Rinvoq (Upadacitinib): Comprehensive Clinical Guide

Approved Indications

Rinvoq is FDA-approved for multiple immune-mediated inflammatory diseases, but should NOT be used as first-line systemic therapy in most circumstances. 1

Rheumatologic Conditions

Rheumatoid arthritis (moderate-to-severe): 15 mg once daily in adults 2
Psoriatic arthritis (active): 15 mg once daily in adults; weight-based dosing for pediatric patients ≥2 years 2, 3
Ankylosing spondylitis: 15 mg once daily 2
Non-radiographic axial spondyloarthritis: 15 mg once daily 2
Polyarticular juvenile idiopathic arthritis: Weight-based dosing for patients ≥2 years 2, 3

Dermatologic Conditions

Atopic dermatitis (moderate-to-severe): Approved for patients who have failed other systemic therapies (immunosuppressants, corticosteroids, antimetabolites, injectable biologics) or when these are inadvisable 1
- Adults <65 years: Start 15 mg once daily; may increase to 30 mg once daily if inadequate response 2
- Adults ≥65 years: 15 mg once daily only 2
- Pediatric ≥12 years (≥40 kg): Same as adults <65 years 2

Gastrointestinal Conditions

Ulcerative colitis:
- Induction: 45 mg once daily for 8 weeks 2
- Maintenance: 15 mg once daily; may use 30 mg once daily for refractory/severe/extensive disease 2
Crohn's disease:
- Induction: 45 mg once daily for 12 weeks 1, 2
- Maintenance: 15 mg once daily; may use 30 mg once daily for refractory/severe/extensive disease 1, 2

Mechanism of Action

Upadacitinib is a selective JAK1 inhibitor that blocks multiple pro-inflammatory cytokine pathways simultaneously. 4, 5

Preferentially inhibits JAK1 over JAK2, JAK3, and TYK2 1, 5
Blocks signaling of Type I/II interferons (IFNα/β/γ), IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and IL-10 family cytokines 4
This broad cytokine inhibition explains efficacy across diverse immune-mediated diseases 4, 5

Dosing Regimens

Standard Adult Dosing by Indication

Indication	Dose
RA, AS, nr-axSpA, PsA	15 mg once daily [2]
Atopic dermatitis (<65 years)	15 mg once daily; may increase to 30 mg [2]
Atopic dermatitis (≥65 years)	15 mg once daily [2]
UC (induction)	45 mg once daily × 8 weeks [2]
UC (maintenance)	15 mg once daily (30 mg for refractory disease) [2]
CD (induction)	45 mg once daily × 12 weeks [2]
CD (maintenance)	15 mg once daily (30 mg for refractory disease) [2]

Pediatric Dosing

pJIA and PsA (≥2 years): Weight-tiered dosing available as extended-release tablets (once daily) or oral solution (twice daily) 2, 3
Atopic dermatitis (≥12 years, ≥40 kg): Same as adults <65 years 2

Dose Modifications

Severe renal impairment (CrCl <30 mL/min): 15 mg once daily 2

Severe hepatic impairment (Child-Pugh C): NOT recommended 1, 2

Strong CYP3A4 inhibitors: Dose reduction required for atopic dermatitis, UC, and CD patients 2

Strong CYP3A4 inducers: Coadministration NOT recommended 2

Contraindications

Absolute Contraindications

Known hypersensitivity to upadacitinib or excipients 2
Severe active infections (including localized infections) 1, 2
Active tuberculosis 1
Severe hepatic impairment (Child-Pugh C) 1, 2

Relative Contraindications (Use Only if No Alternative)

Current malignancy 1, 4
Age ≥65 years with cardiovascular risk factors (based on tofacitinib data in RA patients) 1
Pregnancy and lactation 4, 2

Pre-Treatment Screening

Complete the following assessments before initiating upadacitinib: 1, 4

Laboratory Testing

Complete blood count with differential 1
Liver function tests (AST, ALT) 1
Renal function (creatinine clearance) 4
Lipid panel 4
Viral hepatitis B and C serology 1
Pregnancy test in women of reproductive potential 1

Infectious Disease Screening

Tuberculosis screening per national guidelines (tuberculin skin test or interferon-gamma release assay, chest X-ray if positive) 1
HIV testing in high-risk populations 4

Immunizations

Update all needed vaccinations BEFORE starting treatment 1
Avoid live vaccines during treatment 2

Contraception Counseling

Advise women of reproductive potential to use effective contraception during and after treatment 2

Monitoring Requirements

Laboratory Monitoring Schedule

At baseline and after initiation/dose escalation:

CBC with differential: At baseline, then per routine management 1
Liver enzymes: At baseline, then per routine management 1
Lipids: Check 12 weeks after initiation 1

Optimal frequency of ongoing monitoring for continuous JAK inhibitor use remains unclear 1

Hold or Interrupt Treatment If:

Absolute lymphocyte count <500 cells/mm³ 2
Absolute neutrophil count <1000 cells/mm³ 2
Hemoglobin <8 g/dL 2

Clinical Monitoring

Herpes zoster: Monitor for signs/symptoms (rates: 2.4-6.6 per 100 patient-years across indications) 6
Serious infections: Monitor closely (rates: 1.3-4.6 per 100 patient-years) 6
Cardiovascular events: Monitor patients with risk factors 1, 6
Venous thromboembolism: Especially in patients with VTE risk factors 1, 6
Creatine phosphokinase elevations: Usually not clinically significant 1, 6

Adverse Effects

Common Adverse Events (≥1%)

Across rheumatologic indications: 2

Upper respiratory tract infections
Herpes zoster
Herpes simplex
Bronchitis
Nausea, cough, pyrexia
Acne, headache

Atopic dermatitis-specific (≥1%): 2

All of the above plus:
Blood creatine phosphokinase increased
Folliculitis, increased weight
Neutropenia, myalgia, fatigue

Inflammatory bowel disease (≥5%): 2

Upper respiratory tract infections
Increased creatine phosphokinase
Acne, neutropenia
Elevated liver enzymes, rash
Anemia (CD), pyrexia (CD)

Serious Adverse Events

FDA class warnings for all JAK inhibitors (based on tofacitinib data in RA patients ≥50 years with cardiovascular risk factors): 1

Increased risk of serious cardiovascular events
Increased risk of malignancies
Increased risk of blood clots (VTE)
Increased risk of death

Critical caveat: This warning is based on a trial in RA patients aged ≥50 years with ≥1 cardiovascular risk factor, which differs substantially from most patients initiating systemic treatment for atopic dermatitis or inflammatory bowel disease. 1

Infection Risks

Herpes zoster: Most notable infectious complication; rates higher with upadacitinib than active comparators 6
Serious infections: Rates comparable to biologics but higher in patients >65 years 4
COVID-19: Frequently reported in recent trials 6

Hematologic Effects

Lymphopenia, thrombocytopenia, neutropenia may occur 1
Anemia especially with JAK2 inhibition 1

Cardiovascular and Thrombotic Events

Dose-dependent VTE risk, particularly pulmonary embolism in patients with risk factors 1
MACE rates: 0-0.5 per 100 patient-years across indications 6
VTE rates: 0-0.9 per 100 patient-years across indications 6

Metabolic Effects

Lipid elevations (monitor at 12 weeks) 1
Creatine phosphokinase elevations (usually not clinically significant) 1
Creatinine elevations (not associated with renal failure or hypertension) 1

Gastrointestinal

GI perforations: Monitor patients at risk and evaluate promptly if symptoms develop 2

Medication Residue

May be observed in stool/ostomy output in patients with shortened GI transit times; consider alternative treatment if inadequate response 2

Efficacy Data

Comparative Efficacy

Upadacitinib 30 mg daily demonstrates the highest efficacy for reducing EASI scores among all currently available atopic dermatitis treatments in network meta-analysis. 1

Head-to-head trials show upadacitinib superior to dupilumab for atopic dermatitis, though superiority was primarily for patient-reported outcomes rather than objective measures. 1

For rheumatoid arthritis, upadacitinib 15 mg plus methotrexate showed superior efficacy to adalimumab plus methotrexate, primarily for patient-reported outcomes. 1, 7

Disease-Specific Outcomes

Rheumatoid arthritis: Upadacitinib 15 mg outperformed placebo, methotrexate, and adalimumab in ACR20 response and DAS28 scores 7

Crohn's disease: Upadacitinib 45 mg significantly improved stool frequency, abdominal pain, CDAI remission, and endoscopic response (RR=2.47 for clinical remission vs placebo) 7

Ulcerative colitis: Upadacitinib 45 mg increased clinical remission rates 6.92-fold vs placebo 7, 8

Axial spondyloarthritis: Upadacitinib 15 mg enhanced ASAS 20/40 response (RR=1.28/1.47) with better rates of low disease activity 7

Combination Therapy

Do NOT combine upadacitinib with: 2

Other JAK inhibitors
Biologic DMARDs
Potent immunosuppressants (azathioprine, cyclosporine)

May combine with conventional synthetic DMARDs (especially methotrexate) in rheumatologic conditions if patient tolerates the csDMARD, as combination therapy shows better efficacy than monotherapy. 4

Alternative Treatment Options

For Atopic Dermatitis

Dupilumab (IL-4/IL-13 inhibitor): First-line biologic; no laboratory monitoring required; conjunctivitis common but usually self-limited 1
Tralokinumab (IL-13 inhibitor): Similar efficacy to dupilumab; no laboratory monitoring required 1
Abrocitinib (JAK1 inhibitor): Similar efficacy profile to upadacitinib 1
Baricitinib (JAK1/JAK2 inhibitor): Less efficacious than upadacitinib/abrocitinib per network meta-analysis 1
Traditional immunosuppressants: Methotrexate, azathioprine, cyclosporine, mycophenolate mofetil 1

For Rheumatoid Arthritis

TNF inhibitors (adalimumab, etanercept, others): Established first-line biologics 1
Other JAK inhibitors: Tofacitinib, baricitinib 1
Other biologics: Abatacept, rituximab, tocilizumab 1

For Inflammatory Bowel Disease

Anti-TNF agents: Infliximab, adalimumab 1
Anti-integrin agents: Vedolizumab 1
IL-12/23 inhibitors: Ustekinumab 1
Tofacitinib: Alternative JAK inhibitor for UC 1

Special Populations

Elderly Patients (≥65 years)

Atopic dermatitis: Use 15 mg once daily only (do not escalate to 30 mg) 2
Higher risk of serious infections, particularly with higher doses 1
Consider cardiovascular risk factors before initiating (based on tofacitinib RA data) 1

Renal Impairment

Severe (CrCl <30 mL/min): Reduce to 15 mg once daily 2
Mild-to-moderate: No dose adjustment needed 2
Upadacitinib undergoes 20% renal excretion 1

Hepatic Impairment

Severe (Child-Pugh C): NOT recommended 1, 2
Mild-to-moderate: No dose adjustment specified 2
Upadacitinib undergoes hepatic oxidation via CYP3A4 1

Pregnancy and Lactation

May cause fetal harm based on animal studies 2
Advise effective contraception during treatment 2
Advise not to breastfeed 2

Clinical Pearls and Pitfalls

Common Pitfalls to Avoid

Using as first-line therapy in atopic dermatitis: Upadacitinib is approved only after failure of other systemic therapies or when inadvisable 1
Forgetting pre-treatment TB screening: Always screen for latent TB before initiating 1
Administering live vaccines during treatment: Update all vaccinations BEFORE starting 1, 2
Ignoring cardiovascular risk factors in elderly: Particularly relevant in patients ≥65 years based on class warnings 1
Not monitoring for herpes zoster: This is the most notable infectious complication 6

Optimizing Treatment

For UC/CD maintenance: Use lowest effective dose; discontinue if inadequate response to 30 mg dose 2
For atopic dermatitis: Start at 15 mg; only escalate to 30 mg if inadequate response (except in patients ≥65 years) 2
Medication residue in stool: If observed with shortened GI transit, monitor clinically and consider alternative treatment 2
Drug interactions: Rifampicin increases metabolism (consider dose increase); ketoconazole inhibits metabolism (consider dose reduction) 1

Long-Term Safety Considerations

Infection rates remain stable over time 6
Malignancy, MACE, and VTE rates remain stable over time 6
No evidence that one JAK inhibitor is safer than another 1
Variations in adverse event rates across indications likely reflect differences in populations and underlying comorbidities 6

1, 4, 2, 7, 3, 8, 5, 6

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