Can upadacitinib (a Janus kinase inhibitor) increase blood pressure in patients, particularly those with pre-existing hypertension or cardiovascular risk factors?

Can Upadacitinib Increase Blood Pressure?

Upadacitinib does not directly increase blood pressure as a primary adverse effect, but requires careful cardiovascular monitoring in patients with pre-existing hypertension or cardiovascular risk factors due to increased risks of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). 1, 2

Evidence from Clinical Guidelines and Safety Data

The available evidence does not identify hypertension or blood pressure elevation as a characteristic adverse effect of upadacitinib, distinguishing it from other kinase inhibitors:

• VEGF receptor tyrosine kinase inhibitors (sorafenib, sunitinib) cause marked hypertension with prevalence ranging from 17-43% for sorafenib and 5-24% for sunitinib, with increases of 20-30 mmHg systolic and 9-17 mmHg diastolic pressure 3
• Bevacizumab causes hypertension in 7-36% of patients through VEGF receptor inhibition, which reduces nitric oxide formation and increases peripheral resistance 3
• Upadacitinib, as a JAK1 inhibitor, operates through a different mechanism and does not share this hypertensive profile 1, 4

Cardiovascular Risk Profile of Upadacitinib

While upadacitinib does not directly elevate blood pressure, it carries important cardiovascular considerations:

MACE and VTE Rates

• Across rheumatoid arthritis and psoriatic arthritis populations, MACE rates were 0.3-0.6 events per 100 patient-years and VTE rates were 0.2-0.4 events per 100 patient-years 2
• These rates were similar across upadacitinib 15 mg and 30 mg doses and comparable to adalimumab and methotrexate comparators 2
• In a pharmacovigilance analysis of 13,556 cardiovascular adverse event reports, upadacitinib showed signals for embolic and thrombotic events (ROR025 = 1.23) but not for hypertension 5

High-Risk Patient Populations Requiring Enhanced Monitoring

The American Gastroenterological Association and FDA provide clear guidance on which patients require special consideration 1:

• Age ≥65 years with any cardiovascular risk factor: avoid upadacitinib unless no alternatives exist 1
• Current or previous long-term smokers with cardiac history require careful evaluation 1
• History of venous thromboembolism is a specific risk factor 1
• Pre-existing cardiovascular disease requires enhanced cardiovascular monitoring 1

Most patients experiencing MACE or VTE events had two or more baseline cardiovascular risk factors 2

Clinical Management Algorithm

For Patients with Pre-existing Hypertension

Baseline Assessment:

• Complete blood count with differential, liver enzymes 1
• Lipid panel (check at 12 weeks post-initiation) 1
• Viral hepatitis and tuberculosis testing 1
• Document all cardiovascular risk factors including smoking status, diabetes, coronary disease 1

Risk Stratification:

• Low risk (controlled hypertension, age <65, no other CV risk factors): upadacitinib can be used with standard monitoring 1
• Moderate risk (age ≥65 OR multiple CV risk factors): requires enhanced cardiovascular monitoring, consider TNF inhibitors first 1
• High risk (age ≥65 AND multiple CV risk factors): avoid upadacitinib unless TNF antagonists have failed or are not tolerated 1

Monitoring During Therapy:

• Blood pressure should be monitored as part of routine cardiovascular assessment, though not specifically for upadacitinib-induced hypertension 3
• Focus monitoring on signs of thrombotic events, MACE, and VTE rather than blood pressure elevation 2, 5
• For patients with inflammatory rheumatic diseases (which includes rheumatoid arthritis), blood pressure should be controlled preferentially with RAS-inhibitors and CCBs 3

Dose Adjustments for Special Populations

• Severe renal impairment (CrCl <30 mL/min): maximum dose 15 mg daily 1
• Severe hepatic disease (Child-Pugh C): upadacitinib not recommended 1
• Age ≥75 years: consider dose reduction to 15 mg daily 1

Important Clinical Caveats

Do not confuse upadacitinib with VEGF inhibitors: Unlike tyrosine kinase inhibitors targeting VEGF receptors (sorafenib, sunitinib, bevacizumab), which cause hypertension through nitric oxide pathway disruption, upadacitinib's JAK1 inhibition mechanism does not directly affect blood pressure regulation 3, 5

If blood pressure increases in a patient on upadacitinib, investigate alternative causes:

• Concurrent NSAIDs (can elevate BP) 3
• Decongestants (phenylephrine, pseudoephedrine) 3
• Corticosteroids used for disease flares 3
• Underlying inflammatory disease activity 3

The primary cardiovascular concern with upadacitinib is thrombotic risk, not hypertension: The FDA and European Medicines Agency recommend JAK inhibitors only after TNF antagonist failure or intolerance, with cautious first-line use in patients at cardiovascular risk 1

Safety Profile Across Indications

In an integrated analysis of 6,991 patients across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and atopic dermatitis representing 15,425 patient-years of exposure, hypertension was not identified as a treatment-emergent adverse event of particular concern 6. The most common adverse events were infections, herpes zoster, and laboratory abnormalities (creatine phosphokinase elevations), not cardiovascular events 6.

Most comparative safety studies (64%) reported no statistically significant difference in cardiovascular safety outcomes between upadacitinib and other active treatments or placebo 7