What is the recommended treatment protocol for rituximab (rituximab) in a middle-aged or older adult patient with moderate to severe pemphigus vulgaris, considering potential comorbidities and medications?

Rituximab Treatment Protocol for Pemphigus Vulgaris

First-Line Treatment Recommendation

Rituximab combined with short-term prednisolone is now recommended as first-line therapy for moderate to severe pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years—a paradigm shift from reserving rituximab only for refractory cases. 1, 2

Standard Dosing Protocol

Initial Treatment Course

• Administer rituximab 1000 mg IV on days 0 and 14 1, 3
• Combine with prednisolone 0.5-1 mg/kg/day, tapered over 3-6 months 1, 2
• Methylprednisolone 100 mg IV (or equivalent glucocorticoid) should be given 30 minutes prior to each rituximab infusion 3

Maintenance Dosing

• Give rituximab 500 mg IV at month 12, then every 6 months thereafter based on clinical evaluation 3, 4
• Subsequent infusions may be administered no sooner than 16 weeks after the previous infusion 3

Relapse Management

• Upon relapse, administer rituximab 1000 mg IV 3
• Consider resuming or increasing glucocorticoid dose based on clinical evaluation 3

Expected Clinical Timeline

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

Combination with Existing Immunosuppressants

Critical Dose Reduction Strategy

• If patient is already on azathioprine, mycophenolate mofetil, or tacrolimus, continue these agents BUT reduce doses to minimize infection risk 2, 7
• For tacrolimus specifically: reduce to 2-3 mg/day (targeting trough levels of 6 ng/mL) when combined with rituximab 7
• This dose reduction is mandatory—do not continue full-dose conventional immunosuppressants when adding rituximab 2, 7

Mandatory Pre-Treatment Screening

Hepatitis B Screening (Critical)

• Screen all patients for hepatitis B before rituximab initiation, as reactivation can be fatal 2, 7, 3
• If hepatitis B core antibody positive (regardless of surface antigen status): prophylactic antiviral therapy is strongly recommended over monitoring alone 1

Tuberculosis Screening

• Obtain chest radiograph to evaluate for active or latent tuberculosis 2
• If IGRA-positive: initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy 2

Baseline Laboratory Assessment

• Complete blood count 2, 7
• Liver and renal function tests 2, 7

Monitoring Protocol

Initial Phase (First 3-6 Months)

• Complete blood count every 2-4 weeks initially after starting rituximab 2, 7
• Liver and renal function tests regularly 2, 7
• If on tacrolimus: monitor trough levels (target 6 ng/mL) 7

Ongoing Monitoring

• Monitor for TB symptoms monthly during treatment and for at least 12 months after completion 2
• Assess for clinical improvement at each visit 5

Infection Management

• Temporarily discontinue tacrolimus or other immunosuppressants if serious infection develops requiring antibiotics—continuing immunosuppression during active infection increases mortality risk 7
• Consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis when using triple immunosuppression (rituximab + steroid + another immunosuppressant), particularly with additional risk factors 2, 7
• Complete vaccinations before starting rituximab whenever possible 7

Relapse Patterns and Retreatment

• Relapse occurs in 40-65% of patients, typically 13-17 months (range 13-145 months) after rituximab 1, 2, 5
• Upon relapse: administer rituximab 1000 mg IV with consideration to resume or increase glucocorticoid dose 3
• Most patients (60-90%) require additional rituximab courses 8

Comparative Efficacy Data

• Rituximab achieved sustained complete remission in 40% of patients versus 10% with mycophenolate mofetil at 52 weeks 9
• Rituximab resulted in mean cumulative glucocorticoid dose of 3545 mg versus 5140 mg with mycophenolate mofetil over 52 weeks 9
• Disease flares: 6 in rituximab group versus 44 in mycophenolate mofetil group 9
• In treatment-refractory patients, rituximab reduced monthly prednisone intake by 73% (from 658.57 mg/month to 177.22 mg/month) 4

Special Populations Requiring Greater Caution

• Advanced age: More frequent adverse events and need for additional courses 10
• Diabetes or other comorbidities impairing immune function: Require more aggressive dose reduction or closer monitoring 7
• Impaired renal function: Require dose reduction or avoidance of tacrolimus to minimize toxicity risk 7
• History of recurrent infections: Require more aggressive dose reduction or closer monitoring 7

Management of Rituximab-Resistant Cases

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

Critical Pitfalls to Avoid

1. Do not delay rituximab until after multiple failed conventional therapies in appropriate candidates—early use provides better outcomes (89% complete remission at 2 years) and fewer adverse effects compared to prolonged high-dose systemic corticosteroids 1, 2

2. Do not continue full-dose conventional immunosuppressants when adding rituximab—dose reduction is mandatory to prevent severe infections 2, 7

3. Do not skip hepatitis B screening—reactivation can be fatal 2, 7, 3

4. Do not administer rituximab as IV push or bolus—only as IV infusion, and only by healthcare professionals with appropriate medical support to manage severe infusion-related reactions 3

5. Do not continue immunosuppressants during active serious infection requiring antibiotics—temporarily discontinue to reduce mortality risk 7

Administration Details

• Rituximab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal 3
• Administer only as intravenous infusion; do not administer as IV push or bolus 3
• Fatal infusion-related reactions have occurred within 24 hours of rituximab infusion, with approximately 80% occurring with first infusion 3