What are the potential side effects of Janus Kinase (JAK) inhibitors?

Potential Side Effects of JAK Inhibitors

JAK inhibitors are associated with several serious side effects including increased risk of venous thromboembolism, major adverse cardiovascular events, malignancies, serious infections (particularly herpes zoster), and various laboratory abnormalities. 1, 2

Major Safety Concerns

Cardiovascular and Thrombotic Risks

• Venous thromboembolism (VTE): Including deep vein thrombosis and pulmonary embolism
  • Risk appears dose-dependent (0.33 events/100 patient-years at lower doses vs 0.70 events/100 patient-years at higher doses) 1
  • FDA has applied boxed warnings for increased risk of serious heart-related events 1
• Major adverse cardiovascular events (MACE): Including myocardial infarction, stroke, and cardiovascular death 2, 3
  • Particularly concerning in patients >65 years old, smokers (current or previous), and those with history of cardiovascular disease 1

Infection Risks

• Serious and opportunistic infections: JAK inhibitors can suppress immune function 1, 2
• Herpes zoster (shingles): Significantly increased risk compared to placebo 1, 4
  • Vaccination with recombinant zoster vaccine is recommended before initiating therapy 1, 2
• Upper respiratory tract infections: Among the most common adverse events 4, 5

Malignancy Risks

• Increased risk of malignancies: Including skin cancers and lymphomas 2, 3
  • Rates of non-melanoma skin cancer range from 0-0.9% in clinical trials 6
  • Rates of other malignancies range from 0-0.7% 6
• Periodic skin examinations are recommended while using JAK inhibitors 3

Laboratory Abnormalities

• Hematologic changes:
  • Thrombocytopenia (decreased platelet count) 3, 4
  • Anemia (may worsen, especially at treatment initiation) 1, 3
  • Neutropenia 3
• Lipid elevations: Require monitoring after treatment initiation 1, 2
• Liver enzyme elevations: Require baseline and follow-up monitoring 2, 3
• Elevated creatine phosphokinase levels 4

Common Non-Serious Side Effects

• Nausea 4, 5
• Headache 4, 5
• Acne 4, 6
• Upper respiratory tract infections 4, 6
• Nasopharyngitis 6

Monitoring Requirements

Pre-Treatment Screening

• Complete blood count with differential
• Liver function tests
• Lipid profile
• Tuberculosis screening
• Hepatitis B and C testing
• Pregnancy testing
• VTE risk assessment 2

Follow-Up Monitoring

• Complete blood count: 4-12 weeks after initiation and every 3-6 months thereafter
• Liver enzymes: 4 weeks after initiation for abrocitinib, routine management for upadacitinib
• Lipids: 4 weeks after initiation for abrocitinib, 12 weeks for upadacitinib 1, 2

Special Considerations

High-Risk Populations

• Older adults (>65 years): Higher risk of cardiovascular complications 1, 2
• Smokers: Increased risk of cardiovascular events 1, 2
• Patients with history of VTE or cardiovascular disease: Consider alternative therapies 2
• Pregnant women: Limited safety data; should be avoided in women contemplating pregnancy 1, 2

Abrupt Discontinuation Risk

• Sudden withdrawal of JAK inhibitors (particularly ruxolitinib) can provoke a shock-like syndrome due to reemergence of suppressed inflammatory cytokines
• Tapering is recommended rather than abrupt discontinuation 1

Differences Between Oral and Topical JAK Inhibitors

• Topical JAK inhibitors (e.g., ruxolitinib cream): Generally not associated with systemic effects seen with oral formulations 4
• Oral JAK inhibitors: Associated with more systemic side effects and require more intensive monitoring 4, 7

The safety profile of JAK inhibitors requires careful patient selection, appropriate pre-treatment screening, and vigilant monitoring during treatment. The risk-benefit assessment should be individualized based on the patient's disease severity, comorbidities, and risk factors for adverse events.