What is the updated protocol for using rituximab (rituximab) in the treatment of adults with pemphigus vulgaris 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 considered first-line therapy for newly diagnosed pemphigus vulgaris, achieving 89% complete remission off all treatment at 2 years, representing a major paradigm shift from reserving rituximab only for refractory cases. 1, 2

First-Line Treatment Approach

• Initiate rituximab as first-line therapy in combination with a tapering course of prednisolone starting at 0.5-1 mg/kg/day for most newly diagnosed patients, rather than waiting for treatment failure with conventional immunosuppressants 1, 2
• This approach is FDA-approved for moderate to severe pemphigus vulgaris in adults 3
• The superior efficacy (89% vs 34% complete remission at 2 years) and fewer severe adverse events compared to prolonged high-dose prednisolone alone justify early use 1

Dosing Protocols

• Administer rituximab 2 x 1000 mg infusions given 2 weeks apart (rheumatoid arthritis protocol) OR 375 mg/m² weekly for 4 weeks (lymphoma protocol) 4, 5
• The pemphigus-specific protocol differs from older rheumatoid arthritis dosing and should be followed 4
• First infusion: initiate at 50 mg/hr, increase by 50 mg/hr increments every 30 minutes to maximum 400 mg/hr in absence of infusion toxicity 3
• Subsequent infusions: initiate at 100 mg/hr, increase by 100 mg/hr increments every 30 minutes to maximum 400 mg/hr 3

Combination with Immunosuppressants

• Reduce doses of adjuvant immunosuppressants (azathioprine, mycophenolate mofetil) when adding rituximab to minimize infection risk from cumulative immunosuppression 1, 2, 6
• For tacrolimus specifically: reduce to 2-3 mg/day targeting trough levels of 6 ng/mL (versus standard 4-6 mg/day) when combined with rituximab 6
• Continue adjuvant immunosuppressants during rituximab therapy but plan for dose reduction as clinical improvement occurs 1
• Do not continue full-dose conventional immunosuppressants when adding rituximab—this is a critical error that dramatically increases infection risk 2, 6

Pre-Treatment Mandatory Screening

• Screen all patients for hepatitis B (HBsAg and anti-HBc) before initiating rituximab, as HBV reactivation can result in fulminant hepatitis, hepatic failure, and death 2, 3
• Obtain chest radiograph to evaluate for active or latent tuberculosis; if IGRA-positive, initiate latent TB treatment and delay rituximab for at least 1 month after starting anti-tubercular therapy 2
• Obtain baseline complete blood count with differential and platelets before first dose 3

Expected Clinical Response Timeline

• Clinical improvement typically begins within 6 weeks of rituximab administration 2, 4
• Complete healing of skin and mucosal lesions averages 15 weeks (range 3-8 weeks) 2
• Mean time to disease control is 11 months, with remission achieved at 58 months on average 1, 4
• Clinical remission on therapy occurs in 90-95% of patients, with complete resolution within 3-4 months 5

Monitoring Protocol During Treatment

• Complete blood count every 2-4 weeks initially after starting rituximab, then at 2-4 month intervals during ongoing therapy 2, 6
• Monitor liver and renal function tests regularly 2, 6
• Monitor tacrolimus trough levels if used (target 6 ng/mL when combined with rituximab) 6
• Monitor for tuberculosis symptoms monthly during treatment and for at least 12 months after completion 2
• Continue monitoring for cytopenias after final dose until resolution 3

Relapse Management

• Expect relapse in 40-65% of patients, typically occurring 13-17 months (range 13-145 months) after rituximab 1, 2, 4
• Retreatment with rituximab during relapses is effective and well-tolerated, with 60-90% of patients requiring additional rituximab cycles 5, 7
• Readminister rituximab using the same protocol (2 x 1000 mg doses 2 weeks apart) for relapses, which again results in complete or partial remission 7

Infection Prevention and Management

• Consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis when using triple immunosuppression (rituximab + corticosteroids + another immunosuppressant), particularly with additional risk factors 2, 4
• Temporarily discontinue tacrolimus or other adjuvant immunosuppressants if serious infection develops requiring antibiotics, as continuing immunosuppression during active infection increases mortality risk 2, 6, 4
• Resume immunosuppressants at reduced doses once infection resolves 4
• Complete vaccinations before starting rituximab whenever possible, as the combination dramatically increases infection risk 6

Premedication Requirements

• Premedicate before each rituximab infusion to reduce infusion-related reactions 3
• Rituximab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal 3

Refractory Disease Options

• For rituximab-resistant patients, consider novel anti-CD20 agents like veltuzumab (subcutaneous administration), which has shown efficacy in rituximab-refractory cases 1, 2
• Consider immunoadsorption combined with rituximab, which can reduce circulating desmoglein antibody levels by up to 95% in patients resistant to or intolerant of other approaches 2, 4

Critical Pitfalls to Avoid

• Do not delay rituximab until after multiple failed conventional therapies in appropriate candidates—early use provides better outcomes (89% complete remission) and fewer adverse effects compared to prolonged high-dose corticosteroids 1, 2
• Do not administer rituximab as intravenous push or bolus—only administer as intravenous infusion 3
• Do not ignore hepatitis B screening—reactivation can be fatal and must be screened before treatment initiation 2, 3
• Patients with clinically significant cardiovascular disease or circulating lymphocyte count ≥5,000/mm³ should not receive accelerated 90-minute infusions 3
• Do not use rituximab in patients with active serious infections until infection is controlled 3

High-Risk Populations Requiring Greater Caution

• Patients with advanced age, diabetes, or other comorbidities impairing immune function require more aggressive dose reduction of adjuvant immunosuppressants or closer monitoring 6
• Patients with impaired renal function require dose reduction or avoidance of tacrolimus to minimize toxicity risk 6
• Patients with history of recurrent infections require more aggressive dose reduction of adjuvant agents or closer monitoring 6

Advantages of Early Rituximab Use

• Early rituximab use reduces the chance of adverse effects from prolonged high-dose corticosteroids and results in superior efficacy compared to conventional therapy 2
• NHS England approved routine commissioning of rituximab for pemphigus that has failed steroids plus adjuvant immunosuppressants, ensuring consistent access 1
• The ability to discontinue all immunosuppressive therapy including prednisone in many patients represents a major quality-of-life advantage 8