Abstract

Psoriatic arthritis is a multigenic autoimmune disease that involves synovial tissue, entheseal sites and skin, and that may result in significant joint damage. Although there are no diagnostic tests for psoriatic arthritis, research has identified consistent features that help to distinguish the condition from other common rheumatic diseases. Comparison of HLA- and HLA-C regions in psoriatic arthritis !ith those in psoriasis !ithout joint involvement demonstrates significant differences, such that psoriatic arthritis cannot be vie!ed simply as a subset of genetically homogeneous psoriasis. "cell receptor phenotypic studies have failed to identify antigendriven clones, and an alternative hypothesis for C#$ stimulation involving innate immune signals is proposed. %inally, imaging studies have highlighted entheseal involvement in psoriatic arthritis, and it is possible that entheseal-derived antigens may trigger an immune response that is critically involved in disease pathogenesis.

&ntroduction

"here has been considerable progress in advancing our understanding and treatment of psoriatic arthritis 'PsA(, but major challenges and parado)es remain, and in some instances these have become more clearly defined. &t is our objective to revie!, concisely and critically, some of these topics and provide an interpretive frame!ork.

*vidence is increasing that PsA is an autoimmune disease in !hich the C#$+ " cell plays a central role. "his revie! highlights evidence supporting the follo!ing, autoimmune features of the disease, including the genetic susceptibility associated !ith class & human leukocyte antigen 'HLA( genes in the major histocompatibility comple) '-HC(. the finding of a predominance of clonally e)panded C#$+ " cells in the synovial tissue and fluid /01. the independence from participation of C#2+ " cells, as indicated by the development of PsA in the setting of advanced A&#3. the interesting observation of PsA developing for the first time after syngeneic bone marro! transplantation from a psoriasis donor

Arthritis 4esearch 5 "herapy 6778, 00,602 'doi,07.00$9:ar6;$7(

/61. and the response to therapeutic agents directed at activated " cells 'for e)ample, #A <$8&L-6 or alefacept(, as !ell as to effector path!ays resulting from "-cell activation. Autoantibodies are not detectable in PsA, distinguishing this and the other class & associated diseases, such as ankylosing spondylitis, from the autoimmune diseases associated !ith class && -HC alleles, in !hich autoantibodies presumably engendered through C#2+ "-cell help are conspicuous. As is the case !ith all autoimmune diseases, the nature of the peptide that drives the "-cell response remains unkno!n, and

some of the reasons for the difficulty of this identification in PsA are mentioned.

&n this revie! considerable stress is placed on important insights resulting from the application of ne!er imaging modalities. "hese modalities greatly e)pand the clinical spectrum in PsA, and they assist in advancing the conceptual frame!ork of this disease and point to tissues and cell types that might e)press driving autoantigens.

=enetic susceptibility

Compared !ith most other rheumatic diseases, heredity plays a particularly strong role in the development of PsA. About 0;> of the relatives of an inde) patient !ith PsA !ill also have PsA, and an additional <7> to 2;> !ill have psoriasis. Accordingly, the presence of either psoriasis or PsA in a family member of a patient suspected of having PsA provides support for the diagnosis. &dentification of the genes responsible for this high degree of familial aggregation remains an ongoing process but, among the identified genes, the HLA genes in the -HC are of primary importance in the development of PsA. "he patterns of inheritance of psoriasis and PsA are those of a genetically comple) multigenic disease, and may range from those that simulate a dominant mode of inheritance to families in !hich the illness appears to

have a recessive mode '%igure 0(.

#&P ? distal interphalangeal. HLA ? human leukocyte antigen. &L ? interleukin. -HC ? major histocompatibility comple). -4& ? magnetic resonance imaging. @A ? natural killer. BP= ? osteoprotegerin. PsA ? psoriatic arthritis. 4A ? rheumatoid arthritis. 4A@A ? receptor activator of nuclear factor-. . "C4 ? "-cell receptor. "@% ? tumour necrosis factor. C3 ? ultrasound.

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%igure 0

&nheritance of psoriatic arthritis. "!o families are sho!n in !hich psoriatic arthritis 'half-filled shapes( appears to e)hibit a different pattern of inheritance. &n the first it appears that the disease is inherited as a simple dominant, although the absence of disease in the parents is not consistent !ith this. &n the second, there is an interplay bet!een the psoriasis phenotype 'Guarter-filled shapes( in the parent and child in the third generation, and the instances of psoriatic arthritis in the second.

&t is increasingly being recogniEed that the genetic features of PsA differ according to !hether the case series is ascertained in a rheumatology clinic, reflecting presentation as a musculoskeletal disorder, or !hether it is ascertained in a dermatology unit, !here psoriasis patients !ith more severe skin disease are first identified and then a subset !ith musculoskeletal features is delineated after a decade or more of skin disease /<1.

&n contrast to most other autoimmune diseases in !hich susceptibility is specified by HLA-#4 or other class && -HC genes, in PsA it is the class & genes, notably alleles at the HLA- and HLA-C loci, that are involved. "hese include the HLA-C allele C!H7976, !hich is the major determinant of susceptibility to psoriasis, and the HLA- alleles H6I and

H<8, and possibly some additional alleles /<,21. Ho and co!orkers /;1, in a careful immunogenetic study, re-emphasiEed that HLA-#4 0H72 alleles encoding the shared epitope, and strongly associated !ith susceptibility to rheumatoid arthritis '4A(, !ere not associated !ith PsA. %urthermore, they sho!ed that HLA-C!H79 and HLA-#4 0H7I !ere indeed associated !ith patients !ith PsA having type & 'onset before age 27 years( but not type && psoriasis 'onset after age 27 years(. "his report sho!s that patients !ith PsA !ho have type & psoriasis have a genetic background different from those !ith type && psoriasis and in turn from 4A.

Bngoing analyses indicate that these several -HC alleles operate independently in specifying the disease phenotype of PsA. "his suggests that there could be t!o genetic path!ays to PsA /<,21. Bne is through the function of the HLA- alleles

H6I and H<8, and another is through the function of haplotypes containing the HLA-C allele C!H 7976 'Psors0(. *vidence is emerging that these t!o forms of PsA that share the psoriasis phenotype are subtly different. &t appears that the C!H7976 alleles confer a phenotype !ith more severe skin disease and, on average, a long interval '?07 years( bet!een the appearance of psoriasis and the development of the musculoskeletal features of PsA. &n those !ith H6I or H<8, the musculoskeletal component appears more

synchronously !ith the cutaneous component, and PsA is more likely than in the presence of C!H7976. "he comple) relationship bet!een these t!o different genetic substrates in terms of developing PsA is illustrated in %igure 6.

"his emerging genetic information has the potential to be integrated into the challenge of validating the PsA diagnostic criteria. "hese genetic advances, if applied to series of cases, should also identify the misclassification as PsA of patients !ith psoriasis !ho simply also have fibromyalgia, osteoarthritis or a repetitive motion injury.

&n vie! of the high degree of familial aggregation and the overall heritability of PsA, it is unlikely that the HLA genes account for more than a portion of the genetic susceptibility. "here are likely to be non--HC genes that specify important aspects of the development of PsA.

&mmunopathogenesis

"he presence of susceptibility genes in an individual defines the first preclinical stage of the development of PsA. "he "-cell

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%igure 6

4epresentation of the comple) relationship bet!een HLA susceptibility and psoriatic arthritis. "he areas on the diagram are not e)actly dra!n to scale. "he right side of the diagram depicts the presence of the C!H7976 allele in healthy people, its strong association !ith cutaneous psoriasis susceptibility, and the fact that appro)imately 27> of those !ith psoriasis lack C!H7976. "he left side depicts the almost complete association of H6I !ith ankylosing spondylitis. Psoriatic arthritis, !hich includes psoriasis plus the musculoskeletal phenotype, is sho!n as the thick rimmed circle. oth C!H7976 and H6I alleles contribute independently to psoriatic arthritis susceptibility. HLA, human leukocyte antigen.

repertoire that is developed on the individualJs self-peptides and self--HC is poised for autoreactivity, but remains Guiescent until triggered. Bnce triggered the immune process results in the development of the t!o main features of PsA, the inflammatory infiltrate of " cells and accessory cells into the entheses and synovium, and the response of the synovial and entheseal tissues to the products and conseGuences of the inflammatory infiltrate. "hese alterations are summariEed in this section of the revie!.

3ome insight into the immune and pathogenetic events that

underlie PsA came from an une)pected source. #uring the early stages of the H&D pandemic the de novo appearance of PsA and of reactive arthritis in those !ith advanced loss of C#2+ " cells !as an e)periment of nature that distinguished these t!o spondyloarthritis disorders from most other rheumatic diseases such as 4A and systemic lupus erythematosus, !hich !ere ameliorated by the loss of C#2+ " cells. "his occurrence directed attention to the possibility that the pathogenesis of PsA differed substantively from that of 4A and systemic lupus erythematosus. &t emphasiEed that, in the pathogenesis of PsA, one had to consider the role of C#$+ " cells activated by the innate immune system, as !ell as elevated cytokines and triggering by persisting microbes.

iology of -HC class & molecules and the roles they may play in PsA

"he function of -HC molecules is to bind and present small soluble peptides to " cells. "he "-cell receptor '"C4(

inspects the comple) of peptide and -HC, and if the fit is sufficiently good this results in triggering of the "C4. "he biological roles played by class & molecules, such as are encoded by HLA- and HLA-C alleles involved in PsA susceptibility, differ greatly from those of class && molecules. Class & molecules function in the immunosurveillance for intracellular

infection, typically by a virus, by presenting peptides derived from cytoplasmic proteins to the "C4 of C#$+ lineage " cells. Csually, the presence of a virally infected cell results in it being killed by the C#$+ " cell.

ecause the entire repertoire of " cells is selected in the thymus on self peptides presented by the various self -HC molecules of the person, the repertoire is latently selfreactive. Bne e)planation for the association of the HLA alleles H6I and H<8, and C!H7976 !ith PsA susceptibility is that the molecules encoded by these alleles recogniEe selfpeptides derived from proteins found in entheseal and synovial sites. "-cell clones specific for these self-peptides !ould be inappropriately activated, perhaps by dendritic cells, and the activated state perpetuated by the continual supply of self-peptides. "his is the classic e)planation of an autoimmune disease as a conseGuence of driver clones, and one !ould e)pect to recogniEe one or a fe! immunodominant "C4 seGuences in the inflammatory infiltrate. Another e)planation that could be relevant to disease immunopathogenesis in the appro)imately 0;> of PsA patients !ho have HLA- H6I is the nature of the HLA- H6I molecule itself, as initially suggested by the development of an arthrocutaneous

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syndrome in rats transgenic for multiple copies of HLA- H6I /91. Ho!ever, the large majority of PsA patients lack HLA- H6I, and the development of PsA in association !ith other HLA alleles is not accounted for by this mechanism.

"he Guestion of !hether the disease has the characteristics of a single peptide-driven "-cell response !as addressed in detailed studies of the nature of the population of " cells found in the inflammatory joint fluid and in the synovium. Lymphocyte phenotypic subpopulations can be readily isolated from the joint fluid by fluorescence activated cell sorting techniGues. y isolating the 4@A from the lymphocyte subpopulations and determining the seGuence of the " cell receptors, the composition of the " cell repertoire can thus be enumerated. "he objective of these studies !as to define the e)tent to !hich the synovial infiltrate consists of one or a fe! dominant e)panded clones, suggesting antigen drive, or conversely a large number of unrelated " cells that are not clonally e)panded.

"he results of these analyses of the character of the infiltrating " cells in PsA joint fluids and tissues /I,$1 revealed t!o features. "he first is the presence of large e)pansions of

C#$+ "-cell clones implicating the adaptive immune response in the disease. Ho!ever, these e)panded clones lacked obvious common structural motifs that !ould imply the presence of an antigen drive by one or a fe! peptide autoantigens. "his implies that there is some set of specific events that triggers the adaptive immune response of clonal e)pansion, but that this trigger is broader than usually anticipated in the study of "-cell responses /81. "he finding of different "-cell clones in different joints and at different times is not consistent !ith a simple driver clone hypothesis, and it suggests that a more intricate e)planation is likely to account for the puEEling combination of high e)pansion of a fe! clones but the presence of a succession of different dominant clones in time and space. "he second feature !as the additional presence of a background of nonclonally e)panded polyclonal " cells, presumably reflecting the attraction of the " cells by chemokines. Bnly this latter polyclonal population is markedly reduced by methotre)ate therapy /$1.

Co-stimulation of C#$+ "-cell clones by stress-induced ligands

Fhat could account for this clonal activationK Diruses use various strategies to prevent their identification by the -HC class & surveillance mechanism, and principal among these is inhibition of class & -HC e)pression, !hich results in lo!ering

of surface class & -HC molecules on the surface of the infected cell. "o cope !ith this ancient viral strategy, higher organisms have responded !ith the development of a lineage of lymphocytes, the natural killer '@A( cells, !hich are specialists in recogniEing the absence of a normal amount of -HC class & 'Lmissing selfJ(. "here are several kinds of @A receptors, found on @A cells and also on memory effector C#$+ " cells that are specialists in this recognition.

Additional @A receptors on memory effector C#$+ " cells, along !ith those that recogniEe missing self, respond to molecules induced by inflammatory cues or cellular stress. "hese molecules replace the co-stimulatory molecule C#6$ e)pressed on naMve " cells. Fe hypothesiEe that an overbalance of stimulatory signals and triggering of the C#$+ " cells through @A receptor engagement is responsible for triggering these "-cell clones. "riggering of @A cells by killer immunoglobulin receptors, a subset of @A receptors, has been proposed to be a feature of PsA /071. 3imilarly, triggering of memory effector cells produced in the response to pathogens by "oll-like receptor ligands induces their activation. "hrough this combination of innate immune signals, a "-cell clone !ith relatively lo! affinity for a target can be driven to respond to self-peptide.

*pidemiological studies support the potential role of infection

and trauma in the period before the development of PsA in those !ith psoriasis /001. Among 8$ PsA patients and 09< control individuals, a number of environmental e)posures occurred that !ere associated !ith the onset of arthritis in patients !ith psoriasis. "hese included rubella vaccination and injury sufficient to reGuire a medical consultation /001. Fe consider one hypothetical e)planation for the events in the "-cell repertoire in PsA is that an array of " cells !ith "C4s that have lo! specificity for peptides e)pressed in the enthesis or the synovium are differentiated to memory effector status and have their @A receptors engaged by these innate ligands. "he ongoing inflammation and stress induced by infection or trauma compensate for the diminished "C4 affinity for self-peptides and the clones are triggered to e)pand and continue to mediate synovial tissue injury.

3ynovial tissue

"he clinical criterion of tender and s!ollen joints reflecting underlying synovitis is not specific for PsA, and at the bedside it is often not distinguishable from the synovitis of 4A. "his has t!o conseGuences. "he first of these is that in the clinic it may be difficult to determine the e)tent and nature of joint involvement - a difficulty that is being resolved by advances in imaging technology, as discussed belo!. 3econd, the important Guestion to address is !hether the

synovial tissue in PsA e)hibits any differentiating immunological features that !ould provide further insight into disease pathogenesis.

3ynovial tissue in PsA is characteriEed by a sublining infiltrate !ith " cells and cells, vascular proliferation and a relatively

thin lining layer of proliferating intimal synoviocytes. &ndeed, studies !ould suggest that the synovitis in PsA can be distinguished from 4A, !ith Guantitative differences in the features of the tissue, although there are no uniGue pathological hallmarks in either disease /061. A recent study compared synovial immunohistological features in spondyloarthropathy, including PsA, !ith those of 4A /0<1. 3pondyloarthropathy tissue e)hibited greater vascularity 'P N 7.770( and neutrophil

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'P ? 7.707( and C#09<+ macrophage counts 'P N 7.7;(, !hereas lining layer thickness and the number of C#$<+ dendritic cells !ere greater in 4A 'P N 7.7;(. &n 4A, 22> of samples e)hibited positive staining for intracellular citrullinated proteins and 29> for -HC human cartilage gp<8 peptide comple)es, !hereas no staining for these markers !as observed in spondyloarthropathy samples 'both P ? 7.770(. "he authors concluded that the synovial histopathology of PsA resembles that of other spondyloarthropathy subtypes and, like spondyloarthropathy, can be differentiated from 4A on the basis of these synovial features, suggesting that peripheral synovitis in PsA belongs to the spondyloarthropathy concept. "his difference is consistent !ith the genetic difference bet!een 4A and PsA emphasiEed in the studies conducted by Ho and co!orkers /;1

3ynovial tissue in PsA is also characteriEed by e)pression of pro-inflammatory cytokines, including &L-0, interferon-., tumour necrosis factor '"@%(-a, &L-9, &L-06, &L-0;, &L-0I and &L-0$ /02-091. Lymphoid aggregates are described and, as in 4A, occur in association !ith peripheral lymph node addressinpositive high endothelial venules and !ith the e)pression of the chemokines COCL0< 'C-O-C chemokine ligand 0<( and

CCL60 'C-C chemokine ligand 60( /0I1. &n keeping !ith the prominent vascular changes described both on arthroscopy and on immunohistology, promoters of angiogenesis are also upregulated, !ith e)pression of vascular endothelial gro!th factor, its receptors %lt-0 and A#4, and of angiopoietin-0 and -6 /0$1.

%inally, 4itchlin and colleagues /081 sho!ed that PsA peripheral blood mononuclear cells readily formed osteoclasts in vitro. &n further immunohistochemical analysis of subchondral bone and synovium, receptor activator of nuclear factor-. '4A@A(-positive perivascular mononuclear cells and osteoclasts !ere seen. 4A@A ligand e)pression !as dramatically upregulated in the synovial lining layer, !hereas osteoprotegerin 'BP=( immunostaining !as restricted to the endothelium. Although bone erosions are not a striking feature in all patients !ith PsA, a model for understanding the pathogenesis of aggressive bone erosions in PsA !as proposed in !hich osteoclasts, derived from "@%-a-activated peripheral blood mononuclear cells, migrate to the inflamed synovium and subchondral bone, !here they are e)posed to unopposed 4A@A ligand and "@%-a, leading to osteoclastogenesis at the erosion front. "hese findings have been confirmed by others /671. Ho!ever, the e)pression of 4A@A ligand and BP= !as not different bet!een patients !ith nonpsoriatic spondyloarthropathy,

those !ith psoriatic spondyloarthropathy and those !ith 4A. !as not related to the degree of systemic or local inflammation. and !as not significantly modulated by highly effective treatment !ith "@%-a blockers. "hus, differences in the synovial e)pression of 4A@A ligand, BP= and 4A@A cannot alone e)plain the radiological features observed in PsA.

"aken together, the above data confirm a histological pattern of joint inflammation similar to that in other spondyloarthropathies but sharing cytokine, chemokine and osteoclast promoting path!ays found in chronic arthropathies. #espite e)tensive analysis, specific diagnostic features have not emerged though reproducible Guantitative differences, in particular related to vascularity and perhaps to neutrophil infiltration, have been sho!n in several controlled studies. "he presence of common cytokine path!ays certainly e)plains the utility of several biologic therapies, such as "@% blockers, in a number of chronic arthropathies. #ifferential responses do occur, ho!ever, from !hich !e may further clarify the relative importance of certain path!ays. %or e)ample, targeting cells in 4A has proven efficacy, !hereas

several reports have suggested that PsA patients may not respond. Like!ise, efaliEumab - a humaniEed anti-C#00a monoclonal antibody - is licensed for treatment of psoriasis

but appears to be ineffective in joint disease and may indeed trigger joint features /601.

"he ans!er to the Guestion LFhat is PsA and ho! is it diagnosedKJ remains of great importance. &n the absence of complete kno!ledge of the pathogenic mechanism, a definitive laboratory test remains a distant goal. Accordingly, there has been a considerable emphasis on the development of syndromic criteria used for diagnosis and classification. "he recently developed CA3PA4 'ClA3sification criteria for Psoriatic A4thritis( criteria have largely been accepted by those !orking in the area /661. &t !ill be important to validate these criteria by determining !hether they identify a genetically and pathogenetically distinctive group of individuals !ho may be e)pected to have a similar response to therapies.

&maging

"he detailed changes !ithin the tissues and the underlying pathogenic mechanisms that they signify are not readily appreciated at the bedside, e)cept in terms of their ultimate conseGuences of painful, tender s!ollen and stiff joints. Ho!ever, imaging techniGues, particularly those involving the ne!er modalities of magnetic resonance imaging '-4&( and ultrasound 'C3( provide a much more detailed characteriEation of the tissue abnormalities.

"he classic radiological features of PsA include ne! bone formation at entheseal sites. bone resorption or osteolysis. sacroiliitis, !hich is often asymmetrical. and the hallmark pencil-in-cup type deformity, !hich results from a combination of ne! bone formation and osteolysis. "hese features sometimes have diagnostic utility but none are specific, and more often the radiological features in PsA are either minimal or nonspecific. %or e)ample, erosions do occur in PsA but less freGuently than in 4A, and the rate of development of ne! erosions is much slo!er. &n one study of early PsA, 2I> of patients had developed erosive disease at 6 years but the number of erosions only increased from a mean of 0.6 'P 6.8( to a mean of < 'P ;.6( /6<1. Although this increase !as

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significant 'P ? 7.776(, the number of ne! erosions is fe!er than are described in 4A /621. &n contrast, ne! bone formation is not a feature of 4A.

#espite these differences from 4A, clinical trials in PsA have used instruments developed for 4A 'usually the 3harp score or a modification thereof( !hen assessing radiological progression /6;,691. "aken together !ith the fact that joint involvement in PsA is freGuently oligoarticular and asymmetrical, the use of such instruments to assess radiological progression of PsA may not be appropriate. A radiological scoring system developed for PsA that !ould reflect differences both in joint distribution and radiological features !ould be a !elcome addition. 3ignificant changes bet!een active treatment and placebo have been demonstrated in clinical trials using these instruments borro!ed from 4A, affording some utility to their application to PsA, although the changes !ere less impressive than in 4A.

Plain radiography certainly suggests that mechanisms of joint damage in PsA differ from those in 4A, !ith the combination of ne! bone formation and erosions. Preliminary studies have e)amined !hether these differences

might be reflected in levels of soluble markers of bone turnover. &n a study of 96 patients '6I PsA and <; 4A(, bone alkaline phosphatase measurements, reflecting ne! bone formation, !ere significantly higher in PsA than in 4A 'mean " score, 0.26 versus 7.68. P N 7.7;( /6I1. "hese preliminary results emphasiEe the importance of further studies aimed at improving our understanding of the mechanisms of joint damage in PsA.

"he application of both C3 and -4& techniGues to PsA has also improved our understanding of disease mechanisms. A recent study comparing C3, -4& and plain radiography has sho!n that both C3 and -4& are more sensitive for visualiEation of inflammatory and destructive changes in fingers and toes of patients !ith PsA /6$1. C3 has highlighted tendon and ligament involvement to an e)tent not appreciated clinically. &n a comparative study, ;9> of entheseal sites !ere abnormal on C3 as compared !ith 66> detected clinically /681. *)amination of dactylitic digits using C3 has demonstrated that both synovitis and tenosynovitis contribute to disease features /<71.

"he use of -4& in PsA has emphasiEed the importance of enthesitis !ith bone marro! oedema occurring at entheseal sites /<01. &ndeed, as a result of these observations, it has been proposed that involvement of the enthesis is the primary

event in PsA, !ith synovial involvement occurring in a nonspecific manner /<61. Although this proposal has provoked debate and is controversial, it has helped to focus research on the enthesis and surrounding structures. &t certainly could be that disease is triggered after perturbation of the enthesis and conseGuent e)posure of entheseal-derived antigens to a genetically primed immune system.

*ntheseal changes have also been demonstrated in distal interphalangeal '#&P( joints in PsA. "an and co!orkers /<<1 compared the -4& and histological findings of the #&P joint in 07 patients !ith PsA, 07 !ith osteoarthritis and 07 normal control individuals. &n PsA, the dorsal capsular enthesis !as the epicentre of an inflammatory reaction. "his e)tended to involve the soft tissues adjacent to the nail in eight out of 07 PsA patients, but only in four of 07 cases !ith osteoarthritis and in none of the normal fingers. "he #&P joint capsule !as intimately linked !ith the nail comple) on histology, !ith the dorsal, volar and lateral aspects of the nail bed being ensheathed in fibres e)tending from the entheses. "his study suggests that the nail is as much an integral part of the enthesis organ as it is of the skin, !hich has implications for enhanced understanding of the disease. &n a further study of 0< PsA dactylitic digits, synovitis and soft tissue oedema !ere the most freGuent abnormalities, being present in 98> of tender dactylitic digits, but bone oedema and fle)or

tenosynovitis !ere also freGuently seen /<21.

"aken together, -4& studies in PsA have demonstrated considerable capsular, entheseal and bony changes in PsA that are Guite different from those observed in 4A /6$1. "hese imaging studies should be useful clinically in supporting a diagnosis of PsA in an individual !ho presents only !ith synovitis and psoriasis, and ultimately in clinical trials as an inde) of response.

Current disease paradigm

"he current paradigm of PsA places the lymphocyte, and in particular the C#$+ " cell, at the root of the pathogenic scheme. Fe accept this as a paradigm, and it is supported by many observations, but it should be kept in mind that this is not yet an established fact. "he most likely implication of the HLA associations is that the susceptible personJs "-cell repertoire contains C#$+ " cells that can recogniEe peptides derived from proteins in a still unkno!n triggering or target cell, !hich !e !ill arbitrarily designate a fibrocartilage cell. "hese peptides are bound in the conte)t of the -HC molecules that confer susceptibility, !hich are e)pressed on the surface of these triggering cells. "he possible mechanisms that lead to activation of this cell have been discussed, but once activated the C#$+ " cells differentiate

to memory effector phenotype and acGuire the ability to injure target cells and release cytokines 'for e)ample, interferon-.(, reprogramming gene e)pression of nearby cells and, importantly, activating macrophages and vascular endothelium.

&n considering the pathogenesis of PsA, the follo!ing findings - referred to above - must be considered.

Q Although there are strong heritability factors, PsA is genetically not simply a subset of psoriasis. Additional HLA and probably other genes contribute to disease e)pression. Q "issue involvement in PsA includes synovium and skin, but -4& and C3 studies have highlighted the involvement Page 9 of 8

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%igure <

&mmunopathogenesis of psoriatic arthritis. A proposed model for psoriatic arthritis immunopathogenesis is illustrated in !hich a genetically primed individual is e)posed to a bacterial, stress, or entheseal-related peptide. "his in turn activates the innate immune response, resulting in C#$ infiltration and chemokine:cytokine release. "he process is amplified !ith angiogenesis and cellular infiltration of involved tissues. HLA and other genes e)pressed may determine the e)act pattern of tissue involvement. HLA, human leukocyte antigen. -HC, major histocompatibility comple). @A4, natural killer cell receptor. "C4, "-cell receptor. "L4, "oll-like receptor.

of the enthesis as !ell as the joint capsule and tenosynovial tissues.

Q Angiogenesis, endothelial activation and neutrophil infiltration are prominent features in PsA synovial tissue. Q &n keeping !ith a class & HLA association, C#$+ " cells predominate in synovial fluid !ith clonal e)pansion identified. Antigen-driven " cells responses have proven difficult to demonstrate. Q

A striking feature in the tissue and joint fluid is the e)treme clonal e)pansion that persists even during treatment !ith methotre)ate. Parado)ically, ho!ever, there is no evidence to indicate that one or a fe! structurally or cognitively related "-cell clones drive the process, as is the case for most autoimmune diseases. 4ather, it appears that a succession of different clones seGuentially dominate the repertoire of infiltrating " cells. Q *vidence is emerging that innate immune responses may be triggered in PsA, !ith signalling through the "oll-like receptors or @A receptors on memory effector " cells. &ndeed, there is evidence of nonclonally specific infiltration or local e)pansion in the tissues and joint fluids. Ho!ever, it remains to be e)plained !hy only certain clones are e)panded in an inflammatory site. &n a summary illustration of the pathogenesis of PsA '%igure <(, the key elements are the operation of environmental triggers on a genetically and environmentally primed host. oth non--HC and -HC polymorphisms associated !ith susceptibility predispose the "C4 repertoire to autoreactivity and recognition of target self-peptides that are likely

to be e)pressed in target tissues. Additionally, prior response to e)ogenous ligands encoded by pathogens results in memory effector C#$+ " cells. %urthermore, prior episodes of

inflammation may similarly result in memory effector C#$+ " cells that recogniEe stress-related self-antigens. "he threshold for triggering these memory effector " cells by crossreacting structures e)pressed or present in additional encounters !ith pathogens or stress activates the C#$+ memory-effector " cells and initiates path!ays of inflammation mediated by the e)pression of transcription factors such as nuclear factor-. and activator protein-0. "his results in the tissue response of PsA that is also manifest histopathologically and by imaging techniGues.

"herapy

&n vie! of the still emerging picture of the details of these biological events that are responsible for PsA, it is some!hat premature to envision the ideal properties of drugs for use in this disease. Ho!ever, some more peripheral Guestions appear to be ans!ered in the negative, for instance a drug that depletes C#2+ " cells is unlikely to be effective in established PsA. 3imilarly, it !ould not be anticipated that a -cell-depleting agent such as ritu)imab !ould be efficacious. "here is also some Guestion about the role that tolerance-inducing agents !ould have, because the fundamental "-cell alteration does not appear to be due to one or a fe! autoimmune driver "-cell clones that could readily be eliminated. Conversely, in vie! of the role played by

"-cell activation, proliferation and differentiation, and cytokine release by " cells and macrophages, there is gro!ing support

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Arthritis 4esearch 5 "herapy Dol 00 @o 0 %itE=erald and Finchester

for agents that interfere !ith cytokine path!ays, "-cell responsiveness and macrophage effects. Anti-"@%-a inhibition is an e)ample of this approach applied to macrophages. Agents may be effective at the level of blocking naMve "-cell activation, for e)ample !ith agents such as abatacept, or even more likely by blocking the response of @A and C#$+ effector " cells to innate immune danger signals.

@onspecific

-ethotre)ate is the prototype of an effective nonspecific agent. 3ome insight into the role of methotre)ate in PsA !as provided by the "C4 repertoire studies, in !hich clinical response !as accompanied by a significant depletion of the polyclonal nonclonally e)panded component of the "-cell infiltrate, !hereas the monoclonal e)pansions persisted, perhaps accounting for the clinical rebound often seen after stopping the drug. "his suggested that the effect of methotre)ate in PsA !as immunomodulatory, probably by diminishing chemokine production /<;1, but certainly not tolerance induction.

3pecific

"he most significant advance in terms of therapy in PsA and indeed in psoriasis is the development of anti-"@%-a inhibition. "hese agents have been remarkably successful in controlling all aspects of disease. @ot all patients respond, but some e)perience significant adverse effects and for most patients treatment must be continued long term in order to maintain the therapeutic effect. Having demonstrated clinical efficacy, the pharmaceutical companies are no longer supporting clinical trials in PsA of these e)isting anti-"@%-a products, even though there are major unans!ered Guestions !ith regard to optimal usage. %or e)ample, !e do not kno! !hether anti-"@%-a products !ork best in conjunction !ith methotre)ate, and neither do !e kno! !hether early introduction of an anti-"@%-a product is more likely to result in long-lasting and possibly drug-free remission. %inally, the recent and une)pected reports of psoriasis developing for the first time in patients on anti-"@%-a therapy are intriguing /<9,<I1. Although the clinical psoriasis phenotype is often not plaGue but the more distinctive pustular form, the pathogenesis of this response is currently obscure, but it further emphasiEes the heterogeneity of PsA and the involvement of innate immune mechanisms.

Bther specific therapies are sho!ing promising initial responses. "hese include anti-&L-6< and abatacept 'cytoto)ic "-lymphocyte antigen 2-immunoglobulin(, a naMve "-cell costimulatory blocker that has been licensed for use in 4A. &mproved understanding of pathogenic mechanism in PsA !ill undoubtedly serve to open up additional therapeutic opportunities.

Conclusions

Current evidence suggests that PsA occurs in a genetically primed individual in !hom stress or entheseal-derived antigens may perturb the immune response, resulting in

angiogenesis, "-cell infiltration and cytokine release. %urther detailed analysis testing this hypothesis is reGuired.