What is the mechanism of action, adverse effects, boxed warning, and FDA-approved uses of Rituximab (rituximab)?

Rituximab: Mechanism of Action, Adverse Effects, Boxed Warnings, and FDA-Approved Indications

Mechanism of Action

Rituximab is a chimeric murine-human monoclonal IgG1 antibody that targets the CD20 antigen expressed on pre-B and mature B-lymphocytes, mediating B-cell lysis through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). 1

• Upon binding to CD20, rituximab causes rapid and sustained depletion of circulating and tissue-based B cells maintained for 6-12 months 2, 1
• CD20 is expressed on >90% of B-cell non-Hodgkin's lymphomas but not on hematopoietic stem cells, allowing eventual B-cell recovery 3
• B-cell recovery typically begins at approximately 6 months, with median B-cell levels returning to normal by 12 months following treatment completion 1
• In rheumatoid arthritis, B cells contribute to pathogenesis through production of rheumatoid factor, autoantibodies, antigen presentation, T-cell activation, and proinflammatory cytokine production 1

FDA-Approved Indications

Rituximab is FDA-approved for multiple B-cell malignancies and autoimmune conditions, including:

• Non-Hodgkin's Lymphoma: Relapsed or refractory, low-grade or follicular, CD20-positive B-cell NHL 3, 4
• Aggressive NHL: CD20-positive diffuse large B-cell lymphoma in combination with CHOP chemotherapy 2, 3
• Chronic Lymphocytic Leukemia: B-cell CLL (though approval status varies by region) 2, 3
• Rheumatoid Arthritis: Moderate to severe disease with inadequate response to TNF inhibitors 1
• Granulomatosis with Polyangiitis (Wegener's) and Microscopic Polyangiitis 1
• Pemphigus Vulgaris 2, 1

Boxed Warnings and Critical Safety Concerns

Fatal Infusion Reactions

Fatal infusion reactions have been reported, primarily with the first infusion, characterized by hypoxia, pulmonary infiltrates, respiratory distress, myocardial infarction, ventricular fibrillation, and cardiogenic shock. 2, 5

• Severe infusion reactions occur in approximately 10% of patients, including bronchospasm and hypotension 3, 5
• Premedication with antipyretics, antihistamines, and sometimes corticosteroids is recommended to reduce infusion reactions 2, 5
• Close monitoring during and after infusion is mandatory, particularly for patients with high tumor burden 5

Hepatitis B Reactivation

All patients must be screened for hepatitis B before initiating rituximab, as reactivation can cause fulminant liver failure and death. 2, 5

• Patients testing positive for HBV require preemptive antiviral therapy before rituximab administration 5
• Rituximab can reverse the deacetylation status of silent HBV mini-chromosomes, leading to active viral transcription and reactivation 2

Progressive Multifocal Leukoencephalopathy (PML)

PML, a lethal encephalitis caused by JC polyomavirus, has been reported with increasing frequency in rituximab-treated patients. 2, 5

• Two patients with systemic lupus erythematosus died from PML following rituximab treatment 2
• This represents a critical risk requiring vigilant neurological monitoring 5

Adverse Effects Profile

Infusion-Related Reactions

• Occur in the majority of patients, typically mild to moderate flu-like symptoms that decrease with subsequent infusions 3, 4
• Include fever, rigors, chills, nausea, vomiting, and constitutional symptoms related to cytokine release syndrome 5
• IgM flare occurs in approximately 50% of patients, particularly those with baseline high serum IgM levels (≥4000 mg/dL), potentially leading to hyperviscosity complications 2

Infectious Complications

Rituximab significantly increases infection risk through B-cell depletion and immunosuppression. 5

• Pneumocystis pneumonia risk is elevated, particularly with concomitant immunosuppression; prophylaxis should be considered 2, 5
• Late-onset neutropenia (LON) occurs, especially when combined with chemotherapy, through cellular immune mechanisms and/or antibody-mediated complement cytotoxicity 2
• Fatal sepsis has been reported, including deaths from nosocomial pneumonia and bacterial sepsis 2, 5
• Antibody responses to recall antigens are dramatically reduced, with median recovery time of 9 months (range 5.9-14.4 months) 5

Immunologic Effects

• Sustained reductions in IgM and IgG serum levels occur, with 14% of NHL patients having levels below normal range 1
• In rheumatoid arthritis patients, 23.3% experienced decreased IgM, 5.5% decreased IgG, and 0.5% decreased IgA below normal limits during repeated treatment 1
• Persistent hypogammaglobulinemia has been reported, including in a 2-year-old child following infection series 2

Severe Cutaneous Reactions

DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms), AGEP (Acute Generalized Exanthematous Pustulosis), Stevens-Johnson syndrome, and toxic epidermal necrolysis require permanent drug avoidance. 5

Cardiovascular Complications

• Myocardial infarction, shock, and cardiogenic shock have been reported 5
• Hypotension occurs as part of severe infusion reactions 3

Gastrointestinal Effects

• Nausea and vomiting occur particularly during infusion reactions 5
• Mast cell-mediated reactions can include diarrhea and abdominal pain 5

Pulmonary Complications

• Interstitial pneumonitis, cough, rhinitis, nasal congestion, wheezing, and dyspnea can occur 5
• Pulmonary infiltrates and respiratory distress characterize severe reactions 2

Critical Monitoring Requirements

Pre-Treatment Screening

• Mandatory hepatitis B screening (HBsAg, anti-HBc, anti-HBs) before initiating therapy 5
• Baseline CBC count, hepatic function, and renal function 2
• Assessment for high tumor burden to stratify cytokine release syndrome risk 5

During Treatment

• Continuous monitoring during infusion for signs of infusion reactions, pulmonary edema, and systemic inflammatory response syndrome 2
• Daily CBC count and hepatic/renal function during therapy initiation 2
• Subsequent testing intervals depend on clinical response 2

Post-Treatment

• Periodic CBC count and hepatic/renal function monitoring throughout therapy 2, 5
• Vigilant monitoring for infections, particularly atypical bacterial, fungal (including Pneumocystis), and viral (including CMV) infections 2
• Neurological monitoring for signs of PML 5

Important Clinical Considerations

Contraindications and Precautions

• Patients with baseline serum IgM ≥4000 mg/dL should undergo prophylactic plasmapheresis or avoid rituximab during first 1-2 courses until IgM decreases 2
• Concurrent treatment with multiple biologic agents is explicitly contraindicated due to increased infection risk without additional benefit 6
• Rituximab should not be used as first-line therapy in rheumatoid arthritis without prior TNF inhibitor trial 6

Drug Interactions

• Additive or synergistic immunosuppression occurs when combined with other immunosuppressive agents 2
• Rituximab pharmacokinetics are similar whether administered with or without CHOP chemotherapy 3

Special Populations

• Elderly patients (≥65 years) experience higher rates of serious adverse reactions, infections, malignancies, and cardiovascular events 1
• In CLL patients ≥70 years, no observed benefit from rituximab addition to fludarabine and cyclophosphamide, with higher grade 3-4 adverse reactions 1