Comparing adalimumab and infliximab in the prevention of postoperative recurrence of Crohn’s disease: a systematic review and meta-analysis

Manesh Kumar Gangwania*, Mohamad Nawrasa*, Muhammad Azizb, Anooja Ranic, Fnu Priyankad, Dushyant Singh Dahiyae, Zohaib Ahmeda, Amir Humza Sohailf, Rahul Karnag, Wade Lee-Smithh, Faisal Kamali, Abdallah Kobeissyb, Yaseen Alastalb

University of Toledo Medical Center, Toledo, Ohio, USA; Dow University of Health Sciences, Karachi, Pakistan; Shaheed Mohtarma Benazir Bhutto University, Larkana, Pakistan; Central Michigan University College of Medicine, Saginaw, MI, USA; New York University Langone Health, Long Island, NY, USA; Alleghany General Hospital, PA, USA

aDepartment of Medicine, University of Toledo Medical Center, Toledo, Ohio, USA (Manesh Kumar Gangwani, Mohamad Nawras, Zohaib Ahmed); bDivision of Gastroenterology and Hepatology, University of Toledo Medical Center, Toledo, Ohio, USA (Muhammad Aziz, Abdallah Kobeissy, Yaseen Alastal); cDepartment of Medicine, Dow University of Health Sciences, Karachi, Pakistan (Anooja Rani); dDivision of Medicine, Shaheed Mohtarma Benazir Bhutto University, Larkana, Pakistan (Fnu Priyanka); eDepartment of Medicine, Central Michigan University College of Medicine, Saginaw, MI, USA (Dushyant Singh Dahiya); fDepartment of General Surgery, New York University Langone Health, Long Island, NY, USA (Amir Humza Sohail); gDepartment of Medicine, Alleghany General Hospital, PA, USA (Rahul Karna); hUniversity of Toledo Libraries, University of Toledo, Toledo, Ohio, USA (Wade Lee-Smith); iDivision of Gastroenterology, University of San Francisco, San Francisco, USA (Faisal Kamal)

Correspondence to: Manesh Kumar Gangwani, MD, Division of Medicine, University of Toledo Medical Center, 3000 Arlington Avenue, Toledo, OH, 63141 USA, e-mail:
* Co-first authors
Received 16 November 2022; accepted 17 January 2023; published online 03 April 2023
© 2023 Hellenic Society of Gastroenterology


Background Crohn’s disease is a relapsing disease that often requires operative management. Prevention of postoperative recurrence (POR) is critical to maintain remissions. Biologic agents have proven to be most successful in remission maintenance. We made a direct head-to-head comparison of the 2 anti-tumor necrosis factor agents, infliximab (IFX) and adalimumab (ADA), to compare endoscopic and clinical POR of Crohn’s disease.

Methods We conducted a comprehensive literature search in 7 databases, including Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science Core Collection, KCI-Korean Journal Index, SciELO, and Global Index Medicus. Odds ratios (OR) were calculated with 95% confidence intervals (CI) and P-values (<0.05 considered significant). We evaluated the total rates of endoscopic recurrence, endoscopic recurrence at 1 year, and clinical recurrence rates of IFX and ADA in a direct head-to-head comparison.

Results The search strategy yielded a total of 393 articles. Three studies with a total of 268 participants were included. Our meta-analysis showed no statistically significant difference in total endoscopic recurrence rate between ADA and IFX (27.1% vs. 32.3%, OR 0.696, 95%CI 0.403-1.201; P=0.193; I2=0%). Nor was there any significant difference between the drugs in endoscopic recurrence rate at 1 year (OR 0.799, 95%CI 0.329-1.940; P=0.620) or clinical recurrence rate (OR 0.477, 95%CI 0.477-1.712; P=0.755).

Conclusions ADA and IFX show comparable efficacy in preventing POR endoscopically and clinically. The clinical decision should be based on cost, side-effects, tolerability, and patient preferences. Additional studies, particularly randomized controlled trials, are needed to determine generalizability.

Keywords Postoperative recurrence, Crohn’s disease, adalimumab, infliximab, biologics

Ann Gastroenterol 2023; 36 (3): 293-299


Crohn’s disease (CD) is a chronic inflammatory bowel disease (IBD) with a relapsing and remitting nature and a disabling progression with complications such as intestinal strictures, enteric fistulae, inflammatory masses, or abscesses [1]. Although rates of surgical management are declining over the years, as newer biological therapies emerge, surgical management is still warranted in a significant proportion of patients within 10 years of diagnosis [2]. Considering the disease process, postoperative recurrence (POR) remains high, with clinical recurrence rates at around 30-60% within 3-5 years, and a significant percentage of patients may require a second resection within 5 years [3]. Endoscopic recurrence with mucosal lesions can be up to 70% occurring within 1 year of surgery, and histologic recurrence can occur as early as 1 week after surgery. The rates of POR are even higher in high-risk patients such as smokers, cases of early diagnosis, or those with a history of perianal disease or prior intestinal resection [4]. Endoscopic POR severity correlates fairly well with the likelihood of developing clinical POR in the near future and can serve as a surrogate marker for the risk of clinical POR to drive therapeutic decisions in clinical practice [2].

There have been a variety of therapeutic agents evaluated to prevent POR endoscopically and clinically to induce and maintain remission, though with inconsistent results. Postoperative prophylaxis with anti-tumor necrosis factor (TNF) agents or thiopurines (azathioprine, 6-mercaptopurine) has been shown in the literature to reduce the risk of POR [5]. Anti-TNF agents, such as adalimumab (ADA), a self-injected, fully humanized recombinant monoclonal antibody, and infliximab (IFX), a chimeric immunoglobulin G human (75%)/murine (25%) administered by intravenous infusion, have been shown to be effective in preventing endoscopic and clinical POR [3,6]. According to a recent meta-analysis, anti-TNF therapy outperformed other therapeutic strategies, including thiopurines, but the study did not include a direct comparison between anti-TNF therapies [7].

Considering the better outcomes of biologics compared to other therapeutic strategies, as seen in various studies, we aimed to make a head-to-head direct comparison between the most commonly used biologics, ADA and IFX, to evaluate their efficacy in preventing POR endoscopically and clinically, with a view to optimizing therapeutic management strategies.

Materials and methods

Search strategy

The “Meta-analysis of observational studies (MOOSE)” guidelines for systematic reviews were used to plan the study; we adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines; no language restriction was applied [8,9]. A comprehensive literature search from inception through September 9th 2022 was conducted using the Medline (PubMed, NCBI), Embase (, Elsevier), Cochrane Central Register of Controlled Trials (Cochrane Library, Wiley), Web of Science Core Collection, KCI-Korean Journal Index, SciELO (Web of Science, Clarivate), and Global Index Medicus (World Health Organization) databases. An experienced librarian (WLS) assisted with the search methodology. The core concepts of “Crohn’s disease”, “infliximab”, “adalimumab”, “recurrence or remission” and the postoperative period, and their corresponding subject heading terms, were searched in the above databases (Supplementary Table 1). We added manual searching and cross-referencing to the computerized literature search. Results were exported to EndNote 20 (Clarivate, Philadelphia, Pennsylvania, United States) and duplicates were removed by successive algorithmic deduplication and manual inspection.

Inclusion and exclusion criteria

We limited the screening to include randomized controlled trials (RCTs) and observational studies with head-to-head comparisons between ADA and IFX. Outcomes assessed included clinical recurrence rate, endoscopic recurrence at 1 year and overall endoscopic recurrence. Abstracts were included in the search strategy, as we anticipated a lower number of full-text studies overall. We excluded case reports, case series (<10 patients), editorials, guidelines and review articles.

Study definitions

Study definitions, including endoscopic recurrence and clinical recurrence of each study, are described in Supplementary Table 2.

Screening and data extraction

Two independent investigators (FP and DSD) conducted the screening and data extraction. Conflict resolution was achieved through mutual discussion. Initially, titles and abstracts were screened, followed by full texts. Data pertaining to technical and clinical success rates, adverse events, length of hospital stay, and procedure time were recorded using Microsoft Excel (Microsoft, Redmond, Washington, United States).

Data synthesis and statistical analysis

Statistical analysis was performed using Open Meta-Analyst (CEBM, University of Oxford, Oxford, United Kingdom). We calculated the pooled rates of each outcome. Dichotomous variables were compared using the odds ratio (OR) with a 95% confidence interval (CI) and P-value (<0.05 was considered statistically significant). We used the random effects model and DerSimonian-Laird method for pooling data [10]. Study heterogeneity was calculated with the I2 statistic, in which values of 0%, 25%, 50%, and 75% indicate absent, low, moderate and high heterogeneity, respectively.

Bias assessment

A risk-of-bias assessment for the observational studies was performed using the Newcastle-Ottawa scale. One study was a randomized control trial and the risk of bias for RCTs was assessed using the Cochrane risk-of-bias tool [11,12]. Funnel plots were used for the qualitative and Egger regression tests for the quantitative analysis of publication bias; a P-value of <0.05 was considered significant for the latter.


Baseline study characteristics

The search strategy yielded a total of 393 articles. From these, 286 studies were screened by title and abstract, leaving 116 studies for full text screening after removal of duplicates. Three studies with 268 participants [1,13,14], 144 in the ADA group and 124 in the IFX group, were selected for final inclusion after strict inclusion and exclusion criteria had been applied (Fig. 1). No abstracts met the inclusion criteria to be included in final analysis. The studies were published between 2014 and 2019. The mean age of participants ranged from 30.5-41.1 years; 115 (42.9%) of the subjects were female (69 in ADA and 46 in IFX group) and 153 (57.1%) were male (75 in ADA and 78 in IFX group), as described in Table 1. The duration of disease ranged from 48-84 months; 19.7% participants had a history of smoking, 41.5% had prior resections, 68.3% had previous biologic use, and 30.2% subjects had history of perianal disease (Table 2).


Figure 1 PRISMA flowchart of included studies

Table 1 Baseline characteristics of included studies


Table 2 Characteristics of included studies



Our meta-analysis showed no difference in the total endoscopic recurrence rate between ADA and IFX (27.1% vs. 32.3%, OR 0.696, 95%CI 0.403-1.201; P=0.193; I2=0%) in 3 studies (Fig. 2A). Two studies evaluated endoscopic recurrence at 1 year and no statistically significant difference was found between the 2 groups (21.3% vs. 26.1%, OR 0.799, 95%CI 0.329-1.940; P=0.620; I2=0%) as shown in Fig. 2B. There was no significant difference in overall clinical recurrence rates between the 2 groups (18.1% vs. 18.5%, OR 0.477, 95%CI 0.477-1.712; P=0.755; I2=0%) as shown in Fig. 2C.


Figure 2 (A) Comparing endoscopic recurrence rate between IFX and ADA. (B) Comparing endoscopic recurrence rate between IFX and ADA at 1 year. (C) Comparing clinical recurrence rate between IFX and ADA

ADA, adalimumab; IFX, infliximab; CI, confidence interval

Risk of bias

Evaluation of publication bias using funnel plots and Egger’s regression was impractical because of the low number of studies. Two studies were assessed using the Newcastle-Ottawa scale (Table 3). The score was 7, reflecting a moderate to high quality of studies. The risk of bias for the one RCT was determined to be high, because of its open label format with unblinded clinical and endoscopic evaluations.

Table 3 Newcastle-Ottawa scale for illustration of quality of studies



In a direct head-to-head comparison between the biologics, ADA and IFX did not yield any statistically significant difference in endoscopic or clinical recurrence rate. The study characteristics and risk factors were similar in both groups. The recurrence of CD post-surgery has been under investigation for many decades. Postoperative prophylaxis has been greatly studied, with a variety of therapeutic classes. Current guidelines for initiation of postoperative prophylaxis are variable [2,15]. The latest American Gastroenterology Association guidelines recommend using preoperative risk stratification to consider POR therapy with anti-inflammatory monoclonal antibodies in high-risk patients, including those aged <30, smokers and those with >2 prior surgeries [16]. IBD guidelines from the European Crohn’s and Colitis Organization include additional risk factors, such as extensive small bowel resection (>50 cm), perianal disease, histologic evidence of granulomas or myenteric plexitis on resected specimens [15].

Tursi et al observed that active smoking, penetrating disease and previous surgery all significantly increased the possibility of postoperative relapse [13]. Cañete et al determined that pan-colonic involvement, rectal involvement and perianal disease were significantly associated with endoscopic POR in a univariate analysis [1]; however, only rectal involvement and a history of perianal disease were shown to be independent risk factors in a multivariate analysis.

The determination and reduction in postoperative endoscopic recurrence rates are critical in managing risk, as these rates can serve as an essential marker to prevent future clinical recurrences. Postoperative recurrence rates have been variable in the literature, as a result of advances in pre- and postoperative therapeutics over the years [15]. Our overall postoperative endoscopic recurrence rate for any biologic use was noted to be 29.4%. Our results are similar to those of large independent studies evaluating anti-TNF therapies. In the Prevent trial, which evaluated IFX, a postoperative endoscopic recurrence rate of 22% was reported, similar to our finding of 27.1% in the IFX group [17]. Similarly, in the Apprecia trial, which evaluated ADA, the postoperative endoscopic recurrence rate was 33%, similar to our results at 32.3% [18]. Regarding the efficacy of anti-TNF agents to treat recurrent disease, a study by Preda et al, which compared ADA and IFX in treating POR, showed a complete remission in 68% of patients over long-term follow up, with an endoscopic recurrence of 35% and re-resection rate 11.7% [5].

Both therapeutic options are reasonable and have their individual merits, and decisions should be based on individual patient characteristics and availability. Both therapies have relatively similar side-effect profiles. Including cutaneous musculoskeletal complications or pruritus, dyspnea, urticaria or skin reactions, with some risk of opportunistic infections. Theoretically, ADA can be considered less immunogenic, as it is fully humanized compared to IFX, a chimeric antibody. Therefore, it can potentially be expected to be associated with fewer side-effects and opportunistic infections; however, there are few publications that evaluate the comparison [19].

Patient factors, costs and logistics may also play an important role in therapeutic determination. IFX is an intravenous infusion lasting about 2 h, whereas ADA is a self-administered subcutaneous injection, potentially favoring better compliance and ease of logistics [20]. Cañete et al observed that the time to the start of treatment with IFX was significantly longer than with ADA, but this had no effect on treatment efficacy [1]. The most likely explanation for this difference in timing is that IFX has more logistical requirements than ADA, including the need for an infusion unit, which may delay the first administration of the drug [1]. There are no direct postoperative cost analysis comparisons in relation to POR. Previous studies of anti-TNF use in ulcerative colitis have showed that induction and maintenance therapy with IFX or ADA were less expensive than standard care when administered for 1 or 2 years only. In one review, induction and maintenance treatment with ADA was less expensive than IFX infusions. However, these cannot be extrapolated to the postoperative CD population, given the variation in therapy duration and the complex nature of the pharmaceutical and insurance coverage systems in the United States [20].

In patients with a high risk of POR, especially after failed anti-TNF therapy, combination therapy of a biologic agent with an immunomodulator could be a reasonable treatment strategy. In a recent study by Huinink et al, patients with preoperative anti-TNF treatment failure demonstrated a lower treatment failure rate at 2 years postoperatively under combination therapy of anti-TNF with an immunomodulator compared to anti-TNF monotherapy (30% vs. 49%, P=0.02) [21].

For newer biologics, such as ustekinumab and vedolizumab, there are only limited data evaluating their role in POR [22]. One retrospective study, which evaluated 22 patients with CD receiving vedolizumab compared with 58 patients who received anti-TNF for POR prophylaxis, demonstrated that patients in the vedolizumab group were at greater risk of endoscopic recurrence (75% vs. 34.2%, P=0.005) [23]. In another propensity-matched analysis, endoscopic POR was lower for ustekinumab than for azathioprine (28% vs. 54.5%, P=0.03) with rates similar to other anti-TNF medications, but the data were insufficient to suggest any definitive superiority [24].

Our study had various limitations. We did not stratify for potential risk factors or their impact on our analysis, as the data were too limited for meaningful cumulative analysis. There were only 2 studies evaluating endoscopic recurrence at one year for comparative analysis. Some studies have shown anti-TNF therapy to be effective in patients who are biologic-naïve, with lower reoperation rates, but not in patients who had failure of biologic therapy prior to surgery. Given the limited data and heterogeneity, we could not stratify for prior therapeutic classes or any history of biologic failure when comparing 2 outcomes [25]. Additionally, we could not include other newer biologics, such as ustekinumab or vedolizumab, since direct comparator data were not available [25]. Data to compare adverse event rates were limited or unavailable. The length of follow up was variable among the studies; therefore, we added a 1-year cutoff for endoscopic recurrence, so as to have a homogenous cutoff point as an outcome.

Our review is the first and only head-to-head direct comparison between IFX and ADA therapy for preventing POR in patients with CD. We believe both therapies have comparable efficacy in preventing POR endoscopically and clinically. The clinical decision should be based on costs, side-effect profile, tolerability and patient preferences. Additional studies, particularly large RCTs, should be performed to determine generalizability, assess the role of anti-TNF in combination with thiopurines to reduce POR and evaluate the newer biologics.

Summary Box

What is already known:

  • Crohn’s disease has endoscopic recurrence in up to 70% of patients, occurring within 1 year of surgery, and histologic recurrence can occur as early as 1 week after surgery

  • A variety of therapeutic agents have been evaluated to prevent postoperative recurrence endoscopically and clinically, and to induce and maintain remission

  • Anti-tumor necrosis factor (TNF) agents, including adalimumab (ADA) and infliximab (IFX), are superior to other therapeutic agent

  • There has been no direct head-to-head comparison between these 2 anti-TNF agents

What the new findings are:

  • ADA and IFX have comparable efficacy in preventing postoperative recurrence endoscopically and clinically

  • The clinical decision should be based on costs, side-effect profile, tolerability, and patient preferencesy

  • Large randomized controlled trials should be performed to determine the generalizability of these findings and the role of anti-TNF agents in combination with thiopurines


1. Cañete F, Mañosa M, Casanova MJ, et al;ENEIDA registry by GETECCU. Adalimumab or infliximab for the prevention of early postoperative recurrence of Crohn disease:results from the ENEIDA registry. Inflamm Bowel Dis 2019;25:1862-1870.

2. Frolkis AD, Dykeman J, Negrón ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time:a systematic review and meta-analysis of population-based studies. Gastroenterology 2013;145:996-1006.

3. Doherty GA, Cheifetz AS. Targeting TNF in postoperative recurrence of Crohn's disease:can we extinguish the fire before it starts?Inflamm Bowel Dis 2009;15:1925-1926.

4. Shah RS, Click BH. Medical therapies for postoperative Crohn's disease. Therap Adv Gastroenterol 2021;14:1756284821993581.

5. Preda CM, Fulger LE, Negreanu L, Manuc M, Sandra I, Diculescu MM. Adalimumab versus infliximab in treating post-operative recurrence of Crohn's disease:a national cohort study. Rev Esp Enferm Dig 2016;108:642-647.

6. Sedger LM, McDermott MF. TNF and TNF-receptors:From mediators of cell death and inflammation to therapeutic giants - past, present and future. Cytokine Growth Factor Rev 2014;25:453-472.

7. Yang Z, Ye X, Wu Q, Wu K, Fan D. A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease. Int J Surg 2014;12:516-522.

8. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology:a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-2012.

9. Page MJ, Moher D, Bossuyt PM, et al. PRISMA 2020 explanation and elaboration:updated guidance and exemplars for reporting systematic reviews. BMJ 2021;372:n160.

10. DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials 2015;45:139-145.

11. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-560.

12. Deeks JJ, Dinnes J, D'Amico R, et al;European Carotid Surgery Trial Collaborative Group. Evaluating non-randomised intervention studies. Health Technol Assess 2003;7:iii-x

13. Tursi A, Elisei W, Picchio M, et al. Comparison of the effectiveness of infliximab and adalimumab in preventing postoperative recurrence in patients with Crohn's disease:an open-label, pilot study. Tech Coloproctol 2014;18:1041-1046.

14. Kotze PG, Yamamoto T, Danese S, et al. Direct retrospective comparison of adalimumab and infliximab in preventing early postoperative endoscopic recurrence after ileocaecal resection for Crohn's disease:results from the MULTIPER database. J Crohns Colitis 2015;9:541-547.

15. Bemelman WA, Warusavitarne J, Sampietro GM, et al. ECCO-ESCP Consensus on surgery for Crohn's disease. J Crohns Colitis 2018;12:1-16.

16. Nguyen GC, Loftus EV Jr, Hirano I, Falck-Ytter Y, Singh S, Sultan S;AGA Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the management of Crohn's disease after surgical resection. Gastroenterology 2017;152:271-275.

17. Regueiro M, Feagan BG, Zou B, et al;PREVENT Study Group. Infliximab reduces endoscopic, but not clinical, recurrence of Crohn's disease after ileocolonic resection. Gastroenterology 2016;150:1568-1578.

18. López-Sanromán A, Vera-Mendoza I, Domènech E, et al;Spanish GETECCU group [APPRECIA study]. Adalimumab vs azathioprine in the prevention of postoperative Crohn's disease recurrence. A GETECCU randomised trial. J Crohns Colitis 2017;11:1293-1301.

19. Kestens C, van Oijen MG, Mulder CL, et al;Dutch Initiative on Crohn and Colitis (ICC). Adalimumab and infliximab are equally effective for Crohn's disease in patients not previously treated with anti-tumor necrosis factor-a agents. Clin Gastroenterol Hepatol 2013;11:826-831.

20. Yokomizo L, Limketkai B, Park KT. Cost-effectiveness of adalimumab, infliximab or vedolizumab as first-line biological therapy in moderate-to-severe ulcerative colitis. BMJ Open Gastroenterol 2016;3:e000093.

21. Ten Bokkel Huinink S, Beelen EMJ, Ten Bokkel Huinink T, et al;Dutch Initiative on Crohn and Colitis (ICC). Retreatment with anti-tumor necrosis factor therapy in combination with an immunomodulator for recurrence of Crohn's disease after ileocecal resection results in prolonged continuation as compared to anti-tumor necrosis factor monotherapy. Eur J Gastroenterol Hepatol 2023;35:45-51.

22. Hanzel J, Drobne D. Contemporary management of postoperative Crohn's disease after ileocolonic resection. J Clin Med 2022;11:6746.

23. Yamada A, Komaki Y, Patel N, et al. The use of vedolizumab in preventing postoperative recurrence of Crohn's disease. Inflamm Bowel Dis 2018;24:502-509.

24. Mañosa Ciria M, Fernandez-Clotet A, Hernández-Camba A, et al. P462 Efficacy of ustekinumab for the prevention of postoperative recurrence in Crohn's disease. Data from clinical practice from the eneida registry. J Crohns Colitis 2020;14(Suppl 1):S410.

25. Dasharathy SS, Limketkai BN, Sauk JS. What's new in the postoperative management of Crohn's disease?Dig Dis Sci 2022;67:3508-3517.


Conflict of Interest: None