Serum biomarkers identify patients who will develop inflammatory bowel diseases up to 5 years before diagnosis
Torres J, Petralia F, Sato T, et al.
Inflammatory Bowel Disease is a chronic relapsing-remitting, immune-mediated condition with increasing prevalence globally . Despite novel agents targeting different disease pathways, the likelihood of achieving sustained clinical remission and mucosal healing remains low . One of the potential reasons may be that patients seek help and clinicians treat IBD once the disease is in its clinical phase. A sub-clinical phase of variable length may precede the symptoms that lead to a diagnosis and perhaps contribute to tissue damage which, once established, is difficult to reverse with currently available medical treatments.
In this study, Torres and colleagues set out to test the hypothesis that a pre-clinical phase of IBD may well be present and could be identified by proteomic markers .
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].
Nowadays, IBD treatment not only targets symptomatic disease control but also aims to heal the intestinal mucosa  In Ulcerative Colitis (UC) there is mounting evidence that histological healing of the intestinal mucosa is associated with incremental benefit compared to endoscopic healing alone [2–8]. In a very recent meta-analysis of ten studies including 757 UC patients with complete endoscopic remission (Mayo Score 0 or equivalent) and with a minimum follow-up of >12 months, patients with histological remission had a 63% lower risk of clinical relapse (RR 0.37, 95% CI 0.24–0.56) than patients with ongoing microscopic inflammation .
The positioning of medical therapies in the management of Crohn’s Disease (CD) continues to be debated  whilst surgery is reserved for cases with disease complications or failure of medical therapy. The LIR!C trial  provided evidence for surgical resection as an alternative to infliximab (IFX) in the management of localised terminal ileitis, a common presentation of CD .
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)] 
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 . 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.
The aetiopathogenesis of CD is multifactorial but includes the interaction between the microbiome and the host’s immune response. Up to 80% of patients with Crohn’s Disease (CD) require surgery during their lifetime and many factors are associated with postoperative recurrence (POR). Differential abundance of bacterial species is seen in patients with IBD compared with healthy individuals and several studies have suggested an association between microbiota composition and CD recurrence [1–3]. Altered mucosal gene expression and abundance of specific microbiota are associated with, and specific to, ileal CD .
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 .
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 . 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 . 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.
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 growing arsenal of therapies available for Inflammatory Bowel Disease (IBD) is improving IBD physicians’ ability to target remission. However, risk of infectious complications associated with immunosuppression is a reality that weighs in the minds of physicians and patients alike, affecting the acceptability of these treatments . Both treatment- and patient-related risk factors for infection have been identified in observational studies. Systemic steroids and combination anti-tumour necrosis factor (anti-TNF) and immunomodulator therapy are particularly associated with increased risk of infection, while non-modifiable patient factors include older age and non-IBD comorbidities [2–4]. Accordingly, this perceived risk results in reduced use of effective therapies in older people, despite risk of disease progression and a need for surgery similar to that in young people [5,6].
As explained by Kochar et al., however, chronological age does not capture the physiological heterogeneity in older populations, possibly leading to treatment being unnecessarily conservative in some. Furthermore, reliance on chronological age may lead to underappreciation of risk in younger people. Accordingly, more accurate tools for risk stratification of patients in the setting of immunosuppressive therapies are required.
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) . 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 . 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%) . 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 . 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) . 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.