When to check Interleukin-6 (IL-6) or Tumor Necrosis Factor-alpha (TNF-alpha)?

From the Guidelines

Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) should be checked when evaluating inflammatory conditions, autoimmune disorders, or certain infections, particularly in the context of cancer immunotherapy with checkpoint inhibitors, as recommended by the EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events 1.

Key Considerations

• These inflammatory markers are most useful in diagnosing and monitoring conditions like rheumatoid arthritis, inflammatory bowel disease, sepsis, and certain cancers.
• For rheumatoid arthritis, these markers help assess disease activity and treatment response, particularly when considering biologics like tocilizumab (an IL-6 inhibitor) or TNF inhibitors such as adalimumab, infliximab, or etanercept.
• In sepsis, elevated IL-6 levels correlate with severity and mortality risk.
• For cancer patients, these markers may help monitor treatment response and disease progression, especially in cancers with inflammatory components.

Clinical Context

• When ordering these tests, it's essential to interpret results in clinical context, as levels can be elevated in various inflammatory conditions.
• Normal IL-6 levels are typically below 7 pg/mL, while TNF-alpha is usually below 8.1 pg/mL, though reference ranges vary by laboratory.
• The stability of these markers over time is crucial, with single measures providing a reliable index of stable individual differences in the short term (<6 months) 1.

Recommendations

• Repeated measurement of inflammatory biomarkers is necessary to accurately characterize health risk, with measurements repeated every 3 years or more frequently in certain cases.
• The decision to check IL-6 or TNF-alpha should be based on a shared decision-making process between patients, oncologists, and rheumatologists, considering the severity of rheumatic immune-related adverse events, the extent of required immunosuppressive regimen, and the tumor response and its duration 1.

From the Research

When to Check IL-6 or TNF Alpha

• IL-6 and TNF alpha are inflammatory mediators that can be used as markers of the severity of sepsis 2
• In patients with sepsis, serum IL-6 and TNF alpha levels were correlated with the severity of sepsis 2
• Patients with severe sepsis exhibited higher IL-6 and TNF alpha levels than patients with mild sepsis 2
• IL-6 can promote TNF alpha production by activating NF-κB in monocytes from patients with systemic inflammation without infection 3
• The expression of IL-6 and TNF alpha can be suppressed by tocilizumab, an IL-6 receptor inhibitor, in a cell model of sepsis 4

Clinical Relevance

• Early recognition and management of sepsis is crucial, and IL-6 and TNF alpha can be used as markers of the severity of sepsis 2, 5
• Severe sepsis is a common condition among emergency department patients with a clinically suspected serious infection, and mortality rates can be high if left untreated 6
• The clinical presentation of sepsis is highly variable, and fever is often the first manifestation of sepsis 5
• Early goal-directed therapy completed within the first six hours of sepsis recognition significantly decreases in-hospital mortality 5

Laboratory Tests

• Plasma IL-6 and TNF alpha levels can be measured by enzyme-linked immunosorbent assay (ELISA) 2
• Serum nitric oxide (NOx), nitrotyrosine (NT), oxidized LDL (oxLDL) levels, serum paraoxonase 1 (PON1) activity, and erythrocyte glutathione (GSH) levels can also be measured as oxidative stress parameters in patients with sepsis 2