Efficacy and safety of different Janus kinase inhibitors combined with methotrexate for the treatment of rheumatoid arthritis: a single-center randomized trial

Abstract Objective To compare the efficacy and safety between baricitinib (BARI) and tofacitinib (TOFA) for the treatment of the rheumatoid arthritis (RA) patients receiving methotrexate (MTX) in clinical practice. Methods This retrospective study recruited 179 RA patients treated with BARI (2-4 mg/d) or TOFA (10 mg/d) at The First Affiliated Hospital of Guangxi Medical University from September 2019 to January 2022. The rate of low disease activity (LDA) was used as the primary end point. Secondary end points included the Disease Activity Scale-28 (DAS-28)-C-reactive protein (CRP); the rate of DAS28-CRP remission; visual analogue scale (VAS) for pain, swollen joint, and tender joint counts; and adverse events at the 6-month follow-up. Several factors affecting LDA achievement were also analyzed. Results Seventy-four patients were treated with BARI and 105 were treated with TOFA, including 83.24% females, with a median (IQR) age of 56.0 (53.0-56.0) years old and disease duration of 12.0 (6.0-12.0) months. There was no difference of the rate of LDA between the BARI and TOFA treatment groups. All disease indices in the two groups were significantly improved, including a significantly lower VAS in the BARI group (P < 0.05), reflecting the drug efficacy after 1 and 6 months of treatment. The incidence of adverse reactions was similar in these two groups. Conclusion The treatment efficacy and safety of BARI and TOFA in the RA patients were similar, but BARI was more effective in pain relief than TOFA. An older baseline age was more likely to achieve LDA in the BARI group, while a low baseline erythrocyte sedimentation rate (ESR) was more likely to achieve LDA in the TOFA group.

Targeting the JAK-STAT signaling pathway in the treatment of psoriasis / 中华皮肤科杂志

The Janus kinase (JAK) -signal transducer and activator of transcription (STAT) signaling pathway is closely related to the occurrence of psoriasis. Various cytokines, including interleukin (IL) -23, IL-22, interferon (IFN) -γ, etc., can promote some key pathologic processes (such as the proliferation and abnormal differentiation of keratinocytes, and infiltration of inflammatory cells) via the JAK-STAT pathway in psoriasis, which suggests that targeting JAK-STAT pathway is a new strategy for the treatment of psoriasis. In recent years, small-molecule JAK inhibitors have shown good efficacy and safety in the treatment of psoriasis, and drugs targeting STAT pathway have been under development, which provide more treatment options for psoriasis. This review summarizes progress in drugs targeting the JAK-STAT signaling pathway in the treatment of psoriasis.

Dermatite atópica grave: guia prático de tratamento da Associação Brasileira de Alergia e Imunologia e Sociedade Brasileira de Pediatria / Severe atopic dermatitis: a practical treatment guide from the Brazilian Association of Allergy and Immunology and the Brazilian Society of Pediatrics

A dermatite atópica (DA) é uma doença cutânea inflamatória, crônica, comum, complexa e de etiologia multifatorial, que se manifesta clinicamente com prurido muitas vezes incapacitante, lesões recorrentes do tipo eczema, xerose e que pode evoluir para liquenificação. Embora o conhecimento sobre a sua fisiopatologia venham crescendo nos últimos anos, ainda as formas graves são frequentes e representam um desafio para o clínico. Para o presente guia realizou-se revisão não sistemática da literatura relacionada à DA grave refratária aos tratamentos habituais com o objetivo de elaborar um documento prático e que auxilie na compreensão dos mecanismos envolvidos na DA, assim como dos possíveis fatores de risco associados à sua apresentação. A integridade da barreira cutânea é um dos pontos fundamentais para a manutenção da homeostase da pele. Além dos cuidados gerais: evitação dos agentes desencadeantes e/ou irritantes, o uso de hidratantes, suporte emocional, entre outros, o uso de agentes anti-inflamatórios/imunossupressores de uso tópico e/ou sistêmico também foi revisado. A aquisição de novos agentes, os imunobiológicos e as pequenas moléculas, melhorou a terapêutica para os pacientes com formas graves de DA, sobretudo as refratárias aos tratamentos convencionais.

Atopic dermatitis is a chronic, common, and complex inflammatory skin disease with a multifactorial etiology. It manifests clinically with often disabling pruritus, recurrent eczema-like lesions, and xerosis, and can progress to lichenification. Although understanding of the disease's pathophysiology has been growing in recent years, severe forms are still frequent and represent a challenge for clinicians. A non-systematic review of the literature on severe atopic dermatitis refractory to conventional treatment was conducted to develop the present guide, whose purpose is to help clarify the mechanisms involved in the disease and possible risk factors. The integrity of the skin barrier is fundamental for maintaining skin homeostasis. In addition to general care, patients should avoid triggering and/or irritating agents and moisturizers and seek emotional support, etc.; the use of topical and/or systemic anti-inflammatory/immunosuppressive agents was also reviewed. New agents, immunobiologicals, and small molecules have led to a broader range of therapies for patients with severe forms of the disease, especially cases refractory to conventional treatment.

Inibidores de JAK no tratamento da dermatite atópica / JAK inhibitors in the treatment of atopic dermatitis

A dermatite atópica é a doença inflamatória cutânea mais prevalente mundialmente. A via JAK/STAT tem papel importante no mecanismo da doença e as pequenas moléculas inibidores de JAK são fármacos com grande potencial de uso na dermatite atópica. Foi realizada uma revisão sistemática da literatura na base de dados PubMed, utilizando os termos "atopic dermatitis" e/ou "JAK inhibitors" e/ou "small molecules" entre 2017 e 2022. Foram incluídos os resultados disponíveis de estudos de fase 3, avaliando o uso de inibidores de JAK em apresentações tópicas e sistêmicas. Entre 646 estudos, foram selecionados 37 em humanos que avaliaram a eficácia e segurança dos inibidores de JAK. Os resultados do uso, quando bem indicados, mostraram-se positivos e em alguns casos superiores a outros tratamentos já preconizados para o controle da dermatite atópica, com um bom perfil de segurança.

Atopic dermatitis is the most common inflammatory skin disease worldwide. The JAK/STAT pathway plays an important role in the disease mechanism, and small-molecule JAK inhibitors are drugs with great potential for use in atopic dermatitis. We systematically reviewed PubMed using the search terms "atopic dermatitis" AND/OR "JAK inhibitors" AND/OR "small molecules" for studies published between 2017 and 2022. Results from phase III trials evaluating both topical and systemic application of JAK inhibitors were included. Of 646 studies retrieved, 37 evaluating the efficacy and safety of JAK inhibitors in humans were selected for analysis. When properly indicated, the use of JAK inhibitors yielded positive results, some of which were superior to those of recommended treatments for the control of atopic dermatitis, with a good safety profile.

T helper type 2 immune response in alopecia areata / 中华皮肤科杂志

Alopecia areata (AA) is a common inflammatory and non-scarring hair loss condition with unknown pathogenesis, and relapses are common in some patients. Evidence has demonstrated that allergy takes part in the early onset, severe condition, recurrence, and prolonged process in AA. Allergy to dust mites may be one of the reasons for refractory severe AA, especially in childhood, possibly due to the predominance of T helper type 2 (Th2) immune response. Desensitization can suppress the Th2 immune response, alter the immune balance, and reduce disease severity during AA relapses. In addition, high IgE levels may predict favorable efficacy of dupilumab in AA patients before treatment, while high interleukin-4 levels may predict the ineffectiveness of topical immunotherapy with diphenylcyclopropenone, which works by antagonizing Th1 immune response. Therefore, serum total IgE, specific IgE to dust mites, and interleukin-4 can be considered as biomarkers, revealing the predominance of Th2 immune response in AA patients. This article focuses on the relationship between allergy and AA, as well as the role of anti-allergic reactions and desensitization in the treatment of AA, aiming to provide ideas for precise and individualized treatment of AA.

Monomorphic epithelial intestinal T-cell lymphoma: a clinicopathological characteristic analysis / 白血病·淋巴瘤

Objective:To investigate the histopathological morphology, immunophenotype, molecular pathological features, clinical prognosis and treatment of monomorphic epithelial intestinal T-cell lymphoma (MEITL).Methods:The clinicopathological data of 5 patients with MEITL in Sichuan Jinyu Medical Laboratory Center Co., Ltd from March 2019 to February 2021 were retrospectively analyzed, and literatures were reviewed. All cases were tested by using histopathology, immunohistochemistry, in situ hybridization of Epstein-Barr virus (EBV) and T-cell clonability assessment, and 1 case had second-generation sequencing (NGS) test. Clinical follow-up was performed in 2 patients.Results:All 5 MEITL cases were middle-aged and old men. The histopathology showed that intestinal wall was diffuse with tumor cells infiltrating, and the cells were obviously epitheliophilic. All the tumor cells CD3, CD8, CD56, GrB were positively expressed, and expressions of other T-cell markers were different, among which 1 case had CD30 positive and 1 case had CD20 positive. All 5 cases were negative for EBV by in situ hybridization. Monoclonal rearrangement of T-cell receptor gene was detected in all 5 cases. Mutations of BCOR, JAK3, STAT5B and ATM were detected in 1 case by using NGS. Among 2 cases followed-up, 1 patient relapsed 7 months after he had the initial onset and underwent the first operation, and then he had another operation. This patient finally died of extensive metastasis in the lung, liver and abdominal cavity as well as ascites 13 months later; another patient died 1 month after emergency surgery for perforation.Conclusions:MEITL is a rare primary T-cell lymphoma of the digestive tract. The oncogenic event in the pathogenesis of MEITL mainly involves mutations in the tumor suppressor gene SETD2 and mutations in one or more genes of the JAK/STAT pathway. Currently, there is no standard treatment for MEITL. Most treatment options include surgical resection and anthracycline-based chemotherapy.

JAK Inhibitors Therapy for Rheumatoid Arthritis ：An Overview of Systematic Reviews / 中国药房

OBJECTIVE：To overview t he s ystematic revi ews on JAK inhibitors in the treatment of rheumatoid arthritis （RA）， and to provide evidence-based basis for the treatment of RA with these drugs. METHODS ：The Cochrane Library ，PubMed， Embase，CNKI，Wanfang database and VIP were electronically searched to collect systematic reviews of JAK inhibitors in the treatment of RA from inception to Dec. 2020. After data extraction of included systematic review ，PRISMA statement ，AMSTAR2 scale and GRADE were used to evaluate the report quality ，methodological quality and the level of evidence for outcome indicators. RESULTS ：A total of 12 systematic reviews involving 103 outcomes were included. PRISMA score of systematic reviews was between 17.5 and 22.5，and the reported quality defects were mainly reflected in scheme ，registration and other aspects. AMSTAR 2 evaluation results showed that there were 6 studies of low quality and 6 studies of very low quality ，without high-quality study and medium-quality study. GRADE assessment results for outcome indicators showed low to medium quality of evidence. The summary of evidence showed that compared to placebo ，JAK inhibitor could alleviate various indicators of RA ； compared to adalimumab ，the advantage was not obvious. JAK inhibitors did not increase the incidence of serious adverse events ， but the systematic reviews were inconsistent in their effects on the incidence of total adverse events and liver injury. CONCLUSIONS：The efficacy of JAK inhibitors in the treatment of RA has certain advantages over placebo ，but more studies are needed to demonstrate the efficacy of JAK inhibitors in the treatment of RA compared to other drugs ；the advantage of safety is uncertain.

Clasificación y manejo actual en dermatomiositis juvenil / Classification and current management in juvenile dermatomyositis

La Dermatomiositis Juvenil representa el 75-80% de las miopatías inflamatorias juveniles. Si bien, tiene baja incidencia y prevalencia, presenta importante morbilidad dada por sus manifestaciones cutáneas, musculares, pulmonares, gastrointestinales, cardiacas, entre otras. Corresponde a un desorden poligénico con múltiples factores gatillantes, que determina el desarrollo de una vasculopatía que lleva a atrofia muscular, inflamación y activación de vías del IFN-1. Actualmente su diagnóstico se basa en las guias EULAR/ACR (2017). En los últimos años, se han descubiertos distintos subtipos de la enfermedad, basados en el perfil de autoanticuerpos específicos de miositis, lo que ha permitido establecer pronóstico y estrategias terapéuticas personalizadas. El manejo farmacológico continúa basándose principalmente en el uso de corticoesteroides y DMARDs, así como también terapia biológica; en los últimos años, los inhibidores JAK han mostrado resultados promisorios, convirtiéndose en la más nueva alternativa terapéutica para el control de la enfermedad.

Juvenile Dermatomyositis represents 75-80% of juvenile inflammatory myopathies. Although it has a low incidence and prevalence, it presents significant morbidity due to its cutaneous, muscular, pulmonary, gastrointestinal and cardiac manifestations, among others. It corresponds to a polygenic disorder with multiple triggering factors, which determines the development of a vasculopathy that leads to muscle atrophy, inflammation and activation of IFN-1 pathways. Currently its diagnosis is based on the EULAR/ACR guidelines (2017). In recent years, different subtypes of the disease have been discovered, based on the profile of myositis-specific autoantibodies, which has made it possible to establish prognosis and personalized therapeutic strategies. Pharmacological management continues to be based mainly on the use of corticosteroids and DMARDs, as well as biological therapy; In recent years, JAK inhibitors have shown promising results, becoming the newest therapeutic alternative for disease control.

Advance in drug treatment of autoimmune diseases / 中国药理学通报

Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.) are diseases characterized by local or systemic abnormal inflammatory immune response. At present, the treatment drugs of autoimmune diseases mainly include nonsteroid anti-inflammatory drugs, steroid anti-inflammatory drugs and disease modifying anti-rheumatic drugs (chemical medicine, natural medicine and biological agents), etc. With the pathological mechanism of autoimmune diseases to be clarified deeply and the discovery of new drug targets, new biological agents targeting cytokines and cell surface molecules have been developed rapidly. In recent years, multiple small molecule drugs targeting Janus kinase/ signal transducers and activators of transcription signaling pathway have been developed and applied in clinic. Soft regulation of inflammatory immune response drugs are the drugs with anti-inflammatory and immunomodulatory effects, as well as less adverse reactions. To develop this type of drug will be a new strategy and one of the main directions for the treatment of autoimmune diseases. The research progress of medicines to treat autoimmune diseases has been reviewed in this paper.

Pathogenic relationship between myeloproliferative neoplasms and lymphohematopoietic neoplasms / 中国实用内科杂志

The pathogenic relationship between myeloproliferative neoplasms(MPN) and lymphoid neoplasms has not been completely elucidated. With the progression of MPN treatment, the patients' survival has been prolonged owing to the use of JAK inhibitors(ruxolitinib). However, the side effects of JAK inhibitors also exist. In order to understand the natural course of this chronic disease accompanied with other hematological diseases and the characteristics and prognosis of secondary MPN, we conducted a literature review.

Treatment advances in myeloproliferative neoplasms: reports from the 56th American Society of Hematology annual meeting / 白血病·淋巴瘤

Great advances have been made in understanding the pathogenesis,diagnosis,risk stratification and treatment of classic bcr-abl-negative myeloproliferative neoplasms (MPN).This article reviews current situation in the treatment of these MPNs presented in the 56th American Society of Hematology (ASH) annual meeting.

Current diagnosis and treatment progress of primary myelofibrosis: reports from the 19th European Hematology Association annual congress / 白血病·淋巴瘤

Primary myelofibrosis is a kind of chronic myeloproliferative neoplasms.The discovery of the JAK2V617F mutation as well as other molecular abnormlities underly the pathogenesis of Philadelphia negative myeloproliferative neoplasms (MPN).The initial description of JAK2V617F mutation in 2005,the reporting of calreticulin (CALR) mutations last year and the clinical application of JAK inhibitors,showed the gradually deepening understanding with regard to the pathogenesis and the development of therapeutic strategies for primary myelofibrosis (PMF).This article reviewed the progress in diagnosis,risk stratification of of PMF,the benefits and potential side effect of JAK inhibitors,which reported on the 2014 European Hematology Association annual congress.