PURPOSE OF REVIEW:Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is a heterogeneous, difficult-to-treat condition in which multiple pulmonary hypertension groups frequently overlap. Recent evidence suggests that vascular involvement may contribute to multiple SSc-PH phenotypes. This review highlights recent advances in understanding vascular features and emerging therapeutic strategies beyond vasodilation. RECENT FINDINGS:Pathological and imaging studies demonstrate that vascular remodeling in SSc-PH extends beyond pulmonary arteries to pulmonary veins, capillaries, and coronary microcirculation, consistent with widespread immune-mediated vascular dysfunction. These features are increasingly recognized across various SSc-PH phenotypes: pulmonary arterial hypertension and pulmonary veno-occlusive disease; pulmonary hypertension associated with left heart disease, most commonly heart failure with preserved ejection fraction (PH-HFpEF); and pulmonary hypertension-associated with interstitial lung disease (PH-ILD); each of which is often accompanied by intrinsic right ventricular (RV) dysfunction. Emerging therapies targeting activin signaling, macrophage-vascular crosstalk, B-cell immunity, and endothelial-to-mesenchymal transition require further study but may be essential to identifying disease-modifying approaches across SSc-PH phenotypes. SUMMARY:There is increasing recognition that vascular remodeling across the cardiopulmonary circulation may underlie multiple SSc-PH phenotypes, providing novel insight into SSc-PH disease mechanisms and rationale for the development of therapies targeting vascular remodeling, fibrosis, inflammation, and intrinsic RV dysfunction beyond conventional vasodilator treatment.
PURPOSE OF REVIEW:Inclusion body myositis (IBM) is the most common acquired myopathy in individuals over 50 years of age and remains refractory to conventional immunosuppressive therapies. This review summarizes recent advances in the understanding of IBM pathogenesis and highlights emerging therapeutic strategies. RECENT FINDINGS:Recent studies have refined the understanding of the interplay between degenerative and immune-mediated mechanisms in IBM. Abnormal protein aggregation, impaired proteostasis, and alterations of the autophagic pathway contribute to muscle fiber degeneration. In parallel, increasing evidence supports a central role for highly differentiated cytotoxic CD8+ T cells invading major histocompatibility complex class I-expressing muscle fibers. Recent immunophenotyping studies have identified expanded populations of terminally differentiated killer cell lectin-like receptor G1-expressing CD8+ T cells in blood and muscle, suggesting a potential role for these cells in sustaining chronic muscle injury. These findings have prompted the development of targeted immunotherapies aimed at selectively modulating pathogenic cytotoxic T-cell populations. SUMMARY:IBM appears to result from a complex interaction between degenerative and immune-mediated pathways. Improved characterization of the immune effector cells involved in muscle injury is opening new avenues for targeted therapies and may ultimately lead to treatments for this condition that currently lacks disease-modifying therapy.
PURPOSE OF REVIEW:The delineation of myositis-specific autoantibody (MSA) subgroups over the past two decades has reframed environmental research in idiopathic inflammatory myopathies (IIMs), making it plausible to examine discrete exposure-phenotype pairings within serologically defined subgroups. This review synthesises evidence on environmental, occupational, infectious, and pharmacological exposures, with attention to phenotypic specificity. RECENT FINDINGS:Ultraviolet radiation shapes MSA-specific geographic distributions at the population level and associates with dermatomyositis onset at the individual level. Disease onset follows MSA-specific seasonal patterns, replicated across geographically independent cohorts. Smoking amplifies antisynthetase syndrome risk through a gene-environment interaction with HLA-DRB1*03:01, whilst protecting against anti-TIF1-γ autoantibodies. Gestational and early-life tobacco smoke exposure is consistently implicated as risks for juvenile IIM. Occupational silica exposure associates with antisynthetase syndrome and overlap myositis, with synergistic lung disease risk when combined with smoking. Statins, immune checkpoint inhibitors, anti-TNFα agents, and interferons each induce immunopathologically distinct myositis phenotypes. Postpandemic surveillance has documented a rise in anti-MDA5 autoantibody-positive disease following SARS-CoV-2 infection. SUMMARY:Environmental exposures in IIM act preferentially in specific serological and genetic contexts, consistent with discrete exposure-phenotype pairings shaped by genetic background and age at exposure. Prospective, MSA-stratified studies with direct exposure quantification represent priority directions for the field.
PURPOSE OF REVIEW:While autoantibodies targeting extracellular antigens, such as those in myasthenia gravis, are established mediators of disease, autoantibodies recognizing intracellular antigens in inflammatory myopathies have traditionally been considered nonpathogenic. This review examines evidence challenging that paradigm and highlights recent advances in understanding the origins and pathogenic functions of autoantibodies in myositis. RECENT FINDINGS:In several forms of myositis, immunoglobulin accumulates within muscle fibers in a distribution mirroring that of the cognate autoantigen. Muscle biopsies demonstrate functional consequences consistent with disruption of the targeted autoantigen, as well as secondary muscle damage and inflammation. These effects are reproduced in vitro by forced autoantibody internalization. Local plasma cells may facilitate this process by releasing cytoplasmic contents into neighboring cells, including immunoglobulin RNA. In paraneoplastic dermatomyositis, genetic alterations of the targeted autoantigen are frequently identified in tumors, suggesting that immune responses to somatic tumor mutations may initiate autoantibody production. In immune checkpoint inhibitor-associated myositis, autoantibodies may contribute to disease by acting as chemoattractants for drug-activated T cells. SUMMARY:Recent findings support a direct pathogenic role for autoantibodies in several autoantibody-defined myositis subtypes and provide new insights into their origins and contribution to immune-mediated muscle injury, while also suggesting broader roles.
Purpose of review Scleromyositis (SM), the muscle-specific manifestation of scleroderma, is increasingly recognized as a distinct myositis subset, yet it remains poorly captured by existing classification criteria and absent from therapeutic guidelines. This review provides recent advances in SM with emphasis on challenging presentations and propose a pragmatic diagnostic framework integrating clinical, serological, capillaroscopic, and histopathological data. Recent findings Recent studies identify capillaropathy as the unifying pathological hallmark of SM across muscle biopsy subtypes. Nailfold videocapillaroscopy reveals a predominantly scleroderma-active or scleroderma-like microangiopathy discriminating SM from potential myositis mimickers. Recent cohort studies demonstrate that SM confers independent mortality burden and substantial cardiac risk warranting immediate cardiac evaluation at diagnosis regardless of autoantibody profile or histological pattern. Pericyte dysfunction may link capillaropathy to fibrosis in SM, while autoantibodies appear to directly disrupt intracellular pathways, contributing to the shared vasculopathic and profibrotic signature that defines SM as a distinct entity. Summary SM represents a clinically severe and underrecognized disease spectrum that frequently escapes current classification frameworks. Early SM diagnosis requires systematic integration of clinical, serological, capillaroscopic, and histopathological data, with capillaropathy as the unifying thread. Establishing a consensus SM definition and securing clinical trial inclusion remain the most urgent research priorities.
PURPOSE OF REVIEW:Patient engagement in research has evolved from passive participation and inclusion toward active partnership and co-leadership. This review examines the current landscape of patient involvement in myositis research, highlights existing initiatives and frameworks, and identifies persistent gaps and overlaps. RECENT FINDINGS:In myositis, or inflammatory myopathies, early onboarding and integration of patients as research partners in preclinical and clinical studies offer invaluable opportunities to improve relevance, feasibility, and impact of research. The findings presented emphasize the importance of early partnership with patient research partners (PRPs), bidirectional training to foster mutual understanding, and expanded outreach to underrepresented regions. SUMMARY:Patient engagement in myositis research has advanced considerably, yet its integration remains inconsistent worldwide. Several existing resources can be leveraged to facilitate patient engagement in myositis research, but achieving meaningful PRP integration requires deliberate effort, adequate resources, and a commitment to cultural change.
Purpose of review Systemic sclerosis (SSc) is a clinically heterogeneous chronic immune-mediated inflammatory disease with the highest mortality rate among all rheumatic diseases. Although current SSc clinical and serological classifications provide valuable prognostic information, predicting disease progression, and therapeutic responses remains challenging. In this context, genomics holds potential to bridge this gap. This review summarizes recent advances in SSc genomics and discusses their potential clinical applications in disease prediction, patient stratification, and therapeutic development. Recent findings Over the past decade, genomic studies, mainly genome-wide association studies (GWAS) and sequencing-based approaches, have expanded our understanding of the genetic architecture of SSc, identifying susceptibility loci and pathways involved in immune dysregulation, vasculopathy, and fibrosis. Several approaches, including polygenic risk scores (PRS) and drug repurposing, have been performed with the potential to translate these results to clinical setting. Summary Genomic discoveries in SSc are increasingly aiming to move beyond disease susceptibility towards clinically relevant applications. The integration of genomic, molecular, and clinical data may improve risk stratification, enable earlier identification of SSc patients at risk of severe complications, and support the development of personalized therapeutic strategies. Continued efforts in identifying causal variants and deciphering their underlying mechanisms through functional genomics will be essential for a better translation of genetic findings into precision medicine approaches for SSc.
Purpose of review This review summarizes the emerging role of the fibrinolytic system in the pathogenesis of systemic sclerosis (SSc) and its potential as a source of novel therapeutic targets. Recent findings Increasing evidence indicates that SSc is characterized by impaired fibrinolysis, largely driven by upregulation of plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin, which limits extracellular matrix degradation and promotes myofibroblast differentiation. A key pathogenic mechanism involves matrix metalloproteinase-12-mediated proteolytic cleavage of the urokinase-type plasminogen activator receptor (uPAR), which compromises angiogenesis and promotes endothelial-to-mesenchymal transition, thereby contributing to both vascular remodeling and fibrosis. Moreover, aberrant crosstalk between cleaved uPAR and N-formyl peptide receptors (FPRs) on fibroblasts induces excessive reactive oxygen species generation and sustained fibroblast proliferation. Clinically, circulating soluble uPAR and PLAUR gene polymorphisms have emerged as candidate biomarkers of severe microvascular dysfunction and internal organ involvement. From a therapeutic perspective, several innovative strategies, including uPAR-targeting peptides, PAI-1 inhibitors, and molecules disrupting uPAR-FPR interaction, have shown encouraging antifibrotic efficacy in preclinical models. Summary The fibrinolytic system has emerged as a central molecular hub linking SSc microvascular dysfunction, immune dysregulation, and fibrosis. Thus, restoring fibrinolytic homeostasis may offer a promising strategy to simultaneously improve angiogenesis, reduce fibrosis, and slow disease progression.
PURPOSE OF REVIEW:A gout flare is an episode of intense inflammation caused by the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome and production of interleukin (IL)-1β. This pathway is involved in pathogenesis of cardiovascular events and provides a plausible mechanism linking gout flares to cardiovascular diseases. RECENT FINDINGS:Gout flares are associated with a transient increased risk of cardiovascular events (myocardial infarction, stroke, and cardiovascular death), venous thromboembolism, and tachyarrhythmia in the subsequent 30-60 days - a finding comparable to that observed after other acute inflammatory states, such as influenza and pneumonia.Treat-to-target urate-lowering therapy lowered the risk of major adverse cardiovascular events in an emulated target trial. It also reduced systemic inflammation in observational studies. Additionally, gout flare prophylaxis with colchicine was associated with lower rates of major adverse cardiovascular events in a nationwide cohort study without evidence of residual confounding. SUMMARY:Patients with gout are at a high risk of cardiovascular diseases. Recent data suggest that patients presenting with gout flares warrant heightened vigilance for cardiovascular events, venous thromboembolism, and tachyarrhythmia over the following 30-60 days. Treating gout to the target serum urate level could prevent cardiovascular events and renal function decline. Gout flare prophylaxis with colchicine may have a similar effect.
PURPOSE OF REVIEW:Systemic sclerosis (SSc) is a progressive autoimmune disease characterized by fibrosis, vasculopathy, and immune dysregulation. Emerging evidence indicates that SSc shares multiple hallmarks of accelerated biological aging, including genomic instability, telomere attrition, mitochondrial dysfunction, cellular senescence, and chronic innate immune activation. This review summarizes recent advances published during the last 18 months supporting the concept of SSc as a disorder of maladaptive or 'hyper-aging'. RECENT FINDINGS:Recent epigenetic clock studies, including DunedinPACE and other DNA methylation-based aging models, demonstrate accelerated biological aging in SSc, particularly in patients with interstitial lung disease and severe organ involvement. Gene expression meta-analysis has confirmed that aging and senescence signatures are markedly enriched in SSc-ILD lung tissue. Multiple aging-associated mechanisms contribute to disease progression, including telomere shortening, mitochondrial dysfunction, micronuclei formation, and chromosomal instability. Cytosolic DNA derived from damaged nuclei or mitochondria activates the cGAS-STING pathway, sustaining type I interferon signaling, inflammaging, and fibrotic remodeling. Recent transcriptomic and spatial studies further support a close relationship between metabolic collapse, mitochondrial stress, immune dysregulation, and tissue fibrosis in SSc. SUMMARY:Current evidence supports the concept that SSc represents a state of accelerated and dysregulated biological aging involving persistent innate immune activation, mitochondrial stress, and defective genome surveillance. Therapeutic strategies targeting aging-associated pathways, particularly mitochondrial dysfunction, cGAS-STING signaling, and cellular senescence, may provide new opportunities to modulate fibrosis, inflammation, and immune imbalance in SSc.
PURPOSE OF REVIEW:A central challenge in systemic sclerosis (SSc) is the inability to distinguish active, potentially reversible disease, from damage, irreversible fibrosis. Current imaging modalities, including high-resolution computed tomography (HRCT) and echocardiography, predominantly capture structural damage and cannot resolve this distinction. This review outlines next generation imaging modalities for SSc with focus on quantitative machine learning algorithms and molecular imaging. RECENT FINDINGS:The unifying advance across organ systems is a shift from documenting damage to measuring disease activity directly. Machine-learning-derived quantitative HRCT detects radiological patterns of ILD sensitive to change in SSc-associated interstitial lung disease. Parametric cardiac magnetic resonance mapping resolves diffuse interstitial fibrosis missed by late gadolinium enhancement. Fibroblast activation protein inhibitor PET (FAPI-PET) visualizes active fibrogenesis in lung and myocardium, identifying biologically active disease even before structural distortion occurs. [18F]Sodium fluoride PET detects metabolically active calcinosis. High-frequency ultrasound, elastography, and optical coherence tomography (OCT)-angiography extend objective assessment of cutaneous and microvascular involvement. SUMMARY:Emerging imaging modalities in SSc may enable earlier detection of active disease amenable to treatment modification and yield more sensitive endpoints for SSc clinical trials.
Purpose of review Erosive gout refers to the presence of at least one gouty bone erosion in a person with gout. This review provides an update on the update on mechanisms, impact, and treatment of erosive gout. Recent findings Erosive gout is usually the consequence of long-standing tophaceous disease. However, bone erosions in association with tophi can be detected on ultrasound before onset of clinical symptoms in some people with asymptomatic hyperuricaemia. SPP1 (osteopontin)-expressing macrophages have been implicated in pathogenesis of tophaceous gout and SPP1-mediated cellular interactions may influence bone remodelling in the context of erosive gout. In addition to joint deformity, people with erosive gout experience more frequent gout flares and have low rates of disease remission, even with intensive urate-lowering therapy. Oral urate-lowering therapy using a treat to target serum urate approach can prevent progression of erosive gout, and small serial imaging studies have demonstrated infilling of monosodium urate crystal-related bone erosion in pegloticase responders. Summary Erosive gout is a consequence of tophaceous gout and causes joint deformity which is difficult to reverse once established. Collectively, these findings provide a rationale for urate-lowering therapy for people with gout to prevent the consequences of tophaceous gout including joint damage.
PURPOSE OF REVIEW:Genetic autoinflammatory conditions constitute an increasing field. Among them, type I interferonopathies (IFNp-I) were conceptualized 15 years ago as inborn errors of immunity due to chronic activation of the type I interferon (IFN-I) signalling pathway. Here, we provide recent insights in genetic mechanisms, clinical phenotypes and therapeutic options for these severe and rare disorders. RECENT FINDINGS:We will cover the novel findings into disease mechanisms, particularly the role of PTP1B in STING and IFNAR signalling, as well as the contribution of endosomal TLR pathways. We will also discuss the expanding phenotypic spectrum highlighted by recent case reports and cohort studies, together with the topic of clinical expressivity, including clinical non-penetrance, and possible mechanistic explanations such as monoallelic expression, the STING HAQ haplotype, and innovative approaches to characterise disease variability. Finally, we discuss current targeted therapeutic approaches for these disabling conditions, as well as potential new treatments for the future. SUMMARY:Overall, these findings highlight the need to consider these rare diseases across a wide range of clinical phenotypes. Advances in next-generation sequencing have enabled a genetic diagnosis in suspected cases and the implementation of targeted treatments, thereby reducing diagnostic uncertainty and providing the possibility of genetic counselling.
Purpose of review IgA vasculitis (IgAV) and IgA nephropathy (IgAN) have historically been treated as distinct disease entities in clinical practice and in drug development, despite growing evidence speaking to a shared pathogenesis. Recent years have seen an explosion in therapeutic trials in the IgAN space, with multiple approvals of targeted therapies and a shifting paradigm of care; meanwhile, IgAV has lagged behind with a paucity of randomized trials. What can rheumatologists learn from IgAN, and can IgAV patients benefit from therapeutic advances in IgAN? Recent findings In this article, we will compare and contrast the epidemiology and clinical presentations of IgAV and IgAN, and explore the evidence supporting a shared pathogenesis including the ‘four hit hypothesis’. We will review emerging therapies in IgAN and their biologic basis for the rheumatology audience, and discuss how lessons learned in IgAN might be applied to IgAV. Summary Rheumatologists should be aware of the therapeutic advances in IgAN, which may inform future management of IgAV patients, particularly those with renal involvement.
Purpose of review The concept of difficult-to-treat (D2T) disease is increasingly recognized across immune-mediated inflammatory diseases, and was recently introduced in spondyloarthritis (SpA). Several terms, including difficult-to-manage (D2M), complex-to-manage (C2M), and treatment-refractory (TR) describe disease states characterized by persistent symptoms and inadequate response to targeted therapies. This review aims to clarify the emerging constructs of D2M and TR disease in axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), and their implications for emerging research in this area. Recent findings Recent initiatives from ASAS, EULAR, and GRAPPA have proposed definitions to frame D2T clinical scenarios in axSpA and PsA. These converge on distinguishing treatment-refractory disease, characterized by persistent objective inflammation despite multiple targeted therapies, from broader D2M/C2M states driven by multifactorial contributors including non-inflammatory factors. Emerging data suggest that clinical and biological heterogeneity across disease domains may contribute to these phenotypes. Challenging phenotypic presentations often display overlapping features between axSpA and PsA, supporting the concept of a continuum across the SpA spectrum. Summary Distinguishing TR disease from broader D2M/C2M states is essential for avoiding inappropriate treatment escalation, and supporting personalized multidisciplinary care. Further research is needed to validate these definitions, determine contributing factors and their prevalence, and clarify the molecular mechanisms underlying treatment refractory disease.
Purpose of review People with Down syndrome experience significant immune dysregulation, conferring elevated risk of autoimmune and inflammatory conditions. Despite the growing prevalence of adults living with Down syndrome, significant gaps remain in understanding and treating immune-mediated disease in this population. This review synthesizes current knowledge of immune dysregulation in Down syndrome, with focus on rheumatic manifestations and emerging therapeutic approaches. Recent findings Trisomy 21 drives constitutive, global immune remodeling characterized by mixed interferon hyperactivation, hypercytokinemia, and myeloid and lymphoid subset remodeling toward an autoimmunity-prone, pro-inflammatory state. Down syndrome associated arthritis is a distinct and aggressive entity warranting recognition separate from juvenile idiopathic and rheumatoid arthritis. People with Down syndrome face elevated risk of SJIA-associated lung disease and diffuse alveolar hemorrhage. Medication tolerance is a significant consideration, including intolerance to methotrexate and diminished response to TNF inhibitors. Early clinical trials of JAK inhibitors demonstrate promising results across multiple immune-mediated manifestations, including skin disease, arthritis, and Down syndrome regression disorder. Summary Immune dysregulation in Down syndrome is pervasive and mechanistically distinct, with interferon signaling as a central therapeutic target. Clinicians should be aware of Down syndrome specific diagnostic and management considerations, and future research should prioritize rigorous placebo-controlled trials and Down syndrome informed outcome measures.
Purpose of review Genetic and multiomics studies are reshaping our understanding of polyarticular juvenile idiopathic arthritis (JIA) and shifting the field from symptom- and phenotype-based categories toward biologically informed disease definitions. We summarize recent findings on disease risk and pathogenesis while focusing on genetic contributions to disease susceptibility and pathogenic mechanisms. Recent findings Classical HLA and non-HLA studies established the polygenic immune-mediated pathogenesis of JIA with distinct, partially overlapping, genetic architectures across the International League of Associations for Rheumatology categories. Rheumatoid factor (RF)-positive polyarticular JIA is increasingly considered a childhood-onset seropositive rheumatoid arthritis, whereas oligoarticular and RF-negative polyarticular JIA, although nonidentical, share substantial immunogenetic features. Recent subtype-integrative genome-wide association studies and transcriptomic and chromatin-interaction analyses prioritized candidate genes mediating lymphocyte activation, cytokine signaling, and immune regulation. Synovial atlas and spatial transcriptomic studies have further connected genetic susceptibility to immune-cell states and organized inflammatory niches, linking inherited risk to the chronic arthritis-sustaining tissue environment. Summary Genetic and multiomic studies support a shift toward biologically informed disease classification, evinced in the proposed Pediatric Rheumatology International Trials Organization framework, and provide a foundation for subtype-aware risk stratification and therapeutic target discovery in JIA. The association of genetic variations with prognosis warrants future investigation.
PURPOSE OF REVIEW:Nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line therapy for axial spondyloarthritis (axSpA), improving pain, function, and disease activity. This review evaluates evidence for NSAID efficacy, potential disease modification, and safety considerations in patients with axSpA, particularly those with inflammatory bowel disease (IBD) or elevated cardiovascular risk. RECENT FINDINGS:Evidence for NSAID-mediated disease modification remains inconsistent. In patients with IBD, contemporary data suggest variable risk of disease exacerbation depending on NSAID selectivity and exposure patterns. Established gastrointestinal toxicities persist outside the IBD context, though risk-mitigation strategies are available. While general-population studies demonstrate increased cardiovascular risk with certain NSAIDs, emerging axSpA-specific observational data suggest a smaller excess risk of major adverse cardiovascular events, potentially reflecting the counterbalancing effect of inflammation control. Pharmacogenomic data increasingly support CYP2C9 variation as a determinant of NSAID exposure and toxicity. SUMMARY:NSAIDs remain foundational in axSpA management, but long-term use requires individualized assessment of gastrointestinal, cardiovascular, and IBD-related risks. Pharmacogenomic considerations may further refine patient selection and dosing strategies.
PURPOSE OF REVIEW:Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized, posing significant challenges to effective management. This review summarizes current United States Food and Drug Administration -approved therapies and management guidelines of the American College of Rheumatology. RECENT FINDINGS:Contemporary SLE management is guided by organ systems involvement and disease severity. Discoveries of molecular mechanisms underlying disease pathogenesis have driven the development of targeted biologic therapies, including natural and engineered antibodies, chimeric antigen receptor-guided cell therapies, and T-cell engagers, transforming the therapeutic landscape of lupus. In addition to traditional B-cell and plasma cell surface targets, emerging molecular targets include transmembrane signaling molecules such as CD40L and intracellular organelles such as endosomes and mitochondria. SUMMARY:While antibody and cell-based biologic therapies target pathogenesis-driving molecules, they suppress key immune pathways and thus infection remains a leading cause of morbidity and mortality. Accordingly, this review also addresses nonpharmacologic strategies - such as dietary modifications - that may confer therapeutic benefit without increasing susceptibility to infection. With a rapidly expanding portfolio of mechanistically driven clinical trials, the future of SLE management appears increasingly promising.
PURPOSE OF REVIEW:Psoriatic arthritis (PsA) outcomes have improved, yet many patients do not achieve sustained control, and a meaningful proportion develop difficult-to-treat disease. This review summarizes relevant new therapies in the PsA pipeline and highlights emerging strategies likely to shape near-term care, including interception, metabolic targeting, combination/sequence approaches, and early precision-medicine efforts. RECENT FINDINGS:Pipeline innovation clusters in three areas: interleukin (IL)-17 pathway advances, including dual IL-17A/IL-17F blockade and engineered formats (nanobodies/small scaffolds) that may alter tissue pharmacology; selective tyrosine kinase 2 inhibition (allosteric and highly selective catalytic-site inhibitors) expanding oral options; and oral IL-23 receptor antagonism progressing from strong psoriasis efficacy into phase 3 PsA development. Beyond new molecules, strategies are evolving. Exploratory evidence supports further evaluation of dual-targeted approaches for highly refractory PsA, while metabolic targeting with incretin-based therapy is being tested as an adjunct to immunomodulation to address obesity-linked inflammatory amplification and cardiometabolic risk. EULAR transition frameworks, prodromal musculoskeletal symptoms and imaging abnormalities support a plausible interception window in at risk psoriasis. SUMMARY:The next wave in PsA will be defined by both new agents and smarter strategies: more oral/selective therapies, testing interception in risk-enriched psoriasis, integrating metabolic approaches, and evaluating optimized sequencing and selected combination therapy while precision tools mature.
