Anti-TNF therapy in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a relapsing inflammation of the intestine, characterised by flares and remission phases. A distinction can be made between two forms of IBD: Crohn’s disease and ulcerative colitis. Crohn’s disease is a transmural disease (affecting different layers of the gastrointestinal wall) and is characterised by discontinuous inflammatory lesions that can appear in the whole gastrointestinal tract from the mouth to the anus. Ulcerative colitis is a mucosal disease (affecting only the mucosal layer of the gastrointestinal wall) and is characterised by continuous inflammatory lesions that appear in the distal part of the gastrointestinal tract.

Patients typically present with abdominal cramps, bloody diarrhoea, urgency and the passage of pus or mucus. The diagnosis is made based on history and physical examination as well as objective findings from endoscopic, radiological, laboratory and histological studies to rule out non-IBD causes of symptoms.

It is commonly believed that in the pathogenesis of IBD, environmental risk factors can induce immunological changes and an onset of the disease in genetically predisposed subjects. The prevalence is highest among Western populations and affects 0.2–0.3% of people. The disease has an early onset, with 25% of IBD patients being diagnosed before the age of 21 years.

Up until now there have been no drugs available to cure IBD, and most of the established and evolving therapies used in the treatment of IBD are also used to treat other chronic inflammatory diseases. This is due to the working mechanism of these anti-inflammatory drugs that interact with downstream targets of an (common) inflammatory cascade.

Historically, a ‘step-up’ approach is followed where more potent drugs are given to patients with a more active or severe disease state. A distinction can be made between drugs to induce remission over a short period of time and to maintain remission over a long period of time. Corticosteroids are used for inducing remission and can either be administered topically or systemically, depending on the disease severity. Antimetabolite therapy with azathioprine, 6-mercaptopurine or methotrexate and 5-amino salicylic acid (for mild-to-moderate ulcerative colitis) are commonly used for maintenance therapy. Patients that are intolerant to immunosuppressive treatment or who become corticosteroid-dependent or corticosteroid-refractory, can be treated with anti-tumour necrosis factor (anti-TNF) monoclonal antibodies (mAbs), whereas beforehand, surgical resection of the inflamed part of the intestine was often the only option.

Anti-TNF therapy allowed targeting treatment goals such as mucosal healing and deep remission that are hard to achieve with conventional immunosuppressive therapies. Interestingly, a ‘top-down’ strategy with early combined immunosuppression with azathioprine and the anti-TNF drug infliximab was found to be more effective than the conventional ‘step-up’ therapy for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn’s disease.¹ This has been an important finding and confirms previous observations that uncontrolled inflammation drives disease progression.

TNF is an important component of the immune system that protects against infections, but this pro-inflammatory cytokine is expressed abundantly in patients with IBD and other chronic inflammatory diseases, such as rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. Anti-TNF antibodies bind very specifically to their target and block both soluble and transmembrane TNF. In Europe, infliximab (Remicade^®), a chimeric IgG1 κ monoclonal antibody and adalimumab (Humira^®), a fully human IgG1 κ monoclonal antibody, are approved for the treatment of moderately to severely active Crohn’s disease and ulcerative colitis. Recently, golimumab (Simponi^®), a fully human IgG1 κ monoclonal antibody, was approved for the treatment of moderately to severely active ulcerative colitis.

Infliximab is administered intravenously in the hospital whereas adalimumab and golimumab are administered subcutaneously and are therefore often preferred by the patient for practical reasons. All anti-TNF antibodies are dosed according to an induction regimen (loading dose) after which patients who respond to the treatment continue treatment according to a maintenance regimen.

Unfortunately 10–30% patients will not respond to anti-TNF treatment (primary non-response), which is often attributed to patients having a non-TNF-driven disease. Of the patients initially responding to induction therapy, 30–60% will lose clinical benefit during maintenance therapy (secondary loss of response), which is often attributed to suboptimal dosing and/or immunogenicity. Secondary loss of response is managed clinically by decreasing the interval between administrations of drug and/or by increasing the dose. If patients do not have an adequate response to dose escalation, switching to another anti-TNF can be considered.

Immunogenicity is defined as the ability of an antigen to elicit a humoral or cell-mediated immune response. In this case, patients will develop anti-drug antibodies that either block the drug’s activity directly or cause a faster clearance of the drug by forming complexes in vivo. All anti-TNF antibodies are immunogenic to a certain extent and, over the years, treatment regimens have been optimised to reduce the risk of immunogenicity: maintenance therapy instead of episodic therapy and treatment with concomitant immunosuppression (such as azathioprine and methotrexate) instead of monotherapy.^2,3

The large inter- (primary non-response) and intra- (secondary loss of response) individual variability in response to anti-TNF agents has sparked the interest of physicians and pharmacologists to investigate the exposure–effect relationship of these drugs. This can be done by measuring concentrations of drug and anti-drug antibodies in serum to establish a concentration–time profile that can be linked with biomarker, clinical or endoscopic outcome measures. Different kits or services are offered by academic research institutes and commercial companies to perform therapeutic drug monitoring (TDM), the majority of which are either enzyme-linked immunosorbent assays or radioimmunoassays.

At different time points, a concentration–effect response was shown for all three anti-TNF agents, indicating higher rates of response, remission and even mucosal healing in those patients with higher serum concentrations of drug, as reviewed elsewhere.⁴ Furthermore, adequate drug trough concentrations early on in the treatment (after induction) were found to be predictive of durable sustained response to the treatment throughout the first year.⁵

These retrospective studies clearly showed an exposure–effect relationship and led to the hypothesis that TDM in individually treated patients could help to guide treatment regimens and optimise dosing. For example, for the management of secondary loss of response, an algorithm-based approach based on TDM has multiple potential advantages over the empirical approach because it will avoid dose escalation in patients who are unlikely to respond due to either immunogenicity or a non-TNF-driven disease. TDM allows for targeted dose adjustment in patients with low drug concentrations due to non-immunogenic pharmacokinetic mechanisms and it directs patients who likely have a non-TNF-driven disease to alternative treatments more efficiently.

This hypothesis was tested in a randomised, multicentre clinical trial in Denmark, where the investigators randomised 69 Crohn’s disease patients with secondary loss of response to maintenance infliximab therapy to either the conventional approach of dose escalation or an approach based on TDM. The co-primary endpoints were the proportion of patients responding to the intervention after 12 weeks in both groups and the accumulated cost related to treatment. Both treatment strategies were found to be equally effective, but interestingly, the approach based on TDM resulted in a 34% decrease in treatment cost compared with the empirical approach of dose escalation.⁶

In Leuven, Belgium, the first prospective randomised clinical trial was conducted on 263 IBD responsive patients on maintenance infliximab treatment. All patients were first-dose optimised to achieve infliximab trough concentrations of 3–7µg/ml by adapting the interval between infusions (4-, 6-, 8-, 10- or 12-weekly) and dose (5 or 10mg/kg), after which patients were randomised to dosing based on clinical symptoms and C-reactive protein (CRP) or dosing based solely on infliximab trough concentrations. The first part of the study – the optimisation phase – showed that dose escalation based on targeting infliximab trough concentrations within the interval of 3–7µg/ml resulted in a significant increase in the proportion of Crohn’s disease patients in remission before and after optimisation (65.1% and 88.4%, respectively; p=0.02) and concomitantly a significant reduction in CRP concentration before and after optimisation (4.3mg/l and 3.2mg/l, respectively; p<0.001). A similar effect was not observed for ulcerative colitis patients, most likely because the majority of patients included in the trial were already in remission and did not have elevated CRP at baseline. The second part of the study – the randomised maintenance phase – did not show an additional effect to continue dosing based on TDM compared with dosing based on symptoms and CRP. However, in the group of patients with dosing based on clinical symptoms, significantly more patients needed an intervention because of loss of response compared with the group of patients with dosing based on infliximab trough concentrations (17.4 and 6.3%, respectively; p<0.01).⁷

The results of these first randomised clinical trials indicate that TDM can add value to current practice, by optimising the dose of anti-TNF in individual patients or guide treatment decisions at times of insufficient or no response.

Future perspectives

Inflectra^® and Remsima^®, two infliximab biosimilars, have been approved for the treatment of IBD in Europe. Monoclonal antibodies are large complex molecules that cannot be chemically synthesised but instead require a biological production process in living cells. As the final product is defined by this multi-step biological production process, Inflectra^® and Remsima^® cannot be regarded as exact copies of the originator Remicade®, but should be seen as biosimilar. This issue has been elegantly reviewed elsewhere,8 but it should be borne in mind that substitution of two similar drugs in one patient can result in a different immunogenic profile and pharmacokinetics, which could potentially alter the pharmacodynamics, and therefore should be avoided. It can be hypothesised that most concepts regarding the exposure–efficacy relationship and immunogenicity rate of the originator molecule can be transferable to biosimilars, but this remains to be shown.

mAbs with a different mechanism of action will soon be added to the armamentarium to treat patients with IBD, as the gut-specific lymphocyte blocking drug, vedolizumab, showed promising results for inducing and maintaining remission. Therefore, together with the increasing options to treat IBD patients chronically throughout the majority of their lives, treatments should be chosen carefully and used optimally at the right time in the right patient.