Janus Kinase Inhibitors: Comprehensive Clinical Overview
What Are Janus Kinases?
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate cytokine signaling through the JAK-STAT pathway, playing essential roles in immune response, inflammation, and cell growth. 1, 2 The JAK family consists of four members: JAK1, JAK2, JAK3, and TYK2, which become activated upon cytokine receptor dimerization and subsequently phosphorylate STAT proteins that translocate to the nucleus to regulate gene transcription. 2, 3
Oral JAK Inhibitors Approved for Adults
Available Agents and Their Selectivity
Three selective JAK inhibitors are FDA-approved for atopic dermatitis and other inflammatory conditions:
Upadacitinib (RINVOQ): Preferentially targets JAK1, approved for moderate-to-severe atopic dermatitis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and Crohn's disease 1, 4
Abrocitinib: Selective JAK1 inhibitor approved for moderate-to-severe atopic dermatitis 1
Baricitinib: Inhibits both JAK1 and JAK2, approved for atopic dermatitis and rheumatoid arthritis 1
Tofacitinib (XELJANZ): Pan-JAK inhibitor (affects JAK1, JAK2, JAK3, and TYK2), approved for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis 5, 6
Standard Dosing Regimens for Adults
Atopic Dermatitis Dosing
| Medication | Standard Dose |
|---|---|
| Upadacitinib | 15 mg or 30 mg PO daily [1] |
| Abrocitinib | 100 mg or 200 mg PO daily [1] |
| Baricitinib | 2 mg or 4 mg PO daily [1] |
The higher doses (upadacitinib 30 mg daily, abrocitinib 200 mg daily) demonstrate superior efficacy in reducing disease severity compared to dupilumab in head-to-head trials, though they carry increased adverse event risks. 1
Rheumatoid Arthritis and Other Indications
- Tofacitinib: 5 mg PO twice daily (immediate-release) or 11 mg PO once daily (extended-release) 5, 6
- Upadacitinib: 15 mg PO daily for rheumatoid arthritis 4
Dose Adjustments for Organ Dysfunction
For moderate-to-severe renal impairment (CrCl <60 mL/min) or moderate hepatic impairment:
- Tofacitinib: Reduce to 5 mg once daily 5, 6
- Upadacitinib: Maximum 15 mg daily for severe renal impairment (CrCl <30 mL/min); no adjustment needed for mild-to-moderate impairment 1, 4
- Baricitinib and Abrocitinib: Not recommended in severe renal impairment (eGFR <30 mL/min); dose adjustment required for mild-to-moderate impairment 1
JAK inhibitors are contraindicated in severe hepatic disease (Child-Pugh C). 1
Critical Safety Concerns and Boxed Warnings
FDA Boxed Warnings Apply to All JAK Inhibitors
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 rheumatoid arthritis patients ≥50 years with cardiovascular risk factors. 5, 6, 4
Serious Infections
- Increased risk of bacterial, fungal, viral, and opportunistic infections including tuberculosis, herpes zoster, and eczema herpeticum 1, 5
- Herpes zoster occurs in <3% of atopic dermatitis patients on JAK inhibitors, with higher rates in selective JAK1 inhibitors compared to dupilumab 1
- Interrupt treatment immediately if serious infection develops until controlled 5, 6, 4
Venous Thromboembolism (VTE)
Increased risk of pulmonary embolism and deep vein thrombosis, particularly with tofacitinib 10 mg twice daily in patients with cardiovascular risk factors. 1, 5
VTE risk factors requiring careful consideration before initiation:
- Age >65 years 1
- History of VTE or inherited thrombophilias 1
- Obesity, smoking, immobility 1
- Exogenous estrogen use (oral contraceptives) 1
- Recent surgery, cancer, uncontrolled hypertension 1
Malignancy Risk
- Higher rates of lymphomas and lung cancers observed with tofacitinib versus TNF blockers in rheumatoid arthritis patients 1, 5, 6, 4
- Incidence rate of malignancies (excluding non-melanoma skin cancer) in atopic dermatitis trials: 0.22/100 patient-years with baricitinib versus 0.66/100 patient-years in placebo groups 1
- Most malignancies occurred in patients aged ≥53 years 1
Cardiovascular Events
Higher rate of MACE (cardiovascular death, myocardial infarction, stroke) with tofacitinib versus TNF blockers in rheumatoid arthritis patients ≥50 years with cardiovascular risk factors. 5, 6, 4
Cytopenias
- Dose-dependent decreases in lymphocytes, neutrophils, and hemoglobin 1
- Do not initiate if absolute lymphocyte count <500 cells/mm³, absolute neutrophil count <1000 cells/mm³, or hemoglobin <9 g/dL 5, 6
Other Common Adverse Events
- Nausea and vomiting: Most common with abrocitinib (7-20% in atopic dermatitis trials), particularly in adolescents and women, typically resolving within 15 days 1
- Acne: Dose-dependent, highest with upadacitinib 30 mg daily (up to 17%), responds well to standard acne treatments 1
- Headache: Commonly reported across all JAK inhibitors 1
- Lipid elevations: Increases in LDL, HDL, and triglycerides requiring monitoring 1, 5
Mandatory Pre-Treatment Screening
Before initiating any JAK inhibitor, the following screening is required: 1, 5
Laboratory Testing
- Complete blood count with differential 1, 5
- Comprehensive metabolic panel (liver enzymes, creatinine) 1, 5
- Lipid profile 1, 5
Infectious Disease Screening
- Tuberculosis testing: Interferon-gamma release assay (IGRA) or tuberculin skin test (TST), plus chest X-ray if indicated 1, 5
- Hepatitis B: HBsAg, anti-HBs, anti-HBc 1
- Hepatitis C: Anti-HCV antibody 1
Risk Assessment
- VTE risk factors (history, age, obesity, smoking, oral contraceptives) 1
- Cardiovascular risk factors 1
- History of malignancy 1
- Pregnancy test in women of childbearing potential 1
Ongoing Monitoring Requirements
Laboratory Monitoring Schedule
For abrocitinib:
- CBC with differential and liver enzymes at 4 weeks after initiation or dose escalation 1
- Lipids at 4 weeks 1
For upadacitinib:
General monitoring for all JAK inhibitors:
- CBC with differential every 4-8 weeks during first 3 months, then every 3 months 5, 7
- Liver function tests every 3 months 5
- Lipid profile at 12 weeks and annually thereafter 5
Discontinuation Criteria
Immediately discontinue if: 5, 7
- Absolute lymphocyte count <500 cells/mm³
- Absolute neutrophil count <500 cells/mm³
- Hemoglobin decreases ≥2 g/dL
- Serious infection develops
- Severe cytopenias occur
Absolute Contraindications
JAK inhibitors are contraindicated in: 1, 5, 7
- Active serious infections
- Severe hepatic disease (Child-Pugh C) 1
- Severe renal impairment (varies by agent) 1
- Pregnancy and lactation 1, 7
- Concurrent use with biologic DMARDs or potent immunosuppressants (azathioprine, cyclosporine, tacrolimus) 1, 5, 6, 4
- Concurrent use with other JAK inhibitors 5, 6, 4
Special Populations and Precautions
Elderly Patients (>65 Years)
Use JAK inhibitors with extreme caution in patients >65 years due to increased risk of serious infections, malignancy, and cardiovascular events. 1, 5
- Baricitinib dose should be reduced to 2 mg daily in patients >70 years due to age-related renal function decline 1
- The European Medicines Agency restricts tofacitinib use in patients >65 years 1
Pregnancy and Fertility
- Contraception is mandatory for both female and male patients during treatment and for 4 weeks after the last dose 1
- Tofacitinib is teratogenic in animal studies 1
- Filgotinib reduces spermatogenesis in animals (human data pending) 1
- JAK inhibitors are contraindicated during breastfeeding 1
Vaccination
All vaccinations should be current before starting JAK inhibitors: 1
- Inactivated vaccines (pneumococcal, influenza) can be given before or during treatment 1
- Recombinant zoster vaccine (Shingrix, two-dose series) is recommended for patients ≥18 years 1
- Live vaccines (if Shingrix unavailable) must be administered at least 3-4 weeks before initiating JAK inhibitors 1
- Consider 1-week pause after COVID-19 vaccination to optimize immune response 1
Herpes Prophylaxis
For patients with recurrent herpes simplex virus or herpes zoster outbreaks, prophylactic antiviral treatment (acyclovir, valacyclovir) should be considered. 1
Positioning in Treatment Algorithms
Atopic Dermatitis
Upadacitinib and abrocitinib are approved for moderate-to-severe atopic dermatitis patients who have failed other systemic therapies (immunosuppressants, corticosteroids, antimetabolites, injectable biologics) or when those therapies are inadvisable. 1
In most circumstances, JAK inhibitors are not considered first-line systemic therapy for atopic dermatitis. 1 Dupilumab and tralokinumab (IL-4/IL-13 antagonists) have moderate certainty evidence with no laboratory monitoring requirements and more favorable safety profiles. 1
Rheumatoid Arthritis and Other Inflammatory Arthritides
JAK inhibitors are indicated for patients with moderately-to-severely active disease who have had inadequate response or intolerance to one or more TNF blockers. 5, 6, 4
Alternative Treatment Options
For Atopic Dermatitis
Biologic therapies with superior safety profiles:
| Medication | Dose | Key Advantages |
|---|---|---|
| Dupilumab | 600 mg SC loading, then 300 mg SC every 2 weeks [1] | No laboratory monitoring required; conjunctivitis most common adverse event (manageable with artificial tears) [1] |
| Tralokinumab | Per product insert [1] | Similar efficacy to dupilumab; no laboratory monitoring required [1] |
Conventional immunosuppressants:
- Methotrexate: 10-25 mg PO or SC weekly 1
- Azathioprine: 3-5 mg/kg PO daily 1
- Cyclosporine: Up to 3000 mg PO daily divided BID (use limited to 1 year) 1
- Mycophenolate mofetil: 500 mg PO (dosing table incomplete in source) 1
For Rheumatoid Arthritis
- TNF inhibitors (adalimumab, etanercept, infliximab, others) 5
- Other biologic DMARDs (abatacept, rituximab, tocilizumab) 5
- Conventional synthetic DMARDs (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine) 5
Dose Flexibility and Long-Term Management
Upon achieving disease control, reduce to the lowest effective dose to minimize adverse event risk. 1
JAK inhibitors do not cause antidrug antibody formation, allowing for treatment breaks and on-demand dose adjustments without risking future loss of efficacy. 1 This rapid-response characteristic enables patients on maintenance therapy to self-adjust doses during flares, though this approach requires flexible prescription refill processes. 1
Risk Minimization Strategies
To minimize long-term risks of JAK inhibitor use: 1
- Encourage healthy lifestyle: maintain ideal body weight, smoking cessation 1
- Ensure vaccinations are current before initiation 1
- Avoid concomitant medications that increase malignancy, VTE, or hematological anomaly risk 1
- Safe combination therapy data exist only for methotrexate, topical corticosteroids, and topical calcineurin inhibitors 1
Key Clinical Pearls
Mechanistic differences matter: Upadacitinib and abrocitinib (selective JAK1 inhibitors) and baricitinib (JAK1/JAK2 inhibitor) may have safer long-term profiles than tofacitinib (pan-JAK inhibitor), though real-world data are still emerging 1
The 10 mg twice-daily tofacitinib dose should be avoided due to markedly higher VTE/PE risk observed in rheumatoid arthritis cohorts 7, 8
JAK inhibitors demonstrate very high efficacy with rapid onset of action (within days to weeks), superior to biologics in some head-to-head trials 1
Long-term safety data (>2 years) are limited, and ongoing studies will clarify durability and safety with continuous use 1