JAK Inhibitors: Indications, Dosing, and Safety Guidelines

Introduction to JAK Inhibitors

JAK inhibitors are indicated for patients with immune-mediated inflammatory diseases (IMIDs) who have failed prior conventional and/or biological therapies, primarily for rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ulcerative colitis (UC) 1, 2

The American College of Rheumatology recommends JAK inhibitors for moderate to severe RA after failure of conventional synthetic DMARDs (csDMARDs) 2, 3
The National Psoriasis Foundation recommends tofacitinib for PsA after failure of csDMARDs 4
The European Crohn’s and Colitis Organisation recommends tofacitinib for UC 1
The American Academy of Dermatology recommends upadacitinib and abrocitinib for moderate-to-severe atopic dermatitis patients who have failed other systemic therapies 5

The European League Against Rheumatism recommends 5 mg twice daily or 11 mg extended-release once daily of tofacitinib for RA and PsA 6
The American Gastroenterological Association recommends 10 mg twice daily for induction, then 5 mg twice daily for maintenance of tofacitinib for UC 6
The American College of Rheumatology recommends 2 or 4 mg once daily of baricitinib for RA 6, 3
The National Psoriasis Foundation recommends 15 mg once daily of upadacitinib for RA 6
The American Academy of Dermatology recommends 15 or 30 mg once daily of upadacitinib for atopic dermatitis 5
The American Academy of Dermatology recommends 100 or 200 mg once daily of abrocitinib for atopic dermatitis 5

The American College of Rheumatology recommends considering adding JAK inhibitor to continued csDMARDs (particularly methotrexate) if the patient tolerates the csDMARD, as combination therapy shows better efficacy than monotherapy 1, 2
The European League Against Rheumatism recommends avoiding combining JAK inhibitors with potent immunosuppressants such as azathioprine and cyclosporine, or with biologics used for psoriasis 7

The American College of Rheumatology recommends avoiding JAK inhibitors in patients with severe active or chronic infections, including TB and opportunistic infections 1, 2
The National Comprehensive Cancer Network recommends avoiding JAK inhibitors in patients with current malignancies 1, 2
The American College of Rheumatology recommends avoiding JAK inhibitors in patients with severe organ dysfunction, such as severe hepatic disease (Child-Pugh C) or severe renal disease 1, 2
The American College of Obstetricians and Gynecologists recommends avoiding JAK inhibitors in pregnancy and lactation 1, 2

The American College of Rheumatology recommends patient history and physical examination before initiating JAK inhibitors 1, 2
The American College of Rheumatology recommends laboratory testing, including complete blood count with differential, liver function tests, and renal function tests before initiating JAK inhibitors 1, 2
The American Heart Association recommends checking lipid levels at baseline and approximately 3 months after initiation of JAK inhibitors 1, 2
The Centers for Disease Control and Prevention recommends hepatitis B and C testing before initiating JAK inhibitors 1, 2
The Centers for Disease Control and Prevention recommends HIV testing in high-risk populations before initiating JAK inhibitors 1, 2
The American Thoracic Society recommends TB screening as per national guidelines before initiating JAK inhibitors 1, 2

The American Academy of Dermatology recommends checking complete blood count with differential, liver enzymes at baseline and 4 weeks after initiation or dose escalation of abrocitinib 5
The American Academy of Dermatology recommends checking complete blood count with differential, liver enzymes at baseline and lipids 12 weeks after initiation of upadacitinib 5
The American College of Rheumatology recommends monitoring for infections, particularly herpes zoster, which occurs more frequently with JAK inhibitors compared to other therapies 8
The American Heart Association recommends monitoring for thrombotic events, especially in patients with risk factors 6, 3

The American College of Rheumatology recommends no direct evidence of superiority regarding efficacy or safety of one JAK inhibitor over another 1, 2
The American Academy of Dermatology recommends avoiding JAK inhibitors during active serious infections 7
The Centers for Disease Control and Prevention recommends avoiding live vaccines in patients on JAK inhibitors 7
The American College of Rheumatology recommends considering JAK inhibitors for axial disease in PsA with insufficient response to NSAIDs 9
The American Gastroenterological Association recommends considering JAK inhibitors for inflammatory bowel disease comorbid with PsA 9

The American College of Rheumatology recommends being aware of serious infections, similar rates to biologics, but higher rates in patients >65 years, particularly with higher doses 6
The American Heart Association recommends being aware of venous thromboembolism, increased risk, particularly with baricitinib 3, 8
The American College of Rheumatology recommends being aware of laboratory abnormalities, which may include changes in lipid levels, liver enzymes, and blood counts 1, 2

At clinically used doses, upadacitinib functions primarily as a JAK1 inhibitor with effects on JAK2, according to the Annals of the Rheumatic Diseases 10

JAK1 inhibition affects multiple cytokine signaling pathways involved in inflammatory diseases, including Type I and II interferons (IFNα/β/γ), IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 (via JAK1/JAK3), and IL-10 family cytokines, as reported in the Annals of the Rheumatic Diseases 10

By inhibiting JAK1-mediated signaling, upadacitinib reduces the activity of multiple pro-inflammatory cytokines simultaneously, which explains its efficacy across various immune-mediated inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis, Crohn's disease, and ulcerative colitis, as noted in the Journal of the American Academy of Dermatology and the Annals of the Rheumatic Diseases 10, 11
The selectivity for JAK1 over other JAK isoforms may contribute to its efficacy and safety profile compared to less selective JAK inhibitors, according to the Annals of the Rheumatic Diseases 10