What are the potential side effects of Actemra (Tocilizumab) in patients with rheumatoid arthritis or systemic juvenile idiopathic arthritis, particularly in older adults or those with a history of immunosuppression or gastrointestinal conditions?

Side Effects of Actemra (Tocilizumab)

Actemra (tocilizumab) most commonly causes infections (particularly upper respiratory tract infections), injection site reactions with subcutaneous administration, and laboratory abnormalities including neutropenia, elevated liver enzymes (ALT/AST), and increased cholesterol levels. 1, 2

Most Common Adverse Events

Infections

• Upper respiratory tract infections are the most frequent adverse event, occurring in patients across all age groups receiving tocilizumab 1, 3
• Respiratory tract infections predominate, with mild to moderate severity in most cases 4
• Serious infections occurred at a rate of 0.11 per patient-year in pediatric systemic JIA trials 2
• Oral herpes simplex and bronchitis have been reported as less common infectious complications 1

Injection Site Reactions (Subcutaneous Formulation)

• ISRs occurred in 10.1% of patients receiving weekly subcutaneous tocilizumab compared to 2.4% with placebo in controlled trials 1
• Reactions include erythema, pruritus, pain, and hematoma, typically mild to moderate in severity 1
• The majority resolved without treatment and none required drug discontinuation 1

Gastrointestinal Effects

• Diarrhea, nausea, vomiting, and abdominal pain occur in 2-6% of patients 1
• Gastric ulcer, stomatitis, and gastritis have been reported 1
• Gastrointestinal hemorrhage has occurred as a serious adverse event in pediatric trials 3

General Symptoms

• Headache and dizziness occur in 3-7% of patients 1
• Fatigue, peripheral edema, and weight gain have been documented 1
• Hypertension develops in approximately 6% of patients 1

Laboratory Abnormalities

Neutropenia

• Neutrophil counts below 1 × 10⁹/L occurred in 2.9-3.7% of patients in controlled trials 1
• Grade 3 neutropenia developed in 17 patients and grade 4 in 2 patients during clinical trials 2
• No clear relationship exists between neutropenia and serious infection occurrence 1
• Neutropenia requires constant monitoring throughout treatment 4

Liver Function Abnormalities

• Elevated ALT/AST levels (>2.5 times upper limit of normal) occurred in 21 patients during tocilizumab trials 2
• Transaminase increases occur in 5-6% of patients receiving tocilizumab plus DMARDs 1
• Total bilirubin elevation has been reported 1

Lipid Abnormalities

• Elevated cholesterol levels are among the most frequent laboratory abnormalities requiring monitoring 4
• Specific incidence rates vary but warrant routine lipid panel surveillance 4

Thrombocytopenia

• Platelet decreases to ≤50,000/mm³ were not observed in 6-month controlled subcutaneous trials 1
• Less common than neutropenia but requires monitoring 1

Serious and Life-Threatening Adverse Events

Hypersensitivity Reactions

• Anaphylactoid reactions have occurred, leading to treatment discontinuation in some cases 3, 2
• Five patients developed medically significant hypersensitivity reactions requiring withdrawal in controlled studies 1
• Hypersensitivity reactions can occur despite low immunogenicity rates 5

Malignancies

• 15 malignancies were diagnosed during 24-week controlled periods in tocilizumab-treated patients versus 8 in control groups 1
• Exposure-adjusted incidence was similar between tocilizumab (1.32 events per 100 patient-years) and placebo plus DMARD (1.37 events per 100 patient-years) 1
• Lymphoma has been reported as a potential toxicity 1

Hepatotoxicity

• Hepatitis and cholecystitis have been documented 1
• Fulminant hepatitis occurred in one patient with concomitant hepatitis B infection receiving infliximab (a related biologic) 5

Other Serious Events

• Nephrolithiasis and renal disorders 1
• Optic neuritis and conjunctivitis 1
• Dyspnea, cough, and pneumonitis (rare) 5, 1
• Hypothyroidism and other endocrine disorders 1

Immunogenicity

• Anti-tocilizumab antibodies developed in 2% of patients (46 of 2876 tested) in 24-week controlled studies 1
• Neutralizing antibodies developed in 1% of patients (30 of 2876) 1
• Antibody development rate was 0.9% in subcutaneous formulation with 0.8% developing neutralizing antibodies 1
• No correlation between antibody development and adverse events or loss of clinical response was observed 1

Special Population Considerations

Pediatric Patients

• Adverse event profile in children with systemic JIA is similar to adults with infections being most common 3, 4
• 39 serious adverse events (0.25 per patient-year) occurred in pediatric trials including 18 serious infections 2
• Tocilizumab is approved for children aged 2 years or older with systemic JIA or polyarticular JIA 4

Older Adults

• No overall differences in safety were reported in elderly patients (≥65 years old) across approved immune checkpoint blockers, though specific tocilizumab data in elderly is limited 5
• Increased vigilance for infections and comorbidities is warranted given immunosuppression 5

Patients with Immunosuppression History

• Risk of infection increases when tocilizumab is combined with other immunosuppressants 5
• Reactivation of latent infections (tuberculosis, hepatitis B) is a concern with IL-6 inhibition similar to TNF inhibitors 5
• Tuberculin skin testing and chest radiograph should be obtained prior to therapy 5

Patients with Gastrointestinal Conditions

• Gastrointestinal hemorrhage occurred as a serious adverse event in clinical trials 3
• Active GI bleeding or peptic ulcer disease represents a relative contraindication requiring careful risk-benefit assessment 6

Critical Monitoring Requirements

Before Initiating Treatment

• Tuberculin skin testing and chest radiograph 5
• Hepatitis B and C serology 5
• Baseline complete blood count, liver function tests, and lipid panel 1, 4
• Baseline renal function 1

During Treatment

• Weekly neutrophil monitoring until platelet counts stabilize, then routine monitoring 5, 1
• Liver function tests every 6-12 months during chronic use 5, 4
• Complete blood count every 6-12 months 5, 4
• Lipid panel monitoring for cholesterol elevation 4
• Temperature monitoring and immediate reporting of fever 5

Important Clinical Caveats

• Live vaccines should be avoided while patients are being treated with tocilizumab 5
• Patients should report signs of infection immediately including cough, fever, chills, burning with urination, or wound infections 5
• Tocilizumab may mask fever, potentially delaying recognition of serious infections 3
• Combination with other immunosuppressants increases infection risk substantially 5
• Most adverse events in pediatric populations were mild to moderate infections that did not require treatment discontinuation 7
• No dose adjustment is recommended for mild to moderate renal impairment (creatinine clearance ≥30 mL/min) or mild hepatic impairment 5