Ulcerative colitis: current pharmacotherapy and future directions.

Review

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Ulcerative colitis: current pharmacotherapy and future directions 1.

Introduction

2.

Current therapy

3.

Maintenance of remission

4.

New therapy

5.

Conclusion

6.

Expert opinion

Cristina Bezzio, Federica Furfaro, Roberto de Franchis, Giovanni Maconi, Anil Kumar Asthana & Sandro Ardizzone† †

“ L. Sacco” University Hospital, Department of Gastroenterology, Oncology and Surgery, Milan, Italy

Introduction: Ulcerative colitis (UC) is a chronic relapsing disease, characterised by alternating of acute and remission phases. Although the aetiology is unknown, in recent years, there has progressively been greater knowledge of the various pathogenetic mechanisms underlying the disease itself. Thus, from therapy based on generically anti-inflammatory or immunosuppressive agents, treatment is gradually moving towards drugs that selectively block specific inflammatory mediators, such as TNF-a. Areas covered: This review provides the most significant data about the therapeutic role of different drugs currently available for the treatment of UC. In addition, the critical therapeutic areas on which research could focus in the near future are discussed. Expert opinion: UC is a disease affecting young patients, whose quality of life may be strongly compromised by the progression of disease. Over time, the disease may lead to an impairment of the normal anatomy and physiology of the colon, and the cumulative incidence of dysplasia and colorectal cancer increases with the time. Thus, the main aims of the near future should be both a better definition of patients at risk for a poor clinical course and progression of disease, and the development of a much more aggressive treatment for patients with a poor prognosis. Keywords: biologics, conventional therapy, future directions, ulcerative colitis Expert Opin. Pharmacother. [Early Online]

1.

Introduction

Ulcerative colitis (UC) is a chronic relapsing disease, characterised by alternation of acute and remission phases. Although the aetiology is unknown, in recent years, there has been a marked increase in the knowledge of the various pathogenetic mechanisms underlying the disease itself. Thus, from a therapy based on generically anti-inflammatory or immunosuppressive agents, we are using more targeted therapies, which selectively block specific inflammatory mediators, such as TNF-a. Corticosteroids, salicylates (sulfasalazine, 5-aminosalicylic acid [5ASA]) in both oral and rectal formulations, thiopurines and, in recent years, the biological therapies (infliximab [IFX], adalimumab, etc.) represent the current therapeutic armamentarium available for treatment of UC. The aim of this review is to provide the most significant data about the therapeutic role of different drugs currently available for the treatment of UC. In addition, we will discuss the critical therapeutic areas in which future research could focus on.

10.1517/14656566.2014.925445 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

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C. Bezzio et al.

Article highlights. .

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Ulcerative colitis (UC) is a chronic relapsing disease, characterised by alternation of acute and remission phases. Salicylates, corticosteroids, cyclosporine, apheresis, tacrolimus and biological agents can be used to induce remission in active UC. Salicylates and biological agents can be used also to maintain remission in UC. Thiopurines are effective as maintenance treatment in steroid-dependent/refractory patients, and in patients not tolerating salycilates. The use of anti-TNF-a agents in UC is becoming increasingly frequent; it is promising but still needs to be optimised. New molecular targets are under study and some of the new drugs have yielded promising results.

This box summarises key points contained in the article.

2.

Current therapy

2.1

Induction of remission Salicylates (sulphasalazine, 5ASA, mesalamine)

2.1.1

Aminosalicylates are effective agents to induce remission in patients with mild-to-moderate UC. For treatment of mild or moderately active proctitis, the preferred initial treatment is mesalazine 1 g suppository once daily [1]. The combination of oral and topical mesalazine is more effective than either alone [2] and should be considered in cases of escalation. Combining topical mesalazine and topical steroids also helps [3]. For management of left-sided mild-tomoderate active colitis, the combination of oral (> 2 g/day) and topical mesalazine is first-line therapy [4,5]. Topical therapy with steroids or aminosalicylates alone, as well as monotherapy with oral aminosalicylates, is less effective than combined oral and topical 5ASA therapy. In mild-to-moderate extensive UC, the treatment of choice is oral 5ASA > 2 g/day, which should, again, be combined with topical mesalazine [1]. A recent Cochrane meta-analysis, which included 48 randomised controlled trials (RCTs) of parallel design (7776 patients), evaluated the efficacy, dosage and safety of a 4-week course of oral mesalamine (5ASA) formulations, sulphasalazine (SASP) and placebo for the induction of remission in mild-tomoderate UC: 5ASA was superior to placebo for induction of clinical remission (72% of 5ASA patients failed to enter clinical remission compared to 85% of placebo patients -- relative risk (RR) 0.86, 95% CI 0.81 -- 0.91). No statistically significant difference in efficacy or adherence was found between once-daily and conventionally dosed 5ASA and there was no difference in efficacy among the various 5ASA formulations; a dose-response trend for 5ASA was also observed [6]. ASCEND (Assessing the safety and Clinical Efficacy of New Dose) I and II trials showed that, at week 6, there was 2

no statistically significant difference in mucosal healing rate between 5ASA 4.8 versus 2.4 g/day, used for the treatment of mild UC. However, mucosal healing at week 6 (endoscopy subscore of 0 or 1) was achieved in 80% of moderately active UC patients on 4.8 g/day versus 68% of patients on 2.4 g/day (p = 0.012) and the change in Inflammatory Bowel Disease Questionnaire at week 6 showed a significant relationship with mucosal healing (p < 0.0001) [7]. A multicentre, randomised, double-blind, 6-week, activecontrol study (ASCEND III) confirmed the non-inferiority and safety of delayed-release mesalamine 4.8 g/day compared to 2.4 g/day in 772 patients with moderately active UC. Seventy per cent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% CI for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (p = 0.04). A therapeutic advantage for the 4.8 g/day dose was observed only amongst patients who were previously treated with corticosteroids, oral mesalamines, rectal therapies or multiple UC medications. Both regimens were well tolerated with similar adverse events [8]. Common adverse events of 5ASA included flatulence, abdominal pain, nausea, diarrhoea, headache and worsening of UC. There were no statistically significant differences in the incidence of adverse events between 5ASA and placebo, once-daily and conventionally dosed 5ASA, 5ASA and comparator 5ASA formulation or 5ASA dose ranging (high dose vs low dose) studies. Similarly, no statistically significant differences in efficacy were found between 5ASA and SASP (54% of 5ASA patients failed to enter remission compared to 58% of SASP patients -- RR 0.90, 95% CI 0.77 -- 1.04). SASP was not so well tolerated as 5ASA (29% of SASP patients experienced an adverse event compared to 15% of 5ASA patients -- RR 0.48, 95% CI 0.37 -- 0.63) [6]. Systemic corticosteroids Systemic corticosteroids are indicated for active UC in patients who do not respond to topical and oral 5ASA therapy within 10 -- 14 days or if there is no sustained relief from all symptoms after 40 days of 5ASA treatment [1]. Two studies showed that, in extensive UC, oral prednisolone (starting at 40 mg daily combined with steroid enemas) is effective in inducing remission. In the first study, including 118 patients with mild-to-moderate disease, corticosteroids induced remission within 2 weeks in 76, versus 52% in patients treated with 8 g/day sulfasalazine plus steroid enemas [9]. The second study proved that the combination of oral and rectal steroids was better than either alone [10]. The appropriate dosage for moderately active UC is prednisolone 40 mg/day for 1 week, tapering 5 -- 10 mg weekly resulting in an 8-week course. Doses of prednisolone £ 15 mg day are ineffective for 2.1.2

Expert Opin. Pharmacother. (2014) 15(12)


Ulcerative colitis

active disease, while shorter courses are associated with early relapse [11]. In severe UC of any extent, systemic corticosteroids are first-line conventional therapy [11]. This is the treatment of choice after investigations to confirm the diagnosis and exclude co-infections, such as Cytomegalovirus infection [12]. A 5-day intensive intravenous (i.v.) regimen, for the treatment of severe attacks of UC, has been introduced, by Truelove and Jewell, in 1974. They demonstrated that when used in the treatment of first attacks of the disease, this regimen gives a considerable chance of a prolonged remission. The study showed a reduction in mortality from 24% in the placebo group to 7% in the steroid-treated group. Two-thirds of the first-attack patients who went into remission remained symptom-free during the period of follow-up, which averaged > 3 years [13]. Corticosteroids are generally given as either hydrocortisone 100 mg four times daily, methylprednisolone 60 mg daily or prednisone 1 mg/kg/day. Higher doses (including 500 mg -1 g of methylprednisolone) are not more effective, but lower doses have been shown to be less effective [14]. If the patient objectively responds to treatment, oral prednisolone is instituted at 40 mg daily and subsequently tapered. It is important to attain full remission before beginning tapering of steroids, since a rapid recurrence of symptoms may ensue if tapering is initiated too early. In Ja¨rnerot et al. trial (1985), there were high remission rates in 158 patients treated with i.v. steroids; in particular, the remission rates of severe, moderate or mild attacks were 55.7, 86.9 and 91.8%, respectively. Pancolitis had a great impact on the results, especially in severe attacks, where 52.8% of patients with severe pancolitis were operated on within 3 weeks; 48.1% of the patients in remission relapsed. The extent of the colitis, severity of the attack and duration of intensive i.v. treatment had no influence on the time of relapse. Twelve patients with chronic continuous disease were given intensive i.v. treatment. No long-term benefit was seen in patients with pancolitis, but half of those with less extensive colitis showed a good-to-excellent response to treatment [15]. A systematic literature search for cohort studies and controlled trials, published between 1974 and 2006 (including 32 trials and 1991 patients), showed an overall response of 67% (95% CI 65 -- 69%) to corticosteroids (prednisone, i.v. hydrocortisone, methylprednisolone or betamethasone) in severe UC. Out of the 1991 patients included, 565 (29%, 95% CI 28 -- 31%) eventually underwent colectomy; mortality was 1% (22/1991, 95% CI 0.7 -- 1.6%). A methylprednisolone dose > 60 mg/day or extension of therapy beyond 7 -- 10 days carried no additional benefit [16]. A randomised, double-blind trial compared the efficacy and safety of different modalities of steroid administration. Sixty-six patients were randomised to receive 1 mg/kg/day of 6-methyl-prednisolone administered as a bolus injection (group A) or continuous infusion (group B). The differences

between these groups were not statistically significant with respect to clinical remission (16/32 in group A vs 17/34 in group B), total colectomy (12 in group A vs 9 in group B) and steroid-related adverse reactions [17]. In a study of 2011, Manõsa et al. evaluated 94 consecutive patients treated with prednisone 1 mg/kg/day for moderateto-severe attacks of UC. The aim of the study was to identify predictors of response to systemic steroids in moderate-tosevere UC. The number of bowel movements, rectal bleeding, platelet count and C-reactive protein levels at 3 and 7 days after starting steroids were recorded. These parameters can predict rapid response to steroids, in active UC attacks, after 3 days of treatment [18]. A Cochrane database systematic review of three RCTs concluded that oral budesonide was significantly less likely to induce clinical remission than oral mesalazine (RR 0.72, 95% CI 0.57 -- 0.91) and placebo (RR 1.41, 95% CI 0.59 -- 3.39) [19]. In a multicentre, randomised, single-blind study, 177 patients with active mild-to-moderate left-sided UC were assigned to a 4-week treatment with beclomethasone dipropionate (BDP) 5 mg/day versus 5ASA 2.4 g/day. Clinical remission was achieved in 63.0% of patients in the BDP group versus 62.5% in the 5ASA group (not statistically significant), without systemic steroid side-effects [20]. In the recent randomised, double-blind, double-dummy, placebo-controlled CORE I trial, Sandborn et al. evaluated the efficacy of budesonide Multi-Matrix System (MMX) for induction of remission in 509 patients with active, mild-to-moderate UC. Patients were randomised to receive budesonide MMX (9 or 6 mg), mesalamine (2.4 g, as reference) or placebo for 8 weeks. Budesonide MMX (9 mg) was safe and more effective than both placebo and mesalamine in inducing remission (remission was achieved in 17.9% of patients in the 9 mg budesonide MMX group, in 13.2% of those in the 6 mg budesonide MMX group, in 12.1% of those in the mesalamine group, compared with 7.4% for placebo -- p = 0.01, p = 0.14 and p = 0.22, respectively); the study did not show a significant benefit, using budesonide MMX, in clinical improvement (clinical improvements among patients given 9 or 6 mg budesonide MMX or mesalamine were 33.3, 30.6 and 33.9%, respectively, compared with 24.8% for placebo -- p = 0.14, p = 0.31 and p = 0.12) and in endoscopic improvement (endoscopic improvement among subjects given 9 or 6 mg budesonide MMX or mesalamine were 41.5, 35.5 and 33.1%, respectively, compared with 33.1% for placebo -- p = 0.17, p = 0.68 and p = 0.99, respectively). Adverse events occurred at similar frequencies among groups [21]. In the randomised CORE II trial, 410 patients were randomly assigned to groups that were given budesonide MMX 9 or 6 mg, or budesonide 9 mg (budesonide controlled ileal-release capsules; reference arm) or placebo once daily for 8 weeks. Budesonide MMX 9 mg was safe and more effective than placebo at inducing combined clinical and endoscopic


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remission in patients with active, mild-to-moderate UC. The difference between budesonide MMX 9 mg and placebo was significant (odds ratio [OR] 4.49; 95% CI 1.47 -- 13.72; p = 0.0047). Clinical improvement (42.2 vs 33.7%), endoscopic improvement (42.2 vs 31.5%), the rate of histological healing (16.5 vs 6.7%; p = 0.0361) and proportion of patients with symptom resolution (23.9 vs 11.2%; p = 0.0220) were significantly higher for budesonide MMX 9 mg than placebo. Adverse event profiles were similar across groups [22].


2.1.3

Calcineurin inhibitors Cyclosporine-A

2.1.3.1

Cyclosporine A (CyA) is a calcineurin inhibitor used as secondline (rescue) therapy in acute severe UC, refractory to corticosteroids. It is a lipophilic peptide that inhibits the cellular and humoral immune systems. Cyclosporine acts to down-regulate the cellular immune response by blocking the production of interleukin-2 by T-helper lymphocytes. At the molecular level, cyclosporine binds with the cyclosporine-binding protein, cyclophilin, forming a cyclosporine--cyclophilin complex, which binds to and inhibits calcineurin, a cytoplasmic phosphatase enzyme involved in the activation of T cells. In addition, cyclosporine indirectly inhibits B-cell function by blocking the production of B-cell--activating factors and interferon-c, by T-helper cells. These cyclosporine-induced effects on cellular and humoral immunity are the probable therapeutic mechanisms in UC [23]. The two existing RCTs comparing CyA with placebo were examined in a Cochrane meta-analysis. The results should be interpreted with caution because of the small number of trials and patients evaluated and of the limited follow-up (few weeks in one trial and 1 year in the other). These two trials could not be pooled for analysis because of major differences in design and patient populations. In Lichtiger et al. [24] trial (1994), 20 steroid-refractory patients were enrolled, of whom 11 received i.v. cyclosporine (4 mg/kg) and 9 received placebo. Nine of 11 (82%) in the CyA group responded to therapy compared with none of 9 (0%) in the placebo group (RR 0.18, 95% CI 0.05 -- 0.64). However, 3/11(27%) and 4/9 (44%) eventually underwent colectomy in the i.v. CyA and placebo groups, respectively (RR 0.6, 95% CI 0.18 -- 2.06), and follow-up was less than a month. In D’Haens et al. [25] trial (2001), 30 patients were enrolled: 15 were treated with i.v. cyclosporine and 15 with i.v. methylprednisolone. Nine of 15 patients (60%) in the CyA group responded to therapy as compared to 8/15 (53%) in the methylprednisolone group (RR 0.71, 95% CI 0.29 -- 1.75). After 1 year, 7/9 responders in the CyA group were still in remission compared with 4/8 in the steroid group (p > 0.05) and the colectomy rate was similar in both groups (20% -- RR 1.0, 95% CI 0.24 -- 4.18). The mean time to response in the CyA group in the two trials was short (7 and 5.2 days). The precise assessment of the occurrence of adverse events was difficult because the trials described different adverse reactions, which reversed after discontinuation of CyA; the main 4

adverse events, observed in both RCTs, were hypertension, paraesthesia and vomiting [26]. No statistically significant difference was observed between high dose of CyA (4 mg/kg) i.v. and low dose of the drug (2 mg/kg) for the induction of remission in severe UC [27]. Data from a recent meta-analysis, including 6 retrospective cohort studies (321 patients), did not show significant differences between IFX and CyA in the 3-month colectomy rate (OR 0.86, 95% CI 0.31 -- 2.41, p = 0.775), in the 12-month colectomy rate (OR 0.60, 95% CI 0.19 -- 1.89, p = 0.381), in adverse drug reactions (OR 0.76, 95% CI 0.34 -- 1.70, p = 0.508) and in postoperative complications (OR 1.66, 95% CI 0.26 -- 10.50, p = 0.591) [28]. There is only one randomised trial, with 115 patients, comparing the efficacy of CyA with IFX: 58 patients were allocated to receive i.v. CyA (2 mg/kg/day followed by oral drug administration until day 98) and 57 to receive IFX (5 mg/kg at weeks 0--2--6). In both groups, azathioprine (AZA) was started at day 7 in patients with a clinical response. The trial showed that CyA was as effective as IFX in patients with acute severe UC refractory to steroids. No statistically significant difference was observed in treatment failure rate, which occurred in 35 (60%) patients in the CyA group and in 31 (54%) in the IFX group (absolute risk difference 6%; 95% CI -7 to 19; p = 0·52); clinical response occurred in 50/58 (86%) in the CyA group versus 48/57 (84%) in the IFX group (absolute risk difference 2%, 95% CI -11 to 15; OR 1.2, 95% CI 0.4 -- 3.3; p = 0.76); mucosal healing was achieved in 26/55 (47%) patients given cyclosporin and in 25/55 (45%) given IFX (absolute risk difference 2%, 95% CI -17 to 20; OR 1.1, 95% CI 0.5 -- 2.3, p = 0.85); concerning colectomy rate, 22 patients had colectomies during the study, 10 (17%) in the CyA and 12 (21%) in the IFX group; time to colectomy did not differ between the groups (p = 0.60). Nine patients (16%) in the CyA group and 14 (25%) in the IFX group had severe adverse events. In clinical practice, treatment choice should be guided by physician and centre experience [29]. A small retrospective study (including 19 patients) evaluated the remission rates obtained using acute salvage therapy by crossing over from IFX to CyA or from CyA to IFX in patients with severe, corticosteroid-refractory UC, who failed first treatment with CyA or IFX. Remission occurred in 4/10 patients (40%) in the IFX-salvage group and 3/9 (33%) in the cyclosporinesalvage group. Remission lasted a mean of 10.4 months (range, 4.4 -- 17.03 months) and 28.5 months (range, 5.0 -- 41.5 months), respectively. Severe adverse events, including one patient who developed sepsis and died after receiving IFX salvage, were observed in 16% of patients, suggesting that the risks of acute salvage therapy may outweigh the benefits [30]. CyA can also be administered orally with good tolerability and may be used as a bridging strategy to AZA. In a retrospective study from Cambridge University Hospital, they showed the use of CyA as a bridging therapy to AZA, and in their cohort of patients 84% of those who responded to CyA have not required surgery. It is not clear what whole blood


Ulcerative colitis

Table 1. ACT 1 and ACT 2 studies (IFX 5 mg/kg vs placebo). Outcome

ACT 1


Placebo (n = 121) Clinical response, n (%) Week 8 45 (37.2) Week 30 36 (29.8) Week 54 24 (19.8) Clinical remission, n (%) Week 8 18 (14.9) Week 30 19 (15.7) Week 54 20 (16.5) Mucosal healing*, n (%) Week 8 41 (33.9) Week 30 30 (24.8) Week 54 22 (18.2)

p value IFX 5 mg/kg (n = 121)

ACT 2

p value

Placebo (n = 123)

IFX 5 mg/kg (n = 121)

84 (69.4) 63 (52.1) 55 (45.5)

< 0.001 £ 0.001 £ 0.001

36 (29.3) 32 (26.0) -

78 (64.5) 57 (47.1) -

< 0.001 £ 0.001

47 (38.8) 41 (33.9) 42 (34.7)

< 0.001 £ 0.001 £ 0.001

7 (5.7) 13 (10.6) -

41 (33.9) 31 (25.6) -

< 0.001 0.003

75 (62.0) 61 (50.4) 55 (45.5)

< 0.001 £ 0.001 £ 0.001

38 (30.9) 37 (30.1) -

73 (60.3) 56 (46.3) -

< 0.001 0.009

*Absolute Mayo subscore for endoscopy of 0 or 1. IFX: Infliximab.

concentrations of cyclosporine are necessary to produce clinical improvement in patients with inflammatory bowel disease (IBD), but some studies suggest that patients receiving cyclosporine should have whole blood cyclosporine levels in the 251 -- 350 ng/ml range [31]. Tacrolimus Tacrolimus is a macrolide antibiotic with immunomodulatory properties similar to cyclosporine. One randomised placebocontrolled trial comparing high-target serum concentration and low-target serum concentration of tacrolimus versus placebo showed significant benefit over placebo in patients with UC. This study included 27/60 patients with severe colitis and none of the patients achieved complete remission in any group. A partial response was seen in 66.7% (4/6) of patients on tacrolimus adjusted to trough levels of 10 -- 15 ng/ml, in 50% (5/10) of patients on tacrolimus adjusted to trough levels of 5 -- 10 ng/ml and in 18.2% (2/11) of patients on placebo. This study demonstrated dose-dependent efficacy and safety of oral tacrolimus for remission-induction therapy of refractory UC (optimal target range appears to be 10 -- 15 ng/ml with 2 weeks therapy). However, more studies are necessary to assess the efficacy and safety of this drug in treating UC [32]. In a recent retrospective study, 10 patients under age 18, with severe steroid-resistant UC, were enrolled and treated with oral tacrolimus. For patients who initially respond to tacrolimus and whose response is maintained beyond 12 months, the likelihood of colectomy decreases drastically should they continue with this immunomodulation therapy. Thus, tacrolimus may also be used as bridging therapy for corticosteroid-dependent patients until the new maintenance therapy takes effect [33]. 2.1.3.2

Infliximab ACT 1 and 2 (Active Ulcerative Colitis trials) were the first randomised placebo-controlled, double-blind trials evaluating 2.1.4

the safety and efficacy of IFX for induction (and maintenance) therapy in UC, and results are summarised in Tables 1 and 2 [34]. In a study consisting of 728 patients, Fasanmade et al. determined the association of baseline albumin concentration and IFX disposition in patient with UC; patients with higher serum albumin concentrations (SAC) maintained higher IFX concentrations, lower clearance and longer half-life than patients with lower SAC and clinical response [35]. The SUCCESS trial included 239 patients with moderateto-severe UC, who were biologically naı¨ve. The aim of the study was to investigate the best therapeutic strategy in UC patients failing steroid treatment. Patients were randomised to receive AZA 2.5 mg/kg/day, IFX 5 mg/kg or IFX + AZA for 16 weeks. At week 16, endpoints were steroid-free remission, clinical response and mucosal healing (Table 3) [36]. Leucocitapheresis There are two systems of leucocitapheresis used in UC patients, and both are able to selectively deplete the activated pro-inflammatory cytokine-producing granulocytes and monocytes/macrophages from the patient’s blood circulation (granulocyte--monocyte apheresis -- GMA), which are thought to be part of the immunopathogenesis of disease. One of the two systems is the Adacolumn consisting of the ADA monitor and a column packed with cellulose acetate beads capable of adsorbing granulocytes and monocytes and through which the blood of the patient is circulated. A post-marketing surveillance in Japan showed efficacy and safety data of the Adacolumn therapeutic leucocytapheresis in patients with UC. Baseline granulocyte count was convincingly an independent predictor of clinical response [37]. A recent Italian review suggested that the major indication for this treatment is for patients with steroid dependency or with major contraindications to the use of steroids. Most of 2.1.5


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Table 2. ACT 1 and ACT 2 studies (IFX 10 mg/kg vs placebo). Outcome

ACT 1


Placebo (n = 121) Clinical response, n (%) Week 8 45 (37.2) Week 30 36 (29.8) Week 54 24 (19.8) Clinical remission, n (%) Week 8 18 (14.9) Week 30 19 (15.7) Week 54 20 (16.5) Mucosal healing*, n (%) Week 8 41 (33.9) Week 30 30 (24.8) Week 54 22 (18.2)

p value

IFX 10 mg/kg (n = 122)

ACT 2 Placebo (n = 123)

IFX 10 mg/kg (n = 120)

p value

75 (61.5) 62 (50.8) 54 (44.3)

< 0.001 0.002 £ 0.001

36 (29.3) 32 (26.0) -

83 (69.2) 72 (60.0) -

< 0.001 £ 0.001

39 (32.0) 45 (36.9) 42 (34.4)

0.002 £ 0.001 0.001

7 (5.7) 13 (10.6) -

33 (27.5) 43 (35.8) -

< 0.001 < 0.001

72 (59.0) 60 (49.2) 57 (46.7)

< 0.001 < 0.001 < 0.001

38 (30.9) 37 (30.1) -

74 (61.7) 68 (46.7) -

< 0.001 < 0.001

*Absolute Mayo subscore for endoscopy of 0 or 1. IFX: Infliximab.

Table 3. Success study. Outcomes

UC success IFX + AZA (n = 78)

IFX (n = 77)

AZA (n = 76)

Clinical endpoints, week 16 (proportion of patients) Steroid-free remission 39.74%*,z Mayo score response 76.92%z Mucosal healing 62.82%z

22.08% 68.83%z 54.55%z

23.68% 50.00% 36.84%

*p < 0.05 compared to infliximab. z p < 0.05 compared to AZA. AZA: Azathioprine; IFX: Infliximab; UC: Ulcerative colitis.

the experimental demonstrations of the efficacy of GMA in IBD have been derived from uncontrolled studies with homogeneous data, showing favourable responses (remission or partial response) in 60 -- 84% of patients treated, but results are contrasting [38]. The second system is the Cellsorba -- the range of efficiency, indications and procedure are very similar to the Adacolumn. Cellsorba, in addition, removes lymphocytes and could cause lymphopenia and to increase the risk of autoimmune disease. Concerning side effects, GMA has been demonstrated to be very safe, with a low incidence of adverse events; however, ASFA recommendations for GMA in inflammatory bowel disease are 2B, due to the fact that we need more randomised double-blind studies to proof the efficacy of this treatment [39]. 3.

Maintenance of remission

Salicylates (SASP, 5ASA, mesalamine) Oral 5ASA are the first-line maintenance treatment in patients responding to 5ASA or steroids (oral or rectal). Rectal 3.1

6

5ASA is first line in maintenance for proctitis and an alternative option for left-sided colitis. A combination of oral and rectal 5ASA can be used as a second-line maintenance treatment [1]. A Cochrane meta-analysis of 38 RCTs of parallel design (including 8127 patients) showed that 5ASA was significantly superior to placebo for maintenance of clinical or endoscopic remission (41% of 5ASA patients relapsed compared to 58% of placebo patients). No statistically significant differences in efficacy or adherence were found between once-daily and conventionally dosed 5ASA (29% of once daily patients relapsed over 12 months compared to 31% of conventionally dosed patients in 7 studies, including 2826 patients; RR 0.92, 95% CI 0.83 -- 1.03). Fourteen per cent of patients in the once-daily group failed to adhere to their medication regimen compared to 11% of patients in the conventional dosing group (5 studies, 1161 patients; RR 1.21, 95% CI 0.90 -1.63). This study showed that SASP was significantly superior to 5ASA for maintenance of remission (48% of 5ASA patients relapsed compared to 43% of SASP patients in 12 studies, including 1655 patients; RR 1.14, 95% CI 1.03 -- 1.27). A pooled analysis of two studies showed no statistically significant difference in efficacy between balsalazide 6 g and 3 g/day (23% of patients in the 6 g/day group relapsed compared to 33% of patients in the 3 g/day group -- 216 patients; RR 0.72; 95% CI 0.46 -- 1.13). One study found balsalazide 4 g to be superior to 2 g/day (37% of patients in the 4 g/day balsalazide group relapsed compared to 55% of patients in the 2 g/day group -- 133 patients; RR 0.66; 95% CI 0.45 -- 0.97). One study found a statistically significant difference between 5ASA granules 3 g and 1.5 g/day (35% of patients in the 5ASA 3 g/day group relapsed compared to 39% of patients in the 1.5 g/day group -- 429 patients; RR 0.65; 95% CI 0.49 -- 0.86).



Ulcerative colitis

Common adverse events included flatulence, abdominal pain, nausea, diarrhoea, headache, dyspepsia and nasopharyngitis. There were no statistically significant differences in the incidence of adverse events between 5ASA and placebo, 5ASA and SASP, once-daily and conventionally dosed 5ASA, 5ASA and comparator 5ASA formulations and 5ASA dose-ranging studies. High-dose therapy appears to be as safe as low dose and is not associated with a higher incidence of adverse events [40]. A recent Cochrane meta-analysis of 77 RCTs (including 2925 patients) reviewed and compared the efficacy and safety of oral mesalamine formulations (sustained release, delayed release and prodrugs) used for induction and maintenance of remission in UC. The main objective of this review was to determine if there are any differences in efficacy or safety among the oral 5ASA drugs. No difference was observed between oral 5ASA and comparator 5ASA formulations in patients with clinical remission (RR 0.94; 95% CI, 0.86 -- 1.02), clinical improvement (RR 0.89; 95% CI, 0.77 -- 1.01) or relapse at 12 months (RR 1.01; 95% CI, 0.80 -- 1.28). No significant difference was demonstrated in rates of adverse events or withdrawal due to adverse events [41]. In patients with UC, 5ASA formulations appear to reduce the risk of colorectal cancer (CRC): there are several cohort and case-control studies that showed a significant reduction in the incidence of CRC in patients treated by 5ASA [42], but it is very difficult to perform a randomised controller trial to confirm the chemopreventive effect of 5ASA, because such a study would require a very high number of patients (1000 -- 3000 in each trial arm) in order to be adequately powered. In a meta-analysis of 2006, the risk of CRC was significantly reduced in patients exposed to 5ASA for 1 -- 5 years (OR 0.51, 95% CI 0.37 -- 0.69). Longer-term 5ASA use showed a protective trend that failed to reach statistical significance [43]. Other studies on this topic have been published more recently; however, most of them did not differentiate the risk of CRC from that of other forms of dysplasia [44]. A large study published in 2003 enrolled a group of patients, extracted from the population of the University of Manitoba Inflammatory Bowel Disease Epidemiology Database, with a new diagnosis of CRC and a control group of IBD patients, who did not develop CRC, between the years 1997 and 2000. The authors evaluated the use of 5ASA within 2 years before the diagnosis of CRC. Twenty-five cases of IBD with CRC were identified. These were matched with 348 cases of IBD who did not develop CRC. CRC cases were more likely to have been exposed to 5ASA (OR 1.46; 95% CI 0.58 -- 3.73), but this result was not statistically significant. In conclusion, this study does not support the protective effect of 5ASA in preventing CRC. However, the extent of disease was not reported in the study, and there is the possibility that 5ASA was prescribed specifically to the patients at highest risk for CRC [45].

Thiopurines (AZA and 6-mercaptopurine) The ECCO guidelines recommend the use of thiopurines for patients with mild-to-moderate UC with early or frequent relapses whilst taking 5ASA at optimal dose, or with intolerance to 5ASA, for steroid-dependent patients, and for patients responding to cyclosporine (or tacrolimus) for induction of remission. In patients responding to antiTNF agents, to maintain remission are appropriate AZA/ mercaptopurine or continuing anti-TNF therapy with or without thiopurines [1]. Several RCTs were performed to assess the efficacy of thiopurines for maintenance of remission in UC and the data are controversial. A Cochrane meta-analysis evaluated 6 studies, including 286 patients with UC. In four trials, AZA was superior to placebo for the maintenance of remission: failure to maintain remission in the AZA group was 44% (51/115) compared to 65% (76/117) of the placebo group (232 patients; RR 0.68, 95% CI 0.54 -- 0.86). A GRADE analysis showed that the overall quality of the evidence for this outcome was low due to the risk of bias and imprecision. Two trials that compared 6-mercaptopurine to mesalazine and AZA to sulfasalazine, respectively, showed significant heterogeneity [46]. A randomised, investigator-blind, controlled trial showed that AZA is effective in the treatment of steroid-dependent patients with UC. Seventy-two steroid-dependent patients, with clinically and endoscopically active UC on systemic prednisolone, were randomised to receive AZA 2 mg/kg/day or oral 5ASA 3.2 g/day, for a 6-month follow-up period. The outcomes assessed were clinical and endoscopic remission, steroid discontinuation or colectomy. Significantly more patients in the AZA group achieved clinical and endoscopic remission, and discontinued steroid therapy than in the 5ASA group, both in the intention-to-treat analysis (AZA vs 5ASA: 19/36 patients (53%) versus 7/36 (21%); OR 4.78 (95% CI 1.57 -- 14.5)) and per-protocol analysis (AZA vs 5ASA: 19/33 patients (58%) versus 7/34 (21%); OR 5.26 (95% CI 1.59 -- 18.1)) [47]. A retrospective, observational study from the Oxford IBD clinic followed from 1968 to 1999 supported the use of thiopurine to treat UC and Crohn’s disease. A total of 622 of 2205 patients were treated with AZA (346 patients with UC). Mean duration of the initial course of treatment was 634 days. The overall remission rate was 58%, and for patients who received > 6 months of treatment, the remission rate was 87%. Duration of AZA treatment did not affect the relapse rate after stopping treatment (p = 0.68). The efficacy of AZA is reasonably well sustained over 5 years [48]. The treatment with AZA alone is not effective to induce remission in active UC: in a double-blind trial, the remission rates after 1 month were comparable between patient receiving AZA + corticosteroids and patients receiving placebo + corticosteroids (78 vs 68% -- p = n.s.) [37]. 3.2


7


C. Bezzio et al.

According to the meta-analysis by Timmer et al. there was no statistically significant difference between AZA and placebo in the incidence of adverse events. Nine per cent (11/127) of AZA patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 -- 8.01). Patients receiving AZA were at significantly increased risk of withdrawal due to adverse events (5 studies, 199 patients; RR 5.43, 95% CI 1.02 -- 28.75). Adverse events related to study medication included significant bone marrow suppression (five cases) and acute pancreatitis (three cases). Deaths, opportunistic infections and neoplasms were not reported [46]. Patients treated with thiopurines have an increased risk of lymphoma (RR = 4.18; 95% CI 2.07 -- 7.51). The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease or a combination of the two [49]. In a review, Kotlyar et al. estimated the RR of hepatosplenic T-cell lymphoma (HSTCL), a rare and usually fatal lymphoma, among IBD patients treated with AZA or 6-mercaptopurine and anti-TNF. Of 36 patients (29 male, 2 female and 4 unknown gender) with HSTCL, 20 received therapy with IFX and a thiopurine (4 patients also received adalimumab and 1 had been given IFX, adalimumab and natalizumab) and 16 received a thiopurine as monotherapy. Most patients with HSTCL who received long-term therapy (at least 2 years) with thiopurines for IBD were men younger than 35 years old (27/30 patients of known age). There were no reported cases of HSTCL in patients with IBD who received only anti-TNF therapy [50]. The metabolism of AZA/6-mercaptopurine depends on three enzymes: thiopurine xanthine oxidase, thiopurine methyl transferase (TPMT, which catalyses the formation of 6methylmercaptopurine (6-MMP), an inactive metabolite of 6-mercaptopurine) and hypoxanthine phosphoribosyltransferase that converts AZA/6-mercaptopurine into 6-thioguanine nucleotides [51]. Patients with low activity of TPMT have an increased risk of bone marrow toxicity and sepsis and should not be treated with thiopurine. An increased level of 6-MMP is associated with hepatotoxicity. However, the need to test TPMP activity (phenotype or genotype) before starting therapy with thiopurines is unclear [52]. Concerning the use of thiopurines for chemoprevention of CRC, the studies published before 2010 failed to demonstrate a decreased risk of CRC in patients receiving thiopurines. On the contrary, a recent study showed that thiopurine therapy reduces the risk of CRC in patients with IBD and longstanding extensive colitis. To explain the discrepancy between their study and previous ones, the authors hypothesise that, in previous studies, a closer surveillance in patients receiving thiopurines might have led to an artificially increased detection of neoplastic lesions and thus introduced a bias against the real protective effect of thiopurines [53]. However, there are insufficient data on the role of immunomodulators in chemoprevention [42]. 8

Methotrexate Methotrexate is a folic acid analogue, with inhibitory activity against some enzymes in the metabolic pathway of folic acid. Methotrexate therapy (low dose like 25 mg or less once a week) inhibits production of thymidylate, purines and methionine and leads to accumulation of adenosine, a potent anti-inflammatory substance. Methotrexate inhibits cellular proliferation and decreases formation of antibodies and of mediators of inflammation, such as interleukins and eicosanoids [54]. Prospective studies on methotrexate for UC are small, use varying doses or routes of administration and have inconsistent outcomes [1]. The only randomised placebo-controlled trial using a dose of 12.5 mg/week of oral methotrexate in UC showed no benefit [55] and a Cochrane database systematic review concludes that there is insufficient evidence to support its use at present [56]. A study of 2012 evaluating the efficacy of methotrexate in combination with IFX in patients with Crohn’s disease showed that patients who received methotrexate were less likely to develop antibodies to IFX (4% compared with 20%; p = 0.01) than those who received IFX alone. Although not statistically significant, the median serum trough IFX concentration was higher in patients who received methotrexate (6.35 mg/ml compared with 3.75mg/ml; p = 0.08) [57]. 3.3

Infliximab ACT 1 and 2 also evaluate the safety and efficacy of IFX for maintenance therapy in UC. In both studies, patients who received IFX were significantly more likely to have a clinical response and a sustained clinical remission as shown in Tables 1 and 2. The ACT trials showed also that patients who achieve mucosal healing after 8 weeks of IFX have better clinical outcomes including fewer colectomies [34], as demonstrated in a following study [58]. 3.4

4.

New therapy

A lot of studies are continuing to identify potential therapeutic targets for UC, some therapies will be on the Italian market soon, and some are on the market in several countries [59-71]. Some new therapies or strategies seeking the future direction of medical treatment being studied include autologous transplantation of haemopoietic stem cells, mesenchymal stem cells and genome-wide association studies; additional ones are listed in Table 4. 5.

Conclusion

As reported, a significant amount of data shows that steroids, salicylates, conventional immunosuppressants and biological agents are effective for inducing and maintaining remission in UC. However, there are many aspects of therapy with these


Ulcerative colitis

Table 4. Emerging new therapies.


Compound

Company

AM-3301 Adalimumab Anrukinzumab ASP-2002 BBIC

Amalyte AbbVie Pfizer Asphelia ProtoMed, Inc

CyCol Dersalazine DIMS-0150 ELND-004 Enkorten Etrolizumab Golimumab GSK-1399686 GSK-1607586 HE-3286

Sigmoid Pharma Palau InDex Elan Farmacija Genentech MSD GSK ChemoCentryx-GSK Harbor BioSciences

HPML-004

Hutchinson

LMW heparin LT-02 MDX-1100 PF-547659 PUR-0110 RDP58 Sotrastaurin

Cosmopharm Bio-Pharma Medarex Pfizer PurGenesis Technologies Genzyme Novartis

Tasocitinib Tofacitinib Vedolizumab Vidofludimus

Pfizer Pfizer Takeda 4SC

Mechanism of action Immunomodulator TNF-a inhibitor IL-13 inhibitor CAM inhibitors Protein kinase inhibitors IL inhibitors TNF-a inhibitor Immunomodulator CAM inhibitors IL inhibitors CAM inhibitors TNF-a inhibitor Immunomodulator Chemokine receptors IL inhibitors through NF-kB modulation IL inhibitor, Chinese herb extract Antioxidant Antioxidant Chemokine receptors CAM inhibitors IL inhibitors Immunomodulator Protein kinase C inhibitor JAK 3 inhibitors JAK 1-2-3 inhibitors a4b7 inhibitor IL-17A and IL-17F inhibitor

agents for which data are currently lacking or inadequate, especially with regard to the capability of preventing the progression of disease, including colectomy. Additional agents are necessary and prospective data are needed to resolve the areas of controversy. 6.

Expert opinion

As reported in two studies of the Northern European population [72,73], around 50% of patients with UC are in remission each year. Thus, the remaining half of the patients followed for a period of 10 -- 25 years may have a more aggressive clinical course of the disease, with frequent relapses, severe onset of disease, refractoriness and steroid dependency. UC is a disease affecting young patients, whose quality of life may be strongly compromised by the progression of disease. Over time, disease progression may lead to an impairment of the normal anatomy and physiology of the colon, with proximal

extension, stricturing, pseudopolyposis, dysmotility, anorectal dysfunction (tenesmus, urgency, incontinence) and impaired permeability [74]; the occurrence of extraintestinal manifestations can further compromise the clinical course of the disease. Moreover, the cumulative incidence of dysplasia, CRC and colectomy increases with the time. In addition, compared to patients with other chronic conditions, patients with UC perceive a more negative impact of the disease upon their quality of life. The working and reproductive ability of UC patients may be reduced, with an increased RR for disability pension and work disability. Another important aspect to consider is the impact of persistent mucosal lesions on the clinical course of disease, even in patients in clinical remission. In a recent hospitalbased inception cohort study, the lack of mucosal healing after the first course of corticosteroids therapy in patients with newly diagnosed UC was associated with negative outcomes at 5 years. In detail, there was a significantly increased rate of immunosuppression, hospitalisation and colectomy rates, thus emphasising that failure to reach mucosal healing is strongly associated with a poor subsequent clinical course. With this background, it is extremely important to optimise the use of therapies, which are available nowadays and commonly used in daily clinical practice. It is also very important to continue and stimulate the search for more powerful drugs for the induction and maintenance of sustained and durable remission, thus preventing further complications. However, the main challenge is to identify the patients who may experience a more aggressive clinical course. Therefore, studies aimed at identifying the prognostic variables associated with a more aggressive clinical course are urgently needed. Once this is done, it will be possible to test the most potent therapies in patients stratified according to such prognostic variables. A population-based inception cohort of 519 UC patients diagnosed in south-eastern Norway and followed for 10 years showed that young patients, with extensive colitis, ESR > 30 and who needed CS at diagnosis, had a risk of colectomy 15 times higher in comparison to patients without these characteristics. In conclusion, the main aims of research in the near future should be to, both, develop a better definition of patients at risk for a poor clinical course and progression of disease as well as the development of a much more aggressive treatment for patients with a poor prognosis.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.


9

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Affiliation Cristina Bezzio1 MD, Federica Furfaro1 MD, Roberto de Franchis1 MD, Giovanni Maconi1 MD, Anil Kumar Asthana2 & Sandro Ardizzone†1,3 MD † Author for correspondence 1 Chair of Gastroenterology, “L. Sacco” University Hospital, Department of Gastroenterology, Oncology and Surgery, Via GB Grassi, 74, 20157 Milan, Italy Tel: +39 02 3904 2486; Fax: +39 02 3904 2232; E-mail: [email protected] 2 “The Alfred Hospital”, Department of Gastroenetrology, 55 Commercial Road, Melbourne, Victoria, 3004, Australia 3 Polo Universitario, Ospedaliera ‘L. Sacco’, Cattedra e Divisione di Gatroenterologia, ed Endoscopia Digestiva, Azienda, Italy

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