What is the risk of gastrointestinal perforation in older adult patients with a history of gastrointestinal issues taking Prednisone and Upadacitinib (Rinvoq)?

Risk of Gastrointestinal Perforation with Prednisone and Upadacitinib

The combination of prednisone and upadacitinib creates a substantially elevated risk of gastrointestinal perforation in older adults with pre-existing GI issues, and this combination should be avoided whenever possible or used only with extreme caution and intensive monitoring. 1

Magnitude of Combined Risk

Both medications independently increase perforation risk, and their combination creates additive or potentially synergistic danger:

• Upadacitinib alone causes gastrointestinal perforations at clinically significant rates: 4 patients on 45 mg, 1 patient on 30 mg, and 1 patient on 15 mg developed perforations in the U-ENDURE maintenance trial 2
• The FDA label explicitly warns that corticosteroids are a known risk factor for gastrointestinal perforation in patients taking upadacitinib 1
• High-dose corticosteroids (≥20 mg prednisone daily) are associated with 85% mortality from GI perforation, compared to only 11.8-13.3% in low-dose or perioperative steroid groups 3
• Corticosteroids increase the risk of GI bleeding or perforation by 40% overall (OR 1.43,95% CI 1.22-1.66), with even higher risk in hospitalized patients (OR 1.42,95% CI 1.22-1.66) 4

Critical Risk Factors in Your Patient Population

Older adults with GI history face compounded danger:

• Age ≥60 years automatically increases gastrointestinal risk by 2-3.5 fold 5
• History of peptic ulcer disease increases risk by 2.39-fold for first GI event and 4.76-fold for subsequent events 6
• History of diverticulitis is specifically identified as a risk factor for perforation with upadacitinib 1
• The 2019 AGS Beers Criteria strongly recommends avoiding NSAIDs and corticosteroids in older adults due to increased risk of GI bleeding, ulcers, and perforation 7

Dangerous Clinical Presentation Pattern

The most lethal aspect of this combination is that high-dose corticosteroids mask perforation symptoms:

• High-dose steroids (≥20 mg prednisone daily) suppress clinical signs of peritonitis, with only abdominal tenderness consistently present 3
• Mean delay from symptom onset to treatment is 8.3 days in high-dose steroid patients versus 1.7-2.2 days in low-dose or no-steroid patients (p<0.005) 3
• JAK inhibitors like upadacitinib may further mask perforation by blunting fever and acute phase reactant elevation 8
• This diagnostic delay directly contributes to the 85% mortality rate in high-dose steroid patients with perforation 3

Mandatory Risk Mitigation Strategy

If this combination cannot be avoided, implement the following protocol:

Immediate Actions:

• Discontinue all NSAIDs immediately—NSAIDs independently increase perforation risk and are contraindicated with this combination 7, 1, 6
• Reduce prednisone to lowest effective dose (ideally <20 mg daily) to minimize the masking effect on peritonitis 3
• Screen for and treat diverticulitis before initiating upadacitinib if any history exists 1

Patient Education (Critical):

• Instruct patient to report ANY new abdominal discomfort immediately—do not wait for severe pain 1, 3
• Warn about specific symptoms: new onset abdominal pain, fever, chills, nausea, vomiting, change in bowel habits, or abdominal distension 8, 1
• Emphasize that symptoms may be subtle due to steroid effects 3

Monitoring Protocol:

• Maintain extremely low threshold for imaging—obtain CT abdomen for any new abdominal symptoms, even without fever or elevated inflammatory markers 8
• Do not delay imaging while awaiting laboratory results 8
• Consider weekly clinical assessment during the first month of combined therapy 9
• Arrange urgent surgical consultation if perforation is suspected 8

Alternative Approaches to Consider

Before accepting this high-risk combination, exhaust these options:

• Biologic agents with lower perforation risk: Vedolizumab shows 32% lower risk of serious infections compared to TNF antagonists in UC patients 7
• Steroid-sparing strategies: Prioritize achieving steroid-free remission, as ongoing corticosteroid use is itself a major determinant of adverse safety outcomes 7
• Lower upadacitinib dose: The 15 mg dose has lower perforation risk than 30 mg or 45 mg doses 2

Specific Contraindications

Do not use this combination if patient has:

• Active diverticulitis or recent diverticulitis episode 1
• History of GI perforation 1
• Concurrent NSAID requirement that cannot be discontinued 7, 1, 6
• Severe underlying disease requiring high-dose corticosteroids (≥20 mg prednisone daily) 3

Documentation Requirements

For medicolegal protection and patient safety:

• Document discussion of specific perforation risk with patient and family 1
• Record that patient understands to seek immediate care for any abdominal symptoms 1
• Note that alternative therapies were considered and reasons for proceeding with this high-risk combination 7