Although the focus of JAK inhibitors for the treatment of chronic inflammatory conditions has been on RA and IBD, there are other conditions in which JAK inhibitors could serve as therapeutic options. In fact, also taking into account the role of the JAK pathways in the transmission of intracellular signals of type 2 cytokines involved in asthma pathogenesis, new therapeutic strategies interfering with JAK appear at the horizon for treating patients suffering from the severe form of bronchial asthma, CRS and atopic dermatitis. Actually, many JAK inhibitors, which also inhibit STAT phosphorylation, have been developed for treating inflammatory diseases
[24,25][56][57]. Tofacitinib is a potent pan-JAK antagonist that is notably more selective against JAK1 and JAK3, which are critical in Th2 signaling, than against JAK2 and TYK2
[96][58]. Experimental data obtained in mouse model of pulmonary eosinophilia, show that systemic administration of the JAK3 inhibitor tofacitinib (CP-690550), approved for the treatment of rheumatoid arthritis, ulcerative colitis and moderate-to-severe chronic plaque psoriasis
[97[59][60][61][62][63][64][65],
98,99,100,101,102,103], effectively inhibited antigen-induced pulmonary eosinophil influx, IL-13 and eotaxin expression
[99][61]. These data are consistent with the previous demonstration that JAK3
−/− mouse models failed to exhibit efficient recruitment of Th2 cells to the lungs following antigen challenge
[104][66]. In addition, by considering that IL-9 uses the JAK3 pathway for the signal transmission and has also been implicated in the development of allergic pulmonary inflammation, the effects of JAK3 block could be related to the downstream inhibition signal
[13,31][67][68]. More recently, topical tofacitinib effectively reduced overall inflammation in a murine model of CRSwNP by suppressing Th2-dominant inflammation
[105][69]. The possible use of topical JAK inhibitors has also been evaluated in asthma patients. In fact, in adult subjects with mild asthma and FENO higher than 40 parts per billion (ppb), inhaled tofacitinib induced dose-dependent reduction of FENO
[106][70]. In the group of type 2 diseases, JAK inhibitors have been largely evaluated in patients suffering from atopic dermatitis. In moderate-to-severe atopic dermatitis, a small open-label clinical trial with oral tofacitinib in six patients who were refractory to standard treatment showed a decrease in SCORAD from 36.5 at week 8 to 12.2 at week 29, with no adverse events
[106][70]. More importantly, 2% topical tofacitinib in mild-to-moderate atopic dermatitis patients showed a significantly decrease of EASI score compared with the control group (–81.7% vs. −29.9%)
[99][61]. In addition, baricitinib, an oral small molecule with potent JAK1 and JAK2 antagonism, has been demonstrated to be effective in reducing the skin lesions and pruritus in atopic dermatitis patients and improving HRQoL
[107][71]). The JAK1 inhibitor abrocitinib, which reduces IL-4 and IL-13 signaling, is being investigated for the treatment of atopic dermatitis. The 200 mg dose of abrocitinib was superior to dupilumab with respect to itch response at week 2 but not with respect to most other key clinical features of the disease
[108][72]. Taking this into account, it could be hypothesized that JAK inhibition in type 2-low asthma endotype may also be effective in a proportion of asthmatic patients; the endotype is represented by the type 2-low pattern. This observation seems to suggest that tezepelumab, a monoclonal anti-TSLP antibody being studied in patients with asthma, proves to be effective regardless of type 2 endotype in producing a consistent reduction in asthma exacerbations, considering that TSLP exerts its biological effects through the JAK1/JAK2 pathway
[83][43]. One of the major concerns during treatment with biological agents has been related to the safety profile. Data obtained from the clinical trials and in real-life studies have been clearly confirmed not only the efficacy but also the safety of the biological agents targeting type 2 cytokines
[109][73]. In addition, the high safety profile is also confirmed by the authorization to administer omalizumab, the first biological agent for treating severe asthma, in pregnant women
[110][74]. To date, the safety profile of JAK inhibitors represents a key point of discussion specifically when these drug are used systemically for the treatment of immune-mediated diseases such as asthma and atopic dermatitis. Most of the safety data come from the large trials of in rheumatic and inflammatory bowel diseases. In recently published analysis using data from long-term extension studies in patients suffering from rheumatoid arthritis and treated with tofacitinib, emerges a major incidence for severe infections but similar to those observed biologics as anti-TNF-α monoclonal antibodies, currently used in clinical practice for the treatment of this disease, as noted in
[111][75]. However, an increase of the risk of herpes zoster infection compared with biologics is observed
[112][76]. Cardiovascular risk was one of the concerns raised about JAK inhibitors, largely related to the alterations in lipid profile noted with this class of drugs
[113][77]. To avoid rapid absorption across the lung and into systemic circulation, design of lung-restricted molecules must include a lung retention strategy. To maximize this objective, inhaled design must contemplate not only retention of the compound within the lung, but also access of the drug to the relevant biological target. In addition, to reduce the possible negative impact of a systemic treatment, a selective potent inhaled JAK inhibitor (GDC-0214) has been used in patients with mild asthma. The biological effect caused dose-dependent reductions in FENO for mild asthma. There were no major imbalances in adverse events or laboratory findings, or evidence of systemic JAK inhibition. As the authors mentioned, however, subsequent trials will be needed to confirm whether or not the observed reduction in FENO will translate to improvements in airflow obstruction, symptoms and exacerbations among populations with a broader spectrum of asthma severity
[26][78].