What is the best approach to manage a patient with newly elevated blood pressure, reading in the range of hypertensive crisis, who has been on an increased dose of methotrexate (disease-modifying antirheumatic drug) for the past 2 months?

Management of Methotrexate-Associated Hypertension

Immediate Assessment and Testing

Stop methotrexate immediately and evaluate for methotrexate toxicity, as blood pressure readings of 170s/80s-90s represent stage 2 hypertension that requires urgent intervention, and methotrexate can cause renal dysfunction leading to secondary hypertension. 1

Essential Laboratory Testing

• Obtain complete blood count with differential, serum creatinine, liver enzymes (ALT/AST), and albumin immediately to assess for methotrexate-induced organ toxicity, as these are the core monitoring parameters recommended when methotrexate toxicity is suspected 1

• Calculate estimated glomerular filtration rate (eGFR), as methotrexate is 85% renally excreted and renal impairment can cause both methotrexate accumulation and secondary hypertension 1, 2

• Check serum potassium before initiating antihypertensive therapy, particularly if considering ACE inhibitors or ARBs, as hyperkalemia risk increases with renal dysfunction 1

• Perform urinalysis to detect proteinuria or hematuria suggesting methotrexate nephrotoxicity 1

Methotrexate Toxicity Evaluation

• If ALT/AST is elevated >3 times upper limit of normal, discontinue methotrexate permanently until values normalize, then consider reinitiation at lower dose 1

• If creatinine is elevated or eGFR <60 mL/min, hold methotrexate as renal dysfunction dramatically increases toxicity risk and can cause delayed methotrexate elimination 1, 3, 2

• If white blood cell count or platelet count is significantly decreased, administer folinic acid (leucovorin) 10 mg/m² immediately and repeat every 6 hours, as this is the antidote for methotrexate hematologic toxicity 1, 4

Hypertension Management Strategy

Initial Antihypertensive Therapy

Add amlodipine 5-10 mg daily as the first antihypertensive agent, as calcium channel blockers are preferred initial therapy and do not require dose adjustment in renal impairment 1, 5

• For blood pressure 170s/80s-90s without acute end-organ damage symptoms (severe headache, visual changes, chest pain, dyspnea, altered mental status), this represents severe asymptomatic hypertension manageable in outpatient setting with urgent medication adjustment 1, 6

• Target blood pressure <140/90 mmHg minimum, ideally <130/80 mmHg, and reassess within 1 week given severity of elevation 1, 6

Second-Line Agent Selection

If blood pressure remains uncontrolled after 1-2 weeks on amlodipine, add an ACE inhibitor (lisinopril 10-20 mg daily) or ARB (losartan 50-100 mg daily) as second agent, provided renal function is stable (eGFR >30 mL/min) and potassium is normal 1, 5

• Check serum creatinine and potassium 1-2 weeks after starting ACE inhibitor/ARB, as these agents can cause acute kidney injury and hyperkalemia, especially in patients with underlying renal dysfunction 1

Third-Line Agent if Needed

Add chlorthalidone 12.5-25 mg daily or hydrochlorothiazide 25 mg daily as third agent if blood pressure remains ≥140/90 mmHg after optimizing first two agents 1, 5

• Monitor serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect hypokalemia or worsening renal function 1

Methotrexate Management Decisions

If Renal Function is Normal (eGFR ≥60 mL/min)

Resume methotrexate at reduced dose (decrease by 25-50%) once blood pressure is controlled and liver enzymes are normal, with more frequent monitoring every 1-1.5 months initially 1

• Ensure folic acid supplementation of at least 5 mg/week to reduce methotrexate toxicity, though this does not prevent all adverse effects 1

If Renal Function is Impaired (eGFR 30-59 mL/min)

Consider permanent discontinuation of methotrexate or dose reduction of 50-75% with very close monitoring, as renal impairment dramatically increases toxicity risk 1, 2

• If eGFR <30 mL/min, methotrexate is contraindicated and should be permanently discontinued 2

Alternative DMARD Consideration

If methotrexate must be discontinued, consider switching to hydroxychloroquine, sulfasalazine, or leflunomide as alternative disease-modifying antirheumatic drugs that do not cause hypertension 1

Critical Monitoring Schedule

• Week 1: Recheck blood pressure, CBC, creatinine, liver enzymes, potassium 1, 6

• Week 2-4: Recheck blood pressure, creatinine, potassium (especially if ACE inhibitor/ARB or diuretic added) 1

• Monthly for 3 months: CBC, creatinine, liver enzymes if methotrexate resumed 1

• Every 3-4 months thereafter: CBC, creatinine, liver enzymes on stable methotrexate dose 1

Common Pitfalls to Avoid

• Do not resume methotrexate at full dose without confirming normal renal function and liver enzymes, as this risks severe toxicity 1, 2

• Do not use beta-blockers as initial antihypertensive therapy unless compelling indication (heart failure, coronary disease), as they are less effective for stroke prevention 1, 5

• Do not combine ACE inhibitor with ARB, as dual RAS blockade increases adverse events without benefit 1, 5

• Do not delay treatment intensification if blood pressure remains ≥160/100 mmHg, as this represents stage 2 hypertension requiring prompt action 1, 6

• Do not attribute hypertension solely to methotrexate without ruling out other secondary causes (primary aldosteronism, renal artery stenosis, obstructive sleep apnea) if blood pressure remains severely elevated despite treatment 1

Lifestyle Modifications

• Restrict sodium intake to <2 g/day, which provides 5-10 mmHg systolic reduction 1, 5, 6

• Limit alcohol to <100 g/week (approximately 7 standard drinks) 5, 6

• Encourage weight loss if BMI >25 kg/m², as 10 kg weight loss reduces blood pressure by 6/4.6 mmHg 5, 6

• Recommend regular aerobic exercise ≥150 minutes/week, which reduces blood pressure by 4/3 mmHg 5, 6