What are the contraindications to Tumor Necrosis Factor (TNF) inhibitors?

Contraindications to TNF Inhibitors

TNF inhibitors are absolutely contraindicated in patients with severe heart failure (NYHA class III-IV), active tuberculosis, active sepsis or serious infections, and demyelinating diseases, while relative contraindications include latent tuberculosis, hepatitis B, recurrent infections, and mild-to-moderate heart failure. 1, 2

Absolute Contraindications

Severe Heart Failure

• TNF antagonist therapy must be avoided in patients with NYHA class III and IV cardiac failure due to increased mortality and hospitalization rates. 2
• High-dose infliximab (10 mg/kg) was associated with increased mortality in severe heart failure patients, leading to premature trial discontinuation. 2
• Etanercept trials in severe CHF were terminated early due to lack of efficacy or failure to show benefit on CHF morbidity or mortality. 2

Demyelinating Diseases

• TNF inhibitors should be avoided entirely in patients with a personal history of demyelinating disorders, representing an absolute contraindication. 1, 3
• If neurological symptoms suggestive of demyelinating conditions develop during treatment, the TNF inhibitor should be immediately withheld and urgent neurological evaluation obtained. 1, 3
• The incidence of peripheral neuropathy with TNF inhibitors is 0.4-0.6%. 3

Active Tuberculosis

• Active tuberculosis is an absolute contraindication to TNF inhibitor therapy; patients must complete 6 months of TB treatment before TNF inhibitors may be considered. 4
• TNF inhibitors, particularly infliximab, are associated with increased risk of tuberculosis reactivation and disseminated disease. 1

Active Serious Infections

• TNF inhibitors are contraindicated during active infections requiring medical intervention and should be discontinued if serious infection develops. 1
• Active sepsis or opportunistic infections (including C. difficile) are contraindications to initiating therapy. 1

Relative Contraindications Requiring Risk Mitigation

Latent Tuberculosis Infection

• All patients must undergo tuberculosis screening (PPD skin test ≥5 mm or QuantiFERON-TB Gold test plus chest X-ray) before initiating TNF inhibitors. 4, 5, 6
• Patients with latent TB must receive at least 1 month of TB chemoprophylaxis (6 months isoniazid or 3 months isoniazid plus rifampin) before starting TNF inhibitors. 4, 7
• If the contraindication to TNFi use was tuberculosis, other chronic infection, or high risk of recurrent infections, sulfasalazine was preferred over TNF inhibitors, secukinumab, ixekizumab, and tofacitinib. 1
• TNF inhibitors other than infliximab should be considered for patients at higher risk of tuberculosis exposure (through travel or household contacts). 1

Hepatitis B Infection

• Patients with active or history of hepatitis B may receive TNF inhibitors only after evaluation by an appropriate specialist and may require concomitant antiviral medication. 1
• Hepatitis B core antibody testing is recommended before initiating therapy. 1
• Ongoing monitoring with HB surface antigen, anti-HB core antibody, and liver function tests should be performed due to potential risk of reactivation. 1
• Treatment with infliximab and methotrexate can reactivate chronic hepatitis B viral infection. 1

Hepatitis C Infection

• Exercise great caution when considering TNF therapy in patients with chronic hepatitis C infection. 1
• Consultation with liver specialists and interval monitoring of serum aminotransferases and hepatitis C viral load are recommended. 1

Mild-to-Moderate Heart Failure (NYHA Class I-II)

• Obtain a screening echocardiogram before initiating TNF antagonist therapy in patients with well-compensated heart failure. 2
• Do not initiate TNF antagonist therapy if ejection fraction is <50% of normal. 2
• Withdraw treatment immediately at the onset of new symptoms or worsening of pre-existing heart failure. 2
• Consider IL-17 inhibitors (secukinumab or ixekizumab) as preferred alternatives, since these medications have not been shown to worsen congestive heart failure. 1, 2

Recurrent or Chronic Infections

• TNF inhibitors should be avoided in patients with chronic, serious, or recurring infections. 1
• Patients with history of recurrent infections should preferentially receive TNF inhibitors other than infliximab, which has increased risks of tuberculosis and infections generally. 1
• In patients with contraindications due to high risk of recurrent infections, efforts to mitigate the infectious contraindications should be undertaken so that TNF inhibitors might be safely used. 1

HIV Infection

• Patients with HIV may receive TNF inhibitors only if they are receiving highly active antiretroviral therapy (HAART) that has effectively normalized their CD4+ T-cell counts with no detectable viral load and no recent history of opportunistic infection. 1
• Consultation with the patient's infectious disease provider is advised before initiating therapy. 1

Special Considerations

Malignancy History

• Patients with a history of solid tumor malignancy who have failed other therapies may receive TNF inhibitors without expectation of increased risk of tumor recurrence. 1
• TNF inhibitors used as monotherapy are not associated with risk of solid tumor or lymphoreticular malignancy, though addition of other immunosuppressant agents may alter the safety profile. 1

Live Vaccines

• Avoid administration of live vaccines concurrently with TNF inhibitors. 1
• Complete all recommended vaccinations (pneumococcal vaccine and inactivated influenza vaccine) prior to initiating TNF inhibitor therapy where feasible. 1

Combination with Other Immunosuppressants

• Coadministration of TNF inhibitors with other IL-1 blocking agents is not recommended due to increased risk of serious infections and neutropenia. 8

Common Pitfalls to Avoid

• Do not assume BCG vaccination at birth affects PPD test interpretation in adults—a PPD ≥5 mm is considered positive regardless of BCG history. 4
• Do not switch to a biosimilar of the same TNF inhibitor in patients with treatment failure—this is strongly recommended against. 1
• Do not delay TB screening or chemoprophylaxis—even with prophylaxis, some patients develop active TB (incidence 449 per 100,000 annually in treated populations). 7
• Do not overlook that infliximab carries higher infection risk than etanercept, particularly for tuberculosis and opportunistic infections. 5, 9