What are the complications of elevated anti-Tumor Necrosis Factor (anti-TNF) levels?

From the Guidelines

Elevated anti-TNF levels can lead to several complications, including increased risk of infections, autoimmune reactions, and malignancies, emphasizing the need for careful monitoring and management. Having too high anti-TNF levels can cause various complications, primarily due to the suppression of TNF activity, which plays a crucial role in immune regulation, inflammation control, and tumor surveillance. The potential complications include:

• Increased risk of infections, particularly tuberculosis, fungal, and opportunistic infections, as reported in a meta-analysis of clinical trial data of 4135 patients receiving anti-TNF therapy, which found a 0.9% incidence of opportunistic infection 1.
• Autoimmune reactions, such as lupus-like syndrome, psoriasis, and demyelinating disorders, with 92 cases of lupus-like reactions, including 15 patients treated with adalimumab, identified in a detailed analysis of reported cases 1.
• Injection site reactions and infusion reactions, which have been reported in patients treated with anti-TNF agents.
• Hematologic abnormalities, including neutropenia, thrombocytopenia, and pancytopenia, which can occur due to the altered natural defense mechanisms.
• Cardiovascular complications, such as heart failure exacerbation, and rare cases of demyelinating disorders like multiple sclerosis, which have been reported in patients treated with anti-TNF agents.
• Hepatotoxicity, requiring liver function monitoring, as TNF-a promotes viral clearance in hepatitis B infection and may be involved in the pathogenesis of hepatocyte destruction in chronic hepatitis C infection 1. Patients on anti-TNF therapy should undergo regular monitoring, including complete blood counts, liver function tests, and screening for tuberculosis before and during treatment, to promptly identify and manage any potential complications. Any new symptoms, such as persistent fever, unusual infections, rash, neurological symptoms, or shortness of breath, should prompt immediate medical evaluation to ensure timely intervention and prevent long-term consequences. The most recent and highest-quality study, published in 2019, provides evidence for the efficacy and safety of anti-TNF therapy in patients with inflammatory bowel disease, highlighting the importance of careful patient selection and monitoring 1.

From the FDA Drug Label

WARNINGS AND PRECAUTIONS Do not start Enbrel during an active infection. If an infection develops, monitor carefully and stop Enbrel if infection becomes serious. (5.1) Consider empiric anti-fungal therapy for patients at risk for invasive fungal infections who develop a severe systemic illness on Enbrel (those who reside or travel to regions where mycoses are endemic). (5. 1) Demyelinating disease, exacerbation or new onset, may occur. (5.2) Cases of lymphoma have been observed in patients receiving TNF-blocking agents. (5.3) Congestive heart failure, worsening or new onset, may occur. (5.4) Advise patients to seek immediate medical attention if symptoms of pancytopenia or aplastic anemia develop, and consider stopping Enbrel. (5. 5) Monitor patients previously infected with hepatitis B virus for reactivation during and several months after therapy. If reactivation occurs, consider stopping Enbrel and beginning anti-viral therapy. (5.6) Anaphylaxis or serious allergic reactions may occur. (5.7) Stop Enbrel if lupus-like syndrome or autoimmune hepatitis develops. (5.9)

The FDA drug label does not answer the question.

From the Research

Complications of Elevated Anti-TNF Levels

Elevated anti-Tumor Necrosis Factor (anti-TNF) levels can cause various complications, including:

• Increased risk of serious infections, such as bacterial, viral, fungal, and opportunistic infections 2, 3, 4, 5
• Increased risk of cancer, including solid organ, hematological, and viral-related malignancies 2, 5
• Infusion reactions, blood disorders, autoimmune disorders, dermatological disorders, cardiac and neurological conditions 5
• Adverse effects on quality of life, particularly regarding systemic symptoms and emotional status, in patients with inflammatory bowel disease 6

Risk Factors for Complications

Several factors can increase the risk of complications associated with elevated anti-TNF levels, including:

• Concomitant use of steroids 4
• Advanced age at the start of anti-TNF treatment 4
• Type of anti-TNF agent used, with infliximab and adalimumab associated with a higher risk of serious infections compared to etanercept 4
• Presence of underlying conditions, such as inflammatory bowel disease or rheumatoid arthritis 2, 3, 4, 5

Management of Complications

To minimize the risk of complications, it is essential to:

• Monitor patients closely for early signs of infection and other adverse events 3, 5
• Manage adverse events promptly and appropriately, including withdrawal of anti-TNF therapy if necessary 3, 5
• Balance the benefits and risks of anti-TNF therapy, taking into account individual patient factors and underlying conditions 2, 3, 4, 5