Updated review of Janus kinase inhibitors for the management of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) management has evolved with the advent of Janus kinase inhibitors (JAKi), oral small molecules that modulate cytokine-driven inflammation via the Janus kinase-signal transducer and activator of transcription pathway. This narrative review synthesizes current evidence for JAKi in ulcerative colitis (UC) and Crohn’s disease (CD), detailing their efficacy, safety, positioning, and special contexts. Tofacitinib has demonstrated robust induction and maintenance efficacy in moderate-to-severe UC, including steroid-refractory and acute severe cases, while failing to meet endpoints in CD. Upadacitinib shows high rates of clinical, endoscopic, and durable remission in both UC and CD across pivotal trials, and emerging real-world data support its superiority in certain refractory settings. Filgotinib is effective in UC, with more limited but promising data in CD. Safety concerns span infectious complications (notably herpes zoster), cytopenias, dyslipidemia, thromboembolic risk, and potential impacts on pregnancy and lactation; long-term data remain largely extrapolated from rheumatologic cohorts. Combination regimens with other biologics have been explored but warrant caution due to additive immunosuppression. Data on pediatric IBD and extraintestinal manifestations are nascent. Limitations include sparse long-term safety data specific to IBD, unclear carcinogenesis implications, and reliance on indirect comparisons for positioning. Despite these gaps, JAKi - particularly tofacitinib and upadacitinib - offer effective alternatives in biologic-experienced and refractory IBD, with careful patient selection, screening, and monitoring essential to mitigate risks. Future prospective studies should clarify optimal sequencing, long-term safety, and gut-selective strategies.

Key Words: Janus kinase inhibitors; Inflammatory bowel disease; Ulcerative colitis; Crohn’s disease

Core Tip: Janus kinase inhibitors are reserved for moderate-to-severe inflammatory bowel disease (IBD) after biologic failure or steroid dependence. Carefully selecting patients based on their cardiovascular, thromboembolic, and infection-related risks is of paramount importance. Tofacitinib is an excellent choice for patients with moderate to severe ulcerative colitis (UC) and acute severe UC. Upadacitinib is currently approved for both refractory UC and Crohn’s disease (CD); however, emerging data suggest its beneficial role in acute severe UC. Limited evidence exists for the combination of small molecules and other biologicals in patients with difficult-to-treat IBD and peri-anal CD. Close monitoring of side effects is advocated in such patients. More data is warranted on their role in extraintestinal manifestations, pediatric and pregnant patients with IBD.

INTRODUCTION

Ulcerative colitis (UC) and Crohn’s disease (CD) are characterized by intestinal ulceration secondary to the altered innate and adaptive immune system, and gut dysbiosis in the background of genetic susceptibility[1-3]. It often follows a chronic relapsing-remitting course[4,5]. Immunosuppression is the mainstay of treatment in patients with inflammatory bowel disease (IBD). Janus kinase inhibitors (JAKi) are novel, orally administered small molecules. By inhibiting Janus kinase (JAK), they attenuate various cytokine-dependent pathways in the inflammatory cascades[6-9]. JAKi has been widely used in connective tissue disorders and autoimmune diseases. More data pertaining to JAKi comes from rheumatological diseases[10]. Intravenous or subcutaneous biologicals like tissue necrosis factor inhibitors [anti-tumor necrosis factor α (anti-TNF-α)] require therapeutic dose monitoring[11]. In long-term use, reactivation of tuberculosis (TB) in endemic regions and secondary loss of response are the main concerns associated with infliximab (IFX) and adalimumab[12,13]. On the other hand, intestinal surgeries in IBD are associated with morbidity, mortality and often a poor quality of life[14,15]; hence, small molecules like JAKi efficiently bridge the gap in managing IBD[8,16].

Recently, various landmark trials have been instrumental in demonstrating the excellent safety and efficacy profile of JAKi against UC and CD[17]. Tofacitinib, upadacitinib, and filgotinib have been found to be effective compared to placebo in moderate to severe UC, whereas tofacitinib has also been used for acute severe UC (ASUC) with encouraging results[17,18]. Upadacitinib was recently approved for use in patients with CD[19]. Despite having an excellent efficacy, they are not devoid of adverse events (AEs)[18,20,21]. Physicians and gastroenterologists must be aware of the long-term safety, efficacy and monitoring protocol while using JAKi in patients with IBD[20]. This comprehensive overview will focus on the current evidence-based role of JAKi in patients with IBD and provide a practical guide for treating physicians.

MECHANISM OF ACTION

Tofacitinib was introduced in 2019. It was the 1^st approved JAKi for IBD[22,23]. JAKs are the non-receptor tyrosine kinases. They are linked to the cytoplasmic part of type I and type II cytokine receptors. There are four cytokine isoforms, i.e., JAK-1, JAK-2, JAK-3, and TYK[22-25]. The isoforms are linked to the transcription of different cytokines, hormones, interleukins (ILs), and growth factors. Phosphorylation of JAK leads to activation of the signal transducer and activator of transcription (STAT) pathway[24,25] (Figure 1). In the context of IBD, the JAK-STAT pathway is important as it is responsible for cytokine and IL production, as well as the recruitment of inflammatory cells into the intestinal lumen. Recruitment of inflammatory cells leads to damage to intestinal cells and produces ulceration[25].

Figure 1 Mechanism of action of various Janus kinase inhibitors and their downstream effects. IL: Interleukin; IFN: Interferon; JAK: Janus kinase; TYK2: Tyrosine kinase 2; STAT: Signal transducer and activator of transcription.

Tofacitinib preferentially inhibits JAK-1 and JAK-2, whereas upadacitinib and filgotinib selectively inhibit JAK-1 (Table 1). Peficitinib inhibits all four isomers of JAK. Newer JAKi TD-1473 acts on intestinally restricted JAK-1, JAK-2 and JAK-3[26,27]. JAK-STAT pathways are also involved in erythropoietin and other growth factors production. Use of JAKi is associated with the theoretical risks of developing anaemia and cytopenia[24-28].

Table 1 Indications and pharmacological properties of approved Janus kinase inhibitors for the management of inflammatory bowel disease.

Parameter	Tofacitinib	Upadacitinib	Filgotinib
JAK selectivity	JAK1 > JAK3 > JAK2	JAK1 > JAK2 > JAK3 > TYK2	JAK1 > JAK2 > JAK3
Approved indication	Moderate to severe UC	Moderate to severe UC and CD	Moderate to severe UC (EMA-approved only)
Induction dosing	10 mg BID for 8 weeks	45 mg OD for 8-12 weeks	200 mg OD
Maintenance dosing	5 mg BID (or 10 mg if needed short-term)	15 mg or 30 mg OD based on response	200 mg OD
Efficacy (induction)	Clinical remission: 18%-20% (OCTAVE 1 & 2)	Clinical remission: 26%-34% (UC trials), 44% (CD-CELEST)	Clinical remission: 26.1% vs 15.3% placebo (SELECTION)
Efficacy (maintenance)	34%-41% remission at 52 weeks (OCTAVE sustain)	42%-52% remission in UC; 40%-47% in CD (CELEST-OLE)	37.2% remission at 58 weeks
Real-world data	Established role in UC, encouraging data in ASUC, however no benefit in CD	Effective in UC and CD, including tofacitinib-refractory patients	Emerging for UC, limited data in CD
Pregnancy category	Category C (not recommended)	Category D (not recommended)	Contraindicated (reproductive toxicity in animal studies)
Regulatory approval	FDA & EMA approved for UC	FDA & EMA approved for UC and CD	EMA approved; FDA rejected application

JAK: Janus kinase; TYK2: Tyrosine kinase 2; UC: Ulcerative colitis; CD: Crohn’s disease; EMA: European Medicines Agency; BID: Twice daily; OD: Once daily; FDA: Food and Drug Administration.

TOFACITINIB

Role in moderate to severe UC

The landmark studies on tofacitinib, OCTAVE and OCTAVE sustain have established its role in patients with moderate to severe UC[29-35]. In the OCTAVE Sustain trial, remission at 52 weeks was seen in 34.2% of patients receiving 5 mg tofacitinib and 41% in the 10 mg tofacitinib group. Tofacitinib was found to be more effective than placebo for managing moderate to severe UC. Around half of the patients in the OCTAVE and OCTAVE sustain group were biological-experienced. Thus, the trial established the role of tofacitinib in patients with anti-TNF-α antagonist-experienced UC (Table 2). Serious AEs were similar in both groups. However, the incidence of infection and herpes zoster (HZ) infection was higher in the tofacitinib group[34,35].

Table 2 Tofacitinib in moderate to severe ulcerative colitis: Results from trials and real-world data.

Ref.	Number of patients	Dose	Response	Adverse events
OCTAVE 1[34]	476	10 mg BID	Remission at 8 weeks: 18.2%	AEs: 60%; SAEs: 3.4%
OCTAVE 2[34]	429	10 mg BID	Remission at 8 weeks: 16.6%	AEs: 54.1%; SAEs: 4.2%
OCTAVE sustain[34,35]	397	198: 5 mg BID; 197: 10 mg BID	Remission at 52 weeks: 34.3% vs 40.6%	AEs: 72%-80%; SAEs: 5.1%-5.6%
Ollech et al[36]	30	10 mg BID	At 8 weeks clinical response and remission: 40% and 20% respectively	Not mentioned
Giri et al[37]	47	10 mg BID	After 8 weeks: 70.2% achieved clinical remission. By 24 weeks 60% patients were at remission	AEs: 21.2% (two tuberculosis, one cytomegalovirus, and one HZV)
Hoffmann et al[38]	38	10 mg BID	At 8 weeks: Steroid free remission was seen in 29% of patients	Three patients developed SAEs (pneumonia, colectomy, and colonic perforation)
Sandborn et al[23]	194	10 mg BID: 33; 15 mg BID: 49	10 mg BID: Clinical response at 8 weeks: 42% with 10 mg BID	Nasopharyngitis (six patients), post-operative abscess, anal abscess (one patients), neutropenia (three patients)

SAE: Serious adverse events; OD: Once daily; BID: Twice daily; UC: Ulcerative colitis; CD: Crohn’s disease; AEs: Adverse events; HZV: Herpes zoster virus.

Contemporary real-world data have yielded similar results. A prospective study by Ollech et al[36] included 30 patients with moderate to severe UC (Table 2). Most of them (96.7%) previously failed on biological therapy and had extensive colitis (86.6%). At eight weeks, clinical, biochemical response (faecal calprotectin < 250 μg/g stool) and endoscopic healing were seen in 40%, 47.6% and 33.3% of patients, respectively. A multi-centre retrospective study from India documented the efficacy of tofacitinib in biologics-naïve patients. The study included 47 patients, and 70.2% achieved clinical remission at eight weeks, and eight patients (17%) had a primary failure[37]. Similar results were noted in a study by Hoffmann et al[38]. A meta-analysis included 1220 patients with moderate to severe UC who previously had inadequate response, loss of response or intolerance to standard medical therapy, including steroids, azathioprine, 5-aminosalicylic acid, or biologicals. Tofacitinib use was associated with higher clinical response, clinical remission, and endoscopic response in such patients[29,39,40].

Positioning tofacitinib in the algorithm of the treatment for moderate to severe UC has been a challenge. However, recent data did not show any statistically significant differences between tofacitinib, anti-TNF and ustekinumab for outcomes in patients with biological-naïve moderate to severe UC[38-40]. A network meta-analysis suggests that for biological-naïve patients, IFX ranked the highest for induction of clinical remission (odds ratio vs placebo, 4.07; 95% confidence interval: 2.67-6.21). Patients who received anti-TNF responded equally to tofacitinib and ustekinumab[40]. They were superior to vedolizumab and adalimumab[29,40,41].

Role in ASUC

Intravenous steroid remains the cornerstone of therapy in patients with ASUC[42]. 30%-40% of patients with ASUC may not respond to steroids and require other salvage therapies[43]. Tofacitinib has been used as a salvage therapy for patients with ASUC, not responding to steroids or even biologicals[44,45]. Overall efficacy ranges from 60%-70%[46-51]. A systematic review by Jena et al[46] included 21 patients with ASUC. Tofacitinib showed efficacy of 75% as the first-line therapy, 85.7% as the second-line therapy and 67% as the third-line therapy. A randomised controlled trial (RCT) from India has assessed the efficacy of tofacitinib combined with steroids in patients with ASUC (Table 3). While continuing steroids, at day seven, a higher response was seen in patients who received tofacitinib compared to placebo (83% vs 58%; P = 0.007). The need for rescue therapy was lower in patients receiving tofacitinib and steroids. Another series has also reported the usefulness of tofacitinib in patients with ASUC. Of eight patients with ASUC[52], seven patients responded to tofacitinib. One of the eight patients developed varicella zoster (VZ) infection, and another one required colectomy (Table 3). Other reports are listed in Table 3[53]. An open-label interventional study included 24 patients with ASUC. Among them, eight patients were anti-TNF-experienced, two received vedolizumab, and two received ustekinumab. At seven days, clinical response was seen in 58.3% of patients. The mean number of days to achieve clinical response was 2.4 days. In six months, colectomy was required in 25% patients[54].

Table 3 Tofacitinib in acute severe ulcerative colitis.

Ref.	Evidence	Number of patients	Anti-TNF-experienced	Response rate
Berinstein et al[44]	Case series	4	2 patients	75%; one patient failed to respond
Berinstein et al[45]	Case control	40	100%	Lower rate of 90% colectomy compared to the control group
Uzzan et al[47]	Retrospective	55	98%	Clinical response: 40% at week 6; clinical remission: 46% at week 14; colectomy free survival 74% at 6 months
Singh et al[48]	RCT	53	Not available	Day 7 response rate of tofacitinib: 83%; need of rescue therapy lower in tofacitinib group
Honap et al[49]	Case series	7 (5 ASUC)	100%	Three patients had colectomy-free survival
Sedano et al[50]	Case report	1	100%	Complete remission
Kotwani et al[51]	Case series	4	100%	All patients had complete remission
Malakar et al[52]	Case series	8	12.5%	87.5% patients responded by the fifth day of treatment
Bercier and Niland[53]; Narula et al[54]	Case report; open label interventional trial	1, 24	100%, 33.3%	Complete remission; day-7 clinical response was seen in 58.3% with colectomy rate of 24%

ASUC: Acute severe ulcerative colitis; TNF: Tumor necrosis factor; RCT: Randomised controlled trial.

Tofacitinib in CD

Tofacitinib was the 1^st JAKi to be tried in patients with moderate to severe CD. In a large multicenter RCT in 2017, at eight weeks, the proportion of patients with clinical remission was 43.5% and 43% in the 5 mg and 10 mg twice a day groups, respectively. It was not statistically significant as compared to the placebo group (36.7%; P > 0.05)[55]. After the RCT failed to demonstrate the efficacy of tofacitinib in patients with moderate to severe CD, the major focus shifted to establishing the efficacy of upadacitinib in such patients with CD[29].

UPADACITINIB

Role of upadacitinib in moderate to severe UC

In a phase 3 RCT, upadacitinib was found to be safe and effective in patients with moderately severe UC. 319 patients in the UC1 group and 354 patients in the UC2 group received 45 mg/day upadacitinib for 8 weeks. After 8 weeks, 26% of patients in UC1 and 34% of patients in the UC2 group achieved clinical response, which was statistically significant compared to the placebo (Table 4). The patients who achieved clinical remission were randomly assigned to receive upadacitinib 15 mg/day vs 30 mg/day, vs placebo. In the maintenance study, 42% of patients in the 15 mg/day group and 52% in the 30 mg group achieved clinical remission. Most common adverse effects include nasopharyngitis and creatine phosphokinase (CPK) elevation (Table 4)[56]. In the phase 2b study, upadacitinib showed promising results for patients with moderately severe UC. At 8 weeks, clinical and endoscopic remission in 15 mg/day, 30 mg/day, and 45 mg/day were seen in 14.3% and 13.5%, 19.6% and 30.6%, 27% and 35.7% patients, respectively[57]. Similarly, real-world data established the safety and efficacy of upadacitinib in both UC and CD. In the real-world cohort, 44 patients with UC received upadacitinib, and at 8 weeks, 85.2% of patients achieved a clinical response (Table 4)[58]. The role of long-term upadacitinib was assessed in the U-ACTIVATE study. Most patients who achieved initial clinical and endoscopic remission maintained the remission at 48 weeks and 96 weeks. At 48 weeks, clinical remission was maintained in 81% of patients in the 15 mg once a day (OD) and 30 mg OD groups. At 96 weeks, endoscopic remission was maintained in 47% and 45% of patients in the 15 mg OD and 30 mg OD groups, respectively[59].

Table 4 Upadacitinib in ulcerative colitis.

Ref.	Number of patients	Clinical response at 8 weeks	Clinical remission on maintenance	Major adverse events
Danese et al[56], UC1	319	26%	UC3: 30 mg group: 52%; 15 group: 43%	Nasopharyngitis (5%) and creatine phosphokinase elevation (4%)
UC2	345	34%	UC3: 30 mg group: 52%; 15 group: 43%	Same as above
Sandborn et al[57], phase 2b	250	At 8 weeks clinical remission, 14.3%, 13.5% and 19.6% in 15 mg, 30 mg and 45 mg group	Endoscopic remission: 30.6%, 27% and 35.7% in 15 mg, 30 mg and 45 mg group	One patient herpes zoster, one pulmonary thromboembolism and deep venous thrombosis
Friedberg et al[58], Panaccione et al[59], U-ACTIVATE	44; 369 (15 mg OD: 142 patients and 30 mg OD: 227 patients)	At 4 weeks clinical response: 60% and remission: 77%; not available	At 8 weeks clinical response: 67% and clinical remission: 83%; at 48 weeks, 81% of patients maintained clinical remission in 15 mg OD and 30 mg OD groups; at 96 weeks 47% of patients in 15 mg OD group and 45% patients in 30 mg OD group had endoscopic remission	Acne (23%); treatment emergent adverse events: 15 mg OD: 238.5 events per 100 patient years; 30 mg OD: Group: 233.4 events per 100 patient-years. Most common adverse events were hepatic dysfunction, rise in the CPK and lymphopenia

UC: Ulcerative colitis; OD: Once a day; CPK: Creatine phosphokinase.

Upadacitinib in CD

The landmark CELEST trial, published in 2020, assessed the safety and efficacy of upadacitinib in patients with moderate to severe CD[60,61]. In this double-blind RCT, adults with non-response or intolerance to immunosuppressant or anti-TNF-α were randomised into a 1:1:1:1:1 group to receive either placebo or 3 mg, 6 mg, 12 mg or 24 mg of upadacitinib OD (Table 5). Patients completing 16 weeks of therapy were re-randomised for another 36 weeks of maintenance therapy. The upadacitinib group achieved higher clinical and endoscopic remission at 16 weeks compared to placebo (clinical response: 13% in 3 mg BD; 27% in 6 mg BD; 11% in 12 mg BD; 22% in 24 mg BD; 14% in 24 mg OD and 11% in placebo group; endoscopic remission: 10% in 3 mg BD; 8% in 6 mg BD; 8% in 12 mg BD; 22% in 24 mg BD and 14% in 24 mg OD and 0% in the placebo group; P ≤ 0.05) (Table 5). The remission rate was maintained at 52 weeks (Table 5). CELEST-OLE was the extension trial of CELEST. It recruited patients who responded to upadacitinib at 12 weeks. At 52 weeks, clinical remission was seen in 37.3% of patients receiving a 15 mg/day dose and 47.6% of patients receiving a 30 mg/kg dose. Endoscopic remission was seen in 40.1% and 28.6% of patients, respectively (Table 5). However, higher doses were associated with an increased number of HZ infections (4% in the 10 mg/day group vs 7.2% in the 15 mg/day group). In the U-EXCEL and U-EXCEED trials, patients with moderate to severe CD disease were randomly assigned to receive 45 mg OD upadacitinib or placebo (2:1). Patients who had a clinical response were included in the U-ENDURE maintenance trial (upadacitinib 15 mg vs 30 mg vs placebo). At 12 weeks, a significantly higher number of patients achieved clinical remission in the upadacitinib group as compared to the placebo (U-EXCEL: 49.5% vs 29.1%; U-EXCEED: 38.9% vs 21.1%). After 52 weeks (U-ENDURE), 37.3% and 47.5% patients had clinical remission in the 15 mg OD and 20 mg OD groups, respectively, as compared to the placebo (7.3%). HZ infection was common in the 15 mg and 30 mg groups[60].

Table 5 Janus kinase inhibitors in Crohn’s disease.

Drugs	Induction of remission	Induction rates	Long term outcome	Adverse events
Tofacitinib[55]	180	At 8 weeks clinical remission: 43.5% and 43% with 5 mg and 10 mg group	At 26 weeks, clinical response was maintained in 55.8% and 39.5% patients in 5 mg and 10 mg group respectively	Severe adverse events at 26 weeks 11.7% in 5 mg group and 9.8% in 10 mg group
Upadacitinib, Friedberg et al[58]	40	At 4 weeks clinical response: 60%; clinical remission: 87%	At 8 weeks clinical response 76%; clinical remission: 70.6%	Acne (23%)
Loftus et al[60], U-EXCEL, U-EXCEED and U-ENDURE	U-EXCEL: 526; U-EXCEED: 495; U-ENDURE: 502	At 12 weeks clinical response was seen in U-EXCEL: 49.5% (vs 29.1% in placebo); U-EXCEED: 38.9% (vs 21.1% in placebo)	At 52 weeks higher patients on upadacitinib had clinical remission vs placebo (15 mg OD: 37.3%; 30 mg OD: 47.6%, 7.3% in placebo)	Herpes zoster; 30 mg group: 7.2 events per 100 person year; 15 mg group: 4.0 events per 100 person year; gastrointestinal perforation: 0.6-0.9 events per 100 person-year
Upadacitinib[61]	CELEST: 220; CELEST OLE: 107	At 12 weeks CLE: Clinical remission: 44.4%; endoscopic response: 40.2%	CELEST OLE: At 52 weeks; clinical: 15 mg: 37.3%; 30 mg: 47.6%; endoscopic: 35.5% with 10 mg/day; 40.1%; remission: 15 mg/day: 19.1%; 30 mg/day: 28.6%	Herpes zoster: 4% in 10 mg group; and 7.2% in 15 mg group

OD: Once daily.

Previously, tofacitinib was used to treat CD. But it did not meet primary and secondary endpoints and failed to prove its clinical efficacy against CD. The earlier-mentioned study by Friedberg et al[58] has shown excellent results with upadacitinib in CD. In that study, 40 patients with moderate to severe CD received upadacitinib, and 76% of patients achieved clinical remission after 8 weeks (Table 5).

Comparison of upadacitinib and tofacitinib in UC

After tofacitinib failed to show clinical efficacy in patients with moderate to severe CD, upadacitinib holds the position as a suitable JAKi in patients with CD. However, against UC, upadacitinib and tofacitinib both have excellent safety and efficacy. The role of tofacitinib or upadacitinib in patients with prior JAK2i exposure is evolving. A comparative real-world data has demonstrated the superior efficacy of upadacitinib in patients with tofacitinib-refractory UC. In that study, 81 patients received upadacitinib, and among them, 30% of patients had previously experienced tofacitinib. After inverse probability of treatment-weighted logistic regression, patients who received upadacitinib were shown to have a higher steroid-free clinical remission[62].

Indirect comparison of both drugs was done from the data of major placebo-controlled trials, which include U-ACHIEVE, U-ACCOMPLISH, GEMINI-1, UNIFI, and OCTAVE. After matching baseline characteristics, upadacitinib was found to be better than tofacitinib or vedolizumab for patients with active UC[60]. Recent meta-analysis has established the superiority of upadacitinib in achieving clinical, endoscopic and histological remission[63,64].

FILGOTINIB

Filgotinib is approved by the European Medicines Agency (EMA) for adult patients with moderate to severe UC who failed to respond to biologicals[27,28,30,65,66]. It is an oral once-daily pill with a half-life of 6 hours. Filgotinib has a long duration of action as its metabolite has a half-life of 27 hours. The safety and efficacy of filgotinib were evaluated in the SELECTION trial[65]. Patients received 100 mg OD, 200 mg OD, or placebo. Patients who received a 200 mg/day dose only performed better compared to placebo (Table 6). At 58 weeks filgotinib group achieved better outcomes than the placebo with a comparable rate of AEs (Table 6). In moderate to severe CD, filgotinib has been used with acceptable safety and efficacy (Table 6). In the FITZROY trial, 47% of patients demonstrated clinical remission after 10 weeks[66].

Table 6 Trials of filgotinib in patients with ulcerative colitis and Crohn’s disease.

Ref.	Number of patients	Response at 10 weeks	Long term results	Adverse events
SELECTION, Feagan et al[65]	UC; 100 mg/day: 277; 200 mg/day: 245; placebo: 137	At 10 weeks; clinical remission was seen in 26.1% of patients compared to 15.3% in placebo	At 58 weeks; 37.2% patients in 200 mg/day group had clinical remission compared to 11.2%	HZ 2 patients in 100 mg group and 4 patients in 200 mg group
FITZROY, Vermeire et al[66]	CD; 130 in 200 mg/day; 44 in placebo	At 10 weeks 47% in filgotinib group achieved clinical remission	At week 20, 50%-71% maintained clinical remission	Serious infection in 3% of patients in filgotinib group

UC: Ulcerative colitis; CD: Crohn’s disease; HZ: Herpes zoster.

Other newer JAKi

Other newer JAKi include peficitinib, izencitinib, ivarmacitinib, brepocitinib, OST-122, ritlecitinib and deucravacitinib[67-72]. Their mechanism of action and major role in IBD are described in Table 7[73,74].

Table 7 Newer Janus kinase inhibitors.

JAK inhibitors	Targets	Target IBD subgroup
Peficitinib[71]	JAK-1/JAK-2	UC
Ivarmacitinib[72]	Selective JAK-1	UC and CD
Brepocitinib[73]	TYK-2	Erythropoietin modulation
Izencitinib (TD-1473)[75]	Pan-JAK (more TYK-2)	CD and UC
Deucravacitinib[73]	TYK-2	CD and UC

JAK: Janus kinase; UC: Ulcerative colitis; CD: Crohn’s disease; TYK: Tyrosine kinase; IBD: Inflammatory bowel disease.

CURRENT RECOMMENDATION

Tofacitinib is currently recommended for managing patients with moderate to severe UC not responding to steroids, azathioprine, or biologicals. The American Gastroenterological Association recommends the use of upadacitinib and tofacitinib in moderate to severe UC[75]. Induction dose is 10 mg twice daily (BID) for at least 8 weeks, followed by a maintenance dose of 5 mg BID. Patients who fail to respond to the initial induction treatment, a 10 mg BID dose, can be extended for an additional eight weeks[29]. Therapeutic failure is considered if patients do not respond to a 10 mg BID dose after 16 weeks of therapy. A higher dose for the long-term period is associated with a higher incidence of AEs[29,76-82]. Upadicitinib is the only JAK-2i recommended in patients with moderate to severe CD. Based on the results of the previous RCT, 45 mg once daily for 12 weeks is used for the induction of remission. Responders received 15 mg OD or a 30 mg dose subsequently for the next 52 weeks[29,61-63]. Filgotinib is approved by the EMA for use in moderate to severe UC, but not by the Food and Drug Administration[29]. Generic JAKis are cheap and readily available in countries like India (tofacitinib)[77].

EVOLVING ROLE OF JAKI AND THEIR OFF-LABEL USE

Upadacitinib in ASUC

Upadacitinib has been used in moderate to severe UC that is not responding to anti-TNF therapy. Recently, upadacitinib has been tried off-label in patients with ASUC. Upadacitinib in ASUC is associated with rapid and sustained improvement with an excellent long-term colectomy-free survival[78,79]. 90-day colectomy rate was 16.3%. A systematic review has shown that among patients who did not undergo colectomy, steroid-free remission was observed in 80% of patients[80]. Prospective data and RCTs are warranted to explore the prospects for upadacitinib in ASUC.

JAKi in pediatric IBD

Approved therapies for pediatric IBD are limited[81]. Anti-TNF and vedolizumab are reserved for refractory IBD in the pediatric population[81]. There have been a few reported cases and series documenting the safety of JAKi in pediatric patients with IBD. Miller et al[82] reported a case of refractory UC who were salvaged with upadacitinib. Based on current data, JAKi are not recommended in pediatric refractory IBD[82,83].

JAKi in IBD with extraintestinal manifestations

The reported prevalence of extraintestinal manifestations (EIM) ranges from 6%-47% in patients with IBD[84,85]. The prevalence and frequency of EIMs increase with longer disease duration, and they are more common in patients with CD[85]. Currently, anti-TNF therapy is the cornerstone in managing such patients; however, JAKi and anti-IL 12/23 are emerging as disease-modifying agents in patients with EIM[79-81]. Upregulation of JAK-STAT pathways is mostly found in various EIMs. Tofacitinib is approved for use in patients with rheumatoid arthritis and psoriatic arthritis[86-91]. Response rate ranges from 42% to 70%. A post-hoc analysis of the OCTAVE sustain study has demonstrated that tofacitinib can improve UC-related peripheral arthritis[92]. A report has demonstrated the efficacy of tofacitinib in patients with pyoderma gangrenosum associated with IBD[93]. Filgotinib has also been used in RA, PsA, and ankylosing spondylitis with a response rate of 64%-80%, 80% and 75%, respectively[94-97]. Among JAKis, only tofacitinib has shown promising results in various EIMs. After a multidisciplinary discussion (dermatologist and immunologist), they can be used in patients with IBD and EIM[98].

Combination therapy in refractory IBD

Combination therapies target different pathways of the inflammatory cascade in patients with IBD. Various combinations, including anti-TNF, vedolizumab, ustekinumab, and anti-IL-23, have been tried[99]. JAKi has been used in combination with vedolizumab and ustekinumab in patients with IBD. In a report by Llano et al[100], nine patients with refractory IBD received tofacitinib and vedolizumab. Others received ustekinumab and adalimumab with vedolizumab. Steroid-free remission was achieved in 67% of patients; however, four patients developed infectious complications[101]. Miyatani et al[101] reported a case series of six patients with refractory CD. After the upadacitinib and ustekinumab combination, five of them responded. Tofacitinib co-therapy has been successfully used with IFX[102,103]. Because of profound immunosuppression, infectious complications are the main concern in these patients and require regular monitoring[103].

AES

AEs associated with JAKi include overwhelming immunosuppression leading to infectious complications, cytopenia, elevated liver enzymes, vascular thrombosis, and dyslipidemia (Table 8)[104-106]. VZ infection is a well-known infectious complication associated with tofacitinib and upadacitinib. Headache (7.8%), nasopharyngitis (7.4%), arthritis (2.9%), and worsening colitis (2.3%) were the most reported AEs in the OCTAVE trial[34,35]. HZ virus and cytomegalovirus (CMV) infections were reported in 0.25%-0.6% of patients. In the OCTAVE sustain trial, HZ virus infection was reported in 1.5% and 5.1% of patients receiving 5 mg BD and 10 mg BD tofacitinib, respectively (Table 8)[34,35,107-109]. Other AEs include non-melanoma skin cancer, basal cell carcinoma, a rise in muscle enzymes, lymphopenia, dyslipidemia, and lymphoma[100-102]. In the OCTAVE sustain trial, after 52 weeks of treatment with tofacitinib, total cholesterol and triglycerides were elevated in 22% and 7% of patients, respectively (Table 8). A rise in CPK was seen in 27% of such patients. On long-term follow-up, around 10% of patients discontinued drugs for intolerable side effects, though serious AEs were present in only 5.1%-5.6% of patients[34-36,106]. In the TROPIC consortium, one of 76 patients developed venous thromboembolism[110].

Table 8 Frequency and management of major side effects for tofacitinib and upadicitinib.

Adverse events	Frequency	Caution	Action
Bacterial infections[34,35,109]	Serious infection: 2.81 per 100 person-years; serious infection: 0.5%-1%; any infection: 36%-40%	Pneumonia, urinary tract infection and sepsis are most common	Proper screening and antibiotics
Varicella zoster reactivation[35,36,109]	OCTAVE sustain: 1.5%-5.1%; overall with JAKi: 2.67 per 100 person-year	More common in Asian population, old age, past IFX-failure, steroid experienced and 10 mg BID dose	Vaccination with Shingrix or GlaxoSmithKline 3-4 weeks prior to the treatment
Reactivation or infection with tuberculosis[37,112,113]	Tofacitinib: TB: Crude IR 0.21, 95%CI: 0.14-0.30 was the most common OI (n = 26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks); 2/47	Test for latent tuberculosis by IGRA, Mantoux and chest imaging	Treat for LTBI infection
Venous thrombosis[56,114]	Tofacitinib: DVT: 0.04 events/100 PYs of exposure (95%CI: 0.00-0.23); PTE: 0.16 PY (95%CI: 0.04-0.41); one DVT and one PTE of 250 patients with UC receiving tofacitinib	History of malignancy, old age and prior history of DVT are the risk factors	Avoid or use with caution in patients with history of malignancy, history of DVT or old aged patients
Dyslipidemia[34,35]	Tofacitinib: 28%-30%	Not associated with major cardiovascular events	Baseline lipids then 4-8 weeks after therapy. And 6 monthly afterwards
Acne[57,111]	Upadacitinib: 15.9%; tofacitinib: 4.3%; filgotinib: 1.9%	History of acne vulgaris is a risk factor for JAKi-associated acne	40% of patients with JAKi-associated acne can be managed with pharmacotherapy and 0.8% patients may require dose reduction
Bone marrow suppression[34,35,118]	2/633 patients	JAK-STAT pathway involved in erythropoietin production, so JAKi may cause anemia	Blood count in baseline then 4-8 weeks after therapy. And 3 monthly afterwards; < 8 g/dL or drop > 2 g/dL: Stop until hemoglobin improves; ANC: < 500: Stop tofacitinib
Major adverse cardiovascular events[119]	Tofacitinib: Increased risk of MACE compared to placebo (OR = 5, 95%CI: 1.7-10)	Risk factors for MACE: Age > 49 years, with hypertension, and the total cholesterol to HDL cholesterol ratio	Use of statin in after proper cardiac risk evaluation using ASCVD risk calculator
Malignancy[116,118,120]	Over risk of malignancy: 4.2% most commonly: NMSC: IR of NMSC was 0.51 per 100 PYE; Others: Lung (22%) > breast (17.7%) > lymphoma (9.3%)	Past NMSC, anti-TNF failure and azathioprine use and age are the risk factors	Avoid in patients with history of NMSC
Hepatotoxicity[118]	3/633 patients	May cause an asymptomatic rise in liver enzymes or worsen pre-existing liver disease	CTP A: No dose reduction; CTP B: 5 mg BID; CTP C: Contraindicated; blood count at baseline, then 4-8 weeks after therapy, and 3 monthly afterwards

IFX: Infliximab; BID: Twice daily; TB: Tuberculosis; VZ: Varicella zoster; MACE: Major adverse cardiovascular events; LTBI: Latent tuberculosis infection; NMSC: Non-melanoma skin cancer; CTP: Child-Turcotte-Pugh score; JAK: Janus kinase; DVT: Deep venous thrombosis; PTE: Pulmonary thromboembolism; ASCVD: Atherosclerotic cardiovascular disease; ANC: Absolute neutrophil count; UC: Ulcerative colitis; IGRA: Interferon gamma release assay; OR: Odds ratio; CI: Confidence interval.

JAKi-associated acne is a well-known cosmetic side effect in patients with IBD. In a multi-centre retrospective study including 2183 JAKi-treated patients, the crude prevalence rate of acne was 15.9% in the upadacitinib group, 4.3% in the tofacitinib group and 1.9% in the filgotinib group. 40% patients with JAKi-associated acne were managed with pharmacological therapy, whereas only 18 patients required a dose reduction of JAKi[111].

Data on the long-term complication rate with upadacitinib originated mostly from the clinical and real-world studies in rheumatological diseases (Table 8). Median duration of onset of all AEs with upadacitinib is 93 days[112-114]. Risk factors of HZ virus infection include old age (> 50 years) and prior infection. 95% of those infections are non-fatal and self-limiting after cessation of the drugs (Figure 2). A recent systematic review and meta-analysis have demonstrated the overall safety profile of upadacitinib; however, it was associated with an increased risk of hepatic disorder, neutropenia, acne, HZ infection, and increased CPK level. Upadacitinib use was not associated with renal dysfunction, non-melanoma skin cancer, cardiac events or thromboembolic complications[115-120].

Figure 2 Checklist before initiation and monitoring after initiation of Janus kinase inhibitors in inflammatory bowel disease. JAK: Janus kinase; IBD: Inflammatory bowel disease; IGRA: Interferon gamma release assay; HRCT: High-resolution computed tomography; HBsAg: Hepatitis B surface antigen; anti-HBc: Hepatitis B core antibody; anti-HBs: Hepatitis B surface antibody; CBC: Complete blood count; LFT: Liver function test.

Pregnancy and breastfeeding

Pre-clinical animal studies suggest that tofacitinib crosses the placental barrier and can be associated with fetal malformations. Most data on the feto-maternal outcome following tofacitinib exposure originates from patients with rheumatological diseases[121-123]. 47 pregnancies from a rheumatological cohort who were exposed to tofacitinib were assessed for feto-maternal complications. Seven patients had spontaneous abortions, and one case of pulmonary valve stenosis was reported. Eight of them underwent medical termination of pregnancy. Spontaneous abortion has been reported from a UC cohort who were exposed to tofacitinib[121-123]. Most data comes from retrospective studies. Currently, the use of tofacitinib is not recommended in pregnancy and breastfeeding[29]. Upadacitinib is not currently recommended in lactating mothers with IBD; however, recent data from lactating mothers receiving upadacitinib have shown that the median upadacitinib milk concentration was below the theoretical cut-off for acceptable excretion in breastmilk[124]. Large prospective data is warranted to establish its safety and efficacy during pregnancy and lactation.

LIMITATIONS AND PROSPECTS

JAKi are relatively newer molecules for managing IBD. The majority of data on the long-term safety and efficacy have emerged from patients with rheumatological diseases like RA and psoriatic arthritis. Unlike 5-aminosalicylic acid, their impact on colorectal carcinogenesis in patients with IBD is unknown[125,126]. Non-melanoma skin cancers have been associated with the use of JAKi; long-term data on patients with IBD would solve the concerns. Acute infectious complications are avoidable if proper screening of latent infection is carried out or risk factors are identified and managed properly before the initiation of JAKi. VZ reactivation is a common AE reported in landmark trials as well as contemporary real-world data (Table 8)[34,35]. CMV belongs to the same family (herpesvirus). So, there is a theoretical risk of reactivation of CMV in patients with UC with JAKi[127,128]. However, data is scarce regarding the issue. There have been cases of reactivation of TB with the use of tofacitinib[37]. With its widespread use in the Asian sub-continent, the risk of reactivation of latent TB will be a major concern[37]. The data on its teratogenicity and safety in breastfeeding are yet to be established[122-124]. Many phase II and clinical trials are ongoing to assess the newer JAKi, including peficitinib, izencitinib, ivarmacitinib, brepocitinib, OST-122, ritlecitinib and deucravacitinib[105]. There is a lack of large data on the safety and efficacy of JAKi in pediatric patients and patients with EIM[76,77]. JAKis are being used with other therapies like IFX, vedolizumab and ustekinumab, though comparative data are lacking[99-101]. Large multicentre prospective data is warranted to assess the safety of combination therapy in IBD.

Despite the risk of infectious and other non-infectious AEs, JAKi are an excellent choice for patients with IBD (Table 8). After properly screening patients for the risk of infections, JAKi can be started safely[129]. Patients on JAKi should be closely monitored for cytopenia, HZ rash, elevated liver enzymes and other infectious complications (Figure 2, Table 8). Well-designed RCTs are warranted to establish the role of tofacitinib in steroid-refractory ASUC. Prospective real-world data with a long follow-up on JAKi in patients with IBD can answer the concerns regarding its long-term safety, efficacy, and implications of colonic carcinogenesis.

CONCLUSION

Tofacitinib and upadacitinib are safe and effective in managing biologics-experienced patients with IBD. Emerging data suggest that tofacitinib can be used as a salvage therapy in steroid-refractory or steroid-dependent UC and ASUC. Tofacitinib is ineffective in patients with CD. Whereas, conversely, upadacitinib has been used in patients with tofacitinib-experienced UC. Combining JAKi with other immunosuppressive therapies should be avoided, as it may lead to profound immunosuppression. Bacterial, viral, and mycobacterial infections and reactivation remain the major concerns while using JAKi. Proper screening and vaccinations can prevent such complications. Patients should be monitored carefully for other side effects. With expanding data on their efficacy and safety, JAKi are poised to transform the therapeutic landscape of IBD. Future research should continue to explore gut-selective agents to maximise benefit and minimise systemic risks.