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Psoriatic Arthritis

Disease Pathophysiology Research Report

2026-01-31
Falcon MONDO:0011849 Model: Edison Scientific Literature 17 citations

Disease Pathophysiology Research Report

Target Disease - Disease Name: Psoriatic Arthritis (PsA) - Category: Complex

Pathophysiology description (narrative synthesis) Psoriatic arthritis is an immune‑mediated inflammatory disease in which enthesis‑resident and synovial immune–stromal circuits converge, driven principally by the IL‑23/IL‑17 axis and amplified by TNF and other cytokines, producing synovitis, enthesitis, dactylitis, osteitis, and a paradoxical combination of bone erosion and new bone formation. Contemporary models emphasize the synovio‑entheseal complex: mechanical microdamage at entheses triggers innate and innate‑like lymphoid responses that can spill into adjacent synovium and nail–DIP units; imaging and anatomical studies support enthesitis as a primary lesion that may predate clinical arthritis and explain nail–DIP co‑localization. Therapeutically validated pathways (IL‑17/IL‑23, TNF, and JAK/TYK2) mirror these mechanisms. Genetic susceptibility implicates HLA class I and antigen processing/presentation (HLA‑B27, ERAP1/2) alongside IL‑23/Th17 and interferon/JAK signaling genes (IL23R, IL12B, TYK2, TRAF3IP2), aligning with observed cell‑type programs (Th17/Tc17, γδ T cells, MAIT, ILC3, dendritic cells including pDCs) and tissue remodeling pathways (RANKL‑osteoclastogenesis; Wnt inhibitors DKK1/SOST shaping new bone). (mcgonagle2024grappa2023debate pages 1-2, dilek2025immuneresponseand pages 1-2, raychaudhuri2024jakstatsignalingand pages 1-3, allardchamard2025exploringthegenetic pages 7-9, dilek2025immuneresponseand pages 10-11)

Direct quotes supporting key concepts - “The enthesitis hypothesis posits that enthesitis is a primary lesion and that inflammation at the enthesis initiates the musculoskeletal symptoms of psoriatic arthritis (PsA) and spondyloarthropathies (SpA).” URL/Date: The Journal of Rheumatology, Aug 2024, doi:10.3899/jrheum.2024-0593 (mcgonagle2024grappa2023debate pages 1-2) - JAK/STAT is emphasized as “a key regulatory role” for cytokines relevant to SpA pathogenesis with therapeutic implications for JAK/TYK2 inhibition. URL/Date: Current Rheumatology Reports, Mar 2024, doi:10.1007/s11926-024-01144-x (raychaudhuri2024jakstatsignalingand pages 1-3)

1) Core pathophysiology - Primary mechanisms: Enthesis‑driven inflammation within the synovio‑entheseal complex; cytokine circuits dominated by IL‑23→STAT3/TYK2/JAK2 signaling sustaining Th17/innate‑like IL‑17 production; IL‑17/TNF acting on stromal cells to induce chemokines/MMPs and maintain synovitis; bone pathways coupling inflammation to osteoclastogenesis (RANKL) and osteoproliferation (Wnt/DKK1/SOST axis). (mcgonagle2024grappa2023debate pages 1-2, raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - Dysregulated molecular pathways: IL‑23/IL‑17 and TNF signaling; JAK/STAT (notably TYK2/JAK2 with IL‑23); interferon/type I IFN networks (pDC‑linked); Wnt antagonism via DKK1/SOST; RANK–RANKL–OPG axis. (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - Affected cellular processes: Cytokine receptor signaling; NF‑κB activation; matrix remodeling (MMP induction); osteoclast differentiation and osteoblast/Wnt regulation; antigen processing/presentation (HLA class I–ERAP). (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2, allardchamard2025exploringthegenetic pages 7-9)

2) Key molecular players - Genes/Proteins (HGNC): HLA‑B27; ERAP1/ERAP2; IL23R; IL12B; TYK2; TRAF3IP2 (Act1); DKK1; RANKL/TNFSF11; SOST. Evidence: recent genetics aggregations and mechanistic reviews place IL‑23/Th17 and antigen‑processing genes among top signals; TRAF3IP2 encodes the IL‑17 signaling adaptor Act1; bone regulators DKK1/SOST vary with inflammatory signaling. URLs/Years: J Rheumatol 2024/2026; Arch Rheumatol 2025; Rheumatol Int 2023. (allardchamard2025exploringthegenetic pages 7-9, dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - Chemical entities: Small‑molecule JAK inhibitors and selective TYK2 inhibitors modulate the implicated cytokine circuits; anti‑IL‑17A/F, anti‑IL‑23p19, anti‑IL‑12/23p40, and anti‑TNF biologics validate the central axes. Current reviews outline mechanisms and therapeutic classes. (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2) - Cell Types (CL): Th17/Tc17; γδ T cells; MAIT; ILC3; dendritic cells (including pDCs); synovial fibroblasts; osteoclasts/osteoblasts; macrophages, neutrophils, mast cells. These cells produce or respond to IL‑23/IL‑17/TNF, coordinate innate‑adaptive crosstalk, and drive tissue changes. (dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11, raychaudhuri2024jakstatsignalingand pages 1-3) - Anatomical locations (UBERON): Enthesis; synovium; nail–DIP unit; sacroiliac joint/spine. The nail–DIP anatomical linkage explains frequent co‑localization of nail disease and DIP arthritis in PsA. (mcgonagle2024grappa2023debate pages 1-2)

3) Biological processes (GO terms; disrupted in PsA) - IL‑23 signaling and Th17 differentiation/effector function (GO:0032622; GO:0072538); IL‑17‑mediated signaling (GO:0032612); JAK/STAT cascade (GO:0007259); TNF signaling via NF‑κB (GO:0033209); type I interferon signaling pathway (GO:0060337); antigen processing and presentation of endogenous peptide antigen via MHC class I (GO:0002474); osteoclast differentiation (GO:0030316); Wnt signaling pathway and negative regulation by DKK1/SOST (GO:0016055; GO:0030178). Mechanistic and therapy literature support these as central. (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2, allardchamard2025exploringthegenetic pages 7-9)

4) Cellular components - Plasma membrane cytokine receptors (IL‑23R, IL‑17R, TNFR); cytoplasmic JAK/TYK/STAT signalosomes; nucleus (STAT‑dependent transcription); endoplasmic reticulum (ERAP1/2 peptide trimming); extracellular space (cytokines; DKK1/SOST; RANKL). (raychaudhuri2024jakstatsignalingand pages 1-3, allardchamard2025exploringthegenetic pages 7-9)

5) Disease progression (sequence of events) - Initiation: Genetic susceptibility (HLA‑B27; ERAP1/2; IL23R, IL12B, TYK2; TRAF3IP2) primes immune circuits. Mechanical microdamage at entheses and local innate sensing recruit myeloid/DC populations and innate‑like lymphocytes. (allardchamard2025exploringthegenetic pages 7-9, mcgonagle2024grappa2023debate pages 1-2) - Propagation: IL‑23 from myeloid cells sustains Th17/innate‑like IL‑17 producers (γδ T, MAIT, ILC3). IL‑17/TNF drive stromal activation (synovial fibroblasts), chemokine/MMP production, and recruitment of neutrophils/macrophages, culminating in synovitis and enthesitis. (dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - Structural change: RANKL‑driven osteoclastogenesis (erosion) occurs alongside Wnt pathway modulation by DKK1/SOST, enabling paradoxical osteoproliferation (enthesophytes, periosteal new bone). (dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - Spread and phenotypes: Nail unit inflammation spreads to the adjacent DIP enthesis/synovium; axial structures (sacroiliac/spine entheses) may be involved in axPsA. (mcgonagle2024grappa2023debate pages 1-2)

6) Phenotypic manifestations (with links to mechanisms) - Enthesitis (HP:0100715): Arises at mechanically stressed insertions, dominated by IL‑23/IL‑17 and innate‑like lymphocytes; central in PsA. (mcgonagle2024grappa2023debate pages 1-2, dilek2025immuneresponseand pages 10-11) - Dactylitis (HP:0005905): Represents a digit‑wide enthesitis/tenosynovitis composite; micro‑enthesis inflammation along pulleys contributes. (dilek2025immuneresponseand pages 10-11) - Synovitis (HP:0004315): Cytokine‑driven stromal and leukocyte activation within synovial tissue. (dilek2025immuneresponseand pages 1-2) - Axial disease/sacroiliitis (HP:0002826): Inflammation at spinal/sacroiliac entheses; response patterns reflect IL‑17/JAK axes. (mcgonagle2024grappa2023debate pages 1-2, raychaudhuri2024jakstatsignalingand pages 1-3) - Bone remodeling (erosion and new bone): RANKL induction and Wnt antagonism integrate inflammatory signaling with structural change. (dilek2025immuneresponseand pages 1-2)

7) Recent developments and latest research (2023–2024 priority) - Enthesitis‑first paradigm and synovio‑entheseal complex reinforced with clinical imaging and anatomical evidence; nail–DIP linkage and cytokine validation (IL‑17/IL‑23/TNF) emphasized in the 2024 GRAPPA debate summary (The Journal of Rheumatology, Aug 2024; DOI above). (mcgonagle2024grappa2023debate pages 1-2) - JAK/STAT and TYK2: 2024 reviews synthesize how IL‑23 and other cytokines signal through JAK2/TYK2/STAT3, aligning with clinical success of JAK/TYK2 inhibitors and next‑generation intracellular targets. (raychaudhuri2024jakstatsignalingand pages 1-3) - Cytokine network integration: Systematic review (2025, includes studies through 2024) details IL‑23/IL‑17, TNF, and their roles in osteoclastogenesis and new bone formation via DKK1/Wnt. (dilek2025immuneresponseand pages 1-2) - Bone remodeling biomarkers: 2023 review highlights variability of circulating DKK1 in PsA and calls for standardized methodologies—underscoring complexity of the inflammatory‑osteogenic axis. (dilek2025immuneresponseand pages 10-11) - Genetics (synthesis through 2025/2026): Aggregated genomic data implicate IL23R, IL12B, TYK2, TRAF3IP2, ERAP1/2, and HLA class I; enrichment of innate, antigen presentation, Th17, and interferon pathways highlight disease‑relevant biology and drug targetability. (allardchamard2025exploringthegenetic pages 7-9)

8) Current applications and real‑world implementations - Biologics targeting IL‑17A/F, IL‑23p19, IL‑12/23p40, and TNF are standard of care and mechanistically validate the dominant cytokine axes; JAK1‑selective and TYK2‑targeted therapies offer oral options that modulate IL‑23 family and interferon signaling. (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2) - Clinical anatomy–guided care: Recognition of nail–DIP–enthesis linkage supports targeted assessment and therapeutic choice in DIP arthritis with nail psoriasis. (mcgonagle2024grappa2023debate pages 1-2) - Bone outcomes: Understanding of DKK1/SOST/Wnt balance informs interpretation of imaging and bone outcomes under anti‑TNF or anti‑IL‑17/23 therapy. (dilek2025immuneresponseand pages 10-11, dilek2025immuneresponseand pages 1-2)

9) Expert opinions and analysis (authoritative sources) - GRAPPA 2023 debate (published 2024) synthesizes two decades of enthesitis research, concluding that enthesis anatomy and imaging data strongly support a primary enthesitis model with cytokine drivers that are therapeutically tractable. (mcgonagle2024grappa2023debate pages 1-2) - Mechanistic rheumatology reviews (2024) argue for JAK/STAT as a unifying intracellular hub across multiple PsA‑relevant cytokines, motivating selective JAK/TYK2 inhibitor development to balance efficacy and safety. (raychaudhuri2024jakstatsignalingand pages 1-3)

10) Relevant statistics and data - Genetics synthesis: Non‑MHC variants account for a substantial proportion of psoriatic disease risk, with multiple protein‑altering signals in IL23R/TRAF3IP2/TYK2/IL12B and others; enrichment across innate, antigen presentation, Th17, and interferon pathways (quantitative counts provided in source review). (allardchamard2025exploringthegenetic pages 7-9) - Bone marker variability: Among 8 original studies, DKK1 serum levels in PsA were reported higher in 4, comparable in 1, and lower in 2 (reviewed up to Aug 2023), underscoring heterogeneity of bone pathway readouts. (dilek2025immuneresponseand pages 10-11)

Ontology‑ready annotations and evidence table |Entity Type|Name (ontology)|Role / Mechanism in PsA (1–2 sentences)|Phenotype link (HP)|Evidence|Source DOI / URL| |---|---|---|---|---|---| |Gene / Protein|HLA-B27 (HGNC:HLA-B)|MHC class I allele associated with PsA susceptibility and axial/enthesitic phenotypes; influences peptide presentation and interacts with ERAP-mediated peptide trimming to modulate inflammation.|Enthesitis; axial disease (HP:0002826)| (allardchamard2025exploringthegenetic pages 7-9, mcgonagle2024grappa2023debate pages 1-2)|doi:10.3899/jrheum.2025-0273; https://doi.org/10.3899/jrheum.2024-0593| |Gene / Protein|ERAP1/ERAP2 (HGNC:ERAP1 / ERAP2)|Endoplasmic reticulum aminopeptidases that trim peptides for HLA class I presentation; genetic variants modify antigen repertoire and PsA risk.|Immune dysregulation leading to arthritis| (allardchamard2025exploringthegenetic pages 7-9, gupta2025genomewidemetaanalysisand pages 21-24)|doi:10.3899/jrheum.2025-0273; https://doi.org/10.1101/2025.08.26.25334362| |Gene / Protein|IL23R (HGNC:IL23R)|Receptor for IL-23 that stabilizes/expands Th17 cells via STAT3 signaling, driving IL-17 production and tissue inflammation.|Synovitis, enthesitis, skin lesions| (allardchamard2025exploringthegenetic pages 7-9, dilek2025immuneresponseand pages 1-2)|doi:10.3899/jrheum.2025-0273; doi:10.46497/archrheumatol.2025.10934| |Gene / Protein|IL12B (HGNC:IL12B)|Encodes p40 subunit shared by IL-12 and IL-23; genetic variation affects IL-23–Th17 axis activity and therapeutic targeting (anti-p40 biologics).|Psoriasis with risk of PsA progression| (allardchamard2025exploringthegenetic pages 7-9, gupta2025genomewidemetaanalysisand pages 21-24)|doi:10.3899/jrheum.2025-0273; https://doi.org/10.1101/2025.08.26.25334362| |Gene / Protein|TYK2 (HGNC:TYK2)|Janus-family kinase involved in IL-23/Type I IFN signaling; genetic/functional modulation influences Th17/IFN pathways and is a therapeutic target (TYK2 inhibitors).|Modulates systemic inflammation and IL-23–driven pathology| (allardchamard2025exploringthegenetic pages 7-9, raychaudhuri2024jakstatsignalingand pages 1-3)|doi:10.3899/jrheum.2025-0273; doi:10.1007/s11926-024-01144-x| |Gene / Protein|TRAF3IP2 (HGNC:TRAF3IP2)|Adapter protein (Act1) in IL-17 receptor signaling; variants associate with PsA and amplify IL-17–mediated inflammatory cascades in skin and joint tissues.|Enhanced IL-17 responses; synovitis| (allardchamard2025exploringthegenetic pages 7-9)|doi:10.3899/jrheum.2025-0273| |Gene / Protein|DKK1 (HGNC:DKK1)|Wnt pathway antagonist regulating bone formation; altered DKK1 levels in PsA link inflammatory cytokines (TNF/IL-17) to dysregulated osteogenesis and erosion/new bone formation.|Bone remodeling imbalance; osteoproliferation| (dilek2025immuneresponseand pages 1-2)|doi:10.46497/archrheumatol.2025.10934| |Gene / Protein|RANKL / TNFSF11 (HGNC:TNFSF11)|Key osteoclast differentiation factor induced by inflammatory cytokines (IL-17, TNF), mediating bone resorption in erosive PsA.|Bone erosion (HP:0003009)| (dilek2025immuneresponseand pages 1-2)|doi:10.46497/archrheumatol.2025.10934| |Gene / Protein|SOST (HGNC:SOST)|Sclerostin, Wnt pathway inhibitor produced by osteocytes; inflammation can alter SOST/DKK1 balance contributing to paradoxical bone loss and formation in SpA/PsA.|Altered bone density/formation| (dilek2025immuneresponseand pages 1-2)|doi:10.46497/archrheumatol.2025.10934| |Cell Type|Th17 cell (CL:Th17)|Adaptive CD4+ subset driven by IL-23/STAT3/RORγt that secretes IL-17A/F and IL-22, promoting synovial inflammation, MMP production, and osteoclastogenesis.|Synovitis, enthesitis, bone damage| (dilek2025immuneresponseand pages 1-2, bonomo2025recentadvancesin pages 5-7)|doi:10.46497/archrheumatol.2025.10934; https://doi.org/10.3390/nu17081323| |Cell Type|Innate-like IL-17 sources (γδ T cells, MAIT, ILC3) (CL:gamma-delta / CL:MAIT / CL:ILC3)|Tissue-resident or mucosa-derived cells that rapidly produce IL-17 in response to IL-23/IL-1β and mechanical triggers, linking mucosal/gut signals to joint inflammation.|Rapid local IL-17 release; enthesitis/dactylitis| (dilek2025immuneresponseand pages 10-11, bonomo2025recentadvancesin pages 5-7)|doi:10.46497/archrheumatol.2025.10934; https://doi.org/10.3390/nu17081323| |Cell Type|Plasmacytoid dendritic cell (pDC) (CL:pDC)|Major source of type I IFNs; pDC activation and IFN signatures can modulate TNF/IL-23 axes and affect treatment responses and local immune priming.|IFN-associated inflammation; therapy-refractory signatures| (bonomo2025recentadvancesin pages 4-5, dilek2025immuneresponseand pages 1-2)|https://doi.org/10.3390/nu17081323; doi:10.46497/archrheumatol.2025.10934| |Cell Type|Synovial fibroblast (CL:synovial fibroblast)|Stromal effector cells that respond to IL-17/TNF by producing cytokines, chemokines and MMPs, sustaining synovial pannus, leukocyte recruitment and tissue destruction.|Chronic synovitis and cartilage damage| (bonomo2025recentadvancesin pages 4-5, dilek2025immuneresponseand pages 10-11)|https://doi.org/10.3390/nu17081323; doi:10.46497/archrheumatol.2025.10934| |Cell Type|Osteoclast / Osteoblast (CL:osteoclast / CL:osteoblast)|Osteoclasts (RANKL-driven) mediate bone erosion; osteoblasts and Wnt inhibitors (DKK1/SOST) control reparative/new bone formation, producing the mixed bone phenotype in PsA.|Bone erosion and osteoproliferation| (dilek2025immuneresponseand pages 1-2, bonomo2025recentadvancesin pages 5-7)|doi:10.46497/archrheumatol.2025.10934; https://doi.org/10.3390/nu17081323| |Cell Type|Innate myeloid cells (macrophage, neutrophil, mast cell)|Provide IL-1, TNF, IL-6 and extrafollicular IL-17 (e.g., from neutrophil NETs/mast cells), amplifying local inflammation and matrix degradation.|Synovitis, enthesitis, neutrophil-driven flares| (bonomo2025recentadvancesin pages 5-7, dilek2025immuneresponseand pages 1-2)|https://doi.org/10.3390/nu17081323; doi:10.46497/archrheumatol.2025.10934| |Anatomical Site|Enthesis (UBERON:enthesis)|Site of tendon/ligament insertion with specialized microanatomy; microdamage/mechanical stress triggers local innate immunity and IL-23/IL-17–mediated enthesitis that can extend to synovium (synovio-entheseal complex).|Enthesitis (HP:0100715), dactylitis (HP:0005905)| (mcgonagle2024grappa2023debate pages 1-2, dilek2025immuneresponseand pages 10-11)|doi:10.3899/jrheum.2024-0593; doi:10.46497/archrheumatol.2025.10934| |Anatomical Site|Synovium (UBERON:synovium)|Primary site of inflammatory pannus formation; cytokine-rich synovium contains infiltrating Th17/innate cells and activated fibroblasts driving joint symptoms.|Synovitis (HP:0004315)| (dilek2025immuneresponseand pages 10-11, bonomo2025recentadvancesin pages 4-5)|doi:10.46497/archrheumatol.2025.10934; https://doi.org/10.3390/nu17081323| |Anatomical Site|Nail–DIP unit (anatomical link)|Anatomical continuity between nail matrix and distal interphalangeal (DIP) enthesis explains frequent co-occurrence of nail disease and DIP joint involvement in PsA.|DIP arthritis; nail changes preceding PsA| (mcgonagle2024grappa2023debate pages 1-2, bonomo2025recentadvancesin pages 4-5)|doi:10.3899/jrheum.2024-0593; https://doi.org/10.3390/nu17081323| |Anatomical Site|Sacroiliac joint (UBERON:sacroiliac joint)|Axial manifestations of PsA (axial PsA) involve sacroiliac/spinal entheses and may show distinct genetics/therapy responses from AS.|Axial disease; sacroiliitis| (mcgonagle2024grappa2023debate pages 1-2, bonomo2025recentadvancesin pages 4-5)|doi:10.3899/jrheum.2024-0593; https://doi.org/10.3390/nu17081323| |Pathway / Process|IL-23 / IL-17 signaling (GO:0032622) & JAK/STAT (GO:0007259)|IL-23 stabilizes Th17 cells (STAT3/TYK2/JAK2-mediated); IL-17 acts on stromal cells to induce NF-κB/MMPs; JAK/STAT signaling integrates multiple cytokine inputs and is a therapeutic axis (JAK/TYK2 inhibitors).|Drives Th17-mediated synovitis, enthesitis; therapeutic target| (dilek2025immuneresponseand pages 1-2, raychaudhuri2024jakstatsignalingand pages 1-3, bonomo2025recentadvancesin pages 5-7)|doi:10.46497/archrheumatol.2025.10934; doi:10.1007/s11926-024-01144-x; https://doi.org/10.3390/nu17081323| |Chemical / Drug (Therapy)|JAK / TYK2 inhibition (e.g., JAKi, TYK2 inhibitors)|Small-molecule inhibitors that blunt JAK-mediated cytokine signaling (including IL-23/IL-12 family effects via TYK2) and reduce both skin and joint inflammation; emerging data support efficacy in PsA and enthesitis.|Therapeutic modulation of synovitis/enthesitis| (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2)|doi:10.1007/s11926-024-01144-x; doi:10.46497/archrheumatol.2025.10934|

Table: A compact ontology-ready table summarizing genes/proteins, cells, anatomical sites, pathways and therapies implicated in psoriatic arthritis pathophysiology, with concise mechanisms, phenotype links (HP terms) and evidence citations to the gathered sources for knowledge‑base integration.

Evidence items (with URLs/dates when available) - McGonagle D, Abacar K, Kirkham B. GRAPPA 2023 Debate: Is Psoriatic Disease Really a Primary Enthesitis… The Journal of Rheumatology. Aug 2024. doi:10.3899/jrheum.2024-0593 (mcgonagle2024grappa2023debate pages 1-2) - Raychaudhuri SP, Shah RJ, Banerjee S, Raychaudhuri SK. JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis… Current Rheumatology Reports. Mar 2024. doi:10.1007/s11926-024-01144-x (raychaudhuri2024jakstatsignalingand pages 1-3) - Dilek G, Unan MK, Nas K. Immune response and cytokine pathways in psoriatic arthritis: A systematic review. Archives of Rheumatology. Mar 2025. doi:10.46497/archrheumatol.2025.10934 (dilek2025immuneresponseand pages 1-2) (dilek2025immuneresponseand pages 10-11) - Biedroń G, et al. Serum concentration of DKK1 in psoriatic arthritis. Rheumatology International. Sep 2023. doi:10.1007/s00296-023-05452-w (dilek2025immuneresponseand pages 10-11) - Allard‑Chamard H, Rahman P. Exploring the genetic landscape of PsA: A narrative review. The Journal of Rheumatology. Aug 2026. doi:10.3899/jrheum.2025-0273 (genetics synthesis spanning up to 2025). (allardchamard2025exploringthegenetic pages 7-9) - Additional mechanistic overviews on microbiome/innate–adaptive crosstalk used cautiously (Nutrients 2025 narrative review) to contextualize IL‑23/JAK/STAT and cell‑type roles. Apr 2025. doi:10.3390/nu17081323 (bonomo2025recentadvancesin pages 5-7, bonomo2025recentadvancesin pages 4-5)

Gene/protein, cell, and phenotype annotations for knowledge base integration - HGNC: HLA‑B; ERAP1; ERAP2; IL23R; IL12B; TYK2; TRAF3IP2; DKK1; TNFSF11 (RANKL); SOST. (allardchamard2025exploringthegenetic pages 7-9, dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - CL: Th17 cell; γδ T cell; MAIT cell; ILC3; plasmacytoid dendritic cell; synovial fibroblast; osteoclast; osteoblast; macrophage; neutrophil; mast cell. (dilek2025immuneresponseand pages 1-2, dilek2025immuneresponseand pages 10-11) - UBERON: Enthesis; Synovium; Distal interphalangeal joint/nail unit; Sacroiliac joint. (mcgonagle2024grappa2023debate pages 1-2) - GO (selected): IL‑23 signaling/Th17 differentiation (GO:0032622/GO:0072538); IL‑17 signaling (GO:0032612); JAK/STAT (GO:0007259); TNF→NF‑κB (GO:0033209); type I IFN signaling (GO:0060337); antigen processing MHC I (GO:0002474); osteoclast differentiation (GO:0030316); Wnt signaling regulation (GO:0016055/GO:0030178). (raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 1-2, allardchamard2025exploringthegenetic pages 7-9) - HP: Enthesitis (HP:0100715); Dactylitis (HP:0005905); Synovitis (HP:0004315); Axial disease/sacroiliitis (HP:0002826); Bone erosion (HP:0003009). (mcgonagle2024grappa2023debate pages 1-2, dilek2025immuneresponseand pages 10-11, dilek2025immuneresponseand pages 1-2)

Conclusions PsA pathophysiology is best conceptualized as an enthesis‑initiated, cytokine‑amplified process integrated through JAK/STAT signal transduction and sculpted by genetic variation in antigen presentation and IL‑23/Th17 pathways. This framework explains clinical phenotypes (enthesitis, dactylitis, axial disease), nail–DIP co‑involvement, and bone remodeling paradoxes, and it underpins current targeted therapies (anti‑IL‑17/23/TNF; JAK/TYK2 inhibitors). Future refinement will benefit from standardized bone biomarker assessment (e.g., DKK1), deeper resolution of cell states across the synovio‑entheseal complex, and genetics‑informed patient stratification. (mcgonagle2024grappa2023debate pages 1-2, raychaudhuri2024jakstatsignalingand pages 1-3, dilek2025immuneresponseand pages 10-11, dilek2025immuneresponseand pages 1-2, allardchamard2025exploringthegenetic pages 7-9)

References

  1. (mcgonagle2024grappa2023debate pages 1-2): Dennis McGonagle, Kerem Abacar, and Bruce Kirkham. Grappa 2023 debate: is psoriatic disease really a primary enthesitis that drives joint synovitis? the enthesitis hypothesis 25 years on. The Journal of rheumatology, 51:101-105, Aug 2024. URL: https://doi.org/10.3899/jrheum.2024-0593, doi:10.3899/jrheum.2024-0593. This article has 5 citations.

  2. (raychaudhuri2024jakstatsignalingand pages 1-3): Siba P. Raychaudhuri, Ruchi J. Shah, Sneha Banerjee, and Smriti K. Raychaudhuri. Jak-stat signaling and beyond in the pathogenesis of spondyloarthritis and their clinical significance. Current Rheumatology Reports, 26:204-213, Mar 2024. URL: https://doi.org/10.1007/s11926-024-01144-x, doi:10.1007/s11926-024-01144-x. This article has 17 citations and is from a peer-reviewed journal.

  3. (dilek2025immuneresponseand pages 1-2): Gamze Dilek, Mehtap Kalcik Unan, and Kemal Nas. Immune response and cytokine pathways in psoriatic arthritis: a systematic review. Archives of Rheumatology, 40:144-156, Mar 2025. URL: https://doi.org/10.46497/archrheumatol.2025.10934, doi:10.46497/archrheumatol.2025.10934. This article has 6 citations.

  4. (dilek2025immuneresponseand pages 10-11): Gamze Dilek, Mehtap Kalcik Unan, and Kemal Nas. Immune response and cytokine pathways in psoriatic arthritis: a systematic review. Archives of Rheumatology, 40:144-156, Mar 2025. URL: https://doi.org/10.46497/archrheumatol.2025.10934, doi:10.46497/archrheumatol.2025.10934. This article has 6 citations.

  5. (allardchamard2025exploringthegenetic pages 7-9): Hugues Allard-Chamard and Proton Rahman. Exploring the genetic landscape of psoriatic arthritis: a narrative review of recent genomic studies. The Journal of rheumatology, Aug 2026. URL: https://doi.org/10.3899/jrheum.2025-0273, doi:10.3899/jrheum.2025-0273. This article has 0 citations.

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