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Mitchell RKL Lie, C Janneke van der Woude Department of Gastroenterology, Erasmus University Hospital, Rotterdam, the Netherlands Disclosure: No potential conflict of interest. Citation: EMJ Gastroenterol. 2013;1:82-91.
Management guidelines offer clinicians clear, evidence-based and often succinct treatment advice. For ulcerative colitis these guidelines describe the use of 5-ASA, corticosteroids, thiopurines, cyclosporine, and anti-TNFα therapies. However, guidelines do have some drawbacks, mainly a lack of concrete advice concerning patients resistant to these aforementioned therapies. This review gives a short overview of current guidelines and addresses treatment alternatives for conventional therapies.
Keywords: Ulcerative colitis, management, therapy, 5-ASA, corticosteroids, azathioprine, 6-mercaptopurine, 6-thioguanine, cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil, infliximab, adalimumab, golimumab, vedolizumab.
The management of ulcerative colitis (UC) remains challenging to even the most seasoned clinician. The choice of therapy depends on disease This is partly due to the non-elucidated aetiology severity and localisation. To properly describe of the disease. Periodically updated guidelines severity and localisation, several classification are valuable instruments that aid clinicians in systems exist. Most often the Mayo score decision-making. However, the management of or the Truelove and Witts’ index is used to UC at an individual level remains challenging due classify severity, whereas localisation is usually to highly variable disease presentations that anatomically described as proctitis (rectum are not specifically covered by the guidelines. only), left-sided (beyond the rectum but distal Decision-making can be difficult for patients of the splenic flexure), or extensive (extending intolerant to conventional therapy, or with beyond splenic flexure). Below, the appropriate treatment-resistant disease limited to only the conventional treatments are summarised. The rectum. Also, a patient’s preference for certain 2012 European Crohn’s and Colitis Organisation treatments can result in more complicated (ECCO) guidelines on UC give more thorough decision-making, for example when patients refuse recommendations in different situations.1 In this review we will summarise the latest guidelines on the management of UC. Additionally, Topical 5-ASA therapy is the first-line therapy for treatment options and evidence for patients proctitis. There is evidence for topical treatment that have exhausted the therapies suggested by only,2-12 with some evidence showing that topical the guidelines will be discussed and a strategy 5-ASA treatment is superior to oral 5-ASA will be proposed for this particular subgroup. treatment alone.13 Topical steroid therapy has Furthermore, the limited evidence of several new been found to be inferior for remission induction14 biological therapies close to registration and and should therefore be used as a second-line approval will be examined. therapy in case of 5-ASA intolerance.
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presentation is relatively rare. In contrast, it is more common to see outpatients who reach remission A combination of oral and topical 5-ASA has but either fail to taper their steroids or relapse proven to be more effective than either agent soon after tapering, making them steroid- alone in the treatment of left-sided UC.15-18 If this dependent. In the following paragraph several fails, oral steroids might be added.
options for the treatment of steroid-dependent disease and their respective evidence will Combined oral plus topical 5-ASA remains the first-line of treatment. If this therapy fails, oral steroids can be added.19-23 If steroid dependence A prospective study43 has shown that azathioprine occurs, thiopurine treatment is recommended.24 (AZA) and its metabolite 6-mercaptopurine (6-MP) are highly effective in achieving steroid- free remission, with persistent long-term results Severe disease is potentially life-threatening and found in observational studies.44in most cases requires hospital admission and Anti-TNFα immediate treatment. All guidelines recommend high-dose intravenous glucocorticoids as the In case of failure or intolerance to thiopurines, first treatment modality, even though only anti-TNFα therapy is considered the next step. limited evidence exists.25-27 Early consideration of Several large trials45 and a Cochrane meta- salvage treatments is of great importance as a analysis46 have conclusively proven the efficacy of precautionary measure as the patient may not infliximab in this setting. Though less extensively studied,47,48 adalimumab has also shown efficacy in steroid-dependent disease and in patients Intravenous Steroid-Refractory Severe Disease intolerant to thiopurine treatment.
Intravenous steroid-refractory disease leaves clinicians with limited drug therapies. Salvage therapy should not be initiated simply to delay surgery, as such delays will lead to greater If conventional therapies fail, colectomy becomes morbidity at surgery.28 If clinical and biochemical a valid treatment option for patients with UC. parameters allow an attempt at salvage, the Clinical experience shows a profound difference guideline recommends cyclosporine, infliximab in acceptability of colectomy in hospitalised or tacrolimus. High quality prospective patients compared with outpatients, though no evidence exists for the use of cyclosporine,27,29-31 formal studies have examined this issue. It is not confirmed by several retrospective studies.32-34 uncommon for outpatients to refuse colectomy, There is also prospective evidence31,35-37 and some despite being informed of the possible benefits of such intervention. In these situations a clinician therapy. The prospective evidence for tacrolimus may need to resort to either enrollment in clinical is less extensive, trials or initiation of an unconventional therapy populations and the use of tacrolimus is therefore in the hope of controlling a patient’s symptoms. not as strongly recommended by the guideline.
The provided algorithm (Figure 1) may help clinicians in their decision-making regarding these There is limited evidence for using infliximab as a therapies, which are described in more detail below. rescue therapy to cyclosporine, or vice-versa.41,42 Therapy-Resistant Proctitis The guideline recommends such a third-line therapy only in select cases treated by a A subset of patients with disease limited to the multi-disciplinary team in specialist centres. rectum is surprisingly treatment-resistant to topical 5-ASA and/or topical steroid therapies. This may present clinicians with a treatment dilemma: escalate to systemic therapies, with all associated adverse effects, or accept the limited disease Though intravenous steroid-refractory disease localisation. There is a paucity of prospective represents the most severe cases of UC, this controlled trials within this patient subgroup. EMJ EUROPEAN MEDICAL JOURNAL
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Figure 1. Management algorithm for therapy-resistant ulcerative colitis. UC: ulcerative colitis; CMV: cytomegalovirus; IBS: irritable bowel syndrome.
There is only one randomised, placebo-controlled ulcerative proctitis resistant to topical 5-ASA trial remotely addressing this issue.49 This study and/or topical steroid therapy. This study used investigated the efficacy of cyclosporine enemas tacrolimus suppositories and assessed efficacy in left-sided disease (disease extent ranging from after 4 weeks of treatment. Clinical remission 10 to 60 cm ab ani). No significant difference in was achieved in 83% (10 out of 12) with complete remission rate between cyclosporine and placebo endoscopic healing in 33% (4 out of 12). These was found.
promising pilots warrant further investigation of topical tacrolimus in treatment-resistant Two open-label pilot studies investigated the efficacy of topical tacrolimus for treatment- resistant proctitis. The first,50 applied tacrolimus Even retrospective data are scarce. One study52 ointment in ulcerative proctitis patients who failed retrospectively investigated the efficacy of previous 5-ASA, steroid, immunosuppressant, infliximab in patients with proctitis resistant to and infliximab therapy. 75% (6 out of 8) achieved at least 5-ASA and steroids. Clinical response was remission after 8 weeks, with reduction or seen in 85% (11 out of 13) after infliximab cessation of steroid usage in five of the induction therapy. Two patients suffered from responders. The second,51 treated 12 patients with adverse events. Other retrospective studies53-55 EMJ EUROPEAN MEDICAL JOURNAL
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regarding infliximab contain only a few subjects Methotrexate with proctitis, and their response is not Few prospective studies have been performed on methotrexate (MTX) in UC. One study in 199660 examines the effectiveness of MTX versus placebo in steroid-dependent UC. No difference in remission No randomised studies have been performed, rates was found (47% in the MTX group), which but the results of one retrospective and three is similar to the results of several case series61-63 open-label prospective studies have been (45-54%). However it has been argued64-65 that published. The first study56 retrospectively the studied dose of 12.5 mg/week is considerably examined the effectiveness of mycophenolate lower than the ‘modern’ dose of 20 to 25 mg/week. inflammatory bowel disease (IBD) patients, of Upcoming results of the French METEOR study which 19 had UC. After an unclear treatment and the North American MERIT-UC study may time (the average treatment time amongst all shed some light on the use of MTX in UC. Both study subjects was 28 months), 35% (6 out of 17) investigate the effectiveness of MTX 25 mg/week of UC patients was in steroid-free remission. for remission induction in treatment-resistant 65% (11 out of 17) failed to respond to MMF or and/or steroid-dependent UC. It should be noted were intolerant.
that whilst according to www.clinicaltrials.gov the MERIT-UC study is currently recruiting, the The three prospective studies consist of two METEOR study already ended in November 2010, uncontrolled, open-label studies, and one but as of yet no results have been published.
unblinded pilot study. The first open-label study57 examined 24 IBD patients, of which 13 had UC with moderate-to-severe steroid-dependent Several retrospective studies66-73 have analysed disease. Patients were treated with combined the effects of tacrolimus on severe, therapy- MMF and high-dose steroids with tapering. In resistant UC. Outcome parameters, concomitant the first 3 months, 46% (6 out of 13) of patients medication, tacrolimus dosage, and target trough achieved remission, but after steroids were levels varied amongst these studies. However, tapered, the disease relapsed in all UC patients. all studies show a high clinical response rate, The other open-label study58 treated 14 patients varying between 61% and 90%. Reported clinical with IBD resistant to conventional therapy. remission rates vary between 33% and 72%.
They included five patients with UC (or IBD unclassified), all of which were steroid-dependent The only randomised, controlled trial38 concerning and intolerant to thiopurines. One patient tacrolimus in UC randomised 62 patients with suffered from side-effects and ceased MMF steroid refractory, moderate-to-severe UC. Changes treatment; the other four reached remission at 8 in the tacrolimus dose were made to achieve a weeks and ceased steroid treatment. Follow-up target trough level of 10-15 ng/mL. This study shows at 12 months showed a maintained remission in a 50% clinical response at 2 weeks, with a clinical 67% of all patients, but the exact data for UC remission rate of 9% (3 out of 32), with greater patients at that time point are not reported. response amongst patients who reached the target trough level. After a 2 week open-label extension Lastly, in the only controlled study59 MMF was period, the clinical remission rate increased to compared to azathioprine in 24 UC patients. Both groups received steroids in a tapering dose. 6-Thioguanine Notably, this study excluded patients with current steroid usage. After 4 weeks of treatment, 67% 6-Thioguanine (6-TG) is a metabolite of (8 out of 12) in the MMF group reached remission 6-mercaptopurine. Because of polymorphisms and five remained in remission throughout the in the enzyme thiopurine methyltransferase, whole follow-up period of 1 year. However during the conversion of 6-MP to 6-TG can differ the entire study, the remission rates were higher markedly between patients. Directly administering in the azathioprine group than in the MMF group, 6-TG should therefore remove dosing issues though no significance value is provided by whilst in theory achieving similar results to AZA EMJ EUROPEAN MEDICAL JOURNAL
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However there is little published data that study extrapolated to direct treatment with 6-TG, it is 6-TG treatment directly. Of additional interest is likely that the clinical efficacy of 6-TG is similar the use of 6-TG in patients with intolerance to to AZA and 6-MP treatment, as long as sufficient AZA or 6-MP. An open-label pilot study was performed in 49 patients with Crohn’s disease, of whom 23 patients had pancreatitis after AZA Summary Regarding Disease Resistant to or 6-MP administration.74 None of these patients Conventional Therapies had recurrence of their pancreatitis after When treating patients with UC resistant to conventional therapies, the first step is to ensure A database analysis75 was performed regarding that it is indeed the UC that is causing the UC patients receiving 6-TG after becoming symptoms. Critical re-assessment of the patient intolerant to conventional thiopurine treatment to rule out any other pathology is highly and/or being steroid-dependent. 46 UC patients important. Secondly, good communication is were examined, of which 83% (37 out of 46) were key since the ‘rescue’ therapies described above on steroids when 6-TG therapy was initiated. 80% (37 out of 46) of patients remained in supporting evidence. Patients should be well remission after a median follow-up time of 22.4 informed on the potential benefits and risks of months, 13% (6 out of 46) were intolerant, and these agents. Specifically, patients should be the remaining 7% (3 out of 46) failed therapy and aware that failure of these therapies will increase underwent colectomy. The amount of patients in the likelihood of requiring colectomy. steroid-free remission is not described.
Figure 1 summarises our recommendations, A prospective, open-label study76 treated 16 whilst Table 1 shows recommended dosage, UC outpatients who had steroid-dependent or laboratory tests, and contraindications. 6-TG refractory disease. After 3 months, 31% (5 out of and tacrolimus have the highest reported 16) had complete response, and 38% (6 out of 16) a partial response.
remission rates; therefore, we would recommend these agents over MMF, MTX or LDN. The other The measurement of 6-TG levels in the setting three agents are still useful in specific of monitoring AZA and 6-MP therapy has been circumstances, for instance LDN is the most studied extensively and has been found to be useful in meta-analyses.77 If these results are become pregnant. Table 1. Recommended dosage, laboratory tests, and absolute contraindications for 6-thioguanine, tacrolimus, mycophenolate mofetil, and methotrexate.
ECG, CBC, LF, RF CBC, LF, RF, TL Aim for trough level 4-8 ng/mL OD: once daily; BD: twice daily; QWK: once weekly; SC: subcutaneous; GFR: glomeruler filtration rate; CBC: complete blood count; LF: liver function; RF: renal function; TL: trough level; TPMT: EMJ EUROPEAN MEDICAL JOURNAL
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We strongly recommend that all the above drug of treatment which was achieved in 53% (275 out treatments should be accompanied by close of 515) of the golimumab groups versus 30% follow-up in order to detect treatment failure (76 out of 256) of the placebo group. Clinical in a timely fashion. Laboratory markers such remission at 6 weeks was 18% (94 out of 515) as faecal calprotectin, reflecting intestinal for the golimumab groups versus 6% inflammation,78,79 may aid in the follow-up (16 out of 256) for the placebo group.
process. In case of treatment failure or clinical deterioration, re-assessment should ensue, At least one study is planned to examine the after which optimising therapy, switching therapy efficacy in paediatric patients, whilst another or, if necessary, colectomy should follow.
study in Japan is recruiting patients. These studies will address the reproducibility of the results found in the PURSUIT-SC study, though its results have already led to FDA approval for A search in the U.S. National Institutes of Health golimumab in moderate-to-severe UC in May 2013.
clinical trial database (http://clinicaltrials.gov) using the term ‘ulcerative colitis’ yields 169 planned Vedolizumabor active studies. 29 of these studies involve new Vedolizumab is an antibody to the α4β7 integrin compounds, which reflect the continuing interest heterodimer complex. Three studies have been of many pharmaceutical companies regarding published on its efficacy in UC. The first study89 treatment for UC. These compounds are still only reported results of a randomised controlled trial known by their study names and mostly involve performed in 181 patients. Patients were either Phase I and Phase II studies, with no results untreated or had only received 5-ASA therapy. currently available on the website. Amongst Vedolizumab or placebo was administered on these drug candidates are OKT-3 (an oral anti day 1 and day 29. Clinical response rates were CD-3 agent), ASP3291 (a melanocortin receptor 66% and clinical remission was achieved in 33% at agonist), KRP203 (a sphingosine-1-phospate 6 weeks of follow-up. receptor modulator), GWP42003 (a cannabinoid), AMG181 (an α4β7 integrin antibody), HE3286 Two other studies90,91 on vedolizumab were a (a synthetic steroid derivative), GL1001 randomised, controlled dose-ranging study, and (an ACE-2 inhibitor), and MDX1100 (an CLCL10 an open-label extension of the first, with antibody). It is anticipated that their role in UC additional enrollment of treatment-naïve patients. will become clear in the near future.
In the controlled trial 47 patients with moderate, but not steroid-resistant, UC participated and Not all new and promising therapies live up to medication or placebo was administered on day our expectations. For instance, basiliximab, 1, 15, 29, and 85. Clinical response at 16 weeks daclizumab and visilizumab were promising in was 60% to 80% (depending on dose). Clinical uncontrolled pilot studies,80-84 but eventually remission is reported as varying from 53% to showed identical remission rates to placebo in randomised controlled trials.
79% between day 29 and 253, compared with 25% to 50% in the placebo group. The study was underpowered for assessment of clinical outcome. The open-label extension study involved Golimumab is a fully human antibody against 72 patients with UC who were administered TNFα. At the Digestive Disease Week, 2012 vedolizumab on day 1, 15, 43, followed by (DDW 2012), the initial results of the PURSUIT-SC maintenance dose every 8 weeks. After 70 weeks trial regarding golimumab in UC were presented. of follow-up, clinical response was achieved in Recently the complete article on this two-part, 92% and remission in 77% of patients with randomised, double-blind, placebo controlled moderate-to-severe UC.
Phase II-III study has been published.88 A total of 1,064 patients were included, 291 in the Recently the results of the GEMINI study, a Phase II dose-ranging study, 774 in the Phase III, multi-centre, randomised, double-blind, efficacy study. All patients had moderate-to- placebo-controlled trial were published.92 This severe UC and an inadequate or failed response study involved two phases, with 895 patients in to at least one conventional therapy. The efficacy the induction and maintenance phase combined. study evaluated clinical response after 6 weeks Notably, patients had active disease and had EMJ EUROPEAN MEDICAL JOURNAL
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failed previous glucocorticoid, immunosuppressive significant difference compared with placebo. or anti-TNFα therapy, though disease limited to Clinical response was 78% compared with 42%, the rectum was an exclusion criterion. After 6 whilst endoscopic response was 78% versus 46%. weeks, coinciding with the end of the induction phase, vedolizumab showed a statistically Currently, the OCTAVE study is recruiting UC significant 47% clinical response rate compared patients to analyse the efficacy in moderate- with 26% for placebo. The maintenance to-severely acute UC, resistant to at least phase ended after 52 weeks, again showing a corticosteroids, azathioprine or anti-TNF therapy. significant difference in clinical remission rates It consists of a remission induction phase, with 42% and 45% for vedolizumab in different examining efficacy at 8 weeks, and is followed by doses, compared with 16% for placebo.
a long-term follow-up study of 52 weeks. No current trials on vedolizumab were identified, CONCLUSION but a request for FDA approval was filed in June 2013, most likely based on the results of the In this paper we have reviewed the most recent abovementioned studies.
guidelines by the ECCO on the treatment of UC. The proper evidence-based approach is described extensively in the guidelines, and we underscore its usefulness in clinical practice. Tofacitinib is an oral inhibitor of Janus kinase Nevertheless, it remains challenging for clinicians (JAK) 1, 2 and 3, and its effect should result to extrapolate the results obtained in clinical trials in reduction of interleukin 2, 4, 7, 9, 15, and 21. to individual patients.
The results of a large, multicentre, randomised, double-blind, placebo-controlled trial were When patients become resistant to conventional published in 2012,93 examining the efficacy of therapies, the situation moves beyond the tofacitinib in patients with active UC. A total of guidelines, and it is for these situations that we 194 patients were randomised between five offer the treatment algorithm described above. groups, one placebo group and four groups Of utmost importance remains the individualised with different tofacitinib dosage (0.5 mg, 3 mg, and tailored approach, based on the patient’s 10 mg, and 15 mg twice daily). 34% of patients preference, the clinician’s preference, and the were using concomitant steroids, whilst 27% availability of therapies. The choice of these were steroid-resistant and 19% had failed unconventional therapies should be made in conjunction with the patient, underscoring the need for clear communication between clinician Significant difference in clinical remission was and patient, regarding the pros and cons of each seen in the 3 mg, 10 mg, and 15 mg groups compared with placebo, with remission rates of 33%, 48%, 41% compared with 10%, respectively. Finally, though the primary aim of these therapies Endoscopic remission showed similar significant is the induction and maintenance of remission, differences, with 18%, 30%, 27% compared with and subsequently the avoidance of surgery, one could also consider these agents as a bridge to novel treatments, either those substances Regarding clinical and endoscopic response, currently awaiting regulatory approval or those in only the highest tofacitinib dose showed a the last stage of their development.
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