What blood pressure medications can be used in a patient on Prednisone (corticosteroid) and Upadacitinib (Janus kinase inhibitor) to minimize the risk of gastrointestinal perforation?

Blood Pressure Medications for Patients on Prednisone and Upadacitinib

ACE inhibitors or ARBs are the preferred blood pressure medications for patients on prednisone and upadacitinib, as they provide cardiovascular protection without increasing gastrointestinal perforation risk, and proton pump inhibitors should be co-prescribed given the substantially elevated GI risk from the combination of corticosteroids and JAK inhibitors. 1

Primary Antihypertensive Choice

ACE Inhibitors or Angiotensin Receptor Blockers (First-Line)

• ACE inhibitors (or ARBs if ACE inhibitors are not tolerated) are specifically recommended for patients with diabetes or cardiovascular disease to reduce cardiovascular events and mortality 1
• These agents do not increase gastrointestinal bleeding or perforation risk, unlike NSAIDs which must be strictly avoided in this population 2
• ARBs serve as appropriate alternatives when ACE inhibitors cause intolerable cough or angioedema 1

Additional Antihypertensive Options

• Calcium channel blockers, thiazide diuretics, and beta-blockers can all be safely used without increasing GI perforation risk 1
• Beta-blockers are particularly indicated if the patient has heart failure with reduced ejection fraction (LVEF <40%) 1
• Mineralocorticoid receptor antagonists (MRAs) are recommended for patients with heart failure and reduced LVEF but require careful monitoring of potassium and renal function 1

Critical GI Protection Strategy

Mandatory Proton Pump Inhibitor Co-Prescription

• Concomitant PPI use is strongly recommended for patients at high risk of gastrointestinal bleeding, which explicitly includes those on corticosteroids 1
• The combination of prednisone and upadacitinib creates a 2-4 fold increased risk of upper GI complications, with corticosteroids alone doubling the risk and high-dose steroids (≥20 mg prednisone daily) associated with up to 85% mortality from GI perforation due to delayed recognition 2, 3
• JAK inhibitors like upadacitinib further mask perforation symptoms by blunting fever and acute phase reactant elevation, creating diagnostic delay 1, 4

Gastrointestinal Perforation Risk Profile

• Gastrointestinal perforations occurred in 4 patients receiving 45 mg upadacitinib and 1 patient each receiving 30 mg or 15 mg upadacitinib in the U-ENDURE trial 1, 5
• High-dose corticosteroids (prednisone ≥20 mg daily) markedly decrease clinical expression of peritonitis, with mean diagnostic delay of 8.3 days versus 1.7-2.2 days in low-dose or perioperative steroid groups 3
• Abdominal tenderness may be the only consistent clinical finding in high-dose steroid patients with perforation 3

Medications to Strictly Avoid

NSAIDs (Absolute Contraindication)

• All NSAIDs must be discontinued immediately, as they increase upper GI bleeding/perforation risk approximately fourfold, and this risk multiplies when combined with corticosteroids 2
• The combination of NSAIDs with corticosteroids creates synergistic toxicity, with risk being dose-dependent and greater with multiple anti-inflammatory agents 2
• Even COX-2 selective inhibitors should be avoided in this high-risk population 2

Medications Requiring Caution

• Aspirin, even at low doses for cardiovascular protection, increases GI complications twofold and should only be used with mandatory PPI co-prescription 2
• Antiplatelet therapy should be reserved for patients with established cardiovascular disease and always combined with PPI 1

Clinical Monitoring Algorithm

Initial Assessment (First Month)

• Consider weekly clinical assessment during the first month of combined prednisone-upadacitinib therapy 4
• Maintain extremely low threshold for abdominal imaging if any new GI symptoms develop 4
• Do not delay imaging while awaiting laboratory results, as inflammatory markers may be falsely reassuring 4

Ongoing Surveillance

• Monitor blood pressure at each visit, as NSAIDs can increase BP by 5 mmHg on average, though this is not relevant if NSAIDs are avoided 6
• Assess renal function periodically, particularly if using ACE inhibitors/ARBs, as combination with JAK inhibitors requires monitoring 1
• Check for new abdominal symptoms at every encounter, as any persistent abdominal discomfort warrants aggressive diagnostic evaluation 1, 3

High-Risk Patient Considerations

Age-Related Risk Factors

• Patients ≥60 years have 2-3.5 fold increased gastrointestinal risk automatically 4
• Older adults should have particularly aggressive GI protection with PPI and avoidance of all NSAIDs 4

Patients with Prior GI History

• JAK inhibitors should be used with extreme caution in patients with history of diverticulitis or prior GI perforation 1
• Any patient with new onset abdominal signs requires prompt evaluation for early identification of perforation 1
• Surgical consultation should be readily available for this high-risk population 1

Common Pitfalls to Avoid

• Never assume normal inflammatory markers rule out perforation in patients on prednisone and upadacitinib, as both agents suppress fever and acute phase reactants 1, 4, 3
• Do not use multiple anti-inflammatory agents simultaneously, as GI risk is dose-dependent and multiplicative 2
• Avoid delaying surgical evaluation when clinical suspicion exists, even with minimal physical findings 3
• Do not prescribe antihypertensives that increase GI bleeding risk (there are none among standard BP medications, but NSAIDs are sometimes mistakenly used for their cardiovascular effects) 2