Upadacitinib Safety Considerations in Rheumatoid Arthritis

Introduction to Safety Risks

The American College of Rheumatology recommends careful patient selection and monitoring due to increased risks of serious infections, venous thromboembolism, herpes zoster, and cardiovascular events with upadacitinib, particularly in patients ≥50 years with cardiovascular risk factors 1.

The FDA has issued black box warnings for all JAK inhibitors, including upadacitinib, based on increased risks of major adverse cardiovascular events (MACE), venous thromboembolism (VTE) including pulmonary embolism, malignancies, and death in patients ≥50 years with cardiovascular risk factors 2.

Numerically increased rates of VTE have been observed with upadacitinib 15 mg once daily in clinical trials, with risk factors including age >65 years, high BMI/obesity, immobilization or recent surgery, concurrent COX-2 inhibitor use, and history of prior VTE 3, 4.
The baseline VTE risk in RA patients is already doubled compared to the general population, and JAK inhibitors further increase this risk 3.

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 5.
Herpes zoster rates are substantially elevated compared to adalimumab and placebo across all populations 2.

Herpes zoster rates are consistently and significantly elevated with upadacitinib compared to both placebo and adalimumab across all patient populations, regardless of age or cardiovascular risk factors 2.
The European League Against Rheumatism recommends recombinant zoster vaccine (Shingrix) before initiating therapy 1, 2.

Malignancy rates (excluding non-melanoma skin cancer) are increased in higher-risk populations but generally similar between upadacitinib and adalimumab 2.

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 4.

CPK elevations occur more frequently with upadacitinib than adalimumab but are usually without clinical sequelae 4.
Creatinine increases are observed without organ dysfunction or hypertension 1.
Lipid elevations require baseline and periodic monitoring 1.

Gastrointestinal perforation has been reported with JAK inhibitors and represents a potential risk with upadacitinib, particularly in patients with history of diverticulitis, concurrent NSAID use, or concurrent glucocorticoid use 4, 2.

The European Medicines Agency recommends using JAK inhibitors in patients ≥65 years only when no alternative treatment exists 3, 2.

Upadacitinib is contraindicated in pregnancy and lactation, with contraception required for both female and male patients 5, 6.

Mandatory monitoring requirements before initiating upadacitinib include tuberculosis screening, complete blood count with differential, liver enzymes and renal function, lipid profile, and hepatitis B and C testing 1.
During treatment, monitoring requirements include CBC with differential and comprehensive metabolic panel at baseline, 4-8 weeks after starting, then every 3 months, as well as clinical monitoring for signs of infection and warning signs of VTE 2.

Absolute contraindications include severe active infections, severe hepatic impairment, pregnancy and lactation, and uncontrolled malignancy or ongoing chemotherapy 5, 2.
Relative contraindications requiring careful risk-benefit assessment include age ≥65 years, age ≥50 years with cardiovascular risk factors, history of VTE, concurrent COX-2 inhibitor use, and history of diverticulitis with concurrent NSAID/glucocorticoid use 5, 2, 3.

Do not use upadacitinib as first-line therapy in patients ≥50 years with cardiovascular risk factors when biologics are appropriate alternatives 1, 2.
Do not overlook cumulative risk factors for VTE, even one major risk factor may make upadacitinib inappropriate 4, 3, 2.
Do not fail to vaccinate against herpes zoster before starting therapy, as this is a consistent and significant risk across all populations 1, 2.
Do not initiate during active serious infections or without completing tuberculosis screening 5, 1.
Do not combine with other potent immunosuppressants or biologics beyond established conventional synthetic DMARD combination therapy 1, 6.