplastic large cell lymphoproliferative disorder; EPBLD: early postmononucleosis B-lymphoproliferative disorder; DBCNL: diffuse big-cellular non-Hodgkin lymphoma; HSTCL: hepatosplenic T cell lymphoma; ETCL: enteropathic T cell lymphoma; MCL: mantle cell lymphoma; IDBCL: intravascular duodenal B-cell lymphoma. View Large Table 1. General characteristics of the eligible studies Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Data are recorded as mean standard deviation: SD], median [minimum-maximum], median [interquatile range: IQR]. Cases: number of lymphoma cases. Controls: number of patients in unexposed to anti-tumour necrosis factor alpha agents group. Y, years; EU. European Union; RCT, randomised controlled trial; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; CI, confidence interval; RR, risk ratio; NA, not available; BL: B-cell lymphoma; HL: Hodgkin lymphoma; NL: nonfollicular lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ML: metastatic lymphoma; NHL: non-Hodgkin lymphoma; TCL: T cell lymphoma; EMP: extra-medullary plasmacytoma; LL: lymphoblastic lymphoma; FBCL: follicular B cell lymphoma; PBLD*: plasmacytic B lymphoproliferative disorder; PBLD: polymorphic B lymphoproliferative disorder; ILBCL: immunoblastic large B-cell lymphoma; EPMBLD: early post-MINI B-lymphoproliferative disorder; ALCLD: anaplastic large cell lymphoproliferative disorder; EPBLD: early postmononucleosis B-lymphoproliferative disorder; DBCNL: diffuse big-cellular non-Hodgkin lymphoma; HSTCL: hepatosplenic T cell lymphoma; ETCL: enteropathic T cell lymphoma; MCL: mantle cell lymphoma; IDBCL: intravascular duodenal B-cell lymphoma. View Large Table 2. Number of patients, lymphoma cases, and patient years in combination therapy group, IMM monotherapy group, ATAs monotherapy group and ATAs or IMM unexposed group   Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200    Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200  ATAs: anti-tumour necrosis factor alpha agents; IMM: immunosuppressives; NA: not available. View Large Table 2. Number of patients, lymphoma cases, and patient years in combination therapy group, IMM monotherapy group, ATAs monotherapy group and ATAs or IMM unexposed group   Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200    Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200  ATAs: anti-tumour necrosis factor alpha agents; IMM: immunosuppressives; NA: not available. View Large Based on the quality assessment of NOS, nine cohort studies were high quality [four studies scored nine points, one study scored eight points, and four studies scored seven points], and one moderate quality [six points]. For RCTs [randomised controlled trials], all were rated as ‘unclear risk’ according to the Cochrane collaboration ROB tool. The quality assessment of the included studies is presented in Supplementary Table 3, available as Supplementary data at ECCO-JCC online. 3.3. Risk of lymphoma in ATAs exposed versus ATAs unexposed groups Based on the total 12 studies [80 cases of lymphoma in 57581 patients exposed to ATAs with 148032 patient-years of follow-up evaluation, and 790 cases of lymphoma in 284449 patients unexposed to ATAs with 1859792 patient-years of follow-up evaluation], the pooled crude incidence rates of lymphoma were 5.40 cases per 10000 patient-years [95% CI, 4.22–6.59] and 4.25 cases per 10000 patient-years [95% CI, 3.95–4.54] in patients exposed to ATAs and unexposed to ATAs, respectively. Twelve studies [two RCTs26,27 and 10 cohorts1,5,6,28–34] evaluated the association between exposure to ATAs and lymphoma risk by comparison of risk, and 11 studies evaluated the association by the comparison of incidence. Overall, both IRRs and RRs of lymphoma were not significantly higher in ATAs-exposed groups compared with non-exposed groups [random effects: IRR = 1.43, 95% CI, 0.91–2.25; P = 0.116; random effects: RR = 0.83, 95% CI, 0.47–1.48; P = 0.534] [Figure 2]. There was no significant heterogeneity detected among studies [IRR:I2 = 35.0%, P = 0.110; RR:I2 = 46.4%, P = 0.045]. Notably, the results of subgroup analyses showed that patients with more than 5 years’ median IBD duration period had increased risk of developing lymphoma, and a protective effect was detected in patients with more than 5 years follow-up period, whereas no significance was detected in other subgroups [Table 3]. We conducted Egger’s linear regression test and the rank correlation test [Begg’s test] to assess publication bias. Funnel plot shapes did not show an obvious asymmetry, and the P-values of Begg’s test and Egger’s test were 0.945 and 0.719 for IRR, and 0.436 and 0.221 for RR, respectively [Supplementary Figure 1, available as Supplementary data at ECCO-JCC online]. Table 3. Subgroup analyses results.   Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99    Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99  EU, European Union; Y, years; RCT, randomisec controlled trial; ATAs: anti-tumour necrosis factor alpha agents; IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR, risk ratio; IRR: incidence rate ratio; CI, confidence interval; NA, not available; NHL: non-Hodgkin lymphoma; HL: Hodgkin lymphoma. View Large Table 3. Subgroup analyses results.   Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99    Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99  EU, European Union; Y, years; RCT, randomisec controlled trial; ATAs: anti-tumour necrosis factor alpha agents; IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR, risk ratio; IRR: incidence rate ratio; CI, confidence interval; NA, not available; NHL: non-Hodgkin lymphoma; HL: Hodgkin lymphoma. View Large Figure 2. View largeDownload slide Forest plots evaluating lymphoma risk in anti-tumour necrosis factor alpha [TNFα] agents exposed versus anti-TNFα agents unexposed groups. Figure 2. View largeDownload slide Forest plots evaluating lymphoma risk in anti-tumour necrosis factor alpha [TNFα] agents exposed versus anti-TNFα agents unexposed groups. 3.4. Risk of lymphoma in the ATAs monotherapy group versus The unexposed to IMM or ATAs group Six studies evaluated the association between exposure to ATAs monotherapy and lymphoma risk. IRs in ATAs monotherapy group and unexposed to IMM or ATAs group were 4.03 cases per 10000 person-years [95% CI, 2.68–5.39] and 3.35 cases per 10000 person-years [95% CI, 3.01–3.68], respectively. Lymphoma risk was significantly greater in the ATAs monotherapy group compared with the unexposed to IMM or ATAs group, with an IRR of 1.65 [95% CI, 1.16–2.35; P = 0.006]. However, the RR of lymphoma was not significantly higher in the ATAs monotherapy group compared with unexposed to IMM or ATAs group [random effects: RR = 1.00, 95% CI, 0.39–2.59; P = 0.996] [Supplementary Figure 2, available as Supplementary data at ECCO-JCC online; and Table 4]. Table 4. Risk ratio and incidence rate ratio in unexposed to IMM or ATAs group, exposed to IMM monotherapy group, exposed to ATAs monotherapy group, exposed to combination therapy group. Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  ATAs: anti-tumor necrosis factor alpha agents; IMM: immunosuppressives; CI, confidence interval. View Large Table 4. Risk ratio and incidence rate ratio in unexposed to IMM or ATAs group, exposed to IMM monotherapy group, exposed to ATAs monotherapy group, exposed to combination therapy group. Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  ATAs: anti-tumor necrosis factor alpha agents; IMM: immunosuppressives; CI, confidence interval. View Large 3.5. Risk of lymphoma in the IMM monotherapy group versus The unexposed to IMM or ATAs group Seven studies evaluated the association between exposure to IMM monotherapy and lymphoma risk. The IR in the IMM monotherapy group was 5.89 cases per 10000 person-years [95% CI, 4.95–6.83]. The IRR of lymphoma was significantly higher in the IMM monotherapy group compared with the unexposed to IMM or ATAs group [random effects: IRR = 2.25, 95% CI, 1.25–4.06; P = 0.007], whereas the RR of lymphoma was not significantly higher in the IMM monotherapy group compared with the unexposed to IMM or ATAs group [random effects: RR = 1.49, 95% CI, 0.82–2.72; P = 0.192] [Table 4; and Supplementary Figure 3. available as Supplementary data at ECCO-JCC online]. 3.6. Risk of lymphoma in the combination therapy group versus The unexposed to IMM or ATAs group Eight studies evaluated the association between exposure to combination therapy and lymphoma risk. The IR in the combination group was 8.18 cases per 10000 person-years [95% CI, 5.54–10.81] The IRR and RR of lymphoma in the combination therapy group compared with the unexposed to IMM or ATAs group was 3.36 [random effects: 95% CI, 2.23–5.05; P < 0.001] and 1.90 [random effects: 95% CI, 0.66–5.44; P = 0.233], respectively [Table 4; and Supplementary Figure 4, available as Supplementary data at ECCO-JCC online]. 3.7. Risk of lymphoma in the combination therapy group versus the IMM monotherapy group Ten studies evaluated lymphoma risk of combination therapy exposure versus IMM monotherapy. The IRR and RR of lymphoma were both not significantly higher in the combination therapy group compared with the IMM monotherapy group [random effects: IRR = 1.47, 95% CI, 0.88–2.46; P = 0.142; random effects: RR = 0.83, 95% CI, 0.54–1.29; P = 0.416] [Table 4; and Supplementary Figure 5, available as Supplementary data at ECCO-JCC online]. 4. Discussion This meta-analysis pooled data of users and non-users of ATAs therapy from 10 cohort studies [seven prospective studies and three retrospective studies] and two RCTs, to systematically evaluate lymphoma risk of IBD patients treated with ATAs. It demonstrated no association between ATAs therapy and lymphoma in IBD patients. Subanalysis was conducted regarding geographical distribution, sample size, follow-up period, duration of IBD, type of IBD, age, lymphoma type, and study design. The results of subgroup analyses showed that patients with more than 5 years IBD duration period had increased risk of developing lymphoma, which indicated that the IBD disease itself might lead to malignancies. It was reported in a previous study that CD was associated with lymphoma in patients with no history of immunosuppressives.35 Consistently, a nationwide cohort study conducted by M. Fallah et al. confirmed the association between autoimmune diseases including IBD and a higher risk of non-Hodgkin lymphoma [NHL].36 Similar to this result, a population-based study on Korean patients showed an increased risk of NHL in both UC and CD.37 Protective effect was detected in patients with a more than 5 years follow-up period, which was inconsistent with previous studies. Due to the limited number of included studies in this analysis, long-term prospective studies are required for further investigation on this issue. Subgroup analysis revealed that age was not a confounding factor in the development of lymphoma, and neither CD nor UC was associated with increased lymphoma risk. No elevated risk of non-Hodgkin lymphoma [NHL] or Hodgkin lymphoma [HL] was detected, respectively. When we extracted information on the specific kinds of drugs taken by IBD patients, a significant difference of elevated risk of lymphoma was detected in the IMM monotherapy group, ATAs monotherapy group, and combination therapy group. No significance was identified in the combination therapy versus IMM monotherapy group. Thus, combination therapy, IMM monotherapy, and ATAs monotherapy can significantly increase the risk of lymphoma. The result of ATAs exposed versus ATAs non-exposed group in this meta-analysis is in accordance with several studies. No excess risk of lymphoma was observed in IBD patients treated with ATAs alone according to a 5-year, prospective, observational ENCORE registry following patients with CD in nine European countries. However, increased risk in further investigations with longer disease duration as well as longer follow-up period could not be excluded.29 Correspondingly, a study involving 6357 IBD patients reported no significantly increased risk of lymphoma with ATAs therapy. The study was limited by its composite measure of analysis, the relatively small sample size, and insufficient follow-up time, as well as duration of anti-TNFα therapy. Its lower incidence rate of lymphoma with ATAs therapy may be due to the selection of comparator therapy for the analysis of IBD, since thiopurines are associated with an increased odds of lymphoma.17 In line with these studies, a systematic review conducted in 2014 among paediatric patients with IBD has reached a similar conclusion.38 It mentioned that older age, sex, and duration of IBD have been associated with an increased risk of lymphoproliferative disorders and may help to explain the non-significantly increased risk of lymphoma in paediatric IBD patients exposed to ATAs therapy. Furthermore, an abundant number of studies on overall cancer risk in ATAs-treated IBD patients have not identified significance either.12,16,17,39–43 A nationwide register-based cohort study in Denmark involving 56146 patients with IBD showed no association between exposure to ATAs among patients with IBD and an increased risk of cancer. An increased risk of malignancy in studies with longer follow-up and increasing number of cumulative doses of ATAs cannot be excluded.33 There are several factors that may lead to the failure in detecting significance in the ATAs exposed versus ATAs non-exposed groups. First, as a slowly progressing disease with relatively rare occurrence, the incidence rate of cancers should be calculated in a cohort with long follow-up time and large sample size. Not all studies included in this group come with a long enough duration of observation and large enough sample size, though we tend to exclude short-term small studies in the selection process. As time to develop lymphoma was not available in published literature, increased risk in future longer-term studies with larger sample size cannot be excluded. Additionally, drug usage was not specified in this comparison. Patients in control and experiment groups could have had previous or concurrent exposure to other biologics or non-biologics. To improve the situation, four other comparisons with specific usage of medications were established. Contrary to these studies, several early studies of the same interest identified significance of lymphoma in IBD patients with ATAs therapy. The increasing reports of lymphoma cases in IBD patients with ATAs therapy in recent years are consistently suggesting an association between lymphoma and ATAs therapy in IBD.34,44–46 Besides, a review showed that the increasing number of reported cases of lymphoma with infliximab and adalimumab was suggesting an undeniable association of lymphoma development with the use of ATAs, though this risk was unquantifiable.47 Moreover, in a single-centre cohort study including 1222 IBD patients, lymphoma cases were identified in CD patients, and an increased risk was observed when using ATAs.35 Additionally, when compared with the general population, significant statistically increased risk of NHL was found in the ATAs therapy group of CD in a meta-analysis conducted by Siegel et al., though the absolute risk remained small [6.1 per10000 patient-years].13 However, limits of the article lay in the lack of an ideal comparison, since patients in the control group were exposed to thiopurines inevitably, which might be a confounding factor for the study on ATAS monotherapy. It is worthy to mention that a cohort study published in 2017,34 which was included in this meta-analysis, detected a small but statistically significant increased risk of lymphoma with ATAs monotherapy in IBD. Lymphoma risk was higher with combination therapy than with ATAs monotherapy or IMM monotherapy. The elevated risk of lymphoma in the ATAs monotherapy group and combination group in this analysis isconsistent with the above studies. ATAs are widely used in the treatment of IBD for their efficiency in alleviating inflammation and maintaining long-term mucosal healing, resulting in decrease in both surgery risk and related complications. But their side effect of elevated risk of malignancies, including lymphoma, has arisen over time. It is universally acknowledged that chemicals, medications, and rapid cell turnover promote the progress of neoplastic transformation. Cell signal transduction can be changed by a disruption in the cell cycle check points, either through alterations in tumour suppressor genes and proto-oncogenes, or the DNA sequence itself. Active chronic inflammation, which initiates constant cell regeneration and rapid turnover, is experienced by IBD patients. ATAs may be the epigenetic factor which enables selective uncontrolled cell proliferation and thus initiation of lymphoma development in the genetically susceptible.47 As it is shown in this analysis that both ATAs monotherapy and IMM monotherapy can increase the risk of lymphoma, the significant difference identified in the combination therapy group can be the result of IMM alone, or ATAs alone, or the synergistic effect of IMM and ATAs. Since higher risk was identified with combination therapy than with IMM or ATAS monotherapy in the large nationwide cohort conducted in 2017, increased risks associated with each of these treatments used alone may accumulate when they are combined.34 As it was verified in previous publications that therapy with IMM can increase risk of malignancies, the elevated risk identified in the IMM group versus the never exposed to IMM or ATAs group in this analysis is therefore reasonable, and corresponds with previous studies. With several strengths, the conclusion of this meta-analysis is reasonable. First, this meta-analysis included latest researches on IMM and ATAs use in IBD patients, abstracting information on different therapies in clinical practice and information on cases of lymphoma manually. Medications were specified and four comparisons were established to systematically evaluate risk of lymphoma in combination therapy and ATAs monotherapy, which set a precedent in giving an overview of the issue. Second, RCTs and cohort studies were both included in the pooled analysis, resulting in a more effective conclusion. The traits of either study type can be interpreted separately. The 10 cohort studies included were conducted in an unselected and well-defined IBD population, and complete history for all patients could be obtained, hence avoiding user bias. Regarding the two RCTs, with strict inclusion and exclusion criteria, the combination of blind, control, and randomisation methods, and definite diagnosis standards, they can present a more reliable result with less selection bias. However, the strengths of this meta-analysis should be weighed against a number of limitations. First, medications of ATAs could be monotherapy with IFX or combination therapy of different kinds of ATAs, since we could not evaluate the potential risks of IFX, ADA, and certolizumab pegol [CTZ] separately, which might obscure the true relationship of lymphoma with any specific kind of ATA. Second, limitation arises due to the characteristics of the included literature. It has been reported in several articles that a certain amount of exposure to radiation48 is a risk factor for developing cancers in IBD patients. Nevertheless, this confounding factor was not well controlled in some of the included studies, and thus we were unable to subanalyse it in this meta-analysis. The outcome might be biased as we failed to exclude certain high-risk populations. Moreover, data evaluating lymphoma risk with various drug doses in published literature was insufficient for further investigation, and therefore we did not include this factor in subgroup analysis. Third, studies included were only conducted in the USA or Europe or the combination of both regions. The inclusion of patients with specific nationality can hinder this meta-analysis in reaching a universal conclusion. Despite the limitations of our meta-analysis, its conclusion is still of importance in clinical practice. The concerns by patients and providers over side effects of treatments for IBD and the fear of developing cancer have been causing great emotional barriers to their use. The result of this meta-analysis, corresponding with other researches focusing on the same issue, has a synergistic effect upon a more reasoned and definite elucidation by physicians towards patients. The conclusions reaffirmed the increased risk of lymphoma in IMM monotherapy, ATAs monotherapy, and combination therapy, which provides physicians and patients with more definite evidence in balancing the efficiency and deficiency of drugs for IBD. Large, long-term, prospective cohort studies and RCTs are expected to assess the incidence ratio of the rare occurrence of lymphoma. In conclusion, exposure to ATAs among patients with IBD was not associated with an increased risk of lymphoma in this systematic review and meta-analysis. However, combination therapy or ATAs monotherapy can increase the risk of lymphoma in patients with inflammatory bowel disease. Further prospective data are required for a more accurate assessment. Funding This work was supported by the National Natural Science Foundation of China [Grant Number: 81300370 to SD], and the China Postdoctoral Science Foundation [Grant Number: 2017M622650 to SD]. Conflict of Interest The authors report no conflicts of interest. Author Contributions CY and JH have contributed equally to this work. SD and CY were responsible for study design, article retrieval, article selection, and data analysis. JHg and SH were responsible for data acquisition and data analysis. 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Desmond AN, O’Regan K, Curran C, et al.   Crohn’s disease: factors associated with exposure to high levels of diagnostic radiation. Gut  2008; 57: 1524– 9. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Crohn's and Colitis Oxford University Press

Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti-tumour Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis

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Elsevier Science
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Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1873-9946
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1876-4479
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10.1093/ecco-jcc/jjy065
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Abstract

Abstract Background and Aims The association between anti-tumour necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti-tumour necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. Methods MEDLINE, EMBASE, and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumour necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Results Twelve studies comprising 285,811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumour necrosis factor alpha agents exposed and anti-tumour necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR] = 1.43, 95% CI, 0.91–2.25; P = 0.116; random effects: risk ratio [RR] = 0.83, 95% CI, 0.47–1.48; P = 0.534). However, monotherapy of anti-tumour necrosis factor alpha agents [random effects: IRR = 1.65, 95% CI, 1.16–2.35; P = 0.006; random effects: RR = 1.00, 95% CI, 0.39–2.59; P = 0.996] or combination therapy [random effects: IRR = 3.36, 95% CI, 2.23–5.05; P < 0.001; random effects: RR = 1.90, 95% CI, 0.66–5.44; P = 0.233] can significantly increase the risk of lymphoma. Conclusions Exposition of anti-tumour necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumour necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease. Inflammatory bowel disease, anti-tumour necrosis factor alpha agents 1. Introduction Conventional therapies of inflammatory bowel disease [IBD] include 5-aminosalicylic acid [5-ASA] agents, corticosteroids, thiopurines, and other biologic agents. Responding to the urgency of developing a kind of treatment that allows long-term efficiency in moderate-to-severe IBD patients, the first of anti-tumour necrosis factor alpha agents [ATAs], infliximab [IFX], was approved for Crohn’s disease [CD] in 1998 and for ulcerative colitis [UC] in 2006, followed by the approval of adalimumab [ADA] and other ATAs.1 They not only prolong the maintenance of clinical remission and long-term mucosal healing, but also reduce surgery risks.2–4 Despite the well-acknowledged benefits of ATAs, their risk of developing cancer on account of the treatment-induced suppression of the immune system has always been a confusing factor in clinical decisions. Lymphoma is one of the reported haematological cancers in IBD patients. As time goes by, the need for reliable and definite risk evaluations on lymphoma has been urgently growing. However, obstacles have been encountered when accessing lymphoma risk with ATAs therapy. In clinical practice, IBD patients are often treated with combination therapy of immunosuppressives [IMM] and ATAs, and the majority of ATAs-treated IBD patients have been treated with IMM previously.5 Therefore, the safety of IMM or when combined with ATAs should be considered in the lymphoma risk evaluation of ATAs monotherapy. Plenty of studies have reported increased risk of lymphoma with monotherapy of thiopurines in IBD patients,6–9 though no consensus has been reached, with several studies showing conflicting results.10,11 Also, evidence consistently indicates that treatment with thiopurines [azathioprine and 6-mercaptopurine] combined with ATAs significantly increases lymphoma risk in IBD.12–14 The risk of ATAs monotherapy therefore has been difficult to evaluate, given that it is hard to fully quantify the risk of lymphoma among patients on ATAs therapy in the absence of concurrent thiopurine therapy. The number of studies investigating the relation between ATAs and lymphoma is abundant but their conclusions remain controversial. A couple of studies demonstrated that using ATAs alone did not reveal an increased risk of lymphoma in IBD,15–18 whereas a systematic review and meta-analysis published in 2006 reported a higher incidence of lymphoma among patients treated with infliximab or adalimumab.19 A certain number of studies reported a numerically, but not statistically, higher odds of lymphoma with ATAs monotherapy compared with IMM monotherapy.1,20 In a nutshell, previous evaluations of the risk of lymphoma associated with ATAs therapy have reached equivocal conclusions. With some but not all studies illustrating that ATAs therapy may increase the risk of lymphoma, the balance of risks and benefits when making prescriptions may consistently baffle physicians. Accordingly, we conducted this meta-analysis to systematically evaluate lymphoma risk in IBD patients with ATAs, aiming at a definite conclusion. 2. Methods 2.1. Data sources The search was conducted using MEDLINE [1966April 2018], EMBASE [1985April 2018], and the Cochrane Central Register of Controlled Trials. The following terms were used in search: [‘Inflammatory Bowel Diseases’ OR ‘Crohn Disease’ OR ‘Ulcerative Colitis’] AND [‘lymphoma*’ OR ‘malignancy’ OR ‘malignancies’] AND [‘anti-TNFα therapy’ OR ‘anti-tumor necrosis factor-α therapy’ OR ‘anti-TNFα agents’ OR ‘infliximab’ OR ‘adalimumab’ OR ‘certolizumab’ OR ‘golimumab’ OR ‘natalizumab’ OR ‘vedolizumab’ OR ‘etanercept’]. No language or publication type was restricted. The reference lists of all studies were also scanned in order to identify additional literature on this topic. The selection process of the studies is shown in Figure 1. Figure 1. View largeDownload slide Flow diagram of literature screening. Figure 1. View largeDownload slide Flow diagram of literature screening. 2.2. Study selection Studies included in this meta-analysis were cohort studies and randomised controlled trials [RCTs] which met the following inclusion criteria: [1] diagnosed IBD according to definite criteria; [2 no previous exposure to ATAs; [3] provision of specific information about the treatment; and [4] reported incidence rate ratios [IRRs] with corresponding 95% confidence interval [CIs] or underlying data enabling calculation of effect measures [including the incident cases of lymphoma and the total number of patient-years of the comparison groups]. Studies lacking necessary data were excluded. Letters, conference abstracts, review articles, case reports, expert opinions, and posters were also excluded. In studies with multiple publications from the same population, only data from the most recent publication were included. All articles were assessed independently by two investigators, and any questions were resolved by discussion. 2.3. Data extraction and quality assessment Data were extracted independently by two investigators onto an Excel database. The following items recorded for each study were extracted: first author, year of publication, mean/median age, geographical distribution, study design, number of cases and controls, treatment strategy, follow-up time, treatment duration, lymphoma type, subtype of IBD (ulcerative colitis [UC] and/or Crohn’s disease [CD]), total number of patient-years, and incident cases of lymphoma. For cohort studies we used the Newcastle–Ottawa scale [NOS] to assess the quality.21 In brief, a maximum of nine points was assigned to each study: four for selection, two for comparability, and three for outcomes. The overall quality of a study was considered ‘poor’ if the total NOS score was lower than four. Studies with a NOS score between four and six were considered to be ‘moderate’, and those with a NOS score between seven and nine were considered to be of high quality. For the randomised controlled trials we used the Cochrane collaboration risk of bias [ROB] tool to examine study validity.22 The overall risk of bias of a study was considered ‘low’ if more than four items in the Cochrane collaboration ROB tool were rated as ‘low risk’. The overall risk of bias of a study was considered ‘moderate’ if two or three items in the Cochrane collaboration ROB tool were rated as ‘low risk’. The overall risk of bias of a study was considered ‘high’ if fewer than two items in the Cochrane collaboration ROB tool were rated as ‘low risk’ or if more than one item was rated as ‘high risk’. 2.4. Data synthesis and analysis The study population was divided into the following six groups to make comparisons: [1] ATAs exposed [exposure to any ATAs, including infliximab, adalimumab, and certolizumab pegol, in the presence or absence of exposure to other agents]; [2] ATAs unexposed [exposure to any agents excluding ATAs]; [3] ATAs monotherapy [exposure to ATAs only, in the absence of other agents]; [4] unexposed to IMM or ATAs [exposure to non-biologics excluding IMM and biologics excluding ATAs]; [5] IMM monotherapy [exposure to IMM only, in the absence of other agents]; and [6] combination therapy [exposure to IMM and ATAs, in the absence of other agents]. Incidence rates [IRs] per patient-year were computed by dividing the incident cases of lymphoma by the number of patient-years of follow-up [the total numbers of patient-years were either calculated or extracted from the included studies]. The RRs and IRRs which represent the risk ratios and incidence rate ratios were used to express the pooled results. RRs and 95% CIs were computed by comparing the lymphoma risk between two groups. IRRs and 95% CIs were used to compare the lymphoma incidence rates per patient-year between two groups. Cochran’s Q test and I2 were used to evaluate the heterogeneity of pooled outcomes. Cochran’s Q < 0.10 or I2 > 50% represented significant heterogeneity among included studies.23,24 Random-effects modelling [DerSimonian–Laird method] was applied to calculate pooled RR and IRR.25 To explore the underlying source of heterogeneity, subgroup analysis was conducted according to geographical distribution, sample size, follow-up period, IBD duration, IBD type, age, lymphoma type, and study design. Egger’s linear regression test and the rank correlation test [Begg’s test] were used to evaluate publication bias. All statistical analyses were performed by STATA statistical software V.13.0 [StataCorp. LP]. All statistical tests used in this study were two-sided and P < 0.05, except for testing for heterogeneity, was considered statistically significant. 3. Results 3.1. Search results The search strategy found 10,744 citations: MEDLINE [n = 4190], EMBASE [n = 6073], Cochrane [n = 481]; 1829 duplicate articles were excluded, and 2995 articles were left for screening. After examining titles and abstracts, 5920 were excluded. Subsequently, 33 potentially relevant articles were retrieved for detailed evaluation. After reading the full text, 21 articles were excluded because of insufficient data of control groups [n = 10], lack of necessary data [n = 10], or duplicate datasets [n = 1]. Eventually, 12 studies were included in this meta-analysis. 3.2. Description of included studies The main characteristics of the 12 studies included are displayed in Supplementary Table 1 [available as Supplementary data at ECCO-JCC online], and in Table 1 and Table 2. Of the 12 study entries, two studies were RCTs, three studies were retrospective cohort studies, and the remaining seven studies were prospective cohort studies. Overall, 285,811 participants were involved. Five studies were conducted in the EU, three studies in the USA, and the remaining four studies were multinational. Patients in five studies had an IBD duration of over 5 years. The numbers of patients with different therapies and the number of lymphoma cases can be extracted from 10 studies [Table 2]. The total numbers of patients involved in the combination therapy group, IMM monotherapy group, ATAs monotherapy group, and non-exposure to IMM or ATAs therapy group, were 20,917, 64,246, 32,074, and 168,574, respectively. The total number of lymphoma cases in patients involved in the combination therapy group, IMM monotherapy group, ATAs monotherapy group and non-exposure to IMM or ATAs therapy group, were 37, 150, 34, and 380, respectively. Detailed information on medication in each group is presented in Supplementary Table 2, available as Supplementary data at ECCO-JCC online. Table 1. General characteristics of the eligible studies Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Data are recorded as mean standard deviation: SD], median [minimum-maximum], median [interquatile range: IQR]. Cases: number of lymphoma cases. Controls: number of patients in unexposed to anti-tumour necrosis factor alpha agents group. Y, years; EU. European Union; RCT, randomised controlled trial; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; CI, confidence interval; RR, risk ratio; NA, not available; BL: B-cell lymphoma; HL: Hodgkin lymphoma; NL: nonfollicular lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ML: metastatic lymphoma; NHL: non-Hodgkin lymphoma; TCL: T cell lymphoma; EMP: extra-medullary plasmacytoma; LL: lymphoblastic lymphoma; FBCL: follicular B cell lymphoma; PBLD*: plasmacytic B lymphoproliferative disorder; PBLD: polymorphic B lymphoproliferative disorder; ILBCL: immunoblastic large B-cell lymphoma; EPMBLD: early post-MINI B-lymphoproliferative disorder; ALCLD: anaplastic large cell lymphoproliferative disorder; EPBLD: early postmononucleosis B-lymphoproliferative disorder; DBCNL: diffuse big-cellular non-Hodgkin lymphoma; HSTCL: hepatosplenic T cell lymphoma; ETCL: enteropathic T cell lymphoma; MCL: mantle cell lymphoma; IDBCL: intravascular duodenal B-cell lymphoma. View Large Table 1. General characteristics of the eligible studies Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Author [year]  Year  Mean/ median age [years]  Geographical distribution  Study design  Cases/ controls  Lymphoma type  IBD type  Follow -up [Y]  Mean duration of IBD [Y]  Hyams  2017  12.3 [3.01]  Multinational [USA AND EU]  Prospective cohort  3869/1897  BL, HL  IBD  4.7  1.6  Lemaitre  2017  43 [32–56]  EU  Retrospective cohort  44523/173474  NL, DLBCL, HL, FL  IBD  6.7  NA  Haens  2016  35 [16–86]  Multinational [USA AND EU]  Prospective cohort  1276/1121  HL, BL, ML  CD  2.5  8.9 [case]/ 7.9 [control]  Andersen  2014  33.7 [13.9] [case]/44.5 [18.3] [control]  EU  Prospective cohort  4553/51593  NHL, HL, TCL, DLBCL, EMP, LL  IBD  9.3  4  Biancone  2011  44 [14–90]  EU  Prospective cohort  198/1024  HL, NHL  IBD  11 [CD]/ 7[UC]  9 [CD]/7 [UC]  Beaugerie  2009  40.3 [15.6]  EU  Prospective cohort  1939/17547  FBCL, DLBCL, TCL, HL, PBLD,* PBLD, ILBCL, EPMBLD, ALCLD, EPBLD  IBD  3  8.2  Beigel  2014  36 [14–82]  EU  Retrospective cohort  404/262  DLBCL, DBCNL, HL, HSTCL  IBD  4  3 [case]/ 1.5 [control]  Herrinton  2011  NA  USA  Prospective cohort  NA  DLBCL, FL, HL  IBD  2.9  NA  Hyams  2009  11.8 [2.9]  USA  Prospective cohort  202/527  HL  CD  1.5  3.75  Khan  2013  60  USA  Retrospective cohort  251/36640  NHL, BL, FBCL, ETCL, TCL, MCL,  UC  6.7  NA  Sandborn  2007  37.5 [12]  Multinational [USA AND EU]  RCT  331/329  HL  CD  1  7.5  Rutgeerts  1999  35 [20–65]  Multinational [USA AND EU]  RCT  37/36  IDBCL  CD  1  9.8  Data are recorded as mean standard deviation: SD], median [minimum-maximum], median [interquatile range: IQR]. Cases: number of lymphoma cases. Controls: number of patients in unexposed to anti-tumour necrosis factor alpha agents group. Y, years; EU. European Union; RCT, randomised controlled trial; CD, Crohn’s disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; CI, confidence interval; RR, risk ratio; NA, not available; BL: B-cell lymphoma; HL: Hodgkin lymphoma; NL: nonfollicular lymphoma; DLBCL: diffuse large B-cell lymphoma; FL: follicular lymphoma; ML: metastatic lymphoma; NHL: non-Hodgkin lymphoma; TCL: T cell lymphoma; EMP: extra-medullary plasmacytoma; LL: lymphoblastic lymphoma; FBCL: follicular B cell lymphoma; PBLD*: plasmacytic B lymphoproliferative disorder; PBLD: polymorphic B lymphoproliferative disorder; ILBCL: immunoblastic large B-cell lymphoma; EPMBLD: early post-MINI B-lymphoproliferative disorder; ALCLD: anaplastic large cell lymphoproliferative disorder; EPBLD: early postmononucleosis B-lymphoproliferative disorder; DBCNL: diffuse big-cellular non-Hodgkin lymphoma; HSTCL: hepatosplenic T cell lymphoma; ETCL: enteropathic T cell lymphoma; MCL: mantle cell lymphoma; IDBCL: intravascular duodenal B-cell lymphoma. View Large Table 2. Number of patients, lymphoma cases, and patient years in combination therapy group, IMM monotherapy group, ATAs monotherapy group and ATAs or IMM unexposed group   Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200    Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200  ATAs: anti-tumour necrosis factor alpha agents; IMM: immunosuppressives; NA: not available. View Large Table 2. Number of patients, lymphoma cases, and patient years in combination therapy group, IMM monotherapy group, ATAs monotherapy group and ATAs or IMM unexposed group   Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200    Exposed to combination therapy of ATAs and IMM  Exposed to IMM monotherapy  Exposed to ATAs monotherapy  Unexposed to ATAs or IMM  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Number of patients  Lymphoma cases  Patient-years  Hyams et al., 2017  2723  4  11416  1134  3  5808  1146  1  4202  763  1  3117  Haens et al., 2016  1276  6  6380  642  0  3210  NA  NA  NA  479  0  2395  Khan et al., 2013  177  1  260  4557  22  7517  74  0  482  32083  119  190944  Beaugerie et al., 2009  1844  5  5466  6832  12  20275  95  0  272  10715  6  22706  Beigel et al., 2014  374  1  1092  262  3  372  30  0  88  0  0  NA  Biancone et al., 2011  129  0  1311  168  1  1596  69  0  683  856  1  7424  Hyams et al., 2009  96  1  552  180  0  1035  104  0  598  347  0  1995  Sandborn et al., 2007  69  0  37  66  1  36  262  0  141  262  0  141  Lemaitre et al., 2017  14229  14  14753  50405  70  129743  30294  32  77229  123069  220  838611  Herrinton et al., 2011  NA  5  3974  NA  38  85090  NA  1  619  NA  33  67867  Total  20917  37  45241  64246  150  254682  32074  34  84314  168574  380  1135200  ATAs: anti-tumour necrosis factor alpha agents; IMM: immunosuppressives; NA: not available. View Large Based on the quality assessment of NOS, nine cohort studies were high quality [four studies scored nine points, one study scored eight points, and four studies scored seven points], and one moderate quality [six points]. For RCTs [randomised controlled trials], all were rated as ‘unclear risk’ according to the Cochrane collaboration ROB tool. The quality assessment of the included studies is presented in Supplementary Table 3, available as Supplementary data at ECCO-JCC online. 3.3. Risk of lymphoma in ATAs exposed versus ATAs unexposed groups Based on the total 12 studies [80 cases of lymphoma in 57581 patients exposed to ATAs with 148032 patient-years of follow-up evaluation, and 790 cases of lymphoma in 284449 patients unexposed to ATAs with 1859792 patient-years of follow-up evaluation], the pooled crude incidence rates of lymphoma were 5.40 cases per 10000 patient-years [95% CI, 4.22–6.59] and 4.25 cases per 10000 patient-years [95% CI, 3.95–4.54] in patients exposed to ATAs and unexposed to ATAs, respectively. Twelve studies [two RCTs26,27 and 10 cohorts1,5,6,28–34] evaluated the association between exposure to ATAs and lymphoma risk by comparison of risk, and 11 studies evaluated the association by the comparison of incidence. Overall, both IRRs and RRs of lymphoma were not significantly higher in ATAs-exposed groups compared with non-exposed groups [random effects: IRR = 1.43, 95% CI, 0.91–2.25; P = 0.116; random effects: RR = 0.83, 95% CI, 0.47–1.48; P = 0.534] [Figure 2]. There was no significant heterogeneity detected among studies [IRR:I2 = 35.0%, P = 0.110; RR:I2 = 46.4%, P = 0.045]. Notably, the results of subgroup analyses showed that patients with more than 5 years’ median IBD duration period had increased risk of developing lymphoma, and a protective effect was detected in patients with more than 5 years follow-up period, whereas no significance was detected in other subgroups [Table 3]. We conducted Egger’s linear regression test and the rank correlation test [Begg’s test] to assess publication bias. Funnel plot shapes did not show an obvious asymmetry, and the P-values of Begg’s test and Egger’s test were 0.945 and 0.719 for IRR, and 0.436 and 0.221 for RR, respectively [Supplementary Figure 1, available as Supplementary data at ECCO-JCC online]. Table 3. Subgroup analyses results.   Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99    Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99  EU, European Union; Y, years; RCT, randomisec controlled trial; ATAs: anti-tumour necrosis factor alpha agents; IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR, risk ratio; IRR: incidence rate ratio; CI, confidence interval; NA, not available; NHL: non-Hodgkin lymphoma; HL: Hodgkin lymphoma. View Large Table 3. Subgroup analyses results.   Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99    Exposed to ATAs  Unexposed to ATAs          Subgroups  Number of patients  Patient-years  Lymphoma cases  Number of patients  Patient-years  Lymphoma cases  RR [95% CI]  P-value  IRR [95% CI]  P-value  Geographical distribution  EU  51617  119334  60  243900  1490601  573  0.68 [0.33, 1.40]  0.29  1.13 [0.59, 2.18]  0.71  USA  451  1892  2  37167  201491  141  1.90 [0.31, 11.79  0.49  2.80 [0.53, 14.97]  0.23  Multinational [USA and EU]  5513  22213  12  3383  14743  5  1.29 [0.28, 5.91]  0.74  1.30 [0.34, 4.99]  0.70  Sample size  <3000  2446  10919  9  3299  18240  6  1.43 [0.35, 5.81]  0.62  1.25 [0.25, 6.23]  0.79  ≥3000  55135  132520  65  281151  1688595  713  0.77 [0.36, 1.62]  0.48  1.44 [0.94, 2.19]  0.09  Mean/median follow-up period  <5 years  8056  30281  19  21719  61126  26  1.40 [0.52, 3.78]  0.50  1.26 [0.44, 3.63]  0.67  ≥5 years  49525  113158  55  262731  1645709  693  0.57 [0.43, 0.76]  <0.01  1.34 [0.85, 2.10]  0.21  Median IBD duration  <5 Y  9026  36388  15  54279  482201  267  0.47 [0.20, 1.10]  0.08  0.69 [0.26, 1.82]  0.45  ≥5 Y  3781  14327  12  20057  57819  21  2.35 [1.02, 5.40]  0.04  2.04 [0.89, 4.68]  0.09  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  IBD type  Mixed  55486  134952  65  245797  1499526  577  0.67 [0.36, 1.22]  0.19  1.08 [0.60, 1.93]  0.79  CD  1844  7745  8  2013  8848  1  3.29 [0.70,15.51]  0.13  3.28 [0.70, 15.47]  0.13  UC  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Age  Adolescent [≤18 Y]  4069  16768  6  2424  11955  4  1.43 [0.13,15.30]  0.77  1.50 [0.17,13.36]  0.71  Adult [>18 Y]  51383  116375  60  242979  1481422  569  0.76 [0.36, 1.61]  0.47  1.40 [0.91, 2.15]  0.13  Adolescent and adult [14 Y80 Y]  1878  9554  7  2407  14997  5  1.22 [0.11,13.84]  0.87  0.93 [0.05,17.02]  0.96  NA  251  742  1  36640  198461  141  1.04 [0.15, 7.37]  0.97  1.90 [0.27, 13.54]  0.52  Lymphoma type  NHL  6978  25895  13  21622  64541  22  1.34 [0.62, 2.89]  0.45  1.18 [0.55, 2.54]  0.67  HL  6978  25895  1  21622  64541  5  1.49 [0.32, 6.90]  0.61  1.26 [0.27, 5.90]  0.77  NA  50352  116802  60  226188  1443833  550  0.62 [0.31, 1.26]  0.19  1.42 [0.75, 2.67]  0.28  Study design  Cohort study  57213  143224  73  284085  1706622  718  0.84 [0.45, 1.56]  0.58  1.28 [0.75, 2.18]  0.37  RCT  368  215  1  365  213  1  0.99 [0.10, 9.43]  1.00  0.99 [0.10, 9.41]  0.99  EU, European Union; Y, years; RCT, randomisec controlled trial; ATAs: anti-tumour necrosis factor alpha agents; IBD: inflammatory bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; RR, risk ratio; IRR: incidence rate ratio; CI, confidence interval; NA, not available; NHL: non-Hodgkin lymphoma; HL: Hodgkin lymphoma. View Large Figure 2. View largeDownload slide Forest plots evaluating lymphoma risk in anti-tumour necrosis factor alpha [TNFα] agents exposed versus anti-TNFα agents unexposed groups. Figure 2. View largeDownload slide Forest plots evaluating lymphoma risk in anti-tumour necrosis factor alpha [TNFα] agents exposed versus anti-TNFα agents unexposed groups. 3.4. Risk of lymphoma in the ATAs monotherapy group versus The unexposed to IMM or ATAs group Six studies evaluated the association between exposure to ATAs monotherapy and lymphoma risk. IRs in ATAs monotherapy group and unexposed to IMM or ATAs group were 4.03 cases per 10000 person-years [95% CI, 2.68–5.39] and 3.35 cases per 10000 person-years [95% CI, 3.01–3.68], respectively. Lymphoma risk was significantly greater in the ATAs monotherapy group compared with the unexposed to IMM or ATAs group, with an IRR of 1.65 [95% CI, 1.16–2.35; P = 0.006]. However, the RR of lymphoma was not significantly higher in the ATAs monotherapy group compared with unexposed to IMM or ATAs group [random effects: RR = 1.00, 95% CI, 0.39–2.59; P = 0.996] [Supplementary Figure 2, available as Supplementary data at ECCO-JCC online; and Table 4]. Table 4. Risk ratio and incidence rate ratio in unexposed to IMM or ATAs group, exposed to IMM monotherapy group, exposed to ATAs monotherapy group, exposed to combination therapy group. Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  ATAs: anti-tumor necrosis factor alpha agents; IMM: immunosuppressives; CI, confidence interval. View Large Table 4. Risk ratio and incidence rate ratio in unexposed to IMM or ATAs group, exposed to IMM monotherapy group, exposed to ATAs monotherapy group, exposed to combination therapy group. Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  Group comparison  Unexposed to IMM or ATAs  Exposed to IMM monotherapy  Risk ratio [95% CI]  P-value  I2  Risk ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  1.49 [0.82–2.72]  0.192  63.8%  /  /  /  Exposed to ATAs monotherapy  1.00 [0.39–2.59]  0.996  23.1%  /  /  /  Exposed to combination therapy  1.90 [0.66–5.44]  0.233  60.7%  0.83 [0.54–1.29]  0.416  0.0%  Group comparison  Incidence rate ratio [95% CI]  P-value  I2  Incidence rate ratio [95% CI]  P-value  I2  Exposed to IMM monotherapy  2.25 [1.25–4.06]  0.007  76.5%  /  /  /  Exposed to ATAs monotherapy  1.65 [1.16–2.35]  0.006  0.0%  /  /  /  Exposed to combination therapy  3.36 [2.23–5.05]  <0.001  0.0%  1.47 [0.88–2.46]  0.142  19.7%  ATAs: anti-tumor necrosis factor alpha agents; IMM: immunosuppressives; CI, confidence interval. View Large 3.5. Risk of lymphoma in the IMM monotherapy group versus The unexposed to IMM or ATAs group Seven studies evaluated the association between exposure to IMM monotherapy and lymphoma risk. The IR in the IMM monotherapy group was 5.89 cases per 10000 person-years [95% CI, 4.95–6.83]. The IRR of lymphoma was significantly higher in the IMM monotherapy group compared with the unexposed to IMM or ATAs group [random effects: IRR = 2.25, 95% CI, 1.25–4.06; P = 0.007], whereas the RR of lymphoma was not significantly higher in the IMM monotherapy group compared with the unexposed to IMM or ATAs group [random effects: RR = 1.49, 95% CI, 0.82–2.72; P = 0.192] [Table 4; and Supplementary Figure 3. available as Supplementary data at ECCO-JCC online]. 3.6. Risk of lymphoma in the combination therapy group versus The unexposed to IMM or ATAs group Eight studies evaluated the association between exposure to combination therapy and lymphoma risk. The IR in the combination group was 8.18 cases per 10000 person-years [95% CI, 5.54–10.81] The IRR and RR of lymphoma in the combination therapy group compared with the unexposed to IMM or ATAs group was 3.36 [random effects: 95% CI, 2.23–5.05; P < 0.001] and 1.90 [random effects: 95% CI, 0.66–5.44; P = 0.233], respectively [Table 4; and Supplementary Figure 4, available as Supplementary data at ECCO-JCC online]. 3.7. Risk of lymphoma in the combination therapy group versus the IMM monotherapy group Ten studies evaluated lymphoma risk of combination therapy exposure versus IMM monotherapy. The IRR and RR of lymphoma were both not significantly higher in the combination therapy group compared with the IMM monotherapy group [random effects: IRR = 1.47, 95% CI, 0.88–2.46; P = 0.142; random effects: RR = 0.83, 95% CI, 0.54–1.29; P = 0.416] [Table 4; and Supplementary Figure 5, available as Supplementary data at ECCO-JCC online]. 4. Discussion This meta-analysis pooled data of users and non-users of ATAs therapy from 10 cohort studies [seven prospective studies and three retrospective studies] and two RCTs, to systematically evaluate lymphoma risk of IBD patients treated with ATAs. It demonstrated no association between ATAs therapy and lymphoma in IBD patients. Subanalysis was conducted regarding geographical distribution, sample size, follow-up period, duration of IBD, type of IBD, age, lymphoma type, and study design. The results of subgroup analyses showed that patients with more than 5 years IBD duration period had increased risk of developing lymphoma, which indicated that the IBD disease itself might lead to malignancies. It was reported in a previous study that CD was associated with lymphoma in patients with no history of immunosuppressives.35 Consistently, a nationwide cohort study conducted by M. Fallah et al. confirmed the association between autoimmune diseases including IBD and a higher risk of non-Hodgkin lymphoma [NHL].36 Similar to this result, a population-based study on Korean patients showed an increased risk of NHL in both UC and CD.37 Protective effect was detected in patients with a more than 5 years follow-up period, which was inconsistent with previous studies. Due to the limited number of included studies in this analysis, long-term prospective studies are required for further investigation on this issue. Subgroup analysis revealed that age was not a confounding factor in the development of lymphoma, and neither CD nor UC was associated with increased lymphoma risk. No elevated risk of non-Hodgkin lymphoma [NHL] or Hodgkin lymphoma [HL] was detected, respectively. When we extracted information on the specific kinds of drugs taken by IBD patients, a significant difference of elevated risk of lymphoma was detected in the IMM monotherapy group, ATAs monotherapy group, and combination therapy group. No significance was identified in the combination therapy versus IMM monotherapy group. Thus, combination therapy, IMM monotherapy, and ATAs monotherapy can significantly increase the risk of lymphoma. The result of ATAs exposed versus ATAs non-exposed group in this meta-analysis is in accordance with several studies. No excess risk of lymphoma was observed in IBD patients treated with ATAs alone according to a 5-year, prospective, observational ENCORE registry following patients with CD in nine European countries. However, increased risk in further investigations with longer disease duration as well as longer follow-up period could not be excluded.29 Correspondingly, a study involving 6357 IBD patients reported no significantly increased risk of lymphoma with ATAs therapy. The study was limited by its composite measure of analysis, the relatively small sample size, and insufficient follow-up time, as well as duration of anti-TNFα therapy. Its lower incidence rate of lymphoma with ATAs therapy may be due to the selection of comparator therapy for the analysis of IBD, since thiopurines are associated with an increased odds of lymphoma.17 In line with these studies, a systematic review conducted in 2014 among paediatric patients with IBD has reached a similar conclusion.38 It mentioned that older age, sex, and duration of IBD have been associated with an increased risk of lymphoproliferative disorders and may help to explain the non-significantly increased risk of lymphoma in paediatric IBD patients exposed to ATAs therapy. Furthermore, an abundant number of studies on overall cancer risk in ATAs-treated IBD patients have not identified significance either.12,16,17,39–43 A nationwide register-based cohort study in Denmark involving 56146 patients with IBD showed no association between exposure to ATAs among patients with IBD and an increased risk of cancer. An increased risk of malignancy in studies with longer follow-up and increasing number of cumulative doses of ATAs cannot be excluded.33 There are several factors that may lead to the failure in detecting significance in the ATAs exposed versus ATAs non-exposed groups. First, as a slowly progressing disease with relatively rare occurrence, the incidence rate of cancers should be calculated in a cohort with long follow-up time and large sample size. Not all studies included in this group come with a long enough duration of observation and large enough sample size, though we tend to exclude short-term small studies in the selection process. As time to develop lymphoma was not available in published literature, increased risk in future longer-term studies with larger sample size cannot be excluded. Additionally, drug usage was not specified in this comparison. Patients in control and experiment groups could have had previous or concurrent exposure to other biologics or non-biologics. To improve the situation, four other comparisons with specific usage of medications were established. Contrary to these studies, several early studies of the same interest identified significance of lymphoma in IBD patients with ATAs therapy. The increasing reports of lymphoma cases in IBD patients with ATAs therapy in recent years are consistently suggesting an association between lymphoma and ATAs therapy in IBD.34,44–46 Besides, a review showed that the increasing number of reported cases of lymphoma with infliximab and adalimumab was suggesting an undeniable association of lymphoma development with the use of ATAs, though this risk was unquantifiable.47 Moreover, in a single-centre cohort study including 1222 IBD patients, lymphoma cases were identified in CD patients, and an increased risk was observed when using ATAs.35 Additionally, when compared with the general population, significant statistically increased risk of NHL was found in the ATAs therapy group of CD in a meta-analysis conducted by Siegel et al., though the absolute risk remained small [6.1 per10000 patient-years].13 However, limits of the article lay in the lack of an ideal comparison, since patients in the control group were exposed to thiopurines inevitably, which might be a confounding factor for the study on ATAS monotherapy. It is worthy to mention that a cohort study published in 2017,34 which was included in this meta-analysis, detected a small but statistically significant increased risk of lymphoma with ATAs monotherapy in IBD. Lymphoma risk was higher with combination therapy than with ATAs monotherapy or IMM monotherapy. The elevated risk of lymphoma in the ATAs monotherapy group and combination group in this analysis isconsistent with the above studies. ATAs are widely used in the treatment of IBD for their efficiency in alleviating inflammation and maintaining long-term mucosal healing, resulting in decrease in both surgery risk and related complications. But their side effect of elevated risk of malignancies, including lymphoma, has arisen over time. It is universally acknowledged that chemicals, medications, and rapid cell turnover promote the progress of neoplastic transformation. Cell signal transduction can be changed by a disruption in the cell cycle check points, either through alterations in tumour suppressor genes and proto-oncogenes, or the DNA sequence itself. Active chronic inflammation, which initiates constant cell regeneration and rapid turnover, is experienced by IBD patients. ATAs may be the epigenetic factor which enables selective uncontrolled cell proliferation and thus initiation of lymphoma development in the genetically susceptible.47 As it is shown in this analysis that both ATAs monotherapy and IMM monotherapy can increase the risk of lymphoma, the significant difference identified in the combination therapy group can be the result of IMM alone, or ATAs alone, or the synergistic effect of IMM and ATAs. Since higher risk was identified with combination therapy than with IMM or ATAS monotherapy in the large nationwide cohort conducted in 2017, increased risks associated with each of these treatments used alone may accumulate when they are combined.34 As it was verified in previous publications that therapy with IMM can increase risk of malignancies, the elevated risk identified in the IMM group versus the never exposed to IMM or ATAs group in this analysis is therefore reasonable, and corresponds with previous studies. With several strengths, the conclusion of this meta-analysis is reasonable. First, this meta-analysis included latest researches on IMM and ATAs use in IBD patients, abstracting information on different therapies in clinical practice and information on cases of lymphoma manually. Medications were specified and four comparisons were established to systematically evaluate risk of lymphoma in combination therapy and ATAs monotherapy, which set a precedent in giving an overview of the issue. Second, RCTs and cohort studies were both included in the pooled analysis, resulting in a more effective conclusion. The traits of either study type can be interpreted separately. The 10 cohort studies included were conducted in an unselected and well-defined IBD population, and complete history for all patients could be obtained, hence avoiding user bias. Regarding the two RCTs, with strict inclusion and exclusion criteria, the combination of blind, control, and randomisation methods, and definite diagnosis standards, they can present a more reliable result with less selection bias. However, the strengths of this meta-analysis should be weighed against a number of limitations. First, medications of ATAs could be monotherapy with IFX or combination therapy of different kinds of ATAs, since we could not evaluate the potential risks of IFX, ADA, and certolizumab pegol [CTZ] separately, which might obscure the true relationship of lymphoma with any specific kind of ATA. Second, limitation arises due to the characteristics of the included literature. It has been reported in several articles that a certain amount of exposure to radiation48 is a risk factor for developing cancers in IBD patients. Nevertheless, this confounding factor was not well controlled in some of the included studies, and thus we were unable to subanalyse it in this meta-analysis. The outcome might be biased as we failed to exclude certain high-risk populations. Moreover, data evaluating lymphoma risk with various drug doses in published literature was insufficient for further investigation, and therefore we did not include this factor in subgroup analysis. Third, studies included were only conducted in the USA or Europe or the combination of both regions. The inclusion of patients with specific nationality can hinder this meta-analysis in reaching a universal conclusion. Despite the limitations of our meta-analysis, its conclusion is still of importance in clinical practice. The concerns by patients and providers over side effects of treatments for IBD and the fear of developing cancer have been causing great emotional barriers to their use. The result of this meta-analysis, corresponding with other researches focusing on the same issue, has a synergistic effect upon a more reasoned and definite elucidation by physicians towards patients. The conclusions reaffirmed the increased risk of lymphoma in IMM monotherapy, ATAs monotherapy, and combination therapy, which provides physicians and patients with more definite evidence in balancing the efficiency and deficiency of drugs for IBD. Large, long-term, prospective cohort studies and RCTs are expected to assess the incidence ratio of the rare occurrence of lymphoma. In conclusion, exposure to ATAs among patients with IBD was not associated with an increased risk of lymphoma in this systematic review and meta-analysis. However, combination therapy or ATAs monotherapy can increase the risk of lymphoma in patients with inflammatory bowel disease. Further prospective data are required for a more accurate assessment. Funding This work was supported by the National Natural Science Foundation of China [Grant Number: 81300370 to SD], and the China Postdoctoral Science Foundation [Grant Number: 2017M622650 to SD]. Conflict of Interest The authors report no conflicts of interest. Author Contributions CY and JH have contributed equally to this work. SD and CY were responsible for study design, article retrieval, article selection, and data analysis. JHg and SH were responsible for data acquisition and data analysis. 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Desmond AN, O’Regan K, Curran C, et al.   Crohn’s disease: factors associated with exposure to high levels of diagnostic radiation. Gut  2008; 57: 1524– 9. Google Scholar CrossRef Search ADS PubMed  Copyright © 2018 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Crohn's and ColitisOxford University Press

Published: May 12, 2018

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