# Inflammation Causes Exacerbation of COVID-19: How about Skin Inflammation?
## 3 Inflammation Exacerbates COVID-19 Infection
### COVID-19 and Inflammatory Skin Disease
#### 3.3.3. JAK Inhibitors  
JAK inhibitors are the emerging small-molecule agents to treat psoriasis and atopic dermatitis, in addition to rheumatoid arthritis, systemic lupus erythematosus, and IBD, and this class of drugs has also been approved for the treatment of cytokine storm in COVID-19 patients [71; 72]. JAKs are cytoplasmic kinases which associate to cytokine receptors to transduce their signals to transcription factors, such as STATs, whose signaling pathway is called the JAK-STAT pathway (Figure 4). Cytokine receptors which can associate JAKs include IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, 22, 23, 31 and IFNs. JAKs are composed of four family members, JAK1, JAK2, JAK3, and Tyk2 [72]. Several specific inhibitors have been developed to block the specific JAKs to inhibit the specific signaling cascades in inflammatory diseases (Figure 5) [73]. Recent advancements in medicine have developed tofacitinib for rheumatoidarthritis and psoriasis (approved in the EU and the USA), baricitinib for RA and atopic dermatitis, upadacitinib for atopic dermatitis, ruxiolitinib for myelodysplastic syndrome, and several other JAK inhibitors are under clinical studies. This class of drugs can block IFN signals, which affects the defensive activity against viral infections, and may result in an increased risk of COVID-19 infection [18]. On the other hand, tofacitinib and baricitinib have been approved for the treatment of severe COVID-19 infection to decrease cytokine storm symptoms [74]. Baricitinib has been shown to have antiviral activity, inhibiting endocytosis and following viral replication in the cells, through blocking the effects of numb-associated kinases (NAKs) family members. Upadacitinib and tofacitinib do not have inhibitory effects on NAKs [75]. JAK inhibitors may be useful in treating the late stage, cytokine storm phase of COVID-19, but may increase the risk of infection of COVID-19; thus, caution is needed when treating patients with AD or psoriasis with this class of medications. However, no increased risk of COVID-19 infection, hospitalization, or mortality has been shown in the treatment with JAK inhibitors in atopic dermatitis, psoriasis, or rheumatic patients so far [76; 77; 78]. [PERSON] et al. [69] published a systematic review on COVID-19-infected skin disease patients treated with immunosuppressive. They reviewed 10 patients with psoriasis/ psoriatic arthritis treated with biologics or immunosuppressive drugs including cyclospor and methotrexate, and 2 patients with immuno-bullous disorders, including 1 pemphighus and 1 mucous pemphigoid patient. They reported that one patient did not stop biologics during the COVID-19 infection, and others did, but the clinical course of psoriasis was preferable, while 1 patient treated with cyclospor and methotrexate experienced severe exacerbation after discontinuation of the previous treatment. Out of these 12 patients, only one patient needed hospitalization. They concluded that dermatologic disease patient treated with biologics had favorable clinical course after the discontinuation of the treatment during COVID-19 infection. Another report by [PERSON] et al. [79] demonstrated their epidemiological survey with gene expression analysis that skin diseases are associated with increased risk of COVID-19 infection, but related to less severe disease course. They found similar gene expression in skin diseases and COVID-19 infection, and speculated that inflammatory skin conditions such as atopic dermatitis and psoriasis have heightened immune response even in normal looking skin, and also in oral mucosa and throat, which may allow increased risk of infection but suppress viral activity with already heightened immune reaction. Figure 4: The scheme of the JAK–STAT pathway. When a cytokine binds to its receptor, the receptor makes a receptor complex, which phosphorylates JAK, and JAK phosphorylates itself and STATs. Phosphorylated STATs make homo- or heterodimers and translocate in the nucleus, where they exert their function as nuclear proteins.