Recent developments in the treatment of inflammatory bowel disease
- Conflict of interest: None.
Correspondence to: Geert R. D'HAENS, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Email: firstname.lastname@example.org
Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases that have been treated with corticosteroids, 5-aminosalicates and thiopurines, but therapeutic options have been broadened with the arrival of anti-tumor necrosis factor antibodies. In this article we reviewed the current evidence-based approach to inflammatory bowel disease, the modifications that have been made to existing therapies and discussed new drugs that have shown success in clinical trials. The new drugs discussed here are those that disturb lymphocyte homing to the gut (natalizumab, vedolizumab and anti-mucosal addressin cellular adhesion molecule); one that blocks interleukin (IL)-12 as well as the IL-23/T helper 17 (Th17) axis (ustekinumab) and one that blocks the signaling of multiple cytokines (tofacitinib).
Crohn's disease (CD) and ulcerative colitis (UC) are distinct disease entities that are grouped under the term inflammatory bowel disease (IBD) because of their common immunological pathophysiology. IBD is most frequently diagnosed in the second or third decade of life and patients typically present with chronic abdominal pain and altered bowel habits. Often there is a delay in diagnosis because abdominal pain and other symptoms can mimic the irritable bowel syndrome (IBS) and gastrointestinal infection. The similarity between CD and UC has in the past resulted in parallel treatments, often with success. The mainstay of remission induction has been based on various formulations of corticosteroids while maintenance therapy has typically relied on 5-aminosalicates (5-ASA) and thiopurines. Anti-tumor necrosis factor (TNF) antibodies are effective for both the induction and maintenance of remission and are usually reserved for those more severe and/or steroid-dependent patients.
In this article we addressed three principal issues to illustrate current developments: first of all, the current evidence-based approach to CD and UC; second, the modifications that have been made to existing therapies; and third, the therapies targeting new pathways that have been tested.
The Current Evidence-Based Approach to CD and UC
For decades the initial medical treatment for IBD has consisted of corticosteroids, typically (methyl)prednisolone or hydrocortisone. While corticosteroids are excellent at inducing remission, maintenance therapy is problematic because the disease may become refractory and many side effects develop. 5-ASA-based therapies are very effective at inducing and maintaining remission in UC but are rarely recommended for CD due to limited evidence of their efficacy.
The introduction of anti-TNF antibodies has been a turning point. Infliximab was the first anti-TNF antibody made available and was proved to be effective in the induction and maintenance of IBD remission, as well as in the treatment of fistulizing disease in the case of CD. Adalimumab, a subcutaneous human anti-TNF antibody, is also effective for the treatment of CD and UC.[2-4]
We typically treat mild to moderate UC first with oral and/or topical 5-ASA preparations. Oral and/or topical corticosteroid preparations (budesonide or beclomethasone) are added if symptoms persist. Once remission has been reached, preferably judged by the normalization of calprotectin or documented by endoscopy, we taper off the admission of steroids and use 5-ASA as maintenance therapy. Unless there is isolated distal disease (proctitis), we try to maintain remission with oral, slow-release 5-ASA preparations. Even in cases of repeated exacerbations, we try to optimize oral and topical 5-ASA therapy (often in combination) to control the disease. If multiple induction courses or steroids are needed, however, the introduction of thiopurine maintenance therapy is recommended.[5, 6] Since thiopurines are slow-acting agents, the first few months of treatment are usually combined with steroids in tapering schedules. In cases of severe UC we use high-dose oral prednisolone. If symptoms persist, however, we rapidly step up the treatment by admitting the patients to the hospital for i.v. prednisolone. If improvement is not evident after 3 days, we consider infliximab or cyclosporine.
In CD, remission is preferably induced with budesonide. More severe disease presentations, for example, with extraintestinal manifestations, however, require systemic steroid treatment with (methyl)prednisolone. Once remission has been reached, many patients receive maintenance treatment with azathioprine/6-mercaptopurine. In a substantial group of moderate to severe cases, however, this does not offer sufficient disease control. If patients have repeated flares, we introduce infliximab or adalimumab to induce and maintain remission, with ongoing concomitant immunosuppressive treatment.
In both UC and CD we rarely discontinue 5-ASA, thiopurines or anti-TNF therapy after successful induction of remission, although the financial burden of biological therapy is considerable, and its long-term cost-effectiveness has not been firmly established for UC.
One of the most important aspects of managing IBD is accurate disease-monitoring and record-keeping throughout the patient's life. This helps to establish the course the disease is taking, the medications that have been tried and the result of the treatment administered.
Modifications That Have Recently Been Made to Existing Therapies
Novel delivery mode of 5-ASA: multi-matrix (MMX) mesalazine
Traditional oral 5-ASA preparations are not very effective in distal UC, probably because sufficient mucosal concentrations are not reached in the rectum. This is the reason why rectal formulations can be combined with oral therapy to ensure more effective treatment of left-sided UC. However, slow release of the active ingredient constitutes a more elegant and patient-friendly option. It has also been shown that split dosing of oral 5-ASA can be replaced by once daily administration.
A new MMX delivery system of 1.2 g of MMX mesalazine was tested in a preliminary trial in UC and showed similar rates of remission induction to the combination of mesalazine enema and oral placebo in patients with left-sided colitis. In two pivotal trials with MMX mesalazine at higher doses[13, 14] patients with active UC were randomized to receive 2.4 g or 4.8 g of MMX mesalazine once daily versus placebo or 800 mg of slow-release mesalazine. Endoscopic and clinical remission rates were superior with MMX mesalazine.
Novel delivery of topical steroids: budesonide MMX
With the emergence of delayed release budesonide, including Entocort (AstraZeneca, Sodertalje, Sweden) and Budenofalk (Dr. Falk Pharma GmbH, Freiberg, Germany), topical corticosteroid therapy of the terminal ileum and colon has become possible. Budesonide MMX (Cosmo Pharmaceuticals, Lainate, Italy) is a once daily oral formulation of budesonide using a MMX technology to extend the release of budesonide throughout the colon. A randomized pilot study showed that budesonide MMX was safe and effective in treating left-sided colitis, which was subsequently confirmed in a randomized, double-blind, double-dummy, placebo-controlled trial in which two doses of budesonide MMX were compared with placebo and mesalazine. The results showed that 9 mg budesonide MMX led to higher rates of clinical and endoscopic remission than the placebo. This drug is currently undergoing regulatory review.
Altering the intestinal microbiome: rifaximin
Gut bacteria play a crucial role in the development and maintenance of IBD. Hence, changing the microbiome is an attractive approach in developing novel therapies. Usually, antibiotics are not recommended for the treatment of inflammation in CD or UC, apart from fistulizing disease, septic complications or pouchitis. While certain trials have shown a beneficial effect, the use of different antibiotics in small groups of patients have made evidence-based recommendations difficult. It is also unclear whether the antibiotic effect is due to the removal of specific detrimental bacteria, or to a new balance in the gut flora.
Rifaximin is a broad spectrum antibiotic that exerts its bactericidal effect mainly in the gut lumen, as it is not absorbed. Following a promising open-label trial in CD, two placebo-controlled trials were performed with a delayed release preparation (rifaximin- extended intestinal release (EIR). Prantera et al. randomized 83 patients with active CD to 800 mg of rifaximin-EIR once or twice daily or placebo. When compared to placebo they demonstrated that the twice daily dose was more effective in inducing a response but the differences in remission rates were not statistically significant. Some of the investigators went on to enroll 402 patients in a trial with three doses of rifaximin-EIR or placebo and showed that a dose of 800 mg twice daily induced remission with few adverse events in patients with moderately active CD over a 12-week period. The authors noted, however, that there was a lack of a dose–response relationship and a higher than expected placebo response.
Rifaximin was also tested in UC in a randomized, double-blind trial in 26 patients. Although there was no statistically significant difference in clinical activity between the two groups, rifaximin resulted in symptomatic and endoscopic improvement compared to the placebo-treated group. We should, however, remain cautious of long-term antibiotic therapy because of the possibility of antibiotic resistance.
New ways of targeting TNF: certolizumab pegol and golimumab
While anti-TNF therapy can hardly be considered new, it is worth mentioning that there have been advances in the types of antibodies that have and will become available. Since the arrival of infliximab, changes have been made in the way TNF is targeted. Infliximab is a mouse–human chimeric antibody and adalimumab is a fully human antibody. Both are large proteins that can elicit antibodies and bind Fc receptors on various cells. The development of antibodies against these preparations reduces efficacy and causes adverse events.
In an attempt to reduce immunogenicity and increase the serum half-life, a pegylated form of an anti-TNF Fab′ fragment was constructed and named certolizumab pegol.
Several trials have shown that certolizumab pegol is effective in the induction and maintenance of remission in patients with CD, especially those with raised C-reactive protein and a short history of disease.[22-26] A meta-analysis showed a particular benefit with certolizumab pegol in the maintainance of remission. Additional data indicated that patients who previously responded to infliximab, but who have lost the response or became intolerant, are likely to respond to certolizumab.
An even more recent anti-TNF antibody is golimumab, another fully human molecule that is s.c. administered. Golimumab has so far only been tested in moderate to severe UC, showing favorable effect on induction and the maintenance of remission as well as on mucosal healing.
New Pathways Being Targeted in IBD
Inhibition of leukocyte homing: natalizumab, vedolizumab and anti-mucosal addressin cellular adhesion molecule (anti-MAdCAM)
Natalizumab is a recombinant humanized antibody that was derived from a murine monoclonal antibody originally raised against human α4 integrin. α4 integrin is expressed on certain lymphocytes and, as part of a dimer with other integrin chains such as β7 or β1, binds ligands on endothelium, such as MAdCAM and vascular cellular adhesion molecule 1 (VCAM-1). The rationale behind natalizumab therapy is that by blocking the α4 molecule in particular, certain lymphocytes are prevented from homing to the gut and entering the intestinal tissues. This strategy has proven successful in multiple randomized placebo-controlled trials in patients with CD[29-32] and was also effective in multiple sclerosis (MS).[33-35] There are, however, significant safety concerns after reports of patients who developed progressive multifocal leukoencephalopathy (PML) due to reactivation of JC virus. The reason for this phenomenon was that α4 blockade reduced lymphocyte homing not only to the gut but also to the central nervous system. Natalizumab is now available only in North America without concomitant immunosuppression and with a strict monitoring program including JC virus serology. Until recently, this monitoring program has identified 212 confirmed cases of PML in 99 571 MS patients (0.213%) who had received natalizumab for more than a month.
Vedolizumab is an antibody directed against both the α4 and β7 integrins when they are in complex, which implies high specificity for gut-homing lymphocytes, thereby avoiding effects on the immunity of central nervous system. An initial trial by Feagan et al. in 2005 showed the efficacy of this antibody in inducing a short-term response and remission in patients with active UC.
In 2012 a large phase III trial showed impressive results for the induction and maintenance of remission, steroid withdrawal and mucosal healing in UC, including in patients who had previously failed anti-TNF treatment. Vedolizumab was also tested in CD and although the primary end point (clinical response at day 57, defined as a 70-point or higher decrement in CD activity index [CDAI] score from baseline) was not met, there seemed to be a dose-dependent effect, mainly beyond week 6. Reports from a recently completed phase III trial have supported these findings as significantly more patients with moderate to severe CD achieved and stayed in remission when treated with 4-weekly or 8-weekly infusion of vedolizumab.[41, 42] The safety data of the studies revealed a very reassuring profile. In particular, there was no increased incidence of infection, adding additional proof to the selective intestinal mechanism of action of this drug. It is likely that vedolizumab will become commercially available in the coming years.
The antibody PF-00547,659 provides an alternative way of blocking the α4β7 interaction with the endothelium by binding and blocking endothelial MAdCAM. This was tested in a preliminary trial to assess its safety and efficacy in UC. While the results were not significant, they were very favorable and further trials are underway in both UC and CD.
Blocking of interleukin (IL-12) signaling and the IL-23/Th17 axis: ustekinumab
Ustekinumab is a monoclonal antibody generated in human immunoglobulin G (IgG) transgenic mice immunized with IL-12. IL-12 has a p40 subunit which shares with IL-23. Ustekinumab was tested in a phase IIa trial in CD and although the primary end point was not met, significant differences with placebo were found in patients who had previously received infliximab. This was an important finding because many patients treated with anti-TNF agents lose response or become intolerant over time. To address this in more detail, an additional trial was performed in patients who were resistant to anti-TNF treatment. Here, significant differences in response rate were found and if the patients did respond initially they were more likely to reach remission when on maintenance therapy.
Ustekinumab probably acts by neutralizing the inflammatory effects of IL-12 and IL-23, thereby disrupting the development and/or function of T helper 1 (Th1) and Th17 cells, which are known to play an important role in the development of CD. The drug is already widely available for the treatment of psoriasis and is likely to become available for refractory CD in the years ahead.
Blocking multiple cytokine signaling: tofacitinib (CP-690550)
Tofacitinib is a selective oral inhibitor of the Janus kinase (JAK) family of kinases that mediates signal transduction activity involving the common gamma chain of the receptors for multiple cytokines. This agent was shown to inhibit a number of innate and adaptive immune responses including the activation and differentiation of T cells and the innate response to lipopolysaccharides. In addition, clinical trials in rheumatoid arthritis were successful,[48-50] leading to the approval of the drug by Food and Drugs Administration (FDA) of USA for this indication. In an 8-week phase II trial of patients with moderately or severely active UC, treatment using tofacitinib resulted in significant improvements in clinical and endoscopic response and remission. The drug is currently being investigated in phase III programs.
We have reviewed therapies that have demonstrated effects in controlled trials but many more interesting therapies are currently being tested. Due to the discovery of susceptibility genes, novel cell subsets and insights into antigen-processing and cell signaling we will have a much better understanding of the basis of CD and UC. With the arrival of targeted therapy in the form of monoclonal antibodies, RNA-antisense, small molecule inhibitors and RNA-interference-based therapy, we have been given tools to manipulate specific processes. By integrating these technologies and the expanding number of candidate pathways, a number of new medications can be expected to reach the market in the coming years. This requires a better understanding of biological mechanisms, drug kinetics and potential side effects. We have found that close collaboration between clinical and research laboratories, other specialisms such as rheumatology, and pharmaceutical companies have been of paramount importance in creating progress in this expanding field.