What are the considerations for combining lisinopril (Angiotensin-Converting Enzyme Inhibitor) with prednisone (corticosteroid) and Rinvoq (upadacitinib) in an adult patient with a history of autoimmune disease, specifically rheumatoid arthritis and hypertension, with potential cardiovascular comorbidities?

Combining Lisinopril with Prednisone and Rinvoq in Hypertension and Rheumatoid Arthritis

Lisinopril is the preferred antihypertensive agent for patients with rheumatoid arthritis and hypertension, and can be safely combined with prednisone and Rinvoq (upadacitinib), though careful monitoring for blood pressure control, cardiovascular risk factors, and infection is essential. 1

Rationale for ACE Inhibitor Use in Rheumatoid Arthritis

ACE inhibitors like lisinopril are specifically recommended as preferred antihypertensive agents in patients with inflammatory rheumatic diseases due to their potential anti-inflammatory properties and evidence of an overactive renin-angiotensin-aldosterone system in these conditions. 1

• The EULAR guidelines explicitly state that ACE inhibitors and angiotensin II blockers are preferred treatment options in rheumatoid arthritis due to their potential anti-inflammatory effects beyond blood pressure control. 1
• These agents may favorably affect inflammatory markers and endothelial function in RA, providing dual benefit for both hypertension management and disease activity. 1
• Blood pressure should be lowered as in the general population, with RAS inhibitors preferentially used alongside effective treatment of the underlying inflammatory disease. 1

Managing Prednisone-Related Cardiovascular Effects

Prednisone should be used at the lowest effective dose possible, as corticosteroids have competing cardiovascular effects—they can worsen traditional risk factors while simultaneously reducing inflammation-driven cardiovascular risk. 1

• Corticosteroids enhance cardiovascular risk through deleterious effects on lipids, glucose tolerance, insulin resistance, blood pressure, and obesity. 1
• Paradoxically, corticosteroids may decrease atherosclerosis risk by suppressing inflammation, which can improve glucose intolerance and dyslipidemia in the context of active RA. 1
• The net cardiovascular effect depends on balancing rheumatic disease features with traditional cardiovascular risk factors—adequate disease control is necessary to lower overall CV risk. 1
• Prednisolone use is independently associated with hypertension presence (OR = 2.39), making blood pressure monitoring particularly important in patients receiving steroids. 2

Upadacitinib (Rinvoq) Safety Considerations

Upadacitinib can be used in patients with cardiovascular risk factors, but requires cautious use in those aged ≥65 years, current or previous long-term smokers, or those with a history of cardiovascular disease, based on extrapolated safety data from the ORAL Surveillance study with tofacitinib. 1, 3, 4

• In the SELECT phase III program, rates of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE) were similar between upadacitinib 15 mg and adalimumab in patients with RA. 3
• Post hoc analysis of higher-risk patients (aged ≥50 years with ≥1 CV risk factor) showed that MACE, malignancy, and VTE were more frequent in higher-risk cohorts but generally similar across upadacitinib and adalimumab treatment groups. 4
• The European Medicines Agency recommends cautious first-line use of JAK inhibitors in patients at risk for adverse cardiovascular outcomes, including those with hypertension as a cardiovascular risk factor. 1

Blood Pressure Monitoring and Target Goals

Target blood pressure should be <140/90 mm Hg minimum, with <130/80 mm Hg preferred for patients with additional cardiovascular risk factors or established cardiovascular disease. 1

• Hypertension is highly prevalent in RA (70.5% in one cohort), frequently under-diagnosed (39.4% undiagnosed), and under-treated (only 21.8% optimally controlled among those receiving therapy). 2
• RA patients receiving steroids should be specifically targeted for blood pressure screening and treatment. 2
• Blood pressure should be reassessed within 1 month after initiating or modifying antihypertensive therapy, with the goal of achieving target BP within 3 months. 1

Drug Interaction Considerations

There are no significant pharmacological interactions between lisinopril, prednisone, and upadacitinib that would preclude their combined use, though NSAIDs should be used cautiously if at all. 1, 5

• NSAIDs and COX-2 inhibitors should be used with caution, especially in patients with documented cardiovascular disease or cardiovascular risk factors, as they may increase cardiovascular risk and interfere with blood pressure control. 1
• One study demonstrated that NSAIDs (ibuprofen, sulindac, diclofenac) did not neutralize the antihypertensive effect of lisinopril combined with hydrochlorothiazide in hypertensive women with arthritis, suggesting the combination's blood pressure-lowering action may not be prostaglandin-dependent. 5
• However, the EULAR guidelines recommend caution with NSAIDs due to potential prothrombotic effects and possible impairment of aspirin's antiplatelet function. 1

Comprehensive Monitoring Strategy

Regular monitoring should include blood pressure measurements, assessment for infection (particularly herpes zoster), cardiovascular risk factor evaluation, and disease activity assessment. 1, 3, 4

• Check blood pressure at each visit, particularly during the first 3-6 months after initiating or changing therapy. 1, 2
• Monitor for herpes zoster, as rates are higher with upadacitinib versus comparators (including adalimumab), with increased risk requiring vigilance. 3, 4
• Assess for serious infections, which occur at higher rates in upadacitinib-treated patients at higher cardiovascular risk compared to methotrexate, though rates were similar to adalimumab. 3, 4
• Evaluate cardiovascular risk factors annually using national guidelines, with risk assessment repeated when antirheumatic treatment is changed. 1
• For RA patients, the cardiovascular risk estimate should be multiplied by 1.5 if at least two of the following criteria are present: disease duration >10 years, RF or anti-CCP positivity, or presence of severe extra-articular manifestations. 1

Optimizing the Treatment Regimen

If blood pressure remains uncontrolled on lisinopril monotherapy, add a calcium channel blocker (amlodipine) or thiazide-like diuretic as the second agent, following standard hypertension treatment algorithms. 1, 6

• The combination of ACE inhibitor plus calcium channel blocker or thiazide diuretic represents guideline-recommended dual therapy with complementary mechanisms of action. 1, 6
• If triple therapy is needed, the preferred combination is ACE inhibitor + calcium channel blocker + thiazide diuretic. 1, 6
• Avoid combining lisinopril with an ARB, as dual RAS blockade increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit. 1

Critical Pitfalls to Avoid

• Do not discontinue or avoid ACE inhibitors in RA patients due to theoretical concerns—they are specifically preferred in this population and should be continued per standard of care. 1
• Do not use high-dose corticosteroids long-term without attempting dose reduction—cardiovascular risk increases with doses ≥7.5 mg prednisone equivalent daily. 1
• Do not ignore blood pressure elevation in patients on prednisone—steroid-induced hypertension requires prompt treatment intensification. 2
• Do not assume upadacitinib is contraindicated in patients with cardiovascular risk factors—it can be used cautiously with appropriate monitoring, particularly at the 15 mg dose. 1, 4
• Do not delay cardiovascular risk assessment—RA itself confers increased cardiovascular risk that should be quantified and managed proactively. 1