Precision and personalized medicine has long been a discussed topic in the management of IBD. It is an aspirational goal to accurately predict those with a complicated and aggressive clinical course, and to administer timely targeted therapy to the individual’s molecular inflammatory profile[15]. Particularly for CD, the emphasis is for appropriately early management within the window of opportunity, before permanent digestive damage is done[16,17]. However, management decisions are still currently made using a one-size-fits-all approach. The conventional strategy is the step-up approach, which will inevitably undertreat patients who are destined to run a more aggressive disease course. With easier access to biologics and small molecules, a top-down approach may be used, which has been shown to improve clinical outcomes in prognostically severe CD[18,19] but this may otherwise expose patients destined to have mild disease to unnecessary risks and overtreatment. This top-down strategy would also be unaffordable in financially constrained health-care settings particularly in the Asia-Pacific region, and may pose a challenge in health jurisdictions that limit the use of expensive novel therapies.

Furthermore, the heterogeneity and variability of the clinical course of IBD between different individuals would mean a suboptimal approach in a substantial group of patients. There is a general consensus that a tailored approach is required, with a need for accurate biomarkers that enable the right patient to be matched to the right treatment (Table 1).

Stratification of treatment approaches can help identify those of a more complicated course and hence tailoring treatment accordingly. Among prognostic biomarkers at diagnosis predicting a more complex CD phenotype and worse outcomes including stricturing phenotype and need for surgery, identified microbial predictors include circulating antibodies against bacterial antigens such as anti-outer membrane protein C, anti-Saccharomyces cerevisiae antibody, perinuclear anti-neutrophil cytoplasmic antibodies, and anti-CBir1 flagellin. However, it is unclear if these represent a cause or effect of severe disease[20-24].

A CD8+ T-cell clonal signature was identified to predict worse outcomes and relapse in IBD patients[25,26]. This genomic biomarker was subsequently validated in independent cohorts of newly diagnosed CD and UC patients in the United Kingdom[27]. There is now a trial in progress in the United Kingdom to assess this whole-blood biomarker to guide treatment for newly diagnosed CD patients[28]. It is currently available in clinical use: PredictSure IBD; PredictImmune, Cambridge, United Kingdom.

Other predictive tools include the use of fecal calprotectin as a predictor of endoscopic disease activity as well as histologic inflammation, and fecal calprotectin values have been shown to be predictive of relapse in asymptomatic patients with IBD[29-33]. In a biomarker discovery trial, the EMBARK study, serum matrix metalloproteinase 9 and serum IL-22 were found to be associated with inflammatory disease activity for patients with UC and CD respectively[34].

Pharmacogenomic testing has also become common place in IBD. A commonly used predictor of risk of adverse drug reactions and pharmacologic response is the utility of thiopurine methyltransferase (TPMT) genotyping and metabolite testing, as well as nudix hydrolase 15 (NUDT15) genotyping. Thiopurine use is associated with adverse effects (AEs) in up to 40% of patients[35]. TPMT genotype testing is cost effective, and heterozygous and homozygous TPMT genotypes correlate with AEs. Dose reduction in the TPMT variants significantly reduce adverse hematologic effects without reducing treatment efficacy[36]. NUDT15 variants, first elucidated in a Korean population, have also been more recently described as associated with thiopurine induced myelosuppression and is more predictive of myelosuppression in East Asians[37-39]. Furthermore, thiopurine metabolite testing can aid in dose optimization and compliance[40] and prevents hepatotoxicity by identifying a subgroup of thiopurine-‘shunters’ who preferentially produce the hepatotoxic metabolite 6-methylmercaptopurine.

Apart from this, several biomarkers as predictors of non-response to anti-TNF include higher oncostatin M expression[41,42] and low expression of triggering receptor expressed on myeloid cells 1[43,44]; antibody formation to anti-TNF is associated with the HLA-DQA1*05 genotype[45]. Higher baseline concentrations of serum cytokine IL-22, whose expression is induced by IL-23, is associated with greater likelihood of response to brazikumab[46].

Introduction of therapeutic drug monitoring (TDM) has guided our approach in going beyond the therapeutic ceiling. Multiple studies have demonstrated an association with serum drug concentration of biologics, mainly in anti-TNF agents, and outcomes of patients[47-55]. It has assisted us in guiding dose modification (dose escalation or reduction), and informed us of primary or secondary loss of response, thus avoiding persistence of potentially ineffective therapy[56]. The approach of proactive vs reactive therapeutic drug monitoring remains a hotly debated topic[57].

Dashboard systems are clinical decision support tools utilizing computer software modelling to predict ideal personalized medication dosing[58,59]. This ‘model-based dosing’ has long been used by pharmacists and pharmacologists, for example, to dose antibiotics such as aminoglycosides. For anti-TNF dosing, dashboard driven pharmacokinetic (PK) dose optimization considers individual patient covariates including C-reactive protein, albumin, body-weight, sex and also serum drug levels. The PRECISION trial demonstrated that dashboard driven personalized dosing resulted in a significantly higher proportion of patients maintaining clinical remission after 1 year of treatment compared with patients that continued treatment without proactive adjustments: 88% vs 64%, respectively[60]. Utilizing the same PK dashboard system during Infliximab induction, Dubinsky et al[61] recently showed improved infliximab durability; and at 52 wk, 119/123 patients remained on infliximab in steroid free remission. The OPTIMISE trial is underway to evaluate the safety and efficacy of proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care dosing in patients with CD[62].

Numerous exposure-response relationship studies including post-hoc analyses of randomized controlled trials show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IBD and other immune-mediated inflammatory diseases; higher drug concentrations are typically associated with improved therapeutic outcomes[63]. Conversely, lower drug concentrations, with or without anti-drug antibodies, are associated with treatment failure and drug discontinuation[64,65].

Multiple clinical studies have provided various TDM targets, especially with the anti-TNF agents infliximab and adalimumab, at various time points that are associated with outcomes of clinical remission[51,66]. Several observational studies have suggested that higher median infliximab concentrations are associated with superior clinical and biochemical remission rates. Given the wide variation in observed concentrations among responders, one may even wonder if the “therapeutic threshold” is identical for all patients and for the different phases of the treatment (induction vs maintenance and active vs quiescent disease).

Yarur et al[67], found that that levels of infliximab ≥ 10 mcg/mL were best associated with fistula healing, though surprisingly, a small number of patients required levels of ≥ 20 mcg/mL to achieve fistula healing. Feng et al[68] demonstrated that on incremental gains analysis, mucosal healing rates gradually increased as infliximab levels went up and reached a brief plateau (> 85%) when the infliximab trough level was 10 μg/mL. However, there was still a small proportion that seemingly benefited from an anti-TNF levels > 12 mcg/mL to achieve mucosal healing. Ungar et al[69] similarly demonstrated in a retrospective study a significant association between serum levels of anti-TNF agents and level of mucosal healing. They went on to propose that serum levels of 6-10 μg/mL for infliximab and 8-12 μg/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with IBD.

Several other studies demonstrated that higher trough levels of infliximab and adalimumab are associated with those achieving mucosal healing in CD[68-79]. In a substudy of the TAILORIX trial, Bossuyt et al[71] found that infliximab trough level of 7.8 μg/mL at the end of induction (week 14) was associated with both radiologic response and remission. Continuously high infliximab exposure (infliximab > 5 μg/mL at all time points) was associated with radiologic response.

Low infliximab trough concentrations and the presence of antibodies to infliximab are associated with worse outcomes. Trough concentrations of > 3 μg/mL during maintenance is associated with sustained clinical outcomes[54,70,80,81]. Vande Casteele et al[82] concluded that an appropriate infliximab therapeutic window is between 3 and 7 μg/mL for IBD responders during maintenance therapy based on previous studies, and prospectively validated it in a randomized controlled trial (TAXIT).

The optimal “therapeutic window” for biologics remains to be elucidated, and the upper limit is unclear. While the abovementioned studies observed an association between certain trough concentration ranges and a corresponding degree of disease remission, the ‘ideal’ trough concentration to induce remission may vary between individuals. This may be due to a variety of factors such as an individual’s disease burden and therefore mucosal TNF burden, early vs advanced disease, and an individual’s unique pharmacodynamic makeup. There may be a subset of patients who might benefit from dose escalation to ‘supratherapeutic’ trough concentrations and reassuringly, there is little evidence to indicate greater toxicity with higher infliximab levels.

While it remains a conventional strategy to offer an anti-TNF agent as the first-line biologic, it has been well established from network meta-analyses that anti-TNF non-responders do not have an optimal response after switching to second-line biologics[12-14]. It thereby raises the question whether certain individuals would benefit from receiving these traditionally second-line biologics as first-line therapy options, and highlights the importance of optimal biologic sequencing.

There are limited head to head trials between biologic agents: In the VARSITY trial (adalimumab vs vedolizumab) for moderate to severe UC, vedolizumab demonstrated superiority in clinical and endoscopic remission but not corticosteroid free clinical remission[83]. In the SEAVUE study (adalimumab vs ustekinumab) for moderate to severe Crohn’s, ustekinumab failed to demonstrate superiority over adalimumab[84].

In the Galaxi-1 study involving participants with moderately to severely active CD, guselkumab was compared to placebo and ustekinumab. It was a phase 2, dose-ranging study[85], not powered to evaluate potential differences in efficacy and safety between guselkumab and ustekinumab.

From the HIBISCUS and GARDENIA trials[86,87] Etrolizumab vs adalimumab or infliximab in moderate to severe UC- failed to demonstrate superiority.

While offering novel alternate pathway biologics as first-line therapy may gain traction in the near future, this approach is often limited by government access in many jurisdictions. Access to newer therapies for adult patients is already limited by licensing authorities, but the pathways remain even more restricted for pediatric patients. Access to biologics in pediatric patients is often on compassionate grounds, due to a significant lag in clinical trials and therefore delaying official approval from medical licensing authorities such as the European Medicines Agency and United States FDA. There is a need for this cohort of patients to have better access to new/emerging therapies through more advanced pharmacogenomic, pharmacokinetic and pharmacodynamic modelling. This is to allow earlier initiation of trials or better ways to “extrapolate” adult data for presentation to licensing authorities to allow for use in children.

Combinations of biologic agents and recently combinations of biologics with newer small molecule agents have been attempted to go beyond our current therapeutic ceiling. This concept is not new, however, and was first attempted by Sands et al[88] as a randomized controlled trial comparing the safety and tolerability of patients on infliximab not in remission and adding natalizumab vs a placebo arm. Although the main trial ran for 10 wk and was not powered to assess for differences in efficacy between the groups, there was a higher proportion of patients achieving a clinical response at each time point and this proportion continues to increase over time in the combination biologic group, compared to response rates for the monotherapy arm which remained unchanged.

Since then, there has been much in the literature of dual biologics or with newer small molecule therapies, but as case reports or case series and observational cohort studies (Table 2). The data is largely heterogenous but reassuringly has demonstrated acceptable safety for patients with refractory IBD with no new concerning signals[89,90].

In the pipeline, there are several randomized controlled trials evaluating the efficacy of combination biologics. The EXPLORER trial (ClinicalTrials.gov Identifier: NCT02764762) in high-risk CD patients involved triple combination therapy with vedolizumab, adalimumab and methotrexate which has completed but not yet reported.

The phase 2a VEGA study evaluated the safety and efficacy of combination induction therapy with guselkumab plus golimumab (GOL) vs monotherapy with guselkumab or GOL in adults with moderately to severely active UC through to week 12, most recently presented at the European Crohn’s and Colitis Organization 2022 congress[91,92]. A greater proportion of patients who received combination therapy achieved clinical response as judged by Mayo score at week 12 (83.1%) vs guselkumab (74.6%) or GOL (61.1%). Similarly, the proportion of patients who achieved clinical remission in the combination group (36.6%) was greater than that in the monotherapy group (21.1% and 22.2%, respectively). The DUET UC (ClinicalTrials.gov Identifier: NCT05242484) is a phase 2b study of combination therapy with guselkumab and GOL (JNJ-78934804) in participants with moderately to severely active UC that is planned; the DUET CD (ClinicalTrials.gov Identifier: NCT05242471) is a phase 2b study of the same biologic combination in individuals with moderately to severely active CD, and is currently recruiting trial participants.

The other considerations to overcome current therapeutic plateaus with biologic agents include added adjunctive therapies such as vitamin D, curcumin, microbiome alteration via dietary modification, exclusive enteral nutrition and probiotics[93].