What is the updated treatment protocol for pemphigus vulgaris, a type of autoimmune bullous disease, using rituximab (anti-CD20 monoclonal antibody) in patients with skin disease?

Updated Rituximab Protocol for Pemphigus Vulgaris Skin Disease

Rituximab combined with short-term prednisolone is now recommended as first-line therapy for newly diagnosed pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years. 1, 2

First-Line Treatment Regimen

Rituximab Dosing

• Administer 1,000 mg intravenous rituximab on Day 1 and Day 15 (two weeks apart) 3
• Give maintenance infusions of 500 mg at months 12 and 18 3
• Premedicate with antihistamine, acetaminophen, and methylprednisolone before each infusion 3

Concurrent Glucocorticoid Protocol

• Start prednisolone 0.5-1 mg/kg/day orally, with dosing based on disease severity 1, 4
• For moderate disease: taper prednisolone off over 3 months 3
• For severe disease: taper prednisolone off over 6 months 3
• Begin tapering once no new lesions appear and existing lesions heal (typically 4-8 weeks), reducing by 5-10 mg weekly initially, then more slowly below 20 mg daily 4

This represents a paradigm shift from historical practice where rituximab was reserved only for refractory cases after multiple failed conventional therapies. 1

Management of Concurrent Immunosuppressants

Critical: Reduce doses of adjuvant immunosuppressive drugs when combining with rituximab to minimize infection risk. 1, 4

• If continuing tacrolimus: reduce to 2-3 mg/day targeting trough levels of 6 ng/mL 1
• Azathioprine or mycophenolate mofetil can be continued but require dose reduction 1, 2
• Do not continue full-dose conventional immunosuppressants when adding rituximab—this is a critical error that increases severe infection risk 1

Pre-Treatment Screening Requirements

Mandatory Screening

• Hepatitis B serology (reactivation can be fatal) 1, 4
• Chest radiograph to evaluate for active or latent tuberculosis 1, 4
• IGRA testing if tuberculosis risk factors present; if positive, initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy 1
• Baseline immunoglobulin levels (IgG, IgM, IgA) 5

Expected Clinical Response Timeline

• Clinical improvement begins within 6 weeks of rituximab administration 1, 2
• Complete healing of skin and mucosal lesions averages 15 weeks (range 3-8 weeks) 1, 2
• Mean time to disease control: 11 months 1
• Mean time to remission: 58 months 1

Monitoring Protocol

Initial Phase

• Complete blood count every 2-4 weeks initially after starting rituximab 1
• Liver and renal function tests regularly 1
• Monitor for TB symptoms monthly during treatment and for at least 12 months after completion 1

Infection Surveillance

• Temporarily discontinue tacrolimus or other immunosuppressants if serious infection develops requiring antibiotics 1
• Consider PCP prophylaxis when using triple immunosuppression, particularly with additional risk factors 1

The FDA label reports that in pemphigus vulgaris patients, 37% experienced treatment-related infections (most commonly herpes simplex, herpes zoster, bronchitis, urinary tract infection), with 8% experiencing serious infections. 3

Relapse Management

• Relapse occurs in 40-65% of patients, typically at 13-17 months (range 13-145 months) after rituximab 1, 2
• For relapse: administer additional 1,000 mg rituximab infusion in combination with reintroduced or escalated prednisolone dose 3
• Maintenance and relapse infusions should be administered no sooner than 16 weeks following the previous infusion 3

Refractory Disease Options

If Inadequate Response by 6-8 Weeks

• Add immunoadsorption combined with rituximab, which can reduce circulating desmoglein antibody levels by up to 95% when administered daily over three consecutive days 1, 2, 4

Rituximab-Resistant Cases

• Consider novel anti-CD20 agents like veltuzumab (subcutaneous) 1, 2

Critical Pitfalls to Avoid

1. Do not delay rituximab until after multiple failed conventional therapies in appropriate candidates—early use provides superior efficacy (89% complete remission at 2 years) and fewer adverse effects 1

2. Do not continue full-dose conventional immunosuppressants when adding rituximab—dose reduction is mandatory to prevent severe infections 1, 4

3. Do not skip hepatitis B screening—reactivation can be fatal 1, 4

4. Do not administer maintenance or relapse infusions sooner than 16 weeks after the previous infusion 3

Infusion-Related Reactions

• Infusion-related reactions occur in 29% after first infusion, 40% after second, 13% after third, and 10% after fourth 3
• Most reactions are mild to moderate (Grade 1 or 2), including headaches, chills, hypertension, nausea, asthenia, and pain 3
• All infusion-related reactions in the FDA pemphigus vulgaris study were mild to moderate except one Grade 3 serious reaction (arthralgia) 3