What is the recommended treatment regimen for pemphigus vulgaris, including first‑line therapy, steroid‑sparing agents, and options for refractory disease?

Treatment of Pemphigus Vulgaris

Rituximab combined with short-term prednisolone is now the first-line treatment for pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years compared to 28% with prednisolone alone. 1

First-Line Therapy: Rituximab Plus Corticosteroids

The 2017 British Association of Dermatologists guidelines represent a paradigm shift based on the first high-quality RCT demonstrating superiority of rituximab over traditional therapy. 1 This combination should be initiated immediately at diagnosis to maximize efficacy and minimize cumulative corticosteroid exposure. 1, 2

Corticosteroid Component

• Initial dosing: Start oral prednisolone at 0.5-1 mg/kg/day for mild disease, or 0.75-1 mg/kg/day for moderate-to-severe disease 1, 3
• Dose escalation: If no response within 5-7 days, increase by 50-100% increments until disease control is achieved 3
• IV pulse therapy: If doses exceed 1 mg/kg/day are required, switch to intravenous methylprednisolone 250-1000 mg daily for 2-5 consecutive days 3
• Disease control timeline: Expect cessation of new lesions within 3 weeks (median), with full healing taking 6-8 weeks 1, 4

Consolidation Phase

Continue the dose that achieved disease control until 80% of lesions have healed (both mucosal and skin) and no new lesions appear for at least 2 weeks. 1 Premature tapering before disease control is established and consolidated leads to relapse and is not recommended. 1

Tapering Protocol

Once consolidation is achieved, reduce prednisolone by one-third to one-quarter every 2 weeks down to 15 mg daily, then by 2.5 mg decrements to 10 mg daily, and finally by 1 mg monthly. 3 The goal is ≤10 mg daily or complete discontinuation. 1, 3

Steroid-Sparing Adjuvant Agents

While rituximab is now preferred first-line, traditional adjuvants remain important when rituximab is unavailable or contraindicated. Add a steroid-sparing agent immediately at treatment initiation, not after corticosteroid failure. 3

Azathioprine (Most Established Alternative)

• Dosing: 2-3 mg/kg/day 3, 5
• Onset: Requires 6-8 weeks before clinical effects manifest 4, 6
• Evidence: Demonstrates 28-45% steroid-sparing effect, though older guidelines noted conflicting RCT data 1
• Monitoring: Consider measuring TPMT activity to guide dosing and predict myelosuppression risk 1

Mycophenolate Mofetil

• Dosing: 2-3 g/day 3, 5
• Onset: 6-8 weeks latency period 6
• Advantage: May be preferred when azathioprine is contraindicated 2
• Caution: Calcium supplements impair absorption; administer at different times 1

Cyclophosphamide

• Oral dosing: Consider as alternative to azathioprine if secondary infertility is not a concern 1
• Pulse therapy: Dexamethasone-cyclophosphamide pulse regimen shows 49% of patients achieving remission with ≤6 pulses, though 11% require >2 years 4
• Long-term outcomes: 63% achieve complete remission, with 41% maintaining remission >2 years 4

Refractory Disease Options

Intravenous Immunoglobulin (IVIg)

• Indication: Patients refractory to oral agents or requiring discontinuation of other therapies 7
• Advantages: Minimal adverse effects, better quality of life, may allow discontinuation of all other therapies 7
• Evidence quality: Promising but based on case series rather than controlled trials 7

Plasmapheresis/Immunoadsorption

• Indication: Severe, nonresponsive cases 5
• Use: Typically combined with immunosuppressive therapy 8

Extracorporeal Photopheresis

• Indication: Recalcitrant cases with failure of conventional therapy 1
• Protocol: 2-day cycles every 2-4 weeks for minimum of two cycles 1
• Evidence: Strength of recommendation B, Quality of evidence III 1

Critical Management Principles

Treatment Duration and Withdrawal

• Minimum duration: Avoid stopping treatment before 1 year, as 47% of successfully treated patients relapse when treatment is stopped at 1 year 4, 3
• Withdrawal sequence: Taper corticosteroids first while maintaining adjuvant immunosuppressants at full dose, then slowly taper adjuvants if remission is maintained 4
• Relapse timing: After rituximab, relapses occur at an average of 145 months but can occur as early as 13-17 months 4

Mandatory Supportive Care

• Osteoporosis prophylaxis: Implement immediately upon starting corticosteroids with calcium, vitamin D, and bisphosphonates for patients expected to take prednisolone ≥7.5 mg daily for ≥3 months 1
• Gastric protection: Proton pump inhibitor for all patients on systemic corticosteroids 1
• Infection surveillance: Daily cleansing with antibacterial products, systematic monitoring for infection, and prompt cultures/treatment when suspected 6
• Pain management: Comprehensive analgesia with baseline and breakthrough dosing, especially for severe oral erosions 6

Topical Adjunctive Therapy for Oral Disease

• Oral hygiene: Soft diet, soft toothbrushes, antiseptic mouthwashes (chlorhexidine 0.2%, hexetidine 0.1%, or 1:4 hydrogen peroxide) 1
• Topical anesthetics: Benzydamine hydrochloride 0.15% before eating or toothbrushing 1
• Topical corticosteroids: Betamethasone sodium phosphate 0.5 mg dissolved in 10 mL water as mouthwash up to four times daily, or triamcinolone acetonide 0.1% paste for isolated erosions 1

Common Pitfalls to Avoid

1. Premature dose reduction: Tapering corticosteroids before achieving and consolidating disease control leads to relapse 1
2. Delayed adjuvant initiation: Waiting for corticosteroid failure rather than starting adjuvants immediately increases cumulative steroid exposure 3
3. Early treatment discontinuation: Stopping therapy at 1 year carries 47% relapse risk 4, 3
4. Inadequate monitoring: Failure to implement osteoporosis prophylaxis and infection surveillance increases morbidity 1, 6
5. Ignoring oral hygiene: Poor dental care leads to decay and secondary candidiasis, prolonging oral disease 1