Tofacitinib as the potent treatment for refractory pemphigus: A possible alternative treatment for pemphigus

Tavakolpour, Soheil

doi:10.1111/dth.12696

Cited by 17 publications

(14 citation statements)

References 12 publications

(11 reference statements)

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“…It is interesting to note that secretion of IL-21 is associated with activation of JAK1 and JAK3. Tofacinib, an inhibitor of both JAK1 and JAK3, was suggested as a possible therapeutic in pemphigus (302). Interestingly, tofacinib has been successfully applied in different autoimmune disorders (303, 304).…”

Section: Emerging Therapiesmentioning

confidence: 99%

Pemphigus: Current and Future Therapeutic Strategies

et al. 2019

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Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.

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Section: Emerging Therapiesmentioning

confidence: 99%

Pemphigus: Current and Future Therapeutic Strategies

et al. 2019

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“…A possible therapeutic role of tofacitinib (pan-JAK inhibitor) in pemphigus has been recently proposed. 53…”

Section: Miscellaneousmentioning

confidence: 99%

Biologics in autoimmune bullous diseases: Current scenario

Bishnoi

Handa

et al. 2021

IJDVL

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Autoimmune bullous diseases can be intraepidermal (pemphigus group of disorders) or subepidermal (pemphigoid group of disorders). The treatment of these disorders chiefly comprises corticosteroids and immunosuppressant adjuvants like azathioprine and mycophenolate mofetil. Autoantibodies are the main mediators of these diseases. Rituximab, a chimeric anti-CD20 monoclonal antibody targeting B-cells, has emerged as an excellent treatment option for refractory pemphigus vulgaris in the last decade. Since then, many new biologics have been proposed/explored for managing autoimmune bullous diseases. These hold potential for greater efficacy and lesser adverse effects than conventional immunosuppressants. In this review, we discuss the role of various biologics in the treatment of autoimmune bullous diseases, followed by a brief discussion on the drawbacks to their use and new developments in this area.

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“…Those results suggest that specific inhibition of the Jak-Stat3 pathway may also be beneficial without the known adverse effects of steroids. T H 2 cytokines like IL-4, IL-9, and IL-21, that utilize Jak-family kinases are known to contribute to the induction and regulation of autoantibody production in pemphigus (161, 162) therefore Jak inhibitors also serve as a potential treatment, but preclinical or clinical studies are yet to be done (163).…”

Section: Tyrosine Kinases In Inflammatory Skin Diseasesmentioning

confidence: 99%

Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

2019

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Tyrosine kinases relay signals from diverse leukocyte antigen receptors, innate immune receptors, and cytokine receptors, and therefore mediate the recruitment and activation of various leukocyte populations. Non-receptor tyrosine kinases of the Jak, Src, Syk, and Btk families play major roles in various immune-mediated disorders, and small-molecule tyrosine kinase inhibitors are emerging novel therapeutics in a number of those diseases. Autoimmune and inflammatory skin diseases represent a broad spectrum of immune-mediated diseases. Genetic and pharmacological studies in humans and mice support the role of tyrosine kinases in several inflammatory skin diseases. Atopic dermatitis and psoriasis are characterized by an inflammatory microenvironment which activates cytokine receptors coupled to the Jak-Stat signaling pathway. Jak kinases are also implicated in alopecia areata and vitiligo, skin disorders mediated by cytotoxic T lymphocytes. Genetic studies indicate a critical role for Src-family kinases and Syk in animal models of autoantibody-mediated blistering skin diseases. Here, we review the various tyrosine kinase signaling pathways and their role in various autoimmune and inflammatory skin diseases. Special emphasis will be placed on identification of potential therapeutic targets, as well as on ongoing preclinical and clinical studies for the treatment of inflammatory skin diseases by small-molecule tyrosine kinase inhibitors.

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Tofacitinib as the potent treatment for refractory pemphigus: A possible alternative treatment for pemphigus

Cited by 17 publications

References 12 publications

Pemphigus: Current and Future Therapeutic Strategies

Pemphigus: Current and Future Therapeutic Strategies

Biologics in autoimmune bullous diseases: Current scenario

Tyrosine Kinases in Autoimmune and Inflammatory Skin Diseases

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