What are the potential side effects of Actemra (tocilizumab) in a patient with a history of autoimmune disease, such as rheumatoid arthritis?

Side Effects of Actemra (Tocilizumab)

Actemra (tocilizumab) carries a significant risk of serious infections, gastrointestinal perforations, laboratory abnormalities (neutropenia, thrombocytopenia, elevated liver enzymes), hypersensitivity reactions including anaphylaxis, and increased cholesterol levels, with infections being the most clinically important adverse effect requiring vigilant monitoring. 1

Serious and Life-Threatening Side Effects

Infections

• Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported, with the most common being pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis 1
• Opportunistic infections including tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have occurred with tocilizumab 1
• The overall infection rate is 104.6 per 100 patient-years, which is higher than IL-1 inhibitors at 94.5 per 100 patient-years 2
• Patients often present with disseminated rather than localized disease, particularly when taking concomitant immunosuppressants like methotrexate or corticosteroids 1

Gastrointestinal Complications

• Gastrointestinal perforations have been reported, primarily as complications of diverticulitis 1
• Use with caution in patients at increased risk for GI perforation 1
• Gastrointestinal symptoms are among the most common reported adverse events 3

Hypersensitivity Reactions

• Anaphylaxis and serious hypersensitivity reactions can occur, representing a contraindication to further use 1
• Serious infusion-related reactions (SIRRs) occur in approximately 1.9% of patients (1/100 patient-years) with intravenous tocilizumab 4
• Positive anti-CCP antibodies increase the risk of infusion reactions (OR = 2.5) 4
• Desensitization protocols exist for patients who need tocilizumab despite prior immediate hypersensitivity reactions 3

Common Laboratory Abnormalities

Hematologic Changes

• Neutropenia: Decrease in neutrophil count below 1 × 10⁹/L occurred in 2.9-3.7% of patients 1
• Thrombocytopenia: Platelet counts can decrease, though severe drops (≤50,000/mm³) are rare 1
• Dose interruption is required when ANC falls between 500-1000 cells/mm³, and discontinuation is mandated when ANC drops below 500 cells/mm³ 1

Hepatic Effects

• Elevated liver enzymes (ALT/AST) are common, occurring in 6% of patients on 8 mg/kg tocilizumab plus DMARD 1
• Transaminase increases occur in 5% of patients 1
• Total bilirubin can increase 1

Lipid Abnormalities

• Hypercholesterolemia and hypertriglyceridemia are known adverse events 5
• Weight gain can occur 1

Frequently Occurring Side Effects (≥2% incidence)

Cardiovascular

• Hypertension occurs in 6% of patients on 8 mg/kg tocilizumab plus DMARD 1, 6

Neurologic

• Headache is a common adverse reaction 6
• Dizziness occurs in 3% of patients 1

Gastrointestinal (Non-serious)

• Upper abdominal pain (3%), gastritis (2%), mouth ulceration (2%), and stomatitis 1
• Gastric ulcer (less common) 1

Dermatologic

• Rash occurs in 4% of patients 1

Respiratory

• Upper respiratory tract infections and nasopharyngitis are among the most common adverse reactions 6
• Bronchitis (4%), dyspnea, and cough 1

Other Common Effects

• Oral herpes simplex, conjunctivitis, nephrolithiasis, hypothyroidism, and peripheral edema 1

Rare but Serious Adverse Events

Malignancy

• During controlled periods, exposure-adjusted incidence was 1.32 events per 100 patient-years with tocilizumab, similar to placebo plus DMARD (1.37 events per 100 patient-years) 1

Pancreatitis

• Acute pancreatitis has been reported as a probable adverse event associated with tocilizumab use, accounting for 70% of all pancreatic adverse events in FAERS database analysis 5
• Cessation of tocilizumab resulted in improvement and decline in elevated laboratory values 5

Injection Site Reactions (Subcutaneous Formulation)

• Frequency of 10.1% with weekly subcutaneous administration versus 2.4% with placebo 1
• Reactions include erythema, pruritus, pain, and hematoma, typically mild to moderate in severity 1
• Majority resolve without treatment and none necessitated drug discontinuation 1

Immunogenicity

• 2% of patients developed positive anti-tocilizumab antibodies in controlled studies 1
• 1% developed neutralizing antibodies 1
• Five patients (of 46 with positive antibodies) had associated medically significant hypersensitivity reactions leading to withdrawal 1

Critical Monitoring Requirements

Pre-Treatment Screening

• Evaluate for tuberculosis risk factors and test for latent infection prior to initiating therapy 1
• Consider anti-tuberculosis therapy in patients with past history of latent or active TB 1

During Treatment

• Close monitoring for signs and symptoms of infection is essential, as acute inflammation markers may be suppressed 1
• Hold tocilizumab if serious infection, opportunistic infection, or sepsis develops 1
• Monitor neutrophil counts, platelet counts, and liver enzymes regularly with dose adjustments per protocol 1

Important Clinical Pitfalls

• Do not administer in patients with active infection, including localized infections 1
• Signs and symptoms of acute inflammation may be lessened due to suppression of acute phase reactants, potentially masking serious infections 1
• Absence of concomitant synthetic DMARD treatment tends to increase the risk of infusion reactions (OR = 1.67) 4
• The overall serious adverse event rate is 36.5 per 100 patient-years, higher than IL-1 inhibitors at 22.6 per 100 patient-years 2