Synovitis in Psoriatic Arthritis Immunohistochemi

Authors: Arno W R van Kuijk Paul P Tak

Publish Date: 2011/04/19

Volume: 13, Issue: 4, Pages: 353-359

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Abstract

Psoriatic arthritis PsA is a chronic inflammatory arthropathy associated with psoriasis that affects the peripheral joints spine and entheses Most patients with PsA present with peripheral synovitis of the oligoarticular or polyarticular subtype As one of the targets of this disease studies on the synovium may provide insight into the mechanisms involved in this condition Key findings from the available studies comparing synovial tissue of PsA and rheumatoid arthritis patients are discussed in this review Also changes in the synovial infiltrate expression of proinflammatory cytokines and adhesion molecules and vascularity in synovial tissue after treatment with various medications are addressed Finally a model for proofofprinciple study design using serial synovial biopsies is described which could be used to predict clinical inefficacy in early clinical trial design in PsAPsoriatic arthritis PsA is a chronic inflammatory arthropathy of unknown etiology that is associated with psoriasis It can affect the peripheral joints spine and entheses Belonging to the spondyloarthritis SpA family PsA is distinguished from rheumatoid arthritis RA the most common inflammatory arthropathy by infrequent seropositivity for rheumatoid factor and anticitrullinated peptide antibodies as well as the presence of distinctive clinical features These features include the involvement of the distal interphalangeal DIP joints an asymmetric distribution of the inflamed joints the presence of dactylitis inflammation of an entire digit finger or toe enthesitis sacroiliitis or spinal involvement and of course psoriasis Radiological changes in PsA can present as erosive lesions or osteolysis but also as periarticular new bone formation Joint destruction is often progressive with almost 50 of PsA patients from an early arthritis clinic showing radiological damage 2 years after first presentation 1 and the the degree of radiological damage in PsA is comparable to RA 2More than 35 years ago Moll and Wright 3 described a large case series of patients with PsA on which they based a subdivision into five clinical phenotypes polyarthritis asymmetrical oligoarthritis spondylitis predominant DIP arthritis and arthritis mutilans This clinical heterogeneity and the difficulty classifying patients with PsA correctly has been a major concern over the years and may have hampered our pathophysiologic understanding of the disease Most patients of the original cohort of Moll and Wright 3 were classified in the oligoarticular subgroup 70 and a minority in the other subgroups In later cohorts polyarticular PsA was usually the largest subgroup at about 60 of the patients as was put forward by Helliwell and Taylor 4 The reasons for this discrepancy are not completely clear but some have argued that these later cohorts may have included patients with seronegative RA with coincident psoriasis 4 Moreover the disease pattern in an individual patient can change over time as a result of evolution of the disease or treatment 5 Recently data from a large cohort were prospectively collected in the CASPAR Classification Criteria for Psoriatic Arthritis study 588 PsA patients 525 controls with other inflammatory diseases 70 of whom had RA with the aim of constructing new classification criteria from patientderived data 6 Interestingly when the collected data from this large cohort were investigated it turned out that the patients with polyarticular PsA resembled those with oligoarticular PsA in several ways much more so than they resembled patients with RA 7 Thus misclassification of seronegative RA as polyarticular PsA does not seem to be a major problemIt has been hypothesized by some authors that PsA is mainly an entheseal disease 8 Anatomically linking mechanical stress entheses to immunologically active tissue synovium the concept of the synovioenthesial complex SEC supports this hypothesis 9 10• 11• Imaging studies have suggested that tendon and ligament insertion points to bone entheses are commonly subject to microdamage Although the normal enthesis is avascular in its fibrocartilaginous region microdamage to the entheses is associated with local cytokine release tissue repair responses and vessel ingrowth which may evolve into subsequent inflammation It also has been suggested that adjuvant molecules derived from bacteria may be preferentially deposited at the site of the SEC hence microdamage and propensity for bacterial molecule deposition in the context of certain genetic factors may lead to the characteristic inflammatory changes seen at the entheses in SpA including PsA 11• Furthermore because the nail is functionally integrated with the SEC associated with the DIP joints this model provides a rationale for the combination of DIP arthritis and nail involvement that is often observed in PsA patients 9Whereas this model may provide a good explanation for enthesealrelated inflammation and arthritis eg as observed in the DIP joints it does not where there is no close relationship between the inflamed joints and enthesis or skin As reported above most patients with PsA in the major cohorts seem to have oligoarticular or polyarticular peripheral synovitis Because the synovium is a primary site of inflammation in this disease there has been increasing interest in studies of the synovial tissue from patients with RA or PsA In addition to the use of synovial biopsies for diagnostic purposes 12 13 and pathogenetic studies 14 15 serial synovial biopsies could be used to evaluate the effects of treatments 16• 17 This approach may have merit in screening for potential efficacy during early drug developmentSeveral studies have characterized the synovium in PsA compared with RA 15 18 19 20 21 22 23 24 25 with variable results In general it is good to realize that there are large differences in synovial infiltrate and expression of proteins on an individual patient level so all findings reported are on the group level Confounding factors such as differences in the use of antirheumatic drugs between both groups and the selection of patients may have influenced the results of some studies Also that synovial tissue was collected in different ways eg arthroscopic or needle biopsies vs tissue obtained during joint replacement surgery may account for some of the observed differencesIt has been suggested by several studies that the PsA synovium is characterized by less pronounced lining layer hyperplasia and fewer monocytes/macrophages than are seen in RA 18 23 One group found fewer T and B cells in SpA synovium 22 while others reported fewer T cells in PsA synovial tissue in comparison with RA 15 23 25 This is remarkable because psoriasis and PsA are thought of as Tcell–driven conditions The lower number of T cells in PsA synovium does not mean however that these cells are not important in the pathogenesis as a subset of specific T cells may be sufficient to promote the inflammatory process and regulatory T cells may have antiinflammatory effects As a matter of fact T cells are likely to be involved in the pathogenesis of psoriasis and PsA 26 The infiltrate in lesional psoriasis skin mainly consists of activated T cells In the synovial infiltrate T cells are present among other cell types and oligoclonal Tcell expansions have been demonstrated in both skin and synovium 27 suggesting that an antigendriven Tcell response could be promoting ongoing inflammation For Tcell migration to the skin the chemokine receptor CCR4 is necessary Interestingly the ligand for CCR4 macrophagederived chemokine MDC also known as CCL22 was recently demonstrated within the synovial membrane and in high concentrations in the synovial fluid of RA and PsA patients 28 The presence of MDC facilitates migration of CCR4expressing memory cells into the inflamed joint supporting the notion that MDC/CCR4 could play a role in attracting skinspecific memory T cells to the synovial compartment The role of T cells is further underlined in psoriasis and PsA by the beneficial effect of therapies against T cells such as cyclosporin A and alefacept 29 30 31 Interestingly a recently published paper on the effects of abatacept a selective inhibitor of Tcell activation via competitive binding to CD80 or CD86 in PsA demonstrated the efficacy of using abatacept on joints but a less strong effect on skin 32 Interleukin IL17–producing Thelper cells Th17 cells are a recently recognized effector Tlymphocyte population playing a role in chronic inflammatory conditions IL23 is highly expressed in psoriatic plaques 33 and this cytokine is responsible for stimulating Th17 cells that produce IL17 as well as tumor necrosis factor TNFα IL21 and IL22 34• An important role for Th17 cells has been demonstrated in murine arthritis models 35 The exact role of Th17 cells in PsA is not clear at this moment but the Th17related cytokines IL17 and IL23 are expressed in the joints of PsA and RA patients 36 Clinical studies targeting the Th17 axis are currently under way to establish the validity of this therapeutic approach in patients with PsA Moreover blocking the p40 subunit which is shared by IL12 and IL23 leads to amelioration of arthritis in PsA 37Lymphoid aggregates of variable size and organization level are not specific for RA but were observed in the synovial biopsies of the majority of 27 PsA patients as well 38 Clear Tcell/Bcell segregation could be observed especially in the larger lymphoid aggregates with many features of lymphoid neogenesis present Interestingly a complete response to treatment was associated with a regression of the lymphoid aggregates

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