Where are we going with ulcerative colitis management?

Abstract

Impressive progress has been made in the treatment of ulcerative colitis. Corticosteroids are nowadays limited to short-term use. The mainstay of current therapy consists of the immunosuppressive drugs (largely thiopurine analogs) and the biologics, often in combination. The calcineurin inhibitors are still in use for acute severe colitis in many centers. However, gastroenterologists can now choose between calcineurin inhibitors and biologics for administration to patients with fulminant disease, although the criteria for selection are not yet resolved. Given the success rates of current therapies, it is obvious that new and better drug development is required if surgery is to disappear from the armamentarium of treatments.

Keywords::

• biologics
• immunosuppression
• therapy
• ulcerative colitis

1. Introduction

It is interesting to note that despite the enormous progress made in the treatment of ulcerative colitis, the principles evoked by Truelove and Witts in their classical articles on corticosteroid therapy [1] are as applicable today as ever! Their principles included adherence to a pre-defined treatment plan, with a defined time horizon, in patients pre-stratified by disease extent (serial barium studies in their time) and severity (clinical and sigmoidoscopy criteria). We have surely come a long way since the 1950s, the understanding of disease pathogenesis at the cellular and molecular level has expanded tremendously, and the armamentarium of drugs targeted at that level has grown. Ardizzone et al. reviewed this subject most carefully in the previous issue of the journal [2]. However, applying all this knowledge in best patient care remains a challenge.

2. Tighter definitions of disease activity

The approach to treating ulcerative colitis has undergone a fundamental change in the past few years. The disease phenotype, now defined according to the landmark Montreal classification of ulcerative colitis, specifies the importance of disease location (extent) and behavior in determining both severity and outcomes [3]. To this a host of other parameters have been shown to be significant, such as the colonoscopic and Mayo activity scores (both require assessment of the condition of the affected mucosa), the PUCAI (pediatric ulcerative colitis activity index) score in children, C-reactive protein, sedimentation rate and albumin [4]. Anemia and weight loss are most important. The response to treatment has been expressed hitherto in the classical concepts of ‘clinical improvement' and ‘clinical remission', as used in reports of drug trials. Rutgeerts et al. proposed recently that mucosal healing should be the determinant of successful treatment [5]. Thus, the concept of success in treatment is best given now as ‘mucosal healing' or ‘deep remission'. The recent revised European Crohn's Colitis Organization guidelines for managing ulcerative colitis specify the outcomes of treatment in those failing to achieve remission as ‘drug-dependent' or ‘drug-refractory' [6]. However, these guidelines should also take into account the findings at colonoscopy. Follow-up too should no longer be just a clinical assessment of the patient, but must include careful appraisal of the mucosa, with biopsies, to establish the degree of mucosal healing (sigmoidoscopy may suffice in many cases). Ulcerative colitis, even the milder cases like proctitis, remains a difficult condition to treat in many patients and requires careful selection of drugs and monitoring of the patient's response to ensure mucosal healing. Corticosteroids are nowadays limited to short-term use in acute flares and as a bridge to other therapies, and do not induce mucosal healing (Table 1). Whether the other drugs at our disposal today can be manipulated to achieve full mucosal healing is the big question. What follows then is an account of what have we learnt.

Table 1. Take-home messages: current usage of therapies in ulcerative colitis.

Medication	Year of introduction (approx.)*	Current recommended usage
Corticosteroids	1955	For short-term use in acute or acute-on-chronic colitis and as a bridge to more definitive treatment
Salazopyrin (sulfasalazine)	1962	For maintenance (seldom used nowadays)
Thiopurine analogs	1966	Maintenance only, with or without biologics (or cyclosporine); may be introduced concomitantly with corticosteroids
5-Aminosalicylates	1981	For short-term use in acute mild colitis, and for maintenance
Methotrexate	1989	Not recommended, pending further investigation
Calcineurin inhibitors^‡	1990	Cyclosporine as rescue therapy in acute severe colitis, not for maintenance
Infliximab	2001	For acute and maintenance therapy
Adalimumab^§	2009	For acute and maintenance therapy

*This refers to landmark reports of open or blinded trials of the use of these agents in ulcerative colitis, not the dates when these agents were approved for use by national regulatory authorities.

^‡Calcineurin inhibitors are not to be co-administered with anti-TNF-α agents.

^§Approved in the USA and Europe in 2012. Further clinical experience is warranted to determine its place in the treatment of ulcerative colitis.

3. Thiopurine analogs

In a retrospective study, Fraser et al. had found that about 60% of ulcerative colitis patients achieved clinical remission on azathioprine [7]. However ‘remission' was not clearly defined and there was no colonoscopic follow-up. Not surprisingly, there was a high relapse rate at 1 year after treatment ceased, likely indicating incomplete healing of the mucosa. Ardizzone et al. reported a randomized, prospective, controlled trial in steroid-dependent ulcerative colitis patients, comparing the efficacy of azathioprine with that of 5-aminosalicylic acid (5-ASA). Some 55% of patients treated with azathioprine had clinical and endoscopic remission, and were able to discontinue steroid therapy [8]. As expected, this was not achieved with the 5-ASA group. The importance of this trial is that it shows clearly that azathioprine can induce endoscopic mucosal healing. Ardizzone et al. then performed a prospective study of ulcerative colitis patients treated with corticosteroids and followed for 5 years. They were able to demonstrate that non-healing of the colonic mucosa was associated with more relapses, hospitalizations and surgery [9]. Clearly, achievement of mucosal healing is important in determining the future course of the disease. Since azathioprine is effective as additive therapy in severe ulcerative colitis, this is a property of the drug be borne in mind when considering drug combinations for acute disease as well as chronic maintenance treatment. Ardizzone et al. also reviewed the importance of thiopurine methyltransferase enzyme measurements [6]. However, given the retrospective nature and paucity of large studies of the use of thiopurine inhibitors based on enzyme measurements and 6-thioguanine levels, it is prudent to await more definitive studies prior to advising on the routine use of treatment based on these determinations. On a related topic, there is increasing use of allopurinol, a purine analog inhibiting xanthine oxidase activity, to augment the response to azathioprine or 6-mercaptopurine. To date, patient numbers in reported studies have been small and more investigation is required to determine the clinical efficacy of this drug and whether mucosal healing is abetted [10].

4. Methotrexate

Methotrexate is usually mentioned together with the thiopurines when inflammatory bowel disease therapy is discussed. Even so, it is not really of value in ulcerative colitis. Methotrexate at a weekly oral dose of 12.5 mg was not found to be better than placebo in treating ulcerative colitis [11]. The proportion of patients entering first remission or relapsing after first remission, the time to relapse and the mean Mayo score were similar in the methotrexate and placebo arms. More recent publications have not shown any better outcomes. Parenteral methotrexate would require study in controlled trials.

5. Calcineurin inhibitors

Concerning the calcineurin inhibitors, Lichtiger et al. demonstrated the efficacy of cyclosporine-A in severe ulcerative colitis patients facing imminent surgery for failure to respond to corticosteroids [12]. In a pioneer study, a randomized, double-blind, controlled trial was performed where cyclosporine (4 mg/kg of body weight per day) or placebo was administered by continuous intravenous infusion to 20 severe ulcerative colitis patients who failed to improve after at least 7 days of intravenous corticosteroid therapy. The results with cyclosporine were quite remarkable, particularly the rapidity of clinical response, and this led to the widespread use of this therapy up to the time when infliximab was introduced. There are however important problems with these drugs in respect of disease outcome. First, re-administration of calcineurin inhibitors for relapse in patients who had remitted on these agents does not seem to be successful. Second, follow-up of patients who responded to cyclosporine reveals a high short-term colectomy rate.

6. Biologic therapies

The biologic agents infliximab and adalimumab constitute the only major advance in the treatment of ulcerative colitis in recent years, although adalimumab was approved for this use in Europe and the USA only in 2012. Both agents are now indicated to treat adult patients with moderate to severe ulcerative colitis, who have had an inadequate response to immunosuppressants, for inducing and sustaining clinical remission. Both agents are anti-TNF-α antibodies, adalimumab being wholly human in composition and self-injectable, features offering some advantages over infliximab. Infliximab has been used in ulcerative colitis for over a decade and offers a rich experience in patient outcomes, whereas there is less knowledge about adalimumab. The Active Ulcerative Colitis Trials (ACT) 1 and 2 formed the basis for advocating the use of infliximab in moderate to severe ulcerative colitis [13]. It was then shown that early mucosal healing with infliximab was associated with improved long-term clinical outcomes in ulcerative colitis [14].

7. Treatment choices in severe ulcerative colitis

The current controversy regarding hospitalized ulcerative colitis patients, who are severely ill and refractory to corticosteroids, rests in the selection of a drug that will avert emergency colectomy. The choice today is between cyclosporine and infliximab. The literature on this topic has been sparse until recently, so that evidence-based decision making was difficult. Among the notable studies aimed at clarifying the issue, two will be mentioned here. In a series of 19 patients with fulminant ulcerative colitis who had failed either cyclosporine or infliximab, each patient was given the other drug as salvage therapy within the next 4 weeks. It was shown that 40% responded to infliximab and 33% to cyclosporine, and avoiding colectomy in the following year [15]. Although a small study, it nonetheless held out the hope of achieving success with an alternative agent. Chaparro et al. reported the use of infliximab as rescue therapy in 47 patients who had failed steroid and cyclosporine therapy [16]. Nearly half of the patients achieved remission after full induction therapy with infliximab. However, 30% required colectomy, and the rate of adverse events was high at 23%, including one death from post-surgery nosocomial pneumonia. Chang et al. [17] and Rolny and Vatn [18] reviewed the current literature comparing cyclosporine and infliximab in severe steroid-resistant ulcerative colitis. Eight studies were examined. Allowing for differences in protocol, population, disease severity, time horizon and definition of clinical remission, it could still not be inferred that any drug was superior to the other. What was required was a well-designed prospective head-to-head comparison of these drugs. This has been provided now by Laharie et al. [19]. They performed a parallel open-label randomized controlled multicenter study of treatment with cyclosporine and infliximab in 119 patients with acute severe ulcerative colitis refractory to intravenous steroids, with time horizon at day 98. Responding patients were given azathioprine as well from day 7. The data basically revealed that the drugs were equally effective. Responses to treatment became evident by day 7 in 86 and 84% of patients on cyclosporine and infliximab, respectively, with no difference in the median time to response. Mucosal healing was achieved in 47 and 45% of patients at the end of the study, and colectomy rates were low at 17% for cyclosporine and 21% for infliximab, with no difference in time to colectomy. However, severe adverse advents were reported in 16 and 25% of cyclosporine and infliximab cases, respectively. Having learnt now that these drugs have equal effect, how does one choose between them? The answer lies in the experience of the gastroenterologist. Since cyclosporine is quite toxic, it should be restricted for use by experienced physicians in an appropriate hospital setting. Physicians having most experience with infliximab will go on using that biologic [19]. There is a note of caution: given the risk of poor outcomes when surgery is delayed, the recently published Toronto Consensus Statements [20] have advised limiting both cyclosporine or infliximab rescue therapy to 5 – 7 days before proceeding to surgery in non-responders (remembering the approach of Truelove and Witts).

8. Summary

In summary, the arsenal of therapeutic options for ulcerative colitis has increased, as has the understanding of their mechanisms of action. Cyclosporine and infliximab do promise improved outcomes quickly, but with a high rate of severe side effects. The latter is also very expensive. The performance of adalimumab in ulcerative colitis has hitherto been under-tested, and remission rates varied greatly between studies [21]. Clearly, the performance of this agent on the open market will be followed keenly. Additionally, there is an urgent need for new drugs for use in patients with severe ulcerative colitis.

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.