What are the guidelines for using Upadacitinib (Janus kinase inhibitor) in patients with moderate to severe autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, or atopic dermatitis?

Upadacitinib Guidelines for Moderate to Severe Autoimmune Diseases

Upadacitinib is a selective JAK-1 inhibitor approved for moderate-to-severe atopic dermatitis (after failure of conventional systemic therapies), rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, ulcerative colitis, and Crohn's disease, with disease-specific dosing and critical safety monitoring requirements. 1, 2

Approved Indications and Positioning

Atopic Dermatitis

• Upadacitinib is NOT first-line therapy—it is reserved for patients who have failed other systemic therapies including immunosuppressants, corticosteroids, antimetabolites, and injectable biologics, or when these are inadvisable 1, 3
• The American Academy of Dermatology provides a strong recommendation with moderate certainty evidence for upadacitinib in moderate-to-severe atopic dermatitis 1, 3
• Dosing: 15 mg or 30 mg once daily orally 1, 2
• Start with 30 mg daily for severe disease, then decrease to 15 mg once control is achieved 1, 3
• The 30 mg dose demonstrates the highest efficacy among all currently available treatments in network meta-analysis and is superior to dupilumab in head-to-head trials 1, 3

Rheumatoid Arthritis

• Approved dose: 15 mg once daily 2
• Do NOT use the 30 mg dose for rheumatoid arthritis—this is not the approved dose and carries increased safety risks 3

Psoriatic Arthritis

• Approved dose: 15 mg once daily 2
• In phase 3 trials, upadacitinib 15 mg achieved 70.6% ACR20 response at week 12 (noninferior to adalimumab), while 30 mg achieved 78.5% (superior to adalimumab at 65.0%) 4
• At 56 weeks, 52.3% of patients achieved PASI75 with upadacitinib 15 mg 5, 6

Ankylosing Spondylitis and Non-radiographic Axial Spondyloarthritis

• Approved dose: 15 mg once daily for both conditions 2

Ulcerative Colitis

• Induction: 45 mg once daily for 8 weeks 2
• Maintenance: 15 mg once daily (30 mg once daily may be considered for refractory, severe, or extensive disease) 2

Crohn's Disease

• Induction: 45 mg once daily for 12 weeks 2
• Maintenance: 15 mg once daily (30 mg once daily may be considered for refractory, severe, or extensive disease) 2

Pre-Treatment Requirements

Mandatory Screening

• Test for latent tuberculosis with PPD or interferon-gamma release assay and treat if positive before initiating therapy 1, 3
• Test for viral hepatitis B and C at baseline 1
• Pregnancy testing at baseline 1
• Baseline laboratory testing: complete blood count with differential, liver enzymes, renal function (eGFR), and lipid profile 1

Vaccination Requirements

• Administer all needed live vaccines BEFORE initiating treatment 1, 3
• Herpes zoster vaccination (Shingrix) is critical—give as a 2-dose series separated by 2-6 months before treatment initiation 3, 7
• Herpes zoster risk is significantly elevated with JAK inhibitors 3, 7

Safety Monitoring and Laboratory Follow-Up

Initial Monitoring

• For atopic dermatitis: Check complete blood count with differential and liver enzymes at 4 weeks after initiation or dose escalation for abrocitinib; per routine management after baseline for upadacitinib 1
• Check lipids at 4 weeks for abrocitinib, 12 weeks for upadacitinib 1

Ongoing Monitoring

• The optimal frequency of ongoing laboratory monitoring for patients continuously using JAK inhibitors is unclear 1
• Monitor for signs of infection, particularly herpes zoster, which occurs at higher rates with upadacitinib 1, 8

Laboratory-Based Dose Interruptions

• Interrupt treatment if absolute neutrophil count (ANC) < 1000 cells/mm³; restart once ANC returns above this value 2
• Interrupt treatment if absolute lymphocyte count (ALC) < 500 cells/mm³; restart once ALC returns above this value 2
• Interrupt treatment if hemoglobin < 8 g/dL; restart once hemoglobin returns above this value 2
• Interrupt treatment if drug-induced liver injury is suspected until this diagnosis is excluded 2

Black Box Warnings and Critical Safety Considerations

Age-Related Risks

• Patients ≥65 years with cardiovascular risk factors should avoid upadacitinib unless no alternatives exist 3
• Exercise particular caution in patients ≥50 years with at least one cardiovascular risk factor 3, 7
• FDA has applied class-wide black box warnings for JAK inhibitors based on increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancies, and death in patients ≥50 years with cardiovascular risk factors 1, 3
• Almost all malignancies in upadacitinib studies occurred in patients aged ≥53 years 1, 7

Venous Thromboembolism Risk

• Prior to initiating upadacitinib, assess VTE risk factors including: history of VTE, age >65 years, inherited thrombophilias (e.g., factor V Leiden), exogenous estrogen use, recent surgery, immobility, uncontrolled hypertension, obesity, current or prior tobacco use, cancer, and pregnancy 1
• In upadacitinib trials for atopic dermatitis, VTE rate was <0.1/100 patient-years, occurring only in patients with VTE history and risk factors 1
• If VTE risk factors are present, consider treatment initiation carefully at the lowest dose with shared decision-making and specialist consultation if needed 1

Infection Risk

• Interrupt upadacitinib if a serious infection develops, including opportunistic infections, until the infection is controlled 2
• Herpes zoster infection rates are elevated with JAK inhibitors—vaccination before treatment is essential 3, 8
• Overall infection rates, particularly herpes zoster, require careful monitoring 8

Malignancy Risk

• All JAK inhibitors carry boxed warnings for increased risk of malignancy 1
• In a randomized safety trial of tofacitinib in rheumatoid arthritis patients, hazard ratio for cancer was 1.48 (95% CI 1.04-2.09) versus TNF inhibitors, with lung cancer most common and higher incidence in patients ≥65 years 1
• For upadacitinib in rheumatoid arthritis, malignancy rates (excluding nonmelanoma skin cancer) were similar to adalimumab through 156 weeks 1

Contraindications

Absolute Contraindications

• Known hypersensitivity to upadacitinib or any excipients 2
• Active serious infections 3
• Severe hepatic impairment (Child-Pugh C) 1, 2

Drug Interactions

• Do NOT use in combination with other JAK inhibitors, biologic immunomodulators, or other immunosuppressants 3, 9
• When using strong CYP3A4 inhibitors with atopic dermatitis patients, reduce upadacitinib dose to 15 mg once daily 2
• For ulcerative colitis or Crohn's disease with strong CYP3A4 inhibitors: induction 30 mg once daily, maintenance 15 mg once daily 2

Dose Adjustments for Organ Dysfunction

Renal Impairment

• For atopic dermatitis with severe renal impairment (eGFR 15 to <30 mL/min/1.73m²): maximum dose is 15 mg once daily 1, 2
• For ulcerative colitis or Crohn's disease with severe renal impairment: induction 30 mg once daily, maintenance 15 mg once daily 2
• For rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis: no dose adjustment needed for any degree of renal impairment 2
• Not recommended for end-stage renal disease (eGFR <15 mL/min/1.73m²) in atopic dermatitis, ulcerative colitis, or Crohn's disease 2

Hepatic Impairment

• Severe hepatic impairment (Child-Pugh C) is a contraindication 1, 2
• For rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis with mild-to-moderate hepatic impairment (Child-Pugh A or B): no dose adjustment needed 2
• For ulcerative colitis or Crohn's disease with mild-to-moderate hepatic impairment: induction 30 mg once daily, maintenance 15 mg once daily 2

Efficacy Highlights

Atopic Dermatitis

• Upadacitinib demonstrates very high efficacy with rapid onset of action 1
• The 30 mg dose shows the highest efficacy at reducing EASI scores up to 16 weeks among all currently available treatments 1, 3
• Superior to dupilumab in head-to-head clinical trials 1, 3

Psoriatic Arthritis

• At week 12, ACR20 response: 70.6% with 15 mg, 78.5% with 30 mg, versus 65.0% with adalimumab 4
• The 30 mg dose was superior to adalimumab; the 15 mg dose was noninferior 4
• Efficacy maintained through 56 weeks with inhibition of radiographic progression 6

Inflammatory Bowel Disease

• For Crohn's disease, upadacitinib 45 mg significantly improved clinical remission (RR 2.47,95% CI 2.12-2.88) compared to placebo 8
• For ulcerative colitis, upadacitinib 45 mg increased clinical remission rates (RR 6.92,95% CI 4.99-9.59) compared to placebo 8

Common Adverse Events

• Unlike dupilumab, conjunctivitis is NOT a prominent adverse event with upadacitinib 3, 9
• Overall adverse event rates are generally similar to non-upadacitinib groups (RR 1.02,95% CI 0.98-1.07) 8
• Serious adverse events: 9.1 events/100 patient-years with 15 mg, 12.3 events/100 patient-years with 30 mg in psoriatic arthritis trials 6
• Herpes zoster infection risk is elevated and requires pre-treatment vaccination 3, 8

Critical Clinical Pitfalls to Avoid

• Do not use 30 mg dose for rheumatoid arthritis—only 15 mg is approved and the higher dose carries increased safety risks 3
• Do not overlook cardiovascular risk assessment in patients ≥50 years, particularly those with cardiovascular risk factors 3, 7
• Do not fail to administer herpes zoster vaccination (Shingrix) before initiating therapy 3, 7
• Do not use upadacitinib as first-line therapy for atopic dermatitis—it is reserved for patients who have failed conventional systemic treatments 1, 3
• Do not combine with other JAK inhibitors, biologics, or immunosuppressants 3, 9
• Do not use in severe hepatic impairment (Child-Pugh C) 1, 2