Current opinion in rheumatology最新文献

Purpose of review: The purpose of this review is to summarize the uses of artificial intelligence for advancing systemic sclerosis (SSc) skin and lung disease research through 2024.

Recent findings: Applications of AI in SSc research have expanded markedly in recent years. The most common artificial intelligence method identified was supervised machine learning for predictive modeling. Supervised machine learning uses input data labeled with a known outcome to train a model to predict outcomes when encountering new data. Using machine learningassisted feature selection and posttraining feature importance techniques also highlighted key predictors within complex datasets, informing possible mechanisms underlying heterogeneous patient outcomes. Additionally, unsupervised machine learning approaches have been used to identify patient subsets with distinct clinical trajectories. Unsupervised machine learning identifies groups with similar characteristics within a dataset, without considering a specific outcome. Digital image analysis using deep learning has also been undertaken in lung imaging studies to quantify interstitial lung disease (ILD) extent and automate ILD subtype classification, as well as skin biopsy analysis to quantify histologic changes. These scalable tools could efficiently automate prognostic assessments for use across centers of varying local expertise.

Summary: Artificial intelligence represents a tool for analyzing high-dimensional, complex datasets to derive robust results, even within relatively small SSc cohorts. To date, artificial intelligence driven insights to SSc skin and lung disease have focused on identifying patient subsets, quantifying disease severity, and building predictive models to inform personalized patient care.

Purpose of review: To synthesize current knowledge on the genetic, immunopathogenic, and clinical presentations of systemic sclerosis (SSc) and primary biliary cholangitis (PBC) with a focus on their co-occurrence as a clinically relevant overlap syndrome. This narrative review summarizes preclinical and clinical studies addressing SSc-PBC overlap.

Recent findings: Genomic studies highlight shared susceptibility loci between SSc and PBC. Furthermore, SSc-PBC overlap patient sera reveals anticentromere antibodies which cross-react with an antigenic motif on pyruvate dehydrogenase-E2 (structural core of pyruvate dehydrogenase complex catalyzing formation of acetyl coA), the most common target of antimitochondrial antibodies in PBC. Similar profibrotic cytokines and T regulatory cell profiles are identified in sera and skin and liver biopsies of patients with SSc and PBC respectively. Analysis of clinical phenotypes reveals that SSc-PBC overlap patients have reduced incidence of pulmonary fibrosis and pulmonary arterial hypertension compared to SSc alone, and less severe hepatic involvement compared to PBC alone.

Summary: SSc-PBC overlap remains an understudied disease process. This review summarizes current knowledge and outlines future directions to guide research and improve care for patients with this distinct clinical overlap.

Purpose of review: Assessing the impact of active therapy on how patients 'feel and function' is considered a necessary requirement by regulatory agencies for the approval of future treatments for SSc. In this context, patient-reported outcome measures (PROMs) have become a cornerstone of therapeutic assessment in randomized controlled trials (RCTs).

Recent findings: This narrative review will discuss a selection of main available PROMs used in SSc RCTs, with a specific focus on recently developed PROMs, highlight ongoing initiatives related to SSc-PROMs, and provide points to consider for future use of SSc-PROMs.

Summary: Several recent initiatives include a patient-centered approach [such as the Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP), the MCQ (Mawdsley Calcinosis Questionnaire], the COAST (Clinical Outcome Assessments for Systemic Sclerosis Clinical Trials), and the CRISTAL (Combined Response index for scleroderma trials assessing limited systemic sclerosis) initiatives] to develop new PROMs and actively involve patient partners in each step of the process. Using a combined response index incorporating PROMs as the primary outcome measure in future SSc trials, such as the CRISS index for diffuse cutaneous SSc, could ensure that the perspectives of both physicians and patients would be incorporated to assess the efficacy of future interventions.

Purpose of review: This review presents evidence for pathways that have genetic underpinnings in gout that should be prioritized for further study and therapeutic development.

Recent findings: Recent genome-wide association studies have identified molecular mechanisms in the pathogenesis of gout that converge on cell metabolism, phagocytosis of crystals and cytokine signalling.

Summary: Understanding how the gene pathways function to influence the gout flare; crystal formation, crystal deposition and the subsequent immune response and inflammation characteristic of the gout flare is critical to developing additional therapies in the gout repertoire.

Purpose of review: Urate-lowering therapy (ULT) plays a pivotal role in treating gout patients. Unfortunately, some patients receiving oral ULT fail to achieve the target serum urate levels of < 6.8 mg/dl, the solubility level of uric acid. Exogenous uricases, considered "enzyme replacement therapy," are a therapeutic option for patients with uncontrolled gout in whom oral ULT has not been efficacious, is not tolerated, or is contraindicated, in some due to underlying comorbidities. Currently, two uricases are available: pegloticase and rasburicase. Pegloticase is indicated for treating uncontrolled gout, while rasburicase is used to prevent tumor lysis syndrome.

Recent findings: The main limitations of pegloticase include gout flares and infusion reactions, which are linked to the formation of antidrug antibodies. Immunomodulation and anti-inflammatory prophylaxis can help reduce these issues. New PEGylated uricases, including nanoencapsulated sirolimus combined with pegadricase (NASP) and PRX-115, are being developed and may offer improved options.

Summary: Exogenous uricases available and those under development are discussed, focusing on immunomodulation and anti-inflammatory prophylaxis to reduce flares, prevent antidrug antibody formation and infusion reactions, and mitigate loss of efficacy in patients with uncontrolled gout needing uricase replacement therapy.

Purpose of review: This review explores the evolving understanding of vascular dysfunction in systemic sclerosis (SSc), from early endothelial injury to clinical manifestations and emerging therapeutic strategies.

Recent findings: Endothelial cell (EC) injury, senescence, and endothelial-to-mesenchymal transition are central to SSc vasculopathy. Single-cell and spatial omics have revealed distinct EC subtypes and dysregulated pathways, including interferon signaling and chromatin remodeling. Immune-mediated damage, viral triggers, and autoantibodies contribute to vascular pathology. Clinically, complications such as Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, and renal crisis drive morbidity and healthcare burden. Diagnostic tools such as nailfold capillaroscopy enable early detection of microvascular changes. Novel therapies including CAR-T therapy, JAK inhibitors, and complement blockade, are under investigation.

Summary: Vascular dysfunction is a hallmark of SSc and a key driver of disease progression. Advances in molecular profiling and imaging have improved our understanding of its mechanisms and opened new avenues for targeted intervention. Early diagnosis, biomarker-guided care, and multidisciplinary management are essential to improving outcomes.

Purpose of review: This review aimed to synthesize the current knowledge regarding the prevalence, underlying mechanisms, and clinical implications of sleep disturbances in patients with systemic sclerosis (SSc). Furthermore, it highlights the potential for targeted interventions to address sleep dysfunction and improve overall disease management and patient quality of life.

Recent findings: Sleep disturbances, including poor sleep quality, insomnia, sleep apnea, and restless leg syndrome, are common in patients with SSc, with multiple contributing factors such as immune activation, fibrosis, pain, and gastrointestinal symptoms. However, comprehensive assessment methods and targeted treatments for sleep disorders in this population remain limited. Evidence suggests a close association between sleep disruption and disease severity or progression, with inflammatory cytokines (e.g., IL-6 and TNFα) implicated in sleep and SSc pathophysiology.

Summary: Sleep disorders are an under-recognized but significant burden in SSc, driven by complex interactions among disease manifestations and psychological and physiological factors. Early comprehensive assessment and integrated management of sleep disturbances and underlying SSc symptoms may improve patient outcomes.

Purpose of review: This review highlights recent advances in the understanding and management of gastrointestinal manifestations in systemic sclerosis (SSc). It is intended for clinicians and researchers aiming to improve diagnostic accuracy and therapeutic strategies in managing SSc-related gastrointestinal disease.

Recent findings: Gastrointestinal involvement in SSc is highly variable in terms of clinical presentation, symptom severity, progression, timing of onset, and response to treatment. Emerging research highlights early immune-mediated damage to neural and muscular gastrointestinal tissues, microbiome alterations, and vascular dysfunction - particularly in patients with late-onset gastrointestinal disease - as key factors guiding the development of personalized, precision-based approaches for well defined patient subgroups. Recent studies underscore the value of early, objective assessment of gastrointestinal motility using tools like whole-gut transit scintigraphy and abdominal vascular ultrasound. New treatment strategies are also being explored for severe manifestations, including investigating mechanisms behind acid-suppressive therapy-resistant gastroesophageal reflux disease and implementing adjunctive therapies for gastrointestinal dysmotility.

Summary: Gastrointestinal involvement in SSc poses a complex clinical challenge, particularly in patients with severe dysmotility and symptoms refractory to standard management strategies. This review offers timely, evidence-based insights to support clinicians in delivering more personalized and effective patient care and highlights critical gaps to address in future research.

Purpose of review: This review examines how metabolic reprogramming drives fibrosis and immune dysregulation in systemic sclerosis (SSc), emphasizing the role of nutrient-sensing and energy pathways in disease progression.

Recent findings: SSc is characterized by a shift from catabolic to anabolic metabolism, defined by reduced AMP-activated protein kinase (AMPK) and enhanced mechanistic target of rapamycin complex 1 (mTORC1) signaling. This promotes biosynthetic activity, with upregulated glycolysis supplying substrates for collagen production and supporting pro-inflammatory immune cell polarization. Remodeling of the tricarboxylic acid cycle yields key metabolites with extrametabolic roles. α-ketoglutarate (αKG) supports epigenetic regulation, collagen maturation, and AMPK activation, offering protective effects. In contrast, succinate and fumarate promote inflammation and fibrotic signaling. Despite increased anabolic activity, oxidative phosphorylation remains elevated in SSc fibroblasts, contributing to excess reactive oxygen species (ROS). Metabolomic analyses consistently show disrupted amino acid and lipid metabolism, including glutamine and tryptophan pathways, linked to immune activation and fibrogenesis. Single-cell transcriptomics reveal diverse fibroblast subtypes with distinct metabolic programs correlating with fibrosis severity.

Summary: SSc is characterized by a metabolic reprogramming that favors anabolic, profibrotic, and proinflammatory states. These interconnected metabolic shifts illustrate how central carbon and nutrient pathways not only sustain energy demands but also actively regulate profibrotic signaling, offering new therapeutic targets for modulating fibrosis.

Purpose of review: Autoimmune glomerulonephritis (GN) emerges when self-reactive humoral and cellular immunity converge in the kidney. Combined immunofluorescence and electron microscopy aids in classifying GN; however, more stratification strategies are required for personalized therapy. We aimed to review biopsy-anchored clinicopathologic classification and pathophysiology of GN-associated disorders based on immunofluorescence and electron microscopy. Additionally, we sought to integrate mechanistic insights from multiomics and spatial profiling that resolve the composition and spatial organization of the cellular "neighborhoods" that drive injury and repair across IgA vasculitis/nephropathy, lupus nephritis, antiglomerular basement membrane disease, and antineutrophil cytoplasmic antibody-associated vasculitis.

Recent findings: Although inciting antigens, immune complexes, and deposition patterns vary among entities, downstream injury pathways overlap. The convergent programs include complement activation, including locally produced renal complement, Fc receptor-driven myeloid effector functions, neutrophil extracellular traps with nucleic-acid sensing, the reprogramming of monocytes/macrophages, interleukin (IL)-23/IL-17, and type 1 interferon-primed cytotoxicity of T cells, and epithelial stress responses in podocytes and parietal epithelial cells.

Summary: Despite diverse triggers, autoimmune GNs share targetable injury pathways. Integrating biopsy-defined immune deposits and the accompanying inflammatory context with spatial, single-cell, and proteomic readouts enables mechanistic subtyping and pathway-aligned therapy. Tailoring treatment to individual dominant injury programs may improve renal outcomes and reduce adverse effects.