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1.
Rev Med Suisse ; 16(685): 477-480, 2020 Mar 11.
Artigo em Francês | MEDLINE | ID: mdl-32167248

RESUMO

If treatment target is not reached with a conventional disease-modifying antirheumatic drug (csDMARD) such as methotrexate in rheumatoid arthritis, it is recommended to use a biologic (bDMARD) or a Janus kinase (JAK) inhibitor, small synthetic molecules recently developed. Oral administration and short half-life can favour the choice of JAK inhibitors, as well as the opportunity to use it in monotherapy, even though co-treatment with csDMARD is recommended. As yet long-term studies are lacking, little is known about adverse effects although risk of herpes virus infections is clearly higher with JAK inhibitors than bDMARD treatments.


Assuntos
Antirreumáticos/química , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Quimioterapia Combinada , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/química , Metotrexato/uso terapêutico , Resultado do Tratamento
2.
Harefuah ; 159(1): 38-42, 2020 Jan.
Artigo em Hebraico | MEDLINE | ID: mdl-31930807

RESUMO

INTRODUCTION: JAK inhibitors are small molecules that are capable of blocking T-cell-mediated inflammation. They have been shown to be beneficial in several inflammatory conditions, such as rheumatoid arthritis, psoriasis and psoriatic arthritis. Treatment with three JAK inhibitors, ruxolitinib, baricitinib and tofacitinib, led to hair regrowth in alopecia areata patients, and similar effects have also been demonstrated in animal models for alopecia areata. Based on these data, JAK inhibitors have gained widespread popularity for the treatment of moderate-to-severe alopecia areata patients. Nevertheless, treatment with JAK inhibitors can lead to adverse events, with infections being the most worrisome. Furthermore, the durability of JAK inhibitors for alopecia areata is still unknown. Clinical trials with topical and systemic JAK inhibitors for alopecia areata are ongoing, and hopefully will provide us with better understanding of the safety and efficacy of these medications. If indeed these treatments will prove to be effective and safe, they might become the first FDA-approved treatment for alopecia areata. Disclosures: Prof. Ramot received lecture fees from Novartis and Lilly.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Animais , Artrite Psoriásica , Artrite Reumatoide , Humanos , Psoríase
3.
N Engl J Med ; 382(3): 256-265, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31940699

RESUMO

Deficiency of ubiquitin-specific peptidase 18 (USP18) is a severe type I interferonopathy. USP18 down-regulates type I interferon signaling by blocking the access of Janus-associated kinase 1 (JAK1) to the type I interferon receptor. The absence of USP18 results in unmitigated interferon-mediated inflammation and is lethal during the perinatal period. We describe a neonate who presented with hydrocephalus, necrotizing cellulitis, systemic inflammation, and respiratory failure. Exome sequencing identified a homozygous mutation at an essential splice site on USP18. The encoded protein was expressed but devoid of negative regulatory ability. Treatment with ruxolitinib was followed by a prompt and sustained recovery. (Funded by King Saud University and others.).


Assuntos
Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Interferons/metabolismo , Interleucinas/metabolismo , Janus Quinase 1/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Mutação com Perda de Função , Pirazóis/uso terapêutico , Ubiquitina Tiolesterase/deficiência , Homozigoto , Humanos , Hidrocefalia/genética , Recém-Nascido , Masculino , Receptores de Interferon/metabolismo , Indução de Remissão , Choque Séptico/genética , Transdução de Sinais/genética , Ubiquitina Tiolesterase/genética , Sequenciamento Completo do Exoma
4.
Oncology ; 98(3): 131-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31958792

RESUMO

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Terapia de Alvo Molecular , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo
6.
Lancet ; 394(10214): 2108-2117, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31732180

RESUMO

BACKGROUND: The JAK pathway is a potential therapeutic target in ankylosing spondylitis. This study assessed the efficacy and safety of upadacitinib, a selective JAK1 inhibitor, in patients with ankylosing spondylitis. METHODS: This multicentre, randomised, double-blind, placebo-controlled, two-period, parallel-group, phase 2/3 study, SELECT-AXIS 1, enrolled adults in 62 sites in 20 countries. Eligible patients had active ankylosing spondylitis, fulfilled modified New York criteria, were previously untreated with biological disease-modifying antirheumatic drugs, and had inadequate response to at least two or intolerance or contraindication to non-steroidal anti-inflammatory drugs. Patients were randomly assigned 1:1 using interactive response technology to take oral upadacitinib 15 mg once daily or oral placebo for the 14-week period 1; only period 1 data are reported here. The primary endpoint was the composite outcome measure of the Assessment of SpondyloArthritis international Society 40 response at week 14. Analyses were done in the full analysis set of patients who were randomly assigned and received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03178487. FINDINGS: Between Nov 30, 2017, and Oct 15, 2018, 187 patients were randomly assigned to upadacitinib 15 mg (93 patients) or to placebo (94 patients), and 178 (95%) patients (89 in the upadacitinib group and 89 in the placebo group) completed period 1 on study drug (by the completion date of Jan 21, 2019). Significantly more patients had an Assessment of SpondyloArthritis international Society 40 response in the upadacitinib group versus in the placebo group at week 14 (48 [52%] of 93 patients vs 24 [26%] of 94 patients; p=0·0003; treatment difference 26% [95% CI 13-40]). Adverse events were reported in 58 (62%) of 93 patients in the upadacitinib group versus 52 (55%) of 94 in the placebo group. The most common adverse event in the upadacitinib group was increased creatine phosphokinase (eight [9%] of 93 patients in the upadacitinib group vs two [2%] of 94 patients with placebo). No serious infections, herpes zoster, malignancy, venous thromboembolic events, or deaths were reported; one serious adverse event was reported in each group. INTERPRETATION: Upadacitinib 15 mg was efficacious and well tolerated in patients with active ankylosing spondylitis who had an inadequate response or contraindication to non-steroidal anti-inflammatory drugs. These data support the further investigation of upadacitinib for the treatment of axial spondyloarthritis. FUNDING: AbbVie.


Assuntos
Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Adulto , Antirreumáticos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Imagem por Ressonância Magnética , Masculino , Mesalamina/uso terapêutico , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Articulação Sacroilíaca/diagnóstico por imagem , Espondilite Anquilosante/diagnóstico por imagem , Sulfassalazina , Resultado do Tratamento
7.
Autoimmun Rev ; 18(11): 102390, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520803

RESUMO

Cytokines play a central role in the pathophysiology of autoimmune and inflammatory diseases. Several cytokines signal through the JAK-STAT pathway, which is now recognized as a major target to inhibit the effect of a wide array of cytokines. JAK inhibitors are increasingly used in the setting of inflammatory and autoimmune diseases. While the currently approved drugs are panJAK inhibitors, more selective small molecules are being developed and tested in various rheumatic disorders. In this extensive review, we present evidence- or hypothesis-based perspectives for these drugs in various rheumatologic conditions, such as rheumatoid arthritis, systemic lupus erythematosus, giant cell arteritis, and autoinflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Animais , Humanos
8.
In Vivo ; 33(5): 1667-1669, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471421

RESUMO

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin. It is highly aggressive and represents the second most common cause of skin cancer-related death. Ruxolitinib is an orally administered selective inhibitor of Janus associated kinases1 and 2, which is used in the management of patients with symptomatic myelofibrosis and polycythemia vera who are non-responders or intolerant to hydroxyurea. Herein, we report the case of a 47-year-old woman with a 14-year history of chronic myeloproliferative syndrome initially treated with hydroxyurea for 4 years. She was then enrolled in the Response trial and treated for 7 years with ruxolitinib subsequently developing an MCC. This report shows the possibility of development of MCC in patients treated with ruxolitinib. Periodic skin examination is indicated in patients who undergo ruxolitinib therapy, especially if they have a history of skin cancer; dermatologists and oncohematologists should be aware of this possibility in order to introduce appropriate preventive strategies.


Assuntos
Carcinoma de Célula de Merkel/etiologia , Inibidores de Janus Quinases/efeitos adversos , Segunda Neoplasia Primária/etiologia , Pirazóis/efeitos adversos , Neoplasias Cutâneas/etiologia , Carcinoma de Célula de Merkel/diagnóstico , Feminino , Humanos , Inibidores de Janus Quinases/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Segunda Neoplasia Primária/diagnóstico , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Neoplasias Cutâneas/diagnóstico
9.
Internist (Berl) ; 60(11): 1215-1220, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31486859

RESUMO

Janus kinases inhibitors (JAKI) are new orally administrable disease-modifying antirheumatic drugs (DMARD) for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), representing a treatment alternative equally effective as biological DMARD that is also classified equivalent in the guidelines. JAKI reversibly inhibit intracellular signal transduction from the cytokine receptor to the nucleus. Tofacitinib and baricitinib, two JAKI already approved for RA treatment, are taken once or twice a day, respectively, and two more are expected to receive approval next year. Tofacitinib is also approved for PsA. Generally, JAKI are initially used in combination with methotrexate (MTX) but are equally effective as monotherapeutic treatment if MTX is contraindicated. In terms of therapy safety, JAKI and bDMARD are generally comparable with one exception: JAKI are associated with an increased risk of herpes zoster infection. JAKI treatment requires laboratory blood tests, especially blood count, transaminases and creatinine. Due to hepatic metabolization, tofacitinib is associated with certain drug interactions. Altogether JAKI enhance treatment possibilities for diseases such as RA and PsA combining the same effectiveness and safety as bDMARD with the option of oral administration.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Metotrexato/uso terapêutico , Azetidinas/uso terapêutico , Quimioterapia Combinada , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do Tratamento
10.
Clin Exp Rheumatol ; 37(5): 862-871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31376250

RESUMO

The latest revision of the European League Against Rheumatism (EULAR) recommendations for rheumatoid arthritis (RA) treatment maintains the indication for the combined therapy of biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), namely Jak-inhibitors as tofacitinib and baricitinib, with conventional synthetic DMARDs (csDMARDs). Moreover, the use of bDMARDs and tsDMARDs should be restricted to patients who failed to achieve an adequate response to one or more csDMARDs, in accordance with the current evidence showing the superiority of combination therapy over monotherapy. In patients who cannot use csDMARDs as comedication, IL-6 inhibitors and tsDMARDs should be preferred to other bDMARDs because they are apparently more effective as monotherapy. Registry and real-world data demonstrate that monotherapy is far more commonly used than expected based on treatment recommendations, currently being about 30% of patients with RA on bDMARD monotherapy. We review here the literature on most commonly used DMARDs in monotherapy for RA. Our review points at an increasing evidence of the potential of some bDMARDs and tsDMARDs in monotherapy, which may become a considerable and realistic option in RA patients.


Assuntos
Antirreumáticos , Artrite Reumatoide , Inibidores de Janus Quinases , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Quimioterapia Combinada , Humanos , Inibidores de Janus Quinases/uso terapêutico , Conduta do Tratamento Medicamentoso , Sistema de Registros , Resultado do Tratamento
11.
Arthritis Rheumatol ; 71(11): 1788-1800, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31287230

RESUMO

OBJECTIVE: To evaluate the efficacy, including capacity for inhibition of radiographic progression, and safety of upadacitinib, a JAK1-selective inhibitor, as compared to placebo or adalimumab in patients with rheumatoid arthritis (RA) who have experienced an inadequate response to methotrexate (MTX). METHODS: In total, 1,629 RA patients with an inadequate response to MTX were randomized (2:2:1) to receive upadacitinib (15 mg once daily), placebo, or adalimumab (40 mg every other week) while continuing to take a stable background dose of MTX. The primary end points were achievement of an American College of Rheumatology 20% (ACR20) improvement response and a Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) of <2.6 in the upadacitinib group compared to the placebo group at week 12; inhibition of radiographic progression was evaluated at week 26. The study was also designed and powered to test for the noninferiority and superiority of upadacitinib compared to adalimumab, as measured both clinically and functionally. RESULTS: At week 12, both primary end points were met in patients receiving upadacitinib compared to those receiving placebo (P ≤ 0.001). An ACR20 improvement response was achieved by 71% of patients in the upadacitinib group compared to 36% in the placebo group, and a DAS28-CRP score of <2.6 was observed in 29% of patients receiving upadacitinib compared to 6% of patients receiving placebo. Upadacitinib was superior to adalimumab based on the ACR50 response rate, achievement of a DAS28-CRP score of ≤3.2, change in pain severity score, and change in the Health Assessment Questionnaire disability index. At week 26, more patients receiving upadacitinib than those receiving placebo or adalimumab achieved low disease activity or remission (P ≤ 0.001). Radiographic progression was significantly inhibited in patients receiving upadacitinib and was observed in fewer upadacitinib-treated patients than placebo-treated patients (P ≤ 0.001). Up to week 26, adverse events (AEs), including serious infections, were comparable between the upadacitinib and adalimumab groups. The proportions of patients with serious AEs and AEs leading to discontinuation were highest in the adalimumab group; the proportions of patients with herpes zoster and those with creatine phosphokinase (CPK) elevations were highest in the upadacitinib group. Three malignancies, 5 major adverse cardiovascular events, and 4 deaths were reported among the groups, but none occurred in patients receiving upadacitinib. Six venous thromboembolic events were reported (1 in the placebo group, 2 in the upadacitinib group, and 3 in the adalimumab group). CONCLUSION: Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms, and physical function in RA patients who were receiving background MTX. In addition, radiographic progression was significantly inhibited by upadacitinib as compared to placebo. The overall safety profile of upadacitinib was generally similar to that of adalimumab, except for higher rates of herpes zoster and CPK elevations in patients receiving upadacitinib.


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Adulto , Idoso , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/fisiopatologia , Creatina Quinase/metabolismo , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Herpes Zoster/epidemiologia , Humanos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Tromboembolia Venosa/epidemiologia
12.
Drugs ; 79(12): 1321-1335, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31317509

RESUMO

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Descoberta de Drogas , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Indanos/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Mesalamina/uso terapêutico , Oxidiazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Triazóis/uso terapêutico
13.
Artigo em Inglês | MEDLINE | ID: mdl-31327403

RESUMO

Orally bioavailable inhibitors of the tyrosine kinases (TYKs), also referred to as Janus kinases (JAKs), are being evaluated for the treatment of patients with Crohn's disease (CD), ulcerative colitis (UC), and other chronic inflammatory disorders. To date, three JAK inhibitors have been tested in patients with moderate-to-severe CD: tofacitinib (pan-JAK inhibitor), filgotinib (JAK1 inhibitor) and upadacitinib (JAK1 inhibitor). Clinical development of tofacitinib was discontinued in CD because the primary endpoint of clinical remission in the phase II induction and maintenance trials was not met, although outcomes may have been influenced by trial design flaws and a high placebo rate was noted. In contrast, filgotinib did meet its primary endpoint of clinical remission at week 10 in the phase II FITZROY trial, in addition to several other clinically important secondary outcomes, spurring a subsequent larger phase III trial. Following promising results for upadacitinib in its phase II trial, larger phase III trials were also initiated to corroborate the efficacy results. Although JAK inhibitors appear to have an acceptable safety profile, higher rates of infections compared to placebo were noted. Overall, JAK inhibitors constitute a new promising class of drugs, given the efficacy signals observed in pivotal clinical trials in several chronic inflammatory diseases. Here we review the existing evidence on the pharmacology, safety and efficacy of JAK-STAT inhibitors that are currently under investigation for the treatment of patients with CD.


Assuntos
Doença de Crohn/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Doença de Crohn/patologia , Humanos , Inibidores de Janus Quinases/farmacologia
15.
Drugs ; 79(14): 1499-1509, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31359326

RESUMO

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for many hematological malignant and non-malignant diseases. A major complication of the procedure is the donor T-cell-mediated graft-versus-host disease (GvHD). GvHD accounts for about 10% of early mortality after transplantation. GVHD is also the major cause of morbidity and disability in the late follow-up phase of transplanted patients, mainly because of the low response to first-line steroids, and the lack of efficient second-line standard treatments. The increasing knowledge regarding GVHD pathogenesis provides new pharmacological targets, potentially exploitable in clinical practice, in order to prevent and treat this complication. This review provides a description of GVHD pathogenesis, with a focus on the central role of the Janus kinase-related mechanisms. The first inflammatory innate-immunity response is triggered by a JAK/STAT dependent pathway, and JAK inhibition impairs antigen-presenting cell differentiation and activation and downregulates the expression of signals for T-cell triggering. The chronic evolution of alloreactivity, characterized by the long-term maintenance of inflammation and fibrosis, is also dependent on JAK/STAT activation. Based on preclinical data, we reviewed the rationale behind the clinical use of JAK-inhibitors in GVHD, presenting available results of clinical trials and reports, and looked at future implementation of this new promising treatment approach.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/metabolismo , Animais , Doença Enxerto-Hospedeiro/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/metabolismo
16.
J Dermatol ; 46(8): 724-730, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237712

RESUMO

Alopecia areata (AA) is a relatively common disease, but no satisfactory treatment has yet been developed. Recently, research progress has been made in the pathogenesis of AA, revealing that autoreactive cytotoxic T cells are important and that the Janus kinase (JAK) pathway is involved. Therefore, the potential of JAK inhibitors as therapeutic agents for AA is attracting attention. Several single-arm clinical trials and retrospective studies demonstrated that oral JAK inhibitors are effective and tolerable treatments for moderate to severe AA. Although JAK inhibitors are emerging as an innovative treatment for AA, further placebo-controlled clinical trials are required to confirm their efficacy and long-term safety.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Administração Oral , Alopecia em Áreas/imunologia , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/metabolismo , Pessoa de Meia-Idade , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Linfócitos T Citotóxicos/metabolismo , Resultado do Tratamento
17.
Dtsch Med Wochenschr ; 144(11): 748-752, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31163474

RESUMO

In Germany, baricitinib and tofacitinib have been approved for the treatment of at least moderately active rheumatoid arthritis after the failure of conventional disease modifying anti-rheumatic drugs in 2017, and tofacitinib also for psoriatic arthritis and ulcerative colitis. Both baricitinib and tofacitinib can be taken orally and reversibly inhibit Janus kinases (JAK) and therefore the signaling of a large number of cytokines via the JAK/STAT pathway. JAK inhibitors have been shown to be at least as efficacious in rheumatoid arthritis as adalimumab and tofacitinib was also efficacious in psoriatic arthritis. Since they inhibit many cytokines, it is likely that in the future they will be applied for the treatment of further chronic inflammatory disorder such as connective tissue diseases and vasculitis. The adverse events of JAK inhibitors are comparable to those observed with biologicals, only herpes zoster is slightly more common. In the placebo-controlled trials, venous thromboembolic events (VTE) were more common in the baricitinib treated patients. The VTE rate does not appear to be elevated in baricitinib treated patients compared to RA cohorts however.In conclusion, JAK inhibitors are a powerful new treatment of RA and likely many other rheumatic diseases and fulfill an unmet need since they may be taken orally.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Azetidinas/uso terapêutico , Alemanha , Humanos , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico
18.
Int J Rheum Dis ; 22(8): 1563-1571, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31211506

RESUMO

OBJECTIVES: The relative efficacy and safety of tofacitinib and upadacitinib were assessed in patients with rheumatoid arthritis (RA) with an inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs). METHOD: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and upadacitinib in combination with methotrexate (MTX) in RA patients with an inadequate cs- or b-DMARD response. RESULTS: Nine RCTs including 5794 patients met the inclusion criteria. There were 15 pairwise comparisons including 10 direct comparisons of 6 interventions. Upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were among the most effective treatments for active RA with an inadequate cs- or b-DMARD response, followed by tofacitinib 10 mg + MTX, tofacitinib 5 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX had the highest probability of being the best treatment in terms of the American College of Rheumatology 20 response rate (SUCRA = 0.820, 0.762), followed by tofacitinib 10 mg + MTX (SUCRA = 0.623), tofacitinib 5 mg + MTX (SUCRA = 0.424), adalimumab + MTX (SUCRA = 0.371), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, upadacitinib + MTX, adalimumab + MTX, or placebo + MTX. CONCLUSIONS: In RA patients with an inadequate response to cs- or b-DMARDs, upadacitinib 15 mg + MTX and upadacitinib 30 mg + MTX were the most efficacious interventions and were not associated with significant risks of serious adverse events.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Teorema de Bayes , Quimioterapia Combinada , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Inibidores de Janus Quinases/efeitos adversos , Metotrexato/uso terapêutico , Meta-Análise em Rede , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
J Pharmacol Exp Ther ; 370(2): 137-147, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085698

RESUMO

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.


Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Asma/imunologia , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Nitrilos/farmacologia , Fosfoproteínas/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Fatores de Transcrição STAT/metabolismo , Administração por Inalação , Animais , Asma/metabolismo , Asma/patologia , Inflamação/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/farmacocinética , Inibidores de Janus Quinases/uso terapêutico , Masculino , Nitrilos/administração & dosagem , Nitrilos/farmacocinética , Nitrilos/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
20.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
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