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

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.

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.

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.

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.

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.

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.

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.

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.