Game changer: How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis management

Abstract

Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.

Key Words: Ulcerative colitis; Janus kinase inhibitors; Filgotinib; Tofacitinib; Upadacitinib

Core Tip: Janus kinase inhibitors such as tofacitinib, filgotinib, and upadacitinib represent a significant advancement in ulcerative colitis (UC) management, offering effective induction and maintenance of remission, especially for patients unresponsive to conventional therapies. Despite potential safety concerns, these agents provide rapid action and the ability to tailor treatment to individual patient needs, marking a paradigm shift in UC treatment strategies.

INTRODUCTION

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) characterized by inflammation and ulceration of the large intestine. It is a debilitating condition that affects millions of people worldwide, significantly impacting their quality of life[1]. While conventional therapies such as corticosteroids, aminosalicylates, and immunomodulators have been the mainstay of treatment for UC, a significant proportion of patients experience limitations with these approaches. These limitations include inadequate response rates, often requiring dose escalation with associated side effects, and the need for parenteral administration for some medications[2].

The emergence of targeted therapies, using biologics such as anti-tumor necrosis factor (TNF), anti-integrin, or anti-interleukin (IL) agents, has revolutionized the treatment landscape for UC by specifically targeting key inflammatory pathways[3]. However, even with biologics, a subset of patients still fails to achieve adequate response or experiences intolerance.

This limitation highlights the importance of seeking a deeper understanding of the immunology of UC. By unravelling the complex interplay between immune cells and signaling pathways involved in the disease process, researchers have been able to develop new and more targeted therapeutic options[4]. The use of Janus kinase inhibitors (JAKis) has redefined the treatment landscape for UC, offering an effective alternative if first-line anti-TNF therapies fail. Drugs such as tofacitinib, filgotinib, and upadacitinib have shown significant improvements in both clinical and endoscopic remission during the induction and maintenance phases of treatment[5]. Although there are concerns regarding safety, the rapid action and adjustable oral dosing of these drugs suggest that they have significant potential for the future management of the disease, for a large number of patients.

In recent years, gastroenterologists have been able to choose from an expanding range of treatments when addressing patients with UC. The progressive increase in available mechanisms of action has heightened interest in this field in achieving a better understanding of immunological processes in this context[4]. A pivotal development in this scientific progression has been the identification of cytokines as key mediators in the pathogenesis of inflammatory diseases.

While JAKis have shown promising results, it is important to acknowledge potential safety concerns associated with their use. These concerns include an increased risk of infection, venous thromboembolism, and cytopenia. Careful patient selection and monitoring are essential to mitigate these risks[6]. Despite these potential drawbacks, JAKis represent a significant advance in the treatment of UC. They provide an effective and well-tolerated option for patients who are intolerant to conventional therapies and even some biologics, or for whom these approaches have failed. As research continues to elucidate the mechanisms of action and safety profiles of JAKis, their role in the management of UC is likely to expand further.

TARGETING JAK-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION SIGNALING IN UC MANAGEMENT

JAKs are intracellular tyrosine kinases that play a crucial role in the signaling pathways of various cytokines, which are key mediators in the pathogenesis of inflammatory diseases such as UC. JAKs are associated with type I and type II cytokine receptors[7]. The type I family includes receptors such as the common gamma, the common beta, and glycoprotein 130, while the type II family includes receptors for interferons (IFNs) and the IL-10 cytokine family. Each receptor family interacts with distinct subsets of JAKs, facilitating specific signaling pathways[8,9].

JAKs were first discovered by Wilks in 1989, and the family now includes four members: JAK1, JAK2, JAK3, and TYK2. JAK3 is predominantly expressed in hematopoietic cells, which are crucial for immune homeostasis and lymphopoiesis. By contrast, JAK1, JAK2, and TYK2 are ubiquitously expressed, with JAK1 mediating inflammatory cytokine signals and JAK2 being vital for myelopoiesis and erythropoiesis[10,11].

In the context of UC, cytokines such as ILs play a pivotal role in driving inflammatory processes within the gastrointestinal tract. Specific cytokines such as IL-6, IL-12, IL-23, and IFN-γ contribute to the pathogenesis of UC by promoting immune cell activation and inflammation[12].

Tofacitinib, a JAKi, targets JAK1 and JAK3 with high affinity, but is less active against JAK2 due to reduced affinity. It is considered a pan-JAKi with a preference for JAK1 and JAK3, impacting the signaling pathways of IL-6 and IL-23. These cytokines are crucial in the activation of T cells and the production of pro-inflammatory mediators in UC[13]. To more selectively target the pro-inflammatory immune system via JAK1, rather than the hematopoietic aspects of JAK2 activity and other immune activities of JAK3, JAK1-selective drugs were subsequently developed. Thus, upadacitinib and filgotinib selectively inhibit JAK1, affecting the IL-12 and IL-23 pathways, which are involved in the differentiation and maintenance of T helper 1 (Th1) and Th17 cells, respectively[14,15].

By blocking these specific cytokine pathways, JAKis help regulate the immune response in UC, reducing inflammation and modulating the gut mucosal environment. This targeted approach aims to achieve and maintain remission by mitigating the chronic inflammation characteristic of UC, while minimizing the systemic side effects associated with broad immunosuppressive therapies[16]. With this mechanism of action, various JAKis have been approved for the treatment of UC and other immune-mediated diseases (Figure 1).

Figure 1 Janus kinase approved for ulcerative colitis and other immunomediated diseases by the United States Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency, except filgotinib, which is only approved by the European Medicines Agency and Pharmaceuticals and Medical Devices Agency.

The selective inhibition of JAK enzymes involved in specific cytokine signaling pathways underscores the importance of precision medicine in managing UC. By modulating the immune response and targeting key inflammatory mediators, JAKis offer a promising therapeutic strategy for patients with moderate to severe UC, with the potential for improved efficacy and a more favorable side effect profile compared to traditional immunosuppressive agents.

THE ROLE OF JAKIS IN UC

The first JAKi approved for moderate-to-severe UC by the Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japan’s Pharmaceuticals and Medical Devices Agency was tofacitinib in 2018. This drug was the first oral advanced treatment for UC, administered twice daily with inhibitory affinity for both JAK1 and JAK3[17]. Clinical trials have established the efficacy and safety of tofacitinib, which alleviates the symptoms of UC, improves the patient’s quality of life and promotes mucosal healing, irrespective of prior anti-TNF treatment.

Following tofacitinib, two additional JAKis, filgotinib and upadacitinib, were approved between 2021 and 2023 by the above organizations, except filgotinib by the FDA. Both drugs should be taken once daily and preferentially inhibit JAK1. These, too, have obtained positive results in clinical trials, with a safety profile comparable to that of tofacitinib[18,19]. These JAKis are also useful for treating other immune-mediated diseases such as rheumatoid arthritis (RA) and psoriatic arthritis. Phase 3 efficacy results from the clinical trials are shown in Table 1.

Table 1 Phase 3 efficacy trials of Janus kinase inhibitors in ulcerative colitis¹.

Clinical trial			Patients, n	Dose	Primary outcome	Response vs placebo
Tofacitinib	Sandborn et al[17] (2017)	OCTAVE Induction 1	598	Placebo (122)	Clinical remission at week 8	8.2%
				10 mg (476)		18.5% (P = 0.007)
		OCTAVE Induction 2	541	Placebo (112)		3.6%
				10 mg (429)		16.6% (P < 0.001)
		OCTAVE Sustain	593	Placebo (198)	Clinical remission at week 52	11.1%
				5 mg (198)		34.3% (P < 0.001)
				10 mg (197)		40.6% (P < 0.001)
Filgotinib	Feagan et al[18] (2021)	SELECTION Induction A	659	Placebo (137)	Clinical remission at week 10	15.3%
				100 mg (277)		19.1% (P = 0.337)
				200 mg (245)		26.1% (P = 0.015)
		SELECTION Induction B	689	Placebo (142)		4.2%
				100 mg (285)		9.5% (P = 0.064)
				200 mg (262)		11.5% (P = 0.01)
		SELECTION Maintenance	664	Placebo (89)	Clinical remission at week 58	13.5%
				100 mg (172)		23.8% (P = 0.420)
				Placebo (98)		11.2%
				200 mg (199)		37.2% (P < 0.001)
Upadacitinib	Danese et al[19] (2022)	U-ACHIEVE Induction	473	Placebo (154)	Remission at week 8	4.5%
				45 mg (319)		26.0% (P < 0.001)
		U-ACCOMPLISH	515	Placebo (174)		4.0%
				45 mg (341)		33.4% (P < 0.001)
		U-ACHIEVE Maintenance	451	Placebo (149)	Remission at week 52	12.1%
				15 mg (148)		42.6% (P < 0.001)
				30 mg (154)		51.9% (P < 0.001)

¹Clinical remission was defined as a total Mayo score of ≤ 2, with no subscore > 1 and a rectal bleeding subscore of 0 in all studies. Filgotinib studies required a 1-point decrease in stool frequency from induction baseline for a subscore of 0 or 1. The Physician Global Assessment was removed from the upadacitinib studies due to subjectivity concerns.

Of these JAKis, tofacitinib has been longest on the market. Real-world data confirm its efficacy for patients with UC, achieving clinical remission rates of 37%-43% after 8 weeks of induction therapy and 34%-61.7% after 52 weeks[20-25]. Moreover, recent studies have provided increasing evidence for the use of filgotinib and upadacitinib. Retrospective and prospective studies with upadacitinib report clinical remission rates with upadacitinib of up to 80% after 8 weeks of induction and 38% after 52 weeks[26,27]. Although studies of filgotinib are less abundant, available data indicate clinical remission rates of 71.9% at week 12 and 76.4% at week 24[28]. Additionally, these JAKis have demonstrated a rapid onset of action, with significant clinical improvement observed as early as days 1 to 3 after treatment initiation. Specifically, upadacitinib led to the absence of rectal bleeding by day 1 and the absence of abdominal pain and bowel urgency by day 3 in a significant proportion of patients compared to placebo[29]. Filgotinib, too, obtained a reduction in stool frequency by day 1 and a decrease in rectal bleeding by day 4 vs placebo[30]. Furthermore, JAKis are orally administered, which may enhance patient adherence compared to injectable or intravenous biologics. Studies have shown that patients with UC often prefer oral medications due to ease of administration and the potential for more convenient dose adjustments[31,32]. This preference for oral formulations highlights the potential of JAKis to improve treatment adherence and increase patient satisfaction.

SAFETY OF JAKIS

The pleiotropic effects of JAKis are apparent in their mediation of growth factors, hormones, and cytokine receptors. Although designed to target specific JAKs, higher doses can affect multiple JAKs, potentially leading to hematological, metabolic, or immunosuppressive adverse effects due to off-target binding[33]. JAKis can also cause idiosyncratic drug hypersensitivity, drug allergies, and/or drug-drug interactions[34].

In the OCTAVE Sustain maintenance study, a higher rate of herpes zoster (HZ) infection was observed in the tofacitinib group, although no severe cases were noted[17]. Factors associated with a higher risk of HZ included age over 65, Asian ethnicity, prior TNF inhibitor failure, and higher doses. Tofacitinib treatment tended to be non-complicated and rarely led to permanent therapy discontinuation or additional HZ recurrence[35]. A population-based study showed that the rate of subsequent recurrent HZ reactivation was not significantly different between patients who continued JAKi treatment and those who did not[36]. The incidence of severe HZ in patients treated with filgotinib is also very low, regardless of dose[19]. Most studies indicate that upadacitinib does not significantly differ in safety outcomes compared to active treatments or placebo in patients with UC or other immune-mediated diseases[37].

Post-marketing data for tofacitinib (ORAL Surveillance study) have sparked concerns about an increased risk of pulmonary embolism and mortality at the 10 mg twice daily dose in RA patients aged over 50 and with cardiovascular risk factors. As a results, boxed warnings were issued for all JAKis, despite the findings being specific to tofacitinib in RA[38]. The FDA and EMA recommend that maintenance dosing should not exceed 5 mg twice daily, and that 10 mg twice daily should only be used beyond the induction period if necessary for response maintenance. They also advise against its use in patients over 65, those with cardiovascular risk factors, those with a history of thromboembolism, current or past smokers, and those with an increased cancer risk. In the same study, the risk for nonmelanoma skin cancer was higher with tofacitinib than with a TNF inhibitor. However, such associations have not been observed in UC patients treated with tofacitinib, filgotinib, or upadacitinib[39]. Moreover, the extrapolation from RA to UC patients regarding JAKi safety has been questioned due to the presence of significant differences between the patient populations considered. RA patients, who were the primary subjects of the ORAL Surveillance trial, are typically older and have more cardiovascular risk factors and comorbidities compared to UC patients, who are generally younger and have fewer comorbid conditions. These differences can impact the risk-benefit assessment of JAKis. For example, the risk of major adverse cardiovascular events and malignancies identified in RA patients may not be as pronounced in younger UC patients. Additionally, the disease progression and urgency of treatment differ between RA and UC, necessitating a tailored approach in evaluating the safety and efficacy of JAKis for each condition. Consequently, broad regulatory restrictions based on RA data might not appropriately reflect the needs and risks of UC patients, leading to potential underutilization of effective treatments in this group[40,41]. Recent expert consensus recommends a patient-personalized approach, in which the proposed algorithm for using JAKis in UC focuses on balancing efficacy with safety. In this approach, patients are screened for risk factors such as age, smoking history and existing cardiovascular, cancer or venous thromboembolism risks. JAKis can be used more freely in low-risk patients, especially those with high inflammation. In the induction phase, the approved dose is administered for 8 weeks, extendable to 16 weeks if necessary. During the maintenance phase, the lowest effective dose should be used to maintain remission, with extra caution in high-risk patients[42].

Regular monitoring of laboratory parameters is essential due to the impact of JAKis on hematopoiesis. Periodic assessments should include lymphocyte and neutrophil counts and monitoring for anemia[43]. Elevated levels of liver transaminases, creatinine and creatine phosphokinase have been reported, but these changes are generally reversible upon discontinuation of therapy and have not been linked to liver or renal failure or rhabdomyolysis[44,45]. The most frequent adverse events related to JAKis and recommendations for surveillance and management are shown in Figure 2.

Figure 2 Most frequent adverse events related to Janus kinase inhibitors and how to manage them.

As with any therapy, the risks and benefits should be discussed with each patient, and treatment plans should be tailored based on their IBD and overall medical history. Overall, JAKis present significant therapeutic benefits for patients with UC, but careful consideration of their safety profile and vigilant monitoring are essential to optimize patient outcomes.

JAKIS AND PREGNANCY

JAKis are generally contraindicated during pregnancy and breastfeeding, according to drug regulatory agencies and international guidelines[46]. This recommendation is due to concerns about the potential teratogenic effects and unknown risks to the infant. Studies of tofacitinib have detected teratogenicity in animal models at high doses, and similar concerns apply to other JAKis such as upadacitinib and filgotinib[47]. Despite these contraindications, there have been instances where women with unplanned pregnancies or medically refractory UC have continued JAKi treatment due to the lack of viable alternatives. In a series of six cases involving women with UC exposed to tofacitinib during conception and pregnancy, no negative pregnancy or infant outcomes were reported[48]. Tofacitinib showed effective placental transfer, with cord plasma concentrations reaching 74% of maternal plasma concentrations at delivery. However, given the lack of comprehensive safety data and the potential risks, breastfeeding is still generally discouraged for women on JAKis due to the unknown risks of infant exposure. The DUMBO registry in Spain presented two cases highlighting the challenges faced by healthcare professionals in managing UC in pregnant patients using tofacitinib. There was no significant safety signal for adverse pregnancy or infant outcomes related to the treatment[49]. While these cases provide some reassurance, the evidence is still limited, and further direct studies are needed to confirm these findings and guide clinical decision making. This includes further investigation into the safety of other JAKis such as upadacitinib or filgotinib during pregnancy[50]. While some case studies suggest that JAKis might be used without adverse outcomes in certain high-risk pregnancies, the overall recommendation remains to avoid these drugs during pregnancy and breastfeeding due to the potential risks.

THERAPEUTIC POSITIONING OF JAKIS IN UC

The Phase 3 trials conducted with JAKis include various arms to assess the efficacy and safety of these treatments, with approximately 50% of the cohorts consisting of patients who have failed one or more biologics. JAKis have demonstrated their utility in both induction and maintenance phases under these circumstances[17-19]. To date, few potential predictors of response to JAKis have been identified, mostly from post-hoc analyses of trials and not externally validated. Given the rapid action of JAKis, early changes in clinical and biological markers (e.g., patient-reported outcomes, C-reactive protein [CRP], and fecal calprotectin) appear to be reliable predictors of response. However, these observations need confirmation from large prospective studies[51].

To date, no direct comparative clinical trials between JAKis and other biologic treatments in this context have been performed. This lack of direct comparison means that clinical guidelines have not established a clear order of treatment following an initial failure with biologics[52,53]. In 2020, the American Gastroenterological Association suggested using ustekinumab or tofacitinib over vedolizumab or adalimumab for induction of remission, as filgotinib and upadacitinib were not yet considered. In contrast, the European Crohn's and Colitis Organization in 2022 did not clearly favor any treatment in these conditions[54,55].

In the absence of head-to-head clinical trials, several meta-analyses have indirectly compared the efficacy and safety of JAKis in moderate-to-severe UC. In these trials, upadacitinib was identified as the most effective for inducing clinical remission but had the highest rate of adverse events, while vedolizumab was noted for its superior safety profile[56]. Another study indicated that upadacitinib 45 mg for induction and 30 mg for maintenance performed best overall in achieving and maintaining clinical response and endoscopic improvement, regardless of prior biologic exposure[57]. A separate analysis found upadacitinib superior to all but tofacitinib for early clinical response, with ustekinumab and ozanimod ranking lowest[58,59]. Infliximab ranked highest for endoscopic improvement in biologic-naïve patients, while ustekinumab and tofacitinib were preferred for those with prior TNF antagonist exposure in a previous study, where upadacitinib and filgotinib were not included[60]. The studies consistently showed high efficacy of all JAKis in treating UC. Notably, none of these analyses found significant differences in serious infections or severe adverse events between all treatments and placebo.

The absence of direct comparative clinical trials between JAKis and other biologic treatments presents a significant challenge in establishing a clear treatment hierarchy for patients with moderate-to-severe UC. This gap in evidence necessitates reliance on indirect comparisons and meta-analyses, which, while informative, cannot fully substitute for head-to-head trials. Consequently, clinical guidelines remain somewhat ambiguous, and treatment decisions often depend on individual patient characteristics and the clinician’s experience. Therefore, clinicians must weigh the benefits of rapid symptom relief and mucosal healing against the potential risks. In the absence of direct comparative trials, the following recommendations can guide the implementation of JAKis in UC treatment regimens: (1) Patient selection: Ideal candidates for JAKi therapy include those with moderate-to-severe UC who have not responded adequately to conventional biologics. Factors such as age, disease severity, prior treatment history and the presence of comorbidities should be considered. Additionally, patients with immune-mediated inflammatory diseases or extraintestinal manifestations, such as arthritis or psoriasis, may particularly benefit from JAKis due to their broader anti-inflammatory effects. Patients with a history of thromboembolic events or other significant risk factors for adverse events may require alternative treatments or closer monitoring; (2) Early indicators of response: Given the rapid action of JAKis, early changes in clinical and biological markers (e.g., patient-reported outcomes, CRP, and fecal calprotectin) can serve as reliable predictors of response. Clinicians should monitor these markers closely to make timely adjustments to the treatment regimen; and (3) Personalized approach: Treatment decisions should be individualized, taking into account patient preferences, lifestyle and overall health status. Shared decision-making between the clinician and patient is crucial to optimize treatment outcomes and adherence.

To enhance clinical decision-making, future research should prioritize direct comparative trials between JAKis and other biologics. Such studies will provide more definitive evidence on the relative efficacy and safety of these treatments, ultimately facilitating more precise and confident clinical recommendations. The inclusion of recently approved drugs such as etrasimod and mirikizumab in these trials will further expand the therapeutic landscape for UC.

THE ROLE OF JAKIS IN SPECIAL SITUATIONS

Acute severe UC

Due to the rapid onset of action of JAKis, their application has been considered for patients experiencing acute severe UC (ASUC), particularly those who have not responded to initial therapy with Infliximab. To date, several trials with tofacitinib have been conducted in this setting, revealing colectomy-free rates exceeding 75%[61,62]. The optimal dosing regimen for ASUC remains undetermined. Standard dosing (10 mg twice daily) is commonly used, but higher doses (10 mg three times daily) have been considered due to the short half-life of tofacitinib. Its safety profile is generally favorable, with a 3% rate of serious adverse events and no deaths attributed to the drug[63-65]. A recent case-control study indicated that 76% of ASUC patients treated with upadacitinib were able to avoid colectomy, with a low incidence of adverse events (8.0%) and readmission (20%)[66]. The role of JAKis in ASUC, especially in hospitalized patients who have been previously exposed to biologics, is promising. However, its position within therapeutic strategies for ASUC is still being evaluated. The efficacy and safety of newer, more selective JAKis such as filgotinib in ASUC are yet to be determined.

Pouchitis

Chronic pouchitis, a complication that can arise after surgery for UC, presents a treatment challenge. While established medications like vedolizumab and ustekinumab offer some relief, recent research explores the off-label potential of JAKis. In this respect, recent studies, though retrospective and with limitations, provide encouraging results. JAKis, particularly tofacitinib, has demonstrated clinical response rates of up to 75% in some patients with chronic pouchitis[67,68]. This effectiveness appears comparable to or slightly lower than that of other medications used for this condition. However, more research, especially in the form of randomized controlled trials, is necessary to definitively confirm their effectiveness and determine their optimal role in treatment strategies for chronic pouchitis.

FUTURE PERSPECTIVES

Future perspectives in the treatment of UC are promising, with several new molecules currently under investigation. Ritlecitinib, brepocitinib, deucravacitinib and ivarmacitinib are all progressing through various stages of clinical trials, with encouraging results[69,70]. These next-generation JAKis and other novel agents hold potential for enhancing treatment efficacy and safety, providing new hope for patients with UC. Preliminary studies of more selective molecules are also underway. For instance, the preclinical to clinical translation of TD-1473, an oral gut-selective pan-JAKi, has shown promising results. Furthermore, the in vitro characterization evidenced in a Phase 1b study in patients with UC demonstrated high intestinal vs plasma drug exposure, local target engagement and trends toward reduced UC disease activity. These advances represent a significant step forward in developing more targeted and effective treatments for UC, thus reducing the risk of adverse events[71,72].

Patients with longstanding UC often face challenges in achieving remission due to limited treatment options after the failure of multiple biologic or small molecule therapies. Dual biologic or small molecule therapy is an appealing option for these refractory patients, but evidence on its efficacy and safety remains limited. Recent systematic reviews and meta-analyses of this treatment strategy have observed similar rates of adverse events, infections and malignancy compared to TNF antagonist monotherapy, with high clinical and endoscopic remission rates[73,74]. Nevertheless, and despite these promising results, further research is needed, especially on the use of JAKis, which target similar pathways and have shown potential in treating moderate-to-severe disease. Some authors emphasize the important role of JAKis may play in this context, due to their potency and rapid onset of action, especially when combined with slower-acting and safer molecules such as vedolizumab or ustekinumab. These combinations could even serve as substitutes for steroids in refractory cases with a high inflammatory burden[75,76]. The exhaustive data analyses conducted to date highlight the importance of exploring new combinations of therapies, including multiple biologics and JAKis, to achieve additive benefits and improve patient outcomes. Though this approach is not generally indicated, nor is it found within product labels, it unveils a thrilling spectrum of possibilities for these patients, highlighting the imperative need for further studies to illuminate the path with hard evidence.

In healthcare systems worldwide, managing treatment costs is crucially important to ensure sustainability and continued accessibility. Biologic therapies, except biosimilars, are often expensive due to the complex processes involved in their development, production and administration. A recent study in Japan evaluated the cost effectiveness of advanced therapies for treating moderate-to-severely active UC, including biologics and JAKis[77], using a cost per responder model and incorporating the costs of drug acquisition, administration serious adverse event management and rescue treatments. Overall, JAKis were found to be more per responder than other treatments, which underscores their potential to reduce the financial burden on healthcare systems while providing effective care for UC patients.

CONCLUSION

The introduction of JAKis such as tofacitinib, filgotinib and upadacitinib represents a milestone in the treatment of UC, offering new perspectives in managing this IBD. The efficacy of these medications in inducing and maintaining remission after anti-TNF failure has been demonstrated, although potential risks like cardiovascular events and HZ infection must be considered. However, their rapid action and ability for individualized adjustment suggest they may play a crucial role in personalized medicine, opening new avenues for improving the management of UC. Although the lack of direct comparative trials with other biologics poses a challenge, meta-analyses have highlighted the efficacy of JAKis in inducing clinical remission compared to biologics. In ASUC and chronic pouchitis, JAKis have obtained favorable outcomes, although questions such as optimal dosing and long-term safety need further exploration. Pregnancy remains a contraindication for JAKis due to their potential teratogenic effects, although some case studies suggest they may be safely administered in specific instances.

The future of UC management lies in ever-more personalized medicine, with treatments tailored to individual patient profiles in order to optimize efficacy and minimize side effects. Newer JAKis and novel agents, such as ritlecitinib and TD-1473, are under investigation and show promising results. Additionally, JAKis have been found to be more cost-effective compared to biologics, potentially easing the financial burden on healthcare systems. Overall, while JAKis have proven to be a valuable addition to UC therapy, ongoing research and direct comparison trials are needed to fully establish their role and guide clinical decision-making.