The Inhibition of Glycolysis in T Cells by a Jak Inhibitor Ameliorates the Pathogenesis of Allergic Contact Dermatitis in Mice.

Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4+ T cells, CD8+ T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.

Baricitinib in severe and refractory peripheral ulcerative keratitis: a case report and literature review.

Ocular disease, such as scleritis and peripheral ulcerative keratitis (PUK), may be a serious ocular complication. We present a patient with severe and refractory PUK treated with baricitinib. A review of the literature on Janus kinase inhibitors (JAKINIB) in refractory ocular surface pathology was also performed. For the literature review, the search in PubMed, Embase, and the Cochrane library was carried out from inception until 31 May 2021, including conference proceedings from four major rheumatology congresses. All original research articles studying JAKINIB treatment in patients with inflammatory eye disease were included. We present an 85-year-old woman with rheumatoid arthritis (RA) and secondary Sjögren's syndrome refractory to methotrexate, leflunomide, certolizumab pegol, adalimumab, and tocilizumab (TCZ). However, 10 months after starting TCZ, the patient suffered a perforation secondary to PUK, requiring urgent surgical intervention. In the absence of infection, she was treated with boluses of intravenous methylprednisolone followed by oral prednisone at high doses in a decreasing pattern together with baricitinib at a dose of 2 mg/day with a very rapid and persistent favorable response to eye and joint symptoms. After 18 months of treatment, the patient had not presented serious side effects or signs of reactivation of her disease. In addition to this report, three other studies including one PUK associated with RA and two non-infectious scleritis treated with tofacitinib were included in this literature review. All three patients had experienced an insufficient response to conventional treatment, including biologic agents, before being switched to JAKINIB, leading to a complete or partial recovery in all of them without significant adverse effects so far. JAKINIBs (baricitinib and tofacitinib) may be an effective and safe therapy in patients with severe autoimmune and refractory ocular surface pathology, such as scleritis and PUK.

In vitro characterization of tofacitinib loaded novel nanoemulgel for topical delivery for the management of rheumatic arthritis.

The purpose of the current study is to prepare the tofacitinib (TFB) nanoemulgel (NEG) for topical administration with optimized particle size, high loading efficiency, and better penetration through the skin for the treatment of rheumatic arthritis. The topical delivery of this drug avoids the hazards associated with oral delivery like upper respiratory tract infections and neutropenia. The formulations were prepared using the high-energy ultrasonication method. Oleic acid, tween 80, and propylene glycol were used to prepare TFB nanoemulsion (NE) which is then homogenized with carbopol-934 hydrogel to get the NEG loaded with TFB. The concentration of independent variables such as X1 (oil phase), X2 (surfactant), and X3 (cosurfactant) was optimized using the Box-Behnken design to check its impact on dependent variables such as Y1 (particle size) and Y2 (loading efficiency) of the NE. The minimum particle size of 106.3 ± 2.8 nm and maximum loading efficiency of 19.3 ± 1.8% were obtained for NE. The NEGs were evaluated for different organoleptic and physicochemical stability which were found within the normal range. The in vitro release studies showed 89.64 ± 0.97% cumulative release of TFB from NEG over the period of 24 h. The drug release data were fitted in different kinetic models and it followed Higuchi and Korsmeyer-Peppas model clearly showing the non-Fickian drug release from matrix system. As a result, the TFB NEG that have been produced could be a viable delivery mechanism for topical route.

Targeted pharmacologic immunomodulation for inborn errors of immunity.

Inborn errors of immunity consist of over 400 known single gene disorders that may manifest with infection susceptibility, autoimmunity, autoinflammation, hypersensitivity and cancer predisposition. Most patients are treated symptomatically with immunoglobulin replacement, prophylactic antimicrobials or broad immunosuppression pertaining to their disease phenotype. Other than haematopoietic stem cell transplantation, the aforementioned treatments do little to alter disease morbidity or mortality. Further, many patients may not be transplant candidates. In this review, we describe monogenic disorders affecting leucocyte migration, disorders of immune synapse formation and dysregulation of immune cell signal transduction. We highlight the use of off-label small molecules and biologics mechanistically targeted to altered disease pathophysiology of such diseases.

JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition.

Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.

Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity.

Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.

The Use of Biologic Modifiers as a Bridge to Hematopoietic Cell Transplantation in Primary Immune Regulatory Disorders.

Recently, primary immune regulatory disorders have been described as a subset of inborn errors of immunity that are dominated by immune mediated pathology. As the pathophysiology of disease is elucidated, use of biologic modifiers have been increasingly used successfully to treat disease mediated clinical manifestations. Hematopoietic cell transplant (HCT) has also provided definitive therapy in several PIRDs. Although biologic modifiers have been largely successful at treating disease related manifestations, data are lacking regarding long term efficacy, safety, and their use as a bridge to HCT. This review highlights biologic modifiers in the treatment of several PIRDs and there use as a therapeutic bridge to HCT.

Efficacy and safety of jakinibs in rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVES: To assess the efficacy and safety of jakinibs for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response or intolerance to conventional synthetic or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library. Randomized placebo-controlled trials (RCTs) of jakinibs in RA patients were eligible. The effective outcome was RA improvement to reach an American College of Rheumatology 20%/50%/70% (ACR20/50/70) response rate at weeks 12 and 24 after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuations due to adverse events, infections, and serious infections. RESULTS: Twenty-eight randomized, double-blind, controlled trials including 14,500 patients were included. At both weeks 12 and 24, the pooled analysis suggested effective treatment with jakinibs, represented as an increased clinical response of ACR20, ACR50, and ACR70. Subgroup analysis based on different types of jakinibs demonstrated that only peficitinib treatment had no impact on the clinical response of ACR50 or ACR70 at week 12. Jakinibs were associated with an increased incidence of infections at week 12 and TEAEs and infections at week 24. No increase in the risk of SAEs, discontinuations due to adverse events, or serious infections was observed in comparisons between treatment with jakinibs and treatment with placebo in these patients. CONCLUSIONS: Jakinibs are efficacious and well tolerated in RA patients up to 24 weeks, although they are associated with an increased risk of infectious complications. Key Points • ACR20/50/70 in patients treated with jakinibs was significantly higher than those in patients treated with placebo. • No difference in ACR50/70 was observed in patients with RA treated with peficitinib and placebo. • Jakinibs are beneficial and well tolerated in RA treatment.

Oral Tofacitinib: Contemporary Appraisal of Its Role in Dermatology.

Tofacitinib, an oral Janus kinase inhibitor (Jakinib), is an emerging treatment modality whose well-established efficacy in systemic inflammatory diseases is now being actively explored for cutaneous disorders (arising due to the patient's dysimmune responses) that are not responding to and/or sustaining intolerable adverse effects with the classical immunosuppressives and other targeted therapies such as the biologics. The most common dermatoses for which oral as well as topical Jakinibs such as tofacitinib have been evaluated and are being used albeit as an off-label indication include psoriasis, psoriatic arthritis, alopecia areata, vitiligo, and atopic dermatitis. This article provides a succinct review on the current status of oral tofacitinib in dermatology through literature search of PubMed database and stresses on the need for further evidence generation to define the drug's place in the therapeutic arsenal of dysimmune cutaneous disorders.

The Jakinibs in systemic lupus erythematosus: progress and prospects.

INTRODUCTION: Multiple pathways are involved in the pathogenesis of systemic lupus erythematosus (SLE). The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway mediates the intracellular signals of more than 60 cytokines, growth factors and hormones from the type I/II cytokine receptors. Dysregulation of the cytokines is a hallmark of SLE; inhibition of downstream signaling mediated by the JAKs is an attractive therapeutic option. AREAS COVERED: This article reviews the preliminary data concerning the efficacy of the JAK inhibitors (Jakinibs) in SLE. JAK inhibition has shown promise in murine lupus dermatitis and nephritis. Ex-vivo studies of human SLE have demonstrated the effect of JAK1/2 inhibition on the activation of the STAT proteins and autoantibody production from B cells. A Phase II trial reported modest efficacy of baricitinib in improving synovitis in SLE patients. EXPERT OPINIONS: Inhibition of the JAK-STAT pathway is an attractive therapeutic option. The convenience of oral administration and lower production cost of the Jakinibs could replace the biological agents in the treatment hierarchy of autoimmune inflammatory diseases. Additional clinical data are needed; results of ongoing studies of the newer Jakinibs in cutaneous and non-life-threatening lupus are eagerly awaited.

Therapeutic potential of JAK/STAT pathway modulation in mood disorders.

Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders. In addition, the antidepressant actions of current treatments have been shown to be mediated by JAK/STAT-dependent mechanisms. To date, two JAK inhibitors (JAKinibs) have been approved by the U.S. Food and Drug Administration and are primarily indicated for the treatment of inflammatory conditions such as rheumatoid arthritis. Indirect evidence from studies in populations with inflammatory conditions indicates that JAKinibs significantly improve measures of mood and quality of life. There is also direct evidence from studies in populations with depressive disorders, suggesting that JAK/STAT pathways may be involved in the pathophysiology of depression and that the inhibition of specific JAK/STAT pathways (i.e. via JAKinibs) may be a promising novel treatment for depressive disorders.