Hydroxychloroquine (HCQ) has been a cornerstone of rheumatic disease therapy for more than half a century. Its best-established immunomodulatory actions arise from endosomal and lysosomal alkalinization, with inhibition of endosomal Toll-like receptor 7/9 signaling and attenuation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) activation. Apart from these well-established mechanisms we also discuss a proposed model in which HCQ might influence CD3ζ/CD4 endocytic turnover. A structured narrative search of PubMed/MEDLINE, Scopus, and Web of Science was performed between July and November 2025. Clinically, HCQ remains foundational in systemic lupus erythematosus (SLE), whereas evidence for antiphospholipid syndrome, primary Sjögren's syndrome, lichen planus, and chronic spontaneous urticaria is limited and does not support routine use outside selected off-label settings. Randomized trials demonstrated no clinical benefit in COVID-19. Retinopathy remains the principal dose- and duration-dependent toxicity. Limiting the daily dose to ≤5 mg/kg actual body weight and following current ophthalmic screening recommendations are the main preventive measures. HCQ blood-level monitoring may support adherence assessment and exposure-informed care, but therapeutic thresholds and laboratory interpretation are not yet universally standardized. This review integrates mechanistic, clinical, and safety evidence while explicitly distinguishing established findings from hypotheses and lower-certainty observations.
INTRODUCTION:Personalization of Janus kinase inhibitor (JAKi) therapy in rheumatoid arthritis (RA) remains an unresolved clinical task. Multi-omics/multimodal (MO/MM) data and artificial intelligence/machine learning (AI/ML) may support treatment-response prediction, but their JAKi-specific application has not been systematically mapped. METHODS:We conducted a JBI scoping review with PRISMA-ScR reporting; the protocol was registered on OSF. Major bibliographic databases and additional sources were searched through 7 July 2025 without language or publication-status restrictions. We included direct JAKi studies using AI/ML or integrated MO/MM data and contextual non-JAKi RA studies combining MO/MM with AI/ML. Risk of bias and reporting completeness were assessed using PROBAST+AI and TRIPOD+AI. Findings were synthesized narratively. RESULTS:Eighteen publications were included, four of which were conference abstracts. The corpus comprised three direct JAKi AI/ML studies, three JAKi-associated MO/MM studies without AI/ML, eleven contextual non-JAKi AI/ML studies, and one mixed JAKi/TNFi study. AI/ML was applied in 15/18 publications. None of the direct JAKi AI/ML studies performed independent external validation. Reported AUROCs ranged from 0.656 to 1.00, with the highest estimates arising under internal or incompletely reported validation. Calibration and explainability were infrequently reported. CONCLUSION:Direct evidence for AI/ML-guided JAKi personalization remains sparse and heterogeneous and does not support selection of a specific JAKi or routine individualized treatment decisions. Progress requires adequately powered JAKi-specific cohorts, class-separated analyses, harmonized measurements, transparent preprocessing, and independent external validation. The "data × methods × JAKi" map identifies both emerging signals and the links that must be strengthened before MO/MM and AI/ML can support clinical decision-making in RA. TAKE-HOME MESSAGE:Current multi-omics and AI/ML evidence is insufficient to guide routine selection of a specific JAK inhibitor in rheumatoid arthritis. Independent external validation, calibration, and prospective assessment of clinical utility are required before these approaches can support treatment decisions.
BACKGROUND:Gender disparities in rheumatology persist despite increasing female representation. This comprehensive global survey, conducted by the Coalition for Health and Gender Equity (CHANGE) group, examined preferences for gender equity interventions among rheumatology professionals. METHODS:A cross-sectional online survey of rheumatologists and allied health professionals was conducted across 105 countries (January 2023-May 2024). Intervention preferences spanned four domains: conference-based, organizational, skills training, and work-based strategies. Gender differences were evaluated using logistic regression adjusted for years of work experience, with subgroup analyses by Human Development Index (HDI), Gender Inequality Index (GII), professional role, and caregiving responsibilities. Multiple comparisons were adjusted using Benjamini- Hochberg correction for false discovery rate. RESULTS:Among 1945 respondents (66.4% female), the most widely endorsed interventions overall were family- and child-friendly conference policies (71.4%), communication and scientific writing training (52.6%), and engagement of national rheumatology groups (46.9%). Women demonstrated significantly stronger support for increasing the visibility of female role models (11.89% vs 5.81%, OR = 3.29, p < 0.01), establishing gender-balanced committees (17.66% vs 16.01%, OR = 1.76, p < 0.01), and gender-sensitive editorial board policies (12.70% vs 10.66%, OR = 1.77, p < 0.01). Respondents from higher-GII countries prioritised scientific writing masterclasses (OR = 4.58, p < 0.05) and career planning training (OR = 3.90, p < 0.05) but showed lower endorsement of unconscious bias training (OR = 0.48, p < 0.05) and male allyship programmes (OR = 0.42, p < 0.05). Women in low/middle-HDI countries more frequently selected grant writing support (40.3% vs 26.4%, p < 0.01). CONCLUSION:Gender equity intervention preferences vary systematically across contexts. These findings provide empirical foundations for developing culturally responsive, evidence-informed intervention frameworks to advance gender equity in rheumatology.
The placebo effect represents a clinically relevant and underexplored phenomenon in modern medicine with significant implications for treatments, particularly in rheumatological conditions, as placebo groups in clinical trial commonly achieve some degree of subjective and objective response, with an unclear correlation from the routine clinical observations. Emerging evidence highlights that the placebo effect extends beyond symptom perception, modulating markers of inflammation through neuroimmune pathways; however, these mechanisms remain poorly understood. In psoriatic arthritis (PsA), the placebo effect is of particular relevance, given the heterogeneous disease manifestations, the frequent neuropsychiatric disturbances, and the relevance of non-inflammatory or nociplastic pain. We herein provide a narrative review of the placebo responses observed in PsA clinical studies, the methodological challenges in isolating real drug effects, particularly in terms of allowed or background medications. We also emphasize the role of the placebo response in PsA and the broad aspects of the disease that influence the perception of pain in those patients, such as the physician and patient expectations, metabolic comorbidities and socio-economic background. A deeper understanding and systematic integration of placebo metrics and contextual determinants into future studies will be essential to accurately interpret drug efficacy and optimize trial methodology in this most heterogeneous disease.
Antibodies against the Dense Fine Speckled 70 kDa protein (anti-DFS70), associated with the anti-cell 2 (AC-2) pattern on immunofluorescence HEp-2 cells, represent a frequent finding in antinuclear antibody (ANA) testing, particularly among healthy individuals, and have been proposed as an exclusion marker for systemic autoimmune rheumatic diseases (SARDs). In systemic lupus erythematosus (SLE), however, their interpretation is more complex. Anti-DFS70 antibodies are uncommon, rarely monospecific, and are not consistently associated with global disease activity, although selective associations with musculoskeletal and mucocutaneous manifestations have been reported. In lupus nephritis (LN), evidence from a single dedicated cohort suggests that anti-DFS70 antibodies are enriched compared with healthy controls and patients with non-lupus chronic kidney disease (CKD), while within biopsy-proven LN they may associate with proliferative histological subtypes and intrarenal inflammatory activity. In this narrative review, we provide a critical overview of the epidemiological, serological, clinical, and experimental evidence on anti-DFS70 antibodies, with a particular focus on SLE and LN. Overall, current evidence supports a context-dependent interpretation of anti-DFS70 antibodies across health, systemic autoimmunity, and organ-specific inflammation.
Extracellular vesicles (EVs) have been shown to be key regulators of intestinal homeostasis and inflammatory responses, offering new insights into the pathogenesis of inflammatory bowel disease (IBD) and the development of targeted therapeutic strategies. EVs in the intestine can be secreted by intestinal epithelial cells (IECs), mesenchymal stem cells (MSCs), immune cell subsets, the gut microbiota, and even dietary sources. Its vesicle internal load contains a variety of biologically active molecules, including proteins, miRNAs, and microbial signals, which mediate immune regulation, intestinal barrier repair, and microbiota regulation. Mechanistically, EVs shape intestinal immune homeostasis by regulating T cell differentiation, macrophage polarization, inflammasome activation and epithelial regeneration, while promoting angiogenesis and fibrosis reversal, and mediating interaction between the host and the microbiota. In clinical settings, EVs are stable and easily accessible biomarkers in blood, feces, and intestinal lavage fluid, which can reflect disease activity, microbiota disorders, and treatment responses. The therapeutic value of EVs lies in their cell targeting ability, stability and drug-loading potential, enabling them to be transformed from biological entities into medical tools. Although it still faces challenges in large-scale production, biodistribution and regulatory standardization, it has broad prospects in promoting the accurate diagnosis and treatment of IBD.
The diagnosis and treatment of multiple sclerosis (MS) remain an evolving challenge in modern neurology. Recent advances are reflected in the 2024 revision of the McDonald criteria, which aim to facilitate earlier, more accurate and biologically informed diagnosis of MS. Key updates include expansion of dissemination in space to incorporate the optic nerve, integration of relapsing and progressive onset MS within a unified diagnostic framework, provision for diagnosis in selected asymptomatic individuals, dispensing with the requirement for dissemination of time in certain situations and incorporation of more specific imaging biomarkers. These include specific radiological features such as the central vein sign and paramagnetic rim lesions, visual pathway assessments using optical coherence tomography, magnetic resonance imaging and visual evoked potentials. Furthermore, oligoclonal bands and kappa free light chain index are now acknowledged as alternative cerebrospinal fluid biomarkers of intrathecal immunoglobulin synthesis. These revisions acknowledge the evolving understanding of MS biology alongside the substantial advances in disease modifying therapies. This review uses the 2024 McDonald criteria as an overarching framework to synthesise and contextualise the recent developments in MS diagnosis and treatment, highlighting their clinical implications, current limitations and future directions.
Immune thrombocytopenia (ITP) is an autoimmune hematologic disorder characterized by immune-mediated platelet destruction and impaired platelet production. In addition to these core abnormalities, ITP is associated with persistent inflammation, metabolic disturbance, oxidative injury, and altered proteostasis in immune cells, megakaryocytes, platelets, and the bone marrow microenvironment. In this narrative review, we examine whether the integrated stress response (ISR) could provide a mechanistic link between these stress phenotypes and cell-specific responses in ITP. Evidence for the involvement of the four canonical eIF2α kinases is uneven and varies substantially by cell type and experimental setting. We therefore propose a cell-specific hematopoietic response model in which sustained stress inputs interact with the distinct response capacities of immune and hematopoietic cell populations. From a therapeutic perspective, we discuss current ITP treatments in terms of their established immunological or hematopoietic actions and distinguish these primary effects from secondary changes in cellular stress that may follow disease control. We also refer to some experimental methods to confirm the participation of ISR. By emphasizing these differences, the review intends to promote future mechanistic research and the assessment of possible therapeutic strategies related to stress.
SLC29A3-related disorders are autosomal recessive conditions characterized by histiocytic infiltration, autoinflammatory and autoimmune manifestations, and variable degrees of immune deficiency. SLC29A3-related disorders are rare and complex, with a broad spectrum of manifestations, even among individuals carrying the same pathological genetic variants. Initially reported as H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID), Faisalabad histiocytosis or familial Rosai-Dorfman disease (RDD), genetics enabled to unify this syndrome under the SLC29A3-related disorders, an autosomal recessive disease. SLC29A3 gene encodes the equilibrative nucleoside transporter 3 (ENT3). The advent of high-throughput sequencing technologies such as exome and genome sequencing has facilitated the identification of new causing variants of SLC29A3 in patients with atypical or previously unrecognized phenotypes.Functional studies have demonstrated that damaging variants in SLC29A3 result in aberrant activation of inflammatory and proliferative signaling cascades, including the MAPK pathway and Toll-like receptor 7/8 (TLR7/8) overactivation. These molecular events lead to macrophage hyperactivation and excessive pro-inflammatory cytokine production, establishing SCL29A3-related disorders as a histiocytic inflammatory condition. Despite these advances, several immunopathological mechanisms remain incompletely understood, warranting further investigation.This article underscores the unmet clinical and research needs in SLC29A3-related disorders, emphasizing the immunological perspective to support the development of new diagnostic and therapeutic approaches for this rare disease with complex immunogenetic landscape.
Neutrophils, traditionally viewed as short-lived, terminally differentiated innate immune cells with no capacity for immunological memory, have recently been recognized as key players in trained immunity. This concept challenges the classical dichotomy between innate and adaptive immunity by demonstrating that prior microbial or inflammatory stimuli can induce long-lasting functional reprogramming of innate immune cells. This review provides a comprehensive overview of neutrophil-trained immunity, covering the central role of the bone marrow niche in storing innate immune memory, the epigenetic and metabolic mechanisms that underpin training, the diverse triggers (microbial ligands, vaccines, and endogenous sterile inducers), and the resulting functional consequences in neutrophils. Crucially, this response operates on a dose-dependent polarity: low-dose priming induces protective memory, whereas chronic or excessive inflammatory stimuli trigger neutrophil exhaustion and persistent tissue injury. We argue that the classical paradigm of autoantibody-driven tissue damage in autoimmune conditions is fundamentally anchored by "maladaptive trained immunity" established at the central hematopoietic level. Finally, this review discusses new strategies for the preparation of trained immunity-based vaccines and adjuvants, enhancement of immunity in immunocompromised patients, and clinical treatment to inhibit chronic inflammation, while also highlighting research gaps regarding the durability of neutrophil-trained immunity, the potential for de-training, and the interplay between trained immunity and other immune components, thereby revealing the significant implications and research prospects of neutrophil-trained immunity.
Rheumatic diseases, traditionally recognized for their joint and systemic inflammatory manifestations, increasingly reveal profound impacts on cerebrovascular integrity and neurovascular homeostasis. Patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), psoriatic arthritis (PsA), and related disorders exhibit heightened risks of stroke, cognitive impairment, and neuropsychiatric syndromes, underscoring the critical interplay between systemic autoimmunity and cerebrovascular health. This review synthesizes evidence on the mechanisms driving cerebral vasculature dysfunction in these conditions, emphasizing endothelial injury, microvascular pathology, and neuroimmune crosstalk. We further delineate disease-specific manifestations, imaging findings, and therapeutic strategies, while identifying current research gaps in subclinical neurovascular assessment and targeted therapy.
Rasmussen's encephalitis (RE) is a rare and devastating immune-mediated epileptic encephalopathy characterized by drug-resistant seizures, progressive hemispheric atrophy, and irreversible neurological decline. Although T-cell-driven neuroinflammation and microglial activation are recognized pathological hallmarks, current models remain insufficient to explain the relentless chronic progression and the limited long-term efficacy of immunotherapies. Here, we propose an integrative neuroinflammation-network remodeling feedback framework to conceptualize RE as a self-sustaining immune-network disorder rather than a purely inflammatory disease. In this model, immune-mediated cytotoxicity, persistent activation of tissue-resident memory T cells, and glial dysregulation converge to disrupt synaptic homeostasis and large-scale network organization. Recurrent epileptic discharges and focal neuroinflammation synergistically compromise blood-brain barrier integrity, facilitating sustained immune infiltration and amplifying glial-driven inflammatory cascades. These processes, in turn, promote excitatory-inhibitory imbalance, pathological network synchronization, and progressive neuronal loss, reinforcing a vicious cycle of network instability and immune activation. This framework integrates immune mechanisms, glial-synaptic interactions, and network-level dysfunction into a unified pathogenic continuum. It thereby explains why interventions targeting only a single aspect, such as immunotherapy or surgical seizure control alone, consistently fail to halt disease progression. Importantly, it highlights the rationale for stage-specific, multi-target therapeutic strategies aimed at simultaneously modulating immune responses and restoring network stability. Beyond RE, this conceptual model provides a broader paradigm for understanding chronic epileptic and neuroimmune disorders driven by maladaptive immune-network coupling.
The nuclear envelope (NE) is a complex intracellular structure unique to eukaryotic cells. The principal components identified by a variety of methods include the inner nuclear lamina comprised primarily of lamin proteins, the inner nuclear membrane (INM), the nuclear pore (NuP) complexes comprised of NuP proteins and the outer nuclear membrane (ONM). Dating to the earliest studies, the specific NE targets of human autoantibodies included: lamins A, B and C of the nuclear lamina, emerin, lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1) and lamina-associated polypeptide 2 (LAP2) of the INM and gp210/p210 and Translocated promoter region (Tpr) of the NuP. While autoantibodies to NE components are reported in a wide variety of diseases, their clinical use and importance have become paramount in autoimmune liver diseases, particularly primary biliary cholangitis. This review provides an overview of these findings and presents an atlas of the nuclear envelope components and molecular autoantibody targets and their intra-NE distribution that is used to interpret routine anti-cellular antibody testing using HEp-2 substrates.
Idiopathic inflammatory myopathies (IIM) are heterogeneous immune-mediated diseases characterized by muscle inflammation that coexists with variable trajectories of lung, skin, cardiac involvement, and malignancy association. Although modern classification criteria and serology have improved phenotyping, evidence remains limited in its applicability across cohorts and trials because broad diagnostic labels obscure major differences in autoantibodies, organ-risk trajectories, disease stage, and outcome selection. We propose a community roadmap that redefines IIM as a damage-data-endotype continuum integrating: (i) tissue damage programs (alarmins/DAMPs, mitochondrial stress/redox imbalance, regeneration-fibrosis transitions), (ii) tissue niches (muscle, lung, skin, heart, vascular-stromal compartment), (iii) immune effector axes (interferon/JAK programs, complement/Fc biology, B cell-plasma cell persistence, cytotoxic T-cell/immunosenescence signatures), and (iv) multi-layered data (myositis autoantibodies, quantitative imaging, digital pathology, omics, and patient-reported/digital outcomes). We define actionable endotypes as the combination of autoantibody profile, dominant organ-risk trajectory, and dominant mechanistic axis, and map these endotypes to therapy classes, measurable biomarker sets, and sensitivity-optimized endpoints. Finally, we propose a minimum dataset (basic and enhanced) to harmonize registries and facilitate adaptive/platform trials, thereby supporting robust machine-learning models with external validation and drift monitoring. This roadmap aims to standardize evidence generation across IIM, accelerate precision trials, and provide a shared, falsifiable research agenda for the next phase of the field.
Thyroid eye disease (TED), also referred to Graves' ophthalmopathy, is a disfiguring and vision-threatening autoimmune disease of the retroocular tissues occurring in patients with Graves' disease (GD). Among the extrathyroidal manifestations of GD, TED is the most frequent, being observed in roughly 30-50% of patients. In the immunopathogenesis of TED, the TSH-R/IGF-1R complex has a determinant role. TED is commonly bilateral, and during its active phase it presents with ocular redness, eyelid edema, photophobia, proptosis, and diplopia. In the most severe cases, the involvement of the optic nerve (dysthyroid optic neuropathy) may endanger vision and requires urgent treatment. Recommendations for the management of TED encompass three aspects: general measures, thyroid treatment, and eye treatment. The management of TED consists in control of hyperthyroidism, local therapies, intravenous pulses of methylprednisolone, and immunosuppressive agents. Recently, the deeper knowledge of TED pathophysiology has led to new potential therapeutic targets, and new biological drugs, such as teprotumumab, that is able to ameliorate clinical activity score and proptosis in these patients. Additional agents are currently under investigation, with promising results that suggest potential advances in the treatment of this disease. The aim of this review is to provide an updated outline of TED, in terms of immunopathogenesis, diagnosis, clinical management and current innovative drugs.
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by loss of immune tolerance and multi-organ inflammation. Although its pathogenesis involves multiple factors, the peak incidence of SLE in individuals over 48 years of age points to immunosenescence as a key driver of the disease.Even in younger patients, SLE frequently often presents as premature aging of the immune system. This review synthesizes recent advances in understanding how immunosenescence drives pathogenesis through immune dysregulation across major lymphocyte and myeloid subsets. Within the chronic inflammatory microenvironment, replicative exhaustion of T cells leads to accelerated telomere attrition, persistent activation of the DNA damage response, and telomerase dysfunction. This cascade culminates in the accumulation of senescent T cells displaying a characteristic CD28-CD57+KLRG1+ phenotype, accompanied by a pro-inflammatory state defined by enhanced cytotoxicity and impaired regulatory function. These characteristics correlated directly with disease activity and cumulative organ damage. The process arises from the interplay of metabolic reprogramming and epigenetic remodeling. In parallel, age-associated B cells (ABCs) accumulate, producing high-affinity anti-dsDNA and other autoantibodies, and potentiating inflammation via enhanced antigen presentation. Meanwhile, an aged bone-marrow microenvironment together with clonal hematopoiesis skews monocyte and macrophage polarization toward a pro-inflammatory (M1) profile. These cells show reduced phagocytic capacity and heightened secretion of senescence-associated secretory phenotype (SASP)-like mediators, further driving inflammaging. This review synthesizes current insights into the relationship between SLE risk and immunosenescence. We discuss the mechanisms through which immune aging instigates autoimmunity and explore emerging therapeutic strategies aimed at mitigating immunosenescence.
Hepato-biliary-pancreatic cancers, notorious for their pronounced heterogeneity and poor prognosis, continue to be a dominant factor in cancer-related deaths globally. Although immunotherapy has dramatically reshaped the cancer treatment landscape, its efficacy in these malignancies remains suboptimal due to the intense immunosuppression in the tumor microenvironment (TME) stemming from metabolic dysregulation. This review provides an in-depth analysis of the fundamental mechanisms of immunometabolic suppression. It highlights the strategies employed by tumor cells to compete with immune cells for nutrients, the accumulation of inhibitory metabolitessuch as lactate and adenosine, and disrupt pivotal metabolic pathways in CD8+ T, NK, and myeloid cells, ultimately leading to functional depletion. The novelty of this work lies in its systematic classification of these metabolic vulnerabilities and the introduction of a tripartite approach to address them: nutrient redistribution, metabolite scavenging, and enhancement of immune cell intrinsic metabolism. This approach aims to complement the next generation of immunotherapies, converting immunologically “cold” tumors into “hot” ones. Additionally, the review emphasizes the potential of integrating multi-omics profiling, artificial intelligence, and biomarker-guided personalized therapy as avenues to overcome resistance and enhance clinical efficacy. By viewing the challenge of therapy resistance through a metabolic perspective, this study not only enriches our foundational understanding of tumor-immune interactions but also presents a practical framework for designing highly efficacious combination therapies, representing a crucial advancement in the management of these formidable cancers.
BACKGROUND:Patients with systemic lupus erythematosus (SLE) present a markedly increased risk of premature atherosclerosis. Statins have been proposed as a possible therapeutic option to reduce cardiovascular risk in this population; however, their efficacy remains uncertain. This systematic review and meta-analysis assessed the impact of statin therapy on atherosclerosis markers and lipid profiles in SLE patients. MATERIAL AND METHODS:We searched PubMed, EMBASE, and Cochrane for randomized controlled trials (RCTs) comparing statins versus placebo in patients with SLE. Eligible studies reported outcomes including carotid intima-media thickness (CIMT), coronary artery calcium score (CAC), high-sensitivity C-reactive protein (hs-CRP), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), LDL cholesterol, and total cholesterol. Mean differences (MD) and standardized mean differences (SMD) with 95% confidence intervals (CI) were pooled using random-effects models. RESULTS:Six RCTs (668 patients) were included; 333 (49.8%) received statin therapy. Mean participant age was 39 years (range 15-51), with mean follow-up of 18.5 months. Statin therapy significantly reduced hs-CRP (MD -0.61 mg/L; 95% CI -1.12, -0.11; p = 0.017), LDL cholesterol (MD -35.49 mg/dL; 95% CI -57.14, -13.83; p < 0.01), and total cholesterol (MD -38.85 mg/dL; 95% CI -66.74, -10.95; p < 0.01) compared to placebo. No significant differences were observed in CIMT (MD -0.0047 mm; 95% CI -0.017, 0.0075; p = 0.45), CAC (SMD -0.10; 95% CI -0.34, 0.15; p = 0.45), or SLEDAI (MD -0.70; 95% CI -1.56, 0.15; p = 0.11). CONCLUSION:Statin therapy in SLE patients significantly improved inflammatory and lipid markers but showed no significant impact on structural atherosclerosis markers or disease activity. Given the low to very low certainty of the available evidence, these findings should be interpreted cautiously and confirmed in adequately powered, long-term RCTs.
Liver cancer is a highly heterogeneous malignancy, still representing a leading cause of cancer-related mortality worldwide. Its pathogenesis is complex and therefore not yet fully understood; however, emerging evidence highlights the interplay of genetic predisposition, environmental factors, and immune dysregulation. Tumor-associated autoantibodies (TAAbs) have recently been considered promising biomarkers thanks to their immune responses to aberrant tumor-associated antigens. These autoantibodies influence tumor progression through antigen recognition, immune surveillance, and microenvironment modulation, although their precise roles require further investigation. This review examines the multifaceted potential of TAAbs in liver cancer, including the description of their generation and function, detection methods, and clinical utility in early diagnosis, treatment monitoring, and prognosis. The liver cancer treatment strategy based on TAAbs is also described. Despite progress in this area, challenges remain regarding standardization, understanding of the mechanism of action, and clinical translation. Future research should integrate multidisciplinary and AI technology to develop TAAbs-based precision medicine strategies. Uncovering TAAbs-related immune networks will enable the development of diagnostic and therapeutic approaches, ultimately improving patient outcomes.
Peptidylarginine deiminases (PAD) 2 and 4 are pivotal enzymes in the pathophysiology of RA, owing to their involvement in protein citrullination, which produces autoantigens recognised by anti-citrullinated protein antibodies (ACPAs). Genetic variations in PADI2 and PADI4, along with autoantibodies targeting these enzymes, have been identified as significant contributors to the susceptibility and heterogeneity of RA. This systematic review with narrative synthesis consolidates existing evidence on the correlations between PADI2/PADI4 polymorphisms and the risk of RA, alongside the prevalence and clinical implications of anti-PAD2 and anti-PAD4 autoantibodies, with particular emphasis on identifying research deficiencies in underrepresented communities. A thorough literature review of PubMed, Web of Science, Scopus, Embase, and Google Scholar was performed until March 2024 for studies examining PADI2/PADI4 genetics or anti-PAD antibodies in patients with RA. No geographical or linguistic restrictions were applied. Forty-two genetic studies and 18 autoantibody studies were included. PADI4 polymorphisms exhibit notable relationships with RA in Asian populations (pooled odds ratio 1.23, 95% confidence interval 1.16-1.31); however, the results are equivocal among Europeans. A protective PADI2 variation (rs1005753) was discovered in Southeast Asians (OR = 0.87 (95% CI =0.77-0.99)). Anti-PAD4 antibodies (18-35% prevalence) were correlated with severe erosive disease, whereas anti-PAD2 antibodies (∼18.5% prevalence) were correlated with milder disease. No studies pertaining to genetics or autoantibody profiles in African populations were found. Substantial advancements have been made in understanding PAD2 and PAD4 in Asian and European populations. The lack of data from African populations constitutes a significant research gap that necessitates immediate focus to guarantee the equitable implementation of biomarkers and therapeutic strategies.
