Side Effects of Upadacitinib in Rheumatoid Arthritis
Upadacitinib carries significant safety risks including increased rates of serious infections, venous thromboembolism, herpes zoster, and cardiovascular events, with these risks substantially elevated in patients ≥50 years with cardiovascular risk factors, requiring careful patient selection and monitoring. 1
Black Box Warnings and Major Safety Concerns
The FDA has issued black box warnings for all JAK inhibitors, including upadacitinib, based on increased risks of: 2, 1
- Major adverse cardiovascular events (MACE)
- Venous thromboembolism (VTE) including pulmonary embolism
- Malignancies
- Death in patients ≥50 years with cardiovascular risk factors
Venous Thromboembolism Risk
Numerically increased rates of VTE have been observed with upadacitinib 15 mg once daily in clinical trials, though not in the head-to-head trial against adalimumab. 3
Risk factors that substantially increase VTE risk include: 3
- Age >65 years (up to 10-fold increased risk with prior VTE history)
- High BMI/obesity
- Immobilization or recent surgery
- Concurrent COX-2 inhibitor use (2-fold increased risk)
- History of prior VTE (up to 10-fold increased risk)
The baseline VTE risk in RA patients is already doubled compared to the general population (0.25/100 patient-years), and JAK inhibitors further increase this risk. 3
Common Adverse Events
The most frequently reported adverse events with upadacitinib 15 mg include: 1, 4
- Upper respiratory tract infections (13.5% vs 9.5% placebo)
- Nasopharyngitis
- Nausea (3.5% vs 2.2% placebo)
- Cough (2.2% vs 1.0% placebo)
- Increased creatine phosphokinase (CPK)
Serious Infections
Serious infection rates with upadacitinib 15 mg are comparable to adalimumab in the overall population but significantly higher in patients ≥65 years with cardiovascular risk factors. 3, 5
Key infection-related risks: 1, 6, 5
- Serious infections: 4.6 per 100 patient-years with upadacitinib 15 mg vs 2.3 per 100 patient-years with placebo
- Herpes zoster: Substantially elevated compared to adalimumab and placebo across all populations
- Opportunistic infections: Higher rates than adalimumab (excluding tuberculosis, herpes zoster, and oral candidiasis)
- Tuberculosis reactivation: Requires mandatory screening before initiation
Herpes Zoster
Herpes zoster rates are consistently and significantly elevated with upadacitinib compared to both placebo and adalimumab across all patient populations. 5, 7
- This risk is present regardless of age or cardiovascular risk factors
- Recombinant zoster vaccine (Shingrix) is recommended before initiating therapy 2, 8
Malignancy Risk
Malignancy rates (excluding non-melanoma skin cancer) are increased in higher-risk populations but generally similar between upadacitinib and adalimumab. 5
- Non-melanoma skin cancer (NMSC): Higher rates with upadacitinib versus comparators across all populations 5
- Three malignancies were reported during the placebo-controlled phase in upadacitinib-treated patients, none in placebo 6
Cardiovascular Events
MACE rates are more frequent in higher-risk cohorts (age ≥50 years with ≥1 CV risk factor) but generally similar between upadacitinib 15 mg and adalimumab. 5
- One MACE was reported during placebo-controlled trials in upadacitinib-treated patients 6
- No increased MACE risk observed in randomized controlled trials and long-term extensions in the overall population 3
Laboratory Abnormalities
Creatine Phosphokinase (CPK) Elevations
CPK elevations occur more frequently with upadacitinib than adalimumab but are usually without clinical sequelae. 3, 7
- Typically occur without muscle weakness or myalgia 3
- One case of rhabdomyolysis has been reported 3
- CPK testing is not routinely necessary unless symptoms develop 3
Other Laboratory Changes
Additional laboratory abnormalities include: 3
- Creatinine increases: Observed without organ dysfunction or hypertension
- Anemia: Most frequent with the 30 mg dose (not approved for RA) 4
- Lipid elevations: Require baseline and periodic monitoring 2
Gastrointestinal Perforation
Gastrointestinal perforation has been reported with JAK inhibitors and represents a potential risk with upadacitinib. 3
Use with extreme caution in patients with: 3
- History of diverticulitis
- Concurrent NSAID use
- Concurrent glucocorticoid use
Critical pitfall: Fever and acute phase reactant elevations may be blunted by JAK inhibitor therapy, delaying diagnosis. Evaluate any new abdominal symptoms promptly. 3
Age-Specific Considerations
The European Medicines Agency recommends using JAK inhibitors in patients ≥65 years only when no alternative treatment exists. 3, 8
For patients ≥50 years with cardiovascular risk factors: 2, 8
- JAK inhibitors should not be first-line therapy when TNF inhibitors remain an option
- Multiple risk factors have cumulative effects
- Serious infection rates are several-fold higher with higher doses
Pregnancy and Lactation
Upadacitinib is contraindicated in pregnancy and lactation. 3
- Contraception is required for both female and male patients 3
- A 4-week gap is recommended after the last dose before attempting conception 3
- Pregnancy testing is required before initiation in all patients of childbearing potential 9
Mandatory Monitoring Requirements
Before initiating upadacitinib: 2
- Tuberculosis screening with IGRA or tuberculin skin test
- Complete blood count with differential
- Liver enzymes and renal function
- Lipid profile
- Hepatitis B and C testing
During treatment: 8
- CBC with differential and comprehensive metabolic panel at baseline, 4-8 weeks after starting, then every 3 months
- Clinical monitoring for signs of infection, particularly herpes zoster
- Warning signs of VTE (leg swelling, chest pain, shortness of breath)
Contraindications
Absolute contraindications include: 3
- Severe active infections (acute or chronic, including latent TB)
- Severe hepatic impairment (Child-Pugh C)
- Pregnancy and lactation
- Uncontrolled malignancy or ongoing chemotherapy
Relative contraindications requiring careful risk-benefit assessment: 3, 8
- Age ≥65 years (use only if no alternatives exist)
- Age ≥50 years with cardiovascular risk factors
- History of VTE
- Concurrent COX-2 inhibitor use
- History of diverticulitis with concurrent NSAID/glucocorticoid use
Critical Clinical Pitfalls to Avoid
Do not use upadacitinib as first-line therapy in patients ≥50 years with cardiovascular risk factors when biologics are appropriate alternatives. 2, 8
Do not overlook cumulative risk factors for VTE (age, obesity, immobilization, COX-2 inhibitors, prior VTE history) - even one major risk factor may make upadacitinib inappropriate. 3, 8
Do not fail to vaccinate against herpes zoster before starting therapy - this is a consistent and significant risk across all populations. 2, 8
Do not initiate during active serious infections or without completing tuberculosis screening. 3, 2
Do not combine with other potent immunosuppressants or biologics beyond established conventional synthetic DMARD combination therapy. 2, 9