What are the different Janus kinase (JAK) inhibitors, their clinical indications, and associated adverse effects?

JAK Inhibitors: Types, Clinical Use, and Adverse Effects

JAK inhibitors are a class of oral targeted synthetic disease-modifying drugs that block intracellular Janus kinase signaling pathways, now approved for multiple immune-mediated inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, atopic dermatitis, ankylosing spondylitis, and myeloproliferative neoplasms, with efficacy comparable to biologics but distinct safety concerns requiring careful patient selection. 1, 2

Types of JAK Inhibitors

The currently approved JAK inhibitors differ in their selectivity profiles and metabolic pathways 1:

First-Generation (Pan-JAK Inhibitors)

• Tofacitinib: Inhibits JAK1, JAK2, JAK3; metabolized via CYP3A4 with 30% renal excretion
• Ruxolitinib: Inhibits JAK1 and JAK2; metabolized via CYP3A4 and CYP2C9

Second-Generation (More Selective)

• Baricitinib: Preferentially inhibits JAK1 and JAK2; >66% renal excretion
• Upadacitinib: JAK1-selective; metabolized via CYP3A4 with 20% renal excretion
• Filgotinib: JAK1-selective; metabolized by hepatic carboxylesterases (CES2)
• Peficitinib: Metabolized via NNMT and SULT2A1 with 16% renal excretion

Third-Generation (Allosteric Inhibitors)

• Deucravacitinib: TYK2-selective inhibitor targeting the pseudokinase domain 3, 4

Approved Clinical Indications

Rheumatoid Arthritis (RA)

• Tofacitinib: 5 mg twice daily or 11 mg extended-release daily
• Baricitinib: 2 or 4 mg daily
• Upadacitinib: 15 mg daily
• Filgotinib: 100 or 200 mg daily
• Peficitinib: 100 or 150 mg daily 1

Psoriatic Arthritis (PsA)

• Tofacitinib: 5 mg twice daily 1

Ulcerative Colitis (UC)

• Tofacitinib: 10 mg twice daily for induction (8-16 weeks), then 5 mg twice daily for maintenance (10 mg twice daily in TNFi-failures)
• Upadacitinib: High efficacy option 1, 5, 6
• Filgotinib: Most favorable safety profile 6

Ankylosing Spondylitis/Axial Spondyloarthritis

• Tofacitinib, Filgotinib, Upadacitinib: All show efficacy with separation from placebo at 4-8 weeks 1

Atopic Dermatitis

• Baricitinib, Upadacitinib, Abrocitinib 7, 8

Myeloproliferative Neoplasms

• Ruxolitinib: 5-25 mg twice daily for polycythemia vera and myelofibrosis 1, 9

Other Indications Under Investigation

• Systemic lupus erythematosus (baricitinib 4 mg showed efficacy in phase 2) 1
• Non-infectious uveitis, CANDLE syndrome, interferonopathies 1

Major Adverse Effects

Serious Infections

Herpes zoster reactivation is significantly increased (incidence rate 3-4 vs. 1 with placebo), occurring more frequently than with biologics and particularly common in Asian populations. 1 Serious infection rates are comparable to adalimumab at standard doses but increase with higher doses. EMA restricts tofacitinib use in patients >65 years due to elevated serious infection risk compared to TNF inhibitors. 1

Venous Thromboembolism (VTE) and Pulmonary Embolism

This is the most critical safety concern. The ORAL Surveillance study demonstrated increased VTE/PE risk with tofacitinib 10 mg twice daily (absolute IR 0.5) compared to 5 mg twice daily (IR 0.3) and TNF inhibitors (IR 0.1) in RA patients ≥50 years with cardiovascular risk factors 1, 10.

Risk factors requiring careful assessment include:

• Prior VTE history (recurrent VTE is a contraindication unless anticoagulated) 1
• Age >65 years
• Obesity (doubles VTE risk)
• Prolonged immobility
• Hereditary thrombophilias (Factor V Leiden, prothrombin mutation)
• Acquired thrombophilias (antiphospholipid syndrome, malignancy)
• COX-2 inhibitor therapy
• Prednisolone ≥7.5 mg/day
• Major surgery 1

Malignancy

Overall malignancy rates are not increased except for non-melanoma skin cancer (NMSC), which may be elevated, necessitating regular skin examinations. 1 Current malignancy (except NMSC and cervical carcinoma in situ) should prompt shared decision-making before initiating therapy 1.

Cytopenias and Anemia

Anemia of chronic disease does not improve with most JAK inhibitors (except filgotinib) and may worsen due to JAK2 inhibition affecting EPO signaling. Neutropenia and lymphopenia can occur but are generally not more frequent than placebo 1.

Cardiovascular Events

The ORAL Surveillance study suggested possible increased major adverse cardiovascular events (MACE) with tofacitinib in high-risk patients, though this remains under investigation 10, 5.

Gastrointestinal Perforation

Tofacitinib is specifically associated with gastrointestinal perforation events (IC025 1.5) 11.

Lipid Abnormalities

Lipid levels should be checked approximately 3 months after initiation (and possibly at baseline if not measured within 12 months) 1.

Contraindications

Absolute contraindications include:

• Severe active or chronic infections (including latent TB and opportunistic infections)
• Severe hepatic disease (Child-Pugh C)
• Severe renal disease
• Pregnancy and lactation
• Recurrent VTE (unless anticoagulated) 1

Relative contraindications requiring shared decision-making:

• Current malignancy
• Age >65 years with cardiovascular risk factors (especially for tofacitinib)
• Multiple VTE risk factors 1, 5

Pre-Treatment Screening Requirements

Mandatory screening includes:

• Complete blood count with differential
• Liver function tests (transaminases)
• Renal function assessment
• Hepatitis B testing (HBsAg, HBsAb, HBcAb, ±HBV DNA)
• Hepatitis C testing (HCV antibody, with RNA if positive)
• HIV testing in high-risk populations
• TB screening per national guidelines
• Vaccination status assessment and updates
• VTE risk factor assessment 1

Drug Interactions and Dose Adjustments

Tofacitinib and upadacitinib require dose adjustments with:

• Ketoconazole (CYP3A4 inhibitor): Reduce dose
• Rifampicin (CYP3A4 inducer): Consider dose increase 1

Baricitinib requires dose reduction to 2 mg daily with organic anion transporter 3 inhibitors (e.g., probenecid) 1.

Renal impairment necessitates dose adjustments for baricitinib and abrocitinib (not recommended if eGFR <30 mL/min), while upadacitinib maximum dose is 15 mg daily with severe renal impairment 7.

Clinical Positioning

For ulcerative colitis: Upadacitinib provides highest efficacy for induction and maintenance, while filgotinib demonstrates the most favorable safety profile. Consider filgotinib first-line for lower disease activity or when safety is prioritized; use upadacitinib or tofacitinib for higher disease activity 5, 6.

For rheumatoid arthritis: JAK inhibitors show similar efficacy to biologics on average. In patients ≥50 years with cardiovascular risk factors, use JAK inhibitors cautiously, preferring TNF inhibitors when possible. 10, 5 In women contemplating pregnancy, avoid JAK inhibitors and S1P receptor modulators due to limited safety data 5.

Common pitfall: The FDA recommends JAK inhibitors only after TNF antagonist failure in the US, while European guidance allows first-line use with caution in high cardiovascular risk patients. Regional regulatory differences must be considered 5.