quo vadis psoriasis treatment? Immunology, pharmacogenomics, and epidemiology

Clinics in Dermatology (2008) 26, 554–561

Future perspectives/quo vadis psoriasis treatment? Immunology, pharmacogenomics, and epidemiology☆ Alexa B. Kimball, MD⁎, Thomas S. Kupper, MD Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA

Abstract Advances in the understanding and treatment of psoriasis in the past several years have been remarkable. New frontiers include better understanding the immunologic pathways that underlie the disease and the development of personalized strategies to maximize the benefit and minimize the risk for patients. Although a cure may not be imminent, there are some strategies under examination that may lead us closer to this goal. © 2008 Elsevier Inc. All rights reserved.

Introduction Psoriasis is an ancient and common human disease that affects millions of people worldwide. A widely accepted current view is that psoriasis is a T-cell–mediated dermatosis1; however, as recently as 20 years ago, psoriasis was fundamentally understood as an intrinsic epidermal disease. The reality has proven to be even more complex, and as such, it may be best to eschew dogmatic views about etiology. There is no doubt that therapies directed against activated T cells, including cyclosporine, are uniquely effective in psoriasis. But it is our premise that although T-cell activation is necessary, it is not sufficient for psoriasis. We believe that the disease(s) we define as “psoriasis” results when there is the appropriate confluence of variables, both genetic and environmental, that come together to generate the unique phenotype of the psoriatic reaction pattern. A clearer

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Dr Kimball has been an investigator and consultant for Centocor, Amgen, Genentech, and Abbott, and an investigator for DNAX. Dr Kupper has been a consultant for Centocor. ⁎ Corresponding author. E-mail address: [email protected] (A.B. Kimball). 0738-081X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2007.11.007

understanding of this complexity may point us to the therapies of the future.

Immunology T cells and psoriasis It has become virtually an article of faith in investigative dermatology circles that T cells are responsible for psoriasis. The efficacy of methotrexate, once attributed to its effects on proliferating keratinocytes,2,3 is likely to work in psoriasis as it does in other autoimmune diseases: by directly inducing apoptosis of activated T cells.4 Similarly, the calcineurin inhibitor cyclosporine, found serendipitously to clear psoriasis in a fashion that was described as “miraculous” by long-afflicted patients, directly acts on T cells.5 The further finding that denileukin difitox, which very specifically targets activated T cells through the interleukin (IL)-2 receptor, can induce psoriasis remission in some individuals6 lent further support to a T-cell etiology of this disease. The biologics alefacept, which targets CD2 expressed on all T cells and at higher levels on memory T cells, works directly on T lymphocytes,7 and efalizumab

Future perspectives/quo vadis psoriasis treatment? appears to preferentially target lymphocyte function-associated antigen 1 on these T cells as well.8 Even anti–tumor necrosis factor (TNF) therapies may bind to TNF-α expressed on the surface of TH1 T cells, thus, depleting them, although these molecules likely have targets distinct from T cells. The most significant sources of TNF-α in psoriasis are, however, not T cells but rather myeloid cells,9,10 suggesting the difficulty of implicating a single cell type in the often dramatic clinical responses to these agents. The clear association of psoriasis with the class I major histocompatibility allele HLA-Cw611 also argues for a T-cell role in psoriasis and specifically implicates CD8 T cells. T cells typically recognize peptide antigens presented to their T-cell antigen receptor in the molecular context of HLA-A, B, C (CD8 T cells), or HLA-D (CD4 T cells). According to this model, CD8+ T cells in patients with psoriasis are responding to a putative autoantigen in the epidermis, and T-cell activation leads to the downstream effects of epidermal hyperplasia, angiogenesis, and other features of this disease. A model for psoriasis that accommodates this view is as follows: An individual of the appropriate genetic background acquires a bacterial (eg, streptococcal) infection through skin or the oropharynx. The immune response to the infection includes stimulation of T cells that recognize antigenic peptides in the context of HLA-C and HLA-D on dendritic cells. These T cells may be activated by bacterial antigens that cross-react with autoantigens or may be polyclonally stimulated independent of peptide antigen by superantigens. Whatever the case, a population of autoreactive T cells emerges. Because they underwent the naïve to memory transition during activation in the correct lymph node environment (lymph node–draining skin or oropharynx), these activated T cells have been “educated” to express skinhoming molecules on their surface (eg, cutaneous lymphocyte antigen, chemokine [C-C motif] receptor 4).12,13 These cells now have the capacity to traffic constitutively from blood to skin, where they may stay for varying lengths of time before a subset returns to blood via afferent lymphatics, only to recirculate again.14 These immunologic events have thus generated a population of skin-homing T cells that are accidentally reactive to a skin autoantigen. These autoreactive memory T cells appear to be necessary, though not sufficient, for psoriasis to manifest.12 Like all skin-homing memory T cells, these T cells can traffic into skin from blood.12 Although resident in or traveling through skin, they have the potential to recognize and respond to the skin autoantigen for which they are specific by virtue of their T-cell receptor. But alone, this potential to recognize and respond to antigen is by itself insufficient to activate the T cells. An antigen-presenting cell, typically a dermal dendritic cell, must internalize and process the autoantigen and then successfully present it to T cells in the context of the appropriate HLA molecule. Dendritic cells in normal skin at rest do not activate T cells; they must first be activated themselves to fulfill this function.12 Activation and maturation of dendritic cells in skin typically occurs as a response to an

555 injurious or infectious environmental challenge, and can be triggered by bacterial products through Toll-like receptors or by cytokines such as IL-1 and TNF-α from resident skin cells.15 These events generate dendritic cells that express high levels of HLA molecules bearing antigens, including autoantigens, and costimulatory molecules on their surface. In this setting, T cells specific for this (auto)antigen/HLA complex become activated in situ and begin to perform effector function, including the release cytokines, chemokines, and other factors. These T-cell–derived factors appear to initiate and sustain the cascade of molecular events that leads to a psoriatic plaque. This model explains not only the Koebner phenomenon, but also the association between flares of psoriasis and local infection of the skin. Although psoriatic T-cell activation by autoantigen is regulated at the level of the dendritic cell and its encounter with activating/maturing stimuli, there are additional levels of regulation. Also residing in skin are populations of T cells whose roles are to inhibit immune responses; these cells are known as regulatory or suppressor T cells.16,17 One population of these cells, so-called natural Tregs, express CD4, high levels of CD25, and FoxP3, and their role is to inhibit weak or modest T-cell receptor stimulation by dendritic cells while permitting strong stimulation to occur.16,18,19 In effect, these Tregs determine at what threshold of stimulation T cells are allowed to be activated. This may be important teleologically because the skin is normally covered with innocuous and weakly immunogenic normal flora, to which vigorous ongoing immune responses would cause immunologic chaos and chronic inflammation.17 Tregs limit T-cell activation to these normal flora while permitting the necessary T-cell activation to acute infection. We have outlined how T cells become activated in skin and have introduced 2 variables that can modulate this activation: the facility with which dendritic cells become activated/ matured and the frequency and efficacy of regulatory T cells. Together, these variables set the threshold for T-cell activation in skin. One could imagine that polymorphisms in cytokine or toll-like receptors that increase or decrease response to infectious pathogen ligands could then influence the ease of dendritic cell activation, which in turn could influence the facility of T-cell activation to autoantigen and, ultimately, the severity of psoriasis. Similarly, genetic variation driven by polymorphisms that influence the frequency or function of Tregs could be another modulatory variable. A recent development in fundamental T-cell biology also sheds light on the etiology of psoriasis. One of the seminal contributions of the last 20 years was the appreciation that T cells can be classified with regard to their profile of cytokines produced upon activation. Mosmann and Coffman20 identified T helper 1 and T helper 2 cells; the former produced interferon (IFN)-γ, TNF-α, and TNF-β, and induced inflammation, whereas the latter produced IL-4, 5, 6, 10, and 13, and favored allergic and atopic responses. Later, it was appreciated that CD4 and CD8 cells could be classified by their production of these cytokines, which were then

556 designated as type 1 or type 2 cytokines.21 Teleologically, type 1 cytokine responses were considered important for viral and intracellular bacterial infections, whereas type 2 cytokines were implicated in the response to intestinal parasites. This, however, left a host response lacuna; it had became increasingly clear that T cells were also implicated in the response to extracellular bacteria and fungi, and the potential role of type 1 or type 2 T cells in this regard seemed inadequate. Very recently, a new class of T cells was identified, based on the production of a group of cytokines collectively called IL-17.22,23 T cells that produce this cytokine, called somewhat inelegantly “TH17 cells,” do not produce TH2 cytokines and produce much lower levels of IFN-γ, if at all. IL-17 isoforms induce production of vascular endothelial growth factor and other angiogenic factors,24 and strongly induce IL-8, a neutrophil chemotactic cytokine, which is also proangiogenic, as well as granulocyte colony stimulating factor, which induces neutrophil maturation.23 Other actions of IL-17 include the induction of antimicrobial peptides by epithelial cells. In other words, TH17 cells appear to be the missing T-cell subset important for controlling extracellular bacterial infections occurring at epithelial interfaces with the environment.25 In animal models, TH17 cells have been implicated in several autoimmune diseases, including arthritis, inflammatory bowel disease, and multiple sclerosis.26,27 The association of TH1 and TH17 cells is also intriguing. IL-12 has long been known to be necessary for the generation of TH1 cells from naïve precursors. IL-12 is a heterodimeric cytokine composed of p35 and p40 chains. The p40 chain is also used by another heterodimeric cytokine, IL-23, in conjunction with a p19 chain. Intriguingly, even though the induction of TH17 cells requires only transforming growth factor (TGF)-β and IL-6, IL-23 appears to be necessary for the expansion of TH17 T cells.28,27 Much circumstantial evidence links IL-23 and TH17 T cells to psoriasis.29-32 First, IL-23 but not IL-12 is strongly up-regulated in psoriatic skin.33 Second, IL-17 has long been identified as being up-regulated in psoriasis lesions.34,35 Third, downstream events attributable to TH17 T cells are also seen in psoriasis, namely, elevated levels of IL-8, a neutrophilic infiltrate in the upper epidermis, abundant angiogenesis, and high expression of antimicrobial peptides. In contrast, TH1 cytokines would not be expected to generate neutrophilic infiltrates or angiogenesis. A recently published trial indicates that therapeutic antibodies to p40, the peptide chain shared by IL-12 and IL-23, are highly effective in psoriasis.36 It is, thus, attractive to speculate that the autoreactive T cells in psoriasis are in fact skin-homing TH17 T cells or their CD8 equivalents.

T cells: not sufficient, but necessary? The above arguments seem to strongly implicate psoriasis as a T-cell–mediated disease. It is, however, important to recognize that the normal response of the immune system

A.B. Kimball, T.S. Kupper to extracellular bacterial pathogens encountered through skin is likely to be very similar. Extracellular bacteria are encountered by the skin and molecules such as LPS, and techoic acid intrinsic to bacterial cell membranes induce activation of toll-like receptors on skin dendritic cells.37 These skin dendritic cells then activate resident skin-homing T cells of the TH17 variety via antigen presentation, leading to production of IL-17 and other cytokines. Antimicrobial peptides, infiltrating neutrophils, and proliferating keratinocytes all contribute to eradicating the bacterial infection. This is likely to occur with great frequency, and it should be obvious that in most individuals, activation of such T cells in skin does not cause psoriasis. The hypothesis that individuals without psoriasis make low-level subclinical immune responses to autoantigens in skin has been suggested, but certainly, patients without psoriasis can develop allergic contact dermatitis mediated by T cells in skin without developing psoriasiform hyperplasia. In contrast, many patients with psoriasis develop psoriasiform hyperplasia in response to developing allergic contact dermatitis. All of these observations lead to the suggestion that there is something unique about the intrinsic cellular elements of the skin in patients with psoriasis that may not depend on the T cell at all. A manuscript published in Nature (in 2005)38 reported that the inducible deletion of a gene known as JunB in epidermal keratinocytes led to spontaneous expression of a murine disease reminiscent of psoriasis that was associated with joint inflammation and that could be reversed by TNF blockade. The authors concluded, and Nature editors agreed, that psoriasis was an epidermal disease after all and did not require T cells to manifest. Since that time, the centrality of Jun has been called into question by the demonstration that human psoriatic keratinocytes overexpress Jun and related proteins.39 Nonetheless, the observation that a disease phenotypically identical to psoriasis could emerge in the absence of T-cell activation was novel. Other recent articles have subsequently implicated monocytes and macrophages rather than T cells as primary drivers of psoriasis in mouse models.10,40-42 These observations implicate the intrinsic cells of the skin including keratinocytes as important variables in this disease. Along the same lines, another set of cytokines that can induce the epidermal hyperproliferation and inflammation seen in psoriasis are the IL-10 family members IL-19, IL-20, IL-22, and IL-24.43,44 Unlike IL-10, which is on balance antiinflammatory, these family members tend to be proinflammatory and growth-promoting in epithelial cells. Overexpression of IL-20 in epidermis leads to features of psoriasis including hyperproliferation of keratinocytes and inflammation. 45,46 Keratinocytes and infiltrating monocytes can produce these cytokines, and keratinocytes express receptors for them. Importantly, most of these cytokines are not produced by T cells, and their production can mimic a psoriatic phenotype. A related cytokine, IL-22, is produced by TH17 T cells and can contribute to this phenotype.47

Future perspectives/quo vadis psoriasis treatment? Genetic studies have suggested that polymorphisms in the genes for these cytokines can serve as positive and negative regulators of the psoriatic phenotype.48,49 There is also a link between TNF-α and these IL-10 family members; IL-17 strongly induces TNF-α,27 which in turn stimulates the production of IL-19, IL-20, and IL-24. Anti–TNF-α therapy could, thus, be viewed as blocking the downstream effects of IL-17. It is also, however, the case that TNF-α can be induced independent of IL-1750 or indeed any T-cell product, and TNF-α might be expected to induce IL-10 family members in the absence of T-cell activation. So what is the link between T-cell activation and psoriasis? T cells provide an anatomically focused response to an immunologic challenge, and under the proper conditions, they become activated at the site of the antigen and in response to it. Cytokines produced by T cells, including IL-17, IL-22, and related molecules for TH17 cells, have direct effects on target tissues. These effects, in the case of TH17 cells being activated in skin, induce TNF production, vascular endothelial growth factor and angiogenic factor induction, antimicrobial peptide generation, IL-8 production, and local release of IL-19, IL-20, and IL-24, all sufficient to induce the inflammation, angiogenesis, neutrophilic infiltration, and epidermal hyperproliferation of psoriasis. These events are precisely the same as the ones that occur after infection with extracellular bacteria, and in concert with the innate immune events such as the antimicrobial peptides induced by TH17 cells, they are typically sufficient to clear the bacterial infection in skin. After infection, the antigen is cleared, and T cells lack a stimulus for chronic activation. If psoriasis is an autoimmune disease and the antigen is intrinsic to the epidermis, then there would be no diminution of antigen load after the immune response, and the immune fire would continue to be fueled in positive feedback loop. The process would persist until a steady state was reached with the establishment of a psoriatic plaque. Whether driven by T-cell activation or innate immune activation, inflammation resolves if the antigen or pathogen is removed. Transgenic mouse models of psoriasis have utility, but can be misleading. When elements that induce epidermal inflammation and epithelial hyperproliferation are expressed constitutively in skin, chronic inflammation and psoriasiform hyperplasia ensues. Psoriasis can, thus, be generated in animal models without T cells, but in decidedly nonphysiologic fashion. In man, it does appear that T cells, although not sufficient, are necessary for disease manifestation. The complex process described above includes many variables, each of which could be a modifier of disease severity and serve as a potential disease-modifying target. Dendritic cell activation can be influenced by many variables, including cytokine (IL-1, TNF-α) and toll-like receptors. Polymorphisms in these molecules can raise or lower the threshold of dendritic cells to become activated, and similarly, variations in the expression of costimulatory molecules and their antagonists can influence T-cell activa-

557 tion. T-cell activation and growth can similarly be influenced by a number of variables. TH17 cells express the IL-23R and respond to this cytokine, and it was recently reported that a polymorphism in the IL-23R is a strong risk factor for inflammatory bowel disease.51 This same polymorphism appears to be a risk factor for psoriasis.52 It may be that polymorphisms in receptors to TGF-β and IL-6, implicated in the differentiation of TH17 T cells, also play a role in other autoimmune diseases. Other receptors or activation molecules on T cells can also represent important genetic variables. Production of T-cell cytokines is also likely to be heterogeneous across populations; polymorphisms in IL-17A and IL-17F may lead to less or more vigorous production. Because the threshold for activation of T cells in skin is determined in part by Tregs, polymorphisms of FoxP3 or other factors influencing the function of these cells could enhance or inhibit their activity. Finally, the targets of T-cell cytokines are also potential genetic variables. As noted, polymorphisms of IL-19, IL-20, and IL-22 have been linked to the risk of developing psoriasis.48,49 And finally, the receptors for these molecules on keratinocytes, as well as molecules involved in the downstream events that involve proliferation, can vary genetically in populations. The list goes on, and nearly every variable that contributes is likely to be subject to genetic variation. Which variations, or polymorphisms, are clinically important and which are purely epiphenomenal will take time to sort out.

The future of therapy Despite numerous advances in the therapy for psoriasis, it can still be a very frustrating disease to treat. We still cannot predict who is likely to respond well to specific therapies. There are 2 major areas where we can expect to see further developments that may profoundly affect our ability to help our patients in the future. First, continued advances in the understanding of the complex immunologic pathways that contribute to the chronic inflammatory state in psoriasis will undoubtedly lead to the identification of new targets and development of additional interventions. Second, personalization of treatment based on genetic and demographic characteristics may lead to better and safer outcomes in patients. Ultimately, of course, what most patients want is a cure. Given the polygenic and protean manifestations of psoriasis, this solution may not be within our immediate reach. Tantalizing concepts, however, include the ideas of preventing the development of psoriasis through blocking immunologic sensitization or immunologic progression.

The future of immunologic therapies In just the past decade, the armamentarium of systemic therapies has moved from small molecules with multiple

558 effects to biologic therapies with specific targets in the immune system. The conventional therapies for psoriasis include methotrexate and cyclosporine. Methotrexate, an inhibitor of dihydrofolate reductase, was originally thought to work primarily by inhibiting proliferation of keratinocytes2 but, more recently, has been shown to inhibit T cells as well.4 Cyclosporine, a calcineurin inhibitor, is a classic drug used to effect general T-cell suppression.5 As discussed in previous chapters, with the remarkable advances in the understanding of the genetic and immunologic basis of psoriasis have come a number of truly revolutionary therapies. There are medications that specifically target activation and localization of T cells, TNF-α, and, most recently, the p40 subunit of IL-12 and IL-23 being used in clinical settings today. Many promising candidates have also fallen by the wayside because of toxicities or modest effects, including anti-CD3 antibodies, CTLA-4 immunoglobulin, denileukin diftitox, IL-10, and antibodies to IL-8, to name a few. Alefacept and efalizumab interrupt T-cell priming and, in the latter case, T-cell trafficking.7,8 The TNF-α inhibitors, adalimumab, infliximab, and etanercept all decrease TNF-α levels and profoundly decrease the clinical signs of psoriasis and psoriatic arthritis.53-55 There do, however, seem to be some differences between the receptor protein, etanercept, and the monoclonal antibodies adalimumab and infliximab that may be related to differences in efficacy and toxicity. For example, the first appears to, in some cases, paradoxically increase TNF levels,56 whereas the latter may decrease IFN-γ and cause cell lysis.57 Indeed, although these therapies are specifically targeted, their effects are manifold, underscoring our incomplete understanding of their mechanism of action. Fortunately, they do not appear to cause the same degree of end-organ damage compared with their predecessors. The immunologic paradigms outlined previously in this chapter suggest that there are other approaches that can and will readily be tried. There will quite likely be continued work on how to inhibit key cytokines such as IL-23, including specific targeting p19 subunit of IL-23 and IL-17A-F. In addition, IL-17 associated cytokines (IL-22) or IL-17 inducible cytokines such as IL-19 and IL- 20 would be other possible targets.

Where will the next therapies come from? Although rebalancing immune networks to correct elements of dysfunction with antibodies or small molecules may be an approach that puts psoriasis into remission, it is unlikely to lead to cure. This approach, moreover, will likely always come at some functional price to the rest of the immune system. More tantalizing targets are to find approaches to prevent initial sensitization, epitope spreading, and clonal T-cell expansion, or somehow induce desensitiza-

A.B. Kimball, T.S. Kupper tion to the triggers that are causing the initial dysfunction. Could the threshold for stimulation of dendritic cells be altered, or are they hardwired? Could the population of Treg cells in the skin be increased chronically, dampening the pathologic response? Could TGF-β be used to increase the activity of these regulatory cells? Could psoriasis be a candidate disease for vaccine development?58 Does it matter when, in the course of the disease, approaches like this are implemented? All of these questions are potentially fruitful for the future and may dramatically alter our approach to treatment. In the past, we have “saved” therapies until patients “really needed” them because of their cumulative toxicity. Perhaps we should, however, be giving them earlier in the course of the disease if we change the natural history of the disease.

Personalized therapy? Despite the revolution in technology, widespread utility of pharmacogenomics has remained elusive. Pharmacogenomics can theoretically be used in multiple ways: gene expression profiles can predict response to therapy or risk for adverse reactions. The technique can also be used to identify new targets that may lead to specific therapies. In the near future, pharmacogenomics is likely to improve diagnosis and could improve the ability to predict responses to therapy or risk profiles. The main limitation in the case of psoriasis is that pharmacogenomics approach tends to work best if a single identifiable genetic variation causes a major clinical result. The mutation also has to appear frequently enough to be detectable in setting of relatively small clinical trials and, frequently enough, to make it worth testing for. Paradoxically, if a mutation is too frequent, it may not make sense to test for it. For example, it was established in 1998 that pravastatin works best at preventing atherosclerosis in people with b1 allele of cholesteryl ester transfer protein gene. Because this allele, however, is so common (85% of the population), and the drug is relatively safe, this group has not routinely been pretested before initiating therapy, almost a decade after this discovery was made.59 In psoriasis, several heritable loci have been identified, and the increased expression of many genes has been identified, but a marker that predicts therapeutic response has yet to be identified. If the concept that a genetic predisposition, such as an HLA type, and/or a receptor or interleukin polymorphism have to be in place, and then an immunologic pathway with memory is triggered by infection or some other event is true, then pharmacogenomic approaches will continue to be limited in the near term. The identification of an IL-23R polymorphism as a risk factor for psoriasis52 and the recent demonstration of the efficacy of an antibody that targets IL-23 are nonetheless a compelling development.

Future perspectives/quo vadis psoriasis treatment? Another obvious application of pharmacogenomics, accurate diagnosis, is not typically a major problem in the clinical care of psoriatic patients. In contrast, predicting the severity of disease, disease progression, or the development of psoriatic arthritis would be a powerful tool that pharmacogenomics may help solve. The development of registries that are collecting patient samples, demographic information, and phenotypic information have the potential to make major advances in this area. The identification of simple tests that would allow us to better predict adverse events would also be highly desirable and is perhaps within reach. For example, testing for the HLA B1502 allele in Chinese patients has 100% sensitivity and 97% specificity for carbamazepine-Steven-Johnson phenotype.60 Given the serious consequences of this reaction and its relatively high frequency, this kind of testing would be of great benefit for patients on systemic therapies. In the meantime, as we await the promise of pharmacogenomics to be delivered, emerging epidemiologic data about demographic profiles and pharmacokinetics may be an interim surrogate to predict response to therapy and risk of adverse events. Interestingly, despite the fact that the Psoriasis Area Severity Index is not a linear scale,61 the uniformity of response across the range of baseline severity has been repeatedly established in studies across several treatments.62 As a result, it appears that regardless of the type of therapy—topical or systemic—severity may not influence response, nor does history of previous therapies. Similarly, the absence or presence of arthritis seems to have a modest effect on the response of skin disease to therapy with the TNF-α blocking agents.63 Other research on the pharmacokinetics of biologic therapy, however, suggests that there are important differences in antibody formation and metabolism of some drugs.64 Body mass index also appears to impact the efficacy of some systemic therapies, especially those that are not dosed on a weight basis.65 Given the prevalence of obesity in the psoriatic population, this relationship may be very important in predicting effects of therapy. There is also new and compelling evidence that some comorbidities may substantially increase the risk of some therapies in psoriasis patients. For example, the presence of diabetes and alcohol intake highly correlates to the development of liver fibrosis while on methotrexate.66 Patients without these risk factors are at very low risk comparatively and may not need to be monitored nearly as closely. Also, on the forefront of research is the compelling question of whether psoriasis is actually a systemic disease— or at least if in some people it becomes one. The prevalence of psoriatic arthritis, believed to be in the 5% to 10% range, increases substantially in patients with more severe disease, although the severity of the arthritis and skin manifestations do not always correspond.67 Cardio-reactive protein levels are elevated in patients with psoriasis, particularly those with

559 arthritis.68 There is also an increased rate of lymphoma, as is seen in several other autoimmune diseases, such as rheumatoid arthritis.69 Importantly, there are several new epidemiologic studies demonstrating an increased rate of cardiovascular risk factors such as hypertension, diabetes, obesity, and smoking in patients with psoriasis, as well as an increased rate of myocardial infarction.70,71 Some recent evidence has even demonstrated an increased rate of coronary artery calcification. 72 Because one of the prominent hypothesis in metabolism currently is that atherosclerotic disease is inflammatory in nature,73 an intriguing set of hypothesis are being generated about whether the inflammatory states of atherosclerosis, psoriasis, and obesity are related or exacerbating each other. In the short and medium term, better use of the epidemiologic data we have about psoriasis patients to predict outcomes is likely to help our patients who require systemic intervention. Gathering better data in registries and from large databases will also be critical as we await the promises of genomics to come to fruition.

Conclusions Tar and light therapy were first used by the ancient Egyptians in the treatment of psoriasis, and we have certainly made dramatic progress since then. We also could not have predicted the therapies we have today. Some of our options in the therapeutic armamentarium have been discovered via a methodical process, but many, ranging from cyclosporine to TNF antagonism, have been discovered through empirical observation that was later linked to disease pathogenesis. With that in mind, predictions concerning the specifics of quo vadis therapy are speculative indeed. Nonetheless, and in contrast to some other areas in medicine, the therapeutic pipeline is that psoriasis is still very active and productive. Our patients are clearly benefiting from the treatments we now have available and are waiting for us to come up with the ones of the future.

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