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Abstract The JAK-STAT signaling pathway mediates important cellular processes such as immune response, carcinogenesis, cell differentiation, division and death. Therefore, drugs that interfere with different JAK-STAT signaling patterns have potential indications for various medical conditions. The main dermatological targets of JAK-STAT pathway inhibitors are inflammatory or autoimmune diseases such as psoriasis, vitiligo, atopic dermatitis and alopecia areata; however, several dermatoses are under investigation to expand this list of indications. As JAK-STAT pathway inhibitors should gradually occupy a relevant space in dermatological prescriptions, this review presents the main available drugs, their immunological effects, and their pharmacological characteristics, related to clinical efficacy and safety, aiming to validate the best dermatological practice.
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With the rapid development of immunology and molecular biology in recent years, great progress has been made in the research on psoriatic pathogenesis, as well as in therapeutic strategies targeting key molecules in the pathogenesis. In addition to biologics, small-molecule targeted agents for psoriasis have also received increasing attention, especially agents targeting phosphodiesterase 4, Janus kinase, and tyrosine kinase 2, etc. An increasing number of small-molecule drug candidates have shown favorable efficacy in clinical studies, and some of them have been approved for clinical application and play a unique role in the treatment of psoriasis.
ABSTRACT
Juvenile idiopathic arthritis(JIA) is one of the most common chronic connective tissue diseases characterized by unknown etiologic arthritis with the onset before the age of 16 years and disease course for more than 6 weeks.JIA may be accompanied by impairment of multiple organ function.Recent studies have shown the important role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of JIA.Tofacitinib is an oral Janus kinase(JAK) inhibitor approved by Food and Drug Administration (FDA) in 2012 for the effective treatment of rheumatoid arthritis.However, there is little clinical evidence for the use of Tofacitinib in pediatrics.This review aims to clarify the mechanisms, efficacy and safety of Tofacitinib on the treatment of JIA.
ABSTRACT
Objective: Treatment options for patients with rheumatoid arthritis on maintenance hemodialysis with an inadequate response to biologic agents have not been reported. In this report, we describe two patients who achieved remission after treatment with peficitinib.Methods: Two 69- and 85-year-old patients with rheumatoid arthritis on maintenance hemodialysis were previously treated with biologics and started on peficitinib 100 mg/day after the secondary failure of biologics.Discussion: In the two cases presented here, rheumatoid arthritis was almost in remission and there were no adverse events, although the patients were switched to peficitinib after secondary failure of the biologic agents. Among Janus kinase inhibitors, peficitinib has the lowest renal excretion; therefore, its administration in patients on dialysis is not contraindicated according to the package insert in Japan. The use of biologic agents in patients on hemodialysis has been reported to be associated with a high incidence of infections; therefore, care should be taken to avoid infections when administering Janus kinase inhibitors.Conclusion: Janus kinase inhibitors with low renal excretion, such as peficitinib, may be effective in patients with rheumatoid arthritis on maintenance hemodialysis who have an inadequate response to biologic agents.
ABSTRACT
RESUMEN La artritis reumatoide (AR) es una enfermedad sistémica que en las últimas décadas ha tenido múltiples opciones terapéuticas. Con la información disponible en la literatura no se recomienda el uso de terapia biológica en pacientes con enfermedad pulmonar difusa, dado que estos medicamentos pueden exacerbar el compromiso pulmonar. Un medicamento de más reciente aparición es el inhibidor de la enzima Janus quinasa, el cual es una opción terapéutica en monoterapia o combinado para pacientes con AR en moderada y alta actividad de la enfermedad, con contraindicación al uso de FARME sintéticos o biológicos, y en pacientes con fallo terapéutico, no obstante, su seguridad a nivel pulmonar no ha sido evaluada en ensayos clínicos y la información disponible es escasa. Describimos el tratamiento, seguimiento y resultados del uso de tofacitinib en 4 pacientes con enfermedad pulmonar secundaria a AR en una serie de casos.
ABSTRACT Rheumatoid arthritis (RA) is a systemic disease for which multiple therapeutic options have been developed in the last decades. Based on the information available in the literature, the use of biological therapy in patients with diffuse lung disease is not recommended because these medications can exacerbate the lung disease. A newer drug is the Janus kinase enzyme inhibitor, which can be used as monotherapy or in combination in patients with moderate to high activity RA, in whom the use of synthetic or biological DMARDs is contraindicated, as well as in patients with therapeutic failure. However, the pulmonary safety of the drug has not been evaluated in clinical trials and the information available is limited. This article discusses the treatment, follow-up, and outcomes of the use of tofacitinib in a series of 4 patients with lung disease secondary to RA.
Subject(s)
Humans , Middle Aged , Aged , Arthritis, Rheumatoid , Biological Therapy , Janus Kinases , Lung DiseasesABSTRACT
Alopecia areata (AA) is a kind of localized scalp hair loss of sudden onset,and patients with severe AA can progress to alopecia totalis (AT) and alopecia universalis (AU).At present,AA is considered as a kind of organ-specific autoimmune disease with a genetic background,and destruction of immune privileged structures of hair follicles is an important pathogenesis of AA.Currently,therapeutic methods for AA include oral or topical glucocorticoids,intramuscular or intralesional injection of glucocorticoids,topical minoxidil tincture,etc.,but some patients still show no response to the treatments.In recent years,various clinical trials have been conducted in abroad using JAK inhibitors for the treatment of AA.Researches have revealed that about half of patients with moderate to severe AA showed almost complete recovery after the treatment with oral JAK inhibitors.Topical ruxolitinib was also reported for the treatment of AA,but patients showed different response.Although some patients suffered from recurrence after drug withdrawal or infections and other adverse reactions during the treatment,JAK inhibitors can be an effective treatment option for moderate to severe AA.
ABSTRACT
ABSTRACT Janus kinases inhibitors have already been incorporated into the management of immune-mediated diseases, such as rheumatoid arthritis, and are being investigated for the treatment of psoriasis and inflammatory bowel diseases, both ulcerative colitis and Crohn's disease. Tofacitinib is an oral small-molecule drug that inhibits Janus kinases 1, Janus kinases 3, and, to a lesser extent, Janus kinases 2. This inhibition ends up blocking signals for several inflammatory cytokines that are involved in the pathogenesis of inflammatory bowel diseases and play a role in many immune signaling routes, including lymphocyte activation, function, and proliferation. We report a patient with active ulcerative colitis with primary non-response to three biologics (infliximab, adalimumab and vedolizumab), with different mechanisms of action, who refused surgical treatment and had a favorable response to tofacitinib with clinical and endoscopic remission. No adverse events were observed with the use of the agent. This case illustrates the difficulties we may face regarding the identification of the expression of proper mechanism of action involved in the pathogenesis of ulcerative colitis patients and the importance of having another treatment option with different mechanism of action, like tofacitinib.
RESUMO Os inibidores das Janus kinases (JAK) têm sido incorporados ao tratamento de doenças imunomediadas, como artrite reumatoide e, além disso, têm sido testados no tratamento da psoríase e doenças inflamatórias intestinais, tanto na retocolite ulcerativa quanto na doença de Crohn. Tofacitinibe é uma droga do grupo das pequenas moléculas de uso oral que inibe as Janus kinases 1 e 3 e, em menor grau, a Janus kinases 2. Esta inibição promove o bloqueio de uma série de citocinas pró-inflamatórias que estão envolvidas na patogênese das doenças inflamatórias intestinais e desempenham importante papel nos processos imunes, tais como ativação, função e proliferação linfocitária. Nesta presente comunicação, relatamos um caso de um paciente portador de retocolite ulcerativa refratária a três agentes biológicos (infliximabe, adalimumabe e vedolizumabe), com diferentes mecanismos de ação, que recusou o tratamento cirúrgico, porém, apresentou boa resposta com o uso de tofacitinibe, com remissão clínica e endoscópica. Não foram evidenciados efeitos colaterais com a droga. O presente caso ilustra as dificuldades que podemos enfrentar em relação à identificação da expressão do correto mecanismo de ação envolvido na patogênese dos pacientes com retocolite ulcerativa e a importância de um novo agente terapêutico com diferente mecanismo de ação, como o tofacitinibe.
Subject(s)
Humans , Male , Adult , Piperidines/therapeutic use , Colitis, Ulcerative/drug therapy , Integrins/therapeutic use , Tumor Necrosis Factor-alpha/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Pyrroles/therapeutic use , Integrins/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Infliximab/therapeutic useABSTRACT
Janus kinase (JAK) inhibitors are a new class of drugs that inhibit JAK enzymes, which are the main signal transducers for the majority of cytokines, growth factors, and interferons. These drugs work from inside the cell and are unique in a way that their action interrupts the signaling involved in the infl ammation. They include drugs like ruxolitinib, tofacitinib, both of which have been US Food and Drug Administration (USFDA) approved, and many others which are currently under trials. Tofacitinib was approved by USFDA in November 2012 for oral use in patients suffering with moderate to severe rheumatoid arthritis and do not respond to methotrexate.