December 14-20 2020
A promising route to treating COVID-19?
Blocking the activity of the TNF (Tumor Necrosis Factor) shows promise as an approach to treating COVID-19.
At the present time there are very few molecules that are effective as treatments, and the large scale deployment of vaccines giving satisfactory results may be a long way off. Their effectiveness and clinical safety has to be proven over the long term.
Continuing infection by SARS-CoV-2 is therefore inevitable. In the meantime we need to be able to rely on treatment options that have already been tested and that are affordable.
Why inhibit the TNF as a means of treating ill patients? Severe cases of COVID-19 are associated with excessive inflammation in the patient, generating abnormally elevated concentrations of pro-inflammatory cytokines in the body for reasons we are not sure of. Following infection, these cytokines regulate the activity, the functioning, the proliferation and the communication between immune cells. Notable amongst these cytokines are the IL-6, the interferons (IFN) and the TNF. In deceased patients a massive infiltration of macrophages into the lungs has been observed. These immune cells play a prominent role in hyper-inflammation and are also a factor in elevated levels of cytokines, thereby perpetuating a vicious pathological circle. The hyper-inflammation engenders a “capillary leak” which is the principal cause of lung failure: the blood and its components are discharged into the interstitial fluid that fills the space between the capillary blood vessels and the lung cells, leading to their destruction. The second factor in the lung failure is thrombosis (obstruction in the veins and arteries). These two phenomena are stimulated by the IL-6 and the TNF.
Limiting inflammation is therefore a clear therapeutic priority. But anti-IL-6 treatments have limited effectiveness. Dexamethasone works in critical cases, but makes things worse in moderate cases.
In theory, blocking TNF activity to treat COVID-19 seems a promising approach for several reasons:
- TNF is overexpressed very quickly since it plays an important role at the onset of inflammation. The anti-TNF drugs should be able to stem this process at the beginning.
- For more than 20 years, millions of people have been treated with anti-TNF drugs for different auto-immune diseases (rheumatoid arthritis, psoriasis, Crohn’s disease, ulcerative colite). As a consequence, the pharmacology of these compounds is well known, and production and distribution chains already exist. Many patents have by now fallen into the public domain.
- The TNF regulate the activity of certain cytokines which control the migration of immune cells (chemokines). Anti-TNF drugs should therefore be able to limit the infiltration of macrophages into the lungs.
- The TNF stimulate capillary leakage and thrombosis. Blocking the TNF should limit lung deterioration.
To support this point of view, much clinical and experimental data is available:
- In cases of rheumatoid arthritis, anti-TNF drugs reduce the level of proteins involved in thrombosis (CRP, haptoglobin, fibrinogen, D-Dimer, pro-thrombin).
- Simply combining TNF and IFN is enough to bring about cellular death, independent of other cytokines. They are capable in themselves of perpetuating the cytokinetic storm. In vivo, blocking their activity significantly increases the survival numbers of mice infected with SARS-CoV-1 and SARS-CoV-2.
- The interaction of SARS-CoV-1 with its ACE2 receptor could trigger the release of TNF into the bloodstream, thus explaining its important role.
- Blocking TNF activity reduces the formation of NETs (Neutrophil Extracellular Traps), sticky extracellular traps whose function is to limit infection. In severe cases of COVID-19, the immune cells (neutrophils) which produce them are excessive in number, favouring thrombosis and lung cell death.
- Observational analysis indicates that anti-TNF drugs do not promote susceptibility to other infections.
- By cross-referencing clinical date, we see that among patients infected by SARS-CoV-2, those suffering from auto-immune diseases and treated with anti-TNF drugs develop less complications.
All these observations have their limits and need to be validated in human experiments. Although small in scale, five clinical tests have begun to evaluate the effect of anti-TNF drugs in the treatment of COVID-19. These tests principally use two generic medicines: Infliximab, administered intravenously and therefore quick-acting, and Adalimumab, administered subcutaneously and so slower to act, though more practical since injections can be carried out at home.
This therapeutic strategy is promising since there are many anti-TNF compounds with different properties, enabling personalized usage according to clinical situations.
All of these anti-TNF compounds should be prescribed as soon as possible to prevent hyper-inflammation. They are not immunogenic and are not contraindicated for patients at risk from COVID-19 (elderly people, obese people, people with cardiac problems, pregnant women…).