What precautions and screenings should be done before administering rituximab (Rituxan)?

Pre-Rituximab Screening and Precautions

All patients must undergo hepatitis B virus screening with HBsAg, anti-HBc, and anti-HBs before initiating rituximab, as this agent carries the highest risk of HBV reactivation among all immunosuppressive therapies, which can result in fulminant hepatitis and death. 1, 2

Mandatory Hepatitis B Screening

Universal HBV screening is non-negotiable before rituximab administration. The FDA label explicitly requires screening all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment 1. This recommendation is reinforced by multiple guidelines emphasizing that rituximab poses the highest reactivation risk compared to other immunosuppressive agents 3, 2.

Required HBV Tests:

• Hepatitis B surface antigen (HBsAg) 3, 1
• Hepatitis B core antibody (anti-HBc) 3, 1
• Hepatitis B surface antibody (anti-HBs) 3, 2

The rationale for comprehensive three-marker screening is that HBV reactivation occurs not only in HBsAg-positive patients but also in those who are HBsAg-negative but anti-HBc-positive (resolved or occult infection) 1. Reactivation has been documented even in patients with apparent resolved infection (HBsAg negative, anti-HBc positive, anti-HBs positive) 1.

Management Based on HBV Screening Results

If HBsAg Positive (Chronic HBV):

• Consult hepatology immediately 1
• Start potent antiviral therapy (entecavir or tenofovir) before rituximab initiation 3, 2
• Continue antiviral prophylaxis for at least 12 months after the last rituximab dose (not 6 months as with other immunosuppressants) 3
• The extended duration is necessary because immune recovery is delayed with B-cell depleting therapy, and reactivation risk persists up to 1-2 years post-treatment 3

If HBsAg Negative but Anti-HBc Positive (Resolved/Occult HBV):

• Obtain baseline HBV DNA to rule out occult active infection 2
• Initiate prophylactic antiviral therapy (entecavir or tenofovir preferred) before rituximab 3, 2
• Guidelines strongly recommend prophylaxis over monitoring alone for all rituximab patients who are anti-HBc positive, regardless of HBsAg status, because HBsAg seroreversion consistently associates with hepatitis flare 2
• Continue prophylaxis until 12 months after last rituximab dose 3
• Monitor HBV DNA (or HBsAg) up to 2 years after last rituximab dose, as late reactivation can occur 3

If All HBV Markers Negative:

• Proceed with rituximab without antiviral prophylaxis 2
• Consider HBV vaccination if anti-HBs is also negative 2

Additional Mandatory Pre-Treatment Testing

Baseline Laboratory Tests:

• Complete blood count (CBC) with differential and platelets 1
• Transaminases (ALT/AST) to establish baseline liver function 2
• Serum creatinine and estimated GFR, particularly for patients with vasculitis or kidney involvement 2
• Baseline IgG level, as low IgG (<3 g/L) predicts higher risk of secondary immunodeficiency 4, 2

Infectious Disease Screening:

• Tuberculosis screening (interferon-gamma release assay or tuberculin skin test) unless already performed before other immunosuppression without subsequent TB exposure 4, 2
• HIV testing for patients with HIV risk factors 2

Vaccination Considerations

Administer indicated vaccines before rituximab whenever possible, as rituximab impairs immune response for at least 6 months after treatment 3. Specifically:

• Pneumococcal and influenza vaccines should be given before rituximab initiation when indicated 3
• Withhold all live-attenuated vaccines during rituximab therapy and for a period after treatment due to risk of vaccine-induced infection 3
• If tetanus exposure occurs within 6 months of rituximab treatment, administer tetanus immunoglobulin rather than vaccine, as antibody response may be inadequate 3

Premedication Requirements

Premedicate before each rituximab infusion to reduce infusion-related reactions 1:

• Antihistamine 1
• Acetaminophen 1
• Methylprednisolone 100 mg IV (or equivalent) 30 minutes before infusion for rheumatoid arthritis, GPA, MPA, and pemphigus vulgaris patients 1
• For pediatric patients with mature B-cell NHL/B-AL, administer prednisone as part of chemotherapy regimen 1

Critical Pitfalls to Avoid

Do not use lamivudine for HBV prophylaxis due to high resistance rates; use entecavir, tenofovir, or tenofovir alafenamide instead 2.

Do not rely on monitoring alone for anti-HBc positive patients—prophylactic antiviral therapy is strongly preferred over monitoring because HBsAg seroreversion consistently associates with hepatitis flare 2.

Do not discontinue antiviral prophylaxis at 6 months as with other immunosuppressants—rituximab requires continuation until 12 months after the last dose, with monitoring potentially extending to 24 months 3.

Do not delay rituximab for recent non-severe infection beyond 7 days, though patients with severe infection in the past 12 months should receive conventional DMARDs instead of biologics 4.

Despite clear guidelines, real-world adherence to HBV screening remains suboptimal, with studies showing only 23-47% of patients receive appropriate screening before rituximab 5, 6, 7. This represents a significant patient safety gap requiring systematic interventions such as electronic order sets, laboratory reporting protocols, and targeted clinician education 5.