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Explore the pathobiology of PsA

PsA= psoriatic arthritis.

The chronic inflammatory pathogenesis of PsA is complex and multifactorial

…involving multiple adaptive and innate immune cells and pro-inflammatory cytokines.1

The pathologic processes leading to PsA

The pathologic processes leading to PsA are not yet completely understood. However, recent studies have revealed that there is an intricate interplay of cytokine pathways and cells responsible for initiating and maintaining the chronic inflammation associated with its various clinical manifestations.1-4 Pathology in PsA often differs by clinical manifestation.1,2

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The role of cytokines in driving inflammation

The latest evidence shows that several different cytokines, including IL-17A, IL-17F, TNF, IL-12, IL-23 as well as direct or indirect involvement of the JAK/STAT pathway and PDE4, have distinct roles in driving inflammation in different tissues in SpA. Although the relative contributions of each is complex, important distinctions are emerging about which cytokines contribute to the various clinical manifestations and SpA disease phenotypes.4,5,6,7-9

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JAK=Janus kinase.

IL-17 family

The IL-17 cytokine family consists of six members that include IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.10,14

IL-17A and IL-17F share ~50% structural homology and have a similar pro-inflammatory function, signaling via the same receptor complex.13 Studies have shown that IL-17A and IL-17F exist as both homo- and heterodimers, meaning three cytokines exist (IL-17A/A, IL-7A/F, and IL-17F/F), all of which have been shown to contribute to inflammation in PsA.13,15

There are 5 members of the IL-17 receptor family. Two IL-17 receptors (IL-17RC and IL-17RA) are thought to act in concert to mediate signaling by IL-17A/A, IL-17F/F and IL-17A/F.12,14

Studies have shown that IL-17A and IL-17F cooperate with other mediators of inflammation, such as TNF, to amplify inflammatory responses.13 The contribution of IL-17A and IL-17F to pathological bone formation has been shown in a model of osteogenic differentiation, indicating the importance of IL-17A and IL-17F in bone pathogenesis.11

In PsA, skin lesions and inflamed synovia have similar patterns of IL-17A and IL-17F expression and upregulation, and although IL-17A is more potent than IL-17F, the protein level of IL-17F is ~30 times higher than that of IL-17A.16

The IL-17A and IL-17F Receptor Complex

Evidence suggests IL-17 is regulated by both IL-23-dependent and IL-23-independent pathways

Role of the IL-17 family and IL-23 in PsA

The IL-23–IL-17 axis process

IL-23 is responsible for promoting the expansion and survival of Th17 subsets, including the production of IL-17A and IL-17F from Th17 cells. This process is commonly referred to as the IL-23–IL-17 axis, and has been implicated in several inflammatory diseases, including PsA.14,15,20,21

Recent evidence suggests that the IL-23–IL-17 axis is not a linear “cascade” in PsA.22 IL-23 and IL-17 display partially overlapping but distinct biology and pathobiology.22 Although the IL-23–IL-17 adaptive immunity pathway is still thought to be a key driver of inflammation in PsA, cells of the innate immune system can also produce IL-17A and IL-17F independently of IL-23.2o,22The adaptive cell signaling pathway in PsA is largely driven by IL-23.21,23


IL-23 is an important upstream regulator of IL-17 in PsA14,22

IL-23 is a member of the IL-12 superfamily and is a heterodimer consisting of both a p40 and p19 chain.14,21 It is an important cytokine involved in the pathogenesis of several immune mediated inflammatory diseases, including psoriasis, PsA, axSpA and IBD.21 However, its interaction with different cells and downstream cytokine pathways may be different across diseases.21

There is some evidence to show that IL-23 can migrate from barrier sites such as the gut and skin, where dendritic cells have been activated, and travel to sites of disease pathogenesis in PsA, although this needs to be further explored.21

A key pro-inflammatory role of IL-23 is stimulation of Th17 cells to produce IL-17, IL-22, and TNF, which subsequently leads to downstream inflammation, bone formation and bone erosion.6,14,21 However, recent evidence has shown that IL-23 may also have a direct role in signaling in PsA.21,23 The dependency on IL-23 in driving pathogenic signaling appears to be different across different inflammatory diseases, and direct IL-23 signaling may have a more prominent role in PsA versus axSpA.21,23 This could be related to the different sites of cytokine expression. For example, expression of cytokines linked to the IL-23–IL-17 axis have been shown to be continuously expressed in diseased skin, but there is variability in its expression in the joints.6,21,23

IL-23 acts on numerous target cells via either an IL-17-dependent or an IL-17-independent mechanism, which both lead to the recruitment of inflammatory cells within the inflamed tissue.23

  • IL-17-dependent pathway: IL-23 stimulates Th17 cells via IL-23R and induces the release of molecules such as IL-17 or IL-22. By binding their cognate receptors IL-17R or IL-22R, eventually activate the “effector cells” keratinocytes, B cells, osteoclast precursors, macrophages and fibroblast-like synoviocytes.23
  • IL-17-independent pathway: The same subset of target cells can be directly challenged by IL-23 in an IL-17-independent manner, via IL-23R.23

IBD=inflammatory bowel disease.

The role of IL-23 in the pathobiology of axSpA is unclear, as clinical trials of biologics blocking this cytokine have failed.

IL-23 in PsA


Role of IL-12 in PsA

IL-12 is a pro-inflammatory cytokine composed of two subunits (p35 and p40), resulting in an active heterodimer p70.26 Produced by innate immune cells, it induces naïve T cell differentiation into IFN-gamma producing Th1 cells and prevents T cell exhaustion.26,27

IL-12 and IL-23 activity is tightly linked. Both of these inflammatory cytokines share the p40 subunit and a receptor chain (IL-12R1), which controls the distinct IL-12 and IL-23 signaling pathways.26

In PsA, over-activation of IL-12 and IL-23 increases the number of circulating Th1 and Th17 cells. This activates signaling from cytokines and proteins, which can lead to the development of psoriatic plaques.28,29 Susceptibility to PsA has been linked to single nucleotide polymorphisms in the IL-12b gene, which encodes the ligand subunit of IL-23R.26

IL-12 Pathway in PsA


TNF signaling plays a role in the pathogenic processes of PsA

The TNF superfamily (TNFSF) consists of 19 structurally related pleotropic cytokines.31,32 TNFSF proteins are important drivers of inflammation and play roles in the mediation of apoptosis, angiogenesis, cell proliferation, and other critical biologic functions.31

TNF-α exists in transmembrane and soluble forms and is mostly created by T-cells, NK cells, and macrophages.33 TNF-α cellular signaling occurs through two receptors TNF-receptor1 (TNFR1) and TNFR2, which have differing mechanisms of cellular signaling, ligand affinity, and patterns of expression.34,35 TNFR1 is the dominant receptor involved in inflammatory and innate immune responses.36

The overexpression of TNF drives a pathogenic pro-inflammatory state thought to be mediated by Th1 and Th17 cells.32 Elevated levels of TNF can be found in the synovium and other locations known for skin manifestations, as well as entheses, joint and spine involvement.30,37 Activated dendritic cells secrete TNF-α and other pro-inflammatory cytokines (e.g., IL-6, IL-12, IL-23) which leads to increased T-cell signaling and Th cell differentiation.32 Th1 and Th17 cells upregulate pro-synovial inflammatory cytokine production, which leads to production of osteoclasts, bone/cartilage erosion, and abnormal bone formation.38

In PsA, TNF can synergize with IL-17 and IL-23 pathways:

  • IL-23 stimulates Th17 cell differentiation, which leads to the production of cytokines such as IL-17, and causes further upregulation of TNF35
  • IL-17 combines with TNF, leading to stronger pro-inflammatory cytokine expression than either cytokine can enact alone39
TNF Signaling in PsA


JAK-STAT pathways may play an important role in the pathogenesis of PsA

JAK molecules are a group of intracellular tyrosine kinases, comprising four isoforms: JAK1, JAK2, JAK3 and tyrosine kinase (TYK) 2.41 These groups are coupled to signal transducer and activator of transcription (STAT) molecules.9 Many immune cells and effector molecules use different combinations of JAK and STAT molecules to convert signals from the cell surface to the nucleus, where they activate transcription and induce gene activation. This downstream gene activation has a role in regulating different biological processes, including the activation of pathological pathways in PsA.9,40,42 Many SpA-associated cytokines are mediated either directly or indirectly via JAK-STAT pathways.40

JAK=Janus kinase; TYK=tyrosine kinase.

JAK-STAT Pathways in PsA


A cellular mediator of the inflammatory response leading to PsA

PDE4 is a member of the phosphodiesterase enzyme family, which catalyze the degradation of intracellular second messengers, including cAMP and cGMP, and are involved in a diverse range of inflammatory mechanisms.4

In PsA, cAMP regulation is impaired, which is thought to be driven by increases in PDE4, which catalyze the hydrolysis of cAMP to AMP.4,43 Increases in AMP levels can, in turn, lead to an inflammatory cytokine imbalance (i.e., increases in inflammatory cytokine expression of TNF, IL-17, IFN, IL-23, and reductions in regulatory cytokines, such as IL-10), which drive inflammatory pathways leading to pathogenic bone formation and erosion.4,44



Take your seats in the Animated Science Theatre

Uncover the mechanisms driving PsA, including the role of IL-17A and IL-17F

Discover how several different cytokines have distinct roles in driving inflammation in axSpA

Gaze upon the axSpA Gallery of Cytokines


Immune dysregulation

Explore how cytokine dysregulation drives inflammation in PsA.

Continue PsA tour

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