INTRODUCTION
Since the release of the first FDA-approved targeted biologic agent in 2017, several years have elapsed since a new systemic therapy has been approved for atopic dermatitis (AD). Now, however, JAKis have arrived and opened an entirely new therapeutic approach to patients with refractory AD. JAKis have previously been utilized to treat other chronic inflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, and now atopic dermatitis and alopecia areata.1 There are three JAKis that have been approved by the US Food and Drug Administration in 2021 and 2022 for the treatment of AD. Upadacitinib and abrocitinib are oral medications that are approved for moderate-to-severe atopic dermatitis,2 and ruxolitinib is a topical that is approved for mild-to-moderate AD, as well as non-segmental vitiligo. Baricitinib is another oral JAK inhibitor that has recently been approved for the treatment of severe alopecia areata and is approved for AD outside of the US.3 Tofacitinib is another JAK inhibitor that is new to dermatology and has been approved for symptomatic psoriatic arthritis.4
The inflammatory pathway of JAK is interlinked with signal transducers and activators of transcription (STAT), to constitute the JAK-STAT pathway. When a cytokine binds to a receptor, JAK phosphorylates the receptor chains. This allows STAT to bind the phosphorylated site and dimerize along with the phosphate molecule. These STAT dimers move to the nucleus and activate gene transcription.5 This pathway is not only relevant for dermatology, but for immune and hematopoietic function. Though inhibition of this pathway is the mechanism for these medications, genetic loss of function of JAK3 causes severe immunodeficiency syndrome.6 Gain of function mutations can cause the JAKs to act as oncogenes in malignancies such as T cell lymphoma7, thus a healthy balance of this proliferative pathway is necessary.
Many sporadic autoimmune and autoinflammatory conditions rely on this JAK-STAT pathway for the pathogenesis of disease, thus JAK inhibitors have been developed to treat these autoimmune conditions.8 This mechanism differs from the biologic drugs, which often are monoclonal antibodies targeted against only one or two specific cytokines, such as IL-13. These pathways are closely intertwined, however, as IL-4, IL-13, IL-31, and other interleukins and cytokines signal via JAK1, JAK2, and JAK3. Inhibition of JAK1/2 leads to decreased IFNgamma with decreased production of Th1 cells. Inhibition of JAK1/3 leads to decreased IL-2, IL-4, and IL-9 with decreased production of Th2 cells and JAK2 inhibition decreases IL-5.9 Legacy immunosuppressive medications such as systemic corticosteroids or cyclosporine have a broad immunomodulatory effect, touching many areas of the immune system and beyond. On the other hand, biologics in this space are extremely targeted, affecting only one or two specific cytokines. The JAK inhibitor class sits between these two extremes.
As the JAK-STAT system is involved in many functions beyond inflammation such as hematopoiesis, tissue repair, and adipogenesis, gross modulation of this pathway may not be desired. Thus, selective JAKis have been developed that preferentially target the JAK members that are most relevant to the desired therapeutic effect. In AD, JAK 1 is involved in the signaling of several key cytokines including IL-4, IL-13, and IL-31, while JAK 3 signaling plays a role in lymphocyte
The inflammatory pathway of JAK is interlinked with signal transducers and activators of transcription (STAT), to constitute the JAK-STAT pathway. When a cytokine binds to a receptor, JAK phosphorylates the receptor chains. This allows STAT to bind the phosphorylated site and dimerize along with the phosphate molecule. These STAT dimers move to the nucleus and activate gene transcription.5 This pathway is not only relevant for dermatology, but for immune and hematopoietic function. Though inhibition of this pathway is the mechanism for these medications, genetic loss of function of JAK3 causes severe immunodeficiency syndrome.6 Gain of function mutations can cause the JAKs to act as oncogenes in malignancies such as T cell lymphoma7, thus a healthy balance of this proliferative pathway is necessary.
Many sporadic autoimmune and autoinflammatory conditions rely on this JAK-STAT pathway for the pathogenesis of disease, thus JAK inhibitors have been developed to treat these autoimmune conditions.8 This mechanism differs from the biologic drugs, which often are monoclonal antibodies targeted against only one or two specific cytokines, such as IL-13. These pathways are closely intertwined, however, as IL-4, IL-13, IL-31, and other interleukins and cytokines signal via JAK1, JAK2, and JAK3. Inhibition of JAK1/2 leads to decreased IFNgamma with decreased production of Th1 cells. Inhibition of JAK1/3 leads to decreased IL-2, IL-4, and IL-9 with decreased production of Th2 cells and JAK2 inhibition decreases IL-5.9 Legacy immunosuppressive medications such as systemic corticosteroids or cyclosporine have a broad immunomodulatory effect, touching many areas of the immune system and beyond. On the other hand, biologics in this space are extremely targeted, affecting only one or two specific cytokines. The JAK inhibitor class sits between these two extremes.
As the JAK-STAT system is involved in many functions beyond inflammation such as hematopoiesis, tissue repair, and adipogenesis, gross modulation of this pathway may not be desired. Thus, selective JAKis have been developed that preferentially target the JAK members that are most relevant to the desired therapeutic effect. In AD, JAK 1 is involved in the signaling of several key cytokines including IL-4, IL-13, and IL-31, while JAK 3 signaling plays a role in lymphocyte
