REVIEW URRENT C OPINION
Complications and surgery in the inflammatory bowel diseases biological era Harry Sokol, Philippe Seksik, and Jacques Cosnes
Purpose of review Therapy for inflammatory bowel diseases (IBD) has changed dramatically in recent years with a wider use of immunomodulators and the introduction of antitumor necrosis factor (anti-TNF) agents. This article reviews the existing data on the long-term efficacy of biologics, that is, anti-TNF agents, for preventing complications and surgery in patients with IBD. Recent findings Anti-TNF agents are effective for preventing endoscopic and surgical recurrence after surgery for Crohn’s disease. They are able to achieve fistula closure and do not increase the risk of stricture. Most randomized short-term trials also showed decreased requirement for hospitalizations and surgery in patients receiving anti-TNF. However, observational studies from referral centers or based on population have shown conflicting results. The need for surgery in Crohn’s disease and the risk of colectomy in ulcerative colitis seem to be decreasing in recent years, but the specific effect of the introduction of anti-TNF agents cannot be currently evaluated. Summary Although anti-TNF agents are the most powerful drugs in IBD, their ability to decrease the need for surgery remains unclear. Conflicting results observed in observational surveys might be because of anti-TNF agents administered too late in the course of IBD. Keywords antitumor necrosis factor, complication, inflammatory bowel disease, surgery
INTRODUCTION Therapy for inflammatory bowel diseases (IBD) has changed dramatically in recent years with a wider use of immunomodulators and the introduction of antitumor necrosis factor (anti-TNF) agents. The efficacy of anti-TNF agents is superior to any of the prior drugs in the IBD armamentarium and has the power to rapidly heal the intestinal mucosa. However, their long-term impact on the development of IBD complications and whether they lead to a decreased necessity of surgery is not clear. AntiTNF agents do not cure IBD. Some patients do not respond to anti-TNF agents and others develop adverse reactions or lose their response over time. The disease recurs in half of the patients within a year following the withdrawal of the anti-TNF agent. Other biologics, such as ustekinumab and vedolizumab, are still in development, and their use in clinical practice is still too limited to evaluate their preventive effect on complications. However, they may be used in place of anti-TNF agents and allow for the postponement of a surgical decision. This www.co-gastroenterology.com
article reviews the existing data on the long-term efficacy of biologics, that is, the effect of anti-TNF agents in the prevention of complications and need for surgery both in patients with Crohn’s disease and ulcerative colitis.
COMPLICATIONS AND SURGERY BEFORE THE ERA OF BIOLOGICS Crohn’s disease is a chronic inflammatory bowel disorder generally characterized by a sequence of flare-up episodes and remissions of varying duration. Over time, in the majority of patients with Crohn’s disease, there is an evolution to fibrostenotic Service de Gastroente´rologie et Nutrition, Hoˆpital St-Antoine, et Universite´ Paris VI, Paris, France Correspondence to Professor Jacques Cosnes, Hoˆpital St-Antoine, 184 rue du Faubourg St-Antoine, Paris 75012, France. Tel: +33 1 49 28 31 70; fax: +33 1 49 28 31 88; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:378–384 DOI:10.1097/MOG.0000000000000078 Volume 30 Number 4 July 2014
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Complications, surgery and biologics in IBD Sokol et al.
KEY POINTS Anti-TNF agents are the most powerful drugs in IBD. Anti-TNF agents are able to achieve fistula closure and do not increase the risk of stricture in Crohn’s disease.
addressed in the RAPID trial. After 3 years, no difference was found between the conventional management group and the thiopurine treatment group regarding intestinal surgery; however, the development of perianal fistulas and the need for perianal surgery was less frequent in the experimental group [9 ]. For patients with ulcerative colitis, indications for colectomy include acute severe colitis that is unresponsive to intensive intravenous therapy, refractory chronic active disease, and development of neoplasia. The cumulative probability of colectomy is highly variable from one study to another, but is approximately 20–30% after 25 years; it is higher in series from referral centers and lower in population-based studies, particularly from Southern Europe [10]. The efficacy of cyclosporine for the treatment of acute severe colitis has been demonstrated, with about two thirds of patients avoiding a colectomy in the short term. However, the long-term results of cyclosporine treatment are not as promising, and even for patients on AZA maintenance therapy, colectomy is required in about half of the patients that initially respond to cyclosporine. AZA may also be effective as a maintenance therapy for patients with steroid dependency [11] and for preventing neoplasia [12]. In summary, at the advent of anti-TNF agents, the proportion of patients with ulcerative colitis requiring colectomy decreased, mainly for elective indications and only slightly for emergency indications [13 ]. &
The ability of anti-TNF agents to decrease the need for surgery remains unclear possibly because anti-TNF agents are given too late in the course of IBD.
strictures and penetrating lesions of the bowel (fistulas and abscesses). These complications may be unresponsive to medicines and thus make surgery necessary. In contrast, mucosal healing is associated with sustained clinical remission and reduced rates of hospitalization and surgical resection [1]. The 20-year cumulative rate of all complications for Crohn’s disease was over 60% in the Olmsted County population [2] and 80% in the series from referral centers. In most of the historical series, the cumulative risk of intestinal resection was 75–80% at 20 years [3]. Moreover, because anatomic recurrence is almost invariable, many patients have to undergo multiple operations. The cumulative risk of a second operation is approximately 30% at 10 years after the first operation [3]. Another concern is perianal disease that develops in nearly half of the patients with Crohn’s disease, particularly those with colonic disease. About onethird of patients with Crohn’s disease eventually develop a penetrating perianal complication requiring surgical drainage, which generates the long-term risk of incontinence or permanent stoma. The above figures remained essentially stable from 1950 to 2000 [4]. The increasing use of immunomodulators (thiopurines and methotrexate) during the nineties did not dramatically change the incidence of these complications. This may be due to the modest efficacy of these drugs and/or to the administration of a prescription too late into the development of the disease, when the intestinal damage has become irreversible. With azathioprine (AZA) treatment, it is estimated that only 40–45% of patients achieve clinical remission and approximately 25% achieve an anatomical remission [5]. AZA responders do have a slightly decreased risk of surgery [6 ], but initiating AZA treatment more than 3 years after diagnosis has no clear effect [7]. A recent meta-analysis of 10 retrospective studies concluded that the use of thiopurines was associated with a decreased need for the first intestinal resection [pooled hazard ratio 0.59; 95% confidence interval (CI): 0.48–0.73] [8 ]. Whether there is an increased efficacy of thiopurines when they are prescribed early, within 6 months following diagnosis, was &
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EFFECTS OF ANTITUMOR NECROSIS FACTOR AGENTS ON LESIONS OF CROHN’S DISEASE Anti-TNF agents block soluble TNF-a, a potent proinflammatory cytokine, and inhibit transmembrane TNF effects such as the activation of T cells, B cells, and macrophages. They stop the inflammatory cascade and may heal the mucosa. They also target mucosal myofibroblasts. Myofibroblasts are involved in injury and wound healing and produce metalloproteinases that degrade the extracellular matrix. In colonic myofibroblasts obtained from patients with Crohn’s disease, infliximab has been shown to induce the production of tissue inhibitors of metalloproteinase, to downregulate some metalloproteinases [especially, matrix metalloproteinase (MMP)-3 and MMP-12], to reduce collagen production, and to enhance myofibroblast migration [14]. These data support a myofibroblastdependent wound healing action of anti-TNF agents that is possibly related to their efficacy at closing fistulas.
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The efficacy of anti-TNF agents in the early phase of Crohn’s disease has been well demonstrated in the model of postoperative recurrence. Anti-TNF agents are able to prevent endoscopic recurrence following surgery [15,16 ]; in a retrospective study, their continued administration after surgery was shown to decrease the need for surgery, that is, disease recurrence requiring reoperation within 3 years after the initial operation [17 ]. Regueiro et al. [18 ] also found that patients who received infliximab therapy for the majority of the follow-up period had a lower rate of surgical recurrence compared with those not on infliximab . &
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Fistula closure Fistulas occur in approximately 35% of patients with Crohn’s disease after 10 years of disease evolution and represent a major burden for the patients. In the majority of cases, external fistulas are located in the perianal area. Infliximab was the first agent shown to be effective in a randomized controlled trial for inducing and maintaining perianal fistula closure [19]. The studies that evaluated adalimumab and certolizumab pegol for short-term fistula closure did not show significant differences from placebo. However, regarding efficacy in maintenance treatment, both adalimumab and infliximab were shown to induce a higher rate of complete fistula closure than placebo at 1 year. A meta-analysis that included infliximab, adalimumab, and certolizumab confirmed that all anti-TNF agents are more effective than placebo at closing fistulas in patients with Crohn’s disease [20 ]. For perianal disease, about two thirds of patients achieve fistula closure, and this result is maintained in more than half of them if the anti-TNF agent is continued [21]. Enterocutaneous fistulas are less common and represent only 7% of cases in controlled trials of anti-TNF agents in fistulas associated with Crohn’s disease. A retrospective study of 48 patients from the Groupe d’Etude The´rapeutique des Affections Inflammatoires Digestives (GETAID) (Amiot et al., unpublished observation) found a closure rate of 33% with the use of anti-TNF agents; however, 15 patients developed an intraabdominal abscess and 26 (54%) required surgery. &
Intestinal strictures Intestinal strictures are common complications in Crohn’s disease. In early inflammation, swelling caused by edema and inflammatory cells that accumulate in the bowel wall may induce a transient obstruction. However, if inflammation persists and becomes chronic, profibrotic events occur with 380
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collagen and other extracellular matrix protein accumulation leading to thickening of the bowel wall and finally to stricture formation. Although an inflammatory component is likely to respond to anti-inflammatory treatments, this is not the case for fibrotic processes. There are conflicting reports regarding the development of intestinal stenosis under anti-TNF agents. Although initial studies suggested that patients treated with infliximab might develop stenosis at the site of earlier severe ulcerations [19,22], a study that analyzed data from the Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry and the A Crohn’s Disease Clinical Trial Evaluating Infiximab in a New Long-term Treatment Regimen in Patients With Fistulizing Crohn’s Disease (ACCENT) I study [23] showed, after adjusting for other factors, that only disease duration, disease severity, ileal disease, and new corticosteroid use (but not infliximab use) were significantly associated with stricture development [24]. Taking into consideration all of the available data, anti-TNF agents do not seem to increase the risk of stenosis development. However, patients with bowel strictures and, notably, with upstream bowel dilation of the stricture have an increased risk of not responding to anti-TNF agents [25,26].
Other complications An abdominal phlegmon is an inflammatory mass that can develop in the setting of penetrating Crohn’s disease. The typical treatment involves antibiotics, drainage of any collections, bowel rest, and, eventually, resection of the mass. As anti-TNF agents have been shown to be effective in closing fistulas, using them in combination with antibiotics in this setting is an attractive strategy. A study of 13 patients with Crohn’s disease and abdominal phlegmon in Boston treated with anti-TNF agents after a course of antibiotics reported a clinical response in all of the patients, with 11 of them avoiding surgery in the long term [27 ]. This strategy is promising, and its efficacy and safety should be confirmed in a randomized controlled trial. A study promoted by the GETAID group is currently pursuing this topic. Anovaginal or rectovaginal fistulas affect 5–10% of women with Crohn’s disease. No randomized control trials are available to evaluate the therapeutic strategy in this setting, and the current treatment guidelines are based on short patient series. A case series of six Spanish university hospitals including 47 patients with genital fistulas was recently reported [28 ]. In this case series, infliximab treatment was associated with a complete response in 17% of patients and a partial response in 43% of &
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patients. The best result was obtained for patients who underwent surgery, with 39% of the surgeries achieving fistula closure; these results support the European Crohn’s and Colitis Organisation (ECCO) recommendations to surgically treat genital fistulas when medicinal treatments have failed [29].
IMPACT OF BIOLOGICS ON THE NEED FOR SURGERY IN PATIENTS WITH CROHN’S DISEASE Data from randomized trials and from observational studies should be examined separately.
Randomized trials Despite response rates of approximately 60%, a majority of patients with Crohn’s disease will display sustained remission when receiving anti-TNF agents. Steroid discontinuation and mucosal healing are also significantly higher with anti-TNF agent treatment than placebo. Considering that the control of inflammation and the induction of mucosal healing are prerequisites for bowel preservation through the long-term control of disease activity, one could expect an impact of anti-TNF agents on the surgery rates for patients with Crohn’s disease. Infliximab treatment has been claimed to reduce serious complications requiring hospitalization and surgery [30–32]. A recent meta-analysis provided data on the rates of hospitalization and surgery in this setting. It showed that through randomized controlled trials [33 ], infliximab treatment was associated with a significant odds ratio (OR) reduction of hospitalization risk (OR 0.48; 95% CI: 0.34–0.67) and surgery rate (OR 0.31; 95% CI: 0.15–0.64). Regarding adalimumab, in a post-hoc analysis of the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) trial, Feagan et al. [34] reported that patients treated with adalimumab had lower 1-year risks of hospitalization and surgery than patients receiving placebo. No evidence for certolizumab pegol is available regarding these outcomes. Although randomized controlled trials suggest that anti-TNF agent use is able to reduce hospitalizations and the need for surgery, several considerations limit the interpretation of this conclusion. Indeed, the key limitations to these studies are their short follow-up period and none of the trials were designed specifically to assess anti-TNF effects on hospitalization or surgery as predefined outcomes. Data coming from observational studies (from community based or referral centers) are more helpful for examining long-term outcomes of Crohn’s disease [35]. &
Observational studies Data coming from large referral centers are scarce and do not support a change in major outcomes of Crohn’s disease because anti-TNF therapy is commonly used at those centers. Data from a referral center in Pittsburgh showed that despite the increased use of infliximab, the rate of small bowel resection as well as the behavior of the population with Crohn’s disease has remained unchanged over time [36]. An analysis of secular trends of hospitalization and surgery rates for patients with Crohn’s disease using the 1990–2003 National Hospital Discharge Survey data showed that, despite advances in therapy, hospitalization and surgery rates for patients with Crohn’s disease in the United States have not decreased since 1990. Still, there has been a significant increase in hospitalizations with stable rates of bowel resection surgery for patients with Crohn’s disease. These observations accrued in referral centers may be partially explained by the overrepresentation of long-standing, complicated Crohn’s disease that is refractory to medical therapy. In contrast, a recent systematic review and metaanalysis found a significant reduction in major surgery and hospitalization rates with the use of anti-TNF agents. A meta-analysis of populationbased studies demonstrated a small but significant decrease in the need for surgery in patients with Crohn’s disease [37 ]. For example, the 5-year surgery risk decreased from 27.7% in the nineties to 24.2% after 2000. In observational studies, infliximab was found to be associated with a decreased hospitalization risk (OR 0.28; 95% CI: 0.18–0.46) and surgery risk requirement (OR 0.32; 95% CI: 0.21–0.49) [33 ]. Heterogeneity exists in the pooled results from these observational studies, and this raises concerns about the interpretation of these findings. Thus, public health and therapeutic decisions cannot be based solely on this type of evidence. Therefore, the question of the efficacy of antiTNF agents remains unresolved, and prospective long-term studies are required to establish definitive conclusions on this topic. The design of these studies should take into account the timing of the use of anti-TNF agents during the course of Crohn’s disease. In fact, two retrospective studies, one from a referral center and the other from claims data, provided clues for a possible impact of anti-TNF agents on surgery rates related to Crohn’s disease, especially when anti-TNF agents are used early in the course of the disease. Indeed, the retrospective observational study conducted by a referral center reported that treatment with anti-TNF agents was associated with a reduction in the need for surgery in patients newly diagnosed with Crohn’s disease
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Cumulative 5 years incidence (%)
p < 0.0001 1996–99 (n = 145)
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2000–03 (n = 221) p = 0.68
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FIGURE 1. Cumulative 5-year therapeutic requirements (immunomodulators or anti-TNF agents), need for surgery, and occurrence of complications in four consecutive calendar cohorts from St-Antoine Hospital (patients seen within 3 months following diagnosis). Although the cumulative rate of use of immunomodulators (P < 0.0001) and anti-TNF agents (P < 0.0001) increased significantly over time, there was no significant change in the need for surgery (P ¼ 0.68), occurrence of intestinal stricture (P ¼ 0.63), or perforation (P ¼ 0.33), but a small decrease in the occurrence of perianal perforation (P ¼ 0.02) was observed. TNF, tumor necrosis factor.
[38]. Real-world claims data from adult patients with Crohn’s disease showed that a top-down approach to anti-TNF therapy was associated with a lower risk of surgery related to Crohn’s disease compared with the step-up and immunomodulators-to-aTNF therapy approaches [39]. Finally, in our referral center where a step-up approach is used, a comparison of several 4-year calendar cohorts from 1996 to 2011 did not show significant changes in surgery rates, even in the recent cohorts where the use of anti-TNF was dramatically increased (Fig. 1). In light of these latest results, one could hypothesize that a change in the major outcomes of Crohn’s disease will occur when well defined patients will be offered anti-TNF agents at the correct time in the course of their disease and before the occurrence of complications. Here, it must be noted that the macroeconomic impact of anti-TNF agents is relevant, as total direct costs associated with Crohn’s disease are mainly driven by hospitalization and surgery.
Ulcerative Colitis Trial (ACT)-1 and ACT-2 studies, which demonstrated the efficacy of infliximab in patients with active ulcerative colitis. In particular, infliximab is effective in patients with acute severe colitis that is unresponsive to intravenous steroids. This efficacy is similar to that of cyclosporine [40 ]. However, in contrast to cyclosporine, infliximab may be administered for years. Maintenance therapy often requires dose escalation or switching to another anti-TNF agent [41], and the colectomy rate of patients under maintenance therapy approaches 20% at 3 years [42,43]. Results are better for patients with milder forms of ulcerative colitis; the 3-year extension of the ACT studies showed a very low rate of colectomy (0.4%) in patients who responded to induction therapy [44]. Adalimumab is effective if used as a second anti-TNF agent when remission had previously been achieved with infliximab [45]. Actually, the achievement of clinical remission and mucosal healing after induction are good predictors of the long-term avoidance of colectomy [46 ]. In total, the risk of colectomy in patients with ulcerative colitis seems to be decreasing in recent years, but the specific effect of the introduction of anti-TNF agents on the rate of colectomy cannot be currently evaluated [37 ]. &&
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EFFECT OF ANTITUMOR NECROSIS FACTOR AGENTS ON COLECTOMY RATE IN PATIENTS WITH ULCERATIVE COLITIS The use of anti-TNF agents in patients with ulcerative colitis began in 2005, after the Active 382
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CONCLUSION Whether anti-TNF agents are able to prevent and treat complications and decrease the need for surgery in IBD patients remains a burning question. Although most short-term trials demonstrated decreased rates of complications and the need for surgery with anti-TNF agents, population surveys have shown conflicting results. Perhaps, anti-TNF agents only delay the occurrence of complications. However, there is a clear relationship between the achievement of mucosal healing and the prevention of complications. The model of postoperative recurrence favors the concept of preventing reoperation through the maintenance of an intact mucosa. It may be hypothesized that often anti-TNF agents are given too late in the course of IBD diseases to modify the natural history of the disease. For Crohn’s disease, there is a need for a randomized trial comparing the early introduction of anti-TNF agents to the common step-up strategy that is used at most centers for patients at a high risk of developing severe disease. For ulcerative colitis, the efficacy of anti-TNF agents in the long term needs to be confirmed. Finally, patients who avoid surgery seemingly as the result of treatment with anti-TNF agents should be followed with caution, as old lesions may increase the cancer risk for these patients. Acknowledgements No funding. Conflicts of interest None declared. H.S. received consulting fees from Danone and Enterome, P.S. received consulting fees from Biocodex, MSD, and Abbott, and J.C. received consulting fees from Abbvie.
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37. Frolkis AD, Dykeman J, Negron ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and metaanalysis of population-based studies. Gastroenterology 2013; 145:996– 1006. This systematic review of 30 population-based studies comprehensively summarizes postdiagnostic surgical risk at 1, 5, and 10 years. Over the past several decades, the risk of surgery has significantly decreased in patients with Crohn’s disease, whereas this finding was statistically significant at 1 and 10 years in patients with ulcerative colitis. Despite limitations (heterogeneity, study not designed to identify the specific cause of the reduction in surgery), this systematic review and meta-analysis showed that the risk of surgery for IBD is decreasing with time and can assist with disease counseling and treatment planning. 38. Peyrin-Biroulet L, Oussalah A, Williet N, et al. Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn’s disease. Gut 2011; 60:930–936. 39. Rubin DT, Uluscu O, Sederman R. Response to biologic therapy in Crohn’s disease is improved with early treatment: an analysis of health claims data. Inflamm Bowel Dis 2012; 18:2225–2231. 40. Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients && with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012; 380:1909–1915. This GETAID study showed a similar efficacy of infliximab and ciclosporine for controlling severe acute colitis unresponsive to steroids. 41. McDermott E, Murphy S, Keegan D, et al. Efficacy of adalimumab as a long term maintenance therapy in ulcerative colitis. J Crohns Colitis 2013; 7:150– 153. 42. Ferrante M, Vermeire S, Fidder H, et al. Long-term outcome after infliximab for refractory ulcerative colitis. J Crohns Colitis 2008; 2:219–225. 43. Rostholder E, Ahmed A, Cheifetz AS, Moss AC. Outcomes after escalation of infliximab therapy in ambulatory patients with moderately active ulcerative colitis. Aliment Pharmacol Ther 2012; 35:562–567. 44. Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies. Inflamm Bowel Dis 2012; 18:201–211. 45. Garcia-Bosch O, Gisbert JP, Canas-Ventura A, et al. Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome. J Crohns Colitis 2013; 7:717–722. 46. Laharie D, Filippi J, Roblin X, et al. Impact of mucosal healing on long-term & outcomes in ulcerative colitis treated with infliximab: a multicenter experience. Aliment Pharmacol Ther 2013; 37:998–1004. In refractory ulcerative colitis, endoscopic appearance after infliximab induction is a good predictor of need for colectomy in patients continuing infliximab; the colectomy rate at 3 years was 4% when the Mayo endoscopic subscore was 0 or 1, and 35% when it was more than 1. &
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Complications and surgery in the inflammatory bowel diseases biological era Harry Sokol, Philippe Seksik, and Jacques Cosnes
Purpose of review Therapy for inflammatory bowel diseases (IBD) has changed dramatically in recent years with a wider use of immunomodulators and the introduction of antitumor necrosis factor (anti-TNF) agents. This article reviews the existing data on the long-term efficacy of biologics, that is, anti-TNF agents, for preventing complications and surgery in patients with IBD. Recent findings Anti-TNF agents are effective for preventing endoscopic and surgical recurrence after surgery for Crohn’s disease. They are able to achieve fistula closure and do not increase the risk of stricture. Most randomized short-term trials also showed decreased requirement for hospitalizations and surgery in patients receiving anti-TNF. However, observational studies from referral centers or based on population have shown conflicting results. The need for surgery in Crohn’s disease and the risk of colectomy in ulcerative colitis seem to be decreasing in recent years, but the specific effect of the introduction of anti-TNF agents cannot be currently evaluated. Summary Although anti-TNF agents are the most powerful drugs in IBD, their ability to decrease the need for surgery remains unclear. Conflicting results observed in observational surveys might be because of anti-TNF agents administered too late in the course of IBD. Keywords antitumor necrosis factor, complication, inflammatory bowel disease, surgery
INTRODUCTION Therapy for inflammatory bowel diseases (IBD) has changed dramatically in recent years with a wider use of immunomodulators and the introduction of antitumor necrosis factor (anti-TNF) agents. The efficacy of anti-TNF agents is superior to any of the prior drugs in the IBD armamentarium and has the power to rapidly heal the intestinal mucosa. However, their long-term impact on the development of IBD complications and whether they lead to a decreased necessity of surgery is not clear. AntiTNF agents do not cure IBD. Some patients do not respond to anti-TNF agents and others develop adverse reactions or lose their response over time. The disease recurs in half of the patients within a year following the withdrawal of the anti-TNF agent. Other biologics, such as ustekinumab and vedolizumab, are still in development, and their use in clinical practice is still too limited to evaluate their preventive effect on complications. However, they may be used in place of anti-TNF agents and allow for the postponement of a surgical decision. This www.co-gastroenterology.com
article reviews the existing data on the long-term efficacy of biologics, that is, the effect of anti-TNF agents in the prevention of complications and need for surgery both in patients with Crohn’s disease and ulcerative colitis.
COMPLICATIONS AND SURGERY BEFORE THE ERA OF BIOLOGICS Crohn’s disease is a chronic inflammatory bowel disorder generally characterized by a sequence of flare-up episodes and remissions of varying duration. Over time, in the majority of patients with Crohn’s disease, there is an evolution to fibrostenotic Service de Gastroente´rologie et Nutrition, Hoˆpital St-Antoine, et Universite´ Paris VI, Paris, France Correspondence to Professor Jacques Cosnes, Hoˆpital St-Antoine, 184 rue du Faubourg St-Antoine, Paris 75012, France. Tel: +33 1 49 28 31 70; fax: +33 1 49 28 31 88; e-mail: [email protected] Curr Opin Gastroenterol 2014, 30:378–384 DOI:10.1097/MOG.0000000000000078 Volume 30 Number 4 July 2014
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Complications, surgery and biologics in IBD Sokol et al.
KEY POINTS Anti-TNF agents are the most powerful drugs in IBD. Anti-TNF agents are able to achieve fistula closure and do not increase the risk of stricture in Crohn’s disease.
addressed in the RAPID trial. After 3 years, no difference was found between the conventional management group and the thiopurine treatment group regarding intestinal surgery; however, the development of perianal fistulas and the need for perianal surgery was less frequent in the experimental group [9 ]. For patients with ulcerative colitis, indications for colectomy include acute severe colitis that is unresponsive to intensive intravenous therapy, refractory chronic active disease, and development of neoplasia. The cumulative probability of colectomy is highly variable from one study to another, but is approximately 20–30% after 25 years; it is higher in series from referral centers and lower in population-based studies, particularly from Southern Europe [10]. The efficacy of cyclosporine for the treatment of acute severe colitis has been demonstrated, with about two thirds of patients avoiding a colectomy in the short term. However, the long-term results of cyclosporine treatment are not as promising, and even for patients on AZA maintenance therapy, colectomy is required in about half of the patients that initially respond to cyclosporine. AZA may also be effective as a maintenance therapy for patients with steroid dependency [11] and for preventing neoplasia [12]. In summary, at the advent of anti-TNF agents, the proportion of patients with ulcerative colitis requiring colectomy decreased, mainly for elective indications and only slightly for emergency indications [13 ]. &
The ability of anti-TNF agents to decrease the need for surgery remains unclear possibly because anti-TNF agents are given too late in the course of IBD.
strictures and penetrating lesions of the bowel (fistulas and abscesses). These complications may be unresponsive to medicines and thus make surgery necessary. In contrast, mucosal healing is associated with sustained clinical remission and reduced rates of hospitalization and surgical resection [1]. The 20-year cumulative rate of all complications for Crohn’s disease was over 60% in the Olmsted County population [2] and 80% in the series from referral centers. In most of the historical series, the cumulative risk of intestinal resection was 75–80% at 20 years [3]. Moreover, because anatomic recurrence is almost invariable, many patients have to undergo multiple operations. The cumulative risk of a second operation is approximately 30% at 10 years after the first operation [3]. Another concern is perianal disease that develops in nearly half of the patients with Crohn’s disease, particularly those with colonic disease. About onethird of patients with Crohn’s disease eventually develop a penetrating perianal complication requiring surgical drainage, which generates the long-term risk of incontinence or permanent stoma. The above figures remained essentially stable from 1950 to 2000 [4]. The increasing use of immunomodulators (thiopurines and methotrexate) during the nineties did not dramatically change the incidence of these complications. This may be due to the modest efficacy of these drugs and/or to the administration of a prescription too late into the development of the disease, when the intestinal damage has become irreversible. With azathioprine (AZA) treatment, it is estimated that only 40–45% of patients achieve clinical remission and approximately 25% achieve an anatomical remission [5]. AZA responders do have a slightly decreased risk of surgery [6 ], but initiating AZA treatment more than 3 years after diagnosis has no clear effect [7]. A recent meta-analysis of 10 retrospective studies concluded that the use of thiopurines was associated with a decreased need for the first intestinal resection [pooled hazard ratio 0.59; 95% confidence interval (CI): 0.48–0.73] [8 ]. Whether there is an increased efficacy of thiopurines when they are prescribed early, within 6 months following diagnosis, was &
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EFFECTS OF ANTITUMOR NECROSIS FACTOR AGENTS ON LESIONS OF CROHN’S DISEASE Anti-TNF agents block soluble TNF-a, a potent proinflammatory cytokine, and inhibit transmembrane TNF effects such as the activation of T cells, B cells, and macrophages. They stop the inflammatory cascade and may heal the mucosa. They also target mucosal myofibroblasts. Myofibroblasts are involved in injury and wound healing and produce metalloproteinases that degrade the extracellular matrix. In colonic myofibroblasts obtained from patients with Crohn’s disease, infliximab has been shown to induce the production of tissue inhibitors of metalloproteinase, to downregulate some metalloproteinases [especially, matrix metalloproteinase (MMP)-3 and MMP-12], to reduce collagen production, and to enhance myofibroblast migration [14]. These data support a myofibroblastdependent wound healing action of anti-TNF agents that is possibly related to their efficacy at closing fistulas.
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Inflammatory bowel disease
The efficacy of anti-TNF agents in the early phase of Crohn’s disease has been well demonstrated in the model of postoperative recurrence. Anti-TNF agents are able to prevent endoscopic recurrence following surgery [15,16 ]; in a retrospective study, their continued administration after surgery was shown to decrease the need for surgery, that is, disease recurrence requiring reoperation within 3 years after the initial operation [17 ]. Regueiro et al. [18 ] also found that patients who received infliximab therapy for the majority of the follow-up period had a lower rate of surgical recurrence compared with those not on infliximab . &
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Fistula closure Fistulas occur in approximately 35% of patients with Crohn’s disease after 10 years of disease evolution and represent a major burden for the patients. In the majority of cases, external fistulas are located in the perianal area. Infliximab was the first agent shown to be effective in a randomized controlled trial for inducing and maintaining perianal fistula closure [19]. The studies that evaluated adalimumab and certolizumab pegol for short-term fistula closure did not show significant differences from placebo. However, regarding efficacy in maintenance treatment, both adalimumab and infliximab were shown to induce a higher rate of complete fistula closure than placebo at 1 year. A meta-analysis that included infliximab, adalimumab, and certolizumab confirmed that all anti-TNF agents are more effective than placebo at closing fistulas in patients with Crohn’s disease [20 ]. For perianal disease, about two thirds of patients achieve fistula closure, and this result is maintained in more than half of them if the anti-TNF agent is continued [21]. Enterocutaneous fistulas are less common and represent only 7% of cases in controlled trials of anti-TNF agents in fistulas associated with Crohn’s disease. A retrospective study of 48 patients from the Groupe d’Etude The´rapeutique des Affections Inflammatoires Digestives (GETAID) (Amiot et al., unpublished observation) found a closure rate of 33% with the use of anti-TNF agents; however, 15 patients developed an intraabdominal abscess and 26 (54%) required surgery. &
Intestinal strictures Intestinal strictures are common complications in Crohn’s disease. In early inflammation, swelling caused by edema and inflammatory cells that accumulate in the bowel wall may induce a transient obstruction. However, if inflammation persists and becomes chronic, profibrotic events occur with 380
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collagen and other extracellular matrix protein accumulation leading to thickening of the bowel wall and finally to stricture formation. Although an inflammatory component is likely to respond to anti-inflammatory treatments, this is not the case for fibrotic processes. There are conflicting reports regarding the development of intestinal stenosis under anti-TNF agents. Although initial studies suggested that patients treated with infliximab might develop stenosis at the site of earlier severe ulcerations [19,22], a study that analyzed data from the Therapy, Resource, Evaluation, and Assessment Tool (TREAT) registry and the A Crohn’s Disease Clinical Trial Evaluating Infiximab in a New Long-term Treatment Regimen in Patients With Fistulizing Crohn’s Disease (ACCENT) I study [23] showed, after adjusting for other factors, that only disease duration, disease severity, ileal disease, and new corticosteroid use (but not infliximab use) were significantly associated with stricture development [24]. Taking into consideration all of the available data, anti-TNF agents do not seem to increase the risk of stenosis development. However, patients with bowel strictures and, notably, with upstream bowel dilation of the stricture have an increased risk of not responding to anti-TNF agents [25,26].
Other complications An abdominal phlegmon is an inflammatory mass that can develop in the setting of penetrating Crohn’s disease. The typical treatment involves antibiotics, drainage of any collections, bowel rest, and, eventually, resection of the mass. As anti-TNF agents have been shown to be effective in closing fistulas, using them in combination with antibiotics in this setting is an attractive strategy. A study of 13 patients with Crohn’s disease and abdominal phlegmon in Boston treated with anti-TNF agents after a course of antibiotics reported a clinical response in all of the patients, with 11 of them avoiding surgery in the long term [27 ]. This strategy is promising, and its efficacy and safety should be confirmed in a randomized controlled trial. A study promoted by the GETAID group is currently pursuing this topic. Anovaginal or rectovaginal fistulas affect 5–10% of women with Crohn’s disease. No randomized control trials are available to evaluate the therapeutic strategy in this setting, and the current treatment guidelines are based on short patient series. A case series of six Spanish university hospitals including 47 patients with genital fistulas was recently reported [28 ]. In this case series, infliximab treatment was associated with a complete response in 17% of patients and a partial response in 43% of &
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patients. The best result was obtained for patients who underwent surgery, with 39% of the surgeries achieving fistula closure; these results support the European Crohn’s and Colitis Organisation (ECCO) recommendations to surgically treat genital fistulas when medicinal treatments have failed [29].
IMPACT OF BIOLOGICS ON THE NEED FOR SURGERY IN PATIENTS WITH CROHN’S DISEASE Data from randomized trials and from observational studies should be examined separately.
Randomized trials Despite response rates of approximately 60%, a majority of patients with Crohn’s disease will display sustained remission when receiving anti-TNF agents. Steroid discontinuation and mucosal healing are also significantly higher with anti-TNF agent treatment than placebo. Considering that the control of inflammation and the induction of mucosal healing are prerequisites for bowel preservation through the long-term control of disease activity, one could expect an impact of anti-TNF agents on the surgery rates for patients with Crohn’s disease. Infliximab treatment has been claimed to reduce serious complications requiring hospitalization and surgery [30–32]. A recent meta-analysis provided data on the rates of hospitalization and surgery in this setting. It showed that through randomized controlled trials [33 ], infliximab treatment was associated with a significant odds ratio (OR) reduction of hospitalization risk (OR 0.48; 95% CI: 0.34–0.67) and surgery rate (OR 0.31; 95% CI: 0.15–0.64). Regarding adalimumab, in a post-hoc analysis of the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM) trial, Feagan et al. [34] reported that patients treated with adalimumab had lower 1-year risks of hospitalization and surgery than patients receiving placebo. No evidence for certolizumab pegol is available regarding these outcomes. Although randomized controlled trials suggest that anti-TNF agent use is able to reduce hospitalizations and the need for surgery, several considerations limit the interpretation of this conclusion. Indeed, the key limitations to these studies are their short follow-up period and none of the trials were designed specifically to assess anti-TNF effects on hospitalization or surgery as predefined outcomes. Data coming from observational studies (from community based or referral centers) are more helpful for examining long-term outcomes of Crohn’s disease [35]. &
Observational studies Data coming from large referral centers are scarce and do not support a change in major outcomes of Crohn’s disease because anti-TNF therapy is commonly used at those centers. Data from a referral center in Pittsburgh showed that despite the increased use of infliximab, the rate of small bowel resection as well as the behavior of the population with Crohn’s disease has remained unchanged over time [36]. An analysis of secular trends of hospitalization and surgery rates for patients with Crohn’s disease using the 1990–2003 National Hospital Discharge Survey data showed that, despite advances in therapy, hospitalization and surgery rates for patients with Crohn’s disease in the United States have not decreased since 1990. Still, there has been a significant increase in hospitalizations with stable rates of bowel resection surgery for patients with Crohn’s disease. These observations accrued in referral centers may be partially explained by the overrepresentation of long-standing, complicated Crohn’s disease that is refractory to medical therapy. In contrast, a recent systematic review and metaanalysis found a significant reduction in major surgery and hospitalization rates with the use of anti-TNF agents. A meta-analysis of populationbased studies demonstrated a small but significant decrease in the need for surgery in patients with Crohn’s disease [37 ]. For example, the 5-year surgery risk decreased from 27.7% in the nineties to 24.2% after 2000. In observational studies, infliximab was found to be associated with a decreased hospitalization risk (OR 0.28; 95% CI: 0.18–0.46) and surgery risk requirement (OR 0.32; 95% CI: 0.21–0.49) [33 ]. Heterogeneity exists in the pooled results from these observational studies, and this raises concerns about the interpretation of these findings. Thus, public health and therapeutic decisions cannot be based solely on this type of evidence. Therefore, the question of the efficacy of antiTNF agents remains unresolved, and prospective long-term studies are required to establish definitive conclusions on this topic. The design of these studies should take into account the timing of the use of anti-TNF agents during the course of Crohn’s disease. In fact, two retrospective studies, one from a referral center and the other from claims data, provided clues for a possible impact of anti-TNF agents on surgery rates related to Crohn’s disease, especially when anti-TNF agents are used early in the course of the disease. Indeed, the retrospective observational study conducted by a referral center reported that treatment with anti-TNF agents was associated with a reduction in the need for surgery in patients newly diagnosed with Crohn’s disease
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Inflammatory bowel disease
100
Cumulative 5 years incidence (%)
p < 0.0001 1996–99 (n = 145)
p < 0.0001
80
2000–03 (n = 221) p = 0.68
2004–07 (n = 249) 2008–11 (n = 184)
p = 0.63
60
p = 0.33
p = 0.02
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20
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FIGURE 1. Cumulative 5-year therapeutic requirements (immunomodulators or anti-TNF agents), need for surgery, and occurrence of complications in four consecutive calendar cohorts from St-Antoine Hospital (patients seen within 3 months following diagnosis). Although the cumulative rate of use of immunomodulators (P < 0.0001) and anti-TNF agents (P < 0.0001) increased significantly over time, there was no significant change in the need for surgery (P ¼ 0.68), occurrence of intestinal stricture (P ¼ 0.63), or perforation (P ¼ 0.33), but a small decrease in the occurrence of perianal perforation (P ¼ 0.02) was observed. TNF, tumor necrosis factor.
[38]. Real-world claims data from adult patients with Crohn’s disease showed that a top-down approach to anti-TNF therapy was associated with a lower risk of surgery related to Crohn’s disease compared with the step-up and immunomodulators-to-aTNF therapy approaches [39]. Finally, in our referral center where a step-up approach is used, a comparison of several 4-year calendar cohorts from 1996 to 2011 did not show significant changes in surgery rates, even in the recent cohorts where the use of anti-TNF was dramatically increased (Fig. 1). In light of these latest results, one could hypothesize that a change in the major outcomes of Crohn’s disease will occur when well defined patients will be offered anti-TNF agents at the correct time in the course of their disease and before the occurrence of complications. Here, it must be noted that the macroeconomic impact of anti-TNF agents is relevant, as total direct costs associated with Crohn’s disease are mainly driven by hospitalization and surgery.
Ulcerative Colitis Trial (ACT)-1 and ACT-2 studies, which demonstrated the efficacy of infliximab in patients with active ulcerative colitis. In particular, infliximab is effective in patients with acute severe colitis that is unresponsive to intravenous steroids. This efficacy is similar to that of cyclosporine [40 ]. However, in contrast to cyclosporine, infliximab may be administered for years. Maintenance therapy often requires dose escalation or switching to another anti-TNF agent [41], and the colectomy rate of patients under maintenance therapy approaches 20% at 3 years [42,43]. Results are better for patients with milder forms of ulcerative colitis; the 3-year extension of the ACT studies showed a very low rate of colectomy (0.4%) in patients who responded to induction therapy [44]. Adalimumab is effective if used as a second anti-TNF agent when remission had previously been achieved with infliximab [45]. Actually, the achievement of clinical remission and mucosal healing after induction are good predictors of the long-term avoidance of colectomy [46 ]. In total, the risk of colectomy in patients with ulcerative colitis seems to be decreasing in recent years, but the specific effect of the introduction of anti-TNF agents on the rate of colectomy cannot be currently evaluated [37 ]. &&
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EFFECT OF ANTITUMOR NECROSIS FACTOR AGENTS ON COLECTOMY RATE IN PATIENTS WITH ULCERATIVE COLITIS The use of anti-TNF agents in patients with ulcerative colitis began in 2005, after the Active 382
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CONCLUSION Whether anti-TNF agents are able to prevent and treat complications and decrease the need for surgery in IBD patients remains a burning question. Although most short-term trials demonstrated decreased rates of complications and the need for surgery with anti-TNF agents, population surveys have shown conflicting results. Perhaps, anti-TNF agents only delay the occurrence of complications. However, there is a clear relationship between the achievement of mucosal healing and the prevention of complications. The model of postoperative recurrence favors the concept of preventing reoperation through the maintenance of an intact mucosa. It may be hypothesized that often anti-TNF agents are given too late in the course of IBD diseases to modify the natural history of the disease. For Crohn’s disease, there is a need for a randomized trial comparing the early introduction of anti-TNF agents to the common step-up strategy that is used at most centers for patients at a high risk of developing severe disease. For ulcerative colitis, the efficacy of anti-TNF agents in the long term needs to be confirmed. Finally, patients who avoid surgery seemingly as the result of treatment with anti-TNF agents should be followed with caution, as old lesions may increase the cancer risk for these patients. Acknowledgements No funding. Conflicts of interest None declared. H.S. received consulting fees from Danone and Enterome, P.S. received consulting fees from Biocodex, MSD, and Abbott, and J.C. received consulting fees from Abbvie.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Froslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007; 133:412–422. 2. Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associated with progression to intestinal complications of Crohn’s disease in a populationbased cohort. Gastroenterology 2010; 139:1147–1155. 3. Munkholm P, Langholz E, Davidsen M, Binder V. Disease activity courses in a regional cohort of Crohn’s disease patients. Scand J Gastroenterol 1995; 30:699–706. 4. Wolters FL, Russel MG, Stockbrugger RW. Systematic review: has disease outcome in Crohn’s disease changed during the last four decades? Aliment Pharmacol Ther 2004; 20:483–496. 5. Bourrier A, Seksik P, Cosnes J. Is there still a room for azathioprine monotherapy in inflammatory bowel disease? Curr Drug Targets 2013; 14:1471– 1479. 6. Camus M, Seksik P, Bourrier A, et al. Long-term outcome of patients with & Crohn’s disease that responds to azathioprine. Clin Gastroenterol Hepatol 2013; 11:389–394. Patients with Crohn’s disease who respond to azathioprine have in the long term a decreased requirement of intestinal surgery when compared to controls.
7. Lakatos PL, Golovics PA, David G, et al. Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 19772009. Am J Gastroenterol 2012; 107:579–588. 8. Chatu S, Subramanian V, Saxena S, Pollok RC. The role of thiopurines in & reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis. Am J Gastroenterol 2014; 109:23–34. This meta-analysis reports a marked decreased risk for surgery in patients with Crohn’s disease treated on thiopurines. 9. Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs & conventional management of Crohn’s disease: a randomized controlled trial. Gastroenterology 2013; 145:758–765. In patients with Crohn’s disease at risk for disabling disease, starting thiopurines within the 6 months following diagnosis did not change the disease course during the three following years when compared to the conventional strategy of thiopurines on demand. 10. Hoie O, Wolters FL, Riis L, et al. Low colectomy rates in ulcerative colitis in an unselected European cohort followed for 10 years. Gastroenterology 2007; 132:507–515. 11. Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012; 9:CD000478. 12. Beaugerie L, Svrcek M, Seksik P, et al. Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 2013; 145:166–175. 13. Kaplan GG, Seow CH, Ghosh S, et al. Decreasing colectomy rates for & ulcerative colitis: a population-based time trend study. Am J Gastroenterol 2012; 107:1879–1887. In ulcerative colitis, increased use of thiopurines from 1997 to 2009 and use of infliximab after 2005 were associated with a decrease of elective colectomy rates. In contrast, emergency colectomy rates remained stable. 14. Di Sabatino A, Saarialho-Kere U, Buckley MG, et al. Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab. Eur J Gastroenterol Hepatol 2009; 21:1049–1055. 15. Regueiro M, Schraut W, Baidoo L, et al. Infliximab prevents Crohn’s disease recurrence after ileal resection. Gastroenterology 2009; 136:441–450. 16. Savarino E, Bodini G, Dulbecco P, et al. Adalimumab is more effective than & azathioprine and mesalamine at preventing postoperative recurrence of Crohn’s disease: a randomized controlled trial. Am J Gastroenterol 2013; 108:1731–1742. This small study of 51 patients with Crohn’s disease showed that adalimumab given postoperatively is greatly effective in preventing endoscopic and clinical recurrences as compared to azathioprine and mesalamine. 17. Araki T, Uchida K, Okita Y, et al. The impact of postoperative infliximab & maintenance therapy on preventing the surgical recurrence of Crohn’s disease: a single-center paired case-control study. Surg Today 2014; 44:291– 296; 34% after a median follow-up of 51 months. This is the first study demonstrating that the prevention of recurrence in patients with Crohn’s disease given infliximab postoperatively is followed by a decreased requirement for resurgery. Note, however, that there was an usually high incidence of reoperation in the control group. 18. Regueiro M, Kip KE, Baidoo L, et al. Postoperative therapy with infliximab & prevents long-term Crohn’s disease recurrence. Clin Gastroenterol Hepatol 2014. [Epub ahead of print] The prolongation of the pilot study of Regueiro et al., which demonstrated the efficacy of infliximab for preventing endoscopic recurrence, shows that, irrespective of initial assignment to placebo or infliximab, patients on infliximab therapy for the majority of the entire follow-up period had a higher rate of endoscopic remission and lower rate of surgical recurrence compared to those not on infliximab. 19. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340:1398–1405. 20. Kawalec P, Mikrut A, Wisniewska N, Pilc A. Tumor necrosis factor-alpha & antibodies (infliximab, adalimumab and certolizumab) in Crohn’s disease: systematic review and meta-analysis. Arch Med Sci 2013; 9:765–779. This recent meta-analysis including only randomized or clinical controlled trials evaluating infliximab, adalimumab, and certolizumab in Crohn’s disease confirmed that anti-TNF agents are more effective than placebo to close fistula. 21. Bouguen G, Siproudhis L, Gizard E, et al. Long-term outcome of perianal fistulizing Crohn’s disease treated with infliximab. Clin Gastroenterol Hepatol 2013; 11:975–981. 22. D’Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab antitumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999; 116:1029–1034. 23. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359:1541– 1549. 24. Lichtenstein GR, Olson A, Travers S, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn’s disease. Am J Gastroenterol 2006; 101:1030–1038. 25. Miehsler W, Novacek G, Wenzl H, et al. A decade of infliximab: the Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease. J Crohns Colitis 2010; 4:221–256.
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Inflammatory bowel disease 26. Matsumoto T, Iida M, Motoya S, et al. Therapeutic efficacy of infliximab on patients with short duration of Crohn’s disease: a Japanese multicenter survey. Dis Colon Rectum 2008; 51:916–923. 27. Cullen G, Vaughn B, Ahmed A, et al. Abdominal phlegmons in Crohn’s & disease: outcomes following antitumor necrosis factor therapy. Inflamm Bowel Dis 2012; 18:691–696. This article reports the experience of a tertiary center regarding treatment of abdominal phlegmons with anti-TNF agents (after antibiotics). This strategy was effective in 85% of cases (11 out of 13). 28. de la Poza G, Lopez-Sanroman A, Taxonera C, et al. Genital fistulas in female & Crohn’s disease patients: clinical characteristics and response to therapy. J Crohns Colitis 2012; 6:276–280. This article reports the experience of six Spanish university hospitals on 47 patients with genital fistula. It confirms that surgery is associated with the best results and supports the ECCO recommendations to surgically treat genital fistula when medical treatments failed. 29. Van Assche G, Dignass A, Reinisch W, et al. The second European evidencebased consensus on the diagnosis and management of Crohn’s disease: special situations. J Crohns Colitis 2010; 4:63–101. 30. Bernstein CN, Loftus EV Jr, Ng SC, et al. Hospitalisations and surgery in Crohn’s disease. Gut 2012; 61:622–629. 31. Danese S, Peyrin-Biroulet L. IBD: mucosal healing – EXTENDing our knowledge in Crohn’s disease. Nat Rev Gastroenterol Hepatol 2012; 9:309–311. 32. Ordas I, Feagan BG, Sandborn WJ. Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change. Gut 2011; 60:1754–1763. 33. Costa J, Magro F, Caldeira D, et al. Infliximab reduces hospitalizations and & surgery interventions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2013; 19:2098–2110. This meta-analysis suggests the role of infliximab in hospitalization and surgery risk reduction at least for patients with Crohn’s disease through randomized clinical trials (RCTs) and observational studies. The magnitude of this effect was similar in randomized clinical trials but heterogeneity was seen in observational studies analysis. This article emphasizes the need for prospective specifically designed studies to address these questions. 34. Feagan BG, Panaccione R, Sandborn WJ, et al. Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn’s disease: results from the CHARM study. Gastroenterology 2008; 135:1493–1499. 35. Behm BW, Bickston SJ. Efficacy of infliximab for luminal and fistulizing Crohn’s disease and in ulcerative colitis. Curr Treat Options Gastroenterol 2007; 10:171–177. 36. Lazarev M, Ullman T, Schraut WH, et al. Small bowel resection rates in Crohn’s disease and the indication for surgery over time: experience from a large tertiary care center. Inflamm Bowel Dis 2010; 16:830–835.
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37. Frolkis AD, Dykeman J, Negron ME, et al. Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and metaanalysis of population-based studies. Gastroenterology 2013; 145:996– 1006. This systematic review of 30 population-based studies comprehensively summarizes postdiagnostic surgical risk at 1, 5, and 10 years. Over the past several decades, the risk of surgery has significantly decreased in patients with Crohn’s disease, whereas this finding was statistically significant at 1 and 10 years in patients with ulcerative colitis. Despite limitations (heterogeneity, study not designed to identify the specific cause of the reduction in surgery), this systematic review and meta-analysis showed that the risk of surgery for IBD is decreasing with time and can assist with disease counseling and treatment planning. 38. Peyrin-Biroulet L, Oussalah A, Williet N, et al. Impact of azathioprine and tumour necrosis factor antagonists on the need for surgery in newly diagnosed Crohn’s disease. Gut 2011; 60:930–936. 39. Rubin DT, Uluscu O, Sederman R. Response to biologic therapy in Crohn’s disease is improved with early treatment: an analysis of health claims data. Inflamm Bowel Dis 2012; 18:2225–2231. 40. Laharie D, Bourreille A, Branche J, et al. Ciclosporin versus infliximab in patients && with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet 2012; 380:1909–1915. This GETAID study showed a similar efficacy of infliximab and ciclosporine for controlling severe acute colitis unresponsive to steroids. 41. McDermott E, Murphy S, Keegan D, et al. Efficacy of adalimumab as a long term maintenance therapy in ulcerative colitis. J Crohns Colitis 2013; 7:150– 153. 42. Ferrante M, Vermeire S, Fidder H, et al. Long-term outcome after infliximab for refractory ulcerative colitis. J Crohns Colitis 2008; 2:219–225. 43. Rostholder E, Ahmed A, Cheifetz AS, Moss AC. Outcomes after escalation of infliximab therapy in ambulatory patients with moderately active ulcerative colitis. Aliment Pharmacol Ther 2012; 35:562–567. 44. Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies. Inflamm Bowel Dis 2012; 18:201–211. 45. Garcia-Bosch O, Gisbert JP, Canas-Ventura A, et al. Observational study on the efficacy of adalimumab for the treatment of ulcerative colitis and predictors of outcome. J Crohns Colitis 2013; 7:717–722. 46. Laharie D, Filippi J, Roblin X, et al. Impact of mucosal healing on long-term & outcomes in ulcerative colitis treated with infliximab: a multicenter experience. Aliment Pharmacol Ther 2013; 37:998–1004. In refractory ulcerative colitis, endoscopic appearance after infliximab induction is a good predictor of need for colectomy in patients continuing infliximab; the colectomy rate at 3 years was 4% when the Mayo endoscopic subscore was 0 or 1, and 35% when it was more than 1. &
Volume 30 Number 4 July 2014
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