Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After Ileocolonic Resection

Regueiro, Miguel; Feagan, Brian G.; Zou, Bin; Johanns, Jewel; Blank, Marion; Chévrier, Marc; Plevy, Scott E.; Popp, John; Cornillie, Freddy; Sandborn, William J.; Rutgeerts, Paul; Debinski, Henry; Florin, Tim; Hetzel, David J.; Lawrance, Ian C.; Radford‐Smith, G.; Sloss, Andrew; Sorrentino, Dario; Gassner, S; Haas, T; Reicht, G; Reinisch, Walter; Straßer, Michael; Vogelsang, Harald; Bossuyt, Peter; Dewit, Olivier; Franchimont, Denis; Louis, Édouard; Vermeire, Séverine; Bernstein, Çharles N.; Bourdages, Raymond; Chiba, Naoki; Dhalla, Sonny S; Fedorak, Richard N.; Lachance, Jean-René; Panaccione, Remo; Ropeleski, Mark J.; Salh, Baljinder; Lukáš, Milan; Colombel, J.F.; Allez, Matthieu; Desreumaux, Pierre; Dupas, Jean Louis; Grimaud, J. C.; Hébuterne, Xavier; Laharie, David; Lerebours, Éric; Peyrin–Biroulet, Laurent; Reimund, Jean‐Marie; Viennot, Stéphanie; Zerbib, Frank; Antoni, C; Atreya, Raja; Baumgart, Daniel C.; Berg, Christoph; Boecker, Ulrich; Bramkamp, G.; Bünning, C.; Ehehalt, Robert; Howaldt, S; Kucharzik, Torsten; Lamprecht, Hein; Mudter, Jonas; Preiß, J; Schreiber, Stefan; Seidler, Ursula; Altorjay, István; Banai, János; Lakatos, László; Varga, Márta; Vincze, Áron; Avni-Biron, Irit; Fishman, Sigal; Fraser, Gerald; Goldin, Ehud; Rachmilewitz, Daniel; Annese, Vito; Ardizzone, Sandro; Biancone, Livia; Bossa, Fabrizio; Danese, Silvio; Fries, Walter; Gionchetti, Paolo; Maconi, Giovanni; Terrosu, Giovanni; Usai, Paolo; D’Haens, Geert R.; Gearry, Richard B.; Hill, Jeffrey; Rowbotham, David; Schultz, Michael; Stubbs, R. S.; Wallace, Daniel F.; Walmsley, Russell; Wyeth, John; Małecka‐Panas, Ewa; Paradowski, Leszek; Reguła, Jarosław; Beales, Ilp; Campbell, Simon; Hawthorne, A. B.; Parkes, Miles; Travis, Simon; Achkar, Jean Paul; Behm, Brian W.; Bickston, Stephen J.; Brown, K. J.; Chiorean, Michael; deVilliers, Willem; Elliott, David E.; Grunkmeier, D.; Hamilton, J.W.; Hanauer, Stephen B.; Hanson, John S.; Hardi, Robert; Helper, Debra J.; Herfarth, Hans H; Higgins, Peter; Holderman, William; Kottoor, Ravindranath; Kreines, Michael; Leman, Bernard I.; Li, X.; Loftus, Edward V.; Noar, Mark D.; Oikonomou, Ioannis; Onken, Jane E.; Peterson, KH; Phillips, Rebecca; Randall, Charles; Ricci, Massimo; Ritter, Timothy E.; Rubin, David T.; Safdi, Michael; Sauberman, Lisa; Scherl, Ellen; Schwarz, Richard P.; Sedghi, Shahriar; Shafran, Ira; Sninsky, Charles A.; Stein, Irving F.; Swoger, Jason M.; Vecchio, James; Weinberg, David I.; Wruble, Lawrence D.; Yajnik, Vijay; Younes, Ziad

doi:10.1053/j.gastro.2016.02.072

Cited by 270 publications

(176 citation statements)

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“…In 3 small randomized controlled trials, anti-TNFs compared with placebo or mesalazine were highly effective in preventing endoscopic recurrence in CD patients at high and low risk of recurrence [18,21]. This finding was recently confirmed by the results of the PREVENT study, in which the rates of endoscopic recurrence, prior to or at week 76, were 30.6 and 60% in the infliximab and placebo groups, respectively ( p < 0.001) [22]. …”

Section: Discussionmentioning

confidence: 93%

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Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting

Allocca¹,

Landi

Bonovas³

et al. 2017

Digestion

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Background: Most Crohn's disease (CD) patients develop endoscopic recurrence within one year of intestinal resection. The best treatment method to prevent post-operative CD recurrence remains uncertain. Methods: A total of 155 CD patients from 2 referral centres, who were undergoing intestinal resection with ileo-colonic anastomosis (January 2004-January 2015), were included. All subjects received preventive therapy with tumour necrosis factor antagonists (anti-TNFs), thiopurinesor mesalazine. The primary outcome was the rate of endoscopic recurrence (Rutgeerts score ≥i2) in the 3 treatment groups. Results: Patients treated with anti-TNFs were at significantly lower risk of endoscopic recurrence during the follow-up than those receiving thiopurines or mesalazine (incidence rates of 2.2, 3.0 and 4.8 per 100 person-months, respectively, log-rank, p = 0.011). The median time to recurrence was significantly longer in patients treated with anti-TNFs than in those who received thiopurines or mesalazine (37.0, 13.7, and 16.8 months, respectively, log-rank, p = 0.011). Anti-TNFs were more effective than mesalazine (univariable analysis, hazard ratio [HR] 0.45, 95% CI 0.26-0.77, p = 0.004; multivariable analysis, HR 0.45, 95% CI 0.26-0.77, p = 0.004), and non-significantly superior over thiopurines. Conclusion: Anti-TNF therapy was the most effective strategy for the prevention of endoscopic CD recurrence.

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Section: Discussionmentioning

confidence: 93%

“…Recently, infliximab has been shown to be more effective than placebo in preventing endoscopic but not clinical recurrence [22]. The POCER study showed that a strategy based on endoscopic lesions rather than clinical symptoms is effective for the prevention and treatment of post-operative recurrence, at least in high-risk patients [23].…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting

Allocca¹,

Landi

Bonovas³

et al. 2017

Digestion

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“…The PREVENT trial showed an efficacy of infliximab vs placebo in preventing endoscopic POR at 18 months, although this was not the case for its primary outcome, namely clinical POR. 7 The effect of infliximab was lower than expected, according to the pilot study by Regueiro et al, 3 which could be explained by differences in study populations. The first study concerned 24 high-risk patients, whereas in PREVENT a wider group of less risky patients was included.…”

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confidence: 86%

“…Furthermore, in APPRECIA, the estimated drop-out rate of 10% was clearly underestimated [26% in PREVENT; 15% in POCER]. 7,8 Second, Lopez-Sanroman et al chose to include all operated patients, without taking into account risk factors for POR like active smoking, previous resection, or penetrating disease. Although these risk factors have not been validated in a prospective setting, retrospective studies repeatedly showed their implication in POR.…”

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confidence: 99%

“…3 Although the recently published PREVENT study also showed a significant difference between infliximab and placebo, the difference was much smaller, with 22% of POR in the infliximab group and 51% in the placebo group [delta 29%, p < 0.001]. 7 In both trials, POR was defined as a Rutgeerts' score of at least i2. Furthermore, in APPRECIA, the estimated drop-out rate of 10% was clearly underestimated [26% in PREVENT; 15% in POCER].…”

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confidence: 99%

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Management of Postoperative Crohn’s Disease: Missing Pieces of the Puzzle

Rivière

Ferrante

2017

Journal of Crohn's and Colitis

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Despite the development of biological therapy, surgery is still needed in patients with refractory or complicated Crohn's disease. Thirty years ago, Rutgeerts et al. showed that postoperative clinical recurrence occurred early, affecting already one in five patients at 1 year, with endoscopic lesions preceding symptoms.1 Prevention and treatment of postoperative recurrence [POR] are important to avoid multiple resections and bowel destruction. Both thiopurines and antibodies targeting tumour necrosis factor [TNF] proved to prevent the development of postoperative endoscopic recurrence. 2,3 However, data on thiopurines in this setting are scarce and a Cochrane meta-analysis, published in 2014, could not conclude on a superiority of thiopurines over placebo. 4 Although indirect evidence suggested a better outcome with anti-TNF therapy, no head-to-head trials existed in order to choose between these two options.In that regard, the APPRECIA study─published in this issue of Journal of Crohn's and Colitis─is an interesting work addressing the head-to-head comparison of azathioprine [AZA] vs adalimumab [ADM] in the prevention of postoperative endoscopic recurrence. 5In this randomised controlled open-label study, 84 patients were randomised to receive either AZA 2.5 mg/kg body weight or ADM [160/80 mg induction and 40 mg fortnightly thereafter] within 2 weeks after the surgery. The primary endpoint was postoperative endoscopic recurrence at 1 year, defined as a modified Rutgeerts' score of at least i2b─more than five aphthous ulcers or larger lesions in the neoterminal ileum with normal mucosa in between [with or without anastomotic lesions]. 6 The superiority of ADM could not be proven: endoscopic recurrence rate in the AZA group was 59% [23/39] vs 42% [19/45] in the ADM group [p = 0.12].Although the study had a good design, it seems difficult to draw strong conclusions from these probably underpowered data. For their sample size calculation, the authors expected a 35% difference in POR between ADM and AZA groups. This was based on the tremendous effect of infliximab observed in the pilot study by Regueiro et al., with only 9% of POR at 1 year in the infliximab group vs 85% in the placebo group [delta 76%, p = 0.0006].3 Although the recently published PREVENT study also showed a significant difference between infliximab and placebo, the difference was much smaller, with 22% of POR in the infliximab group and 51% in the placebo group [delta 29%, p < 0.001].7 In both trials, POR was defined as a Rutgeerts' score of at least i2. Furthermore, in APPRECIA, the estimated drop-out rate of 10% was clearly underestimated [26% in PREVENT; 15% in POCER]. 7,8 Second, Lopez-Sanroman et al. chose to include all operated patients, without taking into account risk factors for POR like active smoking, previous resection, or penetrating disease. Although these risk factors have not been validated in a prospective setting, retrospective studies repeatedly showed their implication in POR.9 In POCER, the benefit of endoscopy-driven tr...

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Management of Crohn Disease

Cushing

Higgins

2021

JAMA

220

117

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ImportanceCrohn disease, a chronic gastrointestinal inflammatory disease, is increasing in incidence and prevalence in many parts of the world. Uncontrolled inflammation leads to long-term complications, including fibrotic strictures, enteric fistulae, and intestinal neoplasia. Therefore, early and effective control of inflammation is of critical importance.ObservationsThe optimal management approach for Crohn disease incorporates patient risk stratification, patient preference, and clinical factors in therapeutic decision-making. First-line therapy generally consists of steroids for rapid palliation of symptoms during initiation of anti–tumor necrosis factor α therapy. Other treatments may include monoclonal antibodies to IL-12/23 or integrin α4β7, immunomodulators, combination therapies, or surgery. Effective control of inflammation reduces the risk of penetrating complications (such as intra-abdominal abscesses and fistulae), although more than half of patients will develop complications that require surgery. Adverse reactions to therapy include antibody formation and infusion reactions, infections, and cancers associated with immune modulators and biologics and toxicity to the bone marrow and the liver. Both Crohn disease and corticosteroid use are associated with osteoporosis. Vaccinations to prevent infections, such as influenza, pneumonia, and herpes zoster, are important components of health maintenance for patients with Crohn disease, although live vaccines are contraindicated for patients receiving immune suppression therapy.Conclusions and RelevanceThe treatment of patients with Crohn disease depends on disease severity, patient risk stratification, patient preference, and clinical factors, including age of onset and penetrating complications, and includes treatment with steroids, monoclonal antibody therapies, immunomodulators, and surgery. Physicians should be familiar with the advantages and disadvantages of each therapy to best counsel their patients.

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Infliximab Reduces Endoscopic, but Not Clinical, Recurrence of Crohn’s Disease After Ileocolonic Resection

Abstract: Infliximab is not superior to placebo in preventing clinical recurrence after CD-related resection. However, infliximab does reduce endoscopic recurrence. ClinicalTrials.gov ID NCT01190839.

Cited by 270 publications

References 52 publications

Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting

Effectiveness of Mesalazine, Thiopurines and Tumour Necrosis Factor Antagonists in Preventing Post-Operative Crohn's Disease Recurrence in a Real-Life Setting

Management of Postoperative Crohn’s Disease: Missing Pieces of the Puzzle

Management of Crohn Disease

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