TO THE EDITOR
In recent decades, significant progress has been made in the management of inflammatory bowel disease (IBD) in the field of combined therapy involving biopharmaceuticals and immunomodulators[1]. The letter from Lowell et al[2] provides us with a deep insight into the status of IBD combination therapy and an optimistic outlook on the future of biopharmaceutical therapy[2].
Historically, combination therapy in IBD is centered on pairing biologics, such as tumor necrosis factor (TNF)-α inhibitors, with immunomodulators like mercaptopurine or methotrexate[3,4]. The approach aims to not only enhance the therapeutic effects of biologics but also mitigate immunogenicity, ultimately enhances the bioavailability of the biologics and prolongs treatment efficacy[5]. While initial studies have demonstrated short-term benefits in controlling inflammation, the long-term use of immunomodulators alongside biologics poses significant concerns on heightened risks of infections and malignancies[6]. Kotlyar et al[7] collected and analyzed the correlation between hepatosplenic T-cell lymphoma (HSTCL) and treatment with anti-TNF biologics and azathioprine in patients with IBD. They found that the incidence of HSTCL was highest among young males (under 35 years of age) who were treated with combination therapy. In IBD patients treated exclusively with anti-TNF therapy, no cases of HSTCL were reported[7]. Additionally, azathioprine exhibited a higher rate of adverse reactions in the Asian population. Therefore, when employing traditional combination therapies, physicians must carefully consider the specific circumstances of the patient, taking into account factors such as age, gender, and ethnicity, to make the best treatment choice.
In the current treatment of IBD, combining biologics with adjunctive therapies plays a critical role in developing new therapeutic strategies. Among these, the gut microbiota represents a promising target. The gut microbiota is closely linked to the development and treatment response in IBD. Microbiota imbalance is thought to potentially trigger or worsen IBD symptoms. A meta-analysis of seven randomized controlled trials (RCTs) conducted over the past two decades suggests that probiotic supplementation positively impacts IBD by reducing clinical symptoms, lowering serum inflammatory markers such as C-reactive protein, and increasing beneficial gut bacteria, including Bifidobacteria and Lactobacilli[8]. A French RCT further demonstrated that in patients achieving clinical remission after three weeks of glucocorticoid therapy, the endoscopic severity index of Crohn's disease (CD) significantly decreased by week six following fecal microbiota transplantation (FMT) from healthy donors, while no significant changes were observed in the control group. At week ten post-FMT, 87.5% of patients maintained clinical remission compared to 44.4% in the control group[9]. Thus, combining microbiota therapy, such as probiotics and FMT, with dual-biologic therapy (DBT) could significantly improve outcomes for IBD patients. This direction warrants further research[10]. Currently, FMT is recommended in clinical guidelines in several countries for recurrent or refractory Clostridium difficile infection. However, evidence-based support for its use in IBD remains insufficient, and it is mainly conducted through clinical trials or considered when traditional treatments fail. Due to FMT’s dual role as a biological agent and an organ transplant therapy, its implementation requires strict caution. Treatment must be halted immediately if extensive intestinal ulceration, bleeding, or obstruction of the transplantation pathway occurs.
Furthermore, it is particularly noteworthy that mesenchymal stem cells (MSCs) play a role in promoting intestinal healing and regulating immune responses. They can secrete a variety of growth factors and immune regulatory factors, which help to repair damaged intestinal mucosa and suppress excessive immune responses[11,12]. Currently, MSC therapy for IBD predominantly focuses on limited fistulas and severe ulcerative colitis (UC). Additionally, Phase III clinical trial results indicate that Darvadstrocel, an allogeneic adipose-derived MSC therapy, is an effective treatment for complex perianal fistulas associated with CD[13]. However, with the deepening of research, the latest studies have found that MSCs exhibited heterogeneity and different subgroups may play contraryroles in the progression of IBD. For example, the CCL2+DPP4+ subgroup of MSCs plays a key role in the formation of creeping fat in CD[14]. Based on this understanding of heterogeneity, future stem cell therapy research can be targeted at specific subgroups of MSCs to achieve more precise treatment.
Several clinical trials have raised DBT as a promising candidate combined therapy strategy: A prospective trial by Sands et al[15], which evaluated IFX in combination with natalizumab, revealed that combination therapy demonstrated superior efficacy and tolerability, with a reduction in the mean CD Activity Index scores observed in the combination therapy groups. Feagan et al's recent VEGA study[16] is a global multicenter Phase IIa study designed to assess the efficacy and safety of combination therapy with guselkumab and golimumab in adult patients with moderate to severe active UC. At week 12 of treatment, 40.8% of patients in the combination therapy group achieved a composite endpoint of histological remission and endoscopic improvement, compared to 26.8% in the guselkumab group and 15.3% in the golimumab group[16]. Furthermore, safety analysis indicated no significant safety concerns associated with this combination therapy, and no increased risk of malignancy has been reported. The DUET-UC study, a Phase IIb dose-ranging study, has been conducted in the direction of UC treatment with guselkumab in combination with golimumab. The efficacy and safety in patients with moderate to severe active CD are being investigated in the DUET-CD study. However, a multitude of further trials comparing different biologics or combination therapy in UC and CD have highlighted the complexity and variability in treatment responses among patients with different clinical presentations[17,18]. Considering the restrictive conditions of RCTs, the broad applicability and long-term effects of DBT still require further exploration. We need to re-evaluate the design and outcomes of these studies to determine whether DBT offers substantial benefits to all IBD patients or is only effective for specific subgroups. Moreover, safety data to support its widespread use is still limited[19-21]. Therefore, further larger-scale, multicenter, and long-term follow-up studies is needed to explore the safety and efficacy of DBT application in IBD treatment and the optimal treatment combinations.
In addition, the prospects of DBT are evolving with the advent of newer biologics and small-molecule inhibitors targeting different aspects of the immune response, such as Janus kinase inhibitors[22]. These innovations present new opportunities for novel dual and triple therapy combinations, potentially offering enhanced efficacy and better disease management outcomes. However, the transition from traditional to advanced combination therapies necessitates robust clinical data to definitively establish safety and efficacy profiles.
The above underscores the critical need for high-quality, prospective trials to address existing gaps. RCTs akin to the landmark SONIC trial are essential to validate clinical hypotheses and establish evidence-based treatment guidelines[23]. Moreover, longitudinal studies are crucial for comprehensively assessing the safety and durability of newer combination therapies, particularly in diverse patient populations. The future treatment of IBD may require a more personalized approach. With the advancement of genomics and the study of individual differences in response to treatment, we may be able to precisely predict which patients will benefit from the next generation of DBT and tailor treatment plans for each patient. The 2024 European Crohn's and Colitis Organisation Guidelines indicate that there is currently insufficient evidence to guide the decision-making for various advanced therapies in the treatment of CD. Treatment decisions should consider a combination of factors including efficacy, safety, patient characteristics, disease features, treatment costs, and accessibility[24]. For instance, the use of azathioprine should take into account age and racial factors; the use of Janus kinase inhibitors should consider cardiovascular risks, etc. By targeting different disease phenotypes and risk stratification, further personalized treatment for IBD patients can be achieved.
While challenges persist, recent advancements offer optimism. Trials like the EXPLORER trial on triple therapy[25] and ongoing DUET studies indicate a shifting paradigm towards more tailored and effective treatment strategies. Collaboration between academia, industry, and healthcare providers is pivotal in driving these advancements forward and ensuring that patients with IBD benefit from the latest therapeutic innovations.
In brief, the journey towards optimizing combination therapies in IBD requires a balanced approach of innovation, evidence-supported care, and patient-centric care.
In summary, the letter from Lowell et al[2] has provided us with a glimpse into the future of IBD treatment. Future directions involve exploring dual and triple biologic combinations, alongside emerging small-molecule therapies and adjunctive therapies, to optimize treatment outcomes for IBD patients. However, to realize this future, we need to conduct a more in-depth analysis of existing data, develop an enhanced and detailed research plan, and adopt an interdisciplinary approach. At the same time, we should also maintain an open attitude towards emerging therapies and pay attention to the long-term effects of DBT. Through these efforts, we hope to be able to provide IBD patients with more effective and safer treatment options.
