What are the side effects of adalimumab (Humira) and how should they be monitored and managed?

Adalimumab Side Effects and Management

Adalimumab carries significant risks including serious infections (particularly tuberculosis reactivation), injection site reactions, and potential malignancy, requiring mandatory pre-treatment screening with tuberculin skin testing, chest radiograph, and hepatitis B serology before initiation. 1

Common Side Effects

Injection site reactions are the most frequent adverse event, occurring in approximately 15% of patients compared to 9% receiving placebo. 2 These typically manifest as redness, rash, swelling, itching, or bruising and usually resolve within the first 2 months of therapy without requiring discontinuation. 2, 3

Upper respiratory infections affect a substantial proportion of patients:

• Nasopharyngitis occurs in 19% of patients 2
• Upper respiratory tract infections including sinusitis and rhinitis are common 2
• Headaches, dizziness, and vertigo are frequently reported 2

Gastrointestinal symptoms including nausea, abdominal pain, and upset occur regularly. 2, 4

Musculoskeletal complaints such as arthralgia, back pain, myalgia, asthenia, and malaise are documented. 2

Serious Infections: The Primary Safety Concern

The overall serious infection rate is 2.03 per 100 patient-years in long-term studies. 1, 2, 4 This represents a two-fold increased risk compared to non-biologic therapy. 5

Tuberculosis reactivation is the most notable infectious complication requiring specific attention:

• Tuberculin skin testing and chest radiograph are mandatory before therapy initiation 1, 4
• Consider risk for histoplasmosis, blastomycosis, or coccidioidomycosis in patients living in or visiting endemic areas 1
• Active TB has developed even in patients with negative pre-treatment TB skin tests 3

Other serious infections documented include:

• Legionella pneumophila pneumonia (cluster cases reported) 2
• Pneumocystis jirovecii pneumonia 2
• Atypical mycobacteria 2
• Deep fungal infections including histoplasmosis, coccidioidomycosis, candidiasis, and aspergillosis 2
• Sepsis, cellulitis, pyelonephritis, peritonitis 2
• Herpes zoster 2

Hepatitis B Reactivation

Hepatitis B serology is required before treatment initiation. 1, 2, 4 Patients who are chronic HBV carriers (positive for surface antigen) are at risk for viral reactivation during adalimumab therapy. 1 Patients with a history of viral hepatitis or chronic carrier states should be monitored for viral hepatitis reactivation throughout therapy. 1

Malignancy Risk

The risk for malignancy with anti-TNF agents remains unclear but warrants attention. 1, 2

Lymphoma risk shows a standardized incidence ratio of 3.19 in some analyses, though similar increases are observed in severe rheumatoid arthritis without biologic interventions. 2

Skin cancer risk is more clearly defined:

• Non-melanoma skin cancer: standardized incidence ratio 1.7 (95% CI 1.3-2.2) 2
• Melanoma: standardized incidence ratio 2.6 (95% CI 1.0-6.7) 2

Hepatosplenic T-cell lymphoma has been reported rarely in adolescent and young adult patients with Crohn's disease receiving concomitant azathioprine or 6-mercaptopurine. 2

Autoimmune and Immunologic Reactions

Lupus-like syndrome has been reported in 15 patients treated with adalimumab in systematic analysis. 1, 2, 4 Anti-double-stranded DNA antibodies can be measured if lupus-like symptoms develop during therapy. 1

Vasculitis was reported in 5 cases with adalimumab in detailed analysis. 1, 2, 4

Pulmonary Complications

Pulmonary fibrosis can occur as either a new event or exacerbation of underlying fibrosis. 1, 2, 4 Interstitial pneumonias have been reported in at least 18 patients receiving various anti-TNF agents. 1, 2, 4

Paradoxical sarcoidosis has been reported in patients treated with anti-TNF agents, though the mechanism remains unclear. 1, 2, 4

Hematologic Effects

Cytopenias including pancytopenia can occur, though relatively uncommon. 2, 4 Aplastic anemia, isolated leukopenia, and thrombocytopenia have been reported. 2

Thromboembolic events have a hazard ratio of 7.6 in patients developing anti-adalimumab antibodies. 2, 4, 6

The American Society of Clinical Oncology recommends hematology consultation for serious hematologic effects and potential treatment discontinuation. 2, 4, 6

Neurologic Effects

CNS events including demyelination disorders have been sporadically reported with an incidence rate of 0.08 per 100 patient-years. 1, 2 Signs include numbness, tingling, vision problems, weakness in extremities, and dizziness. 3

Cardiovascular Effects

New heart failure or worsening of existing heart failure can occur with an incidence rate of 0.28 per 100 patient-years. 2 Symptoms include shortness of breath, sudden weight gain, and swelling of ankles or feet. 3

Dermatologic Reactions

Paradoxical psoriasis can develop or worsen in patients using adalimumab, manifesting as red scaly patches or raised bumps filled with pus. 3 These tend to respond to adequate therapy without requiring adalimumab discontinuation. 7

Pregnancy and Lactation

FDA has designated adalimumab as Category B for all trimesters. 1, 2, 4 There appears to be an increased rate of first trimester miscarriages. 1, 2, 4 Insufficient data exist to establish safety in breastfeeding, though antibodies are secreted in milk. 2, 4

Mandatory Pre-Treatment Screening

Before initiating adalimumab therapy:

• Tuberculin skin testing and chest radiograph 1, 4
• Hepatitis B serology 1, 2, 4
• Assessment for endemic fungal infection risk based on geographic location 1

Critical Patient Education

Patients must be instructed to:

• Check temperature frequently and report fever immediately 1
• Report signs of infection including cough, aches, fever, chills, wound infections, urinary symptoms, or gastrointestinal symptoms 1
• Report shortness of breath or breathing changes 1
• Avoid live vaccines during therapy 1, 4

Common Pitfalls to Avoid

Do not initiate adalimumab during active infection. 5 The drug should be held if serious infection develops. 3

Do not overlook geographic risk factors for endemic fungal infections when screening patients. 1

Do not dismiss injection site reactions that persist beyond a few days or worsen – these require medical evaluation. 3

Do not assume negative TB testing eliminates risk – active TB has developed in previously negative patients. 3