What are the indications and usage guidelines for Janus Kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and baricitinib (Olumiant), in treating conditions like rheumatoid arthritis and psoriatic arthritis?

JAK Inhibitors: Indications and Usage Guidelines

JAK inhibitors are indicated for patients with immune-mediated inflammatory diseases (IMIDs) who have failed prior conventional and/or biological therapies, with approved indications including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, atopic dermatitis, and polyarticular course juvenile idiopathic arthritis. 1

Approved Indications

Rheumatoid Arthritis (RA)

• First-line JAK inhibitors after failure of conventional synthetic DMARDs (csDMARDs) like methotrexate
• Should be considered in patients with peripheral arthritis and inadequate response to at least one bDMARD 1
• Preferably used in combination with methotrexate for better efficacy 1

Psoriatic Arthritis (PsA)

• Indicated after failure of at least one csDMARD and at least one bDMARD 1
• Consider safety factors when prescribing, especially in patients aged ≥65 years, smokers, and those with cardiovascular risk factors 1

Ankylosing Spondylitis/Axial Spondyloarthritis

• Recommended for patients with clinically relevant axial disease with insufficient response to NSAIDs 1
• Can be considered alongside TNF inhibitors and IL-17 inhibitors 1

Ulcerative Colitis

• Tofacitinib is approved for moderate to severe ulcerative colitis 2
• Particularly useful when anti-TNF therapy has failed 1

Atopic Dermatitis

• Baricitinib is effective for moderate-to-severe atopic dermatitis as second-line therapy 3
• Recommended dose: 2-4 mg daily 3

Available JAK Inhibitors

1. Tofacitinib (Xeljanz)

   • Approved for RA, PsA, ankylosing spondylitis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis 2
   • Inhibits JAK1 and JAK3 primarily 4

2. Baricitinib (Olumiant)

   • Approved for RA and atopic dermatitis 1, 3
   • Inhibits JAK1 and JAK2 4

3. Upadacitinib

   • Approved for RA and PsA 4
   • More selective for JAK1 4

4. Filgotinib

   • Approved for RA 4
   • Suppresses interferon signaling 4

5. Peficitinib

   • Approved for RA in some regions 4
   • Suppresses common gamma cytokines 4

Dosing Considerations

• Use the dose recommended for the specific disease 1
• Consider dose adjustments in:
  • Patients >70 years old
  • Impaired renal or hepatic function
  • Risk of drug interactions
  • Other comorbidities 1
• Consider dose reduction in RA patients who achieve sustained remission 1

Safety Considerations

Contraindications

• Severe active or chronic infections, including TB and opportunistic infections
• Current malignancies
• Severe organ dysfunction (hepatic/renal disease)
• Pregnancy and lactation
• Recurrent venous thromboembolism (unless anticoagulated) 1

Special Precautions

• Cardiovascular risk: Caution in patients ≥65 years, current/past smokers, history of atherosclerotic cardiovascular disease 1, 5
• Thromboembolism risk: Monitor patients with risk factors for VTE 1, 5
• Malignancy risk: Consider risk factors before initiating therapy 1
• Infections: Increased risk of herpes zoster, herpes simplex, and upper respiratory infections 3
• Lipid profile changes: 43% of patients may experience worsening lipid profiles 5

Pre-treatment Screening

1. Laboratory testing:

   • Complete blood count with differential
   • Liver function tests
   • Renal function tests
   • Lipid profile (baseline and 3 months after initiation)
   • Hepatitis B and C testing
   • HIV testing in high-risk populations
   • TB screening 1, 3

2. Vaccinations:

   • Assess and update vaccination status
   • Complete shingles vaccination before starting treatment (preferably with recombinant zoster vaccine)
   • Avoid live vaccines during treatment 1, 3

Monitoring During Treatment

• Regular monitoring for infections, particularly herpes zoster
• Laboratory monitoring (optimal frequency unclear)
• Monitor lipid profiles due to potential increases in cholesterol and LDL levels 3, 5
• Watch for adverse effects including:
  • Acne/folliculitis (responds well to standard treatments)
  • Gastrointestinal symptoms (typically resolve after ~15 days)
  • Headache (usually mild and brief) 3

Treatment Algorithm for JAK Inhibitor Selection

1. For RA patients:

   • First try methotrexate or other csDMARDs
   • If inadequate response, add JAK inhibitor to continued csDMARD therapy
   • Consider JAK inhibitor monotherapy if csDMARDs not tolerated 1

2. For PsA patients:

   • First try csDMARDs
   • If inadequate response, try bDMARDs
   • Consider JAK inhibitors after failure of at least one bDMARD 1
   • For patients with concomitant IBD, consider JAK inhibitors earlier 1

3. For axial spondyloarthritis:

   • First try NSAIDs
   • If inadequate response, consider JAK inhibitors alongside TNF inhibitors and IL-17 inhibitors 1

4. For atopic dermatitis:

   • Consider baricitinib after failure of other systemic treatments 3

Important Caveats

• No direct evidence of superiority regarding efficacy or safety of one JAK inhibitor over another 1
• FDA warnings include serious heart-related events, cancer risk, blood clots, and risk of death 3
• Real-world data suggests JAK inhibitors do not significantly raise the risk of MACE in RA patients but do increase cholesterol levels that should be monitored closely 5
• The choice of mechanism of action should reflect non-musculoskeletal manifestations related to the condition being treated 1