Psoriasis: epidemiology

Abstract

Psoriasis is a chronic, inflammatory and hyperproliferative skin disease with a genetic basis. While epidermal hyperplasia and altered keratinocyte differentiation are prominent features, considerable evidence indicates that psoriasis is immunologically mediated. Recently, the identification of HLA-Cw6 as the disease allele conferring susceptibility to psoriasis has provided a focus for elucidation of these events. In this article, we will focus on the epidemiology of psoriasis and its associated arthritis.

Introduction

Psoriasis affects 1 to 2 percent of the U.S. population at an estimated cost of over 3 billion dollars per year.1, 5 It has several clinical presentations, most of which eventuate into chronic plaque psoriasis, which has a lifelong, waxing and waning course. Many patients develop nail disease, and/or an arthritis, which can be very painful and deforming. Microscopically, psoriasis is characterized by markedly increased proliferation and incomplete differentiation of the epidermis, a marked increase in cutaneous blood flow, and leukocytic infiltration of the papillary dermis and the epidermis. Evidence indicating that psoriasis is immunologically-mediated includes therapeutic response to immunosuppressant medications, transfer of the disease via bone marrow transplantation in humans and by purified T-cells in mice bearing human prepsoriatic skin, and the presence of clonal T-cell receptor (TCR) rearrangements in psoriatic skin. However, the molecular events triggering this state of immunologic activation remain unclear. Recent detailed genetic mapping of the MHC Class I region indicates that HLA-Cw6 itself is likely to be the functional variant predisposing to psoriasis, rather than a marker for some other disease gene nearby. This discovery provides a molecular target for elucidation of the immunologic basis of psoriasis.2, 4 This article focuses on the epidemiology of psoriasis and its associated arthritis.1, 2

Psoriasis is found worldwide, although its frequency varies widely among different ethnic groups. According to published reports, prevalence in different populations varies from 0% to 11.8%.³ Many confounding variables must be considered when considering these data, most particularly the method of ascertainment (clinic-based or population-based, examination-based, or questionnaire-based).⁴ Nevertheless, examination of available population-based studies reveals prevalences ranging from 0.2% to 4.8%. The highest prevalence, observed in Norway, was obtained by relying on ascertainment by questionnaire without validation of positive responses (Table 1). In another study from Denmark, after validation of a subset of positive questionnaire respondents by dermatological examination, prevalences were adjusted downward by 25%.⁹ With the exception of the Norwegian questionnaire study, the highest reported incidences in Europe have been in Denmark (2.9%) and the Faeroe Islands (2.8%), with the average for northern Europe being around 2%. Population-based (but not examination-validated) studies in the United States have yielded prevalences ranging from 2.2% to 2.6% with approximately 150 000 newly diagnosed cases per year.²⁰ The incidence of psoriasis appears to be lower in Asians, with several large population-based studies recording prevalences around 0.3%,⁵ but one large (but incompletely described) study yielding a prevalence of 1.2%.⁷ Remarkably, in population-based examinations of more than 12 500 Samoans and nearly 26 000 South American Indians, not a single case of psoriasis was seen (Table 1).

Although the only available studies are clinic-based, and several are rather small, investigations from Africa revealed a generally higher prevalence of psoriasis in East Africans (average of 7 studies = 2.0%) as opposed to West Africans (average of 5 studies = 0.3%).³ This difference might explain the relatively low prevalence of psoriasis in African Americans, most of whom originated from West Africa (1.3% in African Americans vs 2.5% in white Americans).²⁰

Associations between psoriasis and HLA-Cw6 have been appreciated for many years (see below for details). It is instructive to consider the aforementioned variations in psoriasis prevalence in the context of variations in population HLA allele frequencies, particularly HLA-Cw6. As determined by serologic methods in the 1991 HLA Workshop,²¹ the frequency of HLA-Cw6 in 25 white populations averaged 9.3% ± 3.3% (mean ± SD). In contrast, it was 4.4% in Northern Chinese Han, 2.2% in Southern Chinese Han, 1.0% in Japanese Wajin, 2% in New Guinea highlanders, 0% in aboriginal Taiwanese, 0.7% in Javanese, 1.0% in Eskimos, 2.9% in North Amerindians, and 0.0% in Brazilian Amerindians. Thus, as noted by Farber and Nall,³ there appears to be a parallel decline in HLA-Cw6 frequency and psoriasis prevalence in peoples whose ancestors migrated to the Orient and, ultimately, to the Americas. Low frequency of HLA-Cw6, however, does not appear to account for a lower frequency of psoriasis in blacks, as this allele was relatively common in the 11 black African populations sampled (15.1% + 8.4%).

Published estimates of the prevalence of psoriatic arthritis (PsA) vary widely, between 0.04% and 0.4%,²² probably because of differences in ascertainment and case definition. A recent population-based survey sponsored by the National Psoriasis Foundation determined that the prevalence of PsA in the United States is 0.5%.²³ In another population-based study of the residents of Olmstead County, MN, the prevalence of PsA was 0.1%, and the prevalence of psoriasis vulgaris (pv) was 0.7%.²⁴ Because the case definition for PsA included the presence of pv, approximately 14% of pv cases also had PsA. This value is well within the range of estimates of 5% to 40% described in the literature²² and not far from the value of 23% determined by the National Psoriasis Foundation survey.²³

Although some studies find minor deviations, psoriasis is equally common in males and females.3, 25 Several studies have reported an earlier age of onset in females, but this is not universally observed.³ There is no evidence for morphological differences in psoriasis between males and females.

Several authors have discussed the difficulties associated with accurate assessment of age at onset in psoriasis (reviewed in Ref.³). Nevertheless, as noted by Lomholt,¹⁰ age at onset is a very important piece of epidemiological information. Psoriasis may first appear at any age. It is most likely to appear between the ages of 15 and 30 years but ranges from birth to the eighth or ninth decade. There is 1 case report documenting onset at 108 years of age.²⁶ Unlike atopic dermatitis, onset before 10 years of age is uncommon. Different age of onset peaks in patients with psoriasis were reported by Henseler and Christophers²⁷ in 1985, who showed that the possession of certain HLA class I antigens, particularly HLA-Cw6, is associated with an earlier age of onset and with a positive family history. These findings led Henseler and Christophers to propose that 2 different forms of psoriasis exist: type I psoriasis with age of onset before 40 years and HLA-associated, and type II, with age of onset after 40 years and lacking HLA associations. Not all age-at-onset studies have observed this bimodality (reviewed in Ref.³). There is broad agreement in white populations, however, that early age at onset is associated with a higher likelihood of positive family history and with the carriage of disease-associated HLAs (reviewed in Ref.³). As will be discussed below, there is a subset of Oriental psoriatic patients with a different HLA association, and these individuals do not manifest early disease onset.

The genetic basis of psoriasis has been appreciated for nearly 100 years.²⁸ Only about one third of psoriatic patients, however, have an affected first-degree relative.³ As Gunnar Lomholt lamented in 1963 in his classic study of psoriasis in the Faroe Islands,¹⁰ “…That psoriasis is genetically conditioned is beyond doubt. But when the mode of inheritance appears to have been almost demonstrated, it again slips out of the fetters of fixed rules!” What, then, is the epidemiological evidence for the genetic basis of psoriasis?

Twin studies provide some of the strongest evidence for the genetic basis of psoriasis. Identical twins share all their alleles in common, whereas fraternal twins only share half. So, even if many genes contribute to the risk of psoriasis, disease should be concordant (present in both) in identical twins more often than in fraternal twins. Twin studies have indicated that many of the clinical features observed in psoriasis are determined by genetic factors.²⁹ They have, however, also consistently found less-than-perfect concordance for psoriasis in monozygotic twins, ranging from 35% to 73% in various studies.29, 30, 31 In each of these studies, psoriasis is concordant about 3 times more often in identical twins, compared with fraternal twins. Interestingly, monozygotic and dizygotic concordance rates are markedly lower in Australia than in the United States or in Denmark. Given that solar irradiation is greater in Australia than in Denmark and most of the United States, these differences suggest that ambient UV irradiation may be a therapeutic environmental factor (see below). Because the T-cell receptor and immunoglobulin system are generated by DNA recombination during development and are then selected by the individual's major histocompatibility complex (MHC), there are random effects of T-cell receptor and immunoglobulin repertoire selection within the individual that are not germline but also are not environmental. However, one would not expect these recombination events to vary geographically.

Currently, there are no published reports of twin studies in PsA, probably because of the lower frequency of PsA. Moll et al,³² however, reported a triplet born with an identical twin and a nonidentical third triplet. Both identical twins developed psoriasis with twin 1 manifesting spondylitis, and the other, polyarthritis. The nonidentical triplet had no psoriasis or arthritis.

Epidemiological evidence for heritability of psoriasis also comes from a variety of pedigree studies and population surveys, many of which have been reviewed by Farber and Nall.³ From these studies, single-gene recessive, 2-gene recessive, dominant with reduced penetrance, polygenic, and multifactorial (ie, polygenic plus environmental factors) models have been suggested for psoriasis. A non-Mendelian mode of transmission referred to as genomic imprinting has also been proposed for psoriasis and PsA,33, 34 as it has in other autoimmune diseases.³⁵ Genomic imprinting refers to an epigenetic effect that causes differential expression of a gene, depending on the sex of the transmitting parent. The imprinting process, exemplified by the Prader-Willi Syndrome,³⁶ allows gene expression from only the maternally or paternally derived chromosome.

A useful way to distinguish between Mendelian and polygenic models is recurrence risk analysis, involving the risk ratio λ_r. This parameter describes how much more common a disease is in their relatives of relatedness (r) compared with the general population. Three major population-based epidemiological studies—from the Faeroe Islands and Sweden10, 16 and 1 clinic-based study from Germany³⁷—have revealed a substantially higher incidence of psoriasis in relatives compared with the general population. Our analysis of these studies using recurrence risk analysis demonstrated that λ_r-1, the excess recurrence risk for relatives of degree r, dropped by a factor of 6 to 7 as r increased from 1 to 2, as opposed to the factor of 2 predicted for monogenic disorders.³⁸ This analysis favors a polygenic/multifactorial model.³⁹

Based on population studies, the risk of psoriasis in an offspring has been estimated to be 41% if both parents are affected, 14% if 1 parent is affected, and 6% if one sibling is affected, compared with 2% when no parent or sibling was affected.⁴⁰ Similar risks were determined by Watson et al.⁴¹ Like recurrence risk analysis, these results are also most consistent with a multifactorial model.

The calculated λ₁ for first-degree relatives is 8 for the Faeroe Islands cohort, 4 for the Swedish cohort, and 10 for the German cohort.³⁹ These findings have major significance for genetic linkage studies of psoriasis (genetic linkage refers to the cotransmission of marker and disease alleles within families). It has been shown that if λ₁ is at least 4, and at least one of the loci is of major effect, then a search for the genes by genetic linkage techniques is feasible.³⁸ Subsequent linkage analyses from many laboratories proved this to be the case, with a strong genetic effect arising from within the MHC (see below).

Reports of large families displaying strong evidence for linkage to the long arm of chromosome 17q42, 43 raise the possibility that a small number of families may carry non-MHC psoriasis susceptibility alleles with high penetrance, which may act in a Mendelian dominant fashion. Based on the foregoing studies, however, it would appear that in most cases, psoriasis behaves as a multifactorial genetic disorder. Twin studies and pedigree studies can be used to calculate the heritability (h²), a parameter used to measure the proportion of the variability of a multifactorial trait that is due to genetic factors. As reviewed previously, various estimates have placed the heritability of psoriasis in the range of 52% to 90%, among the highest of the multifactorial genetic disorders.3, 39

Epidemiological family studies demonstrating the magnitude of genetic burden of PsA are sparse. The most robust study estimating the strong familial clustering of PsA was performed by Moll and Wright in 1973.³² First and second-degree relatives of 88 patients with PsA were assessed from a hospital population, using unselective, consecutive sampling. Of the probands with PsA, 12.5% had at least 1 relative with confirmed PsA. Of the 181 first-degree relatives assessed, 10 relatives had PsA, including 5 siblings, yielding a 5.5% prevalence of PsA among first-degree relatives. As the calculated prevalence of PsA in the UK population is 0.1%, the risk for affected first-degree relatives (λ₁) is 55, a figure substantially higher than those obtained for psoriasis. This study also noted a 19-fold increase in prevalence of psoriasis among first degree relatives of probands with PsA, as compared with the general population. The remaining studies assessing the familial tendency of PsA were small and were often flawed by poor phenotypic ascertainment and inadequate controls. Nevertheless, these remaining studies also found familial clustering of PsA.³²

A non-Mendelian mode of transmission referred to as genomic imprinting has also been proposed for psoriasis and PsA11, 12, as it has for several other autoimmune diseases.²⁵ Genomic imprinting refers to an epigenetic effect that causes differential expression of a gene depending on the sex of the transmitting parent.¹⁰ The imprinting process, exemplified by the Prader-Willi Syndrome,¹⁰ allows gene expression from only the maternally or paternally derived chromosome. In one study, the birth weight of children from parents with psoriasis was found to be influenced by the sex of the psoriatic parent, with offspring of male psoriatic patients weighing 270 g more than offspring of female psoriatic patients.²³ The same authors reanalyzed the Faroe Island kindreds and noted a higher penetrance of psoriasis if the father was affected or a presumed gene carrier. Interestingly, others also noted evidence of a parental sex effect in psoriasis, with more psoriatic probands having an affected father than an affected mother.²⁶

A parent-of-origin effect has also been demonstrated in PsA.²⁴ The proportion of probands with an affected father (0.65) was significantly greater than the expected proportion of 0.5 (P = .001).²⁴ Similar trends were noted in the offspring and second-degree relatives of the proband. A recent linkage study in PsA, furthermore, noted significant linkage only when assessing the transmission of alleles of paternal origin.⁴⁴ Thus, the presence of this epigenetic phenomenon should be considered for incorporation in the genetic model for linkage studies, as its inclusion may influence the evidence for a linkage.

Fig. 1 depicts a model in which disease alleles at each of 4 loci on different chromosomes are required to develop psoriasis and that only 1 copy of each disease allele is required to develop disease (ie, each disease allele acts in a dominant fashion). Although this model is unproven and ignores the potential role of environmental factors, it is instructive in explaining the low frequency of families with multiple psoriatic members. Under this model, the chance of any given individual developing psoriasis would be (1/2)⁴ = 1/16. Thus, families would need to be very large to encounter more than 1 case per family. That familial involvement is observed in one third of cases suggests that the “burden” of psoriasis genes in the healthy population may be even higher than that shown in Fig. 1.

Based on the long-standing evidence for HLA associations in psoriasis (see below), we have hypothesized that a major psoriasis susceptibility gene resides in the MHC and that several other psoriasis genes are scattered throughout the human genome. Some of these non-MHC genes may be general regulators of inflammation and/or immunity and, therefore, can be thought of as “severity genes.” Others may make a distinctive contribution to the psoriatic phenotype and can be thought of as disease-specific susceptibility genes. Below, we will briefly review the accumulated evidence for these genes. Interested readers are referred to more detailed reviews.45, 46, 47, 48

Although multiple genome-wide linkage studies of psoriasis have been performed, only 1 locus, termed psoriasis susceptibility 1, has been identified consistently by linkage studies.⁴⁶ Psoriasis susceptibility (PSORS) 1 is located in the MHC (chromosome 6p21.3), which contains the HLA genes as well as more than 200 other genes.⁴⁹ Because serologic HLA typing techniques were available, the MHC was an early target of genetic association studies. Indeed, HLA associations with psoriasis were first reported in 1972.⁵⁰ Several HLA loci and alleles are associated with psoriasis, including HLA-B13, HLA-B37, HLA-B46, HLA-B57, HLA-Cw1, HLA-Cw6, HLA-DR7, and HLA-DQ9.39, 51 HLA-Cw6 has consistently demonstrated the highest relative risk for psoriasis in white populations, and many of the alleles at other loci are in linkage disequilibrium (LD) with HLA-Cw6 (ie, found together on the same chromosome more often than would be predicted by chance). Besides HLA-Cw6 and those alleles in LD with it, a haplotype containing HLA-Cw1 and HLA-B46 is strongly associated with psoriasis in Thailand and Japan.51, 52 This haplotype is specific to Southeast Asian populations. In studies from Thailand, approximately one third of psoriatic patients are HLA-Cw6–associated, one-third are HLA-Cw1-B46–associated, and one third are not HLA-associated.⁵¹ In Southeast Asians and whites, psoriasis is associated with the class I, rather than the class II, end of the extended HLA haplotypes carrying the risk alleles, thereby implicating the MHC class I region.51, 53, 54 This association is unusual among autoimmune disorders because most of them demonstrate stronger associations with MHC class II genes. HLA-Cw6 is associated with early age of onset in Southeast Asian psoriatic patients, as it is in whites. In contrast, the HLA-Cw1-B46 haplotype is equally prevalent in early- and late-onset psoriatic patients.⁵¹ Unlike HLA-Cw6, there is no evidence for an association between the HLA-Cw1-B46 haplotype and guttate psoriasis.⁵⁵ Interestingly, the HLA-Cw1-B46 haplotype has been associated with other autoimmune diseases, including myasthenia gravis and Graves disease.⁵⁶

HLA-Cw6 is also associated with psoriatic arthritis, with a tendency for early onset of skin lesions.⁵⁷ HLA-B27, HLA-B38, and HLA-B39 are also associated with psoriatic arthritis, with HLA-B27 being most strongly associated with the axial variant.48, 58 None of these HLA-B alleles are in linkage disequilibrium with HLA-Cw6 in white populations, but a relatively common haplotype containing HLA-B27 and HLA-Cw6 has been identified in the Chinese Han population.⁵⁹ At present, it is unknown whether this population is at greater risk for psoriatic arthritis.

HLA-Cw6 remains strongly associated with psoriasis in the presence of any of several different HLA-B alleles on the same chromosome,⁶⁰ suggesting that the PSORS1 gene must reside telomeric to HLA-B (Fig. 2). These studies, however, could not prove that HLA-C was the PSORS1 gene. As has been the case in several autoimmune diseases, LD has been the major obstacle to confirming or refuting the role of a specific MHC gene in psoriasis. The MHC is characterized by a reduced rate of meiotic recombination relative to the genomic average, with defined subregions of low recombination.⁶¹ One of these regions resides just telomeric to HLA-C and manifests a 2.3-fold reduction in recombination relative to the genomic average.⁶¹ Ten genes have been identified within this region.⁴⁹ As would be expected based on the high LD between them, several of these genes also display strong associations with psoriasis (Fig. 2). Most studies, however, have failed to identify any association independent of HLA-Cw6. Recently, by comparative DNA sequencing of risk vs nonrisk haplotypes, we were able to exclude all structural variants of these genes as candidates for PSORS1, with the exception of HLA-C and corneodesmosin.² Both of these genes are interesting functional candidates for PSORS1. HLA-C presents antigens to CD8⁺ T cells, which are increased in number in the epidermis of psoriatic lesions.⁶² Corneodesmosin plays an important role in regulating the desquamation of keratinocytes, and its expression is increased in psoriasis.⁶³ By typing each of these genes in our entire sample, and by typing additional genetic markers located between them, we could exclude the CDSN gene, leaving HLA-Cw6 as the only remaining candidate.² Additional work, however, is needed to rule out the possibility of regulatory variant(s) in this region that do not fall within genes. It is also possible that additional genes capable of modifying the risk associated with HLA-Cw6 remain to be identified within the MHC, as haplotypes carrying HLA-Cw6 along with different HLA-B alleles carry different risks of disease.50, 64

Despite the clear evidence for HLA-Cw6 as a major disease allele in psoriasis, only about 10% of HLA-Cw6 carriers develop psoriasis, and the gene-specific recurrence risk in siblings (λ_s) is estimated at 1.6 for PSORS1,⁶⁵ as opposed to an overall λ_s of 4 to 10.³⁹ This implies that PSORS1 accounts for less than 50% of the familial clustering observed in psoriasis, meaning that additional non-MHC genes are likely to be involved as well. Despite identification of at least 18 susceptibility loci outside the MHC region,⁶⁶ most of these loci remain to be replicated in independent studies. The PSORS2 (17q24-q25), PSORS5 (3q21), and PSORS9 (4q28-31) loci show the strongest evidence for reproducibility. Four studies42, 67, 68, 69 have provided confirmatory evidence (P < .01) in support of the original report of linkage to PSORS2,⁴³ and in another study, the P value was below .05.⁷⁰ It has been reported that genetic variations influencing the expression of the SLC9A3R1, NAT9, and/or RAPTOR genes may account for the PSORS2 locus.⁷¹ Others, however, have been unable to confirm these findings.72, 73 At the PSORS5 locus, the SLC12A8 gene has been implicated by 2 independent association studies.72, 74 The product of this gene shares amino acid homology with a large family of cation-chloride–coupled transporters of unknown function. This gene, however, is not detectably expressed in normal skin, nor is it overexpressed in psoriasis.⁷⁴ No disease-associated coding variations in the gene, moreover, have yet been identified. The PSORS9 locus was originally identified in a Chinese Han population.⁷⁵ Less significant evidence for linkage (P < .08), however, was reported in 4 other genome-wide linkage scans. A meta-analysis of these studies found that only PSORS1 and PSORS9 displayed significant evidence for linkage.⁷⁶ Other areas of biologic interest that are less well replicated genetically include PSORS4 and PSORS8. PSORS4 is located in the epidermal differentiation complex (1q21.3), home to many genes that are coordinately up-regulated in psoriatic lesions.77, 78 The PSORS8 locus (16q12-q13) contains with a known susceptibility gene for Crohn's disease (CARD15),⁷⁹ which is significantly more prevalent in patients with psoriasis than in controls.⁶⁷ Although several studies have failed to implicate CARD15 in psoriasis (reviewed in Ref. ⁸⁰), one association study from Newfoundland has implicated CARD15 in psoriatic arthritis.⁸¹ Readers interested in additional details on psoriasis linkage studies are referred to excellent recent reviews.45, 46, 82

The future of gene identification in psoriasis and PsA is likely to rest upon studies of allelic association (ie, comparison of allele frequencies in cases and controls or measuring the transmission of alleles from parents to affected offspring), rather than genetic linkage (ie, transmission of marker alleles within families). This is because sample collection is easier in association studies (large families are not required) and because association is much more powerful than linkage in the search for the genes contributing to polygenic diseases.⁸³ The major disadvantage of association studies is that their “effective range” is short, and therefore, hundreds of thousands of genetic markers are required to cover the genome in an association study.⁸³ Current microarray technologies allow approximately 300 000 to approximately 1 000 000 genetic markers (single nucleotide polymorphisms) to be typed for a given subject at the same time. Although expensive, costs for these microarray platforms are steadily decreasing. Ongoing and future studies of psoriasis genetics will involve the testing of thousands of cases and controls for genetic association using hundreds of thousands to millions of single nucleotide polymorphisms, as opposed to the traditional strategy in which tens to hundreds of families are tested for genetic linkage using hundreds of microsatellite markers. Although this strategy entails a very large number of tests and therefore increases the risk of false-positive results, the ability to test the strongest candidate markers in independent replication cohorts will minimize false-positive results. In the meantime, the genetic association approach is being applied to numerous candidate genes in psoriasis and PsA. Reports of significant non-MHC associations include the interleukin (IL)–1 gene cluster84, 85; the vitamin D receptor⁸⁶; Peroxisome proliferator–activated receptor γ⁸⁷; apolipoprotein E⁸⁸; vascular endothelial growth factor⁸⁹; the structurally-related genes IL-10 IL-19, IL-20, and IL-2490, 91; the chemokine receptor CX3CR1⁹²; the metabolizing enzyme CYP1A1⁹³; and the p40 subunit of IL-12.⁹⁴ Many of these studies, however, were conducted on relatively small samples, were of marginal significance, and require independent confirmation (see Note added in proof).

Multiple environmental factors have been implicated in the pathogenesis of psoriasis. Although only a few of these appear to be able to trigger the disease, many others have been shown to exacerbate or modify the disease. The role of environmental factors in psoriasis is probably best demonstrated by the less-than-perfect disease concordance in monozygotic twins, which has been shown to range from 35% to 73% in various studies.29, 30, 31 Although somatic mutations could account for some portion of this lack of perfect concordance, that would otherwise be expected for a “pure” genetic disease, this discordance strongly supports a major role for environmental factors in the initiation and pathogenesis of this disease.

Of infectious agents, the best characterized environmental factor in psoriasis is streptococcal throat infection. This infection appears not only to be able to trigger the disease but also to exacerbate preexisting chronic plaque psoriasis.⁹⁵ The association of streptococcal pharyngitis and guttate psoriasis was first reported in 1916⁹⁶ and has since then been repeatedly confirmed in multiple studies.97, 98 Given the great number of published cases of guttate psoriasis associated with streptococcal throat infections, it is of interest that there are very few case reports associating streptococcal skin infection with the development of psoriasis.⁹⁹ Thus, in general, primary skin infections do not appear to be able to trigger or exacerbate psoriasis. Interestingly, guttate psoriasis is also strongly associated with HLA-Cw6.⁵⁵ We have identified epitopes of streptococcal M protein that are structurally homologous to the so-called hyperproliferative keratins K16 and K17 and that are predicted to bind preferentially to the antigen-binding groove of HLA-Cw6. Using synthetic peptides containing these epitopes to pulse peripheral blood mononuclear cells, we have shown that CD8⁺ T cells taken from HLA-Cw6 positive patients respond to peptides common to K17 and M-protein, whereas nonpsoriatic HLA-Cw6 positive controls respond only to M-protein peptides.¹⁰⁰ Importantly, the skin-homing (CLA⁺) T-cell subset was enriched 10-fold for responsive T-cells.¹⁰⁰ These data suggest that although all HLA-C alleles efficiently present peptides derived from streptococcal M proteins to CD8⁺ skin homing memory T-cells, HLA-Cw6 is most efficient at presenting M protein–like peptides derived from K16 and K17. Recently, T-cells carrying the same T-cell receptor gene rearrangements have been identified in the lesional skin and tonsils of psoriatic patients.¹⁰¹ Based on these findings, we have proposed that guttate psoriasis is provoked by cross-reactive T cells activated by streptococcal infection of the tonsils, whereas chronic plaque psoriasis is maintained by autoreactive T-cells that continue to respond to keratin peptides long after the streptococcal infection has been cleared (Fig. 3).100, 102

HIV infection has been associated with severe exacerbation of psoriasis.¹⁰³ Interestingly, HIV infection does not appear to trigger the disease in these patients as the prevalence of psoriasis in HIV infection is the same as in the general population (1%-2% of patients).104, 105 Thus, HIV infection appears to be more of a modifying agent in psoriasis than a trigger. With progression of the immunodeficiency, the disease tends to become increasingly more severe but remits in the terminal phase.106, 107 This exacerbation, which has been speculated to be due to loss of regulatory CD4⁺ T cells and subsequent increase in the activity of the CD8⁺ T-cell subset,⁶² can be effectively treated with highly active antiretroviral therapy.¹⁰⁸

Acute stressful events have frequently been related with psoriasis flare or onset.109, 110, 111, 112 In a study of 132 patients with psoriasis followed up for 3 years after clearing with dithranol treatment, 39% of patients recalled the occurrence of a stressful event within 1 month before a flare.¹⁰⁹ The stresses included death, accidents, examinations, and sexual assaults. The interval from the event to development of psoriasis ranged from 2 days up to 1 month.¹⁰⁹ In another more recent study, 38 patients with psoriasis were divided into 2 groups—low-stress and high-stress groups, based on specific questionnaires.¹¹⁰ When these groups were compared, the patients in the high-stress group were found to have higher disease severity score (psoriasis area and severity index (PASI)).¹¹⁰ As psoriasis can be emotionally disabling, carrying with it significant psychosocial difficulties, particularly in those severely afflicted,¹¹² it is not particularly surprising that patients with more severe disease would score higher on a questionnaire evaluating stress.¹¹⁰ The finding, however, that actively spreading psoriasis was also associated with stressful live events, although only observed in men¹¹⁰ and the high frequency of flare observed to follow shortly after stressful events¹⁰⁹ supports the notion of this phenomenon of stress-related exacerbation. The mechanisms involved are mostly unknown but may involve neuroendocrine modulation of immune functions.113, 114

Trauma to the skin is a well-known inducer of psoriasis on nonlesional skin. Many different types of injuries may induce a Koebner response in psoriasis, but well-known examples are from cuts or scratching of the skin and even occasionally after sunburn. The Koebner phenomenon (also known as the isomorphic response) is an all-or-none phenomenon, such that if psoriasis occurs at one site of injury, it will occur at all sites of injury. It usually manifests itself around 7 to 14 days after injury and is often seen in patients with active disease or during periods of flare. Approximately one fourth of patients with psoriasis ¹¹⁵ may have a history of this reaction but when other factors, such as emotional stress, drug reactions and infections are included the lifetime incidence of the Koebner phenomenon may reach 76%.¹¹⁶

Lifestyle and body habitus have been demonstrated to influence the manifestations of psoriasis. Obese individuals have been shown to be more likely to present with severe psoriasis,¹¹⁷ but interestingly, obesity does not seem to have a role in triggering the disease as no difference in body mass index between psoriatic patients, and controls could be found at the onset of the disease¹¹⁸ and the weight was normal at the time of onset.¹¹⁷ Case reports showing near complete remissions of psoriasis in markedly obese patients after gastric bypass surgery have indicated that weight loss may have a role in the management of psoriasis.119, 120 So far, no prospective studies have been done that specifically evaluate the role of weight loss in psoriasis, but one study evaluating the effect of low-energy diet showed significant improvement after only 4 weeks when compared with a control group.¹¹³ It has been hypothesized that changes in the levels of metabolic hormones such as ghrelin and leptin may induce these changes by their potency to release proinflammtory mediators such as tumor necrosis factor α.¹²¹

Apart from energy intake and body habitus, diet may play a role in modifying the disease pathogenesis.¹²² Dietary factors such as polyunsaturated fatty acids, gluten, and alcohol have been shown to be able to influence the disease process in significant number of patients.¹²² Alcohol consumption appears to be prevalent in psoriasis,¹²³ and a significant proportion of the excess mortality observed in moderate to severe psoriasis can be attributed to its use or abuse.¹²⁴ Interestingly, in one study, alcohol use was only associated with the disease after, but not before, its onset.¹²³ Likewise, increased skin surface area involvement has been associated with alcohol intake,¹²³ indicating that its use can lead to exacerbation of the disease. Polyunsaturated fatty acids have been implicated in many inflammatory and autoimmune disorders secondary to overproduction of arachidonic acid derived eicosanoids.¹²² Diets rich in n-3 fatty acids, such as eicosapentaneoic acid, can result in the substitution of arachidonic acid and thus inhibit arachidonic acid conversion to proinflammatory mediators such as prostaglandins (prostaglandin E₂) and leukotrienes (LTB₄) ¹¹². Studies on the evaluating the effects of n-3 polyunsaturated fatty acids in the treatment of psoriasis have so far been inconsistent,¹²² and at this time, the role of their use in the management of psoriasis is unclear.

A very large recent study has found a substantial and highly significant increase in the risk of myocardial infarction (MI) in patients with psoriasis, compared with controls.¹²⁵ Risk of MI was higher in severe psoriasis (defined as requiring systemic therapy) and was greatest in younger patients. This study also confirmed previously reported findings that psoriatic patients were more likely to have diabetes, hyperlipidemia, history of MI, a higher body mass index, and to be a current smoker.111, 126, 127 The increased risk, however, of MI persisted even after adjusting for all these covariates. This important finding, which has long been recognized in rheumatoid arthritis,128, 129 suggests that a state of systemic inflammation that predisposes to atherosclerosis of the coronary arteries may be generated in both disorders.

Patients with psoriasis have been shown to have higher frequency of antibodies against gliadin, which is found in wheat gluten. In a study of 302 patients, antigliadin antibodies (AGA) were found in 16% of the patients. These patients had immunoglobulin (Ig) A AGA levels above the 90th percentile of the reference group, but IgG AGA levels were not increased, although there was a correlation between the levels of IgA and IgG AGA antibodies.¹³⁰ Interestingly, in a follow-up study on 33 AGA-positive and 6 AGA-negative patients maintained for 3 months on gluten-free diet, significant decrease in mean psoriasis area and severity index was observed, but only for those patients with prior positive AGA.¹³¹ Importantly, when regular diet was resumed, clinical deterioration was observed in 18 of the 30 patients with positive AGA who had finished the first phase of the study.¹³¹ Thus, available evidence indicates that gluten-free diet may be beneficial for those patients who have known antigliadin serum antibodies.

Ultraviolet (UV) radiation is a potent therapeutic agent commonly used for the treatment of moderate to severe psoriasis. Therefore, it might not be surprising that natural UV radiation has been speculated to be an environmental factor in psoriasis as the correlation in monozygotic twins is less pronounced in countries located closer to the equator.¹³² Although the exposure to UV is greater as one moves closer to the equator, this should not necessarily be associated with reduced prevalence of psoriasis in nonexposed areas such as the scalp and body areas that are normally covered by clothing. It is possible, however, that before psoriasis becomes detectable clinically, there is a prepsoriatic state in which there are more “psoriasis-specific” T cells in the epidermal and upper dermis. A high degree of UV exposure might delete and/or suppress these T cells to the extent that a threshold of clinically apparent disease is not achieved. This observation may therefore be interpreted that UV exposure may counteract the onset of psoriasis. No studies, however, have been done to address this specifically.

Other factors that have been implicated in psoriasis are smoking and medications such as antimalarials, β-blockers, lithium, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors and gemfibrozil, interferons α and γ, and imiquimod (Aldara).¹³³ The mechanism whereby these medications cause exacerbation is variable and often unknown, but the interferons and imiquimod are known to stimulate the T_H1 arm of the immune system.¹³⁴ Unlike obesity, smoking is associated with the onset of psoriasis,¹¹⁷ and high-intensity smoking, as defined by a consumption of more than 20 cigarettes daily, has been associated with more than a 2-fold increased risk of severe disease.¹³⁵ Although improvement with cessation of smoking has been described for the palmoplantar pustulosis variant of psoriasis,¹³⁶ no such studies have yet been done on chronic plaque psoriasis.

As reviewed earlier, considerable evidence suggests that multiple genes contribute to the development of psoriasis in any given patient. Thus, it is likely that several or even many different genetic combinations may precipitate the psoriatic phenotype. If this is the case, it is probable that different genetic subgroups of psoriasis exist and will be triggered by different environmental factors (ie, Streptococcus pyogenes and HLA-Cw6 in guttate psoriasis, smoking and unknown gene(s) in pustular psoriasis, etc).

In this review, we have endeavored to update previous comprehensive reviews on the epidemiology of psoriasis (eg, Ref.³), emphasizing recent advances in the genetics of this disease. We have only briefly discussed the fascinating immunopathogenesis of this disorder, which is discussed in detail elsewhere in this volume and in several excellent reviews.102, 137, 138, 139 In the coming years, we anticipate that genome-wide association analysis with dense marker maps will yield important insights into the many genes that determine risk of psoriasis, and that identification of these genes, in turn, allows us to define interactions with specific environmental factors which influence the disease process. These discoveries should accelerate the development of highly active, specific, and nontoxic treatments for psoriasis and psoriatic arthritis and hold the potential for cure of these enigmatic disorders.