JAK Inhibitors

Janus kinase (JAK) inhibitors are oral small molecules that block intracellular signalling for many cytokines. Tofacitinib, baricitinib, upadacitinib, filgotinib, abrocitinib and ruxolitinib treat rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis, alopecia areata and myelofibrosis.

They act quickly, but carry warnings for infection, thrombosis, cardiovascular events and cancer.

Mechanism. JAK1, JAK2, JAK3 and TYK2 transmit signals from cytokine receptors to STAT transcription factors. Different agents inhibit different JAKs: tofacitinib JAK1 and JAK3; baricitinib JAK1 and JAK2; upadacitinib and filgotinib JAK1; ruxolitinib JAK1 and JAK2.

Pharmacokinetics. Oral, rapidly absorbed, half-lives 3 to 12 hours; metabolism through CYP3A4 (tofacitinib, upadacitinib) or renal clearance (baricitinib).

Topical form. Ruxolitinib cream 1.5% for atopic dermatitis and vitiligo.

Response. Pain and function improve within 1 to 2 weeks; review at 12 weeks.

• First-line. Not usual first-line; used after csDMARD or biologic failure in rheumatoid arthritis, ulcerative colitis and psoriatic arthritis.
• Alternative. Patients who cannot use or prefer not to inject biologics; atopic dermatitis and alopecia areata when other treatments fail.
• Specialist. Myelofibrosis, polycythaemia vera, graft-versus-host disease, juvenile arthritis, interferonopathies.
• Emergency. None.

Selection. Use the lowest dose in patients over 65, current or past smokers, those with cardiovascular risk factors, previous venous thrombosis or malignancy; in those groups choose a different drug class first.

Contraindications. Active serious infection including tuberculosis; active hepatitis B or C; severe hepatic impairment; pregnancy and breastfeeding; neutrophils under 1 x 10^9/L; lymphocytes under 0.5 x 10^9/L; haemoglobin under 80 g/L; history of venous thromboembolism (relative).

Serious adverse effects.

• Serious infection including herpes zoster (common), tuberculosis and opportunistic infection.
• Venous thromboembolism, major adverse cardiovascular events and malignancy (higher with tofacitinib 10 mg twice daily; class warning for over 50 years with risk factors).
• Raised lipids and creatine kinase; cytopenias; raised transaminases.
• Gastrointestinal perforation; acne.

Major interactions. Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) and inducers (rifampicin); immunosuppressants; live vaccines; probenecid raises baricitinib levels.

Common prescribing errors.

• Starting in older smokers with cardiovascular disease.
• Missing baseline lipids and counts.
• No zoster vaccination before treatment.
• Combining with biologics or high-dose immunosuppression.
• Not adjusting dose for renal impairment or CYP3A4 inhibitors.

Special groups.

• Pregnancy: contraindicated; stop at least 1 week to 4 weeks before conception (depends on agent).
• Breastfeeding: avoid.
• Children: baricitinib and tofacitinib licensed for juvenile arthritis in some regions.
• Older adults: lower dose; higher risk.
• Kidney: reduce or avoid by agent.
• Liver: avoid in severe impairment.
• East Africa: tuberculosis, hepatitis B, HIV and strongyloidiasis screening; oral dosing suits settings without injection supply, but cost and cardiovascular risk profile need assessment; check rifampicin use with tuberculosis therapy.

Monitoring. Full blood count, liver tests and lipids at baseline, 4 to 8 weeks, then every 3 months; blood pressure; infection symptoms; skin examination; thrombosis symptoms.

Referral and escalation. Suspected deep vein thrombosis, pulmonary embolism, myocardial infarction or stroke; serious infection; abnormal counts; planned pregnancy.

Comparison with alternative classes. JAK inhibitors are oral, fast and effective, matching or beating TNF inhibitors in some studies, but have greater thrombosis, cardiovascular and zoster risk. TNF inhibitors are generally preferred first in patients at risk.