What is the recommended treatment approach for a patient with adrenal insufficiency and vasculitis?

Treatment of Adrenal Insufficiency in the Context of Vasculitis

For patients with both adrenal insufficiency and active vasculitis, treat the vasculitis aggressively with high-dose glucocorticoids (which simultaneously addresses the adrenal insufficiency) combined with either cyclophosphamide or rituximab, while providing stress-dose steroid coverage and careful monitoring for adrenal crisis. 1

Immediate Management Priorities

Active Vasculitis with Adrenal Crisis

• Administer hydrocortisone 100 mg IV bolus immediately, followed by 100-300 mg/day as continuous infusion or divided doses every 6 hours 1
• Provide rapid IV fluid resuscitation with 3-4 L isotonic saline or 5% dextrose in isotonic saline, with initial infusion rate of approximately 1 L/hour 1
• Do not delay treatment for diagnostic procedures—draw blood for cortisol, ACTH, electrolytes, and ANCA testing, then treat immediately 1
• The high-dose hydrocortisone (100 mg) saturates 11β-HSD type 2 receptors, providing necessary mineralocorticoid effect during acute crisis 1

Organ-Threatening or Life-Threatening Vasculitis

• Initiate remission-induction therapy with glucocorticoids plus either cyclophosphamide OR rituximab (Level 1A evidence, Grade A recommendation for GPA/MPA) 1
• Administer 1,000 mg pulse IV methylprednisolone daily for 1-3 days prior to immunosuppressive therapy 2
• Follow with oral prednisone 1 mg/kg/day (maximum 60 mg/day) with structured tapering 1, 2

Immunosuppressive Regimen Selection

Rituximab Protocol (Preferred in Most Cases)

• Rituximab 375 mg/m² IV weekly for 4 weeks is the standard induction regimen 3, 2
• Rituximab is particularly preferred over cyclophosphamide in relapsing disease, women of childbearing age, or when cyclophosphamide poses fertility risks 3
• Pre-medicate with antihistamine and acetaminophen before each infusion 2
• Provide Pneumocystis jirovecii prophylaxis with trimethoprim/sulfamethoxazole during therapy 3, 2

Cyclophosphamide Alternative

• Oral cyclophosphamide 2 mg/kg/day for 3-6 months can be used as alternative to rituximab 2
• Monitor for leukopenia (occurred in 27% vs 10% with rituximab in trials) 2
• Investigate persistent unexplained hematuria in patients with prior cyclophosphamide exposure 1

Glucocorticoid Management During Vasculitis Treatment

Tapering Strategy with Concurrent Adrenal Insufficiency

• Maintain initial high-dose prednisolone (1 mg/kg/day, max 60 mg) for one month 1
• Taper gradually—at 3 months, target dose should be 10-15 mg/day 1
• Do not use alternate-day therapy, as this increases relapse risk 1
• When hydrocortisone dose falls to <50 mg/day, restart fludrocortisone for mineralocorticoid replacement 1

Monitoring for Secondary Adrenal Insufficiency

• Adrenal insufficiency is common during glucocorticoid withdrawal—49% of patients tested during tapering had initial non-response to ACTH stimulation 4, 5
• Mean time to recovery of adrenal function is 14 months (range up to 51 months) after long-term glucocorticoid therapy 4
• Risk factors for prolonged adrenal suppression include: glucocorticoid >15 mg/day at 6 months, >9.5 mg/day at 12 months, treatment duration >19 months, cumulative dose >8.5 grams, and basal cortisol <386 nmol/L 4
• 5% of patients never recover adrenal function and require lifelong replacement 4

Maintenance Therapy After Remission Induction

Preferred Maintenance Regimen

• Rituximab 500 mg IV every 6 months is superior to azathioprine for maintenance therapy 3
• The MAINRITSAN trial demonstrated major relapses in only 3 patients with rituximab versus 17 with azathioprine (hazard ratio 6.61, P=0.002) 3
• Continue maintenance therapy for at least 18-24 months following induction of sustained remission 1, 3
• Monitor immunoglobulin levels every 6 months, as hypogammaglobulinemia occurs in 27-58% of rituximab-treated patients 1, 2

Alternative Maintenance Options

• Low-dose glucocorticoids combined with azathioprine, methotrexate, or mycophenolate mofetil (Level 1B evidence, Grade A for GPA/MPA) 1
• Continue low-dose glucocorticoids (approximately 5 mg/day prednisolone) during maintenance phase 2

Critical Monitoring and Prevention

Adrenal Crisis Prevention

• Educate patients to increase glucocorticoid doses during intercurrent illness, infections, injuries, or stressors 1, 6
• Provide emergency card warning about acute glucocorticoid replacement needs 6
• Major precipitating factors include gastrointestinal diseases, infections, surgery, strenuous activity, and heat exposure 6
• Mortality rate from adrenal crisis is 0.5 per 100 patient-years despite treatment availability 6

Vasculitis Disease Monitoring

• Use structured clinical assessment rather than ANCA testing to guide treatment changes (Level 4 evidence, Grade D recommendation) 1, 3
• For refractory disease after 4 weeks or <50% reduction in disease activity at 6 weeks, switch from cyclophosphamide to rituximab or vice versa 3
• Manage refractory patients in close collaboration with expert centers 1

Special Considerations

Severe Renal Involvement

• Consider plasma exchange for serum creatinine >3.4 mg/dL (>300 μmol/L), patients requiring dialysis, or rapidly increasing creatinine (Level 1B evidence, Grade B recommendation) 1
• Plasma exchange can also be considered for severe diffuse alveolar hemorrhage with hypoxemia 1

Long-term Complications

• Assess cardiovascular risk periodically 1
• Provide bone protection therapy according to local guidelines for all patients on glucocorticoids 1
• Higher cumulative glucocorticoid doses lead to worse toxicity, including mood disturbance early and adrenal insufficiency later in treatment 7
• Adrenal insufficiency requiring long-term replacement occurs in approximately 4% (15/353) of GCA patients treated with standard regimens, with median cumulative prednisolone dose of 11.53 grams over 121 weeks 5