What are the treatment guidelines and recommendations for using Janus Kinase (JAK) inhibitors, such as tofacitinib (Xeljanz), baricitinib (Olumiant), and ruxolitinib (Jakafi), in adult patients with chronic inflammatory conditions like rheumatoid arthritis or myelofibrosis?

JAK Inhibitors: Key Clinical Facts

Available Agents and Approved Indications

JAK inhibitors are oral targeted synthetic DMARDs approved for multiple immune-mediated inflammatory diseases, with specific agents having distinct selectivity profiles and approved indications. 1

Currently Available JAK Inhibitors:

• Tofacitinib (Xeljanz): Approved for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), ulcerative colitis (UC), and polyarticular juvenile idiopathic arthritis 2

  • Dosing: 5 mg twice daily or 11 mg extended-release once daily for RA/PsA/AS 1, 2
  • Metabolism: CYP3A4; 30% renal excretion 1

• Baricitinib (Olumiant): Approved for RA and moderate-to-severe atopic dermatitis 1, 3

  • Dosing: 2 or 4 mg daily 1
  • Metabolism: >66% renal excretion 1

• Upadacitinib: Approved for RA and moderate-to-severe atopic dermatitis 1, 3

  • Dosing: 15 mg daily for RA; 15-30 mg daily for atopic dermatitis 1, 3
  • Metabolism: CYP3A4; 20% renal excretion 1

• Ruxolitinib (Jakafi): Approved for polycythemia vera and myelofibrosis 1

  • Dosing: 5-25 mg twice daily 1
  • Metabolism: CYP3A4, CYP2C9 1

• Filgotinib: Approved for RA in some regions 1

  • Dosing: 100 or 200 mg daily 1

Critical Safety Warnings and Boxed Warnings

All JAK inhibitors carry FDA boxed warnings for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE), and thrombosis based on data from the tofacitinib ORAL Surveillance trial in RA patients ≥50 years with cardiovascular risk factors. 2

Mortality Risk:

• Higher all-cause mortality, including sudden cardiovascular death, observed with tofacitinib compared to TNF blockers in RA patients ≥50 years with cardiovascular risk factors 2

Cardiovascular Events:

• Increased rate of MACE (cardiovascular death, myocardial infarction, stroke) with tofacitinib versus TNF blockers in high-risk RA patients 2
• Current or past smokers have additional increased risk 2
• Discontinue JAK inhibitors in patients who experience myocardial infarction or stroke 2

Thrombotic Events:

• Increased incidence of venous thromboembolism (VTE), pulmonary embolism, and arterial thrombosis with JAK inhibitors versus TNF blockers 2
• Risk particularly elevated in patients ≥50 years with cardiovascular risk factors 1
• Avoid JAK inhibitors in patients at risk for thrombosis; discontinue promptly if thrombotic symptoms develop 2
• Risk factors include: previous VTE, high BMI, hormone replacement therapy, advanced age 4

Malignancy:

• Higher rates of lymphomas and lung cancers observed with tofacitinib versus TNF blockers in RA patients 2
• Current or past smokers at additional increased risk 2
• Most clinical trials excluded patients with malignancy within 5 years prior to enrollment 1
• Using JAK inhibitors in patients with prior malignancy requires shared decision-making considering timing and type of malignancy 1

Infection Risk:

• Serious infection rates comparable to adalimumab at approved doses, but higher rates at higher doses 1
• Tofacitinib in RA patients >65 years with cardiovascular risk factors showed higher serious infection rates versus TNF inhibitors; EMA recommends use only if no alternative exists 1
• Herpes zoster infections occur more frequently with JAK inhibitors than TNF inhibitors 3, 5, 4
• Interrupt JAK inhibitor therapy if serious infection occurs until controlled 2

Absolute Contraindications

Do not use JAK inhibitors in the following situations: 1

1. Severe active infections (acute or chronic), including latent TB and opportunistic infections 1
2. Current malignancies 1
3. Severe hepatic disease (Child-Pugh C) 1
4. Severe renal disease (CrCl <30 mL/min) - baricitinib not recommended; tofacitinib requires dose reduction to 5 mg once daily 1
5. Pregnancy and lactation - contraception advised for both female and male patients 1
6. Recurrent VTE (unless anticoagulated) 1

Pre-Treatment Screening Requirements

Before initiating JAK inhibitor therapy, complete the following mandatory screening: 1, 3

1. Patient history and physical examination 1
2. Laboratory testing:
   • Complete blood count with differential 1, 3
   • Liver transaminases 1, 3
   • Renal function tests 1, 3
   • Lipid panel (baseline or within 12 months) 1
3. Infectious disease screening:
   • Hepatitis B (HBsAg, HBsAb, HBcAb, ±HBV DNA) 1, 3
   • Hepatitis C (HCV antibody, with HCV RNA if positive) 1, 3
   • HIV testing in high-risk populations 1, 3
   • TB screening per national guidelines 1, 3
4. Vaccination status assessment and updates 1, 3
   • Recombinant zoster vaccine (Shingrix) should be completed 3-4 weeks before JAK inhibitor initiation in adults ≥50 years or immunocompromised adults ≥19 years 3
5. Assess VTE risk factors, especially past history of VTE 1

Do not initiate JAK inhibitors if: 2

• Absolute lymphocyte count <500 cells/mm³
• Absolute neutrophil count <1000 cells/mm³
• Hemoglobin <9 g/dL

Monitoring During Treatment

Perform the following monitoring during JAK inhibitor therapy: 1

Laboratory Monitoring:

• Complete blood count with differential and liver transaminases at 1 and 3 months, then every 3 months 1
• Lipid levels at 3 months after initiation 1
• CPK testing not routinely recommended 1

Clinical Monitoring:

• Monitor for infections, particularly herpes zoster 3
• Monitor for thrombotic events, especially in patients with cardiovascular risk factors 3
• Annual skin examination for detection of skin cancer 1
• Evaluate disease activity using validated measures; note that CRP and ESR may be reduced independently of disease activity and possibly even during infections 1

Dose Adjustments for Organ Dysfunction

Renal Impairment:

• Tofacitinib: CrCl <30 mL/min: reduce to 5 mg once daily; CrCl 30-60 mL/min: use with caution 1
• Baricitinib: CrCl <30 mL/min: not recommended; CrCl 30-60 mL/min: use 2 mg daily 1, 3
• Other JAK inhibitors: No current dose reduction recommendations 1

Hepatic Impairment:

• Child-Pugh C (severe): Do not use JAK inhibitors 1
• Moderate hepatic impairment: Consider dose reduction 1

Drug Interactions

Important drug interactions requiring dose adjustments: 1

• Rifampicin (for TB): Increases hepatic metabolism of tofacitinib and upadacitinib; consider dose increase 1
• Ketoconazole: Inhibits tofacitinib and upadacitinib metabolism; dose reduction suggested 1
• Probenecid: Interacts with baricitinib; reduce baricitinib to 2 mg daily with normal renal function 1

Positioning in Treatment Algorithms

JAK inhibitors are indicated for patients with immune-mediated inflammatory diseases who have failed prior conventional and/or biological therapies. 1

Rheumatoid Arthritis:

• Use after inadequate response or intolerance to one or more TNF blockers 2
• Can be used as monotherapy when methotrexate is contraindicated or not tolerated 4
• In RA, consider adding JAK inhibitor to continued csDMARDs if patient tolerates the csDMARD 1
• Do not combine with biologic DMARDs or potent immunosuppressants (azathioprine, cyclosporine) 2

Atopic Dermatitis:

• JAK inhibitors should be considered first-line for moderate-to-severe atopic dermatitis in patients without cardiovascular risk factors, age <50 years, no malignancy history, and no active infections 3
• Upadacitinib and abrocitinib demonstrate superior efficacy to dupilumab 3

Psoriatic Arthritis with Enthesitis:

• JAK inhibitors recommended after inadequate response to NSAIDs, local glucocorticoid injections, and at least one bDMARD 5

Special Populations

Elderly Patients (>65-70 years):

• Consider dose adjustments in patients >70 years 1
• Tofacitinib in patients >65 years with cardiovascular risk factors: use only if no alternative available per EMA 1

Pregnancy and Lactation:

• Contraception advised for both female and male patients 1
• Tofacitinib teratogenic in animal studies 1
• Recommend 4-week gap after last dose if pregnancy contemplated 1
• Tofacitinib contraindicated during breastfeeding 1
• Filgotinib reduces spermatogenesis in animals (human data pending) 1

Comparative Efficacy

Currently, there is no direct evidence of superiority regarding efficacy or safety of one JAK inhibitor over another. 1

• Tofacitinib demonstrates efficacy superior to placebo and comparable to methotrexate, with non-inferiority to adalimumab when combined with methotrexate 4, 6
• All three JAK inhibitors (tofacitinib, baricitinib, upadacitinib) share similar safety concerns despite different selectivity profiles 4

Dose Reduction in Remission

Consider dose reduction of JAK inhibitor in RA patients in sustained remission (CDAI or Boolean remission) on background csDMARDs. 1