JAK Inhibitors: Uses and Dosing in Autoimmune Diseases

Approved Indications

JAK inhibitors are FDA-approved for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), ulcerative colitis (UC), atopic dermatitis, and polyarticular juvenile idiopathic arthritis, with specific agents approved for specific conditions. 1, 2

Rheumatoid Arthritis

Tofacitinib (Xeljanz) is approved for moderately to severely active RA after inadequate response to one or more TNF blockers 2
Baricitinib (Olumiant) is approved for moderately to severely active RA after failure of conventional synthetic DMARDs 3, 1
Upadacitinib (Rinvoq) is approved for RA with similar indications 1

Psoriatic Arthritis

Tofacitinib is approved for active PsA when one or more TNF blockers have failed or cannot be tolerated 2
Tofacitinib demonstrated PASI75 response rates of 43% in methotrexate-inadequate responders and 21% in TNF-inhibitor failures at 12 weeks with the 10 mg twice daily dose 3

Ankylosing Spondylitis

Tofacitinib and upadacitinib are approved for active AS after inadequate response to NSAIDs 2
Upadacitinib showed 52% ASAS40 response at week 14 versus 26% with placebo, with response observed as early as week 2 3

Ulcerative Colitis

Tofacitinib is approved for moderately to severely active UC after inadequate response, loss of response, or intolerance to conventional therapy or biologics 3, 2

Dermatologic Conditions

Upadacitinib and abrocitinib are approved for moderate-to-severe atopic dermatitis after failure of other systemic therapies 1, 4
Tofacitinib has shown efficacy in psoriasis but is not widely approved for this indication (except in select countries like Russia) 3

Dosing Regimens

Tofacitinib (Xeljanz)

For RA and PsA:

Standard dose: 5 mg orally twice daily 1, 5, 2
Extended-release: 11 mg orally once daily 1, 5, 2
Critical safety note: The 10 mg twice daily dose is NOT recommended for RA due to increased thromboembolic risk (VTE and PE) 3, 5

For ulcerative colitis:

Induction: 10 mg orally twice daily for 8 weeks (or up to 16 weeks if adequate benefit not achieved) 3, 1
Maintenance: 5 mg orally twice daily 3, 1
In TNF-inhibitor inadequate responders, 10 mg twice daily may be used for maintenance 3

Dose adjustments required:

Reduce to 5 mg once daily in patients with moderate to severe renal impairment (CrCl 30-60 mL/min), moderate to severe hepatic impairment (Child-Pugh B or C), or concurrent use of strong CYP3A4 inhibitors (e.g., ketoconazole) 3, 5, 2
Reduce to 5 mg once daily with concurrent moderate CYP3A4 inhibitors plus potent CYP2C19 inhibitors (e.g., fluconazole) 5
Tofacitinib is 70% hepatically metabolized via CYP3A4 and 30% renally excreted 3, 2

Baricitinib (Olumiant)

For RA:

Standard dose: 2 mg or 4 mg orally once daily 3, 1
Baricitinib is 70% renally excreted, requiring dose adjustment in renal impairment 3
Not recommended with severe renal impairment (eGFR <30 mL/min) 4

For systemic lupus erythematosus (investigational):

4 mg daily showed significant efficacy in phase 2 trials, while 2 mg did not 3

Upadacitinib (Rinvoq)

For RA:

Standard dose: 15 mg orally once daily 1

For atopic dermatitis:

15 mg or 30 mg orally once daily 1, 4
Upadacitinib is predominantly hepatically metabolized with 20% renal excretion 3

Abrocitinib

For atopic dermatitis:

100 mg or 200 mg orally once daily 1, 4

Combination Therapy Recommendations

JAK inhibitors should be combined with methotrexate or other conventional synthetic DMARDs when tolerated, as combination therapy demonstrates superior efficacy to monotherapy. 1

Critical contraindications to combination:

Never combine JAK inhibitors with potent immunosuppressants (azathioprine, cyclosporine) or biologics 1, 4
This restriction is due to excessive immunosuppression risk 1

Pre-Treatment Screening Requirements

Before initiating any JAK inhibitor, the following screening is mandatory:

Infectious Disease Screening

Tuberculosis screening per national guidelines (tuberculin skin test or interferon-gamma release assay) 1, 5, 4
Hepatitis B and C testing 1, 4
HIV testing in high-risk populations 1, 4

Laboratory Testing

Complete blood count with differential (to assess lymphocyte, neutrophil, and hemoglobin levels) 1, 4, 2
Liver function tests 1, 4
Renal function tests (creatinine clearance) 1, 4
Lipid panel 1, 4

Vaccination

Herpes zoster vaccination (Shingrix) should be completed 3-4 weeks before JAK inhibitor initiation in adults ≥50 years or immunocompromised adults ≥19 years 5, 4
Live vaccines are contraindicated once JAK inhibitor therapy begins 2

Monitoring During Treatment

Laboratory Monitoring

For tofacitinib:

Monitor complete blood count, liver enzymes, and renal function regularly during treatment 2
Check lipid levels 4-8 weeks after initiation and as needed thereafter 2

For upadacitinib:

Check complete blood count, liver enzymes at baseline, and lipids at 12 weeks 1, 4

For abrocitinib:

Check complete blood count and liver enzymes at baseline and 4 weeks after initiation or dose escalation 1, 4

Clinical Monitoring

Monitor for infections, particularly herpes zoster, which occurs more frequently with JAK inhibitors than other therapies 1, 4, 2
Monitor for thrombotic events, especially in patients with cardiovascular risk factors 1, 4, 2
Monitor for gastrointestinal perforation symptoms (fever, persistent abdominal pain, change in bowel habits), particularly in patients with history of diverticulitis or peptic ulcer disease 2

Absolute Contraindications

Do not initiate JAK inhibitors in the following situations:

Active serious infections (including active tuberculosis and opportunistic infections) 1, 4, 2
Current malignancies 1
Severe hepatic impairment (Child-Pugh C) 1, 5
Severe renal disease (ESRD not on hemodialysis for most agents) 1
Pregnancy and lactation 1, 2
After tofacitinib, do not breastfeed for 18 hours; after extended-release, wait 36 hours 2

Critical Safety Warnings

Black Box Warnings (FDA)

The FDA has issued black box warnings for JAK inhibitors based on the ORAL Surveillance trial in RA patients ≥50 years with cardiovascular risk factors: 4, 2

Increased risk of major adverse cardiovascular events (MACE) 4, 2
Increased risk of venous thromboembolism (VTE), including pulmonary embolism 3, 4, 2
Increased risk of malignancies 4, 2
Increased risk of death 4, 2

These risks are particularly elevated in:

Current or past smokers 2
Patients ≥65 years 5, 2
Patients with cardiovascular risk factors 5, 4, 2

Infection Risk

Serious infections occur at rates similar to biologics, but higher in patients >65 years and with higher doses 1
Herpes zoster is notably more common with JAK inhibitors than biologics 3, 1, 4

Laboratory Abnormalities

Lymphopenia, neutropenia, and anemia may occur and require dose adjustment or discontinuation 2
Elevated liver enzymes may necessitate treatment interruption 2
Lipid elevations are common and require management 2

Clinical Decision Algorithm

For patients <50 years without cardiovascular risk factors, no malignancy history, and no active infections:

JAK inhibitors are appropriate first-line options after csDMARD failure 4

For patients ≥50 years with cardiovascular risk factors:

Prefer biologics over JAK inhibitors due to black box warnings 4, 2
If JAK inhibitor is chosen, use the lowest effective dose and monitor closely for thrombotic events 4, 2

For patients with prior biologic failure:

JAK inhibitors are effective alternatives, though efficacy after JAK inhibitor failure with another JAK inhibitor is unknown 3
Efficacy and safety of biologics after JAK inhibitor failure is also unknown 3

Efficacy Timeline

Patients can expect:

Initial response within 2-4 weeks for most indications 5
Maximal benefit by 3-6 months 5
For AS, response may be observed as early as week 2 with upadacitinib 3

Common Pitfalls to Avoid

Do not use 10 mg twice daily tofacitinib for RA—this dose is associated with increased VTE/PE risk and is only appropriate for UC induction 3, 5
Do not combine JAK inhibitors with biologics or potent immunosuppressants—this significantly increases infection risk 1, 4
Do not forget dose adjustments for renal/hepatic impairment or drug interactions—failure to adjust can lead to toxicity 3, 5, 2
Do not skip pre-treatment TB screening—reactivation of latent TB is a serious risk 1, 5, 4
Do not overlook herpes zoster vaccination—this is the most common infection with JAK inhibitors and is preventable 5, 4

What are the uses and dosing regimens of Janus Kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and baricitinib (Olumiant), in the treatment of autoimmune diseases like rheumatoid arthritis and psoriatic arthritis?

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