Updated review of Janus kinase inhibitors for the management of 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.