What are the adverse effects of upadacitinib and how should they be monitored?

Upadacitinib Adverse Effects and Monitoring

Most Common Adverse Events

The most frequently reported adverse events with upadacitinib include upper respiratory tract infections, nasopharyngitis, acne, elevated creatine phosphokinase (CPK), headache, and anemia. 1, 2, 3

• Acne and folliculitis occur in up to 17% of patients receiving the highest dose (30 mg daily), with a clear dose-dependent relationship; these lesions typically present with classic distribution on face, upper chest, and back and respond well to standard acne treatments 4
• Headache affects up to 10% of patients, is generally mild in severity, and brief in duration (median <1 day) 4
• Nasopharyngitis and upper respiratory tract infections are among the most common infectious complications across all indications 2, 5, 3
• Elevated CPK is frequently observed and requires monitoring, though most elevations are asymptomatic 4, 2, 3

Serious Adverse Events and Events of Special Interest

Infections

• Serious infections occur at rates of 1.3–4.6 events per 100 patient-years across indications 2
• Herpes zoster rates range from 2.4–6.6 events per 100 patient-years, with higher rates compared to TNF antagonists 2, 3
• Recombinant zoster vaccine (Shingrix) should be administered before initiating upadacitinib, with a 2-dose series separated by 2–6 months for all adults ≥18 years 4, 6
• Opportunistic infections (excluding tuberculosis, herpes zoster, and oral candidiasis) occur at higher rates with upadacitinib versus adalimumab 3
• Tuberculosis screening with interferon-gamma release assay (IGRA) or tuberculin skin test is mandatory before initiation 4, 6

Cardiovascular and Thrombotic Events

The FDA has applied class-wide warnings for JAK inhibitors regarding increased risk of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and death, based primarily on data from tofacitinib in older rheumatoid arthritis patients. 4

• MACE rates with upadacitinib range from 0–0.5 events per 100 patient-years across indications 2
• VTE rates range from 0–0.9 events per 100 patient-years 2
• The European Medicines Agency recommends cautious use of JAK inhibitors as first-line agents in patients ≥65 years, current or long-term smokers, those with cardiovascular disease history, or history of cancer 4
• Upadacitinib should be used with caution in patients with risk factors for VTE including obesity, exogenous estrogen use, recent surgery, immobility, and inherited thrombophilias 4, 6

Malignancy

• Malignancy rates (excluding nonmelanoma skin cancer) range from 0.2–0.9 events per 100 patient-years 2
• Nonmelanoma skin cancer (NMSC) rates range from 0–1.4 events per 100 patient-years, with numerically higher rates versus active comparators in rheumatoid arthritis and psoriatic arthritis 2
• Baseline skin examination should be performed in at-risk patients 6

Hepatic Effects

• Liver enzyme elevations have been reported, particularly with upadacitinib 4
• Baseline liver enzymes must be <1.5× upper limit of normal (ULN) to initiate treatment 6
• Treatment modification thresholds: dose reduction or interval extension for 1–3× ULN; withhold for >3× ULN; permanently discontinue for >5× ULN 6

Hematologic Effects

• Lymphopenia, neutropenia, and anemia are reported adverse events of special interest 5
• Thrombocytopenia has been reported rarely, mostly within a few weeks of starting abrocitinib (a related JAK1 inhibitor) 4
• Treatment should be interrupted if hemoglobin decreases below 8 g/dL, absolute lymphocyte count <0.5×10⁹ cells/L, or absolute neutrophil count <1×10⁹ cells/L 4

Lipid Abnormalities

• JAK inhibitors increase total cholesterol, HDL, LDL, and triglycerides 4
• Lipid monitoring should occur at 4 weeks (abrocitinib) or 12 weeks (upadacitinib) after initiation, then annually 4, 6
• Treat lipid elevations according to national guidelines; the clinical impact of these changes remains unclear 4

Pregnancy and Lactation

Upadacitinib is teratogenic in animal studies and should not be used during pregnancy. 7

• Animal studies demonstrate skeletal malformations, cardiovascular malformations, embryolethality, and decreased fetal body weights at exposures equal to or greater than therapeutic doses 7
• Pregnancy testing is required before initiation in all patients of childbearing potential 6, 7
• Effective contraception must be used during treatment and for 4 weeks after the final dose 7
• Breastfeeding is not recommended during treatment and for 6 days (approximately 10 half-lives) after the last dose 7
• A pregnancy surveillance program exists; healthcare providers should report exposures by calling 1-800-633-9110 7

Mandatory Baseline Testing and Monitoring

Before Initiation

• Complete blood count (CBC) with differential: ensure absolute neutrophil count ≥1000 cells/mm³, lymphocyte count ≥500 cells/mm³, hemoglobin ≥9 g/dL, platelet count ≥150×10⁹/L 4, 6
• Comprehensive metabolic panel (CMP): including liver enzymes (must be <1.5× ULN), renal function 4, 6
• Fasting lipid profile: total cholesterol, LDL, HDL, triglycerides 4, 6
• Tuberculosis screening: IGRA or tuberculin skin test, plus chest X-ray if not recently performed 4, 6
• Hepatitis B and C screening: anti-HBs, anti-HBc, HBsAg, and HCV antibody 6
• Pregnancy test in all patients of childbearing potential 6, 7

Vaccination Requirements

• Recombinant zoster vaccine (Shingrix): 2-dose series separated by 2–6 months for all adults ≥18 years 4, 6
• Inactivated pneumococcal vaccine for adults ≥18 years 4, 6
• Annual inactivated influenza vaccine 4, 6
• Complete all non-live vaccines at least 2 weeks before initiation, as JAK inhibition attenuates vaccine responses 6
• Live vaccines are contraindicated during treatment 4

Post-Initiation Monitoring

• CBC with differential: at 4–8 weeks, then every 3 months 4, 6
• Liver enzymes: at 4 weeks, then every 3 months 4, 6
• Lipid profile: at 4 weeks (abrocitinib) or 12 weeks (upadacitinib), then annually 4, 6
• Renal function: every 3 months 4, 6

Long-Term Safety Profile

• Treatment-emergent adverse event rates range from 112.0 to 401.1 events per 100 patient-years across indications 2
• Serious treatment-emergent adverse events range from 4.5 to 11.0 events per 100 patient-years 2
• Events leading to discontinuation range from 2.9 to 8.3 events per 100 patient-years 2
• Deaths range from 0 to 0.7 events per 100 patient-years 2
• Rates of serious infections, herpes zoster, malignancy, NMSC, MACE, and VTE remain stable over time with up to 3 years of exposure 2, 5, 3

Special Populations

• Patients ≥65 years have higher rates of overall adverse events, including serious infections, compared to younger patients 7
• The FDA label recommends use of JAK inhibitors in patients with prior failure or intolerance to TNF antagonists in the United States 4
• Dose adjustment is required in patients with moderate-to-severe renal impairment 4
• Avoid concomitant use with biologic DMARDs or potent immunosuppressants (cyclosporine, tacrolimus) due to heightened infection and lymphoma risk 6