Inflammatory bowel disease (IBD) is a group of idiopathic chronic inflammatory conditions that includes Crohn’s disease (CD) and ulcerative colitis (UC) with both overlapping and distinct clinical features, including extraintestinal manifestations.
IBD is rising in westernised and in newly industrialised societies and is now a global disease with increasing prevalence. IBD affects about one million people in the USA and 2.5 million in Europe1 and commands a considerable amount of the national health care cost not taking into account the real price of IBD to the patient, a disease of the young, which can affect career prospects, quality of life, fertility and mental well-being. In the UK the incidence of admission for CD among 16–29-year-olds increased by over 300% between 2003 and 2013.2 There are no clear reasons for this increase in disease triggers.
Understanding the features and their significance in treatment choices is essential, but stratification of IBD is in its infancy and still very poorly understood. It is increasingly becoming clear that the intestinal flora contributes considerably to the disease manifestation, and research targeting the understanding and influence of the gut biota on IBD is increasing.
Therapy needs to become more tailored to the diverse symptoms, complications and extraintestinal manifestations of CD and UC, and in view of the limited therapy options, optimising treatments is essential.
Therapy pathways are different for CD and UC and need to be tailored to the patient and symptoms. Mesalazine (5-ASA) is the very effective first-line choice for UC in mild to moderate disease whereas it does not seem to be effective in CD.3 Corticosteroids should only be used in a flare to induce remission and for bridging to a suitable maintenance therapy. The aim of all treatment strategies should be to reduce and minimise the use of steroids, prevent flares, hospital admissions, surgery and reducing the intestinal cancer risk over the lifetime of the patient.
Failing 5-ASAs and/or having two courses of steroids within 12 months requires a step-up of treatment and there is currently the discussion over the benefit and efficacy of using either a thiopurine as first-line treatment before biologics (bottom up), or biologics as a first-line treatment (top down). The strategies are often determined by national commissioning constraints due to the high cost of biologics.
Optimising thiopurines through therapeutic drug monitoring (TDM) is cost-effective when measuring thiopurine methyltransferase, thioguanine nucleotides, methylmercaptopurine and co-prescribing allopurinol4 to manipulate the pharmacokinetics. It allows for the successful treatment of patients who would otherwise be labelled as thiopurine failures. More controversial is the TDM of biologics. The practice is still in its infancy, with many questions around blood levels and antibody titres still unanswered.
Dysregulation of immune cells and their cytokines may lead to chronic inflammation and autoimmune diseases. Classes of biologics for the management and treatment of symptoms targeting immune cells are anti-tumour necrosis factor α (anti-TNFs), anti-integrins for CD and UC, and anti-interleukins (anti-ILs) for CD only.
Induction dose trials need to be reviewed carefully as their patient cohort is very disparate, often not comparable and do not necessarily correspond to real life patient cohorts. Earlier trials tend to have longer disease history than newer trials. Endpoints are not standardised and often manipulated to fit the trial.
Overall the response rate is between 44% and 60% depending on drug, class and indication, of which only 20–35% of patients will achieve remission. It is estimated that every year about 15% of patients experience loss of response (LOR) to their biologic therapy. This means that a considerable number of patients fail to respond or lose response to biologics. In view of the limited options available, it is essential to optimise therapy and manage failure carefully.
Anti-TNFs are a class of biologics that target TNFα, which is raised in IBD patients with active disease. Infliximab (IFX), adalimumab (ADA), golimumab and certolizumab pegol (not licensed in the EU for IBD) belong to this group. There is considerable discussion around the management of primary and secondary loss of response to anti-TNFs and the effect of TDM on the outcome of anti-TNF therapy choices.
Safety profiles are common to the whole class and concentrate on risk of bacterial infection and potential cancer risk. However, the data, particularly on lymphoma and non-melanoma skin cancer risk, are not conclusive. It is beyond the remit of this article to discuss the safety profile of biologics in sufficient depth.
In the ACCENT I5 and ACCENT II6 trials, IFX demonstrated its efficacy in CD, including in fistulating disease. In the ACT I and Act II7 trials, maintenance of remission in UC after successful induction was shown.
Adalimumab, the second anti-TNF licenced for IBD showed similar efficacy in the trials CLASSIC 1&2, CHARM and EXTEND 8–11 in CD and in ULTRA 112 and ULTRA 213 in UC.
Certolizumab, a pegylated anti-TNF, did not demonstrate sufficient effectiveness and the European Medicines Agency (EMA) refused marketing authorisation in 2008 based on the opinion that the benefits of certolizumab did not outweigh the risks.
Golimumab was licensed in 2015 in Europe and has the advantage of being administered once every four weeks. PERSUIT-SC14 and PERSUIT-Maintenance15 demonstrated efficacy in UC only and showed similar safety profile as the other anti-TNFs.
Anti-integrins are selective adhesion-molecule inhibitors that bind receptors on a subset of memory T lymphocytes that preferentially migrate into the gastrointestinal (GI) tract and are known to express integrin. They then bind to mucosal addressin cell adhesion molecule-1 (MAdCAM-1). This facilitates the migration of lymphocytes into the GI tract, which contributes to the chronic inflammation seen in IBD.
Anti-integrins specifically bind to the α4β1 and/or α4β7 integrin, blocking its interaction with MAdCAM-1, which is mainly expressed on gut endothelial cells. This inhibits the migration of these memory T lymphocytes from the blood into inflamed GI tissue.
Anti-integrin α4β1 and α4β7 (natalizumab) was the first of its class, but showed risk of progressive multifocal leukoenphalopathy (PML). As it was found to affect lymphocyte trafficking to the brain it was never licensed for IBD. Its successor, vedolizumab, a gut-selective humanised anti-integrin α4β7 only, showed efficacy in the GEMINI II16, 17 trials in CD and UC with a slightly better performance in UC and I. Currently it is only available as an infusion of 300mg at week zero, two and six, and every eight weeks thereafter. A subcutaneous preparation is under investigation.
The safety profile seems to be favourable, with nasopharyngitis, headaches and arthralgia as the very common side effects and infection rates similar to the placebo group. Currently it is used as second-line treatment for patients with anti-TNF failure but with increased familiarity of the drug and its efficacy, its use is likely to increase.
Anti-ILs are monoclonal antibodies that neutralise IL-12/23 by targeting the p40 shared subunit, which has been shown to be effective in colitis. This prevents IL-12/23 cytokine binding with IL-12Rß1 receptor, thereby reducing immune cell activation.
Ustekinumab, an anti-IL 12 and 23, was licensed in November 2016 for CD only. Ustekinumab is a fully humanised IgG1κ monoclonal antibody that binds to the p40 shared unit of unbound IL-12 and Il-23. The IM-UNITI18 trial showed effectiveness in CD. It is administered as a loading infusion of approximately 6mg/kg and followed by 90mg injections subcutaneously eight weeks later and 90mg every 12 weeks thereafter.
The dosing interval can be reduced to eight-weekly depending on symptom control. The safety profile also is favourable, with nasophyrnagitis and headaches the most common side effects and infection rates similar to the placebo group. As with all new drugs, it will have to find its place in therapy over the next few years, most likely as a second-line treatment for anti-TNF failures.
A recent systematic review by Mao et al19 investigates the comparative efficacy of currently available IBD therapies to reduce hospitalisation and surgery. It concluded that in CD and UC, anti-TNF biologics are efficacious in reducing the odds of hospitalisation by half and surgery by 33–77%. Azathioprine (AZA) and vedolizumab were not associated with a similar improvement, but robust conclusions may be limited due to paucity of randomised control trials.
Safety in pregnancy
The European Crohn's and Colitis Organisation (ECCO) guidelines in pregnancy20 suggest that biologics should be maintained during pregnancy up to week 24–26, at which point they should be stopped and reintroduced post-partum if necessary. High levels of biologics can be detected in the neonate up to six months after birth as the placenta becomes more permeable to large molecules in the third trimester in order to supply the foetus with parental immunoglobulin.
The PIANO21 registry informed guidelines in the 2016 Toronto consensus,22 which support the continuation throughout the pregnancy for patients with higher risk. Both guidelines advise on the management of pregnancy with biologics, and biologics and thiopurines, suggesting that both strategies are safe. However it must be stressed that parents need to be advised that the newborn cannot have live vaccinations such as rotavirus, MMR or BCG within the first six months of life and vaccination schedules need to be adapted accordingly. Breastfeeding is deemed safe and encouraged
Safety in surgery
The evidence for safety in surgery is conflicting, with some studies showing no increase in postoperative complication risks and others an increase in some complications. The GETAID Group23 came to the conclusion that preoperative anti-TNF therapy increases the risk of morbidity after surgery for ileocolonic CD. Surgeons have to take into account the small but significant risk of increased postoperative complications in patients on biologics particularly in complicated pouch surgery, which should be done in stages if the patient is on biologics.24
Optimisation of biologics therapy
In view of the response and remission rates of biologics, optimisation of therapies is essential and IBD clinicians are grappling with the optimal therapy pathway for IBD patients. The most likely outcome is that a treatment needs to be individualised and adapted to the patient’s symptoms and response.
The co-prescribing of thiopurines and biologics has been investigated for most agents.
The Sonic25 study looked at single agent and combination agent therapy in CD and concluded that combination of thiopurine and IFX was superior at week 26 and week 50 than each agent alone.
The SUCCESS26 trial concluded that in anti-TNF naïve patients with moderate to severe UC treated with IFX plus AZA were more likely to achieve corticosteroid-free remission at 16 weeks than those receiving either monotherapy.
There is debate about the mechanism of action and the dose of AZA. It is not clear if the thiopurine suppresses immunogenicity of the biologic or if it has a complementary action. An oral presentation at ECCO 201627 demonstrated that an AZA dose reduction in patients with IBD on combination therapy is as effective as the maintenance of AZA at the same dose. This may improve the AZA safety profile, which would indicate the suppression of the immunogenicity as a more likely action.
This benefit of combination therapy has not been replicated with adalimumab. In view of the immunogenicity of all biologics creating anti-drug antibodies, it could be speculated that adding thiopurines would benefit all biologics and reduce loss of response due to antibody formation. The safety of combination therapy will need to be investigated further with regards to malignancies.
There is a signal from unpublished data that antibodies against adalimumab are a worse prognostic factor when switching to an IFX compared with antibodies against IFX when switching to adalimumab. It is speculated that fewer patients create antibodies against the humanised adalimumab. Therefore, this process selects patients who have a higher immunogenic risk than patients producing antibodies against IFX, and who would profit from combination therapy. Unpublished data from the PANTs Study28 signals a smaller but beneficial benefit of adding thiopurines to adalimumab therapy in contrast to the original CHARM data, which could not prove any benefit.
Rutgeens29 showed that episodic treatment in CD has worse outcomes than continuous treatment, with a lower proportion of patients developing antibodies to IFX in the scheduled groups than in the episodic group.
Immunogenicity needs to be taken into account when contemplating long-term treatment strategies for patients. This is particularly important when stopping therapies with the risk of antibody-induced reactions in the future, when patients need to be re-challenged during a flare.
TDM of anti-TNFs has been at the forefront of IBD research in recent years and it has been shown that anti-TNF levels predict clinical response and the presence of antidrug antibodies predicts low drug levels, treatment failure and infusion reactions.
Until recently LOR was managed with either dose increase or reduction of infusion interval. In view of the cost of these drugs only patients in whom dose intensification has a successful outcome need to be selected. In recent years, TDM has gained interest in managing anti-TNF therapy and immunogenicity to biologics.
The Trough level Adapted infliXImab Treatment (TAXIT) study30 enrolled patients in remission and adjusted their IFX dose to obtain a target serum drug level; subsequently this cohort was randomised to either standard care, or continued adjustment of IFX dose, based on drug levels. In the optimisation phase, only 44% of patient were in range; 26% had high levels, 21% had low IFX trough levels and 9% of patients had no trough levels. The subsequent maintenance phase with the two arms failed to demonstrate benefit of continued adjustment of IFX dose, based on drug levels vs standard of care.
In view of the fact that all patients were initially optimised, it is implied that a number of patients are under-dosed or overdosed and can either be stopped, dose-reduced or need to change therapy depending on symptoms and response. The TAXIT study showed that a considerable number of patients stable in IFX are not at the ideal range and could potentially stop or reduce the dose incurring cost savings, but that continuous drug monitoring is not cost effective and does not contribute to the overall management of patients on IFX.
Multiple algorithms have been proposed but essentially drug levels and antibody titres need to be interpreted as part of a holistic review of the patient using TDM mainly as a support to guide therapy decisions.
Currently, response-guided TDM seems to be most cost effective and supports treatment decisions for when therapy changes are immediately required and help guide the subsequent therapeutic approach. It has to be noted that tests are not interchangeable and reference ranges need to be made clear at reporting.
In 2016, the National Institute for Health and Care Excellence (NICE)31 reviewed the tests as part of their diagnostic reviews and concluded that there was insufficient evidence to recommend their routine adoption across the National Health Service (NHS). NICE recommended that laboratories should have specialist expertise in immunoassay analysis, including an understanding of the technical factors that may affect the results of the ELISA kits. They also recommend working closely with the treating or referring clinician, in a network, to ensure appropriate use of the tests and interpretation of the results.
The EMA approved CT-P13 (IFX) as the first biosimilar for use in IBD in 2015. The initial trials were conducted in rheumatology and together with the pharmacokinetic and pharmacodynamics tests it was concluded that there is sufficient data from observational studies to show that safety and clinical efficacy of CT-P13 are comparable to the originator drug. This included similarity in immunogenicity and all indications for which the originator drug was licensed.
An independent study sponsored by the Norwegian government (NOR-SWITCH)32, which was designed to assess the efficacy, safety and immunogenicity of switching adult patients to Remsima® showed that after 52 weeks of treatment, Remsima® was non-inferior to Remicade® with regard to disease worsening in adult patients who had been on stable Remicade® treatment for at least six months.
Another study showed no difference in immunogenicity between the originator and the biosimilar.33
With the increase in multiple anti-TNF biosimilars in development for both IFX and ADA, the question that will need to be addressed in the future is if all biosimilars are interchangeable and if patients can be switched back and forth between the different biosimilars. Unpublished data from the PANTS study25 signal that body mass index of <18 or >35 adversely affects the outcomes of currently used infliximab dosing. Published data are awaited to see what this means for clinical practice.
There are a number of new agents in the pipeline. Etrolizumab is an anti-integrin blocking α4/β7 receptors in the gut and αE/β7receptors in the skin in Phase III development.34 Similar to vedolizumab, it does not affect the leukocytes trafficking to the brain and is not associated with PML.
Janus kinase inhibitors (JAK) inhibitors block a variety of pro-inflammatory cytokines. The oral JAK inhibitor tofacitinib is currently in Phase III studies for UC35 and is expected to be licensed in 2017. The drug seems to be highly effective in anti-TNF naïve and experienced patients with moderate to severe UC. Filgotinib, another oral JAK inhibitor is about to enter Phase III studies for the treatment of CD and UC and a selective JAK 1 inhibitor, ABT-494 (Abbvie), is also in Phase II for CD.
Another selective anti-IL has entered Phase III trials inhibiting the p-19 section of IL-23 and shows promise in CD. Risankizumab is well tolerated by the patients and showed fewer adverse effects than the placebo and, if successful, will be positioned for CD after anti-TNF failures.
Ozanimod, an oral selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation, is currently in Phase II trials for UC.36
Mongersen (GED-0301, Celgene) is an investigational oral antisense oligonucleotide targeting Smad7 that was shown to induce clinical remission in about 60% of patients with active CD in a previous Phase II trial. It is designed to act locally and is thought to reduce inflammation-causing Smad7 levels with minimal systemic exposure.37
Multiple new targets are under investigation. New agents will increase options available to treat IBD bringing increased complexity to treatment decisions and cost to healthcare systems. Pharmacists are ideally placed as part of the multidisciplinary team to address these challenges.
In the UK, incidence of admission for Crohn's disease (CD) among 16–29-year-olds increased by over 300% between 2003 and 2013.
Anti-TNFs are a class of biologics that target TNFa, but maintenance trial data of biologics on clinical responses and remissions are not comparable due to disparate trial set ups.
Ustekinumab is a fully humanised anti-IL with a favourable safety profile, which is newly licensed in the UK.
Vedolizumab is the only anti-integrin licensed in th UK. It targets a subset of memory T lymphocytes that are involved in chronic inflammation seen in inflammatory bowel disease.
Therapy pathways are different for CD and ulcerative colitis and needs to be tailored to the patients and their diverse symptoms.
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