Latest Treatment for Pemphigus
The current standard first-line treatment for pemphigus combines oral corticosteroids (prednisolone 0.5-1 mg/kg/day) with a steroid-sparing immunosuppressant, either azathioprine or mycophenolate mofetil, initiated simultaneously at treatment onset. 1
First-Line Treatment Protocol
Corticosteroid Initiation
- Start with oral prednisolone at 1 mg/kg/day for most cases; use 0.5-1 mg/kg/day for milder disease 1
- If no response within 5-7 days, increase dose in 50-100% increments until disease control is achieved 1
- For severe disease requiring doses above 1 mg/kg/day, switch to pulsed intravenous methylprednisolone 250-1000 mg daily for 2-5 consecutive days 1, 2
- Disease control is defined as no new lesions and onset of healing in pre-existing lesions 1
Mandatory Adjuvant Steroid-Sparing Agents
Add one of the following immediately at treatment initiation (not after corticosteroid failure):
- Azathioprine: 2-3 mg/kg/day (if TPMT enzyme activity is normal) 1, 3
- Mycophenolate mofetil: 2-3 g/day in divided doses 1, 3
The British Association of Dermatologists guidelines emphasize that these agents should be started concurrently with corticosteroids, not sequentially 3. There is a critical 6-8 week latent period before steroid-sparing effects manifest, during which adequate corticosteroid coverage must be maintained 1, 2.
Comparative Efficacy: Azathioprine vs. Mycophenolate Mofetil
Recent evidence shows nuanced differences between these two first-line agents:
- Azathioprine achieves lower cumulative corticosteroid doses in randomized trials (azathioprine < IV cyclophosphamide < mycophenolate mofetil) 3
- Mycophenolate mofetil achieves faster time to complete remission on therapy (7.3 vs. 12.5 months, p=0.019) and requires significantly lower cumulative steroid doses to achieve complete remission both on and off therapy 4
- Both agents show similar efficacy rates, with 88-95% of patients achieving remission 3, 4
- Mycophenolate mofetil has fewer grade 3-4 adverse events (19% vs. 33% for azathioprine) 3
Common pitfall: One randomized trial found no advantage of mycophenolate mofetil 3 g/day over corticosteroid monotherapy 5, but this contradicts multiple other studies and likely reflects study design limitations rather than true lack of efficacy.
Corticosteroid Tapering Strategy
Once remission is achieved:
- Reduce prednisolone by one-third to one-quarter every 2 weeks down to 15 mg daily 2
- Then taper by 2.5 mg decrements down to 10 mg daily 2
- Finally reduce by 1 mg monthly with goal of ≤10 mg daily or complete discontinuation 1, 2
- Continue adjuvant immunosuppression throughout the entire taper 2
Critical caveat: Avoid premature treatment withdrawal—47% of successfully treated patients relapse when treatment is stopped after 1 year 1. Up to 77% of deaths in pemphigus patients are corticosteroid-related, emphasizing the importance of aggressive steroid-sparing strategies 1.
Second-Line Treatment Options
Treatment failure is defined as continued disease activity despite 3 weeks of prednisolone 1.5 mg/kg/day, or 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) 1.
For treatment failure with first-line adjuvant drug:
- Switch to the alternate steroid-sparing agent (azathioprine ↔ mycophenolate mofetil) 1
- For gastrointestinal intolerance to mycophenolate mofetil, switch to mycophenolic acid 720-1080 mg twice daily 1
Rituximab: The Game-Changing Third-Line Option
Rituximab combined with short-term corticosteroids represents the most significant advance in pemphigus treatment and is now FDA-approved for moderate-to-severe pemphigus vulgaris. 6
Rituximab Dosing Protocol
- Pemphigus-specific protocol: 2 doses of 1000 mg IV rituximab given on days 1 and 15 7, 6
- Maintenance infusions of 500 mg at months 12 and 18 6
- Pre-medicate with antihistamine, acetaminophen, and methylprednisolone 6
Efficacy Data
- 89% complete remission off all treatment at 2 years when rituximab is combined with short-term prednisone (0.5-1 mg/kg/day tapered over 3-6 months) 7, 6
- In the FDA-approved study, 89% of rituximab-treated patients achieved complete remission off corticosteroids for ≥2 months at 24 months, compared to only 34% with prednisone monotherapy 6
- Clinical improvement typically begins within 6 weeks, with complete healing averaging 15 weeks 7
- Mean time to disease control is 11 months 7
Relapse Management
- Expect relapse in 40-65% of patients, typically occurring 13-17 months after rituximab (range 13-145 months) 7
- For relapse, administer additional 1000 mg infusion no sooner than 16 weeks following previous infusion 6
Critical Safety Considerations
- Perform hepatitis B screening before initiation—reactivation can be fatal 7
- Obtain chest radiograph to evaluate for active or latent tuberculosis 7
- Consider PCP prophylaxis during and following rituximab, particularly with triple immunosuppression 7
- Reduce doses of adjuvant immunosuppressants (azathioprine, mycophenolate mofetil) to minimize infection risk when adding rituximab 7
- Temporarily discontinue adjuvant immunosuppressants if serious infection develops requiring antibiotics; resume at reduced doses once infection resolves 7
Current Approval Status
NHS England approved routine commissioning of rituximab in 2016 for pemphigus that has failed systemic steroids plus adjuvant immunosuppressants 3. The FDA approved rituximab for moderate-to-severe pemphigus vulgaris based on randomized controlled trial data 6.
Advanced Third-Line Therapies for Refractory Disease
For patients resistant to or intolerant of conventional therapy and rituximab:
Immunoadsorption
- Extracorporeal apheresis technique that selectively removes immunoglobulin 3
- Daily treatment over 3 consecutive days can reduce desmoglein antibody levels by up to 95% 3
- Most effective when combined with rituximab to prevent rebound antibody production 3, 7
- In one protocol combining immunoadsorption with rituximab, pulsed dexamethasone, and azathioprine/mycophenolate mofetil, 83% of patients with severe, treatment-resistant pemphigus achieved long-term complete remission 8
- Reserved for recalcitrant cases where conventional therapy has failed 3
Cyclophosphamide
- Can be administered orally (50-150 mg daily) or as intravenous pulse therapy (500-1000 mg monthly) 3, 1
- Dexamethasone-cyclophosphamide pulse (DCP) regimen: 3 × 100 mg IV dexamethasone plus 500 mg IV cyclophosphamide on day 1, repeated every 2-3 weeks initially 3
- Efficacy and adverse events similar to azathioprine in randomized trials, but may achieve lower cumulative corticosteroid doses 3
- Major limitation: potential risk of secondary infertility 3
Plasma Exchange/Plasmapheresis
- Cannot be recommended as routine treatment in newly presenting patients due to lack of demonstrated benefit and risk of fatal sepsis (4 deaths in one randomized trial) 3
- May be considered in refractory cases only if combined with corticosteroids and immunosuppressants to prevent rebound antibody production 3
- Removes pathogenic immunoglobulins but also important plasma proteins including clotting factors 3
Other Options
- Intravenous immunoglobulin (IVIg): Used in refractory cases, often in combination with other therapies 1
- Methotrexate: Alternative steroid-sparing agent, typically 15-20 mg/week 1
- Extracorporeal photopheresis: Small case series show promise (complete remission in 7 of 8 patients), but no RCTs available 3
Agents NOT Recommended
- Ciclosporin cannot be recommended as an adjuvant drug based on current evidence 3
- Gold therapy is rarely used now, though historical data showed some benefit 3
Essential Supportive Care
Osteoporosis Prevention
- Implement osteoporosis prophylaxis immediately upon starting corticosteroids 1, 2
- Assess fracture risk at baseline 3
Infection Surveillance
- Infection and sepsis are significant risks and major causes of mortality 1
- Maintain high vigilance for signs of infection throughout treatment 1, 2
Monitoring Parameters
Baseline assessment should include:
- Weight, blood pressure, height (in children) 3
- Blood glucose and HbA1c, diabetes history 3
- Pregnancy test if appropriate 3
- Full blood count, renal and liver function tests 3