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Developments in psoriasis and psoriatic arthritis
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 5, No. 1 2008
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Skin diseases MECHANISMS
Developments in psoriasis and psoriatic arthritis Marie Feletar1, Peter Foley2, Matthew A. Brown3,4,* 1
Melbourne, Australia Saint Vincents Hospital Melbourne, Melbourne, Australia 3 Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Australia 4 Botnar Research Centre, University of Oxford, Oxford, England, United Kingdom 2
Psoriasis and psoriatic arthritis are common conditions for which treatment options have until recently been extremely limited. Recent advances in our understand-
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia
ing of the immunology and genetics underlying these conditions have been rapid, and have contributed to the development of new therapies for these diseases. This article discusses the current state of the art in our understanding of the aetiopathogenesis of psoriasis and psoriatic arthritis, and current therapies for the diseases. Pathogenesis of psoriasis Psoriasis was given its name by the eminent Viennese dermatologist Ferdinand von Hebra in 1841, but reference to it dates back to antiquity [1]. In 1808, Robert Willan, a British dermatologist gave what is described as the first accurate description of psoriasis, proposing ‘the scaly psora’, psora leprosa be differentiated from leprosy [2]. This common condition, afflicting approximately 2–3% of the population [3], appears to result from a genetic predisposition (discussed below) combined with an environmental response (e.g. drug or infection induced) [4]. As recently as the early 1980s, the accepted hypothesis of psoriasis development was that it was primarily an epidermal disorder characterised by excessive keratinocyte proliferation and loss of normal differentiation, with the cutaneous inflammatory infiltrate a secondary phenomenon. *Corresponding author: M. Feletar ([email protected]), P. Foley ([email protected]), M.A. Brown ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.05.001
Currently psoriasis is understood to be a chronic immunemediated disorder in which the clinical and histological epidermal manifestations are secondary to an underlying disturbance of the immune system. Both innate (non-adaptive) and acquired (antigen specific) immune mechanisms are believed to be involved [5,6]. Activated T cells present in excess in the dermis (and to a lesser extent the epidermis) produce and release cytokines (in particular interferon and tumour necrosis factor), which in turn causes other inflammatory cells to release inflammatory mediators that result in cutaneous inflammation and epidermal keratinocyte hyperproliferation [7,8]. Leucocyte adherence promoting adhesion molecules such as ICAM-1 (intercellular adhesion molecule1) on epidermal keratinocytes and E-selectin on dermal capillaries are expressed more highly on psoriatic skin [9,10]. An ever-increasing understanding of the crucial immune pathways underlying the pathogenesis of psoriasis has permitted new agents tailored to target specific components to be developed. T cell activation is thought to initiate a psoriatic cascade leading to the cutaneous changes observed clinically [11]. This T cell activation (cell mediated adaptive immune response) is believed to be similar to what is seen in allergic contact dermatitis. It is hypothesized that an as yet unidentified antigen, either endogenous (perhaps keratin) or exogenous (immunogen), is captured and processed by dendritic cells [2]. The dendritic cells migrate via afferent lyme47
Drug Discovery Today: Disease Mechanisms | Skin diseases
phatics to regional lymph nodes where the putative antigen is presented to T cells that undergo clonal expansion. The predominant T cell type in the cutaneous infiltrate are memory effector CD45 RO+, most of which are positive for the skin homing protein – cutaneous lymphocyte associated antigen (CLA) [12,13]. These cells travel via the vasculature to the skin where LFA-1 and other cell surface proteins allow attachment to ICAM-1 expressing endothelial cells, followed by migration into the skin. The T cells are then reactivated after coupling with antigen presenting cells. This process requires two signals: 1, antigen presentation via MHC/TCR binding and 2, co-stimulatory signals from the binding of additional cell surface molecules (LFA-3-CD2, ICAM-1-LFA-1, B7-CD28). This results in release of cytokines that in turn activate keratinocytes, causing proliferation and epidermal hyperplasia and releasing chemokines that promote further cell migration into the skin [14]. The innate immune system is also involved with natural killer cells, natural killer T cells and neutrophils present at various times [15,16]. Plasmacytoid dendritic cells might also be involved. They produce interferon after activation via surface Toll-like receptors, further driving Th1 responses [17]. Imiquimod, a therapeutic agent approved for the treatment of basal cell carcinoma and genital warts, acts via Toll-like receptors 7 and 8. Binding to these receptors results in increased production by plasmacytoid dendritic cells of interferon that has antiviral and anti-tumoral activities [18]. Anecdotal reports have noted exacerbation of psoriasis following the application of imiquimod [19,20], suggesting that interferon production by plasmacytoid dendritic cells plays a role in the development of psoriasis [19]. Loss of normal immune response at any step (or steps) along the psoriatic cascade might result in a predisposition to psoriasis. Excessive or abnormal production of an epidermal protein might result in the underlying antigen; loss of normal barrier function due to filaggrin mutation might permit antigen penetration, inappropriate antigen uptake and processing by antigen presenting cells, over expansion of T cell clones, overexpression of cell surface proteins (LFA-1, CLA, ICAM-1, etc.), excessive cytokine (especially TNFa) production, abnormal response to cytokines by keratinocytes or inflammatory cells or an inability to switch off the process might all be genetically determined factors in psoriasis aetiology with a common final pathway. In addition, IL23 overexpression/production or an abnormal response to IL-23 (receptor gene polymorphisms (see below)) might result in increased Th17 cell production or activity. These cells secrete an array of pro-inflammatory cytokines including TNFa, IL-6, IL-17A, 17-17F, IL-22 and IL-26, which might be important in the inflammatory process [21]. Agents that target any of the potential drivers might result in treatment of psoriasis. e48
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Vitamin D and analogues including calcipotriol act on keratinocytes to induce differentiation and inhibit proliferation [22]. However, vitamin D also has immunosuppressive effects because vitamin D receptor polymorphisms might be associated with downregulation of the Th1 response [23]. Phototherapy, particularly PUVA (psoralen plus UVA), initially believed to work in psoriasis owing to inhibition of keratinocyte proliferation, is now considered to be a locally acting immunosuppressive therapy [24]. Retinoids including the topical retinoid tazarotene and the systemic agents etretinate and its metabolite acitretin were developed to bind to the nuclear retinoid receptors, modulating gene transcription and resulting in differentiation and proliferation of keratinocytes returning to a more normal pattern [25]. Methotrexate, which inhibits dihydrofolate reductase acting as a folic acid antagonist, downregulates purine synthesis, inhibiting DNA synthesis. This inhibition of replication was thought to result in a direct effect on epidermal keratinocytes. However, it is now believed that methotrexate works primarily as an immunosuppressive by suppressing T cell activities through the folate metabolic pathway, as well as other mechanisms such as thymidylate synthase (an enzyme that catalyses conversion of deoxyuridylate to deoxythymidylate – essential for DNA synthesis and repair). Cyclosporin first noted to be effective in psoriasis during investigation of efficacy in arthritis [26], was responsible for a refocusing of attention on the underlying pathogenesis of psoriasis with a shift from a belief that this was a primary epidermal keratinocyte disorder to considering psoriasis to be an immune mediated disease. More recently it has been noted that cyclosporin might directly influence epidermal keratinocytes by interactions with calcineurin, p21, NFA-1 and 2, and Sp-1/Sp-3-dependent transcription [27]. Rosiglitazone, an anti-diabetic drug that acts on insulin resistance was noted in case reports to improve the psoriasis of some patients [28]. Rosiglitazone mechanism of action is by selective activation of a specific peroxisome proliferatoractivated receptor (PPAR), PPARg. Via its binding to PPARg, rosiglitazone appears to have an anti-inflammatory effect with downregulation of nuclear factor kappa-B (NF-kB) levels and an increase in inhibitor (IkB) levels [29]. Unfortunately in controlled trials, the early clinical and theoretical benefits were not borne out [30]. Leflunomide, a disease modifying anti-rheumatic drug (DMARD) acts as an inhibitor of pyrimidine synthesis. It acts as an immunomodulatory agent inhibiting dihydroorotate dehydrogenase (a de novo pyrimidine synthesis enzyme). In addition to anti-proliferative activity, it also has been demonstrated to have anti-inflammatory effects. Although effective in psoriatic arthritis (discussed below), and showing statistical improvement in psoriatic skin disease in psoriatic arthritis patients [31], this study showed efficacy not much better than
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Drug Discovery Today: Disease Mechanisms | Skin diseases
Table 1. The CASPAR criteriaa; to meet the CASPAR (classification criteria for psoriatic arthritis) criteria, a patient must have inflammatory articular disease (joint, spine or entheseal) with three points from the following five categories 1. Evidence of current psoriasis, a personal history of psoriasis or a family history of psoriasis Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologistb A personal history of psoriasis is defined as a history of psoriasis that might be obtained from a patient, family physician, dermatologist, rheumatologist or other qualified health care provider A family history of psoriasis is defined as a history of psoriasis in a 1st- or 2nd-degree relative according to patient report 2. Typical psoriatic nail dystrophy including onycholysis, pitting and hyperkeratosis observed on current physical examination 3. A negative test result for the presence of rheumatoid factor by any method except latex but preferably by enzyme-linked immunosorbent assay or nephelometry, according to the local laboratory reference range 4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis recorded by a rheumatologist 5. Radiographic evidence of juxta-articular new bone formation, appearing as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot a b
The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%. Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.
placebo for the cutaneous psoriasis in patients with skin disease alone. The role of biological agents in management of psoriasis and psoriatic arthritis is discussed in more detail below.
Clinical aspects and management of psoriatic arthritis Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis that might affect as much as 1% of the population [32]. Approximately 2–3% of the population suffers from psoriasis and studies demonstrate that between 7 and 42% [32–34] of these develop an associated inflammatory arthritis. This broad ranging estimate reflects the multi-factorial difficulties and biases of prevalence ascertainment in addition to the absence of internationally recognised classification criteria, which has significantly hindered research in PsA. Although by definition PsA implies the presence of psoriasis, in approximately 10–15% of patients, the arthritis precedes the psoriasis. In the majority, skin disease predates joint disease by 8–10 years. The initial description and characterisation of PsA by Moll and Wright [35] 40 years ago remains a foundation stone for much current research into this condition. They documented an increased prevalence of inflammatory arthritis in those suffering from psoriasis, characterised different patterns and characteristics of that arthritis and reported that these patients were typically rheumatoid factor negative. Although this definition of inflammatory arthritis in the presence of psoriasis with seronegative rheumatoid factor has pervaded the literature, many researchers from that time on have proposed more inclusive criteria. Recently the classification of psoriatic arthritis (CASPAR) study, a major international collaborative study of PsA, has developed a modified classification set for PsA [36]. A large cohort of physician diagnosed PsA patients (n = 588) was studied and compared with 536 controls with other forms of arthritis (rheumatoid arthritis (n = 376), ankylosing spondylitis (n = 72), undifferentiated arthritis (n = 38), connective tissue disorders (n = 14) and other diseases (n = 28)). Classification criteria developed by
CASPAR were demonstrated to have high specificity (98.7%) and sensitivity (91.4%) for PsA (see Table 1). The great majority of these 588 PsA patients had long standing rather than early disease, but the criteria were subsequently demonstrated to also perform well in early PsA [37]. Universally agreed criteria serve the vital purpose of facilitating comparable information from cohorts across the globe, set a standard for inclusion criteria in clinical trials and facilitate genetic projects and broader research worldwide. Although the therapeutic armamentarium for PsA has been borrowed from rheumatoid arthritis, there are few well controlled prospective trials in PsA to support their use [38]. This is even the case for methotrexate, one of the most commonly used disease modifying agents. The advent of newer therapies, such as leflunomide [39] and the biologic agents have altered this landscape.
Biological therapies for psoriasis and psoriatic arthritis Biological agents are protein molecules with pharmacological activity, extracted from human or animal tissue or, more commonly, manufactured using recombinant DNA techniques and animal cell lines. They are usually designed on the basis of genetic sequence rather than discovered and typically are similar or identical to proteins produced by humans. Classes of biological agents include recombinant proteins (replicas of normal human proteins, for example, insulin, cytokines), monoclonal antibodies (specific to cell surface or circulating proteins that trigger immune responses) and fusion proteins that combine sections of different proteins (e.g. ligand to specific cell surface proteins or receptors combined with a toxin or an immunoglobulin tail). The first biological agents to be widely used in psoriasis and PsA are the tumour necrosis factor-a (TNF)-antagonists. Tumour necrosis factor a acts on many different cells types potentially important in psoriasis. These include T lymphocytes, which produce pro-inflammatory cytokines such as IL1, IL-6 and IL-8 resulting in increased inflammation, endothelial cells that express adhesion molecules and vascuwww.drugdiscoverytoday.com
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lar endothelial growth factor (VEGF) resulting in increased cell infiltration and angiogenesis, respectively, and keratinocytes, hyperproliferation of which results in the formation of psoriatic plaques [40]. Etanercept, the first TNF-antagonist to be trialled in PsA [41], is a recombinant human TNF receptor comprising an IgG1 tail bound to two copies of the p75 protein that binds both TNFa and TNFa. It is given in a dose of 50 mg once weekly or 25 mg twice weekly and is usually self-administered. Subsequent to this, other TNF-antagonists have also demonstrated efficacy in reducing disease activity, in randomised controlled trials for PsA [42–47]. This is the first group of treatments to demonstrate retardation of radiographic progression in addition to improved clinical activity, supporting the concept that disease modifying agents do exist for PsA. Infliximab is a chimeric monoclonal antibody that binds with high specificity, affinity and avidity to TNFa [48]. Infliximab binds both circulating and cell surface TNFa, neutralising its activity [49]. In psoriasis it is given as an intravenous infusion at a dose of 5 mg/kg over 2 h at week 0, 2 and 6, followed by regular infusions at 8 weekly intervals [50]. Adalimumab is fully human TNFa monoclonal IgG1 antibody that binds with high specificity and affinity to soluble and membrane bound TNFa. Adalimumab neutralises biological activity of TNFa by blocking the interaction of TNFa with the p55 and p75 cell surface receptors [51]. In addition it lyses cells that express surface TNFa in the presence of a complement. It is given in a subcutaneous dose of 40 mg alternate weekly. Like etanercept, adalimumab is usually selfadministered. Golimumab is the next addition to the family of TNFantagonists offering an alternative with a more attractive dosing regimen of just monthly subcutaneous injection. By contrast etanercept is given bi-weekly, adalimumab as fortnightly s/c injections, and infliximab is administered by intravenous infusion every 8 weeks. Golimumab demonstrated efficacy in a large phase 3 placebo-controlled trial of 405 PsA patients, with low toxicity [52]. A significant observation in the TNF-antagonist trials is the apparent lack of synergistic therapeutic action with methotrexate in psoriatic arthritis, which is in contrast to the experience with rheumatoid arthritis. The PsA randomised trials have not been designed with this as a primary outcome measure; however, the analyses of subgroups in the etanercept [41], adalimumab [47], infliximab [43] and golimumab trials have not shown an augmented response to TNF inhibition in the presence of methotrexate. Recently several case series have been reported in which psoriasis has developed or flared in patients treated with TNFantagonists [53–55]. The distribution of psoriasis appears to be predominantly lower limb, and pustular in form. The skin rash settles rapidly with withdrawal of the TNF-antagonist e50
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therapy. This paradoxical effect awaits an immunological explanation. Given available evidence to support a prominent role of T cells in psoriasis and PsA, newer biological therapies targeting T cells have been the focus of investigation in these conditions. Abatacept (Orencia, Bristol Myers Squibb) is a recombinant fusion protein comprising the extracellular domain of human CTLA4 and a fragment of the Fc domain of IgG1. Cytotoxic T lymphocyte antigen-4 (CTLA4) is the naturally occurring inhibitor of T cell activation. It competitively inhibits binding of the co-stimulatory molecule CD80/86 expressed on antigen presenting cells (APCs) with the CD28 molecule expressed on T cells. It has been approved for use in RA by the United States Food and Drug Administration and studies are underway in Crohn’s disease, ankylosing spondylitis and systemic lupus erythematosus, and trials in PsA are expected in the near future. Evidence linking IL23 and the TH17 subset of CD4 lymphocytes with psoriasis has led to trials of targeted therapies against this system in the disease. A humanised monoclonal antibody to Interleukin (IL)-12p40 and IL-23p40 subunits (CNTO1275 (Centocor)) has undergone a phase 2 trial in PsA [56]. These studies demonstrated favourable responses for PASI 75 and ACR 20 responses in comparison to placebo. This is the first successful demonstration of targeting interleukin-12/23 in treating inflammatory arthritis. This represents one of the most exciting therapeutic advances incorporating immunopathological studies with therapeutic targets. Alefacept (‘Amevive’, Biogen Idec) is a fully human dimeric fusion (recombinant) protein that combines the first extracellular domain of LFA-3 (leucocyte function associate antigen-3) with the Fc portion of IgG1 (hinge, CH2 and CH3 domains). The LFA-3 component binds to CD-2 receptors on memory effector T cells, selectively blocking the interaction with antigen presenting cells (and hence T cell activation) [57]. The IgG1 component binds to FcgRIII receptors on NK cells resulting in granzyme-mediated apoptosis of CD45RO positive memory effector T cells [58,59]. Administered intramuscularly weekly for a 12 week treatment course, it has been shown to be effective in psoriasis [60] and was the first biologic approved for chronic plaque psoriasis in the US. Improvement to psoriasis correlates (following a lag period) reduction in CD45RO+ memory affected T cells [60]. Recurrence of psoriasis follows return of these cells. In PsA, a randomised trial in methotrexate failure patients demonstrated that the addition of alefacept enhanced the ACR 20 response to 54%, compared with 23% in those continuing methotrexate alone, at the 24-week assessment [61]. Alefacept is given in 12 weekly courses, 15 mg/week intramuscularly for 12 weeks, followed by an interval of at least 12 weeks between courses.
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Efalizumab (Raptiva, Genentech), another T cell active agent, is a T cell modulator, formulated as a humanised monoclonal antibody targeting CD11a, the alpha subunit of lymphocyte function associated antigen 1 (LFA-1), and is administered by weekly subcutaneous injections [62,63]. Although efficacious for psoriasis, it was shown to be neutral for PsA in a phase 2 trial [64]. Several interesting reports have recently emerged suggesting that some patients might develop a florid inflammatory arthritis in the context of Efalizumab treatment [65,66]. In a French series, 12 patients with significant skin response developed arthritis within 11.4 7.4 weeks of Efalizumab initiation, 11 of these with no prior history of PsA [65]. Most cases of arthritis were severe, leading to cessation of Efalizumab treatment in nine. Two patients remitted spontaneously, four commenced methotrexate, three were changed to TNF-antagonist therapy to manage arthritis symptoms and one re-challenged with Efalizumab developed a relapse of PsA. Myers et al. [65] also report two cases of aggressive arthritis in patients in whom psoriasis had remitted on Efalizumab therapy. Although no firm conclusions can be drawn from these reports, exploring the mechanisms of dissociated skin and joint activity might shed further light on the immune effectors of disease. The therapeutic promise of B cell depleting biologic agents in RA, the success of anti-CD20 B cell depleting biologics in rheumatoid arthritis has helped to resurrect interest in the pathogenic role of B cells in rheumatoid arthritis. Rituximab (Mabthera, Roche) is the first in this class to become available, with others under investigation in both RA and systemic lupus erythematosus. This group of agents, however, might not have a beneficial effect on psoriasis because this is a strongly T cell driven disease. The advent of the biologics era, with its more specific targeting of key components of the immunological pathways involved in inflammatory arthritis, is likely to further inform our understanding of the differences in aetiopathogenesis of PsA and other forms of inflammatory arthritis. There is clearly no guarantee that treatments that are effective in one form of inflammatory arthritis will be effective or even safe in other types of arthritis, and future research will need to carefully consider the likely impact of novel treatments given what is known about the aetiopathogenesis of these conditions. Future research objectives in PsA are numerous and include a re-evaluation of assessment tools and outcome measures for PsA, which to date have largely been borrowed from RA trials for peripheral joint assessment [67,68]. These tools must incorporate all features of PsA, including the peripheral arthritis, particularly distal interphalangeal joint involvement, enthesitis, axial disease, skin and nail assessments. Although the expansion of therapeutic options for PsA is encouraging, the new class of drugs are expensive and their long-term toxicity is unknown. Many therapeutic questions remain unanswered, including the efficacy of combination
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therapy, optimal timing of therapeutic intervention and therapy stratification. However, the increasing number of trials of treatments specifically for PsA is clearly a welcome development likely to lead to major advances in the management of this common, disabling disease.
Genetics of psoriasis and psoriatic arthritis As with most common human diseases, the genetic component of susceptibility to psoriasis and PsA is probably complex, involving many genes most probably interacting with one another and with environmental factors. The heritability of psoriasis has been assessed in twins; the concordance rate in MZ twins is significantly higher than in DZ twins (35–72% vs. 12–23%), indicating greater sharing of risk factors, most probably genetic. PsA is known to run strongly in families, with a reported sibling recurrence risk ratio of 48 (i.e. that brothers and sisters of a first-degree relative with PsA are 48 times more likely to develop the condition themselves than the individuals in the general community) [69]. Thus both psoriasis and PsA are thought to have significant genetic components, but the extent to which these overlap is uncertain. To some extent this depends on disease definitions. For example, psoriasis commonly occurs in association with ankylosing spondylitis. In that setting, is this psoriatic spondyloarthritis, or ankylosing spondylitis with complicating psoriasis? Then there is the question about ‘PsA sine psoriasis’, a small group of PsA cases that do not have psoriatic skin disease. The genetic findings to date in the major ‘seronegative’ diseases suggest that there is a core set of genes influencing susceptibility to psoriasis, ankylosing spondylitis and inflammatory bowel disease, favouring ‘lumpers’ ahead of ‘splitters’ with regard to these diseases [70]. Genes that are unique to ankylosing spondylitis and inflammatory bowel disease have also been identified, but no gene has yet been demonstrated to be specifically associated with PsA but not either psoriasis or these other conditions. This suggests that the genes causing PsA might largely be a subset of the genes causing psoriatic skin disease. These findings have prompted extensive searches for genetic associations with psoriasis and psoriatic arthritis. Until recently, these studies consisted either of candidate gene association studies, or genomewide screens by linkage. Linkage studies were used to identify broad regions likely to contain psoriasis genes, of which 10 have been defined. Apart from PSORS1, which includes the HLA-C locus, these loci are of uncertain significance, although in some cases candidate genes have been identified within those loci that might be responsible for the observed linkages. The MHC associations of psoriasis and PsA are clearly complex. Although strong association is observed with HLA-Cw6, whether it is the primary associated gene is unclear. The PSORS1 locus is thought to extend over a region of 200 kb, a region containing eight genes in linkage diswww.drugdiscoverytoday.com
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equilibrium with this allele. At least two of these are good candidates for involvement in psoriasis. Corneodesmosin, encoded by the gene CDSN, is expressed in keratinocytes, mutations of the CDSN gene cause a form of hypotrichosis of the scalp (OMIM 164520) and its expression is upregulated in involved psoriatic skin. Similarly, HCR (a-helix-coiled-coilrod homologue) is overexpressed in psoriatic skin but is of unknown function, and unlike CDSN, there are no known human diseases due to mutations in HCR. Because of the strong linkage disequilibrium in this region, it has not yet been possible by population genetics approaches to distinguish which of these genes is the primary associated variant in psoriasis. Association of the HLA-DRB1 allele, DR7, with psoriatic arthritis, has also been reported widely [71]. This too might represent linkage disequilibrium with HLA-Cw6 because both alleles lie on a common MHC ancestral haplotype [72]. Outside the MHC there have been some major recent advances, with the identification of association of psoriasis with polymorphisms of the gene IL12B and IL23R [73,74]. IL12B encodes the protein IL-12p40, which is a shared component of the cytokines IL-12 and IL-23. These two cytokines are involved in increasing differentiation of CD4 lymphocytes towards, respectively the Th1 or Th17 lineages. A further study has reported suggestive evidence of association of polymorphisms of IL15 with psoriasis. IL15 is known to stimulate cytokine production by Th17 lymphocytes among other effects [75]. These findings strongly implicate the highly pro-inflammatory Th17 lymphocyte subset in the aetiopathogenesis of psoriasis. IL12B has also been associated with Crohn’s disease [76], and IL23R with both Crohn’s disease [76] and ankylosing spondylitis [77], thereby at least partially explaining the co-occurrence of these diseases. These findings also support the targeting of this system in psoriasis. A recent trial of anti-IL12p40 antibodies has demonstrated good efficacy and safety in psoriasis [78], and it is likely that other treatments will be trialled such as targeting IL-23 specifically, or Th17 produced pro-inflammatory cytokines, such as IL-17. A recent study investigating loci associated with Crohn’s disease in psoriasis has demonstrated suggestive association of psoriasis with three regions, 1q24, 6p22 and 21q22 (P = 0.009–0.00015). The gene underlying the 6p22 association is thought to be CDKAL1 (CDK5 regulatory subunit associated protein), which in addition to being associated with psoriasis and Crohn’s disease [79], is known to be associated with type 2 diabetes mellitus [80,81]. The functions of this gene and the mechanism of its association with these conditions are unknown. Several other genes have been associated with psoriasis generally with less strong evidence or replication. A region on chromosome 17q lying between the genes SLC9A3R1 and NAT9, which affects a RUNX1 binding site, has been reported e52
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to be associated with psoriasis [82]. Another solute carrier gene, SLC12A8, has been associated with psoriasis in two studies [83,84]. A study of PsA associations identified no association with either gene [85]. Association with variants of the CARD15/NOD2 gene, which is a major gene in Crohn’s disease, has been reported with PsA [86], but many other studies have not shown any association [87–92]. None of these genes were identified in the only genomewide association reported to date in psoriasis, although this study is underpowered and had low genomic coverage, perhaps explaining the failure to demonstrate these associations [74]. It is likely that over the next couple of years major advances will be made in the genetics of psoriasis and psoriatic arthritis, brought about by the advent of genomewide association studies. Autoimmune diseases appear particularly tractable to this type of study, and it is also apparent that their productivity is related to the familiarity of the conditions being studied. Therefore, there is a high likelihood that at least in psoriasis progress will be rapid. Whether the clinical heterogeneity of PsA will adversely influence the outcome of studies in this condition, we will have to wait and see.
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Gaspari, A.A. (2006) Innate and adaptive immunity and the pathophysiology of psoriasis. J. Am. Acad. Dermatol. 54 (3 Suppl. 2), S67– S80 Nickoloff, B.J. (1999) Skin innate immune system in psoriasis: friend or foe? J. Clin. Invest. 104, 1161–1164 Nestle, F.O. et al. (2005) Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J. Exp. Med. 202, 135–143 Gaspari, A.A. (2007) Mechanism of action and other potential roles of an immune response modifier. Cutis 79 (4 Suppl.), 36–45 Gilliet, M. et al. (2004) Psoriasis triggered by Toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch. Dermatol. 140, 1490–1495 Fanti, P.A. et al. (2006) Generalized psoriasis induced by topical treatment of actinic keratosis with imiquimod. Int. J. Dermatol. 45, 1464–1465 Wilson, N.J. et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat. Immunol. 8, 950–957 Takahashi, H. et al. (2003) Similarly potent action of 1,25dihydroxyvitamin D3 and its analogues, tacalcitol, calcipotriol, and maxacalcitol on normal human keratinocyte proliferation and differentiation. J. Dermatol. Sci. 31, 21–28 Halsall, J.A. et al. (2005) Vitamin D receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet. Genomics 15, 349–355 Beissert, S. and Schwarz, T. (2002) Role of immunomodulation in diseases responsive to phototherapy. Methods 28, 138–144 Menter, A. and Griffiths, C.E. (2007) Current and future management of psoriasis. Lancet 370, 272–284 Mueller, W. and Herrmann, B. (1979) Cyclosporin A for psoriasis. N. Engl. J. Med. 301, 555 Santini, M.P. et al. (2001) Cross talk among calcineurin, Sp1/Sp3, and NFAT in control of p21(WAF1/CIP1) expression in keratinocyte differentiation. Proc. Natl. Acad. Sci. U. S. A. 98, 9575–9580 Pershadsingh, H.A. et al. (2005) Improvement in psoriasis with rosiglitazone in a diabetic and a nondiabetic patient. Skinmed 4, 386–390 Mohanty, P. et al. (2004) Evidence for a potent antiinflammatory effect of rosiglitazone. J. Clin. Endocrinol. Metab. 89, 2728–2735 Ellis, C.N. et al. (2007) Placebo response in two long-term randomized psoriasis studies that were negative for rosiglitazone. Am. J. Clin. Dermatol. 8, 93–102 Nash, P. et al. (2006) Leflunomide improves psoriasis in patients with psoriatic arthritis: an in-depth analysis of data from the TOPAS study. Dermatology 212, 238–249 Gladman, D.D. (1994) Natural history of psoriatic arthritis. Baillieres Clin. Rheumatol. 8, 379–394 Salvarani, C. et al. (1995) Prevalence of psoriatic arthritis in Italian psoriatic patients. J. Rheumatol. 22, 1499–1503 Green, L. (1981) Arthritis in psoriasis. Ann. Rheum. Dis. 40, 366–369 Moll, J.M. and Wright, V. (1973) Psoriatic arthritis. Semin. Arthritis Rheum. 3, 55–78 Taylor, W. et al. (2006) Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 54, 2665–2673 Chandran, V. et al. (2006) CASPAR criteria are sensitive in early psoriatic arthritis. Arthritis Rheum. (Suppl. 1), Soriano, E.R. and McHugh, N.J. (2006) Therapies for peripheral joint disease in psoriatic arthritis. A systematic review. J. Rheumatol. 33, 1422– 1430 Kaltwasser, J.P. et al. (2004) Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, doubleblind, randomized, placebo-controlled clinical trial. Arthritis Rheum. 50, 1939–1950 Wakefield, P.E. et al. (1991) Tumor necrosis factor. J. Am. Acad. Dermatol. 24 (5 Pt 1), 675–685 Mease, P.J. et al. (2004) Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum. 50, 2264–2272 Antoni, C.E. et al. (2005) Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results
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from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 52, 1227–1236 Antoni, C. et al. (2005) Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann. Rheum. Dis. 64, 1150– 1157 Kavanaugh, A. et al. (2006) The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT): results of radiographic analyses after 1 year. Ann. Rheum. Dis. 65, 1038–1043 van der Heijde, D. et al. (2007) Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: results from the induction and maintenance psoriatic arthritis clinical trial 2. Arthritis Rheum. 56, 2698–2707 Mease, P.J. et al. (2005) Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 52, 3279–3289 Gladman, D.D. (2007) Adalimumab for long-term treatment of psoriatic arthritis: forty-eight week data from the adalimumab effectiveness in psoriatic arthritis trial. Arthritis Rheum. 56, 476–488 Knight, D.M. et al. (1993) Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol. Immunol. 30, 1443–1453 Scallon, B.J. et al. (1995) Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine 7, 251–259 Menter, A. et al. (2007) A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J. Am. Acad. Dermatol. 56 31 e1–e15 Papoutsaki, M. et al. (2007) Adalimumab for severe psoriasis and psoriatic arthritis: an open-label study in 30 patients previously treated with other biologics. J. Am. Acad. Dermatol. 57, 269–275 Kavanaugh, A. et al. (2007) Golimumab, a new, human, TNF-alpha Antibody administered as a monthly subcutaneous injection in psoriatic arthritis: 24-week efficacy and safety results of the randomized, placebocontrolled GO-REVEAL study. Arthritis Rheum. 56 (Suppl. 1), 1 Beuthien, W. et al. (2004) Skin reaction to adalimumab. Arthritis Rheum. 50, 1690–1692 Grinblat, B. and Scheinberg, M. (2005) Unexpected onset of psoriasis during infliximab treatment: comment on the article by Beuthien et al. Arthritis Rheum. 52, 1333–1334 author reply 1334 Grinblat, B. and Scheinberg, M. (2008) The enigmatic development of psoriasis and psoriasiform lesions during anti-TNF therapy: a review. Semin. Arthritis Rheum. 37 (4), 251–255 Gottlieb, A. et al. (2007) Phase II, randomized, placebo-controlled study of CNTO 1275, a human interleukin-12/23 monoclonal antibody, in psoriatic arthritis. Arthritis Rheum. 56 (Suppl. 1), Wallner, B.P. et al. (1987) Primary structure of lymphocyte functionassociated antigen 3 (LFA-3). The ligand of the T lymphocyte CD2 glycoprotein. J. Exp. Med. 166, 923–932 Majeau, G.R. et al. (1994) Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/ function analysis in vitro and in human CD2 transgenic mice. J. Immunol. 152, 2753–2767 Chamian, F. et al. (2005) Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in Psoriasis vulgaris. Proc. Natl. Acad. Sci. U. S. A. 102, 2075–2080 Ellis, C.N. and Krueger, G.G. (2001) Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 345, 248–255 Mease, P.J. et al. (2006) Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: results of a randomized, double-blind, placebo-controlled study. Arthritis Rheum. 54, 1638–1645 Krueger, J. et al. (2000) Anti-CD11a treatment for psoriasis concurrently increases circulating T-cells and decreases plaque T-cells, consistent with inhibition of cutaneous T-cell trafficking. J. Invest. Dermatol. 115, 333 Lebwohl, M. et al. (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl. J. Med. 349, 2004–2013 Papp, K.A. et al. (2007) Efalizumab for the treatment of psoriatic arthritis. J. Cutan. Med. Surg. 11, 57–66
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Myers, W.A. et al. (2006) New-onset, debilitating arthritis in psoriasis patients receiving efalizumab. J. Dermatol. Treat. 17, 353–354 Bang, B. and Gniadecki, R. (2006) Severe exacerbation of psoriatic arthritis during treatment with efalizumab. A case report. Acta Derm. Venereol. 86, 456–457 Gladman, D.D. et al. (2007) Outcome measures in psoriatic arthritis. J. Rheumatol. 34, 1159–1166 Mease, P.J. et al. (2005) Psoriatic arthritis assessment tools in clinical trials. Ann. Rheum. Dis. 64 (Suppl. 2), ii49–ii54 Moll, J.M. and Wright, V. (1973) Familial occurrence of psoriatic arthritis. Ann. Rheum. Dis. 32, 181–201 Nash, P. et al. (2005) Seronegative spondyloarthropathies: to lump or split? Ann. Rheum. Dis. 64 (Suppl. 2), ii9–ii13 Jenisch, S. et al. (1998) Linkage analysis of human leukocyte antigen (HLA) markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region. Am. J. Hum. Genet. 63, 191–199 Degli-Esposti, M.A. et al. (1992) Ancestral haplotypes: conserved population MHC haplotypes. Hum. Immunol. 34, 242–252 Tsunemi, Y. et al. (2002) Interleukin-12 p40 gene (IL12B) 30 -untranslated region polymorphism is associated with susceptibility to atopic dermatitis and Psoriasis vulgaris. J. Dermatol. Sci. 30, 161–166 Cargill, M. et al. (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 Ziolkowska, M. et al. (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J. Immunol. 164, 2832–2838 Duerr, R.H. et al. (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 Burton, P.R. et al. (2007) Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329– 1337 Krueger, G.G. et al. (2007) A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592
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79 Consortium WTC-C, (2007) Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 447, 661–678 80 Steinthorsdottir, V. et al. (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 81 Zeggini, E. et al. (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316, 1336–1341 82 Helms, C. et al. (2003) A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis. Nat. Genet. 35, 349–356 83 Huffmeier, U. et al. (2005) Systematic linkage disequilibrium analysis of SLC12A8 at PSORS5 confirms a role in susceptibility to Psoriasis vulgaris. J. Invest. Dermatol. 125, 906–912 84 Hewett, D. et al. (2002) Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics 79, 305–314 85 (2005) Lack of association of SLC22A4, SLC22A5, SLC9A3R1 and RUNX1 variants in psoriatic arthritis. Rheumatology (Oxford) 44, 820–821 86 Rahman, P. et al. (2003) CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis. Am. J. Hum. Genet. 73, 677–681 87 Ho, P. et al. (2005) Evidence for common genetic control in pathways of inflammation for Crohn’s disease and psoriatic arthritis. Arthritis Rheum. 52, 3596–3602 88 Jenisch, S. et al. (2006) CARD15 mutations in patients with plaque-type psoriasis and psoriatic arthritis: lack of association. Arch. Dermatol. Res. 297, 409–411 89 Plant, D. et al. (2004) CARD15/NOD2 single nucleotide polymorphisms do not confer susceptibility to type I psoriasis. Br. J. Dermatol. 151, 675–678 90 Giardina, E. et al. (2004) Psoriatic arthritis and CARD15 gene polymorphisms: no evidence for association in the Italian population. J. Invest. Dermatol. 122, 1106–1107 91 Young, C. et al. (2003) A Crohn’s disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with Psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis. Exp. Dermatol. 12, 506–509 92 Nair, R.P. et al. (2001) Lack of association between NOD2 3020InsC frameshift mutation and psoriasis. J. Invest. Dermatol. 117, 1671–1672
DRUG DISCOVERY
TODAY
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Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Skin diseases MECHANISMS
Developments in psoriasis and psoriatic arthritis Marie Feletar1, Peter Foley2, Matthew A. Brown3,4,* 1
Melbourne, Australia Saint Vincents Hospital Melbourne, Melbourne, Australia 3 Diamantina Institute of Cancer, Immunology and Metabolic Medicine, University of Queensland, Brisbane, Australia 4 Botnar Research Centre, University of Oxford, Oxford, England, United Kingdom 2
Psoriasis and psoriatic arthritis are common conditions for which treatment options have until recently been extremely limited. Recent advances in our understand-
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia
ing of the immunology and genetics underlying these conditions have been rapid, and have contributed to the development of new therapies for these diseases. This article discusses the current state of the art in our understanding of the aetiopathogenesis of psoriasis and psoriatic arthritis, and current therapies for the diseases. Pathogenesis of psoriasis Psoriasis was given its name by the eminent Viennese dermatologist Ferdinand von Hebra in 1841, but reference to it dates back to antiquity [1]. In 1808, Robert Willan, a British dermatologist gave what is described as the first accurate description of psoriasis, proposing ‘the scaly psora’, psora leprosa be differentiated from leprosy [2]. This common condition, afflicting approximately 2–3% of the population [3], appears to result from a genetic predisposition (discussed below) combined with an environmental response (e.g. drug or infection induced) [4]. As recently as the early 1980s, the accepted hypothesis of psoriasis development was that it was primarily an epidermal disorder characterised by excessive keratinocyte proliferation and loss of normal differentiation, with the cutaneous inflammatory infiltrate a secondary phenomenon. *Corresponding author: M. Feletar ([email protected]), P. Foley ([email protected]), M.A. Brown ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.05.001
Currently psoriasis is understood to be a chronic immunemediated disorder in which the clinical and histological epidermal manifestations are secondary to an underlying disturbance of the immune system. Both innate (non-adaptive) and acquired (antigen specific) immune mechanisms are believed to be involved [5,6]. Activated T cells present in excess in the dermis (and to a lesser extent the epidermis) produce and release cytokines (in particular interferon and tumour necrosis factor), which in turn causes other inflammatory cells to release inflammatory mediators that result in cutaneous inflammation and epidermal keratinocyte hyperproliferation [7,8]. Leucocyte adherence promoting adhesion molecules such as ICAM-1 (intercellular adhesion molecule1) on epidermal keratinocytes and E-selectin on dermal capillaries are expressed more highly on psoriatic skin [9,10]. An ever-increasing understanding of the crucial immune pathways underlying the pathogenesis of psoriasis has permitted new agents tailored to target specific components to be developed. T cell activation is thought to initiate a psoriatic cascade leading to the cutaneous changes observed clinically [11]. This T cell activation (cell mediated adaptive immune response) is believed to be similar to what is seen in allergic contact dermatitis. It is hypothesized that an as yet unidentified antigen, either endogenous (perhaps keratin) or exogenous (immunogen), is captured and processed by dendritic cells [2]. The dendritic cells migrate via afferent lyme47
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phatics to regional lymph nodes where the putative antigen is presented to T cells that undergo clonal expansion. The predominant T cell type in the cutaneous infiltrate are memory effector CD45 RO+, most of which are positive for the skin homing protein – cutaneous lymphocyte associated antigen (CLA) [12,13]. These cells travel via the vasculature to the skin where LFA-1 and other cell surface proteins allow attachment to ICAM-1 expressing endothelial cells, followed by migration into the skin. The T cells are then reactivated after coupling with antigen presenting cells. This process requires two signals: 1, antigen presentation via MHC/TCR binding and 2, co-stimulatory signals from the binding of additional cell surface molecules (LFA-3-CD2, ICAM-1-LFA-1, B7-CD28). This results in release of cytokines that in turn activate keratinocytes, causing proliferation and epidermal hyperplasia and releasing chemokines that promote further cell migration into the skin [14]. The innate immune system is also involved with natural killer cells, natural killer T cells and neutrophils present at various times [15,16]. Plasmacytoid dendritic cells might also be involved. They produce interferon after activation via surface Toll-like receptors, further driving Th1 responses [17]. Imiquimod, a therapeutic agent approved for the treatment of basal cell carcinoma and genital warts, acts via Toll-like receptors 7 and 8. Binding to these receptors results in increased production by plasmacytoid dendritic cells of interferon that has antiviral and anti-tumoral activities [18]. Anecdotal reports have noted exacerbation of psoriasis following the application of imiquimod [19,20], suggesting that interferon production by plasmacytoid dendritic cells plays a role in the development of psoriasis [19]. Loss of normal immune response at any step (or steps) along the psoriatic cascade might result in a predisposition to psoriasis. Excessive or abnormal production of an epidermal protein might result in the underlying antigen; loss of normal barrier function due to filaggrin mutation might permit antigen penetration, inappropriate antigen uptake and processing by antigen presenting cells, over expansion of T cell clones, overexpression of cell surface proteins (LFA-1, CLA, ICAM-1, etc.), excessive cytokine (especially TNFa) production, abnormal response to cytokines by keratinocytes or inflammatory cells or an inability to switch off the process might all be genetically determined factors in psoriasis aetiology with a common final pathway. In addition, IL23 overexpression/production or an abnormal response to IL-23 (receptor gene polymorphisms (see below)) might result in increased Th17 cell production or activity. These cells secrete an array of pro-inflammatory cytokines including TNFa, IL-6, IL-17A, 17-17F, IL-22 and IL-26, which might be important in the inflammatory process [21]. Agents that target any of the potential drivers might result in treatment of psoriasis. e48
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Vitamin D and analogues including calcipotriol act on keratinocytes to induce differentiation and inhibit proliferation [22]. However, vitamin D also has immunosuppressive effects because vitamin D receptor polymorphisms might be associated with downregulation of the Th1 response [23]. Phototherapy, particularly PUVA (psoralen plus UVA), initially believed to work in psoriasis owing to inhibition of keratinocyte proliferation, is now considered to be a locally acting immunosuppressive therapy [24]. Retinoids including the topical retinoid tazarotene and the systemic agents etretinate and its metabolite acitretin were developed to bind to the nuclear retinoid receptors, modulating gene transcription and resulting in differentiation and proliferation of keratinocytes returning to a more normal pattern [25]. Methotrexate, which inhibits dihydrofolate reductase acting as a folic acid antagonist, downregulates purine synthesis, inhibiting DNA synthesis. This inhibition of replication was thought to result in a direct effect on epidermal keratinocytes. However, it is now believed that methotrexate works primarily as an immunosuppressive by suppressing T cell activities through the folate metabolic pathway, as well as other mechanisms such as thymidylate synthase (an enzyme that catalyses conversion of deoxyuridylate to deoxythymidylate – essential for DNA synthesis and repair). Cyclosporin first noted to be effective in psoriasis during investigation of efficacy in arthritis [26], was responsible for a refocusing of attention on the underlying pathogenesis of psoriasis with a shift from a belief that this was a primary epidermal keratinocyte disorder to considering psoriasis to be an immune mediated disease. More recently it has been noted that cyclosporin might directly influence epidermal keratinocytes by interactions with calcineurin, p21, NFA-1 and 2, and Sp-1/Sp-3-dependent transcription [27]. Rosiglitazone, an anti-diabetic drug that acts on insulin resistance was noted in case reports to improve the psoriasis of some patients [28]. Rosiglitazone mechanism of action is by selective activation of a specific peroxisome proliferatoractivated receptor (PPAR), PPARg. Via its binding to PPARg, rosiglitazone appears to have an anti-inflammatory effect with downregulation of nuclear factor kappa-B (NF-kB) levels and an increase in inhibitor (IkB) levels [29]. Unfortunately in controlled trials, the early clinical and theoretical benefits were not borne out [30]. Leflunomide, a disease modifying anti-rheumatic drug (DMARD) acts as an inhibitor of pyrimidine synthesis. It acts as an immunomodulatory agent inhibiting dihydroorotate dehydrogenase (a de novo pyrimidine synthesis enzyme). In addition to anti-proliferative activity, it also has been demonstrated to have anti-inflammatory effects. Although effective in psoriatic arthritis (discussed below), and showing statistical improvement in psoriatic skin disease in psoriatic arthritis patients [31], this study showed efficacy not much better than
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Drug Discovery Today: Disease Mechanisms | Skin diseases
Table 1. The CASPAR criteriaa; to meet the CASPAR (classification criteria for psoriatic arthritis) criteria, a patient must have inflammatory articular disease (joint, spine or entheseal) with three points from the following five categories 1. Evidence of current psoriasis, a personal history of psoriasis or a family history of psoriasis Current psoriasis is defined as psoriatic skin or scalp disease present today as judged by a rheumatologist or dermatologistb A personal history of psoriasis is defined as a history of psoriasis that might be obtained from a patient, family physician, dermatologist, rheumatologist or other qualified health care provider A family history of psoriasis is defined as a history of psoriasis in a 1st- or 2nd-degree relative according to patient report 2. Typical psoriatic nail dystrophy including onycholysis, pitting and hyperkeratosis observed on current physical examination 3. A negative test result for the presence of rheumatoid factor by any method except latex but preferably by enzyme-linked immunosorbent assay or nephelometry, according to the local laboratory reference range 4. Either current dactylitis, defined as swelling of an entire digit, or a history of dactylitis recorded by a rheumatologist 5. Radiographic evidence of juxta-articular new bone formation, appearing as ill-defined ossification near joint margins (but excluding osteophyte formation) on plain radiographs of the hand or foot a b
The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%. Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.
placebo for the cutaneous psoriasis in patients with skin disease alone. The role of biological agents in management of psoriasis and psoriatic arthritis is discussed in more detail below.
Clinical aspects and management of psoriatic arthritis Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis that might affect as much as 1% of the population [32]. Approximately 2–3% of the population suffers from psoriasis and studies demonstrate that between 7 and 42% [32–34] of these develop an associated inflammatory arthritis. This broad ranging estimate reflects the multi-factorial difficulties and biases of prevalence ascertainment in addition to the absence of internationally recognised classification criteria, which has significantly hindered research in PsA. Although by definition PsA implies the presence of psoriasis, in approximately 10–15% of patients, the arthritis precedes the psoriasis. In the majority, skin disease predates joint disease by 8–10 years. The initial description and characterisation of PsA by Moll and Wright [35] 40 years ago remains a foundation stone for much current research into this condition. They documented an increased prevalence of inflammatory arthritis in those suffering from psoriasis, characterised different patterns and characteristics of that arthritis and reported that these patients were typically rheumatoid factor negative. Although this definition of inflammatory arthritis in the presence of psoriasis with seronegative rheumatoid factor has pervaded the literature, many researchers from that time on have proposed more inclusive criteria. Recently the classification of psoriatic arthritis (CASPAR) study, a major international collaborative study of PsA, has developed a modified classification set for PsA [36]. A large cohort of physician diagnosed PsA patients (n = 588) was studied and compared with 536 controls with other forms of arthritis (rheumatoid arthritis (n = 376), ankylosing spondylitis (n = 72), undifferentiated arthritis (n = 38), connective tissue disorders (n = 14) and other diseases (n = 28)). Classification criteria developed by
CASPAR were demonstrated to have high specificity (98.7%) and sensitivity (91.4%) for PsA (see Table 1). The great majority of these 588 PsA patients had long standing rather than early disease, but the criteria were subsequently demonstrated to also perform well in early PsA [37]. Universally agreed criteria serve the vital purpose of facilitating comparable information from cohorts across the globe, set a standard for inclusion criteria in clinical trials and facilitate genetic projects and broader research worldwide. Although the therapeutic armamentarium for PsA has been borrowed from rheumatoid arthritis, there are few well controlled prospective trials in PsA to support their use [38]. This is even the case for methotrexate, one of the most commonly used disease modifying agents. The advent of newer therapies, such as leflunomide [39] and the biologic agents have altered this landscape.
Biological therapies for psoriasis and psoriatic arthritis Biological agents are protein molecules with pharmacological activity, extracted from human or animal tissue or, more commonly, manufactured using recombinant DNA techniques and animal cell lines. They are usually designed on the basis of genetic sequence rather than discovered and typically are similar or identical to proteins produced by humans. Classes of biological agents include recombinant proteins (replicas of normal human proteins, for example, insulin, cytokines), monoclonal antibodies (specific to cell surface or circulating proteins that trigger immune responses) and fusion proteins that combine sections of different proteins (e.g. ligand to specific cell surface proteins or receptors combined with a toxin or an immunoglobulin tail). The first biological agents to be widely used in psoriasis and PsA are the tumour necrosis factor-a (TNF)-antagonists. Tumour necrosis factor a acts on many different cells types potentially important in psoriasis. These include T lymphocytes, which produce pro-inflammatory cytokines such as IL1, IL-6 and IL-8 resulting in increased inflammation, endothelial cells that express adhesion molecules and vascuwww.drugdiscoverytoday.com
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lar endothelial growth factor (VEGF) resulting in increased cell infiltration and angiogenesis, respectively, and keratinocytes, hyperproliferation of which results in the formation of psoriatic plaques [40]. Etanercept, the first TNF-antagonist to be trialled in PsA [41], is a recombinant human TNF receptor comprising an IgG1 tail bound to two copies of the p75 protein that binds both TNFa and TNFa. It is given in a dose of 50 mg once weekly or 25 mg twice weekly and is usually self-administered. Subsequent to this, other TNF-antagonists have also demonstrated efficacy in reducing disease activity, in randomised controlled trials for PsA [42–47]. This is the first group of treatments to demonstrate retardation of radiographic progression in addition to improved clinical activity, supporting the concept that disease modifying agents do exist for PsA. Infliximab is a chimeric monoclonal antibody that binds with high specificity, affinity and avidity to TNFa [48]. Infliximab binds both circulating and cell surface TNFa, neutralising its activity [49]. In psoriasis it is given as an intravenous infusion at a dose of 5 mg/kg over 2 h at week 0, 2 and 6, followed by regular infusions at 8 weekly intervals [50]. Adalimumab is fully human TNFa monoclonal IgG1 antibody that binds with high specificity and affinity to soluble and membrane bound TNFa. Adalimumab neutralises biological activity of TNFa by blocking the interaction of TNFa with the p55 and p75 cell surface receptors [51]. In addition it lyses cells that express surface TNFa in the presence of a complement. It is given in a subcutaneous dose of 40 mg alternate weekly. Like etanercept, adalimumab is usually selfadministered. Golimumab is the next addition to the family of TNFantagonists offering an alternative with a more attractive dosing regimen of just monthly subcutaneous injection. By contrast etanercept is given bi-weekly, adalimumab as fortnightly s/c injections, and infliximab is administered by intravenous infusion every 8 weeks. Golimumab demonstrated efficacy in a large phase 3 placebo-controlled trial of 405 PsA patients, with low toxicity [52]. A significant observation in the TNF-antagonist trials is the apparent lack of synergistic therapeutic action with methotrexate in psoriatic arthritis, which is in contrast to the experience with rheumatoid arthritis. The PsA randomised trials have not been designed with this as a primary outcome measure; however, the analyses of subgroups in the etanercept [41], adalimumab [47], infliximab [43] and golimumab trials have not shown an augmented response to TNF inhibition in the presence of methotrexate. Recently several case series have been reported in which psoriasis has developed or flared in patients treated with TNFantagonists [53–55]. The distribution of psoriasis appears to be predominantly lower limb, and pustular in form. The skin rash settles rapidly with withdrawal of the TNF-antagonist e50
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therapy. This paradoxical effect awaits an immunological explanation. Given available evidence to support a prominent role of T cells in psoriasis and PsA, newer biological therapies targeting T cells have been the focus of investigation in these conditions. Abatacept (Orencia, Bristol Myers Squibb) is a recombinant fusion protein comprising the extracellular domain of human CTLA4 and a fragment of the Fc domain of IgG1. Cytotoxic T lymphocyte antigen-4 (CTLA4) is the naturally occurring inhibitor of T cell activation. It competitively inhibits binding of the co-stimulatory molecule CD80/86 expressed on antigen presenting cells (APCs) with the CD28 molecule expressed on T cells. It has been approved for use in RA by the United States Food and Drug Administration and studies are underway in Crohn’s disease, ankylosing spondylitis and systemic lupus erythematosus, and trials in PsA are expected in the near future. Evidence linking IL23 and the TH17 subset of CD4 lymphocytes with psoriasis has led to trials of targeted therapies against this system in the disease. A humanised monoclonal antibody to Interleukin (IL)-12p40 and IL-23p40 subunits (CNTO1275 (Centocor)) has undergone a phase 2 trial in PsA [56]. These studies demonstrated favourable responses for PASI 75 and ACR 20 responses in comparison to placebo. This is the first successful demonstration of targeting interleukin-12/23 in treating inflammatory arthritis. This represents one of the most exciting therapeutic advances incorporating immunopathological studies with therapeutic targets. Alefacept (‘Amevive’, Biogen Idec) is a fully human dimeric fusion (recombinant) protein that combines the first extracellular domain of LFA-3 (leucocyte function associate antigen-3) with the Fc portion of IgG1 (hinge, CH2 and CH3 domains). The LFA-3 component binds to CD-2 receptors on memory effector T cells, selectively blocking the interaction with antigen presenting cells (and hence T cell activation) [57]. The IgG1 component binds to FcgRIII receptors on NK cells resulting in granzyme-mediated apoptosis of CD45RO positive memory effector T cells [58,59]. Administered intramuscularly weekly for a 12 week treatment course, it has been shown to be effective in psoriasis [60] and was the first biologic approved for chronic plaque psoriasis in the US. Improvement to psoriasis correlates (following a lag period) reduction in CD45RO+ memory affected T cells [60]. Recurrence of psoriasis follows return of these cells. In PsA, a randomised trial in methotrexate failure patients demonstrated that the addition of alefacept enhanced the ACR 20 response to 54%, compared with 23% in those continuing methotrexate alone, at the 24-week assessment [61]. Alefacept is given in 12 weekly courses, 15 mg/week intramuscularly for 12 weeks, followed by an interval of at least 12 weeks between courses.
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Efalizumab (Raptiva, Genentech), another T cell active agent, is a T cell modulator, formulated as a humanised monoclonal antibody targeting CD11a, the alpha subunit of lymphocyte function associated antigen 1 (LFA-1), and is administered by weekly subcutaneous injections [62,63]. Although efficacious for psoriasis, it was shown to be neutral for PsA in a phase 2 trial [64]. Several interesting reports have recently emerged suggesting that some patients might develop a florid inflammatory arthritis in the context of Efalizumab treatment [65,66]. In a French series, 12 patients with significant skin response developed arthritis within 11.4 7.4 weeks of Efalizumab initiation, 11 of these with no prior history of PsA [65]. Most cases of arthritis were severe, leading to cessation of Efalizumab treatment in nine. Two patients remitted spontaneously, four commenced methotrexate, three were changed to TNF-antagonist therapy to manage arthritis symptoms and one re-challenged with Efalizumab developed a relapse of PsA. Myers et al. [65] also report two cases of aggressive arthritis in patients in whom psoriasis had remitted on Efalizumab therapy. Although no firm conclusions can be drawn from these reports, exploring the mechanisms of dissociated skin and joint activity might shed further light on the immune effectors of disease. The therapeutic promise of B cell depleting biologic agents in RA, the success of anti-CD20 B cell depleting biologics in rheumatoid arthritis has helped to resurrect interest in the pathogenic role of B cells in rheumatoid arthritis. Rituximab (Mabthera, Roche) is the first in this class to become available, with others under investigation in both RA and systemic lupus erythematosus. This group of agents, however, might not have a beneficial effect on psoriasis because this is a strongly T cell driven disease. The advent of the biologics era, with its more specific targeting of key components of the immunological pathways involved in inflammatory arthritis, is likely to further inform our understanding of the differences in aetiopathogenesis of PsA and other forms of inflammatory arthritis. There is clearly no guarantee that treatments that are effective in one form of inflammatory arthritis will be effective or even safe in other types of arthritis, and future research will need to carefully consider the likely impact of novel treatments given what is known about the aetiopathogenesis of these conditions. Future research objectives in PsA are numerous and include a re-evaluation of assessment tools and outcome measures for PsA, which to date have largely been borrowed from RA trials for peripheral joint assessment [67,68]. These tools must incorporate all features of PsA, including the peripheral arthritis, particularly distal interphalangeal joint involvement, enthesitis, axial disease, skin and nail assessments. Although the expansion of therapeutic options for PsA is encouraging, the new class of drugs are expensive and their long-term toxicity is unknown. Many therapeutic questions remain unanswered, including the efficacy of combination
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therapy, optimal timing of therapeutic intervention and therapy stratification. However, the increasing number of trials of treatments specifically for PsA is clearly a welcome development likely to lead to major advances in the management of this common, disabling disease.
Genetics of psoriasis and psoriatic arthritis As with most common human diseases, the genetic component of susceptibility to psoriasis and PsA is probably complex, involving many genes most probably interacting with one another and with environmental factors. The heritability of psoriasis has been assessed in twins; the concordance rate in MZ twins is significantly higher than in DZ twins (35–72% vs. 12–23%), indicating greater sharing of risk factors, most probably genetic. PsA is known to run strongly in families, with a reported sibling recurrence risk ratio of 48 (i.e. that brothers and sisters of a first-degree relative with PsA are 48 times more likely to develop the condition themselves than the individuals in the general community) [69]. Thus both psoriasis and PsA are thought to have significant genetic components, but the extent to which these overlap is uncertain. To some extent this depends on disease definitions. For example, psoriasis commonly occurs in association with ankylosing spondylitis. In that setting, is this psoriatic spondyloarthritis, or ankylosing spondylitis with complicating psoriasis? Then there is the question about ‘PsA sine psoriasis’, a small group of PsA cases that do not have psoriatic skin disease. The genetic findings to date in the major ‘seronegative’ diseases suggest that there is a core set of genes influencing susceptibility to psoriasis, ankylosing spondylitis and inflammatory bowel disease, favouring ‘lumpers’ ahead of ‘splitters’ with regard to these diseases [70]. Genes that are unique to ankylosing spondylitis and inflammatory bowel disease have also been identified, but no gene has yet been demonstrated to be specifically associated with PsA but not either psoriasis or these other conditions. This suggests that the genes causing PsA might largely be a subset of the genes causing psoriatic skin disease. These findings have prompted extensive searches for genetic associations with psoriasis and psoriatic arthritis. Until recently, these studies consisted either of candidate gene association studies, or genomewide screens by linkage. Linkage studies were used to identify broad regions likely to contain psoriasis genes, of which 10 have been defined. Apart from PSORS1, which includes the HLA-C locus, these loci are of uncertain significance, although in some cases candidate genes have been identified within those loci that might be responsible for the observed linkages. The MHC associations of psoriasis and PsA are clearly complex. Although strong association is observed with HLA-Cw6, whether it is the primary associated gene is unclear. The PSORS1 locus is thought to extend over a region of 200 kb, a region containing eight genes in linkage diswww.drugdiscoverytoday.com
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equilibrium with this allele. At least two of these are good candidates for involvement in psoriasis. Corneodesmosin, encoded by the gene CDSN, is expressed in keratinocytes, mutations of the CDSN gene cause a form of hypotrichosis of the scalp (OMIM 164520) and its expression is upregulated in involved psoriatic skin. Similarly, HCR (a-helix-coiled-coilrod homologue) is overexpressed in psoriatic skin but is of unknown function, and unlike CDSN, there are no known human diseases due to mutations in HCR. Because of the strong linkage disequilibrium in this region, it has not yet been possible by population genetics approaches to distinguish which of these genes is the primary associated variant in psoriasis. Association of the HLA-DRB1 allele, DR7, with psoriatic arthritis, has also been reported widely [71]. This too might represent linkage disequilibrium with HLA-Cw6 because both alleles lie on a common MHC ancestral haplotype [72]. Outside the MHC there have been some major recent advances, with the identification of association of psoriasis with polymorphisms of the gene IL12B and IL23R [73,74]. IL12B encodes the protein IL-12p40, which is a shared component of the cytokines IL-12 and IL-23. These two cytokines are involved in increasing differentiation of CD4 lymphocytes towards, respectively the Th1 or Th17 lineages. A further study has reported suggestive evidence of association of polymorphisms of IL15 with psoriasis. IL15 is known to stimulate cytokine production by Th17 lymphocytes among other effects [75]. These findings strongly implicate the highly pro-inflammatory Th17 lymphocyte subset in the aetiopathogenesis of psoriasis. IL12B has also been associated with Crohn’s disease [76], and IL23R with both Crohn’s disease [76] and ankylosing spondylitis [77], thereby at least partially explaining the co-occurrence of these diseases. These findings also support the targeting of this system in psoriasis. A recent trial of anti-IL12p40 antibodies has demonstrated good efficacy and safety in psoriasis [78], and it is likely that other treatments will be trialled such as targeting IL-23 specifically, or Th17 produced pro-inflammatory cytokines, such as IL-17. A recent study investigating loci associated with Crohn’s disease in psoriasis has demonstrated suggestive association of psoriasis with three regions, 1q24, 6p22 and 21q22 (P = 0.009–0.00015). The gene underlying the 6p22 association is thought to be CDKAL1 (CDK5 regulatory subunit associated protein), which in addition to being associated with psoriasis and Crohn’s disease [79], is known to be associated with type 2 diabetes mellitus [80,81]. The functions of this gene and the mechanism of its association with these conditions are unknown. Several other genes have been associated with psoriasis generally with less strong evidence or replication. A region on chromosome 17q lying between the genes SLC9A3R1 and NAT9, which affects a RUNX1 binding site, has been reported e52
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to be associated with psoriasis [82]. Another solute carrier gene, SLC12A8, has been associated with psoriasis in two studies [83,84]. A study of PsA associations identified no association with either gene [85]. Association with variants of the CARD15/NOD2 gene, which is a major gene in Crohn’s disease, has been reported with PsA [86], but many other studies have not shown any association [87–92]. None of these genes were identified in the only genomewide association reported to date in psoriasis, although this study is underpowered and had low genomic coverage, perhaps explaining the failure to demonstrate these associations [74]. It is likely that over the next couple of years major advances will be made in the genetics of psoriasis and psoriatic arthritis, brought about by the advent of genomewide association studies. Autoimmune diseases appear particularly tractable to this type of study, and it is also apparent that their productivity is related to the familiarity of the conditions being studied. Therefore, there is a high likelihood that at least in psoriasis progress will be rapid. Whether the clinical heterogeneity of PsA will adversely influence the outcome of studies in this condition, we will have to wait and see.
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