Prof. Georg Schett is Chair of Internal Medicine 3 –Rheumatology and Immunology– at Friedrich-Alexander Universität (FAU) Erlangen-Nuremberg and Universitätsklinikum Erlangen in Germany. His scientific work focuses on creating a better understanding of the molecular basis of immune-inflammatory diseases with rapid translation into clinical practice. His research work lead to the understanding of the phenomenon of LE-cells in 2007. Prof. Schett was awarded the renowned START Award and the ERC Award and is speaker of several DFG- and BMBF-funded joint projects.
COVID-19 and inflammatory diseases share inflammatory pathways
Many familiar pathways which are relevant in autoimmune disease or chronic inflammatory disease seem to be hijacked by coronavirus disease 2019 (COVID-19) [1]. This is probably the reason why most of these inflammatory diseases are linked to the immune dysregulation induced by the SARS-CoV-2 virus. After infection with the virus, massive innate immune activation is seen, which allows neutrophils and monocytes to enter [2], which is observed in many inflammatory diseases as well [3]. Neutrophil infiltration is frequently occurring in psoriasis, rheumatoid arthritis, and Crohn’s disease, amongst others. It is quite interesting that some pathways from chronic inflammatory disease are basically revisited by the virus. This suggests that the steps in these pathways are similar and that some COVID-19 patients might benefit from anti-inflammatory treatment [1]. Of course, this is totally counterintuitive. The general viewpoint is that blocking cytokines places patients at higher risk of infection, which is very dangerous. However, there is currently a lot of rethinking that these cytokines may also be important in the dangerous hyperinflammation seen in COVID-19 patients [4]. This can be compared to checkpoint inhibition, where checkpoint inhibition side effects are treated to mitigate inflammation, for example IL-6 blockers [5,6]. So that was the concept we started working with.
Figure. Schematic of the cytokine signaling instigated by SARS-CoV-2 infection. Modified from [1].
TNF blockers for inflammatory disease
Tumour necrosis factor (TNF) has a role in many of these inflammatory diseases [3]. When you look at atopic dermatitis, however, there are few data indicating that blocking TNF works [7,8]. This weak link is indicated by the dashed line. If TNF blockers work, they only do so weakly, in contrast to many of the other type 2 autoimmune diseases, in which TNF blockade works very well [3]. The dashed line here indicates that atopic dermatitis is strongly linked to IL-4/IL-13 [3], but not that strongly to TNF.
Implications of anti-inflammatory treatment
People with long-standing asthma and other type 2 inflammatory diseases are not per se at higher risk for COVID-19, unless they have severe lung damage [1]. I think therapy that blocks IL-4/IL-13 or IL-5 is not an issue. There is no good data that indicates either an increased viral infection risk in patients with these treatments or higher susceptibility of a severe disease course of COVID-19. I think that is very reassuring.
An interesting question is whether IL-4/IL-13 inhibitors could have a beneficial effect on COVID-19. This is not well known, but cytokine expression data from COVID-19 patients show IL-10 expression [9], which could be a downstream effect of IL-4/IL-13 [10]. Hence, it could well be that some of the T2H cytokines are induced by COVID-19. However, very little is known about this yet.
Another interesting topic is the tissue response in COVID-19, because we see tissue proliferation, fibrotic responses, and mesenchymal responses [11], which is sometimes driven by type 2 immunity. This might not be crucial for the critical inflammation, but type 2 immunity might be important for tissue response inflammation happening in this disease [4]. Considering that COVID-19 causes real damage on the epithelial cells, you would guess that you get a substantial tissue response next to the inflammatory response. That could be guided somehow by type 2 immunity, but very little is known about that.
Hydroxychloroquine as potential treatment for COVID-19
Hydroxychloroquine is not a very specific approach, but it does affect neutrophil function. I think this is interesting, because there is a very strong neutrophil component in COVID-19 [1], which is why hydroxychloroquine might have an effect. Trials investigating hydroxychloroquine were done in a very quick manner, but I think they gave a signal which was picked up by many people, who now use it as treatment for COVID-19. I think hydroxychloroquine is not a very strong cytokine inhibitor, but it works very well in some diseases like systemic lupus erythematosus [12] and sometimes in diseases like Behcet’s disease, in which the primary action of the drug might be on neutrophil cells.
And this is the concept: hydroxychloroquine has the potential to inhibit neutrophil extracellular trap (NET) formation [13] which is potentially happening a lot in COVID-19 [14-16]. Unfortunately, statistically it is not as strong a medication, not a really good cytokine blocker. Hydroxychloroquine is an accessible drug, which is why so many resources were used to assess its efficacy in ameliorating COVID-19.
Other accessible drugs that could be effective are tocilizumab or JAK inhibitors [1]. At this moment, there are 12 ongoing studies investigating JAK inhibitors and the only concern here, from my point of view, is the effect on the type 1 interferon response, because this response is necessary for viral clearance [1]. Although JAK inhibitors might in theory inhibit viral clearance, their benefit could be the decrease in inflammation, which could probably save the life of the patient. Then at a later timepoint the immune system itself might be able to clear the virus.
keywords: COVID-19, inflammatory disease, cytokines, hydroxychloroquine, anti-inflammatory treatment
References
- Schett G, et al. Nat. Rev. Immunol. 2020. doi: 10.1038/s41577-020-0312-7
- Wang, D. et al. JAMA 2020; 323, 1061–1069.
- Schett, G. et al. Nat. Med. 2013; 19, 822–824.
- Pedersen SF, Ho YC. J. Clin. Invest. 2020. doi: 10.1172/JCI137647.
- Li J, et al. Med Sci Monit. 2018; 24:5501–5508. doi:10.12659/MSM.907439
- Tsukamoto H, et al. Cancer Res. 2018; 78(17):5011–5022. doi: 10.1158/0008-5472.CAN-18-0118
- Jacobi A, et al. J Am Acad Dermatol. 2005; 52(3 Pt 1):522‐526. doi: 10.1016/j.jaad.2004.11.022
- Montes-Torres A, et al. J Clin Med. 2015; 4(4):593‐613. doi: 10.3390/jcm4040593
- Zhang W, et al. Clin Immunol. 2020; 214:108393. doi:10.1016/j.clim.2020.108393
- Mitchell RE, et al. Sci Rep 2017; 7, 11315. doi: 10.1038/s41598-017-11803-y
- Ye Z, et al. Eur Radiol 2020. https://doi.org/10.1007/s00330-020-06801-0
- Ponticelli C, Moroni G. Expert Opin Drug Saf. 2017; 16(3):411‐419. doi: 10.1080/14740338.2017.1269168
- Boone BA, et al. BMC Cancer 2018; 18, 678. doi: 10.1186/s12885-018-4584-2
- Zuo Y, et al. medRxiv 2020; 2020.04.09.20059626; doi: 10.1101/2020.04.09.20059626
- Zuo Y, et al. JCI Insight 2020. In-press preview April 24, 2020. doi: 10.1172/jci.insight.138999
- Barnes BJ, et al. J Exp Med. 2020; 217(6):e20200652. doi:10.1084/jem.20200652
Figure. Schematic of the cytokine signaling instigated by SARS-CoV-2 infection. Modified from [1].
https://www.firmenpresse.de/pressrelease651191.html
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