Imperative to trial anti-TNFs in COVID-19: rheumatologists

The anti-TNFs have been overlooked as a potential treatment for the hyper-inflammatory complications of severe COVID-19 lung disease, says rheumatologists.

There is biological plausibility and also data from observational studies to support the use of anti-TNFs in treating the cytokine drivers of adult respiratory distress syndrome (ARDS) in COVID-19 disease, according to Professor Philip Robinson and co-authors from Oxford University in a Lancet Rheumatology commentary published this week.

And with other once-promising therapies failing to show a substantial effect on the continuing deaths from the pandemic it is now time to prioritise anti-TNFs in COVID-19 trials, the authors argue.

In their article, Professor Robinson and co-authors note that many of the key aspects of lung damage in COVID-19 disease – such as capillary leak – are a result of inflammation driven by inflammatory cytokines such as TNF, IL-1, IL-6, and vascular endothelial growth factor (VEGF).

And since anti-TNF therapy reduces all of these key inflammatory cytokines in patients with autoimmune disease, it is conceivable that this would also be the case in patients with COVID-19, with the potential to reduce lung damage  and need for ventilation.

They note that early attention focused on the potential for anti-IL-6 receptor therapies such as tocilizumab for the cytokine release syndrome (CRS) seen in patients with severe COVID-19  disease. However, despite promising results seen in observational studies, IL-6 therapies have not shown significant effects in randomised controlled trials.

They say that experience in rheumatology has shown that anti-TNF therapy differs greatly from anti-IL-6 therapy in leading to rapid (often within 24hours) downregulation of other pro-inflammatory mediators, including IL-1 and GM-CSF as well as  serum amyloid A, haptoglobin and fibrinogen.

“Clotting biomarkers are also rapidly downregulated, with significant reductions in D-dimer and pro-thrombin fragments seen within 1 h of anti-TNF therapy,” they write.

This rationale is backed by observational study data from registries such as SECURE-IBD database, which found that use of anti-TNF therapy was associated with a 40% lower risk of death or hospital admission for COVID-19 (adjusted odds ratio 0·60).

And as one of the leaders of the COVID-19 Global Rheumatology Alliance registry, Professor Robinson notes that it has found similar results. Data from 600 patients showed that use of anti-TNF therapy was associated with a 60% lower rate of hospital admission for COVID-19 (adjusted OR 0·40) compared to no DMARD therapy  – and an even greater reduction when anti-TNF therapy was used as monotherapy.

Meanwhile other case series have found little or no effect of non-TNF biologics on the use of ventilator support and death in patients with COVID-19 disease.

However despite these encouraging observations and the scientific rationale for anti-TNF therapy there are surprisingly few trials examining it as a potential treatment for COVID-19, the authors say.

Currently there is one randomised trial (CATALYST) of infliximab recruiting in the UK a pilot study in 17 patients ongoing at Tufts Medical Center, Boston.

“These trials face considerable recruitment challenges because of the vast array of therapies under investigation, the commentary notes.

As a widely available therapy with a proven record of safe use, the anti-TNFs appear to offer substantial benefits and convenience for treating COVID-19 disease, the author say.

“Anti-TNF therapy now has huge potential. We need to urgently investigate its value through prioritisation of clinical trial resources worldwide,” they conclude.

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