This systematic review and meta-analysis synthesized evidence on the prevalence and determinants of difficult-to-manage (D2M) and treatment-refractory (TR) axial spondyloarthritis (axSpA). A comprehensive literature search (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane Library) identified studies published from inception to August 2026. ASAS-aligned studies requiring failure of ≥2 b/tsDMARDs with different mechanisms plus persistent disease activity were included. Random-effects meta-analyses pooled prevalence estimates, odds ratios (ORs) for binary determinants, and standardized mean differences (SMDs) for continuous measures. Among 11 ASAS-aligned studies (5648 patients), pooled D2M-axSpA prevalence was 10.1% (95% CI 8.2-11.8%; I[2] = 66%), with prospective multicenter studies yielding a stable estimate of 9-10%. Fibromyalgia was most strongly associated with D2M status (OR 3.32 [95% CI 1.93-5.72]), followed by HLA-B27 positivity (OR 1.74 [1.33-2.28]) and smoking (OR 1.31 [1.13-1.51]). Female sex showed no significant association (OR 1.42 [0.93-2.18]; I[2] = 75.7%). Higher baseline BASDAI scores were observed in D2M patients; associations with age and disease duration were inconsistent. Extra-musculoskeletal manifestations showed non-significant trends. D2M-axSpA affects approximately one in ten patients, with true treatment-refractory disease representing a smaller subset. Fibromyalgia, smoking, and HLA-B27 positivity emerged as key associated factors, though cross-sectional designs preclude causal inference. These findings support the distinction between inflammatory and non-inflammatory mechanisms of persistent disease burden to guide clinical management.

Although cytokine-targeted therapies have transformed psoriasis management, persistent tissue abnormalities and relapse after clinical remission indicate that immune suppression alone does not fully restore tissue homeostasis. This critical narrative review evaluates whether extracellular matrix (ECM) remodeling is merely a consequence of inflammation or can help maintain a relapse-permissive tissue state. In lesional skin, basement membrane disruption, disorganized dermal matrix architecture, altered collagen deposition, hyaluronic acid metabolism and proteoglycan expression, together with increased matrix metalloproteinase activity, especially matrix metalloproteinase-2 (MMP-2) and MMP-9, reshape the microenvironment in which keratinocytes, stromal cells, endothelial cells and immune cells interact. Mechanistic studies indicate that these abnormalities can affect dermal-epidermal integrity, leukocyte trafficking, angiogenesis, vascular permeability and matrix-derived inflammatory signaling. Collagen crosslinking and dermal stiffening add a mechanical layer to psoriatic inflammation through mechanotransductive pathways. ECM-derived biomarkers and imaging approaches remain promising research tools for assessing tissue remodeling, but they have not yet been validated as psoriasis-specific clinical biomarkers. ECM-targeted interventions may complement cytokine-directed therapy, although most remain at the preclinical or early translational stage. Overall, ECM remodeling provides a complementary framework for understanding psoriasis as a disease involving both immune activation and persistent tissue-level remodeling.

Bile acids (BAs) have evolved from simple digestive surfactants into central signaling molecules that integrate gut microbiota metabolism with host immunity. In autoimmune diseases (AIDs), alterations in the BA pool, driven by changes in microbial transformation capacity and tissue-specific receptor responsiveness, disrupt the homeostasis of the gut-liver-immune axis. These alterations participate in disease onset, progression, and chronicity by weakening epithelial barrier integrity, regulating inflammasome activity, and skewing the Th17/Treg balance, among other mechanisms. This review synthesizes current knowledge on BA synthesis, enterohepatic circulation, and microbial modification. We examine the immune-regulatory network of BAs, which includes both receptor-dependent pathways and receptor-independent mechanisms, and discuss their dysregulation in common AIDs. Finally, we assess emerging therapeutic strategies, including receptor-targeted modulators, microbiome-directed interventions, and combination regimens aimed at restoring metabolic-immune homeostasis. A mechanistic understanding of this network may help improve early diagnosis, patient stratification, and personalized immunotherapy of AIDs.

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.

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.