What is the treatment protocol for pemphigus vulgaris?

Treatment Protocol for Pemphigus Vulgaris

Begin with oral prednisolone 0.5-1 mg/kg/day for mild disease or 1 mg/kg/day for moderate-to-severe disease, combined with a steroid-sparing agent (azathioprine 2-3 mg/kg/day or mycophenolate mofetil 2-3 g/day) from the outset. 1

Initial Treatment Strategy

Corticosteroid Dosing

• Start prednisolone at 1 mg/kg/day for most patients (40-60 mg/day for mild disease, 60-100 mg/day for severe disease) 2, 1
• If no response within 5-7 days, increase dose in 50-100% increments until disease control is achieved (defined as no new lesions and healing of existing ones) 2, 1
• For doses exceeding 100 mg/day or rapidly progressive disease, switch to pulsed intravenous methylprednisolone 250-1000 mg 2, 1
• Prednisolone is preferred over betamethasone or dexamethasone in pregnant patients as it is 90% inactivated by the placenta 1

Mandatory Adjuvant Immunosuppression

Add a steroid-sparing agent immediately at treatment initiation to minimize corticosteroid exposure and associated mortality (up to 77% of deaths are corticosteroid-related): 2, 1

• Azathioprine 2-3 mg/kg/day (requires normal TPMT testing first) 1
• Mycophenolate mofetil 2-3 g/day in divided doses (or mycophenolic acid 720-1080 mg twice daily if GI intolerance occurs) 1
• Expect a 6-8 week latent period before these agents demonstrate clinical effect 1

Osteoporosis Prevention

• Implement bone protection measures immediately upon starting corticosteroids 2, 1

Tapering Protocol

Once remission is achieved (majority of lesions healed):

• Reduce prednisolone by 5-10 mg weekly initially 2
• Taper more slowly below 20 mg daily 2
• Aim to reach ≤10 mg daily or less 1
• Continue adjuvant immunosuppression during taper 1

Second-Line Therapy for Treatment Failure

Treatment failure is defined as: 1

• Continued disease activity despite 3 weeks of prednisolone 1.5 mg/kg/day, OR
• Failure to respond after 12 weeks of azathioprine (2.5 mg/kg/day), mycophenolate mofetil (1.5 g twice daily), cyclophosphamide (2 mg/kg/day), or methotrexate (20 mg/week)

Switch to an alternate steroid-sparing agent if first-line adjuvant fails 1

Third-Line Therapy: Rituximab for Refractory Disease

For treatment-resistant pemphigus, rituximab is the preferred third-line agent, demonstrating superior efficacy with 89% complete remission rates at 2 years when combined with short-term corticosteroids. 3

Rituximab Dosing (FDA-Approved Protocol)

• Initial treatment: Two 1,000 mg IV infusions separated by 2 weeks, combined with tapering glucocorticoids 4
• Maintenance: 500 mg IV at month 12, then every 6 months thereafter 4
• Relapse treatment: 1,000 mg IV infusion (subsequent doses no sooner than 16 weeks apart) 4
• Premedication: Methylprednisolone 100 mg IV (or equivalent) 30 minutes before each infusion 4
• Clinical response typically begins within 6 weeks 3

Alternative Rituximab Protocol

The 2 g rheumatoid arthritis dosing protocol (1,000 mg × 2 doses) is preferred over the lymphoma protocol (375 mg/m² weekly × 4) due to similar efficacy and lower cost 2

Combination Strategies with Rituximab

• Continue adjuvant immunosuppressants but reduce doses to decrease infection risk 2
• For rituximab-resistant cases, consider immunoadsorption combined with rituximab (can reduce desmoglein antibodies by up to 95%) 3

Alternative Third-Line Options

Cyclophosphamide Protocols

For patients who cannot access rituximab or have contraindications:

Dexamethasone-Cyclophosphamide Pulse (DCP) Therapy

• Phase 1: Monthly IV dexamethasone 100 mg on 3 consecutive days + IV cyclophosphamide 500 mg on day 2, plus oral cyclophosphamide 50 mg daily between pulses, continued until remission 2
• Phase 2: Continue DCP for 6 additional months (consolidation) 2
• Phase 3: Oral cyclophosphamide alone for 1 year 2
• Phase 4: Withdraw all treatment if no relapses 2
• This regimen achieved 86% remission off therapy for ≥2 years with 2% mortality 2

Alternative Cyclophosphamide Regimens

• IV pulse: 15 mg/kg (maximum 1500 mg) monthly with conventional oral corticosteroids 2, 5
• Oral daily: 2 mg/kg/day (treatment failure defined as no disease control after 3 months at this dose) 2, 5
• Always administer mesna with IV cyclophosphamide to prevent hemorrhagic cystitis (occurs in 6% without protection) 2, 5

Other Third-Line Options

• Intravenous immunoglobulin 1
• Immunoadsorption 1
• Methotrexate 1
• Plasmapheresis (though one RCT showed no benefit over steroids alone) 2

Critical Monitoring and Safety Considerations

Infection Prophylaxis

• Pneumocystis jirovecii prophylaxis: Trimethoprim/sulfamethoxazole 800/160 mg on alternate days or 400/80 mg daily for all patients on cyclophosphamide 5
• PCP prophylaxis recommended during and for at least 6 months after rituximab in pemphigus patients 4
• Infection and sepsis are major causes of mortality—maintain high vigilance 1

Common Pitfalls to Avoid

• Do not withdraw treatment prematurely: 47% of successfully treated patients relapse when treatment is stopped after only 1 year 1
• Expect delayed response from adjuvants: Azathioprine and mycophenolate require 6-8 weeks to show effect; maintain adequate corticosteroid coverage during this period 1
• Monitor for cyclophosphamide toxicity: Amenorrhea occurs in 20-85% of menstruating women, azoospermia in men, and pituitary-adrenal suppression in 55% of patients 2, 5
• Relapse after rituximab: Occurs in up to 65% of patients, typically 13-17 months post-treatment; monitor closely 3

Timeline Expectations

• Clinical improvement typically occurs within days of adequate corticosteroid dosing 1
• Complete healing usually takes 3-8 weeks 1, 3
• Immunofluorescence titers lag behind clinical improvement 2, 1