What is the updated evidence-based protocol for using rituximab (Rituxan) for the treatment of pemphigus vulgaris, including pretreatment medications, loading and maintenance dose regimens?

Updated Evidence-Based Protocol for Rituximab in Pemphigus Vulgaris

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

Pre-Treatment Screening Requirements

Before initiating rituximab, complete the following mandatory screening:

• Hepatitis B serology (HBsAg, anti-HBc, anti-HBs) - reactivation can be fatal 2, 3
• Chest radiograph to evaluate for active or latent tuberculosis 2, 3
• IGRA testing (interferon-gamma release assay) if TB risk factors present 2
• Baseline immunoglobulin levels (IgG, IgM, IgA) 2
• Complete blood count, liver and renal function tests 2

If IGRA-positive, initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy. 2

Pre-Medication Protocol

Administer the following 30 minutes prior to each rituximab infusion:

• Methylprednisolone 100 mg IV (or equivalent) 4
• Acetaminophen 4
• H1 antihistamine (diphenhydramine or equivalent) 4

Loading Dose Regimen

The FDA-approved pemphigus vulgaris protocol consists of:

• Two 1,000 mg IV infusions separated by 2 weeks 4
• Combined with tapering glucocorticoids (prednisolone 0.5-1 mg/kg/day for 3-6 months) 1, 2, 3

This differs from the older rheumatoid arthritis and lymphoma protocols. 3 The British Association of Dermatologists' 2017 RCT demonstrated this regimen (1 g on days 0 and 14, then 0.5 g at 12 and 18 months) achieved significantly superior outcomes compared to prednisolone monotherapy. 1

Maintenance Dose Regimen

After initial loading doses:

• 500 mg IV at Month 12 4
• 500 mg IV every 6 months thereafter (or based on clinical evaluation) 4
• Do not administer sooner than every 16 weeks 4

Management of Adjuvant Immunosuppressants

Reduce doses of concurrent immunosuppressants when adding rituximab to minimize infection risk:

• Azathioprine and mycophenolate mofetil require dose reduction 2, 3
• Tacrolimus should be reduced to 2-3 mg/day (targeting trough levels of 6 ng/mL) 2
• In the pivotal RCT, 79-97% of patients received concomitant corticosteroids and/or immunosuppressants 1

The guideline emphasizes that dose reduction is mandatory, not optional, to prevent severe infections. 2, 3

Infection Prophylaxis

PCP (Pneumocystis jirovecii pneumonia) prophylaxis should be considered:

• During rituximab treatment and following completion 4
• Particularly when using triple immunosuppression or with additional risk factors 2, 3

Monitor for TB symptoms monthly during treatment and for at least 12 months after completion. 2

Expected Clinical Response Timeline

• Clinical improvement begins within 6 weeks of rituximab administration 1, 3, 5
• Complete healing of skin and mucosal lesions averages 15 weeks (range 3-8 weeks) 2, 5
• Mean time to disease control is 11 months 1, 2, 3
• Mean time to remission is 58 months 2, 3

Monitoring Protocol

During treatment:

• Complete blood count every 2-4 weeks initially 2
• Liver and renal function tests regularly 2
• Monitor for infection symptoms continuously 2

Relapse Management

Relapse occurs in 40-65% of patients, typically 13-17 months after rituximab (range 13-145 months). 1, 2, 3, 5

Upon relapse:

• Administer 1,000 mg IV infusion 4
• Consider resuming or increasing glucocorticoid dose 4
• Subsequent infusions may be given no sooner than 16 weeks following the previous infusion 4

Some evidence suggests maintaining low-dose adjuvant immunosuppressants long-term may prevent relapses and reduce need for additional rituximab cycles. 6 A retrospective study of 10 severe pemphigus patients showed that those who adhered to low recommended maintenance doses did not relapse, while those who discontinued or tapered experienced disease flares. 6

Critical Pitfalls to Avoid

Do not delay rituximab until after multiple failed conventional therapies - early use as first-line therapy provides better outcomes (89% vs 34% complete remission) and fewer adverse effects compared to prolonged high-dose corticosteroids. 1, 2

Do not continue full-dose conventional immunosuppressants when adding rituximab - dose reduction is mandatory to prevent severe infections, which can be fatal. 2, 3

Do not skip hepatitis B screening - reactivation can be fatal. 2, 3

Temporarily discontinue adjuvant immunosuppressants if serious infection develops requiring antibiotics - resume at reduced doses once infection resolves. 3, 5

Alternative Strategies for Resistant Cases

For patients resistant to or intolerant of rituximab:

• Immunoadsorption combined with rituximab can reduce circulating desmoglein antibody levels by up to 95% when administered daily over three consecutive days 3, 5
• Novel anti-CD20 agents like veltuzumab (subcutaneous) may benefit rituximab-resistant patients 2, 5

Storage and Administration

• Dilute rituximab to final concentration of 1-4 mg/mL in 0.9% sodium chloride or 5% dextrose 4
• Diluted solutions may be stored refrigerated at 2-8°C for 24 hours 4
• Stable for additional 24 hours at room temperature, though refrigeration preferred 4