Treating Crohn’s disease: at “deep” remission and exploring beyond

In the late 1990s, controlled trials confirmed the efficacy of tumour necrosis factor-alpha (TNF-α) antibodies in treating active Crohn’s disease, signalling a major breakthrough in treatment. TNF-α monoclonal antibody therapy has since been shown to lead to significant improvements in quality of life and symptom control and a decrease in the need for surgery and prolonged hospitalisation for patients with Crohn’s disease.1 The development of such an effective form of treatment has led not only to a change in the paradigm for treating Crohn’s disease, but also to an increasing awareness of its limitations.

Rather than merely aiming for clinical remission, anti-TNF-α therapy can produce complete healing of all inflamed mucosa in many patients. This can then be used to predict the future course of the disease, as the likelihood of relapse is significantly less if mucosal healing has occurred.2 From this has emerged the concept of “deep” remission, which includes both clinical and endoscopic remission, as the optimal outcome of any form of treatment.

Two anti-TNF-α agents, infliximab and adalimumab, are currently available on the Pharmaceutical Benefits Scheme in Australia for patients with moderate to severe luminal disease who are intolerant of or refractory to immunomodulator therapy, and those who have complex refractory fistulising disease. The use of anti-TNF-α therapy in the initial treatment regimen at diagnosis, for prevention of postoperative recurrence, has also been proposed but is not yet routine.

Safety concerns related to the mechanism of action of TNF-α antibodies — blocking TNF-α, a major mediator in the pathophysiology of inflammation — have resulted in collection of data in long-term registries3 and from prospective cohorts,4 with hundreds of thousands of patient-years of outcomes amassed. The most notable risk relates to the role of TNF-α in the host defence against Mycobacterium tuberculosis, Listeria monocytogenes and other intracellular pathogens, as neutralisation of TNF-α predisposes to reactivation of latent tuberculosis or hepatitis B virus. Screening for these infections is mandatory before starting treatment. Not only is the risk of opportunistic infection increased, but it is considerably more likely when anti-TNF-α therapy is used in combination with corticosteroids (odds ratio, 14.5 v 4.4).5 When such infection occurs or reactivates, it can be serious, as in the case of invasive L. monocytogenes infection in a patient with Crohn’s disease treated with adalimumab, reported by Willson and colleagues in this issue of the Journal.6 The risk of malignancy (chiefly lymphoma) is also elevated, if modestly, and more likely when anti-TNF-α therapy is used in combination with thiopurine immunomodulators.7

As life-changing as these biological therapies can be, not all patients (only about one in three) respond, while others (about one in two or three) will lose their response over time.8 Further, anti-TNF-α therapy may control but does not cure Crohn’s disease.

These factors have led to an intensive search for other novel treatments. As insights are gained into the pathogenesis of Crohn’s disease, and the immunological interface at the mucosa is probed, new experimental therapeutic targets are emerging.9

There is strong evidence implicating T cells and T-cell migration to the gut in initiating and perpetuating the intestinal inflammatory process and tissue destruction.8,9 Pro-inflammatory T helper 17 (TH17) cells play a central role in Crohn’s disease. TH17 cells express the interleukin-23 (IL-23) receptor, and IL-23 is essential for their activation. IL-23 has a p40 subunit in common with IL-12, a cytokine central to the TH1 inflammatory response. Ustekinumab, a monoclonal antibody against the p40 subunit, has reached Phase III trials and is showing promise in patients who have not responded to anti-TNF-α therapy. Another pro-inflammatory cytokine, IL-6, has been targeted by tocilizumab, a monoclonal antibody against the IL-6 receptor. It is effective in treating rheumatoid arthritis, and early studies in Crohn’s disease are promising.

Preventing traffic of inflammatory cells into the mucosa by inhibiting cell adhesion molecules is another approach that has been tried.8,9 Natalizumab, an inhibitor of α4 integrin, is effective in treating Crohn’s disease. However, it has been associated with rare cases of progressive multifocal leukoencephalopathy caused by the JC virus and, as a result, is not available for the treatment of Crohn’s disease in Australia. An alternative agent, vedolizumab, an inhibitor of the gut-specific integrin α4β7, has completed Phase III trials. Oral agents against chemokine receptor 9 (CCR9), the key receptor for targeting leukocytes to the intestinal mucosa, have also had some success in early trials. Attempts at blocking T-cell stimulation or inducing apoptosis have not yet led to the anticipated benefit.

Numerous other agents and targets are currently under development and evaluation but, so far, targeting individual molecules has not resulted in a form of treatment as effective as anti-TNF-α therapy. This likely reflects the role of TNF-α at the head of the inflammatory cascade.

A more all-round approach is to use cell-based therapies to modify the immune system. Reports from small studies of mesenchymal or autologous stem cell transplantation have been very encouraging, but large trials are needed to confirm these results.9

The development of anti-TNF-α agents has improved the outcome for many patients with inflammatory bowel disease, particularly Crohn’s disease. More importantly, it has led to greater knowledge of the pathogenesis of the disease and a new way of considering what the aim of treatment should be. As new agents continue to become available, it will be increasingly important to understand which targets may be appropriate for each patient, based on genetic, immunological and microbial factors. This will lead, in due course, to individualised treatments with the greatest likelihood of benefit and lowest risk of adverse events.