Lessons to learn from Crohn's disease clinical trials: implications for ulcerative colitis

Transcription

1 Lessons to learn from Crohn's disease clinical trials: implications for ulcerative colitis Aránzazu Jáuregui Amézaga, Elena Ricart, Julián Panés Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain. Address for correspondence: Julián Panés, M.D. Department of Gastroenterology Hospital Clínic of Barcelona Villarroel Barcelona Spain Tel: Fax: e mail: jpanes@clinic.ub.es

2 Abstract The perception that Crohn s disease is a more severe process than ulcerative colitis, led to the initial development of a majority drugs, and testing of treatment strategies, in the former. In the absence of similar studies in ulcerative colitis, information of Crohn s disease studies may help the clinician in decision making in UC. Studies on aminosalicylates show that drugs with a topical effect which are not effective in Crohn s disease may still have efficacy in ulcerative colitis, and this should be considered in future drug development. The best efficacy of corticorteroids is achieved with high doses of 1 mg/kg/day, and reaching remission may be delayed by several weeks, although nonresponse in the initial days should lead to treatment escalation, in particular in severe patients. Thiopurines have a steroid sparing effect, and the duration of treatment should be at least 4 years; caution should be exerted in using these drugs in EBV negative young patients and in the older population for the risk of lymphoma. Anti TNF monoclonal antibody therapy is optimized by use of induction followed by scheduled maintenance as opposed to episodic treatment, resulting in higher sustained response rates and lower immunogenicity. Associations of non biological immunosuppressants with anti TNF antibodies can further increase therapeutic efficacy maintaining a safe profile. Patients under combined therapy with sustained clinical and biological remission and mucosal healing may be candidates to stop anti TNF treatment. The majority of these recommendations need to be specifically studied in patients with ulcerative colitis before generalization in clinical practice. Keywords Inflammatory bowel disease, Crohn s disease, ulcerative colitis, treatment, corticosteroids, azathioprine, infliximab, adalimumab.

3 Under the term inflammatory bowel disease (IBD), two main nosologic entities are included: Crohn s disease (CD) and ulcerative colitis (UC). Whether these are true different diseases, or represent the two ends of a spectrum of chronic inflammatory diseases is still debated. New insights on disease pathogenesis brought about by epidemiologic, genetic, and other molecular and cellular biology studies have not definitively settled this point. Increased prevalence of UC among relatives of patients with CD and vice versa, the identification of a considerable number of common susceptibility genetic variants, documentation of a UC like disease in CD patients with positive serologic UC markers, and shared therapeutic targets (e.g.tumor necrosis factor (TNF) ), favor the view of a continuous disease spectrum [1]. On the other hand, characteristic phenotypic traits such as an almost universal involvement of the rectum and spare of the small intestine in UC, and fistulizing and stenosing complications in CD favor the view of entirely distinct diseases. Studies in recent years have produced highly relevant clinical information on the optimal use of approved drugs for the treatment of CD, including aspects such as timely introduction of drugs, drug combinations, treatment interruption, and identification of patients that can benefit most from particular treatment options. This information is key for tailoring treatment to patients needs and expectations. Also, a majority of new agents and therapeutic modalities are initially tested in CD, with the perception that CD has more unmet therapeutic needs. From a scientific and regulatory point of view, evidence on the efficacy of therapeutic interventions generated in CD cannot be extrapolated to UC, and in this review we will consider how this information may help for the care of patients with UC, and how can it be used to optimize the design of therapeutic studies in UC. Use of Aminosalicylates The benefit of 5 aminosalicylic acid (5 ASA) for induction of remission in CD is limited, and topical corticosteroids (budesonide) are preferred over these drugs for induction of remission in CD located in distal ileum and proximal colon [2;3]. 5 ASA preparations are no more effective than placebo for maintenance of remission in CD [4]. This is in contrast with the well established role of 5 ASA for induction and maintenance of remission in UC [5]. Therefore, there is not much to learn from 5 ASA studies in CD apart from the observation that for induction of remission higher doses are more effective, increasing response and remission rates, and reducing the time to respond. This has been also directly demonstrated in various UC trials and corroborated in a Cochrane systematic review [6]. There is no apparent explanation for the differential effect of 5 ASA in CD and UC. However, it is conceivable that it may be related to pharmacokinetic properties of these drugs. The systemic absorption of 5 ASA is very low, and the drug exerts its effects from the luminal side. UC is a mucosal disease and the inflammatory process might be affected by a non absorbed drug, whereas this is insufficient to modulate a transmural inflammatory process as it occurs in CD. Budesonide is effective in CD, and is also considered a topical drug, but this not because the drug is not absorbed, but due to the high hepatic first pass metabolism. Overall, these observations suggest that for drug development non absorbable compounds should be optimally used in UC.

4 Use of corticosteroids Dosing Historically, corticosteroids have been the most commonly used class of medication for induction of remission in CD. The efficacy of corticosteroids for inducing remission in CD was established in two studies. The American National Co operative Crohn's disease Study achieved a 60% remission rate with prednisone mg/kg/day (higher doses used in more severe disease), compared to 30% on placebo [7]. The European Cooperative Crohn's Disease Study, with a similar design, achieved a 83%remission with 6 methylprednisolone 1 mg/kg/day compared to 38% on placebo [8]. These two studies along with six studies comparing corticosteroids to 5 ASA were included in a recent Cochrane systematic review [9]. Corticosteroids were found to be significantly more effective than placebo at inducing remission in CD (relative risk (RR) 1.99; 95% CI 1.51 to 2.64; P < ), and more effective than 5 ASA at inducing remission in studies with long follow up duration (i.e. > 15 weeks; RR 1.65; 95% CI 1.33 to 2.03; p < ). Corticosteroids induced adverse events in a higher proportion of patients than placebo (RR 4.89; 95% CI 1.98 to 12.07; p = ), or low dose 5 ASA (RR 2.38; 95% CI 1.34 to 4.25; P = 0.003) but did not induce more study withdrawals due to adverse events than either placebo or 5 ASA. No formal studies to determine the optimal duration of treatment and tapering protocol to maximize the efficacy of treatment with corticosteroids in CD have been performed, but very high clinical remission rates were observed in a French study using a high dose (1 mg/kg/day prednisolone), increasing from 63% at week 4 to 92 % at week 7 [10]. Overall the available evidence suggests that in CD a dose of steroids of 1 mg/kg/day over a relatively prolonged period of time is necessary to achieve remission. The question comes whether these concepts may be extended to UC in terms of dosing and time allowed for assessing treatment efficacy. It is out of question that the wide use of glucocorticosteroids in the management of active UC in the second half of the twentieth century had a major role in dramatically reducing the high mortality rate of this condition, from 75% [11] to less than 1% [12]. However, scarce evidence based data are available indicating the optimal dose and route of administration in UC. Only one study including non hospitalized patients with moderate disease compared doses of 20, 40 and 60 mg/day of oral prednisone; a similar efficacy for 40 and 60 mg/day achieving a 65% remission rates at 5 weeks was observed, with significantly lower remission rates (30%) for the 20 mg/day dose {Baron, /id}. Of note, remission rates at 1 week were 20% for higher doses and 5% for the lower dose. For severe UC no trials assessing a dose response rate have been performed, and the majority of studies have used fixed doses, not adjusted to body weight, ranging from mg of methylprednisolone and mg of hydrocortisone. A recently published systematic review of cohort studies and controlled clinical trials assessing the response to corticosteroids in severe UC addressed the issue of dose related efficacy [12]. The dose administered was reported in 24 studies, and no relationship was found between the dose administered standardized as methylprednisolone equivalent while using a mean adult weight of 70 kg and colectomy rate. Nevertheless, the mean daily dose was high (68 ± 13 mg/day, range mg/day); and only 3 studies used doses lower than 50 mg/day. Therefore, doses equivalent to 1 mg of prednisone per kg body weight seem to be the most effective, with higher doses apparently not adding more benefit. These observations parallel the findings of CD studies.

5 Assessment of response The recommendations for time to assess response to corticosteroids in CD and UC seem discrepant. In UC several studies identified factors predictive of treatment failure soon after corticosteroid initiation [14;15]. A pioneering study in this area [15] showed that two simple parameters (stool frequency of > 8 per day, or 3 8 bowel movements per day plus CRP > 45 mg/dl on the third day of therapy) have a positive predictive value (PPV) of 85% for colectomy. A retrospective study produced very similar results [14], showing that when the value of the formula stool frequency/d CRP (mg/dl) was higher than 8 on the 3rd day after initiation of treatment the PPV for colectomy was 72. These results were prospectively validated in the only randomized, placebo controlled study assessing infliximab as rescue therapy in severe UC, showing that patients fulfilling an index criteria of fulminant colitis (value 8) in the placebo arm had a PPV for colectomy of 69% [16]. However, it should be considered that all studies showed also that achievement of complete remission takes longer than response [17]. Whereas lack of response at day 3 of steroid treatment, is associated with a high probability of colectomy and should be used in general as a limit point to define steroid resistance, achieving complete remission will take longer, as in CD, and lack of remission at the early time points should not be categorized as treatment failure. The risks and benefits of prolonging steroid therapy should be carefully weighed, taking into account that the priority in the management of severe UC is to save the patient and, if possible, the colon. Topical steroids Therapeutic benefits of systemic steroids are compromised by an extensive spectrum of side effects. For this reason, topically acting corticosteroids with a more favorable safety profile, such as budesonide and beclomethasone dipropionate have been tested in CD and UC. These topically acting corticosteroids are characterized by a prompt and potent anti inflammatory activity and a low systemic bioavailability, which is mainly achieved through an extensive first pass metabolism. In CD 9 controlled trials compared budesonide with conventional corticosteroids for induction of remission, 2 were placebo controlled, and 1 compared budesonide with mesalazine. A meta analysis of these trials shows that after 8 weeks of treatment, budesonide is significantly more effective than placebo (RR 1.96, 95% CI 1.19 to 3.23) or mesalazine (RR 1.63; 95% CI 1.23 to 2.16) for induction of remission. Budesonide is significantly less effective than conventional steroids for induction of remission (RR 0.86, 95% CI 0.76 to 0.98), particularly among patients with severe disease (Crohn s disease activity index > 300) (RR 0.52, 95% CI 0.28 to 0.95). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better able to preserve adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78) [18]. By contrast, the results of a meta analysis of 11 studies assessing the efficacy of budesonide for maintenance of remission in CD show that the drug is not more effective than placebo or weaning prednisolone for maintenance of remission in Crohn's disease [19]. Efficacy of topical steroids for induction of remission has also been assessed in UC and the agent most extensively studied is beclomethasone. Two randomized controlled studies have shown that an oral dose of 5 mg/day of beclomethasone may be as effective as a standard dose of 2.4 g/day of 5

6 ASA to induce remission in mild to moderate UC within 4 weeks [20], and that combination treatment (oral beclomethasone plus oral 5 ASA) may be more effective than 5 ASA alone [21]. Therefore, in contrast with the data in CD, topical acting steroids in UC do not appear to be more potent than 5 ASA preparations, and some therapeutic gain might be obtained by using these agents as an add on in patients with inadequate response to 5 ASA. As in CD no data is available on the efficacy of topical acting steroids in severe UC, and should not be used in either form of severe IBD. Use of non biologic immunosuppressants Thiopurines: efficacy and steroid sparing effect Solid evidence exists on the efficacy of thiopurines for induction and maintenance of remission in patients with chronic active CD and in steroid dependent CD. A meta analysis including 8 randomized placebo controlled trials of azathioprine and 6 mercaptopurine therapy in adult patients [22] showed that the odds ratio (OR) of a response was 2.43 (95% CI 1.62 to 3.64), and this corresponded to a number needed to treat (NNT) of about 5 to observe an effect of therapy in one patient, with a similar efficacy for azathioprine and 6 mercaptopurine when trials were analyzed separately. A steroid sparing effect was seen with an OR of 3.69 (95% CI ), corresponding to a NNT of about 3 to observe steroid sparing in one patient. Adverse events requiring withdrawal from a trial, principally allergy, leukopenia, pancreatitis, and nausea were increased with active therapy with an odds ratio of 3.44 (95% CI 1.52 to 7.77). The NNT to observe one adverse event in one patient treated with azathioprine or 6 mercaptopurine was 14.However, thiopurines have a slow onset of action and they generally require concomitant corticosteroids for induction therapy, and only in those patients with mild moderate disease that experienced adverse events with steroids, thiopruines are used as monotherapy for induction of remission. In clinical practice thiopurines are mostly used for maintenance of remission and the efficacy of the drug in this setting has been assessed in a meta analysis including 7 trials of azathioprine and one of 6 mercaptopurine, showing a positive effect on maintaining remission [23]. The OR for maintenance of remission with azathioprine was 2.32 (95% CI 1.55 to 3.49) with a NNT of 6. The corresponding OR for 6 mercaptopurine was 3.32 (95% CI 1.40 to 7.87) with a NNT of 4. Higher doses of azathioprine improved response. A steroid sparing effect with azathioprine was noted, with an OR of 5.22 (95% CI 1.06 to 25.68) and NNT of 3 for quiescent disease. Similar to the induction studies, withdrawals due to adverse events were more common in patients treated with azathioprine than with placebo (OR 3.74; 95% CI 1.48 to 9.45, NNT = 20). Despite the widespread use of azathioprine and 6 mercaptopurine for the treatment of patients with UC in clinical practice, the data supporting such use remain limited. Uncontrolled experience has suggested a benefit [24 26], but controlled trials have yielded conflicting results [27 29]. Several studies have shown a beneficial steroid sparing effect of azathioprine with doses ranging from mg/kg daily for six months, but the beneficial effects became less clear with longer follow up [30]. A randomized controlled trial of 72 steroid dependent UC patients treated with either 5 ASA or azathioprine while receiving concurrent tapering doses of steroids showed that azathioprine induced significantly better remission rates compared with 5 ASA (53% vs. 19%; p = 0.006) [31]. A recent meta analysis of four trials confirmed that patients with UC who continued with azathioprine are less likely to experience a relapse than those who received placebo (OR 0.41; 95% CI: )

7 [32]. In coincidence with trials in CD the most effective doses appear to be for azathioprine 2 3 mg/kg and for 6 mercaptopurine mg/kg daily, although there has not been a direct comparison of different dose levels or a comparative study evaluating azathioprine versus 6 mercaptopurine. Methotrexate Methotrexate has been studied for its effect in inducing remission in active CD. A meta analysis identified 5 placebo controlled randomized studies that compared placebo to different formulations of methotrexate [33]. The results showed that high and low dose oral methotrexate had a similar efficacy to placebo. However, methotrexate given at a high dose (25 mg weekly) through intramuscular injections over a 16 week period effectively induced remission of CD and ultimately lead to reduction in dose or cessation of the steroid. In patients with steroid dependent UC who fail to respond to or who are intolerant of thiopurines, methotrexate has been used to maintain remission, although evidence is based on uncontrolled studies with small sample sizes and heterogeneous doses [34;35]. In a retrospective study, 23 patients intolerant or resistant to purine analogs were treated with subcutaneous methotrexate mg weekly. Remission was achieved in 11 patients (48%) and an additional 3 patients (13%) showed symptomatic improvement and/or an ability to reduce their corticosteroid dose [36]. The only double blind, placebo controlled trial in UC using oral methotrexate at a dose of 12.5 mg/week showed no therapeutic benefit when compared with placebo [37]. Provided the results of CD studies showing no efficacy of low dose oral methotrexate, but efficacy of higher parenteral doses, more comparative studies with different doses and different routes of administration are warranted [38]. In that regard a placebo controlled trial of methotrexate in UC is being developed by the Group des Etudes Thérapeutiques des Affections Inflammatoires du tube Digestif (GETAID). While results of this study are not available, methotrexate use at high dose (25 mg/week) and by parenteral route should be only contemplated as a potential rescue therapy in patients failing thiopurines and anti TNF agents, in whom surgery may entail a high risk. Timely introduction of immunosuppressants Where studies of thiopurine efficacy in CD may be more enlightening for treatment of UC patients relates to strategies to start and to withdraw therapy. Thus, it has been suggested that the failure of immunosuppressants to alter the clinical course of CD may be related to the delay of their use until after initiation of systemic corticosteroids [39]. In contrast, earlier introduction of immunosuppressants has led to better clinical outcomes with less need for a corticosteroid in children with newly diagnosed CD and no prior exposure to steroids [40]. Identification of patients with a potential complicated course of UC is even more difficult that the identification of CD patients with worse prognosis, but some aspects such as requirement of corticosteroid therapy at presentation, progression from distal to extensive disease [41], and suffering a severe flare [42] represent risk factors for steroid resistance and colectomy, and these factors, in addition to

8 inadequate response to steroids, should lead to the consideration of initiating thiopurines and/or an anti TNF drug. Stopping immunosuppressant therapy As in patients with CD, in patients with UC treated with thiopurines for maintenance, the question arises of whether this treatment can be stopped without risking early disease flares or complications. The issue of stopping immunosuppressive is only a concern if safety is compromised, and a growing body of evidence indicates that thiopurines may carry a small but significant risk of lymphoma and of serious infections [43]. A prospective French GETAID study randomized 83 patients with Crohn's disease in clinical remission to withdrawal or continuation of azathioprine after at least 42 months of therapy. After 1.5 years the probability of relapse was 21% in patients who stopped azathioprine and (8% in the continuation group; the hypothesis that stopping azathioprine was inferior to azathioprine continuation was not rejected (neither directly proved). Elevated baseline CRP levels, but not the presence of mucosal lesions, predicted clinical relapse [44]. A long term follow up of 66 patients included in this study [45] who stopped azathioprine, during or at the end of the randomized controlled trial, showed that the cumulative probabilities of relapse at 1, 3, and 5 years were 14.0% 52.8%, and 62.7% respectively. C reactive protein concentration of 20 mg/l or greater (risk 58.6; 95% CI, ; p = 0.002), hemoglobin level less than 12 g/dl (risk 4.8; 95% CI, ; p = 0.04), and neutrophil count 4 x 10 9 /L or greater (risk 3.2; 95% CI, ; p = 0.003) were associated independently with an increased risk of relapse. Among the 32 relapsing patients, 23 were retreated by azathioprine alone, all but 1 up to successful remission. Overall this body of evidence suggests that in CD stopping therapy in patients who are in remission under this treatment is associated with a high risk of relapse, and this decision should be personalized based on risk assessment. Also in UC, available evidence suggests that once a patient responds to azathioprine long term therapy should be contemplated. A double blind withdrawal study [46] showed that patients randomly switched from azathioprine to placebo were more likely to relapse than those who continued with azathioprine therapy. A recent Italian multicenter observational retrospective study [47] stopped treatment with azathioprine in 127 UC patients who were in steroid free remission under this treatment. After drug withdrawal, a third of the patients relapsed within 12 months, half within 2 years and two thirds within 5 years, proportions which are very similar to those observed in CD study [45]. Multivariable analysis, of the UC study [47] showed that predictors of relapse after drug withdrawal were lack of sustained remission during azathioprine maintenance, extensive colitis, and treatment duration, with short treatments (3 6 months) more disadvantaged than >48 month treatments (OR 2.783, CI 95 % , p = 0.008). Concomitant 5 ASA was the only predictor of sustained remission during azathioprine therapy (p = 0.009). In keeping with evidence coming from CD studies, withdrawal of azathioprine in patients with UC who are in remission under this treatment should be a decision tailored to the individual patient, and patients should be informed about the high risk of relapse long term. Prospective randomized controlled trials are needed to identify patients with UC at lower risk of relapse upon thiopurine discontinuation.

9 Use of anti TNFs The most significant advance in the last 3 decades for treatment of IBD is the introduction of anti TNF therapy one decade ago. The efficacy of anti TNF drugs for treatment of CD is well established. A meta analysis of placebo controlled trials including 14 studies in luminal CD with a total of 3995 patients demonstrates that anti TNF therapy is more effective than placebo for induction of remission at week 4 (mean difference, 11%; 95% CI, 6% 16%; P <.001) and maintenance of remission at weeks in patients who responded to induction therapy (mean difference, 23%; 95% CI, 18% 28%, p < 0.001), and also when the whole population of patients randomized before induction is considered (mean difference 8%; 95% CI, 3% 12%, p < 0.001). Infliximab, adalimumab, and certolizumab are all effective in luminal CD. Ten studies evaluated anti TNF for treatment of fistulizing Crohn's disease, involving 776 patients. In overall analysis, anti TNF therapy was more effective than placebo for fistula closure only in maintenance trials after open label induction (mean difference, 16%; 95% CI, 8% 25%; P <.001). Efficacy of anti TNF agents other than infliximab in treating fistulizing Crohn's disease requires additional investigations [48]. The efficacy of anti TNF therapy has also been proved in UC. A meta analysis including seven randomized controlled trials showed that in patients with moderate to severe ulcerative colitis whose disease was refractory to conventional treatment using corticosteroids and/or immunosuppressive agents, infliximab (three intravenous infusions at 0, 2, and 6 weeks) was more effective than placebo in inducing clinical remission (RR 3.22, 95% CI 2.18 to 4.76); inducing endoscopic remission (RR 1.88, 95% CI 1.54 to 2.28); and in inducing clinical response (RR 1.99, 95% CI 1.65 to 2.41) at 8 weeks. A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44, 95% CI 0.22 to 0.87) [49]. Another recent study published only in abstract form showed that adalimumab is also more effective than placebo for induction of remission in UC [50]. Despite the success of anti TNF therapy in the clinical trial realm, there remains debate on how best to utilize this agents and when the ideal time is to introduce or withdraw such therapy. In that regard valuable information has been produced recently in CD that may help the clinician in managing anti TNF drugs in patients with UC. Preventing immunogenicity Probably one of the most frustrating and difficult situations for the patient and the physician is the loss of response and/or appearance of allergic reactions to an anti TNF drug after successful induction of remission. This has led to a significant debate regarding the most appropriate strategies to minimize or delay the onset of such events. These events are believed to develop, at least in part, as a result of appearance of antibodies to the anti TNF drug. Data from subgroup analysis of clinical trials as well as prospective cohort studies in patients with CD demonstrated that episodic infliximab therapy leads to significantly higher rates of formation of antibodies to infliximab (ATI) than scheduled therapy [51 53]. The rate of ATI formation with episodic infliximab therapy is approximately 25 30%, whereas in patients receiving scheduled maintenance infusions of infliximab at 8 week intervals the rates of antibody formation are less than 5%. Maser and colleagues [54] studied 105 patients with CD receiving 5 mg/kg infliximab infusions as either maintenance or

10 episodic therapy followed for a median of 23 months. It was observed that after a median of 14 infusions, patients receiving infliximab episodically had higher ATI concentrations than those receiving scheduled therapy (39 versus 16%). Episodic therapy was also associated with higher rates of infusion reactions. Rates of clinical remission were observed to be higher in those individuals with higher trough serum infliximab concentrations. Stratification by the presence or absence of concomitant immunosuppressant therapy revealed that immunosuppression appeared to be protective against the development of ATIs in the group receiving episodic therapy, but not so in the group receiving scheduled therapy. The data from a second and larger cohort of CD patients from Leuven treated with infliximab [55] corroborated the findings of Maser and colleagues. These are important observations also for the management of UC. In patients with chronic active, steroiddependent, or steroid refractory UC the first treatment choice should be induction and maintenance of remission with infliximab, avoiding episodic treatment. In a prospective study premedication with 200 mg hydrocortisone before each infusion of infliximab significantly reduced the proportion of patients developing ATIs from 42% to 26% [56], although the long term clinical implications of this treatment strategy remains to be determined. In clinical practice, pretreatment with hydrocortisone may be particularly considered in patients under infliximab monotherapy. Management of loss of response Confusion also exists in relation to appropriate therapeutic strategy upon secondary loss of response to anti TNF biologic therapy. In the absence of robust controlled trial evidence, an observational cohort of infliximab responders who subsequently lost response during maintenance therapy were treated with 10 mg/kg infliximab. Those treated with the increased infliximab dose experienced an overall decrease in the Harvey Bradshaw Index of 4.7 points, suggesting some benefit of dose escalation [57]. Likewise, an analysis of the data from the ACCENT I trial [52] demonstrated that amongst a subgroup of patients who lost response to 5 mg/kg scheduled infliximab infusions, 90% successfully regained response after receiving a 10 mg/kg dose. Approximately 80% of patients who lost response to the 10 mg/kg dose as scheduled therapy regained response when crossing over to 15 mg/kg infliximab. Similarly, data derived from the adalimumab CHARM study show that 70% of patients who lose response to every other week adalimumab treatment regain response when intensified to weekly doses [58]. A single additional infusion of certolizumab 400 mg has also been shown to be effective for reinduction of response in patients who lost response to the drug. In the large infliximab (ACT1 and ACT2) [59] studies in UC dose escalation was not permitted as a rescue therapy, and evidence of the efficacy of dose escalation in UC is lacking, but considering that development of anti drug antibodies and secondary decrease in drug levels is the main cause of loss of response to anti TNF antibodies, it is conceivable that a similar regain of efficacy should be obtained by dose increase (or reduction of dosing intervals) in patients with UC. If patients have already been dose escalated, or if there is no response to dose escalation, then switching to a second anti TNF may regain response and remission. The data showing efficacy of switching is solid in CD. This has been specifically addressed in a study in 325 patients with active CD despite infliximab therapy or who could not tolerate infliximab [60]. Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points. Twenty one percent of patients in the adalimumab

11 group versus 7% of those in the placebo group achieved remission at week 4 (p < 0.001), demonstrating the efficacy of a second anti TNF in these difficult to treat CD patients. A single series of 20 patients with UC, 13 of which had lost response or developed intolerance to infliximab, demonstrated a response rate to adalimumab of 50% at week 24, which was similar in patients previously exposed or not to infliximab [61]. Phase III studies of adalimumab for UC have been presented in abstract form, and show a higher efficacy than placebo for induction of remission [50]. Therefore, switch to adalimumab is becoming a valid alternative in patients with UC if they lose response or do not tolerate infliximab. Treating early disease The natural behavior of CD is characterized by recurring disease flares alternated with periods of inactive disease and remission, and these flares result in progressive accumulation of damage and loss of function. Cohort studies in French and Belgian referral centers show that most patients will have a disabling disease course leading to complications and surgery [62;63], underlining the need for strategies aimed at interrupting or delaying the natural evolution of the disease. However, for an individual patient predicting a disabling disease course and thus the need for more advanced medical therapy has been difficult. Young patients (<40 years) or patients with invalidating perianal lesions or requiring corticosteroids at diagnosis, appear to be most at risk. Therefore, the question emerges where intense therapy should be started before disease complications or refractoriness to conventional treatment develops, with the aim of changing the course of disease. This point was addressed in a clinical strategy trial from Belgium and the Netherlands that randomized 133 patients with active CD naïve to both steroids and azathioprine to either a conventional step up strategy with full courses of steroids (prednisolone or budesonide) and introduction of azathioprine when they flared after tapering or became dependent on steroids, and introduction of infliximab is they flared or not tolerated immunosuppressants [64]. Patients in the top down arm received three infusions of infliximab and were started on azathioprine at induction. From week 6 azathioprine was continued as a monotherapy. Until 1 year after the start of therapy steroid free remission was more frequent in the early combined immunosuppressive group (61.5 vs. 42.2%, p < 0.05). The median time to relapse was also longer in the early combined immunosuppressive top down group: days, interquartile range (IQR) 91.0 vs days, IQR , p = The trial confirmed that in patients starting corticosteroids to control their CD after 2 years more than two thirds are treated with azathioprine. Although the trial was open label and therefore liable to observer bias, the marked difference in complete ulcer disappearance at endoscopy with 73% of evaluated patients in the early combined immunosuppression group vs. 30.4% in controls was remarkable. The authors concluded that Crohn's disease can be effectively treated without steroids if patients are offered early combined immunosuppressives and that this leads to more rapid clinical remission, fewer relapses and improved mucosal healing (see below). The implications that this trial may have for UC may be less clear than other concepts derived from CD trials. Nevertheless, independent studies in America [65] and Europe [66] are coincident in showing that among UC patients requiring steroids, at one year one third will become steroid dependent, and 20% may require colectomy. In the absence of studies comparing a step up with a top down strategy in patients with UC, combined therapy with an immunosuppressant and anti TNF drug might be considered in early disease in cases

12 requiring steroids, in particular in cases of extensive disease with a severe disease flare at the time of presentation [42]. Monotherapy vs. combination with an immunosuppressant Higher efficacy of combined therapy with an immunosuppressant and an anti TNF drug relative to monotherapy with these drugs has been demonstrated in two pivotal trials. It was first proved by Lemann and cols. from GETEAID in a study enrolling 113 patients with active CD despite prednisone given for more than 6 months [67]. All patients were treated with azathioprine/6 mercaptopurine maintained at a stable dose throughout the 52 weeks of the study and were randomized to combined treatment with infliximab 5 mg/kg or placebo at weeks 0, 2, and 6. The proportion of patients in remission and free of steroids was higher in the infliximab group than in the placebo group at week 12 (75% vs 38%; p < 0.001), at the time of the primary endpoint at week 24 (57% vs 29%; p = 0.003); and at week 52 (40% vs 22% p = 0.04).The benefit of combined therapy was even greater in immunosuppressant naïve patients. However, when subgroup analysis according to previous immunosuppressive exposure was made, both immunosuppressant naïve and experienced patients lost the benefit of initial combined therapy over time, being at 52 week the proportion of patients in steroid free remission no different between those that had received combined therapy at the start of the study in comparison with the groups of patients treated only with azathioprine, suggesting that induction therapy with infliximab affords clinical benefit in the short term but is not sufficient to induce disease modification in patients with steroid dependent CD. The superior benefit of long term combined thiopurine and infliximab therapy over monotherapy with either of these drugs was demoonstrated in SONIC (Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease) [68], a randomized, double blind, three arm trial, comparing the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate to severe CD not previously exposed to these drugs. Infliximab was given at a dose of 5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; and azathioprine at a dose of 2.5 mg/kg oral. Patients received study medication through week 30 and could continue in a blinded study extension through week 50. Of the 169 patients receiving combination therapy, 56.8% were in corticosteroid free clinical remission at week 26 (the primary end point), as compared with 44.4% receiving infliximab alone (p=0.02) and 30.0% receiving azathioprine alone (p<0.001 vs. combination therapy, p=0.006 vs. infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 43.9% of patients receiving combination therapy, as compared with 30.1% of patients receiving infliximab (p=0.06) and 16.5% of those receiving azathioprine (p<0.001 vs combination therapy and p=0.02 vs. infliximab). Importantly the incidence of serious infections was low, and similar across the treatment groups: 3.9% of patients in the combination therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group. The results of the SONIC study may be apparently at odds with the observation of the COMMIT trial (Combination of Maintenance Methotrexate Infliximab Trial), in which CD patients who were receiving induction steroid therapy were randomized to receive combination infliximab and methotrexate, or monotherapy with infliximab. There were no differences in the proportion of patients in remission who were off steroids at 14 or 52 weeks [69]. The reconciliation of these 2

13 trials appears to be the differences in induction regimens and suggests that aggressive therapy with these 2 agents, infliximab with steroids or infliximab with immunosuppressants, is superior to treatment with monotherapy The patient population included in the SONIC study had short disease duration and were naïve to immunosuppressants and anti TNF therapy. With the purpose to assess whether immunosuppressant cotreatment is also superior to monotherapy in a more general population of patients with IBD on scheduled infliximab infusions, a single center study was performed that included 121 consecutive patients (23 UC, 98 CD) treated by infliximab and who had received at least 6 months of cotreatment with azathioprine or methotrexate [70]. IBD flares were less frequently observed during the periods patients were under treatment with immunosuppressants (19.3% ) than in periods without immunosuppressants (32.0%, p<0.003). Appearance of perianal complications (4.1% vs 11.8%, p<0.03) and switch to adalimumab (1.1% vs 5.3%, p<0.006) were also less frequent in periods of combined treatment with infliximab and an immunosuppressant. Higher C reactive protein (CRP) levels and higher requirements of infliximab dose/kg were observed during the periods patients were under combined therapy. The low number of patients with UC included in the study does not allow a subanalysis of this population, but the overall results suggests that independently of disease duration and previous immunosuppressant exposure in patients with IBD receiving infliximab maintenance therapy, double immunosuppression with infliximab and a non biologic immunosuppressant is associated with reduced IBD activity, and prevention of loss of response to infliximab. Thus, consistent evidence is accumulating showing that in CD patients who are candidates for treatment with an immunosuppressor or an anti TNF combined therapy should be preferred over monotherapy with either agent. The extension of this practice to UC needs to wait for the results of an ongoing study in UC with a similar design to the SONIC study, and future studies assessing the differential response in patients with previous immunosuppressant failure. Treatment desintensification Finally, a frequent and relevant question for patients, physicians and health payers is whether in patients under combined therapy achieving a sustained clinical remission either the non biologic immunosuppressant or the anti TNF drug may be safely withdrawn. This question has gained a more relevant dimension after recent data showed an increased risk of lymphoma associated with the use of thiopurines [43], and in contrast registry data did not show a significant increase of cancer risk in patients treated with an anti TNF drug [71]. This is also an aspect that has only been evaluated in CD. This issue was first addressed in a controlled trial [72] including 80 patients started on infliximab and followed prospectively. All patients received concomitant immunosuppression for the first 6 months. Thereafter, patients were randomized to either continue or stop concomitant immunosuppressants. The primary endpoint was the difference in the proportion of patients who lost response or required infliximab dose increase between the two groups. At the end of follow up there was no difference in the pre specified endpoint between the two groups, suggesting that concomitant immunosuppressive therapy may only be required for the first 6 months of infliximab administration to protect against immunogenicity. However, the group who had immunosuppressants withdrawn

14 had lower median serum infliximab trough levels and higher antibody titers. There have been some criticisms of this trial: the study is underpowered as a non inferiority trial, and the follow up period may be short to provide evidence of a clinically relevant difference. Another option to reduce the intensity of immunosupression in patients under combined therapy would be withdrawal of the anti TNF agent. This issue has been directly addressed in another GETAID trial. Preliminary data indicate that, in patients with CD in clinical remission with infliximab and thiopurine maintenance therapy for at least 6 months, interrupting the anti TNF drug leads to clinical relapse in almost half of the patients after a median follow up of 12 [73]. Independet predictors of the risk of relapse include: male gender, previous surgery, use of steroids, hemoglobin, white blood cell counts, high sensitivity CRP, and presence of mucosal lesions. Presence of four or less of these factors entails a risk of relapse of 7% at 18 months compared with a risk of 95% in patients with all factors present. Importantly, in the vast majority of patients who relapsed, reintroduction of the anti TNF drug was very safe and effective. Final results of this important trial are awaited. In keeping with the preliminary results of this study, analysis of a subgroup of patients with Crohn s disease who completed the ACCENT 1 study suggested that achieving mucosal healing increased the duration of clinical remission and the time to clinical relapse after withdrawing the drug [74]. Patients with complete mucosal healing (n = 9) at week 54, after receiving scheduled maintenance treatment with infliximab (5 mg/kg or 10 mg/kg) or episodic treatment with infliximab (5 mg/kg, 10 mg/kg or 15 mg/kg for 40 weeks), remained without clinical relapse for a median of 20 weeks (range weeks) following their last infliximab infusion. By contrast, patients without mh (n = 4) developed clinical relapse after a median of 4 weeks (range 0 8 weeks) [74]. Data generated in CD suggests that a prolonged stable clinical remission, together with absence of biomarkers of clinical activity, and evidence of endoscopic healing of mucosal lesions is associated with a low risk of relapse upon discontinuation of an anti TNF drug, and that in patients who are maintained under immunosujppressants interrupting the biologic drug does not entail a significant risk of immunogenicity, and does not compromise future drug efficacy in case or relapse. While withdrawal studies of anti TNF biologics in UC are not available, these criteria might be used to select potential candidates for withdrawing anti TNF therapy in UC. Therapeutic objectives: Clinical remission and mucosal healing Awareness of the potency of anti TNF treatment to induce not only symptomatic remission but also healing of inflammatory lesions in the intestinal mucosa has fostered an intense debate as to whether mucosal healing is just a measure of efficacy or it should be considered a therapeutic objective, and treatments should be adapted to achieve this goal. In CD, the presence of deep ulcerations at colonoscopy has been found to be a predictor of a more aggressive disease course, with increased rates of penetrating complications and colectomy [75]. The Inflammatory Bowel South Eastern Norway (IBSEN) cohort study confirmed that mucosal healing has a significant influence on disease outcome in both CD and UC. The study included patients who underwent clinical and endoscopic evaluation at baseline, 1 year and 5 years after diagnosis of IBD. In patients with CD, 11% of patients with mucosal healing at 1 year underwent surgical resection by 5 years, compared with 20% of patients without mucosal healing at 1 year (p = 0.10) [76]. The follow up period in this cohort was extended to 10 years and the reduced rates of surgery associated

15 with mucosal healing were found to be significant. A 60% reduction in the risk of surgery was found for patients who had mucosal healing compared with patients who had endoscopic evidence of inflammatory lesions (OR 0.42; 95% CI ) [76;77]. Importantly, data from randomized controlled trials in CD suggests that therapeutic interventions with drugs which are effective to induce mucosal healing have the capacity to alter the course of disease. A substudy of a 1 year trial of infliximab maintenance therapy in patients with Crohn's disease raised the possibility that evidence of mucosal healing at week 10 and week 54 is associated with clinical remission through week 54, however, these results were not statistically significant [78]. As part of the 'step up/top down' study [64], a substudy focused on the value of performing endoscopy after 2 years of treatment to predict clinical outcome in the following 2 years [79]. Combining the two treatment arms, mucosal healing (defined as a simple endoscopic score of 0) at 2 years predicted stable clinical remission in the following 2 years in 71% of the patients. By contrast, endoscopic evidence of persistent disease at 2 years activity (simple endoscopic score score of 1 9) was associated with a marked decrease in the proportion of patients who had a stable clinical remission in the following 2 years (27%, p = 0.036), indicating that in early stage CD complete mucosal healing is associated with significantly higher steroid free remission rates 4 years after therapy began. The endoscopic substudy of the ACCENT 1 trial showed that all patients who achieved mucosal healing both at week 10 and week 54 after infliximab treatment (n = 9) did not require hospitalization [78]. Patients with mucosal healing at either week 10 or week 54 still required fewer hospitalizations (19%) compared with those who did not have mucosal healing at either week (28%). A 2009 study focused on the influence of mucosal healing on the long term course of CD treated with infliximab therapy [55]. A large cohort of 214 patients were followed up for a median duration of 5 years: 64.8% of patients who achieved mucosal healing were in clinical remission until the end of follow up compared with 39.5% of patients who did not achieve mucosal healing (p = ). Importantly, patients in this study who achieved partial or complete mucosal healing during infliximab therapy needed fewer hospitalizations during their follow up (42.2%) compared with patients who did not achieve mucosal healing (59.3%, p = 0.001). A median of 22.3 months after follow up endoscopy had been performed during infliximab therapy, patients with complete mucosal needed major abdominal surgeries significantly less often (14.1%) than patients without mucosal healing (38.4%, p <0.0001). Being CD and UC different diseases, in particular for the characteristics of inflammatory intestinal lesions, the relevance of achieving mucosal healing in CD, may or may not have the same implications of UC. The importance of achieving mucosal healing is becoming also apparent for UC, in terms of reduced risk of clinical relapses and complications. In a preliminary study, 40% of patients with ulcerative colitis who achieved mucosal healing after acute treatment with oral and rectal corticosteroids remained asymptomatic during a 1 year follow up. By contrast, only 18% of patients who still had endoscopic lesions after treatment remained symptom free during the same period [80]. Reduced relapse rates have also been reported in patients who, during acute treatment of a disease flare, achieved both clinical and endoscopic remission. In the 12 month MMX mesalazine, long term, open label extension study, clinical relapse rates were 10% in patients who had previously achieved remission that included mucosal healing [81]. A secondary analysis of two pivotal trials (ACT 1 and ACT 2) [59] of infliximab for the treatment of moderate to severe active ulcerative colitis demonstrated that the proportion of patients in clinical remission at week 30 of therapy was fourfold greater for patients with mucosal healing at week 8 (48.3%) compared with