Current opinion in rheumatology最新文献

Purpose of review: VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) was first described in 2020, where in a cohort of adults with unexplained fever or inflammation, systematic genetic testing was performed and 25 men with a median age of 64 years and somatic mutations in the UBA1 gene were identified. In the current review, we aim to discuss the relevant literature from January 2023 until July 2024 to give new insights into the pathophysiology, epidemiology, diagnosis and treatment of VEXAS.

Recent findings: VEXAS affects 1 : 4269 in men over the age of 50. Janus-Kinase-inhibitors (JAKi) and IL-6-inhibitors are more effective immunosuppressants against hyperinflammation. Ruxolitinib is more effective than other JAKi. Azacitidine induces remission in many patients, but only few MDS-associated patients were treated. Allogeneic stem cell transplantation is feasible for selected cases. Infections are the major cause of death. Prognosis is still poor with a 5-year mortality rate of 18-40%.

Summary: In the current review, we discuss the novelties for VEXAS, including pathogenic pathways, epidemiological data, diagnostic criteria and algorithms, treatment options and complications. We hope that this review may improve rheumatologists understanding of VEXAS. We strongly recommend enrolling VEXAS patients in registries and clinical trials, to improve prognosis of VEXAS in the future.

Purpose of review: There have been advances in the diagnosis and treatment of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR).

Recent findings: Themes in PMR and GCA include classification criteria, ultrasound imaging of temporal and axillary arteries replacing biopsies for diagnosis of GCA, faster diagnosis and treatment with rapid access clinics for suspected GCA, and expanding treatment options with the goal of rapid suppression of inflammation and sparing steroids.

Summary: Treatment is aimed at suppressing inflammation quickly in both GCA and PMR. Randomized trials have demonstrated success in reducing glucocorticoids when adding advanced therapies such as interleukin 6 (IL6) inhibitors. Other treatments including Janus kinase (JAK) inhibitors (especially a phase 3 trial of upadacitinib at 15 mg daily and secukinumab (an IL17 inhibitor) are being tested. Some uncontrolled GCA protocols are limiting glucocorticoids to initial IV pulse therapy only or rapid tapering of oral glucocorticoids with upfront treatment with tocilizumab. There is uncertainty of who should have an advanced therapy and how long to use it for and what order to consider advanced therapies when treatment fails. In PMR, studies are performed when patients cannot taper glucocorticoids effectively, whereas in GCA, advanced therapies are started with disease onset or with recurrent GCA.

Purpose of review: Giant cell arteritis (GCA) is an age-related autoimmune disease with a complex pathogenesis that involves several pathogenic mechanisms. This review provides recent critical insights into novel aspects of GCA pathogenesis.

Recent findings: The use of novel approaches, including multiomic techniques, has uncovered notable findings that broaden the understanding of GCA pathogenesis. TCF1hiCD4+ T cells have been identified as stem-like T cells residing in tertiary lymphoid structures in the adventitia of GCA aortic tissues, which likely supply the pathogenic effector T cells present in vasculitic lesions. Studies have demonstrated that fibroblasts present in GCA-inflamed arteries are not innocent bystanders, but they contribute to arterial inflammation via maintenance of Th1 and Th17 polarisation, cytokine secretion (IL-6, IL-1B, IL-12, and IL-23) and antigen presentation. Additionally, deregulated cellular senescence programs are present in GCA as an accumulation of IL-6 and matrix metalloproteinase 9-producing senescent cells have been identified in vasculitic lesions.

Summary: Recent studies have unravelled interesting findings with potentially significant clinical relevance. Stem-like T cells are likely key contributors to vascular disease persistence, and targeted depletion or modulation of these cells holds promise in GCA management. Fibroblast-targeting therapies and senotherapeutics are also exciting prospects in the treatment of GCA.

Purpose of review: Antinuclear autoantibodies represent a serological hallmark of systemic sclerosis (SSc), with anticentromere, antitopoisomerase-I, and anti-RNA polymerase III antibodies routinely assessed for diagnosis, clinical subset classification, and prognosis. In addition, an increasing number of autoantibodies have been demonstrated to play a pathogenic role by mediating different SSc manifestations. This review aims to give an overview on autoantibodies as putative biomarkers in SSc and discuss their possible pathogenic role as triggers of cell dysfunctions.

Recent findings: Over the years, different autoantibodies have been proposed as biomarkers aiding in diagnosis, disease subtype classification, disease progression prediction, organ involvement, as well as in understanding treatment response. Increasing literature also indicates functional autoantibodies as direct contributors to SSc pathogenesis by exerting agonistic or antagonistic activities on their specific cognate targets.

Summary: In SSc, search and validation of novel autoantibodies with higher diagnostic specificity and more accurate predictive values are increasingly needed for early diagnosis and specific follow-up, and to define the best therapeutic option according to different disease subsets. Moreover, since autoantibodies are also emerging as functional pathogenic players, a better unraveling of their possible pathomechanisms becomes essential to identify new targets and develop promising therapeutic agents able to neutralize their effects.

Purpose of review: This review highlights the role of the gastrointestinal (GI) microbiome in systemic sclerosis (SSc). We describe techniques for evaluating the GI microbiome in humans, and emerging research linking GI microbiome alterations (i.e., dysbiosis) and distinct SSc clinical manifestations. We also address the evolving treatment landscape targeting dysbiosis in SSc.

Recent findings: Recent literature brings into focus the complex relationship between the GI microbiome and SSc pathogenesis. Advanced techniques (e.g., shotgun metagenomics, meta-transcriptomics) provide deeper insights into microbial taxonomy and active gene expression, exposing dysbiosis as a potential driver of SSc. New studies demonstrate that SSc patients who possess specific SSc clinical features, (e.g., interstitial lung disease), have unique GI microbiome profiles.

Summary: Dysbiosis is associated with specific clinical features in patients with SSc. New tools for studying the GI microbiome have furthered our understanding of the relationship between dysbiosis and SSc complications. Therapeutic avenues such as dietary adjustments, probiotics, antibiotics, mindfulness practices, and fecal transplants offer potential for managing SSc and preventing its progression through GI microbiome modulation. By clarifying what is known about the relationship between the GI dysbiosis, GI dysfunction, and SSc, this review enhances our understanding of SSc pathogenesis and proposes targeted interventions.

Purpose of review: Scleroderma and other fibrotic diseases have been investigated using single-cell RNA sequencing (scRNA-Seq), which has demonstrated enrichment in myeloid cell populations in multiple tissues. However, scRNA-Seq studies are inconsistent in their nomenclature of myeloid cell types, including dendritic cells, monocytes, and macrophages. Using cell type-defining gene signatures, I propose a unified nomenclature through analysis of myeloid cell enrichment across fibrotic tissues.

Recent findings: scRNA-Seq of human blood and skin identified a new subset of dendritic cells called DC3. DC3 express similar inflammatory genes to monocytes, including FCN1 , IL1B, VCAN, S100A8, S100A9 , and S100A12 . DC3 can be distinguished from monocytes by expression of EREG and Fc receptor genes such as FCER1A and FCGR2B . scRNA-Seq analyses of scleroderma skin and lung, idiopathic pulmonary fibrosis (IPF), COVID-19 lung fibrosis, myelofibrosis, and liver, kidney, and cardiac fibrosis all showed enrichment in myeloid cell types. Although they were called different names, studies of scleroderma skin and lung as well as liver cirrhosis datasets demonstrated enrichment in DC3. By contrast, lung, heart, and kidney fibrosis were enriched in SPP1 macrophages. High numbers of DC3 in the skin was associated with worse SSc skin and lung fibrosis severity.

Summary: scRNA-Seq of multiple diseases showed enrichment of DC3 in fibrotic skin, lung, and liver, whereas SPP1 macrophages occurred in fibrotic lung, heart, and kidney. Because DC3 and SPP1 macrophages showed organ-specific enrichment, understanding their signaling mechanisms across tissues will be important for future investigation.

Purpose of review: In patients with myositis, interstitial lung disease (ILD) is one of the major causes of morbidity and mortality. Given the limited evidence, there is an urgent need to refine the treatment for myositis-ILD. This review aims to highlight recent updates on the management of myositis-associated ILD, focusing on screening, risk stratification, and treatment.

Recent findings: Asian race and/or residence, dermatomyositis, mechanic's hand, antisynthetase antibodies, and antimelanoma differentiation-associated gene 5 antibodies are risk factors for ILD development. Patients with such risk factors should be screened for ILD using high-resolution computed tomography. Various prediction models for mortality or rapidly progressive ILD (RP-ILD) in patients with myositis-ILD have been proposed, but validation of these models in multiple independent studies is required. Academic societies in Japan, the United Kingdom, and the United States have proposed tentative treatment algorithms for myositis-ILD on the basis of the presence or absence of RP-ILD.

Summary: Knowledge on myositis-ILD risk stratification, potentially useful for personalized management approaches in clinical practice, is accumulating. However, further global joint efforts are necessary to build a strong evidence base for consensus algorithms for myositis-ILD.

Purpose of review: New breakthroughs in our understanding of dermatomyositis (DM) have spawned the recent development of novel agents that specifically target key drivers in DM immunopathogenesis. This review aims to provide a comprehensive overview of new and forthcoming therapies for DM and to highlight their mechanisms of action, best evidence to date, and potential impact on disease management.

Recent findings: Strategies that either counteract dysregulated interferon signaling [via the inhibition of interferon β, the type I interferon receptor subunit 1 (IFNAR1), or janus kinase (JAK)-signal transducer and activator of transcription (STAT) transduction] or induce durable autoreactive B cell depletion through chimeric antigen receptor (CAR) T-cell therapy appear to hold the most promise for sustained remission in DM.

Summary: The trajectory of DM treatments is rapidly evolving, fueled by the unparalleled insights provided by multiomic studies and big data analysis pipelines. Targeted therapies that maximize both efficacy and safety have the potential to complement or replace traditional immunosuppressives and revolutionize the approach to the management of DM.