ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis of psoriatic arthritis

Pathogenesis of psoriatic arthritis
Literature review current through: Jan 2024.
This topic last updated: Feb 01, 2022.

INTRODUCTION — The pathogenesis of psoriatic arthritis (PsA) is complex and likely to be closely related to the mechanisms that underlie psoriasis. Joint and bone changes have features of both spondyloarthritis and rheumatoid arthritis as well.

This topic reviews the pathogenesis of PsA. The clinical manifestations of PsA and the pathogenesis and risk factors for psoriasis are discussed separately. (See "Clinical manifestations and diagnosis of psoriatic arthritis" and "Pathophysiology of plaque psoriasis" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis' and "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Risk factors'.)

OVERVIEW — The etiologic events that underlie the development of psoriasis and psoriatic arthritis (PsA) are not well understood. Available evidence indicates that these disorders show great complexity and heterogeneity, and that genetic and environmental factors converge to trigger inflammatory events in multiple immune pathways [1-3]. The pathogenesis of psoriasis is described in detail separately. (See "Pathophysiology of plaque psoriasis" and "Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)

It is reasonable to assume, although not proven, that psoriasis skin and joint inflammation share pathogenetic origins. Support for this assumption is based upon overlapping genetic risk alleles, environmental triggers, and cytokine pathways; however, the resident cells that populate the skin and joint are considerably different, and cutaneous and musculoskeletal clinical activity are often divergent in individual patients. The majority of patients in two longitudinal United Kingdom cohorts developed psoriasis before PsA diagnosis (82.3 and 61.3 percent) or within the same calendar year (10.5 and 38 percent), and the average intervals between onset of psoriasis and PsA were eight and seven years [4]. Further support for key differences in aspects of skin and joint disease pathogenesis are findings that blockade of either interleukin (IL) 17 or IL-23 are remarkably effective as monotherapies in psoriasis but, while beneficial, are not as highly effective in PsA. (See "Treatment of psoriatic arthritis".)

GENETIC FACTORS

Heritability — Evidence from linkage, candidate gene, and genome-wide association studies (GWAS) support the concept that psoriatic arthritis (PsA) is a highly heritable disorder, facilitated by multiple genes that individually have low to modest effect size (table 1) [5].

Heritability, measured by "gammas" (risk in siblings versus risk in the general population), was reported to be considerably higher in PsA than in psoriasis [6,7], although data based upon a single-nucleotide polymorphism (SNP) analysis indicated that heritability was similar in the two disorders [8]. Data from another recognized measure of heritability, concordance in identical twins, are not available for PsA.

A major challenge when examining risk alleles in PsA is that most of the candidate loci in arthritis are also associated with psoriasis, and only a small number of alleles linked to joint disease [9-13]. The genetic factors important in psoriatic skin disease are discussed separately. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis", section on 'Genetic factors'.)

Risk alleles within the major histocompatibility complex — The discovery of the major histocompatibility complex (MHC) on chromosome 6 permitted further study of genetic factors in PsA; the strongest genetic associations with psoriatic disease are located in the class I MHC region (table 1). The cytotoxic response to pathogens is mediated by CD8 T cells, which selectively recognize antigens bound to MHC class I molecules. Defining risk of individual alleles, however, is complicated by the strong linkage disequilibrium in this location. (See "Human leukocyte antigens (HLA): A roadmap".)

Human leukocyte antigen (HLA) C*0602 is strongly associated with psoriasis, where this allele is found in patients with earlier onset of psoriasis, a longer interval between skin and joint disease, and less joint damage [14,15]. However, the association of HLA-C*0602 with PsA is much weaker than with psoriasis without arthritis and associated with a later onset of PsA in patients with psoriasis, and this allele, along with HLA-B*44, is associated with milder arthritis [16-18]. HLA-B*27 is also increased in PsA, along with B*0801 and B*3801 [18].

Notably, specific extended class I MHC haplotypes have been reported to be preferentially linked to specific disease phenotypes [17]. As examples, dactylitis was linked to the HLA-B*27:05-B*0801 and HLA-B*27:05-C*01:02 haplotypes, while enthesitis was associated with the HLA-B*27:05-C*01:02 haplotype. Additionally, the extended haplotype B*08:0101-C*07:01:01 was observed in patients with synovitis, joint deformity, and fusion [17]; and a subsequent study reported that risk for PsA may be driven by HLA-B amino acid position 45 (glutamic acid), which is critical for peptide binding and antigen presentation [19].

An association of PsA risk with tumor necrosis factor (TNF) alpha promoter polymorphisms [20,21], of progressive erosive disease with TNF-alpha polymorphisms [22], and of an earlier age of onset with TNF-alpha and TNF-beta polymorphisms has also been reported [22]. The polymorphisms were different in each of the associations.

Risk alleles outside the major histocompatibility complex — GWAS have identified risk alleles in patients with both psoriasis and PsA, including the genes for interleukin (IL) 12A, IL-12B, and IL-23 receptor (IL-23R); genes that regulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), including REL, TNIP1, NFKBIA, TRAF3IP2, and CARD14; genes involved in IL-23 signaling, including IL-23A, IL-23R, IL-12B; as well as other genes that regulate NF-kappaB; TNF-alpha-induced protein 3 (TNFAIP3)-interacting protein 1 (TNIP1); and two genes involved in the modulation of T helper 2 (TH2) immune responses, which encode IL-4 and IL-13.

HLA-C, IL-12B, and IL-23R were more significantly associated with psoriasis than PsA [23]. The risk allele, TNFAIP3 or Act1, an adaptor protein in the IL-17R complex, limits NF-kappaB-mediated immune responses, and two single REL nucleotide polymorphisms in this gene were associated with the response to anti-TNF agents in psoriasis and PsA patients [24]. A meta-analysis of GWAS on psoriasis, stratified for PsA, found an association of PsA with c-Rel, a member of the Rel/NF-kappaB family [25]. The mutation in Act1 is associated with increased production of IL-22, a cytokine linked to keratinocyte proliferation in the skin and to mesenchymal stem cell proliferation and osteogenic differentiation in the bone marrow [26].

Additional genes associated with PsA are located near or within the MHC region (MICA-TM, HLA-E, and SEEK1), genes related to interferon (IFN) and IL-23 signaling (IL28RA and TYK2) [27], T cell regulation (RUNX3, IL13, TAGAP, ETS1, and MBD2), glycosaminoglycan metabolism pathway (B3GNT2), and antiviral signaling (IFIH1, DDX58, and RNF114) [28,29].

ENVIRONMENTAL AND OTHER FACTORS — Several environmental factors and features of psoriasis have been incriminated in the pathogenesis of psoriasis and psoriatic arthritis (PsA), including infections (both bacterial and viral) and trauma [30,31]:

Features associated with psoriasis – Several risk factors have been identified as being associated with the development of PsA in patients with psoriasis. These risk factors include the severity of psoriasis, the level of obesity, scalp or inverse psoriasis, psoriatic nail disease, and psoriatic disease in a first-degree relative [32]. It is important to note that obesity, a major risk factor for incident psoriasis, usually precedes the onset of skin and joint inflammation.

Streptococcal infection – For example, an association with streptococcal infection has been proposed, and this view is supported by the strong association between preceding streptococcal infections and guttate psoriasis noted predominately in children, the improvement in skin lesions in psoriasis patients who underwent tonsillectomy, and by the degree of clinical improvement correlated with a decrease in the frequency of peptide reactive (streptococcal M proteins, keratin) CLA+ skin-homing T cells in the circulation [33,34]. The finding that 16S-based sequencing of psoriatic plaques showed increased bacterial diversity, including more Streptococcus, compared with skin biopsies from controls raised the possibility that microbiomal factors may drive inflammatory pathways in psoriatic skin and joint disease [35]. A direct role for streptococcal infection in the pathogenesis has not been demonstrated; however, high levels of peptidoglycan antibodies and 16s ribosomal RNA antibodies were noted in PsA peripheral blood, but these findings have not been confirmed [36,37].

Altered gut and skin microbiomes – Altered composition and function of microbial populations in the skin and gut are linked to an array of diseases including spondyloarthritis [38]. Observations linking dysbiosis in the gut microbiome to PsA include the finding of subclinical colitis in these patients in the absence of gastrointestinal symptoms, the elevated risk of inflammatory bowel disease in patients with PsA, and the correlation between subclinical colonic inflammation with magnetic resonance imaging (MRI) evidence of sacroiliitis in patients with axial spondyloarthritis [39-41]. In addition, the gut microbiology in PsA patients is characterized by lower levels of specific microbial species with a loss of microbial diversity and decreased production of medium-chain fatty acids [42]. Furthermore, the finding that leaky gut, determined by elevated zonulin levels, precedes joint inflammation in arthritis models and patients with rheumatoid arthritis provides further support for the presence of a gut-joint axis in the pathogenesis of inflammatory arthritis [43]. The major question to be addressed, however, is whether the association between gut dysbiosis and joint inflammation is causative or correlative [44].

Trauma and other factors – Psoriasis may develop at sites of trauma (called the Koebner phenomenon). Furthermore, some patients with PsA provide a history of preceding trauma prior to the onset of their disease [45-47]. A case-control study of patients with PsA and psoriasis identified rubella vaccination, injury, house moving, recurrent oral ulcers, and bone fractures to be associated with the development of inflammatory arthritis [47]. Obesity, which is a risk factor for psoriasis, may also convey increased risk for PsA; body mass index consistent with obesity at age 18 increased risk by a statistically significant but small degree [48]. A case-control study identified lifting of heavy loads and infections requiring hospitalization as associated with the development of PsA; this study did not confirm the association of rubella vaccination or fractures with PsA [49]. An inverse association of smoking with PsA has been reported [50]. This association was particularly relevant to patients who did not carry the human leukocyte antigen (HLA) C*06 allele [50].

KEY IMMUNE CELLS AND CYTOKINES — The infiltration of immune cells into the skin and musculoskeletal tissues, coupled with shared disease pathways of innate (tumor necrosis factor [TNF]) and acquired immunity (interleukin [IL] 23/IL-17 pathway), provides strong support for the concept that the pathogenesis of psoriatic arthritis (PsA) is directed by a dysregulated immune response [1].

Evidence suggests that psoriasis is driven by both adaptive and innate immune responses (see "Pathophysiology of plaque psoriasis"), although the interplay of innate and adaptive immune mechanisms in PsA is not well understood [51].

In established PsA, however, a number of immunologic abnormalities involving particular cells and soluble mediators have been reported [52]. These include:

T cells – T cells are critical effectors in psoriasis and PsA. The involvement of CD8+ T cells in disease pathogenesis is supported by the association with human leukocyte antigen (HLA) class I alleles (see 'Risk alleles within the major histocompatibility complex' above) [18], oligoclonal CD8+ T cell expansion [53], and the association of PsA with HIV disease [54]. Type 17 cells, which include CD4+ T helper 17 (Th17) cells, and type 3 innate lymphocytes (cells that produce IL-17A and IL-22), in addition to CD8+ lymphocytes, are increased in psoriatic synovial fluid as compared with rheumatoid synovial fluid [55].

Monocytes – Monocytes are also major effectors of inflammation in the inflamed tissues in the skin, synovium, and entheses, where they serve as progenitors to tissue macrophages, osteoclasts, and dendritic cells. An expansion of CD163+ macrophages was observed in PsA [56]. Monocytes release TNF, IL-1, and IL-6 cytokines [57].

Additionally, another study found that resting monocytes from patients with PsA had a reduced density of beta-2 integrin (CD11b) compared with controls, but activation of the monocytes generated upregulation of most adhesion molecules comparable with controls [58]. The findings suggest the possibility that the impaired adhesion, as well as transendothelial migration of monocytes of patients with PsA, can be explained by the reduced expression of the CD11b/CD18 dimer.

Neutrophils – Neutrophils are present in psoriatic synovium and synovial fluid in higher frequency than in rheumatoid arthritis [56]. They promote inflammation through the process of NETosis and the release of granular enzymes and molecules.

Synovial fibroblasts – Synovial fibroblasts proliferate in the inflamed joints, and the frequency of these cells in synovial tissue is comparable with rheumatoid arthritis [59], but angiogenic function is enhanced compared with rheumatoid arthritis [60]. Fibroblasts from the skin and synovium show enhanced proliferative activity and the capability to secrete elevated levels of IL-1-beta, IL-6, and platelet-derived growth factors.

IL-23/IL-17 and TNF pathways – Abundant evidence points to the importance of the interleukin (IL) 23/IL-17 and tumor necrosis factor (TNF) pathways in the pathogenesis of psoriasis, PsA, and axial spondyloarthropathies [3,61]. In psoriasis, the antimicrobial peptide LL-37 functions as a T cell autoantigen and triggers interferon (IFN) alpha release by plasmacytoid dendritic cells, a critical event in the initiation of psoriasis [62,63]. Anti-LL-37 antibodies are also present in PsA plasma and synovial fluid but not in osteoarthritis patients or controls [64]. The events that trigger musculoskeletal inflammation in approximately 30 percent of psoriasis patients, however, are not well understood.

Synovial fluid cytokines shared by psoriatic arthritis and rheumatoid arthritis – Specific proinflammatory cytokines in PsA synovial fluid are also present in rheumatoid arthritis, including TNF-alpha, IL-1, IL-6, and IL-8, as well as upregulated levels of serum IL-10, IL-13, IFN-alpha, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), fibroblast growth factor, CCL4, and CCL11, and reduced levels of granulocyte-colony stimulating factor [59,65-68].

Synovial tissue cytokines – PsA synovial samples release more of some cytokines (TNF-alpha, IL-1B, IL-2, IL-10, and IFN-gamma) and less of others (IL-4 and IL-5) than explants from patients with rheumatoid arthritis, suggesting that these two disorders may result from different underlying mechanisms [30]. Histologically, PsA is characterized by limited synovial lining layer hyperplasia, marked vascularity, influx of polymorphonuclear leukocytes (PMN), and lack of intracellular citrullinated proteins and major histocompatibility complex (MHC)-C pg 39 peptide complexes, features common to PsA and the other spondyloarthropathies but not to rheumatoid arthritis synovium [69].

IMMUNE-MEDIATED INFLAMMATION AND PATHOLOGY

Synovitis — Activated T cells have generally been found in the affected tissues (both skin and joints) in patients with psoriatic arthritis (PsA) [52]; however, it is unclear whether the activated T cells are responsible for the generation of the arthritis or are the result of unidentified factors such as inflammation arising at the entheses (see 'Enthesitis' below). T helper 17 (Th17) cells, group 3 innate lymphoid cells (ILC3), and natural killer (NK) cells also appear to have important roles.

The T cells in synovial fluid have been shown to be predominantly CD8 positive [70,71], and further studies identified CD8+ T resident memory (TRM) cells in the synovial fluid of patients with PsA [72]. TRM cells, which do not circulate in the blood, are also found in psoriatic plaques and appear to be immune sensors that can detect pathogens in nonlymphoid tissues [73]. In the psoriatic synovial fluid, these cells are polyfunctional, releasing a range of cytokines including interferon (IFN) gamma, tumor necrosis factor (TNF) alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL) 21; in psoriatic plaque, they express alpha-beta T cell receptors and IL-17 [74]. Several studies have shown that cytokines secreted from activated T cells and from other mononuclear proinflammatory cells induce proliferation and activation of synovial and epidermal fibroblasts [75-77].

A central question in PsA is whether Th17 cells are pivotal in the pathogenesis of this disease. One report has documented that peripheral blood CD4+IL-17+ and CD8+IL-17+ T cells stimulated ex vivo were increased in frequency both in patients with PsA and patients with rheumatoid arthritis compared with controls; however, CD8+IL-17+ cells were present at significantly higher frequency in the synovial fluid in patients with PsA, but not in patients with rheumatoid arthritis [53]. Moreover, the increased PsA synovial fluid CD8 cells correlated with increases in the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and with power Doppler ultrasound findings of active synovitis [53].

In another study, ILC3 were enriched in psoriatic compared with rheumatoid synovial fluid. The ILC3 expressed the natural cytotoxicity receptor NKp44 and the chemokine receptor CCR6 and released IL-17 in vitro [78]. Of note was the increased frequency of the NKp44+ILC3 subset in psoriatic skin as well [79].

Additional studies have also found Th17 cells in the psoriatic joint and synovial fluid [80,81]. Together with the efficacy of agents that are directed to targets in the IL-23/Th17 pathway (eg, ustekinumab, secukinumab, ixekizumab, and brodalumab), these observations support a Th17 mechanism coupled with inflammation promoted by TNF as key events in PsA [82]. (See "Treatment of peripheral psoriatic arthritis", section on 'Ustekinumab' and "Treatment of peripheral psoriatic arthritis", section on 'Secukinumab'.)

It is proposed that the direct activation of T cells bearing NK receptors for major histocompatibility complex (MHC) class I triggers psoriasis. NK cell activity in the peripheral blood was shown to be lower than in the synovium in patients with PsA [83]. NK cells that have been detected in psoriatic plaques also carry the IL-18 receptor. IL-18 is overexpressed in psoriatic lesional skin compared with human skin [84] and is elevated in patients with PsA [85]. These findings further support the role of NK cells and killer-cell immunoglobulin-like receptors (KIRs) in the pathogenesis of PsA.

Enthesitis — A prominent feature of PsA, enthesitis is defined as inflammation at sites where tendons, ligaments, and joint capsules attach to bone. Studies support the concept that biomechanical forces on the tendon and adjacent synovial tissue trigger an inflammatory response attracting inflammatory cells that initiate tendon inflammation and pathologic bone remodeling [86]. Transcortical vessels coursing from the endosteum to the periosteum may provide a conduit for inflammatory cells to enter the enthesis and modulate an inflammatory response [87].

The synovial-entheseal complex encompasses the range of structures (tendon, bursae, fibrocartilage, and synovium) present in and around the insertion site [88]. Enthesitis can manifest clinically as Achilles tendonitis, psoriatic nail disease [89], axial pain, and dactylitis where inflammation at sites of tendon insertions in the toes and fingers can present as a diffusely swollen digit. (See "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Periarticular disease'.)

When a mechanically stressed enthesis is injured, the associated inflammatory reaction would be manifested in the juxtaposed synovium. In a collagen-induced arthritis murine model, enthesitis and entheseal new bone formation were directed by CD3+CD4-CD8- T cells in response to IL-23 [90]. The demonstration of altered vascularity at enthesis insertion sites, particularly in the presence of microdamage and ensuing repair, suggests that local biomechanical factors and local trauma may also drive the entheseal inflammatory response [91].

Dactylitis — A hallmark feature of PsA, dactylitis presents as diffuse fusiform swelling of toes or fingers that can be painful or painless. Ultrasound imaging has revealed thickening of the accessory pulleys in the digits in PsA compared with rheumatoid arthritis and controls [92], and magnetic resonance imaging (MRI) has shown a flexor tenosynovitis. In one model, chronic biomechanical stress triggers an inflammatory response or deep koebnerization resulting in the clinical picture of dactylitis [93].

Axial inflammation — Approximately 30 to 40 percent of PsA patients have axial involvement [94]; the underlying pathologic events include synovitis, enthesitis, and osteitis of the sacroiliac joints and any of the spinal vertebrae. The prevalence of human leukocyte antigen (HLA) B27 antigen positivity in patients with PsA is lower than that observed in axial spondyloarthritis (approximately 20 versus 80 percent) but is approximately 40 to 60 percent among patients with PsA who have axial manifestations [94,95].

Animal models revealed an important contribution from IL-23 in the development of axial disease, but clinical trials in axial spondyloarthritis with antibodies to IL-23 were not effective therapy [96]. Both TNF and IL-17 are considered central to disease pathogenesis in the spine; supporting this view, blockade of these antibodies has been effective in axial spondyloarthritis [97], and preliminary observations suggested that inhibition of IL-17 was effective in psoriatic spondyloarthritis [98].

Psoriatic plaque — Interactions between dendritic cells, T cells, keratinocytes, neutrophils, and the cytokines released from immune cells likely contribute to the initiation and perpetuation of the cutaneous inflammation that is characteristic of psoriasis. The pathogenesis of psoriatic skin disease is described in detail separately. (See "Pathophysiology of plaque psoriasis".)

ALTERED BONE AND CARTILAGE REMODELING AND PATHOLOGY — Bone and cartilage changes in psoriatic arthritis (PsA) include features also seen in patients with spondyloarthritis and in rheumatoid arthritis. Abnormal remodeling of bone and cartilage occurs in patients with PsA, with evidence for cytokine-driven osteoclast differentiation and activation in inflamed synovium and subchondral bone, leading to bone erosion. Bone formation (eg, enthesophytes and syndesmophytes) is not well understood, but cytokine-driven osteoclast differentiation also occurs. Matrix metalloproteinases mediate cartilage degradation; their levels have been correlated with cellular infiltration, vascularization, and cartilage degradation. The following studies support these observations:

Osteoclast differentiation – Increased numbers of osteoclast precursors were identified in the peripheral blood of those with erosive PsA when compared with healthy controls [99]. Cultured peripheral blood mononuclear cells from patients spontaneously secreted higher levels of tumor necrosis factor (TNF) alpha than did healthy controls, and receptor activator of nuclear factor kappa B ligand (RANKL, a molecule that promotes osteoclast differentiation) expression was upregulated in the synovial lining layer, while osteoprotegerin (OPG, a soluble molecule that competitively binds RANKL) immunostaining was restricted to the endothelium. Thus, in inflamed synovium and subchondral bone, osteoclast progenitors are exposed to unopposed RANKL and TNF-alpha. This leads to osteoclastogenesis at the erosion front and in subchondral bone. The resulting bidirectional assault on psoriatic bone thus leads to bony erosions.

The mechanisms that lead to peripheral (ankylosis, periostitis, enthesophytes) and central (syndesmophytes) bone formation in PsA are not well understood, although evidence does support the view that bone morphogenetic protein (BMP), Wnt, and prostaglandin E signaling pathways are involved [100].

Osteoclastogenesis and osteoblast differentiation – Cytokines associated with pathologic bone resorption have been shown to promote osteogenic differentiation. In an in vitro cell culture system with bone tissues obtained from ankylosing spondylitis patients, low continuous doses of TNF (1 to 10 mcg/mL) promoted osteoblastic differentiation through the Wnt signaling pathway [101]. The osteoinductive potential of low-dose TNF was confirmed in a murine model. RANK, a cytokine receptor critical for osteoclastogenesis, is released in the vesicles of osteoclasts, where it binds to RANKL expressed on the surface of osteoblast precursors and promotes osteoblastic differentiation through reverse signaling [102]. Studies of the contribution of these newly discovered mechanisms to aberrant bone remodeling in PsA are ongoing.

Cartilage erosion and metalloproteinases – Cartilage erosion, revealed as joint space narrowing, is a relatively common radiographic finding in PsA. The immunopathogenetic mechanisms that dictate cartilage destruction and periarticular bone erosion in psoriatic joints appear to be shared with rheumatoid arthritis and represent the final common pathway for chronic synovitis irrespective of the initiating cause. Cartilage degradation is mediated by matrix metalloproteinase (MMP) 1, 3, and 9 and both MMP 3 and 9 correlated with cellular infiltration, vascularization, and cartilage degradation [59]. The MMPs and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs) were downregulated by TNF blockade. In another study, MMP expression was higher in the synovial lining then the sublining layer except for collagenase, where levels were higher in the sublining. In addition, increased production of monocyte/macrophage-derived metalloproteinases was demonstrated in the synovium of patients with PsA, and MMP 1 staining correlated with synovial lining macrophages. Levels of MMP 1, MMP 3, TIMP 1, and TIMP 2 were similar to those observed in rheumatoid arthritis [59].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriatic arthritis in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Beyond the Basics topics (see "Patient education: Psoriatic arthritis (Beyond the Basics)")

SUMMARY

The precise causes of psoriatic arthritis (PsA) and psoriasis have not been identified. The development of arthritis in 30 percent of psoriasis patients coupled with shared inflammatory pathways suggests a pathogenic linkage between skin and joint disease, although specific mechanisms are poorly understood. Genetic, immunologic, and environmental factors all contribute, and some mechanisms common to both are likely to play a role. (See 'Overview' above.)

A role for genetic factors in the pathogenesis of PsA is supported by evidence of increased prevalence among certain families and in monozygotic twins; the association of disease with certain histocompatibility antigens, which may affect prognosis; linkages on several chromosomes identified with genome-wide scanning; and individual candidate gene studies (table 1). (See 'Genetic factors' above.)

Several environmental factors have been incriminated in the pathogenesis of psoriasis and PsA, including infections (both bacterial and viral) and trauma. (See 'Environmental and other factors' above.)

A role for immunologic mechanisms is suggested by the shared inflammatory response in the psoriatic skin and synovial lesions, coupled with inflammation in the soft tissues (enthesitis, dactylitis) and spine, features shared with axial spondyloarthritis. (See 'Key immune cells and cytokines' above.)

  1. Barnas JL, Ritchlin CT. Etiology and Pathogenesis of Psoriatic Arthritis. Rheum Dis Clin North Am 2015; 41:643.
  2. Ocampo D V, Gladman D. Psoriatic arthritis. F1000Res 2019; 8.
  3. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic Arthritis. N Engl J Med 2017; 376:957.
  4. Tillett W, Charlton R, Nightingale A, et al. Interval between onset of psoriasis and psoriatic arthritis comparing the UK Clinical Practice Research Datalink with a hospital-based cohort. Rheumatology (Oxford) 2017; 56:2109.
  5. Nograles KE, Brasington RD, Bowcock AM. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat Clin Pract Rheumatol 2009; 5:83.
  6. Chandran V, Schentag CT, Brockbank JE, et al. Familial aggregation of psoriatic arthritis. Ann Rheum Dis 2009; 68:664.
  7. Moll JM, Wright V. Familial occurrence of psoriatic arthritis. Ann Rheum Dis 1973; 32:181.
  8. Li Q, Chandran V, Tsoi L, et al. Quantifying Differences in Heritability among Psoriatic Arthritis (PsA), Cutaneous Psoriasis (PsC) and Psoriasis vulgaris (PsV). Sci Rep 2020; 10:4925.
  9. de Vlam K, Gottlieb AB, Mease PJ. Current concepts in psoriatic arthritis: pathogenesis and management. Acta Derm Venereol 2014; 94:627.
  10. O'Rielly DD, Rahman P. Genetic, Epigenetic and Pharmacogenetic Aspects of Psoriasis and Psoriatic Arthritis. Rheum Dis Clin North Am 2015; 41:623.
  11. Eder L, Chandran V, Gladman DD. What have we learned about genetic susceptibility in psoriasis and psoriatic arthritis? Curr Opin Rheumatol 2015; 27:91.
  12. FitzGerald O, Haroon M, Giles JT, Winchester R. Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype. Arthritis Res Ther 2015; 17:115.
  13. Hile G, Kahlenberg JM, Gudjonsson JE. Recent genetic advances in innate immunity of psoriatic arthritis. Clin Immunol 2020; 214:108405.
  14. Chen L, Tsai TF. HLA-Cw6 and psoriasis. Br J Dermatol 2018; 178:854.
  15. Stuart PE, Tsoi LC, Hambro CA, Elder JT. Genetics of psoriasis. In: Oxford Textbook of Psoriatic Arthritis, 1st ed, FitzGerald O, Gladman D (Eds), Oxford University Press, 2019. p.35.
  16. Ho PY, Barton A, Worthington J, et al. HLA-Cw6 and HLA-DRB1*07 together are associated with less severe joint disease in psoriatic arthritis. Ann Rheum Dis 2007; 66:807.
  17. Haroon M, Winchester R, Giles JT, et al. Certain class I HLA alleles and haplotypes implicated in susceptibility play a role in determining specific features of the psoriatic arthritis phenotype. Ann Rheum Dis 2016; 75:155.
  18. Eder L, Chandran V, Pellet F, et al. Human leucocyte antigen risk alleles for psoriatic arthritis among patients with psoriasis. Ann Rheum Dis 2012; 71:50.
  19. Okada Y, Han B, Tsoi LC, et al. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes. Am J Hum Genet 2014; 95:162.
  20. Rahman P, Siannis F, Butt C, et al. TNFalpha polymorphisms and risk of psoriatic arthritis. Ann Rheum Dis 2006; 65:919.
  21. Reich K, Hüffmeier U, König IR, et al. TNF polymorphisms in psoriasis: association of psoriatic arthritis with the promoter polymorphism TNF*-857 independent of the PSORS1 risk allele. Arthritis Rheum 2007; 56:2056.
  22. Balding J, Kane D, Livingstone W, et al. Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum 2003; 48:1408.
  23. Nair RP, Duffin KC, Helms C, et al. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet 2009; 41:199.
  24. Tejasvi T, Stuart PE, Chandran V, et al. TNFAIP3 gene polymorphisms are associated with response to TNF blockade in psoriasis. J Invest Dermatol 2012; 132:593.
  25. Ellinghaus E, Stuart PE, Ellinghaus D, et al. Genome-wide meta-analysis of psoriatic arthritis identifies susceptibility locus at REL. J Invest Dermatol 2012; 132:1133.
  26. Wang C, Wu L, Bulek K, et al. The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nat Immunol 2013; 14:72.
  27. Floss DM, Klöcker T, Schröder J, et al. Defining the functional binding sites of interleukin 12 receptor β1 and interleukin 23 receptor to Janus kinases. Mol Biol Cell 2016; 27:2301.
  28. Korendowych E, Dixey J, Cox B, et al. The Influence of the HLA-DRB1 rheumatoid arthritis shared epitope on the clinical characteristics and radiological outcome of psoriatic arthritis. J Rheumatol 2003; 30:96.
  29. Bowes J, Budu-Aggrey A, Huffmeier U, et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat Commun 2015; 6:6046.
  30. Ritchlin C, Haas-Smith SA, Hicks D, et al. Patterns of cytokine production in psoriatic synovium. J Rheumatol 1998; 25:1544.
  31. Prinz JC. Psoriasis vulgaris--a sterile antibacterial skin reaction mediated by cross-reactive T cells? An immunological view of the pathophysiology of psoriasis. Clin Exp Dermatol 2001; 26:326.
  32. Scher JU, Ogdie A, Merola JF, Ritchlin C. Preventing psoriatic arthritis: focusing on patients with psoriasis at increased risk of transition. Nat Rev Rheumatol 2019; 15:153.
  33. Thorleifsdottir RH, Sigurdardottir SL, Sigurgeirsson B, et al. Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants. J Immunol 2012; 188:5160.
  34. Rasmussen JE. The relationship between infection with group A beta hemolytic streptococci and the development of psoriasis. Pediatr Infect Dis J 2000; 19:153.
  35. Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011; 9:244.
  36. Rahman MU, Ahmed S, Schumacher HR, Zeiger AR. High levels of antipeptidoglycan antibodies in psoriatic and other seronegative arthritides. J Rheumatol 1990; 17:621.
  37. Vasey FB, Deitz C, Fenske NA, et al. Possible involvement of group A streptococci in the pathogenesis of psoriatic arthritis. J Rheumatol 1982; 9:719.
  38. Breban M, Beaufrère M, Glatigny S. The microbiome in spondyloarthritis. Best Pract Res Clin Rheumatol 2019; 33:101495.
  39. Fu Y, Lee CH, Chi CC. Association of Psoriasis With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. JAMA Dermatol 2018; 154:1417.
  40. Rizzo A, Ferrante A, Guggino G, Ciccia F. Gut inflammation in spondyloarthritis. Best Pract Res Clin Rheumatol 2017; 31:863.
  41. Van Praet L, Jans L, Carron P, et al. Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort. Ann Rheum Dis 2014; 73:1186.
  42. Scher JU, Ubeda C, Artacho A, et al. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease. Arthritis Rheumatol 2015; 67:128.
  43. Tajik N, Frech M, Schulz O, et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun 2020; 11:1995.
  44. Gracey E, Vereecke L, McGovern D, et al. Revisiting the gut-joint axis: links between gut inflammation and spondyloarthritis. Nat Rev Rheumatol 2020; 16:415.
  45. Filer C, Ho P, Smith RL, et al. Investigation of association of the IL12B and IL23R genes with psoriatic arthritis. Arthritis Rheum 2008; 58:3705.
  46. Scarpa R, Del Puente A, di Girolamo C, et al. Interplay between environmental factors, articular involvement, and HLA-B27 in patients with psoriatic arthritis. Ann Rheum Dis 1992; 51:78.
  47. Pattison E, Harrison BJ, Griffiths CE, et al. Environmental risk factors for the development of psoriatic arthritis: results from a case-control study. Ann Rheum Dis 2008; 67:672.
  48. Soltani-Arabshahi R, Wong B, Feng BJ, et al. Obesity in early adulthood as a risk factor for psoriatic arthritis. Arch Dermatol 2010; 146:721.
  49. Eder L, Loo T, Chandran V, et al. Environmental risk factors for psoriatic arthritis among patients with psoriasis: A case-control study. Arthritis Rheum 2010; 62:S809.
  50. Eder L, Shanmugarajah S, Thavaneswaran A, et al. The association between smoking and the development of psoriatic arthritis among psoriasis patients. Ann Rheum Dis 2012; 71:219.
  51. McGonagle D, Ash Z, Dickie L, et al. The early phase of psoriatic arthritis. Ann Rheum Dis 2011; 70 Suppl 1:i71.
  52. Panayi GS. Immunology of psoriasis and psoriatic arthritis. Baillieres Clin Rheumatol 1994; 8:419.
  53. Menon B, Gullick NJ, Walter GJ, et al. Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol 2014; 66:1272.
  54. Arnett FC, Reveille JD, Duvic M. Psoriasis and psoriatic arthritis associated with human immunodeficiency virus infection. Rheum Dis Clin North Am 1991; 17:59.
  55. McGonagle DG, McInnes IB, Kirkham BW, et al. The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies. Ann Rheum Dis 2019; 78:1167.
  56. Celis R, Cuervo A, Ramírez J, Cañete JD. Psoriatic Synovitis: Singularity and Potential Clinical Implications. Front Med (Lausanne) 2019; 6:14.
  57. Chimenti MS, Ballanti E, Perricone C, et al. Immunomodulation in psoriatic arthritis: focus on cellular and molecular pathways. Autoimmun Rev 2013; 12:599.
  58. Neumüller J, Dunky A, Burtscher H, et al. Interaction of monocytes from patients with psoriatic arthritis with cultured microvascular endothelial cells. Clin Immunol 2001; 98:143.
  59. van Kuijk AW, Reinders-Blankert P, Smeets TJ, et al. Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis 2006; 65:1551.
  60. Fromm S, Cunningham CC, Dunne MR, et al. Enhanced angiogenic function in response to fibroblasts from psoriatic arthritis synovium compared to rheumatoid arthritis. Arthritis Res Ther 2019; 21:297.
  61. Teng MW, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 2015; 21:719.
  62. Lande R, Botti E, Jandus C, et al. The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis. Nat Commun 2014; 5:5621.
  63. Nestle FO, Conrad C, Tun-Kyi A, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005; 202:135.
  64. Frasca L, Palazzo R, Chimenti MS, et al. Anti-LL37 Antibodies Are Present in Psoriatic Arthritis (PsA) Patients: New Biomarkers in PsA. Front Immunol 2018; 9:1936.
  65. Partsch G, Steiner G, Leeb BF, et al. Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J Rheumatol 1997; 24:518.
  66. Szodoray P, Alex P, Chappell-Woodward CM, et al. Circulating cytokines in Norwegian patients with psoriatic arthritis determined by a multiplex cytokine array system. Rheumatology (Oxford) 2007; 46:417.
  67. Kotake S, Udagawa N, Takahashi N, et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest 1999; 103:1345.
  68. Blauvelt A, Chiricozzi A. The Immunologic Role of IL-17 in Psoriasis and Psoriatic Arthritis Pathogenesis. Clin Rev Allergy Immunol 2018; 55:379.
  69. Kruithof E, Baeten D, De Rycke L, et al. Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis. Arthritis Res Ther 2005; 7:R569.
  70. Costello P, Bresnihan B, O'Farrelly C, FitzGerald O. Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol 1999; 26:1117.
  71. Tassiulas I, Duncan SR, Centola M, et al. Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis. Hum Immunol 1999; 60:479.
  72. Steel KJA, Srenathan U, Ridley M, et al. Polyfunctional, Proinflammatory, Tissue-Resident Memory Phenotype and Function of Synovial Interleukin-17A+CD8+ T Cells in Psoriatic Arthritis. Arthritis Rheumatol 2020; 72:435.
  73. Masopust D, Soerens AG. Tissue-Resident T Cells and Other Resident Leukocytes. Annu Rev Immunol 2019; 37:521.
  74. Matos TR, O'Malley JT, Lowry EL, et al. Clinically resolved psoriatic lesions contain psoriasis-specific IL-17-producing αβ T cell clones. J Clin Invest 2017; 127:4031.
  75. Mori G, Cantatore FP, Brunetti G, et al. Synovial fluid fibroblasts and lymphocytes support the osteoclastogenesis in human psoriatic arthritis. Ann N Y Acad Sci 2007; 1117:159.
  76. Lebre MC, Vieira PL, Tang MW, et al. Synovial IL-21/TNF-producing CD4+ T cells induce joint destruction in rheumatoid arthritis by inducing matrix metalloproteinase production by fibroblast-like synoviocytes. J Leukoc Biol 2017; 101:775.
  77. Colucci S, Brunetti G, Cantatore FP, et al. Lymphocytes and synovial fluid fibroblasts support osteoclastogenesis through RANKL, TNFalpha, and IL-7 in an in vitro model derived from human psoriatic arthritis. J Pathol 2007; 212:47.
  78. Leijten EF, van Kempen TS, Boes M, et al. Brief report: enrichment of activated group 3 innate lymphoid cells in psoriatic arthritis synovial fluid. Arthritis Rheumatol 2015; 67:2673.
  79. Villanova F, Flutter B, Tosi I, et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J Invest Dermatol 2014; 134:984.
  80. Raychaudhuri SP, Raychaudhuri SK, Genovese MC. IL-17 receptor and its functional significance in psoriatic arthritis. Mol Cell Biochem 2012; 359:419.
  81. Leipe J, Grunke M, Dechant C, et al. Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 2010; 62:2876.
  82. Schett G, Elewaut D, McInnes IB, et al. How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med 2013; 19:822.
  83. McQueen FM, Skinner MA, Krissansen GW, et al. Natural killer cell function and expression of beta 7 integrin in psoriatic arthritis. J Rheumatol 1994; 21:2266.
  84. Companjen A, van der Wel L, van der Fits L, et al. Elevated interleukin-18 protein expression in early active and progressive plaque-type psoriatic lesions. Eur Cytokine Netw 2004; 15:210.
  85. Rooney T, Murphy E, Benito M, et al. Synovial tissue interleukin-18 expression and the response to treatment in patients with inflammatory arthritis. Ann Rheum Dis 2004; 63:1393.
  86. Schett G, Lories RJ, D'Agostino MA, et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol 2017; 13:731.
  87. Grüneboom A, Hawwari I, Weidner D, et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat Metab 2019; 1:236.
  88. McGonagle D, Lories RJ, Tan AL, Benjamin M. The concept of a "synovio-entheseal complex" and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum 2007; 56:2482.
  89. McGonagle D, Tan AL, Benjamin M. The nail as a musculoskeletal appendage--implications for an improved understanding of the link between psoriasis and arthritis. Dermatology 2009; 218:97.
  90. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med 2012; 18:1069.
  91. Benjamin M, Toumi H, Suzuki D, et al. Microdamage and altered vascularity at the enthesis-bone interface provides an anatomic explanation for bone involvement in the HLA-B27-associated spondylarthritides and allied disorders. Arthritis Rheum 2007; 56:224.
  92. Tinazzi I, McGonagle D, Aydin SZ, et al. 'Deep Koebner' phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis. Ann Rheum Dis 2018; 77:922.
  93. McGonagle D, Tan AL, Watad A, Helliwell P. Pathophysiology, assessment and treatment of psoriatic dactylitis. Nat Rev Rheumatol 2019; 15:113.
  94. Jadon DR, Sengupta R, Nightingale A, et al. Axial Disease in Psoriatic Arthritis study: defining the clinical and radiographic phenotype of psoriatic spondyloarthritis. Ann Rheum Dis 2017; 76:701.
  95. Feld J, Chandran V, Haroon N, et al. Axial disease in psoriatic arthritis and ankylosing spondylitis: a critical comparison. Nat Rev Rheumatol 2018; 14:363.
  96. Sieper J, Poddubnyy D, Miossec P. The IL-23-IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat Rev Rheumatol 2019; 15:747.
  97. Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol 2019; 71:1599.
  98. Baraliakos X, Gossec L, Pournara E, et al. Secukinumab improves clinical and imaging outcomes in patients with psoriatic arthritis and axial manifestations with inadequate response to NSAIDs: week 52 results from the MAXIMISE trial. Ann Rheum Dis 2020; 79 (suppl 1):35.
  99. Ritchlin CT, Haas-Smith SA, Li P, et al. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest 2003; 111:821.
  100. Beyer C, Schett G. Pharmacotherapy: concepts of pathogenesis and emerging treatments. Novel targets in bone and cartilage. Best Pract Res Clin Rheumatol 2010; 24:489.
  101. Li X, Wang J, Zhan Z, et al. Inflammation Intensity-Dependent Expression of Osteoinductive Wnt Proteins Is Critical for Ectopic New Bone Formation in Ankylosing Spondylitis. Arthritis Rheumatol 2018; 70:1056.
  102. Ikebuchi Y, Aoki S, Honma M, et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature 2018; 561:195.
Topic 7791 Version 22.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟