What are the indications and usage of Janus Kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and baricitinib (Olumiant), in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA)?

JAK Inhibitors for Rheumatoid Arthritis and Psoriatic Arthritis

JAK inhibitors are indicated for patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who have failed prior conventional synthetic DMARDs and/or biological therapies. 1

Indications and Usage

Rheumatoid Arthritis

• JAK inhibitors are approved for adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more TNF blockers 2
• They can be used after failure of conventional synthetic DMARDs (csDMARDs) like methotrexate
• Tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib are currently approved JAK inhibitors for RA in various regions 1

Psoriatic Arthritis

• Tofacitinib is approved for adult patients with active PsA who have had an inadequate response or intolerance to one or more TNF blockers 2
• According to EULAR recommendations, JAK inhibitors should be considered after failure of at least one bDMARD, or when a bDMARD is not appropriate 1
• For peripheral arthritis in PsA, TNF inhibitors, IL-17 inhibitors and JAK inhibitors are equally recommended based on evidence including head-to-head studies 1

Mechanism of Action

JAK inhibitors work by blocking intracellular signaling pathways:

• They inhibit Janus kinases (JAKs), which are essential for the signaling of multiple inflammatory cytokines 3
• Different JAK inhibitors have varying selectivity profiles:
  • Tofacitinib: Preferentially inhibits JAK1, JAK3, and JAK2 1
  • Baricitinib: Primarily inhibits JAK1 and JAK2 1
  • Upadacitinib: JAK1 inhibitor with effects on JAK2 1
  • Filgotinib: Primarily a JAK1 inhibitor 1

Dosing and Administration

• Use the dose recommended for the specific disease 1
• Consider dose adjustments in patients:
  • Over 70 years of age
  • With impaired renal or hepatic function
  • With risk of drug interactions
  • With other comorbidities 1
• For RA patients in sustained remission, consider dose reduction 1
• In RA, consider adding a JAK inhibitor to continued csDMARDs if the patient tolerates the csDMARD 1

Contraindications and Precautions

JAK inhibitors are contraindicated in patients with:

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

Pre-treatment Screening

Before initiating JAK inhibitor therapy:

• Conduct patient history and physical examination
• Perform routine laboratory testing:
  • Complete blood count with differential
  • Liver function tests (transaminases)
  • Renal function tests
  • Lipid levels (at baseline or within 3 months of starting therapy)
• Screen for infections:
  • Hepatitis B and C testing
  • HIV testing in high-risk populations
  • TB screening as per national guidelines
• Assess and update vaccination status
• Evaluate risk factors for venous thromboembolism 1

Monitoring and Adverse Events

Laboratory Monitoring

• Complete blood count and liver transaminase tests at 1 and 3 months, then every 3 months
• Lipid levels at month 3 after starting treatment 1

Common Adverse Events

• Serious infections (similar to bDMARDs)
• Herpes zoster (increased rates compared to bDMARDs)
• Possible elevations in CPK and creatinine levels
• Lymphopenia, thrombocytopenia, neutropenia, anemia 1

Special Concerns

• Increased risk of venous thromboembolism has been reported with tofacitinib 10 mg twice daily and baricitinib 1
• Annual skin examination is recommended for detection of skin cancer 1
• The risk of infectious events can be reduced by eliminating concomitant glucocorticoid use 1

Comparative Efficacy

• Currently, there is no direct evidence of superiority regarding efficacy or safety of one JAK inhibitor over another 1
• In PsA, a single RCT showed superiority of a JAK inhibitor (at higher dose) over a TNF inhibitor for some peripheral arthritis outcomes, but consistent superiority has not been demonstrated 1
• For axial disease in PsA, TNF inhibitors, IL-17 inhibitors, and JAK inhibitors are all recommended based on evidence from axial spondyloarthritis studies 1

Practical Considerations

• JAK inhibitors offer the advantage of oral administration compared to injectable biologics 4
• They should not be used in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine 2
• For evaluation of response, be aware that CRP and ESR may be reduced independently of reduction of disease activity 1

JAK inhibitors represent an important addition to the treatment armamentarium for RA and PsA, particularly for patients who have failed or cannot tolerate conventional DMARDs and biologics.