What is the updated protocol for using rituximab (Rituxan) in the treatment of pemphigus vulgaris, particularly in patients with moderate to severe disease who are refractory to or intolerant of conventional immunosuppressive therapies?

Updated Rituximab Protocol for Pemphigus Vulgaris

Rituximab combined with short-term prednisolone (0.5-1 mg/kg/day for 3-6 months) should now be used as first-line therapy for newly diagnosed moderate to severe pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years compared to only 34% with prednisolone alone. 1, 2

Paradigm Shift in Treatment Approach

This represents a fundamental change from historical practice where rituximab was reserved only for refractory cases. 2 The British Association of Dermatologists now recommends rituximab upfront based on the landmark RITUX 3 trial, which demonstrated superior efficacy and fewer severe adverse events compared to prolonged high-dose corticosteroid monotherapy. 1, 3

FDA-Approved Dosing Protocol

Standard Lymphoma Protocol (FDA-Approved)

• Induction dosing: 375 mg/m² IV weekly for 4 weeks 4
• This remains the FDA-approved regimen for moderate to severe pemphigus vulgaris 4, 3

Alternative Lower-Dose Regimens

• Lower-dose protocols (derived from rheumatoid arthritis dosing: 1000 mg IV on days 1 and 15) are increasingly used in clinical practice and may be equally effective while reducing cost and potentially minimizing adverse effects 5
• The optimal dosing schedule remains uncertain, but lower doses appear sufficient given the lower B-cell burden in pemphigus compared to lymphoproliferative disorders 5

Combination with Corticosteroids

• Combine rituximab with prednisolone 0.5-1 mg/kg/day (not the traditional 1-1.5 mg/kg/day) for 3-6 months, then taper 1, 2
• This short-course steroid approach contrasts sharply with the 12-18 months of high-dose prednisolone used historically 1
• The steroid-sparing effect is substantial and reduces corticosteroid-related grade 3-4 adverse events 1, 3

Managing Concurrent Immunosuppressants

If patients are already on adjuvant immunosuppressants (azathioprine, mycophenolate mofetil, tacrolimus), these can be continued but MUST be dose-reduced to minimize infection risk. 1, 2, 6

Specific Dose Adjustments

• Tacrolimus: Reduce to 2-3 mg/day targeting trough levels of 6 ng/mL (versus standard 4-6 mg/day) 2, 6
• Other immunosuppressants: Consider dose reduction by approximately 50% when adding rituximab 2, 6
• The combination of rituximab with other immunosuppressants dramatically increases infection risk beyond any single agent alone 6

Pre-Treatment Mandatory Screening

Hepatitis B Screening (Critical)

• Screen ALL patients for HBsAg and anti-HBc before initiating rituximab 2, 6, 4
• HBV reactivation can be fatal 2, 4

Tuberculosis Screening

• Obtain chest radiograph and IGRA testing 2
• If IGRA-positive, initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy 2

Baseline Laboratory Studies

• Complete blood count with differential and platelets 4
• Liver and renal function tests 2

Infusion Protocol and Premedication

First Infusion

• Premedicate before each infusion (typically acetaminophen and antihistamine) 4
• Initiate at 50 mg/hr 4
• In absence of infusion toxicity, increase by 50 mg/hr increments every 30 minutes to maximum 400 mg/hr 4
• Must be administered by healthcare professional with capability to manage severe infusion reactions 4

Subsequent Infusions

• Initiate at 100 mg/hr 4
• Increase by 100 mg/hr increments every 30 minutes to maximum 400 mg/hr 4

Expected Clinical Response Timeline

• Initial improvement: Within 6 weeks of rituximab administration 1, 2, 7
• Complete healing: Average 15 weeks (range 3-8 weeks) 2, 7
• Disease control: Mean 11 months 1, 2
• Complete remission: Mean 58 months 1, 2

Monitoring During Treatment

Laboratory Monitoring

• CBC with differential and platelets: Every 2-4 weeks initially 2, 6, 4
• Liver and renal function tests: Regularly throughout treatment 2, 6
• Tacrolimus trough levels: If applicable, target 6 ng/mL 6
• Continue monitoring for cytopenias after final dose until resolution 4

Infection Surveillance

• Monitor for TB symptoms monthly during treatment and for at least 12 months after completion 2
• Consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis when using triple immunosuppression (rituximab + steroid + another immunosuppressant), particularly with additional risk factors 2, 6

Managing Infections During Treatment

• Temporarily discontinue tacrolimus or other immunosuppressants if serious infection develops requiring antibiotics 2, 6
• Continuing immunosuppression during active infection increases mortality risk 6
• Two significant infectious complications were reported in early studies: community-acquired pneumonia with delayed-onset neutropenia and CMV infection in patients on multiple immunosuppressives 8

Relapse Management

• Relapse occurs in 40-65% of patients 1, 7
• Typical relapse timing: 13-17 months after rituximab (range 13-145 months) 1, 2, 7
• For relapse, repeat rituximab infusion using the same protocol 1
• Mean time between cycles when additional courses are needed: 8 months (range 5-60 months) 9

Treatment-Resistant Cases

Immunoadsorption Combined with Rituximab

• For rituximab-resistant or intolerant patients, consider immunoadsorption 2, 7
• Can reduce circulating desmoglein antibody levels by up to 95% when administered daily over three consecutive days 2, 7

Novel Anti-CD20 Agents

• Veltuzumab (humanized anti-CD20 antibody, subcutaneous administration) may benefit rituximab-resistant patients 1, 2, 7
• Case report demonstrated complete remission sustained for 2 years in severe pemphigus refractory to conventional immunosuppression and several cycles of rituximab 1

Critical Pitfalls to Avoid

Do Not Delay Rituximab

• Do not wait until multiple conventional therapies have failed in appropriate candidates 2
• Early rituximab use 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 Immunosuppressants

• Dose reduction of concurrent immunosuppressants is mandatory, not optional 1, 2, 6
• Failure to reduce doses when adding rituximab increases risk of severe infections including fatal outcomes 6

Do Not Skip HBV Screening

• HBV reactivation with rituximab can result in fulminant hepatitis, hepatic failure, and death 2, 4

Do Not Administer as IV Push or Bolus

• Rituximab must only be given as IV infusion per protocol 4

High-Risk Populations Requiring Extra Caution

• Advanced age: Older patients experience more frequent adverse events and require additional courses more often 9
• Diabetes, impaired renal function, or history of recurrent infections: Require more aggressive dose reduction of concurrent immunosuppressants or closer monitoring 6
• Cardiovascular disease or circulating lymphocyte count ≥5,000/mm³: Should not receive accelerated 90-minute infusions 4

Vaccination Considerations

• Complete all vaccinations before starting rituximab whenever possible 6
• Rituximab causes B-cell depletion that impairs vaccine response 6