Understanding patient variability to biologic treatments in inflammatory bowel disease

KEYWORDS:

• Biologics
• IBD
• crohn’s disease
• ulcerative colitis
• patient response

1. Introduction

Inflammatory bowel disease (IBD) is primarily identified by two major conditions: ulcerative colitis (UC) and Crohn’s disease (CD) [1]. These conditions can affect individuals at any age, though they typically emerge during adolescence and early adulthood. In the year 2019, the global incidence of IBD was estimated at roughly 4.9 million individuals, with the highest counts observed in China and the United States, recording 911,405 and 762,890 cases, respectively [1]. Patients with IBD may suffer from symptoms, such as diarrhea, rectal bleeding, abdominal discomfort, fatigue, lethargy, weight loss, and inflammation of organs outside the digestive system, such as the skin, eyes, and joints [1].

Initially, treatments for IBD were designed to alleviate these symptoms. However, advancements in medical treatments and a deeper understanding of the disease have led to a paradigm shift [2]. Now, the goal is not just to relieve symptoms but to heal the mucosa and achieve complete inflammation control. The introduction of biologic therapies marked a revolutionary change in IBD treatment [2,3]. Biologics, including TNF inhibitors like infliximab (the first approved TNF inhibitor in 1998), adalimumab, and certolizumab pegol, target-specific components of the immune system, offering a more targeted approach to treatment [2,3]. Infliximab, for example, has been a game-changer for patients with moderate-to-severe Crohn’s disease and ulcerative colitis, demonstrating significant effectiveness [4]. Adalimumab, approved in 2002, became the first fully human monoclonal antibody, broadening the therapeutic options available for IBD patients [3]. These drugs, along with others like golimumab and integrin receptor antagonists such as natalizumab and vedolizumab, have significantly improved patient outcomes, offering alternatives when traditional therapies fail [2,3].

However, there are several challenges, hindering the utilization of biologics for treating IBD patients. Variability in patient response, which refers to the differences in how individuals react to a medical treatment or drug, is among the most concerning issues. The gap in literature and clinical practice, particularly concerning patient selection, timing of therapy initiation, monitoring of treatment efficacy, and strategies for non-responders, necessitates a focused discussion. This editorial aims to discuss the current evidence regarding inconsistent responses to biologics for IBD and factors related to this heterogenicity.

1.1. Current evidence

Patients with IBD experienced inconsistent responses to biologics when treating IBD [5,6]. This variability in response was documented in several studies. A recent systematic review reported differences in response to biologics such as Ustekinumab and Vedolizumab, with variability in clinical remission rates and symptomatic improvements among IBD patients [6]. This variability was also reported in a cohort study, in which the impact of biological therapies on reducing the need for surgery in IBD patients remains inconsistent [5]. Serre-Yu Wong and colleagues found that IBD patients receiving biologics showed robust serological responses to Pfizer-BioNTech and NIH-Moderna COVID-19 vaccination, achieving high seroconversion rates, which suggests variability in immune response among patients on biologic therapy [7].

1.2. Factors behind response heterogenicity

The variability in response to biologics among patients with IBD can be attributed to several factors; 1) patient-related factors, which include age at diagnosis, number of flares prior to biologic initiation, prior steroid use, female sex, prior intestinal surgery, and disease type (Crohn’s disease vs. ulcerative colitis) [8], 2) Clinical-related factors. Lower blood vitamin D levels are associated with active disease and a loss of response to biologics in IBD patients, with levels of ≥25 ng/mL being optimal for predicting disease activity and treatment response [9]. Additionally, Colombo et al. [10], reported that serum levels of biomarkers such as nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are associated with the severity of IBD. They also show a correlation with C-reactive protein levels and serum IL-6 levels, markers of inflammation. Interestingly, they found that NAMPT levels in patients beginning adalimumab treatment were predictive of the treatment’s effectiveness 3 months later. Specifically, patients with NAMPT levels exceeding 4 ng/ml were substantially less likely to experience benefits from the treatment [10]. Furthermore, Caviglia et al. found that a decrease in serum Interleukin-6 levels during biologic therapy for IBD is associated with a higher likelihood of clinical response at 12 months of treatment [11], 3) molecular and genetic-related factors. For example, Paula Zapata-Cobo and colleagues indicated that genetic polymorphisms could impact the effectiveness of biologics [12]. They identified DNA variants in children with IBD. These were associated with worse long-term response to anti-TNF drugs, specific to disease type, and anti-TNF type. Therefore, they suggested analyzing specific genetic markers through genotyping prior to starting anti-TNF treatment, which could help in predicting which pediatric patients will benefit from the therapy over the long term. Another study addressed the role of MicroRNA-21 (miR-21) in anti-TNF drug resistance. It found that elevated levels of miR-21 expression are associated with an increased response rate in pediatric patients, while in adults, higher miR-21 levels may suggest a likelihood of resistance to anti-TNF therapy. Consequently, miR-21 expression levels might serve as a valuable predictive indicator for the effectiveness of anti-TNF treatments in individuals with IBD [13], and 4) drug-related factors, which include the type of biologics used, route of administration, and duration of therapy [14,15]. A study reported that improper handling of biologics, including shaking or undergoing freeze-thaw cycles, can lead to the formation of protein aggregates. This can result in immunogenicity, which could compromise the safety and efficacy of the biologic therapy, and potentially lead to reduced therapeutic effectiveness [16].

2. Expert opinion

The variability in patient responses to biologic treatments for IBD, as discussed in this editorial, underscores a fundamental issue in the management of IBD: the need for a personalized medicine approach. The findings of this editorial call for a paradigm shift in how we approach IBD treatment strategies. Additionally, there is a need for a deeper investigation into the intricate interplay between genetic predispositions, environmental triggers, and the molecular pathways of IBD. Furthermore, the predictive value of identified biomarkers and genetic markers, while promising, necessitates validation in larger, more diverse patient cohorts to ensure their clinical applicability and reliability.

Therefore, the ultimate goal here is the realization of precision medicine in IBD treatment. To achieve such goal, we need more investments in research and clinical applications of methods for predicting patient response to biologic therapies. Recent studies in IBD have explored a variety of predictive methods for biologic therapy response, including multi-omics biomarkers, mucosal gene expression, and therapeutic drug monitoring. Techniques such as machine learning models and the analysis of gut microbiota as universal biomarkers have shown promise in enhancing the accuracy of predicting treatment outcomes [17]. A recent review article highlighted omics biomarkers, including genomics, transcriptomics, proteomics, microbiome, and metabolomics, as promising tools for predicting response to various biologics in IBD patients. Mucosal transcription of specific genes such as OSM, IL-13RA2, and TREM-1, as well as IL-23A transcription, have been identified as potential biomarkers for specific biologics [18]. Moreover, techniques like probe confocal laser endomicroscopy (pCLE) have been used to identify markers of response to biologics [19].

One particularly promising area of research is the exploration of the microbiome’s role in mediating the effects of biologic therapies [20]. The complex interactions between gut microbes and the host immune system offer a fertile ground for discovering new therapeutic targets and mechanisms of drug resistance. This line of inquiry not only has the potential to enhance the effectiveness of existing treatments but also to pave the way for the development of novel interventions that harness the power of the microbiome.

3. Conclusion

The investigation into the variability of patient responses to biologic treatments for IBD underscores the imperative need for a shift toward personalized medicine. Such an approach necessitates a comprehensive understanding of the intricate interplay among genetic, molecular, clinical, and environmental factors that significantly influence treatment outcomes. The findings of this editorial advocate for increased investment in research and clinical trials to validate these predictive tools and integrate them into clinical practice. The ultimate goal is to customize biologic therapies to the unique profiles of individual patients, thereby markedly improving their quality of life. This approach not only promises to refine the management of IBD but also sets a precedent for addressing the complexities of personalized healthcare.

Declaration of interests

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The paper was not funded.