What are the considerations and precautions for using Rinvoq (upadacitinib) in patients with a history of inflammatory conditions such as rheumatoid arthritis, psoriatic arthritis, or atopic dermatitis?

Rinvoq (Upadacitinib): Clinical Considerations and Precautions

Key Recommendation

Upadacitinib is a highly effective JAK1-selective inhibitor approved for rheumatoid arthritis, psoriatic arthritis, and atopic dermatitis, but should generally be reserved for patients who have failed conventional DMARDs or biologics due to FDA-mandated safety warnings regarding cardiovascular events, malignancy, and thromboembolism in high-risk populations. 1

Approved Indications and Positioning

Rheumatoid Arthritis

• Upadacitinib is indicated for moderate-to-severe rheumatoid arthritis after inadequate response to methotrexate or other conventional DMARDs 2, 3
• Standard dosing is 15 mg once daily orally 1, 3
• Should not be used as first-line therapy; methotrexate remains the initial DMARD of choice 2

Psoriatic Arthritis

• Approved for active psoriatic arthritis in patients with inadequate response to conventional synthetic DMARDs 1, 3
• Dosing: 15 mg once daily 1, 3
• Effective for peripheral arthritis and skin manifestations, but NOT effective for axial disease 4
• For predominantly axial disease, TNF inhibitors or IL-17 inhibitors should be used instead 4

Atopic Dermatitis

• Upadacitinib 15 mg or 30 mg daily demonstrates the highest efficacy among all available treatments for moderate-to-severe atopic dermatitis 1
• The 30 mg dose showed superior efficacy to dupilumab in head-to-head trials 1
• Should be reserved for patients who have failed other systemic therapies (immunosuppressants, corticosteroids, antimetabolites, biologics) or when these are inadvisable 1
• Approved for patients 12 years and older weighing at least 40 kg 3

Critical Safety Warnings and Contraindications

FDA Black Box Warnings - Cardiovascular and Malignancy Risks

The FDA applied class-wide warnings for JAK inhibitors based on the ORAL Surveillance trial in rheumatoid arthritis patients aged ≥50 years with cardiovascular risk factors, showing increased rates of major adverse cardiovascular events, malignancies, and death with tofacitinib versus TNF inhibitors 1

• Use upadacitinib with extreme caution in patients ≥65 years, current/former smokers, those with cardiovascular disease history, or cancer history 1
• In the U.S., FDA recommends JAK inhibitors only after TNF antagonist failure or intolerance 1
• European guidance allows first-line use but recommends caution in high-risk cardiovascular populations 1

Infection Risks

• Increased risk of serious and opportunistic infections, particularly herpes zoster 1
• Vaccinate for shingles BEFORE initiating therapy when feasible, particularly in patients ≥50 years 1
• The recombinant (non-live) zoster vaccine is approved for immunocompromised adults ≥19 years 1
• Hold therapy during active serious infections 1
• Screen for tuberculosis and viral hepatitis at baseline 1

Thromboembolic Events

• Venous thromboembolism risk observed across JAK inhibitor trials 1, 5
• Rates: 0.1-0.4 events per 100 patient-years 5
• Use with caution in patients with VTE risk factors 1

Gastrointestinal Perforation

• Risk of gastrointestinal perforation reported, particularly in patients with diverticulitis history or concurrent NSAID/corticosteroid use 1
• Evaluate promptly for new abdominal symptoms, recognizing that fever and inflammatory markers may be blunted 1

Mandatory Laboratory Monitoring

Baseline Testing Required

• Complete blood count with differential 1
• Liver enzymes (transaminases) 1
• Renal function (creatinine) 1
• Lipid panel 1
• Tuberculosis screening 1
• Hepatitis B and C screening 1
• Pregnancy test in females of reproductive potential 1, 3

Ongoing Monitoring Schedule

Check CBC, liver enzymes, and renal function at 1 month, 3 months, then every 3 months; lipids at 3 months only 1

Hematologic Thresholds for Dose Adjustment

• Hemoglobin: Hold if >20 g/L decrease or <80 g/L until normalized 1
• Absolute neutrophil count: Reduce dose or hold if 500-1000/mm³ on two sequential measures; restart when >1000/mm³ 1
• Absolute lymphocyte count: Reduce dose or hold if 500-750/mm³ on two sequential measures; restart when >750/mm³ 1
• Lymphocyte counts <500/mm³ significantly increase opportunistic infection risk 1

Liver Function

• Monitor transaminases periodically 1
• Do NOT use in severe hepatic impairment (Child-Pugh C) 3
• No dose adjustment needed for mild hepatic impairment (Child-Pugh A) 3
• For moderate hepatic impairment (Child-Pugh B): use reduced dosing per indication 3

Renal Function

• For atopic dermatitis: Maximum 15 mg daily in severe renal impairment (eGFR 15-30) 3
• For ulcerative colitis/Crohn's disease: 30 mg daily for induction, 15 mg daily for maintenance in severe renal impairment 3
• Not recommended in end-stage renal disease for atopic dermatitis, ulcerative colitis, or Crohn's disease 3

Lipid Management

• Check lipids at 12 weeks after initiation 1
• Manage elevations according to national lipid guidelines 1

Special Population Considerations

Pregnancy and Lactation

• Pregnancy Category: May cause embryo-fetal harm based on animal studies 3
• Verify pregnancy status before starting therapy 3
• Females of reproductive potential must use effective contraception during treatment and for 4 weeks after the last dose 3
• Breastfeeding is NOT recommended during treatment and for 6 days (10 half-lives) after the last dose 3
• In women actively contemplating pregnancy, avoid upadacitinib and select alternative therapy (biologics preferred) 1

Geriatric Patients

• Higher rates of serious infections and malignancies observed in patients ≥65 years 3
• No dose adjustment required based on age alone, but heightened vigilance for adverse events is essential 3

Pediatric Use

• Approved for atopic dermatitis in patients ≥12 years weighing ≥40 kg 3
• Approved for polyarticular juvenile idiopathic arthritis and psoriatic arthritis in patients 2 to <18 years 3
• Not established for patients <12 years with atopic dermatitis or <2 years with pJIA/psoriatic arthritis 3

Drug Interactions and Contraindications

Prohibited Combinations

• Do NOT combine with potent immunosuppressants (azathioprine, cyclosporine) or biologics 1
• Can be used with methotrexate 1

Dose Adjustments for Drug Interactions

• Reduce to 5 mg once daily when using potent CYP3A4 inhibitors (ketoconazole) or combined moderate CYP3A4 and potent CYP2C19 inhibitors (fluconazole) 1

Live Vaccines

• Administer all needed live vaccines BEFORE initiating upadacitinib 1
• Live vaccines are contraindicated during therapy 1

Common Adverse Events by Indication

Atopic Dermatitis

• Acne (most common in AD population) 1, 5
• Nasopharyngitis 1, 5
• Creatine phosphokinase elevation 1, 5
• Headache 1
• Upper respiratory tract infections 5

Rheumatoid and Psoriatic Arthritis

• Herpes zoster (1.6-3.6 per 100 patient-years, higher than active comparators) 5
• Non-melanoma skin cancer (0-0.8 per 100 patient-years) 5
• Creatine phosphokinase elevations (4.4-7.9 per 100 patient-years) 5
• Serious infections (0-3.9 per 100 patient-years) 5

Dermatologic Monitoring

• Annual formal skin examination recommended due to increased NMSC risk, particularly with prior methotrexate or TNF inhibitor exposure 1

Clinical Pearls and Pitfalls

When to Avoid Upadacitinib

• Active serious infection 1
• Age ≥65 years with cardiovascular risk factors (consider alternative therapy) 1
• History of malignancy (particularly recent) 1
• Current or long-term smokers 1
• History of venous thromboembolism 1
• Severe hepatic impairment 3
• End-stage renal disease (for atopic dermatitis, UC, Crohn's disease) 3
• Pregnancy or breastfeeding 3
• Women actively planning pregnancy 1

Efficacy Considerations

• Rapid onset of action compared to conventional DMARDs and biologics 1
• Superior efficacy to dupilumab for atopic dermatitis at the 30 mg dose 1
• Effective for both joint and skin manifestations in psoriatic arthritis 6
• Ineffective for axial disease in spondyloarthropathies 4

Monitoring Disease Activity

• Use composite measures without acute phase reactants (e.g., CDAI for RA) since CRP/ESR may be suppressed independently of disease activity 1
• Target remission or low disease activity by 6 months 1
• Expect >50% improvement within 3 months 1