Exabis Library

Learning Objectives:
1. Screening before immunosuppression and immunisation
2. Indications for biological therapy
3. Evaluation of response

IBD patients are eligible to treatment with biologic agents if they have failed or cannot tolerate conventional treatment with corticosteroids and/or immunomodulators (IMMs) or are corticosteroid dependent. Early introduction of biologic therapy is also recommended for patients who at diagnosis have clinical features that predict a disabling course of disease. Ideally, patients should be screened for infectious diseases, malignancies, and complete all essential vaccinations before starting any therapy. Selecting the best biologic amongst the currently available different classes, depends on several patient- and disease-related parameters, such as age, disease activity, comorbidities, and the overall burden of disease. As for any therapy, it is important to define short-, medium- and long-term goals, monitor the progress of disease and adapt treatment accordingly (treat to target).

The first biologic is the best shot. Thus, it is key to adapt dosing to disease activity to avoid primary non-response or partial response and thus achieve a better long-term response. Co-treatment with an IMM may influence the pharmacokinetics in particular of anti-TNF and prevent early development of anti-drug antibodies ADA). Once clinical remission has been achieved, patients should be closely followed by monitoring clinical activity (patient reported outcomes), biomarkers (serum CRP, faecal calprotectin), imaging (US, MRE), endoscopy and/or histology. Treatment optimization in case patient loses response can be achieved either empirically (Standard of Care) by increasing the dose of the biologic or halving the administration interval, or both, or by adding an IMM, or by therapeutic drug monitoring (TDM), i.e., by measuring drug levels and ADA. Pro-active TDM has not been proven superior to reactive TDM, still, it serves to discriminate between pharmacokinetic and pharmacodynamic failure of treatment. However, proactive TDM is increasingly used to achieve clinical response and/or remission during induction, to de-escalate, or stop biologic therapy.

4. Screening before immunosuppression and immunisation
5. Indications for biological therapy
6. Evaluation of response

safety and benefit of drug 
risk and knowledge about a drug 
timing for safety evaluation 

To assess differential conditions mimicking the perianal Crohn's disease
To review and recognize proctological lesions not related to inflammatory bowel disease
To have an overview over the main principles of their management
To assist patients with perianal complains


Summary

The literature on perianal Crohn's disease lesion focuses mainly on primary lesions, ulcerations, fistulae and strictures. However, patients with IBD may present similar proctological conditions as the general population, which will need to be diagnosed and managed in a way that is appropriate to the general disease. Among these lesions, the diagnosis of common proctological lesions will often be easy, but their management, particularly surgery, will have to be carried out with caution and with a drastic selection of patients. Among the alternative perianal lesion, hydradenitis suppurativa, frequently associated with Crohn's disease, is probably the most difficult to diagnose and its management remains complex. Finally, the management of patients with Crohn's disease should not be limited to the treatment of anatomical lesions, but should also take into account the functional complaints that may largely alter the quality of life of these patients.

Educational objectives:
1. To understand growth impairment in paediatric IBD resulting from disease activity & treatment choices
2. To review the current ECCO/ESPGHAN treatment algorithm with regards to growth optimization
3. To provide an overview of strategies to minimize IBD activity-related growth impairment
4. To emphasise the importance of reducing steroid-exposure and improving skeletal growth and lean body mass

1. To review the relative benefits and limitations of drug therapy versus dietary intervention for the treatment of IBD 
2. To understand circumstances in which one may consider using drug therapy, dietary intervention or combine the two
3. To consider how treatment paradigms may change in the future to include increased emphasis on the role of dietary interventions

- understand approaches of using Omics-based medicine in other disciplines (oncology)
- review current mainstays in OMICS-based diagnostics
- get an overview of current trial designs on implementing omics into patient care

Combination therapy with infliximab and anti-metabolites is a standard option for patients with Crohn’s disease (CD). The implications of long term use of combination therapy may lead patients and clinicians to contemplate treatment de-escalation once steroid-free remission has been achieved. The aim of our study was to assess the relapse rates and time spent in remission over 2 years, after withdrawal of infliximab or anti-metabolite compared to continuation of combination therapy.

CD patients treated with a combination therapy of infliximab (IFX) and anti-metabolite > 8 months and in sustained steroid-free remission > 6 months were recruited in 64 centers in France, United Kingdom, Belgium, Sweden, Australia, Germany and The Netherlands. Patients were randomized into 3 arms - continuing combination therapy (arm A); stopping IFX (arm B); or stopping anti-metabolite (arm C). In case of a relapse [defined by CDAI and an objective marker of inflammation (CRP or fecal calprotectin)], patients were retreated by resuming infliximab in arm B or the anti-metabolite in arm C, according to a pre-defined scheme, including optimization of IFX up to 10 mg/Kg if necessary in all arms. The two co-primary endpoints were the relapse rate and mean survival time spent in remission over 2 years. A major secondary endpoint was treatment failure (complications or not recapturing remission).

254 patients were screened, 211 randomized, 5 withdrew consent and 1 was lost to follow-up, leaving 205 patients for the analysis - 67 randomized to arm A, 71 to arm B and 67 to arm C. Demographic and clinical characteristics are shown in Table 1. The two-year relapse rates were 14% (IC95%: 4-23%) in arm A, 40% (IC95%: 28-51%) in arm B, and 10% (IC95%: 2-18%) in arm C (p=0.0003 arm B vs arm A and <0.0001 arm B vs arm C) (figure 1). The time spent in remission was 1.91 yrs (IC95%: 1.83-1.99), 1.89 yrs (IC95%: 1.82-1.96) and 1.93 yrs (IC95%: 1.86-2.00) in arm A, B and C, respectively. Out of the 39 relapsers, 28 were retreated/optimized. Remission was achieved in 1/2 retreated patients in arm A, 22/23 in arm B and 2/3 in arm C.  Treatment failure was observed in 4/67, 4/71 and 3/67 patients, in these three arms, respectively. No malignancy was observed, one tuberculosis in arm C and two severe infections (pneumonia and viral pericarditis) in arm B.

Infliximab withdrawal, but not antimetabolite withdrawal, was associated with a significantly higher risk of relapse than continuation of combination therapy.  Almost all patients who stopped IFX achieved rapid remission when resuming treatment. The time spent in remission over 2 years was similar across groups.

Anti-tumour necrosis factor-α (anti-TNF) has historically been the mainstay of biologic therapy in Inflammatory Bowel Disease (IBD). However, of those who initially respond to anti-TNF, almost 50% will suffer secondary loss of response (SLR) over subsequent years [1,2]. This SLR is primarily predicated on suboptimal anti-TNF trough levels, with or without detectable anti-drug antibodies (ADAs) [3]. Furthermore the prospective, observational study by Kennedy et al. demonstrated that suboptimal anti-TNF trough levels at week 14 predicted ADAs, low trough levels and worse clinical outcomes [4]. This risk was mitigated for both infliximab and adalimumab by the use of immunomodulators such as azathioprine. This corroborates the retrospective data from other cohorts showing how the addition of an immunomodulator can restore clinical response and favourable pharmacokinetics [5–7]. Remission rates when switching to a second anti-TNF have been shown to be lower when the reason to withdraw the first anti-TNF is SLR as compared to intolerance (45% vs 61%) [8]. In the event that SLR to anti-TNF is due to immunogenicity, a switch to another anti-TNF is associated with a risk of ADA to this new therapy [9,10]. A number of patients will also be on anti-TNF monotherapy at the time of switching having de-escalated from previous combination therapy. We know that open-ended prescription of anti-TNF with azathioprine is not without additional risk, notably infection and lymphoma [11]. Furthermore, de-escalation to anti-TNF monotherapy after a period of combination therapy has been shown in most studies not to impact on relapse rates (49% monotherapy versus 48% combination therapy) [12]. It is in precisely this important group of patients that Roblin et al. sought to compare the use of azathioprine in combination with a second anti-TNF versus this second anti-TNF as monotherapy. Over a follow-up period of 2 years, the rates of clinical and immunogenic failure, and of adverse events, were compared.

In the past few years the armamentarium of drugs used to treat Inflammatory Bowel Disease (IBD) has accelerated, with the emergence of new therapies targeting differing immune pathways (ustekinumab and tofacitinib) and lymphocyte trafficking (vedolizumab). Furthermore, a number of promising new drugs are on the horizon (JAK-1 inhibitors, IL23p19 antibodies and S1P inhibitors) [1, 2]. However, as the choice of drugs expands, so the uncertainty over which drug should be selected by the clinician also increases. Drug selection may be determined by a number of factors such as cost, mechanism of delivery (e.g. oral, intravenous or subcutaneous), presence of co-morbidities (such as malignancy or multiple sclerosis) and presence of extraintestinal manifestations. However, no drug is effective in all patients, with between 10% and 40% of patients suffering from primary and secondary loss of response [3–5].

Perianal fistulising Crohn’s Disease is a challenging phenotype affecting more than 20% of patients diagnosed with Crohn’s Disease. It is associated with debilitating symptoms and significant morbidity, with subsequent reduced quality of life and increased disease-related work disability.

Currently treatment remains challenging, incorporating surgical and medical management; the latter is driven largely by biologic agents, specifically anti-tumour necrosis factor (TNF) agents such as adalimumab (ADA) and infliximab (IFX). Whilst ADA and IFX have proven efficacy in inducing and maintaining fistula healing and closure, a significant proportion of patients fail to respond or lose response over time. Increasing evidence suggests that this is in part due to sub-therapeutic drug levels, with or without the presence of antibodies to anti-TNF agents (ATA), with higher target drug levels required for fistula healing compared to mucosal healing in Crohn’s Disease. However, data evaluating the correlation between anti-TNF levels and perianal fistula outcomes, particularly with ADA, remain limited.

The aim of this study was to assess the association between anti-TNF levels and perianal fistula healing and closure with maintenance ADA and IFX therapy.

The anti-TNF monoclonal antibody infliximab offers an effective treatment for patients with Inflammatory Bowel Disease (IBD) refractory to conventional immunomodulator therapies. Successful biologic therapy can lead to clinical and endoscopic remission as well as reduced hospitalisation and requirement for surgery [1].

Unfortunately, as a large protein and chimeric antibody, infliximab is immunogenic and this frequently leads to formation of anti-drug antibodies (ADA), with subsequent secondary loss of response (LOR), drug discontinuation and adverse reactions [2]. Identifying patients at increased risk of developing antibodies prior to treatment may establish which individuals require closer drug level monitoring, concomitant immunomodulator therapy and observation for adverse events.

Previous work by Sazonovs et al. identified the first genetic locus to be robustly associated with immunogenicity to anti-TNF therapies [3]. The HLADQA1*05 allele variant rs2097432, carried by approximately 40% of Europeans, significantly increased the rate of formation of infliximab ADA. In the study reviewed here, Wilson et al. aimed to independently identify whether presence of the variant allele was associated with increased risk of ADA formation, LOR, drug discontinuation and adverse events.

The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated [1] whilst surgery is reserved for cases with disease complications or failure of medical therapy.  The LIR!C trial [2] provided evidence for  surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD [3].

Briefly, the LIR!C trial reported quality of life scores (IBDQ) among 143 adult patients with terminal ileitis (<40 cm) who underwent randomisation to IFX induction/maintenance or ileocaecal resection. Patients were recruited from 29 secondary and tertiary Dutch and British centres. Exclusion criteria included non-inflammatory disease, prestenotic dilatation, abscess and previous surgery. Inclusion criteria included failing at least three months of conventional therapy [immunomodulator (IM) and/or corticosteroid (CS)] [2]

First introduced by Svartz in 1942, 5-aminosalicylates (5-ASAs) are a well-established and effective first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate Ulcerative Colitis (UC). They remain the most frequently prescribed medication for UC and are known to be effective and well tolerated [1]. Between 87% and 98% of UC patients receive 5-ASA treatment within the first year of diagnosis and 60%–87% continue on this treatment at ten years [2, 3].

Escalation to anti-metabolites (thiopurines or methotrexate) and/or biologic or small molecule therapy is often required for UC patients with a more aggressive disease course. Whilst it is now accepted that discontinuing 5-ASA therapy when escalating to a biologic is not associated with adverse outcomes, less is known about the therapeutic benefit of continuation of 5-ASAs with an antimetabolite [2, 4].

Singh et al conducted a retrospective cohort study to evaluate the pattern of 5-ASA use in patients with UC following escalation to an antimetabolite. The study evaluated patients escalated to antimetabolite therapy (stopping 5-ASA vs short-term 5-ASA use for <6 months vs persistent 5-ASA use for >6 months) and compared the risk of clinically important complications based on the pattern of 5-ASA use in these patients. They hypothesised that continuing 5-ASA therapy would not be more beneficial than stopping it.