Optimizing Janus kinase inhibitor therapy for ulcerative colitis: a real-world perspective
Article information
Abstract
In real-world clinical practice, 3 Janus kinase (JAK) inhibitors—tofacitinib, filgotinib, and upadacitinib—are now available for the treatment of ulcerative colitis. Emerging real-world evidence highlights distinct efficacy and safety profiles among these agents, largely attributed to differences in JAK selectivity and dosing strategies. Notably, data are accumulating on differential efficacy, predictors of therapeutic response, and outcomes in patients who switch between JAK inhibitors, contributing to a clearer understanding of the optimal positioning of each agent. Regarding safety, particular attention has been given to risks such as herpes zoster infection and drug-induced acne, underscoring the importance of appropriate patient education and individualized risk assessment. This review summarizes clinical trials and current real-world data on tofacitinib, filgotinib, and upadacitinib in ulcerative colitis, and discusses strategies for optimizing their clinical application.
INTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory condition of the colorectum, characterized by symptoms such as bloody stools, bowel urgency, and diarrhea [1]. Once a diagnosis of UC is established, treatment is guided by a treat-to-target strategy. The initial short-term goal is to alleviate clinical symptoms. Subsequently, normalization of inflammatory markers–C-reactive protein, fecal calprotectin, and leucine-rich alpha-2 glycoprotein– is pursued. Ultimately, the long-term therapeutic target is to achieve endoscopic remission [2].
UC management is tailored based on disease extent and severity. Aminosalicylates remain the cornerstone of treatment. For patients with proctitis, a combination of topical and oral aminosalicylates is typically recommended. In those with mild-to-moderate left-sided colitis or pancolitis, oral aminosalicylates are also the preferred initial therapy. If remission is not achieved, systemic corticosteroids are introduced for achieving induction remission, while remission is maintained with aminosalicylates and/or thiopurines. In steroid-dependent or steroid-refractory cases, escalation to advanced therapies (ADTs) is warranted. Notably, up to 40% of UC patients show an inadequate response to conventional therapies and require ADTs, which include biologics and Janus kinase (JAK) inhibitors [3].
In recent years, a growing number of ADTs have become available, including 3 JAK inhibitors—tofacitinib, filgotinib, and upadacitinib—which are available in oral fromulations [4]. These agents differ in their selectivity for JAK subtypes. For instance, while tofacitinib and upadacitinib inhibit multiple JAK subtypes, filgotinib primarily targets JAK1-mediated signaling, with less inhibition of JAK2- and JAK3-dependent pathways [5]. These pharmacological differences may account for distinct efficacy and safety profiles, suggesting that each JAK inhibitor may be better suited for specific patient subgroups [6].
To determine the optimal use and therapeutic positioning of JAK inhibitors in UC, real-world observational studies are increasingly valuable. This review summarizes clinical trials and current real-world evidence and discusses practical strategies for optimizing the use of JAK inhibitors in UC patients in clinical practice.
METHODS
This narrative review was based on literature searches conducted in PubMed using combinations of the keywords “ulcerative colitis” and “pouchitis” with “tofacitinib,” “filgotinib,” and “upadacitinib.” Relevant studies published up to May 2025 were reviewed, with a particular focus on clinical trials, real-world evidence, and safety data related to JAK inhibitors in UC. Articles were selected for inclusion based on their relevance to current clinical management of UC.
1. Overview of Clinical Trials and Real-World Studies of JAK Inhibitors in UC
1) Tofacitinib
Tofacitinib is approved for the treatment of moderately to severely active UC. The recommended induction dose is 10 mg orally twice daily for 8 weeks. In patients who do not achieve an adequate response, induction therapy can be extended to a maximum of 16 weeks. For maintenance therapy, the recommended dose is 5 mg orally twice daily.
In the OCTAVE Induction 1 trial, clinical remission at week 8 was achieved in 18.5% of patients treated with tofacitinib, compared with 8.2% in the placebo group. The remission rate was higher in biologic-naive patients (25.2%) than in those with prior exposure to tumor necrosis factor (TNF) inhibitors (12.6%). Similarly, in the OCTAVE Induction 2 trial, remission was achieved in 16.6% of the tofacitinib group versus 3.6% of the placebo group. In the OCTAVE Sustain trial, the 52-week remission and mucosal healing rates were 34.3% and 37.4%, respectively, in the 5 mg tofacitinib group, compared with 11.1% and 13.1% in the placebo group. While serious infections occurred at similar rates across all treatment groups, overall infections and herpes zoster infections occurred more frequently in patients receiving tofacitinib compared with placebo. 7 The OCTAVE open-label, long-term extension study demonstrated sustained efficacy and a consistent safety profile of tofacitinib for up to 7.0 years [8].
The ORAL Surveillance study was conducted to compare the safety profile of tofacitinib versus TNF inhibitors in patients with active rheumatoid arthritis (RA) aged 50 years or older, with at least one additional cardiovascular risk factor despite methotrexate therapy. This study showed that tofacitinib was associated with increased risks of major adverse cardiovascular events (MACE) and malignancies, and it failed to demonstrate non-inferiority compared to TNF inhibitors [9]. However, it is important to note that this study included high-risk RA patients, which limits the generalizability of its findings to the UC population, who are typically younger and have a different risk profile.
In contrast, the UC OCTAVE program, which included 1,157 UC patients, assessed cardiovascular safety with tofacitinib in a more relevant population. In this cohort, 83% of patients receiving tofacitinib had no prior atherosclerotic cardiovascular disease (ASCVD) and were at low baseline 10-year ASCVD risk. MACE occurred more frequently in patients with a history of ASCVD or high baseline cardiovascular risk [10]. Furthermore, the safety profile of tofacitinib in UC has remained consistent over long-term follow-up, extending up to 9.2 years [11].
Multiple real-world observational studies have assessed the effectiveness and safety of tofacitinib in UC. A recent systematic review and meta-analysis of 19 real-world studies (n=2,612) reported clinical remission rates of 39% at week 8 and 43% at week 52 [12]. Regarding safety, another meta-analysis including 7 studies (n=759) estimated pooled incidence rate of overall adverse events and herpes zoster infection at 53.0 and 4.2 per 100 person-years, respectively [13].
2) Filgotinib
For the treatment of moderately to severely active UC, the recommended induction dose of filgotinib is 200 mg taken orally once daily for up to 10 weeks. For patients who achieve a clinical response, the recommended maintenance dose is 200 mg once daily.
In the SELECTION trial, at week 10, a greater proportion of patients receiving filgotinib 200 mg achieved clinical remission compared with those receiving placebo: 26.1% versus 15.3% in Induction Study A (biologic-naive patients) and 11.5% versus 4.2% in Induction Study B (biologic-experienced patients), suggesting reduced efficacy in biologic-experienced patients compared to biologic-naive individuals. At week 58, 37.2% and 15.6% of patients in the filgotinib 200 mg group achieved clinical remission and endoscopic remission, respectively, compared with 11.2% and 6.1% in the placebo group. The incidence of serious adverse events and adverse events of interest was similar between treatment arms [14]. The SELECTION open-label long-term extension study evaluated the long-term safety and efficacy of continued filgotinib treatment over approximately 4 years. This study demonstrated that filgotinib effectively induced and maintained symptomatic remission, improved health-related quality of life, and exhibited a favorable long-term safety profile throughout the 4-year extension period [15]. Integrated safety data from the SELECTION and SELECTIONLTE studies showed that exposure-adjusted incidence rates for serious infection, thromboembolic events, and MACE remained consistently low across treatment groups. The exposure-adjusted incidence rate for herpes zoster was numerically higher in the filgotinib 200 mg group (1.44 per 100 patient-years) than in the placebo group (0.26 per 100 patient-years) [16]. These findings suggest that filgotinib is generally well tolerated with no unexpected safety signals.
Real-world evidence on filgotinib is increasingly being reported. In an observational study conducted in the UK involving 91 patients (67% of whom were naive to biologics and small molecules), the median treatment duration was 39 weeks. Clinical remission was achieved in 71.9% of patients at week 12 and 76.4% at week 24. Adverse events were reported in 15 patients (16.5%), including 8 patients who experienced moderate adverse events that led to temporary discontinuation of filgotinib: 5 cases of respiratory infections, 1 case of facial shingles, and 2 cases of mild COVID infections. Serious adverse events resulting in definitive drug discontinuation or death occurred in 2 patients [17]. In a multicenter real-world study conducted in Japan involving 238 UC patients (46% of whom were naive to biologics and small molecules), the median follow-up duration was 28 weeks. Clinical remission rates at weeks 10, 26, and 58 were 47.0%, 55.8%, and 64.6%, respectively. These remission rates were comparable between biologic- or JAK inhibitor-naive patients and those with prior exposure, possibly due to the inclusion of a greater proportion of patients having moderate disease activity with milder symptoms compared to those enrolled in the SELECTION trial. Herpes zoster infection occurred in 3 patients (1.3%), while no cases of thrombosis or death were reported [18]. Subsequent real-world studies have demonstrated showed similar efficacy and safety profiles for filgotinib [19-24]. Comprehensive evaluations through systematic review and meta-analyses are anticipated to further characterize its real-world effectiveness.
3) Upadacitinib
For the treatment of moderately to severely active UC, upadacitinib is administered as an induction therapy at a dose of 45 mg taken orally once daily for 8 weeks. In patients who do not achieve an adequate response, the induction period may be extended up to 16 weeks. Following successful induction, maintenance therapy is continued with either 15 mg or 30 mg orally once daily.
In the induction trials, significantly higher proportions of patients achieved clinical remission at week 8 with upadacitinib 45 mg compared to placebo: 26% in the U-ACHIEVE trial and 33% in the U-ACCOMPLISH trial. In the U-ACHIEVE maintenance trial, clinical remission and endoscopic remission at week 52 were achieved by 42% and 24% of patients receiving 15 mg, and by 52% and 26% of those receiving 30 mg of upadacitinib, respectively—both significantly higher than in the placebo group. Efficacy was consistent regardless of prior biological failure. The most commonly reported adverse event was acne, occurring in 5% and 7% of patients treated with upadacitinib 45 mg in the U-ACHIEVE and U-ACCOMPLISH induction trials, respectively. While herpes zoster infections occurred more frequently in patients receiving upadacitinib compared with placebo, events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently, and no treatment-related deaths occurred [25]. In the interim analysis of the U-ACTIVATE long-term extension study involving patients who received approximately 3 years of upadacitinib treatment, sustained efficacy was observed, and the most common adverse events of special interest included hepatic disorders, lymphopenia, elevated creatine phosphokinase, serious infections, neutropenia, and herpes zoster. In the long-term extension-only safety population, 3 treatment-emergent adverse events leading to death were reported [26].
A recent systematic review and meta-analysis of 24 real-world studies (n=1,388) showed that 94% had previously failed biologics or JAK inhibitors, including 53.2% who had received tofacitinib. Clinical remission was achieved in 68.4% of patients at week 8. Additionally, clinical remission rates at weeks 2–6, 12–16, and 24–36 were 48.3%, 71.1%, and 64.6%, respectively. The incidence rates of serious adverse events and herpes zoster were 2.3, and 1.7 per 100 patient-years, respectively [27].
Acne may be a unique adverse event associated with JAK inhibitors, particularly upadacitinib. A prospective observational study including patients with UC and Crohn’s disease reported that adverse events occurred in 32.4% of those treated with upadacitinib, with the most common adverse event being acne (22.9%) [28]. A meta-analysis including 25 randomized clinical trials of JAK inhibitors (10,839 patients with immune-mediated inflammatory diseases) reported a pooled odds ratio of 3.83 for acne, with an even higher odds ratio observed for upadacitinib (4.79) [29].
2. Overview of Comparative Studies of JAK Inhibitors in UC
1) Network Meta-Analysis and Real-World Studies Comparing 2 JAK Inhibitors
To clarify the positioning of JAK inhibitors in UC management, comparative evaluation of the 3 agents is important. However, no head-to-head clinical trials have directly compared their efficacy and safety. In this context, network meta-analysis, which provides indirect comparisons, offers valuable insights. Across multiple network meta-analyses, upadacitinib has consistently demonstrated the highest efficacy in both induction and maintenance phases. While differences between tofacitinib and filgotinib are modest, tofacitinib generally shows a slight efficacy advantage [30-33].
Several real-world studies conducted in the US comparing upadacitinib and tofacitinib have shown superior efficacy of upadacitinib [34-36]. A 1-year comparative effectiveness study reported that upadacitinib was associated with significantly higher odds of steroid-free clinical remission compared to tofacitinib [36]. A 24-week real-world study from Japan also confirmed this trend, but noted that adverse events were more common with upadacitinib. The herpes zoster rate in the upadacitinib-treated group (5.9%) was higher than in the tofacitinib-treated group (1.5%). The most common adverse event among upadacitinib-treated patients was acne (47.1%) [37].
A multicenter real-world study compared upadacitinib (n =70) and filgotinib (n =98) in UC [24]. Median follow-up was 167.5 days for upadacitinib and 191 days for filgotinib, with upadacitinib showing significantly greater efficacy. While no cases of MACE, thrombosis, or malignancies were reported, the incidence of overall adverse events was higher with upadacitinib (45.7%) than with filgotinib (24.5%). The risk of herpes zoster was similar during the study period (3.1% in filgotinib vs. 2.9% in upadacitinib), while acne was common in the upadacitinib group (10.0%) [24].
A single-center real-world study using propensity score matching compared tofacitinib and filgotinib [22]. Clinical remission rate at week 8 was significantly higher in the tofacitinib-treated patients (50%; 11/22) than the filgotinib-treated patients (15.8%; 3/19). Regarding safety outcomes, the incidence of herpes zoster infection was 3.1/100 patient-years with tofacitinib and 0/100 patient-years with filgotinib. No deaths or life-threatening adverse events were reported in either group [22].
2) Real-World Studies Comparing All 3 JAK Inhibitors
Real-world data comparing all 3 JAK inhibitors have been published. Our multicenter study included 228, 215, and 159 UC patients treated with upadacitinib, filgotinib, and tofacitinib, respectively [38]. Efficacy was evaluated in patients with clinically active UC, while safety was assessed in the overall population. The median follow-up periods for upadacitinib, filgotinib, and tofacitinib were 49 weeks, 56 weeks, and 112 weeks, respectively. Clinical remission rates for upadacitinib were 59.3% at week 10, 74.7% at week 26, and 85.0% at week 58. For filgotinib, clinical remission rates were 44.9%, 58.1%, and 67.8%, respectively. For tofacitinib, clinical remission rates were 45.5%, 67.1%, and 80.2%, respectively. Propensity score matching analyses showed that upadacitinib had significantly greater efficacy than filgotinib and was generally superior to tofacitinib. Filgotinib and tofacitinib showed comparable efficacy, although some efficacy outcomes were numerically higher with tofacitinib. Another real-world study comparing the 3 JAK inhibitors showed similar efficacy results at week 8 [21]. These findings were consistent with previous reports comparing 2 of the agents [22,24,34-37]. Taken together, these data suggest that upadacitinib is the most effective JAK inhibitor, followed by tofacitinib and then filgotinib.
Regarding safety, herpes zoster occurred in 4.9% of patients on upadacitinib, 1.4% on filgotinib, and 8.2% on tofacitinib [38]. While tofacitinib had the longest observation period, approximately 70% of herpes zoster cases occurred within the first year of treatment in each group (data not shown). These findings suggest a higher risk with upadacitinib and tofacitinib compared to filgotinib, which is consistent with the results of a network meta-analysis [6]. Acne was significantly higher with upadacitinib (23%) than with filgotinib (3.7%) or tofacitinib (6.3%). Our propensity score matching analysis showed that upadacitinib was consistently associated with a significantly higher risk of acne compared to both filgotinib and tofacitinib. The analysis also revealed a significantly lower risk of therapeutic discontinuation within 1 year with upadacitinib compared to filgotinib, and a marginally lower risk compared to tofacitinib. Otherwise, no significant differences were observed among the 3 JAK inhibitors in terms of hospitalization and colectomy within 1 year, herpes zoster infection, thrombosis, or death. These findings are consistent with earlier real-world studies [21,22,24,34-37]. While all JAK inhibitors carry a risk of herpes zoster infection, filgotinib may be associated with a lower risk. In contrast, upadacitinib appears to carry a higher risk of acne.
As demonstrated in real-world comparative studies, the risk of herpes zoster is higher with upadacitinib and tofacitinib, whereas it appears to be less pronounced with filgotinib. Acne has also been observed more frequently with upadacitinib. In light of these findings, detailed discussions on the management of herpes zoster and acne are provided in subsequent sections.
3) Intraclass Switching of JAK Inhibitors for UC
Intraclass switching among JAK inhibitors may be a viable treatment strategy for UC, although data remain limited [39]. In our cohort, 92 patients were treated with upadacitinib after prior exposure to JAK inhibitors–31 to tofacitinib, 54 to filgotinib, or 7 to both. Clinical remission rates were 57.3% at week 10, 72.0% at week 26, 82.9% at week 58, and 71.9% at the most recent follow-up (median 53 weeks). Over half of these patients achieved both clinical response and corticosteroid-free remission at each timepoint. These findings align with previous studies. A multicenter retrospective study of 42 patients previously treated with tofacitinib reported clinical remission rates with upadacitinib of 72% at week 8 and 86% at weeks 16 [40]. A prospective study showed that 12 of 15 patients (80.0%) with prior tofacitinib exposure achieved clinical remission with upadacitinib by week 8 [28]. A meta-analysis also demonstrated high rate of clinical remission with upadacitinib as a second-line JAK inhibitor: 76.3% at week 8 and 69.3% at weeks 12–16 [27]. Collectively, these findings suggest that upadacitinib remains highly effective even after prior JAK inhibitor failure.
We also identified 21 patients treated with filgotinib after previous JAK inhibitor use–19 after tofacitinib, 1 after upadacitinib, and 1 after both. The rates of clinical remission were lower than with upadacitinib: 28.6% at week 10, 33.3% at week 26, 62.5% at week 58, and 50.0% at the most recent follow-up (median 52 weeks) [38]. The GETAID J2J multicenter group also evaluated second JAK inhibitor use in UC. Among 169 patients, 81 achieved steroid-free clinical remission at weeks 8–14: 58 of 105 with upadacitinib, 18 of 54 with filgotinib, and 5 of 10 with tofacitinib [41]. These data support the effectiveness of all 3 JAK inhibitors when used as a second JAK inhibitor. However, filgotinib may be less effective than tofacitinib and upadacitinib.
4) Predictors of Effectiveness of JAK Inhibitors for UC
Our real-world study comparing the 3 JAK inhibitors included multivariate analysis to identify predictors of treatment efficacy. We found that UC patients with higher platelet counts were less likely to achieve clinical remission or continue filgotinib therapy [18,38]. The median platelet count was 30×104/μL in patients who achieved clinical remission at the most recent follow-up, compared to 33 ×104/μL in those who did not. One potential explanation involves the role of JAK2-mediated signaling, which is essential for platelet production. Higher platelet count may therefore reflect enhanced JAK2-driven inflammatory activity in UC [5]. Since filgotinib exhibits the greatest selectivity for JAK1 among the 3 JAK inhibitors [5], it may exert weaker inhibition of JAK2-mediated signaling compared to tofacitinib and upadacitinib, leading to reduced efficacy of filgotinib in patients with elevated platelet counts. Therefore, patients with higher platelet counts (e.g., >33–35×104/μL) may benefit more from tofacitinib or upadacitinib than from filgotinib [42].
In contrast, patients with longer disease duration were more likely to achieve clinical remission and maintain tofacitinib therapy. The median disease duration was 9 years in patients who achieved clinical remission at the most recent follow-up, compared to 6 years in those who did not. Similar trends were observed in UK and Japanese real-world studies. A multicenter real-world study in the UK showed that the median disease duration was significantly longer in patients achieving a response with tofacitinib (7.8 years) than in those without a response (2.5 years) [43]. Furthermore, a 3-year result from a real- world study in Japan showed that median disease duration in cases of tofacitinib treatment non-failure (8.9 years) was significantly longer than in cases of treatment failure (5.9 years) [44]. These findings suggest that patients with a longer disease duration, which serves as a surrogate marker for less severe inflammation [43], or an active state of cytokines different from those in the early phase of the disease (e.g., T-helper type 2 cytokines) [45] may be good candidates for tofacitinib.
Our analysis also showed that upadacitinib maintained higher efficacy even after multiple prior ADTs. In contrast, patients who have experienced multiple previous ADTs were less likely to achieve clinical remission with filgotinib or tofacitinib. These findings suggest that earlier use of filgotinib or tofacitinib may be a more effective strategy. When selecting the most appropriate JAK inhibitor between these 2 agents, platelet counts as well as disease duration may serve be useful clinical markers.
3. JAK inhibitors for Chronic Inflammatory Pouch Conditions in UC
Approximately 10% of UC patients require total colectomy with ileal pouch-anal anastomosis [46]. Among these patients, up to 50% develop acute pouchitis, and 10% to 15% progress to chronic pouchitis [47,48], requiring long-term antibiotics or ADTs. Evidence on the efficacy and safety of JAK inhibitors for chronic inflammatory pouch conditions remains limited. A case series from the US reported that approximately 50% of patients with chronic pouchitis or Crohn’s disease-like pouch inflammation [49] achieved a clinical response following the initiation of tofacitinib [50]. A systematic review of 9 studies (n=46) showed a similar response rate of 53% [51]. In contrast, data on the efficacy and safety of upadacitinib and filgotinib for chronic inflammatory pouch conditions are scarce, highlighting the need for further research [52,53].
4. Management of Herpes Zoster Infection in Patients Receiving JAK Inhibitors
Treatment of herpes zoster in patients with inflammatory bowel disease (IBD) depends on the clinical severity. For uncomplicated cases, oral valacyclovir (1 g) or famciclovir (500 mg) three times daily for 7–14 days is recommended [54]. For complicated cases—such as disseminated or visceral involvement—IV acyclovir (10 mg/kg every 8 hours, adjusted for renal function) is preferred. In case of acyclovir resistance, foscarnet (40 mg/kg IV every 8 hours) may be used. Antiviral therapy should begin within 72 hours of rash onset and continue for at least 7–10 days [54].
Herpes zoster events associated with JAK inhibitors are typically mild and manageable with standard antiviral therapy. In clinical trials for RA, psoriasis, and UC (OCTAVE program), most events were nonserious and did not require permanent discontinuation of tofacitinib [55-57]. In the OCTAVE program, among 65 patients with herpes zoster, 44 continued tofacitinib, 16 temporarily stopped or reduced the dose, and only 5 permanently discontinued treatment [57]. These findings support that the majority of patients with herpes zoster can safely continue or resume tofacitinib following appropriate management.
Vaccination is a key preventive strategy. The recombinant zoster vaccine (Shingrix) is preferred over the live vaccine (Zostavax or BIKEN) due to its superior efficacy and favorable safety profile in immunocompromised patients. Guidelines recommend Shingrix for IBD patients aged ≥ 50 years, and for younger patients (aged 19–49) who have risk factors such as corticosteroid use, combination immunosuppressant therapy, or treatment with JAK inhibitors [58]. Early vaccination is important given the elevated risk of herpes zoster in IBD patients receiving JAK inhibitors. For individuals previously vaccinated with live zoster vaccine, revaccination with Shingrix is advised to ensure sustained protection.
Special consideration should also be given to high-risk populations, including elderly patients and East Asians, who have shown a higher incidence of herpes zoster [59]. Our recent analysis revealed that the risk of herpes zoster infection with upadacitinib (14%; 2/14) and tofacitinib (23%; 3/13) was approximately 3-fold higher in elderly patients ( ≥65 years at JAK inhibitor initiation) compared to non-elderly patients. In contrast, filgotinib showed a consistently low herpes zoster incidence of less than 3% in both age groups [60]. Notably, herpes zoster risk appears to be dose-dependent, further underscoring the importance of individualized risk assessment when selecting a JAK inhibitor and its appropriate dose.
5. Management of Acne in Patients Receiving JAK Inhibitors
Drug-induced acne, including that associated with JAK inhibitors, presents a clinical challenge, particularly in IBD patients where immunosuppressive therapy cannot be easily withdrawn [61]. Risk factors for the development of acne in IBD patients treated with upadacitinib include younger age, female sex, and higher dosage of upadacitinib [62]. Consistently, our study found that the risk of acne with upadacitinib was higher in non-elderly patients (24%; 52/214) compared to elderly patients (7.1%; 1/14) [60]. While no formal guidelines exist for JAK inhibitor-associated acne, management generally follows principles used for acne vulgaris [61,63].
Initial management should focus on optimization of skincare, including gentle, soap-free cleansers and avoidance of oil- or alcohol-based products. Patients should be counseled to avoid manipulating lesions to prevent scarring and reassured that JAK inhibitor-associated acne use is typically mild to moderate in severity and responds well to dermatologic treatment [64,65]. Dose reduction of JAK inhibitors may help alleviate symptoms and is often sufficient when combined with topical therapy. Therefore, discontinuation of JAK inhibitors is rarely required [64,65].
Patient education is essential. Before starting JAK inhibitors, patients should be informed of the risk of acne and its typical course [65]. Those with preexisting acne or a history of acneiform eruptions may benefit from pre-emptive skincare adjustments [65]. Clinicians should also inform patients that treatment responses may take several weeks to months and that adherence is key to effective management [66].
Topical therapy remains the mainstay for mild to moderate cases. Recommended agents include retinoids, topical antibiotics (e.g., clindamycin or erythromycin), and benzoyl peroxide [67]. Combination therapy using agents with different mechanisms of action is preferred to improve efficacy and minimize bacterial resistance. Additional agents such as azelaic acid and salicylic acid may also be beneficial, particularly in patients with post-inflammatory hyperpigmentation [67].
For moderate to severe cases, short-term oral antibiotics (e.g., doxycycline or lymecycline) may be used in conjunction with topical therapies [67]. These systemic agents should be limited to a maximum of 3 to 4 months to avoid resistance and adverse effects. Patients should be advised on the risk of photosensitivity and the importance of sun protection during treatment. Dermatology referral is recommended for patients with severe or treatment-resistant acne, significant scarring, or psychological distress, as well as those in whom dose reduction or drug withdrawal is not feasible due to underlying UC activity [61].
In selected refractory cases, oral isotretinoin may be considered under specialist supervision. Although earlier reports raised concerns regarding its association with IBD [68], large-scale meta-analyses have shown no increased risk of IBD with isotretinoin exposure [69,70]. Nevertheless, its use requires careful patient selection and contraception counseling in individuals of childbearing potential due to its teratogenic potential [67].
SUMMARY AND FUTURE DIRECTIONS
JAK inhibitors represent an important class of ADTs in UC, offering the convenience of oral administration. Given that safety concerns such as MACE and malignancy have not emerged as significant issues in UC populations thus far, the overall benefit–risk profile remains favorable. Based on updated real-word data, this review proposes a step-up approach within JAK inhibitor therapy for UC—starting with agents with more favorable safety profiles, such as filgotinib, and escalating to more potent options like tofacitinib or upadacitinib, guided by patient characteristics (e.g., platelet counts, disease duration, history of multiple ADT failures, disease severity, age, and comorbidities)—to optimize treatment outcomes while minimizing associated risks (Fig. 1). Indeed, the American Gastroenterological Association living guideline suggests that in patients previously exposed to 1 or more ADTs, particularly TNF inhibitors, higher-efficacy agents such as tofacitinib, upadacitinib, or ustekinumab should be considered [71].
A step-up approach within Janus kinase (JAK) inhibitor therapy in ulcerative colitis—starting with agents with favorable safety profiles such as filgotinib (FIL), and escalating to more potent options like tofacitinib (TOF) or upadacitinib (UPA) based on patient characteristics—may optimize outcomes while minimizing risks. In this approach, it is reasonable to consider not only intraclass switching among JAK inhibitors but also a transition to a biologic agent. HZ, herpes zoster.
In this step-up approach, treatment selection should incorporate shared decision-making, as physician and patient preferences may prioritize efficacy over safety depending on individual values and clinical goals. It may also be reasonable to consider not only intraclass switching among JAK inhibitors but also a transition to a biologic agent, guided by pivotal recommendations [71]. Regional variation in the availability of JAK inhibitors should be acknowledged, as it may limit the feasibility of implementing a uniform treatment strategy. Furthermore, medical economic factors—including drug cost, insurance coverage, and healthcare system constraints—as well as practical issues such as dosing frequency and treatment adherence, play important roles in real-world therapeutic decision- making. These factors should be carefully considered when applying this approach. Lastly, clinicians should also ensure that patients are informed of the risks of herpes zoster and acne associated with JAK inhibitors, as these adverse events are generally manageable with appropriate monitoring and intervention.
JAK inhibitors offer a unique therapeutic profile, characterized by rapid onset of action and a nonimmunogenic small-molecule structure that minimizes the risk of anti-drug antibody formation [72]. This may enable flexible initiation and discontinuation of treatment, positioning JAK inhibitors as potentially “stoppable” ADTs in future clinical practice. However, real-world data are needed to determine which patients can safely discontinue JAK inhibitors and whether reintroduction can effectively prevent disease relapse. A previous study has shown that a subset of patients who achieve histologic normalization [73] were able to discontinue UC therapies [74]. Therefore, from my perspective, discontinuation of JAK inhibitors may be a reasonable strategy for motivated and well monitored patients who have achieved normal histology.
Moreover, JAK inhibitors are contraindicated during pregnancy due to teratogenic effects observed in animal studies [75]. In cases where mucosal healing is achieved prior to conception, discontinuing JAK inhibitors—rather than switching to a biologic agent with a more favorable safety profile during pregnancy—may offer substantial benefits for both mother and fetus. These scenarios highlight the need for further real-world evidence to guide safe discontinuation strategies and support shared decision-making in clinical practice.
Notes
Funding Source
The author received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Akiyama S has received lecture fees from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Limited, Janssen Pharmaceutical K.K., Pfizer Japan Inc., Gilead Sciences K.K., EA Pharma Co., Ltd., AbbVie GK, Mochida Pharmaceutical Co., Ltd., Viatris Pharmaceuticals Japan Inc., JIMRO Co., Ltd., Celltrion Healthcare Japan Co., Ltd., KISSEI Pharmaceutical Co., Ltd., Sandoz K.K., Kyorin Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Olympus Corporation, Nippon Kayaku Co., Ltd., Bristol-Myers Squibb Company, and Zeria Pharmaceutical Co., Ltd., and research grants from Mochida Pharmaceutical Co., Ltd. Except for that, no potential conflict of interest relevant to this article was reported.
Data Availability Statement
Not applicable.
Author Contributions
Writing and approval of the final manuscript: Akiyama S.