What are the indications and dosing guidelines for Janus kinase (JAK) inhibitors, such as Xeljanz (tofacitinib) and Olumiant (baricitinib), in the treatment of conditions like rheumatoid arthritis and psoriatic arthritis?

JAK Inhibitors: Indications and Dosing Guidelines

JAK inhibitors are indicated for patients with immune-mediated inflammatory diseases (IMIDs) who have failed prior conventional and/or biological therapies, primarily for rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ulcerative colitis (UC). 1

Approved Indications

• Rheumatoid Arthritis: All approved JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) are indicated for moderate to severe RA after failure of conventional synthetic DMARDs (csDMARDs) 1
• Psoriatic Arthritis: Tofacitinib is approved for PsA after failure of csDMARDs 1, 2
• Ankylosing Spondylitis: Tofacitinib is approved for AS 2
• Ulcerative Colitis: Tofacitinib is approved for UC 1, 2
• Atopic Dermatitis: Upadacitinib and abrocitinib are approved for moderate-to-severe AD patients who have failed other systemic therapies 1

Dosing Guidelines

Tofacitinib

• RA and PsA: 5 mg twice daily or 11 mg extended-release once daily 1, 2
• UC: 10 mg twice daily for induction, then 5 mg twice daily for maintenance 1, 2
• Dose adjustment: Reduce to 5 mg once daily when used with potent CYP3A4 inhibitors (e.g., ketoconazole) or medications causing both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole) 1

Baricitinib

• RA: 2 or 4 mg once daily 1
• Dose adjustment: Reduce dose when used with OAT3 inhibitors like probenecid 1

Upadacitinib

• RA: 15 mg once daily 1
• AD: 15 or 30 mg once daily 1

Abrocitinib

• AD: 100 or 200 mg once daily 1

Filgotinib

• RA: 100 or 200 mg once daily 1

Peficitinib

• RA: 100 or 150 mg once daily 1

Combination Therapy

• For RA: Consider adding JAK inhibitor to continued csDMARDs (particularly methotrexate) if the patient tolerates the csDMARD, as combination therapy shows better efficacy than monotherapy 1
• Avoid combining JAK inhibitors with potent immunosuppressants such as azathioprine and cyclosporine, or with biologics used for psoriasis 1
• Consider dose reduction of the JAK inhibitor in RA patients who achieve sustained remission on background csDMARDs 1

Contraindications and Precautions

• Severe active or chronic infections, including TB and opportunistic infections 1
• Current malignancies 1
• Severe organ dysfunction, such as severe hepatic disease (Child-Pugh C) or severe renal disease 1
• Pregnancy and lactation 1
• Recurrent venous thromboembolism (VTE), unless anticoagulated 1
• Caution in patients aged >70 years, those with significantly impaired renal or hepatic function, and those with risk of drug interactions 1
• Special caution for patients aged ≥65 years, current or past long-time smokers, those with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and those with malignancy risk factors 1

Pre-treatment Screening

• Patient history and physical examination 1
• Laboratory testing: Complete blood count with differential, liver function tests, renal function tests 1
• Lipid levels: At baseline (if not measured within the last 12 months) and approximately 3 months after initiation 1
• Hepatitis B and C testing 1
• HIV testing in high-risk populations 1
• TB screening as per national guidelines 1
• Assess and update vaccination status 1
• Evaluate risk factors for VTE, especially past history of VTE 1

Monitoring and Follow-up

• For abrocitinib: Check complete blood count with differential, liver enzymes at baseline and 4 weeks after initiation or dose escalation; check lipids 4 weeks after initiation 1
• For upadacitinib: Check complete blood count with differential, liver enzymes at baseline; check lipids 12 weeks after initiation 1
• Monitor for infections, particularly herpes zoster, which occurs more frequently with JAK inhibitors compared to other therapies 1, 3
• Monitor for thrombotic events, especially in patients with risk factors 1

Special Considerations

• No direct evidence of superiority regarding efficacy or safety of one JAK inhibitor over another 1
• JAK inhibitors should be avoided during active serious infections 1
• Live vaccines should be avoided in patients on JAK inhibitors 1
• For axial disease in PsA with insufficient response to NSAIDs, JAK inhibitors can be considered along with IL-17A inhibitors, TNF inhibitors, or IL-17A/F inhibitors 1
• For inflammatory bowel disease comorbid with PsA, consider TNF monoclonal antibodies, IL-23 inhibitors, IL-12/23 inhibitors, or JAK inhibitors 1

Safety Concerns

• Serious infections: Similar rates to biologics, but higher rates in patients >65 years, particularly with higher doses 1
• Herpes zoster: Higher incidence compared to biologics 3, 4
• Venous thromboembolism: Increased risk, particularly with baricitinib 1
• Cardiovascular events: FDA warning for increased risk of major adverse cardiovascular events 2
• Laboratory abnormalities: May include changes in lipid levels, liver enzymes, and blood counts 1

JAK inhibitors represent an important oral therapeutic option for various immune-mediated inflammatory diseases, with rapid onset of action and efficacy comparable to biologics 5, 6, 7.