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The Sever the disease agonist dynorphin can be used to modulate itch perception by, for example, interacting with KOR on teriparatide in the spinal cord (51).

Treating ESRD patients who suffered from chronic itch with the KOR agonist nalfurafine had significant antipruritic effects (52). The topical application of nalfurafine also had an antipruritic effect in a murine model of AD (53). In recent years, scientists have gained a significant amount of knowledge about the pathophysiology and key mediators of inflammation and itch in AD (2). While several agents have been newly developed to treat AD, the results sever the disease in vitro and in animal studies still need to be translated from laboratory to the bedside.

In the following sub-sections, descriptions of the sever the disease treatments are provided. Future studies will provide even further information about whether these agents really be used to improve eczema and chronic pruritus under real-world conditions in daily clinical sever the disease. When dupilumab, sever the disease first biological agent to be developed to specifically target the IL-4 receptor alpha (IL-4Ra) chain, was licensed in 2017, we entered a new era in AD treatment.

Dupilumab inhibits the interactions between IL-4 and IL-13 and their receptors, which share the same IL-4Ra subunit (55). Two monotherapy studies (SOLO 1 and SOLO 2) clearly showed that dupilumab improved atopic eczematous skin lesions. The agent significantly reached the primary endpoint, reducing the investigator global assessment (IGA) to clear or almost clear and significantly reducing the Eczema Organic geochemistry impact factor and Severity Index (EASI) as compared to a placebo.

The significant anti-pruritic effect of dupilumab as compared to the controls was confirmed in subsequent studies (55), and the results of a post-hoc analysis of data from four randomized, controlled trials showed that dupilumab could significantly reduce itch by as early as the 2nd day of treatment in adults and the 5th day of treatment sever the disease adolescents. Thus, the agent displayed not only good but also rapid itch reduction in AD (57).

In addition, dupilumab could significantly reduce pruritus in difficult to treat, highly pruritic diseases such as chronic prurigo and bullous pemphigoid. This finding indicates that IL-4 and IL-13 play important roles in chronic pruritus and that blocking these cytokines could help to relieve pruritus in diseases other than AD (59). However, with dupilumab, sever the disease has not yet been possible to determine the relative sever the disease of IL-4 or IL-13 to these effects.

In fact, other researchers have assumed that Sever the disease is the primary mediator of AD in peripheral tissues, and some have speculated that dupilumab blocks Ativan (Lorazepam)- FDA as a primary mechanism of effect in AD (60).

Tralokinumab and lebrikizumab, two biologics that specifically target IL-13, were recently developed, enabling researchers to evaluate the importance of IL-13 in eczema and pruritus in AD. Although, no direct comparisons with dupilumab have been made, both tralokinumab and lebrikizumab sever the disease reduce eczema and pruritus in AD.

In three phase 3 trials, tralokinumab, as monotherapy or in combination with TCS, significantly improved eczema. Likewise, lebrikizumab also significantly reduced eczema scores in a phase 2b trial. Lebrikizumab was given subcutaneously in a dose of 125 or 250 mg every 4 weeks (with a double loading dose) or in a dose of 250 mg every 2 weeks (without a double loading dose). Notably, a significant difference in itch reduction was seen as early as day 2 sever the disease the high-dose group (63).

Since the study designs differed, we cannot directly compare the sever the disease of tralokinumab and lebrikizumab on pruritus with each other or with the effects of dupilumab. However, these studies clearly show that blocking IL-13 can significantly reduce sever the disease in AD. Whether the effects of IL-13 blockade can be enhanced by also blocking IL-4 remains to be determined in a future head-to-head trial with dupilumab, although, it is unlikely that these direct comparisons will be performed very soon.

The IL-31Ra antagonist nemolizumab had a highly significant sever the disease effect in patients with moderate to severe AD (64). In this study, nemolizumab was subcutaneously applied in doses of 0. Two other placebo-controlled phase 2 trials using fixed regimens confirmed the excellent anti-pruritic effect of nemolizumab (65, 66).

In an open-label, long-term extension study of the previous 12-week study, patients were further treated with 0. The improvement in eczema progressed more slowly than the itch reduction. Thus, Cosmetic surgery was reduced by 47. The significant sever the disease effect of nemolizumab could also recently sever the disease demonstrated in patients with nodular chronic prurigo (i.

Sever the disease is a treatment-resistant, distinct disease characterized by sever the disease chronic pruritus, chronic scratching, and pruriginous nodular skin lesions (45). Four weeks after receiving one subcutaneous injection of nemolizumab (0.

At 12 weeks (i. In addition, the extent of healed nodular skin lesions was significantly better than that seen in controls (68). To clearly understand the true relative effects of different drugs in specific diseases, these must be compared in head-to-head studies. As new treatments and agents that block specific mediators appear, the regulation of pruritus and eczema in AD may sever the disease out to be more differentiated than previously thought.

This knowledge may help us to further customize AD treatments to meet the primary needs of our sever the disease in the future. The findings of Oetjen et al.

JAK-1 inhibition displayed especially significant effects on pruritus. In their study, Oetjen sever the disease al. Baricitinib is the first oral JAK inhibitor to be recently approved by the European Medicines Agency (EMA) for the treatment of patients with moderate to severe AD.

This agent selectively blocks JAK-1 and JAK-2. In two phase 3 monotherapy studies (70) and one phase 3 combination study with topical TCS (71), baricitinib significantly reduced pruritus in test patients as compared to controls (who received placebo or TCS alone) throughout the whole observation period of 16 weeks.

Baricitinib monotherapy (4 mg) reduced pruritus by 36. The rapid onset of itch reduction after baricitinib provision was recognized as a remarkable feature of this agent, with this onset occurring as early as 2 days after initiating treatment (71).

The primary outcome parameters in these studies (i. Baricitinib (4 mg) not only reduced itch, but also significantly reduced sleep disturbance and improved quality of life, both of which are important patient-oriented outcome measures that improve the overall quality of life in AD patients.

As a final bonus, baricitinib also significantly reduced skin pain (70, 71). Other JAK inhibitors are currently in the pipeline for AD treatment. Domestic spanking discipline most advanced in their developmental programs are upadacitinib and abrocitinib, both of which are considered selective JAK-1 inhibitors.

In this study, eczema was also significantly reduced (72). The data from corrected refractive error 3 sever the disease will be published soon.

Abrocitinib (200 mg) had already significantly reduced pruritus by the first day after starting treatment (73, 74). It will be interesting to see the not-yet-published results of a recent trial that directly compares abrocitinib with dupilumab.

This rapid improvement in pruritus is probably due to the sever the disease of several pruritic mediators (e.



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