Background Anti-TNF therapy has revolutionised treatment of rheumatoid arthritis (RA). This success is partly tempered by the substantially increased risk of granulomatous infectious diseases, particularly tuberculosis (TB). However the mechanisms underlying the effectiveness of the treatment are poorly understood. We used the tuberculin skin test (TST) as an in vivo challenge model to investigate whether TNF activity is attenuated by anti-TNF therapy in a prototypic cell mediated immune response.
Methods 50 stable RA patients (treated with Adalimumab, Etanercept or Methotrexate) and healthy volunteers with immunological memory to TB antigens were identified using an interferon-gamma ELISpot of peripheral blood. TST or saline (controls) was injected into the forearm of study participants and 3mm punch skin biopsies were taken from the injection site after 72 hours. Samples were collected for RNA analysis and histology. Genome wide transcriptional profiling was performed to compare gene expression changes in response to the TST challenge between treatment groups. As a surrogate marker for TNF activity the expression of TNF-regulated genes was quantified using a modular approach.
Results Clinical TST responses were significantly diminished in RA patients compared to healthy controls. Anti-TNF therapy did not have a further significant effect on skin induration compared to those treated with methotrexate. However clinical TST skin induration did not correlate with peripheral blood response to TB antigens, as interferon-gamma responses to TB antigens in peripheral blood were not attenuated by rheumatoid disease or treatment. Genome wide transcriptional profiling showed that TNF was induced following the TST, and this was not attenuated by anti-TNF therapy, compared to RA patients treated with methotrexate or healthy controls. Furthermore, downstream activity of this induced TNF was preserved in patients on anti-TNF therapy.
Conclusions Attenuated clinical TST responses have been previously shown in RA patients with active disease. Our results expand these findings to patients with stable disease, where the clinical TST responses were also diminished. Intriguingly, based on the transcriptional response to a TST challenge, we did not observe any reduction in TNF activity in patients on anti-TNF therapy. We conclude that anti-TNF therapy is unable to block a surge in TNF activity following an acute challenge. Therefore we infer that anti-TNF therapy is more likely to have biological effects on basal levels of TNF activity in steady state and rather than blocking TNF activity at the site of acute inflammation.
Disclosure of Interest None declared
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