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cellular differences.5

Angiogenesis, the

neoformation of vessels required for leukocytes from peripheral blood to reach the joint and provide nutrients and oxygen for synovial growth, is greatly increased in PsA joints compared with RA synovitis6

(Figure 1). Angiogenesis is also characteristic of psoriatic plaques. Tumour necrosis factor (TNF) inhibitor therapy significantly reduces angiogenic factor expression and neovessel density in the synovium and skin of PsA patients with a good therapeutic response.7,8 Although adaptive immune system cells abound in the ST of PsA, the pathogenic relevance of innate immune cells has been demonstrated. CD163+ macrophages, CD15+ neutrophils and mast cells are over-represented in ST of PsA compared with RA,5,9

and CD163+

macrophages and neutrophils are significantly reduced after effective therapy, highlighting their roles as biomarkers of disease activity.10

Figure 1: Angiogenesis in PsA. A) Arthroscopic view of the synovial membrane, from the knee joint (femur is seen below) of a patient with PsA, with villous hypertrophy standing out the typical tortuous, bushy vessels. B) Immunostaining for anti-CD31 monoclonal antibody (endothelial cell marker) of a section from the same synovial membrane showing the high increase in synovial vessels characteristic of angiogenesis in PsA.

Mast cells

and neutrophils are the main producers of IL-17 in ST in PsA and skin psoriasis9,11 (Figure 2). Between pro-inflammatory cytokines, TNF-alpha plays a crucial role in synovial inflammation and RANKL- dependent osteoclastogenesis in PsA.12

Insights from experimental models and studies in patients

Two experimental studies support the crucial role of the IL-17/IL-23 axis in the development of PsA features in animal models. IL-17A gene transfer to BCL6 mice induced arthritis changes and psoriasis-like skin hyperplasia.13

Figure 2: Expression of IL-17 in PsA synovium. A) Immunostaining with anti-IL-17 polyclonal antibody showing cells expressing IL-17 (stained in brown, arrow) around or distant the follicular aggregate, which contain mainly T cells. B) Immunostaining with anti-CD117 (c-kit, mast cell marker) showing the disposition of mast cells (stained in brown, arrow) around or distant to follicular aggregate.

disease activity and power Doppler signal, and were increased in patients with erosive disease.18

In both of these studies, Another

study identified CD3+CD4-CD8- T cells resident in the enthesis that, when stimulated with IL-23, produced TNF alpha, IL-17A, and IL-22, leading to the development of enthesitis, arthritis, spondylitis, aortitis and psoriasis-like skin lesions. IL-17A and TNF-alpha were responsible for inflammation and bone erosion whereas IL-22 was associated with bone neoformation.14

Recent studies suggest Th17 cells are critical effectors in the pathogenesis of PsO and PsA.15

Th17 cell-related cytokines

In another study, CD8+IL-17+ T cells were enriched in the synovial fluid of PsA but not RA joints. These cells correlated with acute phase reactants,

(IL-17, IL-22 and IL-23) are increased in psoriatic plaques and are detected in the synovial tissue and fluid of PsA patients.16 CD4+ IL-17+ T cells are expanded in peripheral blood and synovial fluid of PsA patients and correlate with disease activity.17

cells were isolated from blood or synovial fluid and activated in culture, which could explain the lack of agreement on the subtype of IL-17-producing T cell due to the application of different cell activation protocols.

Insights from clinical trials of targeted therapies

The results of proof-of-concept clinical trials of targeted therapies, the ultimate test to confirm the pathogenic relevance of a specific cellular or molecular target, are crucial in delineating an evidence- based pathophysiology of PsA. Several pivotal clinical trials with the available TNF inhibitors have shown efficacy for all the manifestations of PsA and inhibition of bone damage, thus confirming the role of TNF-alpha in PsA.19 The role of the IL-17/IL-23 cytokine axis was tested using MoA anti-p40 (ustekinumab), which blocks IL-12 and IL-23 and, consequently, Th1 and Th17 responses. Globally, ustekinumab showed efficacy on all musculoskeletal manifestations of PsA and the inhibition

of radiographic progression. However, the kinetics of the ACR response was delayed compared with the effects of TNF inhibitors.20

Large Phase III trials with

IL-17 inhibitors are ongoing, but the Phase II results of anti-IL-17 A MoA (sekunimumab) and anti-IL-17RA (brodalumumab) show clinical efficacy in PsA.21

Awaiting more conclusive

information, it seems that the IL-17/IL-23 axis plays a pathogenic role in PsA, although their effects seem more impressive in skin than in the musculoskeletal manifestations. Several Phase III trials have demonstrated the efficacy of a phosphodiesterase-4 (PDE-4) inhibitor (apremilast) on all manifestations of PsA, revealing new pathogenic pathways in this disease.22


inhibition promotes an increase in intracellular cAMP, which is crucial to reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines.23


The clinical heterogeneity of PsA reflects its complex physiopathology. Although class I HLA (HLA-C*06, HLA-B*) has been confirmed as the main area of


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