New and Emerging Treatments for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic or remitting/relapsing inflammatory disease of the intestinal tract, including ulcerative colitis (UC) and Crohn’s disease (CD); the number of patients with IBD has been increasing worldwide [1]. Although the etiology of IBD remains unclear, elucidating its mechanism has facilitated therapeutic development, especially in the last 2 decades. Among the recently available therapies, anti-tumor necrosis factor α (anti-TNFα) agents are the most notable predecessors (infliximab, adalimumab, etc.), resulting in improved health outcomes and decreased need for surgical intervention [2]. However, treatment failure is observed in many patients treated with anti-TNFα agents, including primary and secondary nonresponders. Additionally, anti-TNF-α agents are associated with rare but serious adverse effects, including serious infection, paradoxical autoimmune reactions, and a small but increased risk of malignancy. In this situation, other novel anti-inflammatory therapies targeting inflammatory pathways, including cellular signaling (e.g., anti-interleukin (IL) 12/23 agents and Janus kinase (JAK) inhibitors) and leukocyte trafficking (anti-integrin agents), have been developed with improved safety or pharmacokinetics (i.e., less frequent injection, short administration time, oral therapy). In addition, translational studies have highlighted the potential of various new therapeutic targets, including B cells, innate lymphoid cells (ILCs), bile acids (BA), the brain-gut axis, and microbiota. This article comprehensively reviewed already or shortly available new treatments (1. New drugs) and a wide range of emerging promising therapies that will be hopefully established for IBD in the new era (2. Future perspectives). The brief mechanisms and roles of the new and emerging treatments are summarized in Figure 1.

The pathogenesis of chronic inflamed intestinal mucosa in IBD consists of multistep processes, including migrating lymphocytes from secondary lymphoid organs (SLOs) to the bloodstream, into the gut mucosa through high endothelial venules (HEVs), and proliferation and activation of inflammatory cells [3]. Most new treatments specifically inhibit these points of action. Table 1 shows the summary of new drugs with mode of action and development status.

The trafficking of T lymphocytes from SLOs to the site of inflamed intestine in IBD is mediated by several enhanced chemokines and selectins, leading to the adhesion of integrins expressed on T cells to ligands on HEVs, followed by their transmigration into intestinal tissue. New pharmacological agents have been developed to prevent leukocyte trafficking by selectively targeting the adhesion molecules involved in the pathogenesis of IBD [3]. Among several adhesion molecules, integrin α4β7 is preferentially expressed on lymphocytes activated in gut SLOs and interacts with mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is highly expressed on HEVs [3]. Natalizumab, a recombinant humanized monoclonal antibody against α4-integrin, was initially approved to treat multiple sclerosis (MS), followed by CD [4]. However, the α4-integrin subunit is critical for the α4β1-dependent central nervous system (CNS) homing of lymphocytes, and natalizumab’s use has been drastically limited by its association with life-threatening CNS infection and progressive multifocal leukoencephalopathy (PML, incidence: 1/100-1/1000) due to JC virus reactivation in cases administered for over 8 months (85% of PML cases were administered for more than 24 months) [5]. Vedolizumab is a humanized monoclonal antibody against α4β7 that selectively prevents lymphocyte migration and improves chronic intestinal inflammation. Vedolizumab effectively induces and maintains remission in IBD patients refractory to conventional therapies, with a generally favorable long-term safety profile (GEMINI LTS study), offering an advantage over natalizumab because of no association with the occurrence of PML [6]. Etrolizumab is a humanized monoclonal antibody against the β7 subunit of the heterodimeric integrins α4β7 and αEβ7 expressed on lymphocytes, thus concurrently inhibiting their interaction with MAdCAM-1 and E-cadherin, respectively, leading to the reduction of inflammatory T cells and cytotoxic intraepithelial lymphocytes in the gut mucosa via blockade of intestinal tissue entry and retention [7]. Carotegrast methyl is an orally active, small molecule with a similar action mechanism to natalizumab and was approved in Japan for UC treatment in 2022 [8]. Theoretically, carotegrast methyl can lead to an increased risk of PML as mentioned above. Therefore, the treatment duration was limited to <6 months and there was no case of PML reported. Ontamalimab is a monoclonal IgG2 antibody against MAdCAM-1, thus preventing lymphocyte migration into sites of intestinal inflammation and is efficacious for IBD treatment [4]. Other potential targets of adhesion molecules for the treatment of IBD include intercellular adhesion molecules, vascular cellular adhesion molecule-1, P-selectin, and P-selectin glycoprotein ligand-1 [9].

The sphingosine-1-phosphate receptor (S1PR) comprises 5 subtypes and plays several important roles, including cell proliferation and migration, intercellular communication, vascular tone maintenance, and other cardiovascular effects. S1PR1 plays an essential role in controlling lymphocyte egress from the thymus, SLOs, and bone marrow [10]. Several S1P modulators have been developed to treat immune-mediated diseases, including IBD, MS, rheumatoid arthritis (RA), systemic lupus erythematosus, and psoriasis, with promising results [10]. Ozanimod, an orally administered small molecule and selective immunomodulator of the S1PR1 and S1PR5 receptors, is effective as an induction and maintenance therapy for IBD by receptor internalization and degradation, thus inhibiting the migration of lymphocytes along a gradient of S1P concentration from SLOs into the systemic circulation [10]. Other S1P modulators, including etrasimod and amiselimod, have also been developed and used in clinical trials [10].

IL-12, a heterodimer of p40 and p35, and IL-23, a heterodimer of p40 and p19, are released from myeloid cells, including dendritic cells (DCs) or macrophages, induce differentiation of naïve CD4+ T cells into T-helper 1 (Th1) and T-helper 17 (Th17) cells, and play important roles in the pathogenesis of IBD [11]. Ustekinumab is a fully human IgG1 monoclonal antibody that targets the IL-12/23 shared p40 subunit, preventing its binding to the receptors on cells [11]. UNITI and UNIFI studies have shown ustekinumab’s long-term efficacy and safety for IBD. Risankizumab is a humanized IgG1 monoclonal antibody that selectively binds the IL-23 p19 subunit with a high affinity. Theoretically, risankizumab may confer fewer side effects than ustekinumab by specifically targeting the IL-23-mediated inflammatory pathway without blocking the IL-12-dependent T cell activation pathway, which is vital for infection and cancer immunity. Studies targeting the IL-23 p19 subunit by other biologics, such as mirikizumab, brazikumab, and guselkumab, also showed effectiveness in controlling intestinal inflammation [11].

After the successful results of these ant-IL-23 p40 and p19 monoclonal antibodies, targeting the IL-23/Th17 axis was expected to be a good strategy for IBD. In the IL-17 subclass, IL-17A and IL-17F are the representative cytokines, and Secukinumab (anti-IL-17A antibody) and Brodalumab (anti-IL-17RA antibody) are effective against psoriasis. However, they showed paradoxical gastrointestinal effects and were not approved for IBD therapy [11], since it is mainly assumed that IL-17F is normally pathogenic in enteritis but IL-17A is protective for intestinal epithelial barrier integrity [12].

Cytokines promote intracellular signaling through induction of the JAK/signal transducer and activator of transcription (JAK/STAT) signaling pathway. JAKs, a family of intracellular tyrosine protein kinases, are comprised of 4 members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Inhibition of the JAK/STAT signaling pathway gets a lot of attention for developing novel IBD therapies [13]. JAK inhibitors are small molecules and the first IBD-targeted therapy administered orally. JAK inhibitors are characterized by a rapid onset of action after entering systemic circulation and may provide fast symptomatic relief. In contrast to the aforementioned monoclonal antibodies that target a single cytokine (TNF-α, IL-12, or IL-23), JAK inhibitors have the potential to affect multiple cytokine-dependent immune pathways (for example, JAK1, JAK2, and TYK2 mediate signaling of IL-6, while JAK2 and TYK2 also mediate signaling of IL-23) [13]. Several JAK inhibitors have already been approved for treating RA. Among them, tofacitinib is a highly effective nonselective JAK inhibitor (preferentially inhibits JAK1 and JAK3) that was first approved for induction and maintenance therapy in UC. Remission rates at 8 weeks in OCTAVE induction 1 and 2 compared to placebo were 18.5% versus 8.2% (p < 0.01) and 16.6% versus 3.6% (p < 0.001), respectively. Remission rates at 52 weeks in the OCTAVE Sustain trial were 34.3% in 5 mg and 40.6% in 10 mg versus 11.1% in placebo (p < 0.0001 in both). The risk of herpes zoster infection increases in patients aged >65 years with previous failure of TNFα agents and Asian ethnicity [13]. In phase 2b clinical trials of CD, primary efficacy endpoints were not significantly different from placebo. The selective JAK1 inhibitors, filgotinib and upadacitinib, are also efficacious for IBD [14, 15]. In the maintenance study of filgotinib (SELECTION trial), clinical remission rate at 58 weeks of moderately and severe UC patients taking 200 mg were 37.2% compared to 11.2% in placebo (p < 0.0001). Filgotinib was assessed in CD in the phase 2 FITZROY study, which showed 47% of patients taking 200 mg achieved clinical remission at week 10 compared to 23% in placebo (p = 0.0077). In the U-ACHIEVE study, clinical remission rate at 8 weeks of moderately and severely UC patients taking upadacitinib 45 mg was 19.6% compared to 0% in placebo (p = 0.002). In the CELEST trial assessing upadacitinib in patients with moderate to severe CD, the clinical remission at week 16 was 27% of patients receiving 6 mg upadacitinib twice daily compared to 11% in placebo (p < 0.1). Deucravacitinib in phase 2 clinical trials of CD and UC is a highly selective TYK2 inhibitor that targets IL-12, IL-23, and type 1 interferon (IFN) [13].

Genome-wide association studies have identified that one of the strongest genetic variants related to IBD is the TNF superfamily member 15 (TNFSF15) locus [16]. The TNFSF15 gene is known as TNF-like ligand 1A (TL1A), which is secreted from antigen-presenting cells upon stimulation and plays a central role in activating innate and adaptive immune pathways by binding to death receptor 3 (DR3). TL1A-DR3 signaling is involved with proinflammatory effects including T cell activation and profibrotic pathways [16], both of which are critical for IBD pathogenesis. An anti-TL1A antibody, PF-06480605, downregulates tissue Th1 and Th17 cytokine responses along with significant endoscopic improvements in moderate to severe UC [17].

Phosphodiesterases (PDEs) are a heterogeneous and large family of enzymes that catalyze the degradation of cAMP and cGMP. PDE4 is expressed in DCs, macrophages, monocytes, and T cells. The inhibition of PDE4 elevates intracellular cAMP levels, reducing the expression of the inflammatory cytokines TNFα, IL-17, IFN-γ, and IL-23, while increasing regulatory cytokine levels, such as IL10. Therefore, the PDE4 inhibitor apremilast has been evaluated as a therapeutic agent in treating active UC and proved effective [18].

The expression of the IL-36 family in IBD is up-regulated during intestinal inflammation. Full-length IL-36α and IL-36γ are secreted by different gut-residing cells (epithelium, lymphocytes, and macrophages) and enzymatically processed by extracellular neutrophil proteases into highly active IL-36R agonists. Ligand binding to the IL-36R complex leads to activation of proinflammatory signaling in several cells, including DCs, macrophages, and T lymphocytes. The humanized monoclonal IgG1 antibody spesolimab that targets IL-36R is a potential therapy for IBD and in clinical trials [19].

Since multiple inflammatory pathways are activated in the inflamed intestine, blocking one of them might not be sufficient to control inflammation, as we now do with targeted monotherapies. Therefore, in the future, we will need to establish treatment strategies, such as sequential/combination therapy, to optimize the efficacy of each drug [20]; for example, using combination therapies in the induction phase of early IBD followed by monotherapy in remission. Meanwhile, therapeutic approaches with different mechanisms of action have been investigated from various perspectives. In this section, we discuss several possible future therapeutic targets.

In this decade, a complex interaction between intestinal epithelial cells, the host immune system, and the gut microbiota has been investigated worldwide. Although the diversity and composition of human gut microbiota are believed to play a critical role in human health and the development of several diseases, there remain so many things to be clarified. The intestinal microbiota of patients has less biodiversity (dysbiosis) than healthy subjects, which is supposed to contribute to the onset of IBD. Therefore, microbiome-modulation gets attention as a new therapeutic approach. The beneficial effects mostly depend on their metabolism and metabolic by-products, including short-chain fatty acids, bacteriocins, hydroperoxides, secondary BA, and lactic acids [21]. Potential therapeutic methods include probiotics, prebiotics, fecal microbiota transplantation (FMT), synthetic combinations of specific bacteria, personalized therapies based on individual microbiome profiles, and regulation of BA [21]. Meta-analysis showed that FMT is a safe, effective, and well-tolerated therapy, although long-term effectiveness and safety need to be assessed more [22]. In IBD, the proportion of conjugated primary BA in feces increases, while the secondary BA proportion decreases due to blocked transformation by dysbiosis (conversion of secondary BA is attributed to limited bacteria with BA-inducible enzymes). Secondary BA exerts anti-inflammatory effects, partly by promoting T cell differentiation and inhibiting Th17 cell differentiation. In addition, BA is a natural ligand for several receptors (FXR, TGR5, PXR, and VDR) that regulate metabolic and immune processes. Based on these facts, several therapies targeting the BA-gut microbiota axis might be novel options for treating IBD [23]. Tryptophan is another metabolite involved in host-microbiota interactions. Tryptophan is metabolized by intestinal microorganisms into indole and its derivatives, many of which are ligands for aryl hydrocarbon receptor (AhR), activating the AhR/IL-22 pathway crucial for intestinal homeostasis partly through enhancing barrier integrity. Another metabolism pathway of tryptophan in microorganisms produces peripheral serotonin, an important gastrointestinal signaling molecule for intestinal peristalsis and motility, secretion, vasodilatation, and the absorption of nutrients. Therefore, microorganisms that manipulate tryptophan metabolism may have beneficial effects [24].

Perianal fistulas are a common complication of CD, and approximately one-third of patients develop this complication within 20 years after diagnosis. They deeply impair the quality of life and are poorly responsive to treatment. Closure of the fistula by surgery for a long time is not easy, with an additional risk of incontinence. Thus, effective treatments for perianal fistulas with fewer side effects have been investigated, and local injection of mesenchymal stem cells has recently been found to have a higher efficacy in managing perianal fistula in CD [25].

Gastrointestinal stricture is the pathological fibrotic stenosis of the gastrointestinal tract and is a common complication of CD. Chronic inflammation activates fibroblast, followed by excessive accumulation of extracellular matrix (ECM) and expansion of mesenchymal cells. Matrix metalloproteinases (MMPs) and MMP inhibitors control the generation and degradation of the ECM, and fibrosis progresses when ECM production exceeds the degradation rate. Recent studies also suggest some potential therapies, including anti-fibrotic drugs, anti-MMP9 antibodies, and inhibition of pH-sensing ovarian cancer G-protein-coupled receptor 1 and BCL2 [26].

The gut-brain axis is bidirectional communication between the gut and nervous system, including the CNS, autonomic nervous system, enteric nervous system, and hypothalamus-pituitary-adrenal axis, and highly complex and driven by neural, hormonal, metabolic, immunological, and microbial signals [27]. The vagus nerve (VN), a key component of the autonomic nervous system, is a pivotal element in brain-gut axis. Blunted vagal tone is related to high TNFα levels in IBD, and VN stimulation is a potential therapy for IBD via 2 pathways [27]. VN activates the hypothalamus-pituitary-adrenal axis through its afferent fibers, leading to the release of glucocorticoids followed by suppression of peripheral inflammation. Another anti-inflammatory pathway is the release of acetylcholine (ACh) at the distal end of the VN, which inhibits the release of TNFα from macrophages by binding to α7-nicotinic ACh receptors. In addition, dysregulation of the gut-brain axis is related to gastrointestinal and neurological diseases and a high risk of developing Parkinson’s disease and MS in IBD [28]. Mechanistically, enteric dysbiosis, translocation of microbial metabolites, and inflammatory factors derived from the inflamed intestinal mucosa across the gut epithelial barrier (leaky gut) and blood-brain barrier have been generally supposed to be major factors for altered structure and function in the CNS.

B cells at the intestinal mucosal surface are critical for immune homeostasis, and the dysregulated B-cell response may be a potential therapeutic target in IBD patients [29]. Since IBD patients show increased T cell-dependent mucosal IgG1+ plasma cells, inhibition of CD40L, which is pivotal for T cell-dependent class switching, may reduce inflammatory IgG1 responses while T cell-independent IgA responses are preserved. B-cell-activating factor (BAFF) is a TNF superfamily cytokine and is released by several immune cells upon stimulation for plasma cell and B-cell survival, B-cell maturation, and class-switch recombination. Since BAFF is overexpressed in IBD and Belimumab, a human monoclonal anti-BAFF IgG1 antibody, is effective in systemic lupus erythematosus and RA by reducing naïve and activated B cells as well as plasma cells, BAFF antagonists may ameliorate intestinal inflammation in IBD. Vedolizumab may inhibit the infiltration of circulating α4β7+ plasmablasts into inflamed mucosa. In addition, since some studies have shown a beneficial role of intravenous immunoglobulin in steroid-refractory IBD patients, blocking the Fcγ receptor function may be an attractive approach, although precise mechanism remains to be clarified [29].

ILCs are involved in IBD pathogenesis through interaction with microbiota, modulation of epithelial barrier integrity, and production of cytokines [30]. ILC3s are the major component of intestinal ILCs in normal state, but during active state, IFN-γ-producing ILC1s and IL-17-producing ILC3s increase while IL-22-producing ILC3s decrease. ILC2s are involved in IBD through their ability to sense microbiota and maintain the intestinal barrier. To develop new approaches for IBD, further research on the mechanisms that change the ILCs subpopulation and function and how these ILCs exert their protective and inflammatory effects is required [30].

New and emerging treatments for IBD were reviewed, and novel therapeutic approaches were presented to foresee future treatments. In these 2 decades, many novel drugs have been developed, and the therapeutic algorithms for IBD patients have drastically changed. However, there still remain many refractory patients and the number of IBD patients is increasing worldwide. Over the next 2 decades, where will we be? We hope that the number of patients with severe IBD will be reduced with many novel emerging treatments.

The authors have no conflict of interest to declare.

A grant from National Defense Medical College was received for the study.

Masaaki Higashiyama and Ryota Hokari drafted the manuscript.