The treatment of inflammatory bowel disease (IBD) experienced a radical change nearly two decades ago with the advent of monoclonal antibodies, particularly tumor necrosis factor antagonists (antiTNFs) such as infliximab (IFX), adalimumab, golimumab and certolizumab pegol. These drugs have allowed more effective control of the disease, a reduction in the number of hospitalizations and surgical procedures, and an improvement in the patients’ quality of life1,2. Despite these benefits, many patients fail to respond to the treatment during the induction phase (primary therapeutic failure), while in others the lack of response occurs during the maintenance phase (secondary therapeutic failure)3,4. Although the reasons behind this failure to respond are not wholly understood, it seems that they may be related of individual pharmacokinetic or pharmacodynamic changes or to the immunogenicity of the medication3,5,6.

The development of antiTNF agents has been accompanied by the design of a series of tools intended to measure the concentration of the drugs in plasma as well as anti-drug antibodies (ADAs) concentrations. AntiTNF therapeutic drug monitoring (TDM) in IBD has gained significant ground in the last decade. Numerous studies have sought to determine the most desirable concentrations for achieving clinical remission (CR) or mucosal healing as a function of: a) the antiTNF agent used; b) the condition diagnosed; and c) the point in the therapeutic process the patient is at7.

Two kinds of TDMare used in clinical practice: reactive8 and proactive9. The former, which has been used for longer, requires that drug and ADAs concentrations only be obtained in the presence of signs that the treatment has failed or that symptoms have worsened; the goal is to explain whether a given relapse is due to low antiTNF concentrations. The latter provides for a regular determination of antiTNF plasma concentrations during quiescent phases of the disease to ensure optimal dosing, maintain drug concentrations within the therapeutic range, predict potential flare-ups of the disease, and prevent therapeutic failure. This may be particularly useful in patients at risk of treatment failure (e.g., those with more severe disease and/or with a history of antiTNF treatment) or to prepare for a change of approach following the loss of response (e.g., indicating a surgical procedure).

In the last few years, several new pharmacogenetic platforms have been developed, based on automated analyses, microarrays, genome wide association studies (GWAS), and next generation sequencing (NGS). These new tools have made it possible to discover multiple polymorphisms capable of predicting the patients’ response to antiTNFs at the time of diagnosis, i.e., even before they are deemed eligible for treatment with biological agents10. Their use is however not widespread in clinical practice.

The purpose of this systematic review is to analyze the potential benefits of proactive TDM and the pharmacogenetic analysis of biological drugs in IBD patients in clinical remission.

The primary search yielded 228 journal and database citations. The secondary search produced one citation (Figure 1). Agreement between the reviewers regarding trial selection was excellent (kappa = 0.97).

Figure 1.

Article selection process.

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The search strategy applied to the different databases yielded a total of 228 references. After removing 85 duplications and applying the inclusion and exclusion criteria a total of 143 references were obtained. Of these, 14 were rejected for not dealing with the subject being reviewed, 55 for not meeting the inclusion criteria (reviews, editorials, and other kinds of texts), and 68 because they were observational studies. Finally, seven studies were included after full-text reading (Figure 1). No RCT containing a pharmacogenetic analysis was found.

The assessment of the quality of the selected articles on the Jadad scale yielded scores between 1 and 5 points, with a median of 2 points (Table 1). The majority of trials included (71.4%) were open-label14–18, which earned them a score of 2 points (low methodological quality). After analyzing the RCTs, it was established that two had a low risk of bias19,20 (Figure 2). The most significant data in each study is summarized in Table 2.

Figura 2.

Risk-of-bias assessment.

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The population included in the different studies was rather heterogeneous, except for one article that was made up exclusively of pediatric subjects17. Nearly all the studies measured the same clinical variables. Analyzed drugs were IFX and adalimumab. The target plasma concentration was between 3 and 8 µg/mL for IFX and between 5 and 10 µg/mL for adalimumab. Mean duration of RCTs was 53 weeks.

The present systematic review analyzed a series of clinical trials dedicated to investigating the results of proactive TDM and the advances made in the pharmacogenetic analysis of IBD patients.

Only two of the studies analyzed found proactive TDM to be superior to reactive strategy as no concentration-guided dose adjustments were made15,17. It should nonetheless be remembered that the first of these studies used IFX in adult patients whereas the second used adalimumab in pediatric patients, which precludes drawing any hard-and-fast conclusions. The study by Strik etal.15 is the only one in the series to include a Bayesian estimation strategy with a population-based pharmacokinetic model to achieve the target plasma level. These systems make it possible not only to consider patient-related data but also factors that affect the pharmacokinetic profile of these drugs (doses and previous concentrations, anti-drug antibody concentrations, etc.), which makes them appropriate dosage individualization tools.

In 2017 the American Gastroenterological Association published a series of recommendations21, which limited the use of reactive TDM to patients with active IBD treated with antiTNFs. Proactive TDM was not recommended as the information available was deemed insufficient. Since then, no further recommendations have been issued by other associations in their guidelines22,23 probably due to the absence of high quality studies in large cohorts contributing conclusive results. Borren et al. recently sought to determine whether IFX levels measured in the context of clinical and endoscopic remission were able to predict loss of response over a 2-year follow-up period. These authors did not observe any differences between IFX plasma levels in patients with and without loss of response24. Despite the uncertainly, it would seem appropriate to measure biological drug concentrations in these cases as personalization of treatment does allow economic savings based on optimizing the administered doses25–27.

Furthermore, in 2019 an expert panel recommended proactive TDM for antiTNF in IBD patients at the end of the induction phase and at least once during the maintenance phase. In patients with primary or secondary loss of response they recommended a reactive monitorization strategy. As regards the new drugs for IBD (e.g., vedolizumab and ustekinumab) proactive TDM may be appropriate at the end of the induction phase and reactive monitoring in case of secondary loss of response. Evidence for this is however still very limited4.

In this regard, Papamichael etal. demonstrated that proactive monitoring was superior to reactive TDM in patients on adalimumab20. Similarly, proactive TDM for IFX showed itself to be superior to reactive TDM when comparing the data with that of a retrospective cohort28. It should be mentioned that most of the information available in the literature comes from observational cohort studies on IFX, data on adalimumab being scarce. Syed etal. observed that proactive TDM for both IFX and adalimumab was superior to reactive strategy [odds ratio (OR): 4.76; 95% CI: 1.65-13.67; p = 0.0019) and to the control group [OR: 6.10; 95% CI: 2.19-17.02; p = 0.0002] in achieving persistence of treatment at one year29.

Giráldez-Montero et al. recently reviewed the TDM strategies for antiTNFs as well as the use of individualized dosing methods in IBD patients. The authors did not describe the inclusion or exclusion criteria of the studies on TDM strategies, with both randomized and observational studies being selected. The conclusion was that there is a trend toward the use of proactive TDM at the expense of reactive one as the former is associated with a longer response to treatment and a lower rate of relapses and discontinuations, although the available evidence is still limited and of poor quality30.

Performance of genetic tests prior to initiating treatment with biological drugs in patients with IBD may constitute one more step on the way towards treatment individualization. The advantages of such tests include an increase in patient safety; a higher effectiveness of the treatment; and less expenses for the health system. One of the most significant findings to date was made by the PANTS prospective study, performed in 1,240 untreated patients. The study revealed an association between the HLA-DQA1*05 (rs2097432) locus and a higher rate of immunogenicity (hazard ratio (HR) 1.90; 95% CI:1.60-2.25; p < 0.001) and of anti-IFX and anti-adalimumab antibody development. The authors observed higher immunogenicity rates at one year (92%) in patients on IFX monotherapy who were carriers of the HLA-DQA1*05 haplotype. The lowest immunogenicity was observed in patients on adalimumab combined with an immunomodulator who were not carriers of that allele31.

Another retrospective study on 252 patients with IBD showed the HLA-DQA1*05 haplotype to significantly increase the risk of anti-IFX antibody formation (HR 7.29; 95% CI 2.97-17.191; p < 0.001) independently of the patient's age, sex, and weight and immunomodulator use, such factors being typically associated with a faster clearance of monoclonal antibodies. It was estimated that including immunomodulators in the patients’ dosing regimen reduced the immunogenicity risk by 38% in both carriers and non-carriers (HR 0.62; 95% CI: 0.30-1.28)32.

A GWAS study identified genetic variants in the CD96 locus (rs9828223; p < 0.001) associated with immunogenicity and with a loss of clinical response33.

A study from the Netherlands reported on a genetic test that included several polymorphisms (among them HLA-DQA1*05, TPMT; NUDT15) associated with the immunogenicity of antiTNF agents or with toxic effects in thiopurines (e.g., myelosuppression or pancreatitis)34. These findings should prompt research into other disciplines where IFX plays a key role in treatment algorithms (e.g., rheumatology). The results of the INHERIT study (NCT04109300), which explores the prospective value of determining the HLA-DQA1*05 haplotype in IBD patients who may be amenable to IFX treatment, may also be relevant in this regard as evaluation of the HLA-DQA1*05 haplotype could be routinely carried out prior to initiating treatment with antiTNF agents35.

The limitations of the present review are related to the differences between the various RCTs included regarding their design and population characteristics, analyzed drugs, activity scores and the phase at which the measurements were performed (induction or maintenance). This heterogeneity prevented a joint analysis of the results of the different trials. There is therefore a need to carry out prospective RCTs with more homogeneous designs and larger patient cohorts to come up with a more robust analysis of the benefits of proactive TDM in IBD patients.

To conclude, TDM allows an individualized adjustment of treatment with biological drugs in patients with IBD. The available evidence is still limited and low-quality, which prevents making hard-and-fast conclusions about the superiority of proactive vs. reactive TDM. On the other hand, the recent development of pharmacogenetic analysis techniques could allow an ex-ante selection of the patients most likely to derive a greater benefit from a specific technique as a function of their genotype. When more data is available, the combination of both strategies could herald a significant transformation in the way IBD patients are managed. It will be essential for pharmacists to play a key role in the multidisciplinary teams taking care of IBD patients.

No funding.

The authors would like to thank SEFH's PKGen Group for inviting them to contribute this paper to the Revista's special issue on personalized pharmacokinetics in clinical practice.

No conflict of interests.