Accumulating data on cellular and molecular pathways help to develop novel therapeutic strategies in skin inflammation and autoimmunity. Examples are psoriasis and atopic dermatitis, two clinically ...and immunologically well-defined disorders. Here, the elucidation of key pathogenic factors such as IL-17A/IL-23 on the one hand and IL-4/IL-13 on the other hand profoundly changed our therapeutic practice. The knowledge on intracellular pathways and governing factors is shifting our attention to new druggable molecules. Multiple cytokine receptors signal through Janus kinases (JAKs) and associated signal transducer and activators of transcription (STATs). Inhibition of JAKs can simultaneously block the function of multiple cytokines. Therefore, JAK inhibitors (JAKi) are emerging as a new class of drugs, which in dermatology can either be used systemically as oral drugs or locally in topical formulations. Inhibition of JAKs has been shown to be effective in various skin disorders. The first oral JAKi have been recently approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Currently, multiple inhibitors of the JAK/STAT pathway are being investigated for skin diseases like alopecia areata, atopic dermatitis, dermatomyositis, graft-versus-host-disease, hidradenitis suppurativa, lichen planus, lupus erythematosus, psoriasis, and vitiligo. Here, we aim to discuss the immunological basis and current stage of development of JAKi in dermatology.
Objectives
Patients with classical Hodgkin lymphoma (cHL) relapsing after second‐line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising ...(pre‐)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL).
Methods
Patients ≥18 years with histologically confirmed r/r cHL who failed second‐line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT‐based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression‐free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2‐stage phase 2 design (Simon 1989).
Results
Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported.
Conclusion
Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1.
CP-690,550 is an orally active and selective inhibitor of the janus kinase (JAK) molecules. The molecular pathways through which the JAK moieties function are described along with the clinical ...mechanisms associated with their inhibition. Animal models of JAK inhibition are reviewed as a background for the possible inhibition of JAK in humans. The pharmacokinetics of CP-690,550 in humans is described, and the Phase IIA and IIB trials are reviewed in some detail. These trials were dose-ranging and showed a general dose response with relatively robust American College of Rheumatology 20 (ACR20) responses. A proof-of-concept 6-week trial in which CP-690,550 was given as monotherapy was associated with highly efficacious responses at the mid and higher twice-daily dose ranges employed. A subsequent 24 week dose-ranging trial in which CP-690,550 was administered in combination with methotrexate showed ACR20 responses, which were also statistically significant versus placebo interventions. CP-690,550 treatment was associated with side effects, which included headache and nausea. Infections were more common versus placebo as were elevations in transaminase enzymes when administered in combination with methotrexate, and increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. Decreases in haemoglobin and white blood cell (WBC) counts were also observed along with small increases in serum creatinine. Occasional significant decreases of haemoglobin (>2 g dl−1 ) were observed, although decreases of WBC to less than 1000 per mm3 were not seen. Plans for long-term follow-up of the described trials are described along with the features of five presently ongoing Phase III trials of the CP-690,550 janus kinase (JAK) inhibitor. Future directions include completion and publication of these trials along with study of JAK inhibition for other indications.
Alopecia Areata (AA) is a common autoimmune disease characterized by non-scarring hair loss ranging from patches on the scalp to complete hair loss involving the entire body. Disease onset is ...hypothesized to follow the collapse of immune privilege of the hair follicle, which results in an increase in self-peptide/MHC expression along the follicular epithelium. Hair loss is associated with infiltration of the hair follicle with putatively self-reactive T cells. This process is thought to skew the hair follicle microenvironment away from a typically homeostatic immune state towards one of active inflammation. This imbalance is mediated in part by the dominating presence of specific cytokines. While interferon-γ (IFNγ) has been identified as the key player in AA pathogenesis, many other cytokines have also been shown to play pivotal roles. Mechanistic studies in animal models have highlighted the contribution of common gamma chain (γ
c
) cytokines such as IL-2, IL-7, and IL-15 in augmenting disease. IFNγ and γ
c
cytokines signal through pathways involving receptor activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). Based on these findings, JAK/STAT pathways have been targeted for the purposes of therapeutic intervention in the clinical setting. Case reports and series have described use of small molecule JAK inhibitors leading to hair regrowth among AA patients. Furthermore, emerging clinical trial results show great promise and position JAK inhibitors as a treatment strategy for patients with severe or recalcitrant disease. Demonstrated efficacy from large-scale clinical trials of the JAK inhibitor baricitinib led to the first-in-disease FDA-approved treatment for AA in June of 2022. This review aims to highlight the JAK/STAT signaling pathways of various cytokines involved in AA and how targeting those pathways may impact disease outcomes in both laboratory and clinical settings.
Janus kinase (JAK) inhibitors have attracted attention for their role in treating inflammatory disorders. This new class of biologics has the potential to significantly affect the field of ...dermatology, especially with the development of topical formulations.
To summarize published evidence on the efficacy, safety, and tolerability of topical JAK inhibitors in the treatment of inflammatory skin conditions.
This is a review of articles available in PubMed and the Cochrane Library up until November 2017.
Fifty-five potential articles were identified; 11 articles were included for review, comprising an aggregate of 924 patients. In randomized clinical trials, topical JAK inhibitors demonstrate modest improvements in psoriasis and atopic dermatitis disease scores, patient-reported outcomes, and quality of life. Results for vitiligo are conflicting, with improvements seen only in facial vitiligo. Conclusive efficacy data for alopecia areata is lacking.
It was not possible to perform a meta-analysis due to the lack of standardization and low number of randomized clinical trials.
Topical JAK inhibitors provide an attractive treatment option for patients with psoriasis, atopic dermatitis, alopecia areata, and vitiligo. Although early phase clinical studies of this novel drug class are promising, large phase 3 and 4 studies are needed to further define the role of topical JAK inhibitors in dermatology.
Upadacitinib, a recently approved Janus kinase (JAK) inhibitor specific for JAK1, may be a promising candidate in patients with ulcerative colitis (UC) who present no response or intolerance to ...first-line JAK inhibitors. We assessed the therapeutic impact of upadacitinib on six UC patients who demonstrated an inadequate response or intolerance to tofacitinib or filgotinib. After 2 months of treatment, 5 patients (83.3%) achieved clinical remission, and all patients experienced decreased levels of CRP. One patient had coronavirus disease 2019 pneumonia and showed a mild increase in transaminase levels. This case series highlights the potential utility of a rotation strategy among JAK inhibitors.
Introduction: JAK inhibitors are used in the treatment of psoriatic arthritis when there is a lack of effective response or intolerance to first-line drugs or their use must be discontinued due to ...the presence of side effects. JAK inhibitors inhibit the JAK-STAT signaling pathway which plays a significant role in the pathogenesis of many inflammatory and autoimmune diseases. This mechanism leads to a reduction in the level of pro-inflammatory cytokines which causes rapid improvement in the patient's clinical condition. Tofacitinib is the best-known drug in this group; its use carries an increased risk of cardiovascular events and reactivation of the varicella-zoster virus. Regular monitoring of patients results in faster detection of the first signs of undesirable effects and the cessation of their progression. The drug's safety profile is acceptable and the benefits outweigh possible complications. Aim of the study: The aim of the study is to summarize the available knowledge about tofacitinib treatment in psoriatic arthritis. The way of work, effectiveness of treatment and potential side effects were summarized and described. Materials and methods: The literature available in PubMed database was reviewed using the following keywords: “Psoriatic arthritis”, “Tofacitinib”, “JAK inhibitors”, “JAK-STAT” Conclusion: Tofacitinib treatment in rheumatology is used in psoriatic arthritis. The rapid improvement in the clinical condition of patients treated with JAK inhibitors is due to their direct impact on the modulation of the pathogenesis of the disease. The predictable benefits of therapy outweigh the side effects which can be detected at an early stage with regular monitoring of the patient.
Refractory dermatomyositis (DM) is defined as cases that do not show improvement after initial treatment with two different immunosuppressives combined with corticosteroids with or without ...intravenous immunoglobulins. In recent years, few studies have reported a positive response to the use of Janus kinase inhibitors (JAK‐inhibitors) for the treatment of refractory DM. A systematic literature review was performed for articles studying the use of JAK‐inhibitors for the treatment of refractory DM. We identified 38 females and 15 males treated with JAK‐inhibitors without serious side effects. Tofacitinib was the most frequently used JAK‐inhibitor followed by ruxolitinib. Significant improvement in CDASI score, muscle strength, body weight, and skin lesions were reported in most of the studies. The duration of follow‐up ranged from 1 to 15 months without relapse. Therefore, the use of JAK‐inhibitors looks promising in the treatment of refractory DM and further high volume research may be required to validate the current concept. As only case reports and series were identified without direct comparison for review, there is a potential risk of bias. Despite these limitations, we believe that the result of this analysis allows a better understanding of treatment options for refractory DM and will help generate a hypothesis that can be further tested.
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