Emerging role of Janus kinase inhibitors in ulcerative colitis management

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease having high morbidity and a significant negative influence on patients’ quality of life. Traditional medicinal strategies available, including amino salicylates, corticosteroids, and biologics, offer limited efficacy, safety, and durability of response. The advancement in small-molecule Janus kinase (JAK) inhibitors has introduced a novel, oral therapeutic option that targets intracellular signaling pathways implicated in UC pathogenesis. Tofacitinib is the first approved JAK inhibitor for the treatment of moderate-to-severe UC. This drug, despite offering promising efficacy, has various safety concerns, especially the occurrence of thromboembolic events. These adverse effects have stressed the development of more selective agents such as upadacitinib and filgotinib. This mini-review explores the current perspectives of JAK inhibitors in UC, particularly focusing on their mechanisms of action, safety profiles, clinical trial outcomes, and emerging strategies to enhance their use. This review also highlights future directions, including the potential of selective JAK1 inhibition and the role of personalized medicine in refining therapeutic decisions. Understanding the emerging place of JAK inhibitors within the UC treatment strategies offers excellent opportunities to increase patient care and long-term disease management.

Key Words: Ulcerative colitis; Janus kinase inhibitors; Tofacitinib; Upadacitinib; Small molecules; Inflammatory bowel disease; Targeted therapy

Core Tip: Ulcerative colitis (UC) is a difficult condition that often doesn’t respond well to standard treatments. This review looks at the growing role of Janus kinase (JAK) inhibitors, a type of oral medication that targets specific pathways involved in inflammation. While older drugs like tofacitinib showed promise, they raised some safety concerns. Newer options, such as upadacitinib and filgotinib, appear to offer better safety alongside strong clinical results. Overall, this review highlights how these treatments could help people with moderate-to-severe UC who need more effective and reliable options to manage their condition.

INTRODUCTION

Ulcerative colitis is an inflammatory disorder of the colon that involves widespread fragility and surface erosion of the colon’s lining, often leading to bleeding. Patients with ulcerative colitis experience alternating periods of active inflammation and inactivity (remission). It is a worldwide growing concern with almost 5 million cases globally[1,2]. In addition to physical health, ulcerative colitis also affects patients' mental health and quality of life significantly. For instance, a study by Zhang has also shown that individuals with ulcerative colitis are at a considerably higher risk of developing anxiety, depression, and sleep disorders compared to patients with Crohn’s disease, affecting their overall health and general well-being[3]. The current management of ulcerative colitis focuses on preventing further disease complications, achieving steroid-free remission, and improving long-term quality of life through both medical and surgical interventions. Amino-salicylates (5-ASAs), corticosteroids, immunomodulators, and anti-tumor necrosis factor-alpha (TNF-α) agents are used in the medical approach; in more severe cases, ileostomy or colectomy are surgical options[4]. Nevertheless, infertility, dysplasia, and an elevated risk of colorectal cancer are among the serious adverse effects of medical therapy, notwithstanding its benefits. Along with other adverse effects like toxicity, infection, and abdominal pain, patients continue to have serious concerns about the gradual loss of response to treatment[5]. Studies indicate that 20%-40% of patients remain unresponsive to conventional medications and may require more aggressive interventions, such as colectomy[6].

These challenges highlight the pressing need for alternative, more effective treatment options. In response to these limitations, Janus kinase (JAK) inhibitors have emerged as a promising therapeutic approach for managing ulcerative colitis, potentially offering significant benefits over traditional therapies[7]. JAK enzymes are the target of JAK inhibitors since they are part of the JAK-signal transducers and activators of transcription (STATs) signaling pathway. JAK inhibitors act on cytokine receptors to block their activity via inhibiting JAKs, thereby reducing inflammatory activity and modifying immune responses. The most commonly used JAK inhibitors include tofacitinib, baricitinib, upadacitinib, and filgotinib[8]. Compared to traditional therapies, these medications can be used to open up more options for managing the patient's disease in the long term with a reduced risk of side effects. This change in treatment has the potential to improve the management of ulcerative colitis greatly. This mini-review explores the mechanisms underlying activity, safety and efficacy, and future outlook for JAK inhibitors in the treatment of ulcerative colitis.

PATHOPHYSIOLOGY

The pathophysiology of ulcerative colitis takes place with a number of crucial complications in the colon. One of the main problems is the aberration of the epithelial barrier, more specifically, the mucin layer. The defect in this layer provides an entry for harmful particles and bacteria into deeper layers of the tissue because of the defective tight junctions between epithelial cells, thus causing an immune response. In addition, in patients with ulcerative colitis, the immune system is inappropriately activated. This is accompanied by a heightened concentration of dendritic cells in the colon that are better suited to identify toxins. Consequently, there is over-activation of T-helper cells, causing inflammation[2]. This inflammatory process is further enhanced by immune molecules such as TNF-α, interleukin (IL)-1, IL-6, IL-12, and IL-23, all of which play a key role in driving the inflammatory response[9]. Cytokines initiate inflammation by binding to specific receptors, activating JAK, which then phosphorylate and activate STATs. These cytokines, including ILs and interferon's (IFNs), activate distinct JAK/STAT pathways to promote inflammation. For example, IL-6, IL-12, and IL-23 from the gp130 receptor family, and IL-2, IL-4, and IL-7 from the common γ-chain receptor family, are involved in JAK/STAT activation, further amplifying the inflammatory process[10].

The JAK-STAT pathway is a signaling cascade with four central non-receptor tyrosine kinases: JAK1, JAK2, JAK3, and TYK2. These kinases are essential for controlling numerous cellular and immune processes. Activation of the pathway occurs through cytokine stimulation, which allows extracellular signals to cross the cell membrane to the nucleus, eventually modifying gene transcription[11]. The participation of the JAK-STAT pathway in immune control renders it a key target for conditions such as ulcerative colitis. Through modulation of this pathway, JAK inhibitors can effectively disrupt the activation of inflammatory cytokines at the core of the disease process. This selective action makes it possible to modulate numerous immune responses and mitigate the chronic inflammation of ulcerative colitis. In addition, JAK inhibitors have an immediate effect and can be given orally, making them a more convenient and potent therapy. Their potential to control various cytokines expands their anti-inflammatory activity, and thus, they have more potential to control the inflammation process of the disease.

Tofacitinib: First-generation JAK inhibitor

Tofacitinib is a small-molecule JAK inhibitor that acts on the JAK/STAT pathway by binding to the JAK kinase domain and inhibiting phosphorylation. This inhibits STAT protein activation and downstream gene transcription. It mainly inhibits JAK1 and JAK3 with less effect on JAK2, producing wide-ranging immunomodulatory effects. These activities decrease cytokine production and modulate innate and adaptive immune response; thus, tofacitinib controls chronic inflammation in diseases like ulcerative coliti[12].

OCTAVE trials proved the efficacy of tofacitinib in inducing and maintaining remission in ulcerative colitis. In Induction 1 (n = 476) and Induction 2 (n = 429), patients receiving tofacitinib 10 mg twice daily achieved clinical remission by Week 8 in 18.5% and 16.6% of cases, respectively, compared with 8.2% and 3.6% on placebo (P = 0.007 and P < 0.001). Mucosal healing (endoscopic Mayo ≤ 1) was twice as common with tofacitinib (31.3% and 28.4%) vs placebo (15.6% and 11.6%) (P < 0.001), and rapid symptom relief was evident as early as day 3. In the Sustain trial (n = 593), week 52 clinical remission was maintained in 34.3% of patients on 5 mg BID and 40.6% on 10 mg BID, vs 11.1% on placebo (P < 0.001), with mucosal healing seen in 37.4% and 45.7% of tofacitinib-treated patients compared to 13.1% of placebo controls; steroid-free remission rates reached 35.4% (5 mg) and 47.3% (10 mg)[13]. Complementing these clinical trials, a United Kingdom real-world cohort of 134 biologic-experienced patients (median age 37, 83% previously on biologics) showed Week 8 clinical response in 74% [88/119; 95% confidence interval (CI): 65%–81%] and Week 26 steroid-free remission in 44% (47/108; 95%CI: 34%–53%). Among primary non-responders, only 23% achieved steroid-free remission at 26 weeks, while dose escalation recaptured response in roughly half[14]. Network metaanalyses and realworld comparisons indicate that tofacitinib offers efficacy comparable to biologics in ulcerative colitis. A 2017 network metaanalysis found no significant differences between tofacitinib and antiTNF therapies or vedolizumab for induction or maintenance outcomes[15]. A broader metaanalysis ranked infliximab highest for induction, while tofacitinib led in maintaining remission[16]. Realworld data show comparable steroidfree remission at one year between tofacitinib and vedolizumab (59% vs 45%, P = 0.07)[17].

Tofacitinib is well-tolerated, with side effects comparable to other UC therapies. It increases HDL and LDL cholesterol without risking cardiovascular events. Herpes zoster infections occur slightly more often (4.07 per 100 PY) due to immunosuppression but are typically mild and preventable with vaccination[18,19]. The drug may increase venous thromboembolic event (VTE) risk, especially in patients with existing risk factors[20]. Older patients and smokers may also face a higher malignancy risk (excluding non-melanoma skin cancers)[21]. Due to elevated VTE risk, the Food and Drug Administration issued a black box warning in 2019[20], along with a risk evaluation and mitigation strategy requiring ongoing assessments. Therapy includes tuberculosis screening, baseline and follow-up lipid and liver tests, and infection monitoring[22].

Next-generation selective JAK inhibitors

Upadacitinib is a highly selective JAK inhibitor that specifically targets JAK1, playing a key role in inflammatory signaling pathways. By blocking JAK1, it prevents the phosphorylation of STAT proteins, thereby inhibiting downstream pathways of several pro-inflammatory cytokines. This selective inhibition results in a more controlled immune response compared to first-generation JAK inhibitors that act on multiple JAK subtypes[23].

Clinical trials, including U-ACHIEVE and U-ACCOMPLISH, have evaluated upadacitinib for the induction and maintenance of remission in ulcerative colitis. Various doses -7.5 mg, 15 mg, 30 mg, and 45 mg-have been studied against placebo, in which upadacitinib demonstrated a rapid onset of action, with symptomatic improvement observed within 1–3 days of starting induction therapy[24]. Efficacy outcomes, such as clinical response, remission, and mucosal healing, have favored upadacitinib. Meta-analysis and clinical trials have suggested that a 45 mg dose has been most effective for induction, while 15 mg and 30 mg doses are used for maintenance in treatment-naïve and treatment-experienced patients, respectively. Safety assessments are based on treatment-related adverse effects and the frequency of drug discontinuation. The most common cause of discontinuation has been worsening disease. Other adverse effects include lymphopenia, elevated creatine phosphokinase, hepatic disorders, serious infections, neutropenia, herpes zoster, acne, venous thromboembolism, and some major cardiovascular events[25,26].

Filgotinib is an orally bioavailable, reversible, and selective JAK1 inhibitor. By inhibiting JAK1, it interferes with the downstream signaling of pro-inflammatory cytokines such as IFN-α and IL-6 while sparing JAK2 and JAK3 pathways. The SELECTION trials assessed 100 mg and 200 mg doses in both biologic-naïve and biologic-experienced patients suffering from moderate to severe ulcerative colitis. Efficacy, based on Mayo Clinic scores, inflammatory biomarkers, and health-related quality of life, showed that filgotinib 200 mg effectively induced clinical remission, mucosal healing, reduced rectal bleeding, and endoscopic improvement, often within 2 weeks of initiation[27,28]. Filgotinib also significantly reduced biomarkers linked to disease activity, including C-reactive protein, IL-6, SAA, neutrophil activation markers, and Th17/Th1 cytokines[29].

Filgotinib is considered well tolerated, with nasopharyngitis being the most common adverse event. Others include headache, arthralgia, nausea, and mild infections. It also demonstrated a relatively low incidence of venous thromboembolism and major cardiovascular events due to its JAK1 selectivity[30]. The MANTA and MANTA-RAy phase 2 trials evaluated its impact on male reproductive health and found no significant effect on testicular function, addressing concerns from earlier animal studies[31].

To date, there are no head-to-head clinical trials directly comparing the efficacy of JAK inhibitors with biologics such as anti-TNF agents. However, indirect evidence from network meta-analyses suggests that upadacitinib demonstrates higher rates of clinical and endoscopic remission. During induction, upadacitinib ranked highest (P-score: 99.08%) with an odds ratio (OR) of 9.43; 95%CI: 5.36–16.61. This was followed by infliximab 5 mg (OR: 1.90; 95%CI: 0.95–3.82; P-score: 84.6%) and infliximab 3.5 mg (OR: 2.26; 95%CI: 0.84–6.11; P-score: 70.93%). In the maintenance phase, upadacitinib again ranked highest (P-score: 95.60%; OR: 7.87; 95%CI: 3.90–15.88), outperforming most therapies. However, the differences were not statistically significant when compared with filgotinib, guselkumab, tofacitinib, and vedolizumab, reflecting competitive efficacy among select agents across different therapeutic classes[32] (Figure 1).

Figure 1 Mechanism of action of Janus kinase inhibitors targeting the Janus kinase-signal transducers and activators of transcription pathway in immune modulation. JAK: Janus kinase; IL: Interleukin; IFN: Interferon; GM-CSF: Granulocyte macrophage-colony stimulating factor; STAT: Signal transducers and activators of transcription.

To facilitate the clinical and pharmacological distinction discussed above, Table 1 provides a concise comparison of clinically relevant JAK inhibitors used in the management of ulcerative colitis[12-49]. This table integrates key considerations side by side, including pharmacokinetics, dosing schedule, clinical trial outcome, and safety considerations between first and second-generation JAK inhibitors to allow a clearer understanding of the therapeutic advantages and limitations of each agent. This overview can be particularly relevant in tailoring therapy for patients who have prior biologic failure, relevant comorbidities, or preferences regarding route and frequency of administration.

Table 1 Comparison of Janus kinase inhibitors in ulcerative colitis.

Parameters	First-generation JAK inhibitors	Next-generation JAK inhibitors
	Tofacitinib	Upadacitinib	Filgotinib
JAK selectivity	It mainly inhibits JAK1 and JAK3 with less effect on JAK2[12]	It specifically targets JAK1[24]	Targets JAK1[27]
Clinical trials	OCTAVE trials[13]	U-ACHIEVE and U-ACCOMPLISH trials[24]	SELECTION trials, MANTA trials[28,31]
Dose available	10 mg drug dose for induction and 5 mg/10 mg for maintenance[14]	45 mg drug dose for induction. And 15 mg/30 mg for maintenance[25]	200 mg drug dose for induction and 200 mg/100 mg for maintenance[28]
Dosing frequency	Twice daily[14]	Once daily[25]	Once daily[28]
Pharmacokinetics	It is primarily metabolized by hepatic cytochrome P450 enzymes (CYP3A4 and CYP2C19), with approximately 70% cleared hepatically and 30% renally[45]	Upadacitinib is mainly metabolized by CYP3A4[47]	Filgotinib is metabolized by carboxyl esterase isoform 2[47]
	It has a half-life of approximately 3 to 6 hours[45]	The half-life of upadacitinib ranges from 8 to 14 hours[46]	For Filgotinib, the half-life is approximately 7 hours for the parent drug and 19 hours for its metabolite[47]
Efficacy	It was proven to be effective in inducing and maintaining remission compared to placebo in randomized controlled trials. Induction remission rates in OCTAVE 1 and 2 were 18.5% and 16.6% vs 8.2% and 3.6% for placebo; maintenance remission at week 52 was 34.3% (5 mg) and 40.6% (10 mg)[11]. Real-world response at week 8 was 74%, with 44% achieving steroid-free remission at week 26[12]	Upadacitinib is considered significantly effective in inducing and maintaining remission, with the 45 mg dose demonstrating relatively higher efficacy compared to tofacitinib and filgotinib[25,26]. At week 96, clinical remission was achieved in 76% (15 mg) and 74% (30 mg) of patients. Endoscopic remission was maintained in 73% of patients receiving 30 mg who had achieved it at baseline[48]	Proven to be significantly effective in inducing and maintaining remission[27,28]. By week 58, 37.2% (200 mg) and 23.8% (100 mg) achieved remission vs 11.2% and 13.5% with placebo[49]
Safety	Its use is associated with various infections (viral, bacterial, fungal, and opportunistic), elevated cholesterol, and malignancies[19]. Major cardiovascular events and venous thromboembolism rates are higher compared to other TNF inhibitors[20]	Adverse effects include lymphopenia, elevated creatine phosphokinase, hepatic disorders, serious infections, neutropenia, herpes zoster, and acne. The incidence of major cardiovascular events and thromboembolism is comparable to other treatments, with higher rates observed primarily in patients with a history of VTE or cardiovascular disease[25,26]	Adverse effects include mild infections and anemia. No major cardiovascular or thromboembolic events have been reported with its use based on the limited available data[30]

JAK: Janus kinase; VTE: Venous thromboembolic event.

EMERGING STRATEGIES AND FUTURE DIRECTIONS

In the rapidly developing therapeutic landscape of ulcerative colitis, JAK inhibitors have developed as an essential class of small-molecule therapies[33]. Plans involve personalized medical approaches, including understanding how genetic variants, particularly JAK polymorphisms, determine the efficacy of drugs and identifying predictive biomarkers for therapy response[34].

Recent efforts for selective isoforms of JAK inhibitors showed promising results, and high dedication and efforts led to the development of highly selective TYK2 inhibitors. Among the most promising developments are TYK2 inhibitors such as deucravacitinib and brepocitinib, which are currently under investigation for their efficacy and safety in ulcerative colitis and other immune-mediated diseases. Brepocitinib (which inhibits both TYK2 and JAK1) and ritlecitinib are being evaluated for inflammatory bowel disease. Specifically, the mean TMS at week 8 was significantly lower, and the rates of clinical remission, modified clinical remission, endoscopic improvement, histologic improvement, and mucosal healing were higher in patients who received ritlecitinib or brepocitinib compared with placebo. Both compounds showed a rapid onset of action, with significant effects on the partial Mayo Score observed after just 2 weeks. Both agents were well-tolerated with acceptable short-term safety profiles[35]. The rates of infections and infestations were not higher in patients treated with baricitinib than in patients treated with placebo through 12 weeks. Serious AEs were uncommon[36].

Additionally, its negative effects have been lessened by its capacity to be limited to the gut alone. Combination treatments, in which medical professionals combine JAK inhibitors with biologics or other small molecules, have been extensively researched recently for the treatment of ulcerative colitis. Furthermore, these combination therapies are being thoroughly studied to find synergistic effects that could improve treatment outcomes; however, the risk-benefit ratio needs to be carefully considered. The therapeutic management of ulcerative colitis has entered an evolutionary era with the arrival of JAK inhibitors, a new class of small-molecule treatments that target crucial signaling pathways involved in the pathophysiology of this chronic inflammatory disease[37].

To assess the long-term effectiveness and safety of JAK inhibitors in a diverse patient population, their post-marketing surveillance and registry data are necessary. Ongoing clinical trials are also evaluating the use of JAK inhibitors in pediatric ulcerative colitis, as well as off-label applications in other inflammatory bowel diseases, such as Crohn's disease, underscoring the versatility of these agents[38].

CLINICAL CONSIDERATIONS AND PRACTICAL APPLICATION

The addition of JAK inhibitors into the treatment of ulcerative colitis is an important advancement, but it requires careful evaluation of where they should be used in the therapeutic algorithm[39]. One significant benefit of their oral administration is that it improves adherence and fits in with patient preferences, particularly for patients who are uncomfortable with injectable treatments. JAK inhibitors provide a useful replacement, especially in situations that are unresponsive to traditional treatments or biologics, because of their oral availability, quick effect, and simultaneous regulation of multiple pro-inflammatory pathways[39].

More precisely, the strategic implementation of JAK inhibitors is most appropriate after instances of therapeutic failure, characterized by an inadequate response or a loss of response, or the development of intolerance to conventional treatments, encompassing corticosteroids, aminosalicylates, and immunomodulators, as well as after the failure of biologic therapies, such as anti-tumor necrosis factor agents and anti-integrin[40]. Considering the expanding array of therapeutic options, including biologics like infliximab, adalimumab, ustekinumab, and vedolizumab, alongside low molecular weight compounds like tofacitinib, the role of JAK inhibitors is especially pertinent in patients for whom these established treatments have proven insufficient[41].

Therapeutic drug monitoring (TDM) is one such method for optimizing therapies. Overall, in clinical practice, the role of TDM for JAK inhibitors remains unclear. Currently, there are no available drug assays to allow for reliable testing. Dose escalation overall will likely only lead to marginal gains in clinical and biochemical response[42]. The safety profile of tofacitinib in the UC clinical development program was manageable. Tofacitinib treatment in patients with UC was associated with a dose-dependent risk of Herpes Zoster. Compared with prior experience with tofacitinib in rheumatoid arthritis, no new or unexpected safety signals were identified. These safety findings support the long-term use of tofacitinib 5 and 10 mg twice daily in patients with moderately to severely active UC[43]. JAK inhibitors have been suspected to induce enhanced risk of infections, changes in lipids, and herpes zoster reactivation and therefore necessitate introducing measures minimizing such potential harms when used long-term. For the purpose of ensuring safer management, it is recommended to perform baseline investigations such as complete blood count, liver function, and renal function, and screening for tuberculosis and monitoring of lipids at regular intervals before starting therapy and during therapy. These tests are helpful in the identification of non-tolerant patients to therapy. Vaccination before immunosuppressive therapy is usually advised, particularly against herpes zoster, pneumococcus, and hepatitis B, especially in patients > 50 years or with risk factors. Live vaccines are not advisable. Alternative preparations may be safer in venous thromboembolism risk or history and should be utilized[44].

CONCLUSION

JAK inhibitors are now recognized as an important addition to the therapeutic resources, offering patients with moderate-to-severe ulcerative colitis a new, focused, oral treatment option. Tofacitinib, the first authorized JAK inhibitor for UC, was an important breakthrough, but concerns about its toxicity profile sparked interest in developing more selective medicines. These more modern inhibitors may be safer and more acceptable, particularly those that target specific JAK isoforms or purely affect the gut.

The future of JAK inhibitor therapy depends on precision medicine, since biomarker-driven approaches provide more customized treatment options. Furthermore, they will need to acquire more clinical experience and real-world data to improve their place in the broader therapy strategy. JAK inhibitors are anticipated to become more and more important in the changing field of ulcerative colitis treatment as research advances and newer medications become accessible. JAK inhibitors can be particularly helpful in patients who do not respond sufficiently to conventional medications. But before going for this option, healthcare providers must consider patient history, comorbidities particularly cardiovascular risk, as JAK inhibitors have been shown to increase the risk of major adverse cardiovascular events, and underlying infections (as JAK inhibitors can weaken the immune system further). While on JAK inhibitors therapy, regular tracking of liver function, thrombotic events, and cholesterol should be monitored. Future research needs to focus on long-term safety information and comparisons with other advanced treatments, as the questions remain regarding the long-term efficacy of JAK inhibitors.