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Induced TNF production in vitro as a test for familial Mediterranean fever
A Schattner1, A Gurevitz, D Zemer
1Department of Medicine 'A', Hebrew University, Jerusalem.
Abstract:
We have previously demonstrated an altered pattern of tumor necrosis factor (TNF) secretion in patients with familial Mediterranean fever (FMF). To examine whether TNF determination could assist in diagnosing FMF, we stimulated heparinized blood of 51 asymptomatic FMF patients with lipopolysaccharide (LPS) and then measured TNF production in response to inducers, compared to unstimulated blood cells and to cells from a control group of 12 matched healthy subjects. Following LPS pretreatment, which induced TNF release, FMF patients produced significantly less TNF than controls, whether production was 'spontaneous' or induced by either LPS or phytohaemagglutinin (p < or = 0.003). Such 'exhaustion' did not occur in untreated cells. We then used these results to classify a further group of 29 FMF patients and 10 matched healthy controls ('validation' group) who underwent the same studies. The test correctly identified 25/29 patients as having FMF and 7/10 controls as not having FMF; a sensitivity of 86% and a specificity of 70% (likelihood ratios 2.9 (positive test) and 0.2 (negative)). Identification of a blunted TNF response following previous stimulation by a simple assay, may help the diagnosis of FMF in asymptomatic patients, provided it is interpreted in conjunction with supportive clinical data.
Insights
Familial Mediterranean fever (FMF) patients exhibit a blunted tumor necrosis factor (TNF) response after stimulation. This altered TNF secretion pattern may aid in diagnosing FMF in asymptomatic individuals.
Area of Science:
- Immunology
- Genetics
- Rheumatology
Background:
- Familial Mediterranean fever (FMF) is an autoinflammatory disorder characterized by recurrent episodes of fever and inflammation.
- Previous studies indicated altered tumor necrosis factor (TNF) secretion patterns in FMF patients.
Purpose of the Study:
- To investigate if measuring TNF production could aid in the diagnosis of FMF.
- To assess TNF secretion patterns in asymptomatic FMF patients compared to healthy controls.
Main Methods:
- Heparinized blood from 51 asymptomatic FMF patients and 12 healthy controls was stimulated with lipopolysaccharide (LPS).
- TNF production was measured in response to inducers (LPS, phytohaemagglutinin) and compared to unstimulated cells.
- A validation group of 29 FMF patients and 10 controls underwent similar studies to assess test accuracy.
Main Results:
- FMF patients showed significantly reduced TNF production compared to controls after LPS pretreatment (p < or = 0.003).
- This 'exhaustion' of TNF response was specific to pre-stimulated cells and not observed in untreated cells.
- The TNF response assay demonstrated 86% sensitivity and 70% specificity in identifying FMF patients in the validation group.
Conclusions:
- A blunted TNF response following prior stimulation is characteristic of FMF patients.
- This simple assay may assist in diagnosing FMF in asymptomatic individuals when interpreted alongside clinical data.