Chapter 18. Psoriasis

Historical Aspects

Prevalence

Psoriasis is universal in occurrence. However, its prevalence in different populations varies from 0.1% to 11.8%, according to published reports.1 The highest reported incidences in Europe have been in Denmark (2.9%) and the Faeroe Islands (2.8%). A recent study of 1.3 million Germans found a prevalence of 2.5%.2 Similar prevalence (ranging from 2.2% to 2.6%) has been measured in the United States. A higher prevalence in East Africans as opposed to West Africans may explain the relatively low prevalence of psoriasis in African-Americans (1.3% vs. 2.5% in white Americans).3 The incidence of psoriasis is also low in Asians (0.4%), and in an examination of 26,000 South American Indians, not a single case was seen. Psoriasis is equally common in males and females.4,5

Age of Onset

Psoriasis may begin at any age, but it is uncommon under the age of 10 years. It is most likely to appear between the ages of 15 and 30 years. Possession of certain HLA Class I antigens, particularly HLA-Cw6, is associated with an earlier age of onset and with a positive family history. This finding led Henseler and Christophers6 to propose that two 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, although many patients do not fit into this classification. There is no evidence that type I and type II psoriasis respond differently to treatment.

Psoriasis is a chronic inflammatory skin disease, with a strong genetic basis, characterized by complex alterations in epidermal growth and differentiation and multiple biochemical, immunologic, and vascular abnormalities, and a poorly understood relationship to nervous system function. Its root cause remains unknown. Historically, psoriasis was widely considered to be a primary disorder of keratinocytes. With the discovery that the T-cell specific immunosuppressant cyclosporine A (CsA) was highly active against psoriasis, research became more focused on T cells and the immune system. Nevertheless, accumulating evidence shows that keratinocytes are an integral part of the cutaneous immune reponse in psoriasis.7

Genetics of Psoriasis

Pathogenesis of Psoriasis

Development of Lesions

Detailed light, electron microscopic, immunohistochemical, and molecular studies of involved and uninvolved skin of both newly appearing and established psoriatic lesions provide a useful framework for inferring cause-and-effect relationships between the many cellular events that take place in a psoriatic lesion. They are illustrated schematically in Fig. 18-1 and with actual photomicrographs in Fig. 18-2.

Uninvolved Psoriatic Skin

The normal-appearing skin of psoriatic patients has long been known to manifest subclinical morphologic and biochemical changes, particularly involving lipid biosynthesis.67,68 These changes were predominantly found in the stratum corneum and included changes in the levels and composition of phospholipids, free α-amino acids, hydrolytic enzymes, and several dehydrogenases. These changes led to the use of the term “histochemical parakeratosis” to describe these findings.67 Much more recent studies using microarray technology to search for differences in gene expression between normal and uninvolved psoriatic skin have identified groups of coordinately regulated genes involved in lipid biosynthesis and innate immune defense.69

Initial Lesion

In the initial pinhead-sized macular lesions there is marked edema, and mononuclear cell infiltrates are found in the upper dermis.70 These findings are usually confined to the area of one or two papillae. The overlying epidermis soon becomes spongiotic, with focal loss of the granular layer. The venules in the upper dermis dilate and become surrounded by a mononuclear cell infiltrate.67 Similar findings have been described in early macules and papules of psoriasis71 and in clinically normal-appearing skin 2–4 cm away from any active lesion in patients undergoing an acute flare of guttate psoriasis.72

Developing Lesion

Studies of the clinical margins of somewhat larger lesions (0.5–1.0 cm) reveal an approximately 50% increase in epidermal thickening in the “normal-appearing” skin immediately adjacent to lesions.67 There is a large increase in the metabolic activity of epidermal cells, including the stratum corneum, increased DNA synthesis, an increased number of mast cells and dermal macrophages, and increased mast cell degranulation.67,73,74 Subsequent studies revealed increased numbers of dermal T cells75 and dendritic cells (DCs)76 in both uninvolved and involved psoriatic skin relative to normal skin. Toward the center of the lesion, a “marginal zone” can be identified, with increasing band-like epidermal thickness, increasing parakeratosis and capillary elongation, and perivascular infiltration of lymphocytes and macrophages, without exudation into the epidermis. More centrally, rete ridges begin to develop in the marginal zone, before finally transitioning into the fully developed psoriatic plaque. Squamous cells manifest enlarged extracellular spaces with only a few desmosomal connections. Parakeratosis is typically mounded or spotty.

Mature Lesion

Mature lesions of psoriasis are characterized by uniform elongation of rete ridges, with thinning of the epidermis overlying the dermal papillae.67,71 Epidermal mass is increased three to five times, and many more mitoses are observed, frequently above the basal layer. About 10% of basal keratinocytes are cycling in normal skin, whereas this value rises to 100% in lesional psoriatic skin.77 Widening of the extracellular spaces between keratinocytes persists but is less prominent than in developing lesions and is more uniform than the typical spongiosis of eczematous skin lesions. The tips of the rete ridges are often clubbed or fused with adjacent ones, with thin, elongated, edematous papillae containing dilated, tortuous capillaries. Parakeratosis, with accompanying loss of the granular layer, is often horizontally confluent but may alternate with orthokeratosis,78 and hyperkeratosis is more extensive than in the transitional zone. The inflammatory infiltrate around the blood vessels in the papillary dermis becomes more intense but still consists of lymphocytes, macrophages, DCs, and mast cells. Unlike the initial lesion and the transitional zone, lymphocytes are observed in the epidermis of the mature lesion. Neutrophils exit from the tips of a subset of dermal capillaries (the “squirting papillae”), leading to their accumulation in the overlying parakeratotic stratum corneum (Munro's microabscesses) and, less frequently, in the spinous layer (spongiform pustules of Kogoj). Collections of serum can also be seen in the epidermis and the stratum corneum.67,71

Cellular Participants in Psoriasis

T Cells79,80

In 1984, it was demonstrated that the eruption of psoriatic skin lesions coincided with epidermal influx and activation of T cells,75 and shortly thereafter it was further shown that resolution of psoriasis during phototherapy was preceded by depletion of T cells, predominantly from the epidermis.81 Several studies found CsA to be highly effective in psoriasis,82,83 and this effect was demonstrated to be primarily through blockade of T cells rather than keratinocytes.84 Furthermore, psoriasis has been triggered or cured by bone marrow transplantation, depending on whether the donor or the host was psoriatic.85,86 The role of T cells in psoriasis was functionally demonstrated in 1996 when it was shown that the psoriasis process could be induced by injecting activated autologous T cells into uninvolved psoriatic skin transplanted onto severe combined immunodeficient mice.87 Available data indicate that the T-cell responses are antigen-specific rather than mediated by superantigens, as clonal populations of both CD4+ and CD8+ T cells have consistently been identified in psoriatic lesions.88–91 However, most of the T cells in a psoriatic lesion are not clonally expanded and may accumulate in response to the cytokine environment of the lesion. There is virtually no evidence for B-cell involvement or antibody-mediated processes in psoriasis.

The best-characterized T cells are the CD4+ and CD8+ subsets. Predominantly of the memory phenotype (CD45RO+), these cells express the cutaneous lymphocyte antigen (CLA), a ligand for E-selectin, which is selectively expressed on skin capillaries and therefore provides them with access to the skin.92 CD8+ T cells are predominantly located in the epidermis, whereas CD4+ T cells are predominantly located in the upper dermis.93,94 The cytokine profile of psoriatic lesions is rich in interferon (IFN)-γ,95 indicative of T helper 1 (Th1) polarization of CD4+ cells, and T cytotoxic 1 (Tc1) polarization of CD8+ cells96 (Fig. 18-3). Two other subsets of CD4+ T cells, stimulated by IL-23 and characterized by production of IL-17 (Th17 cells) and/or IL-22 (Th22 cells), are also found in psoriatic lesions and have been shown to play a major role in maintaining chronic inflammation in psoriasis97,98 as well as other autoinflammatory conditions.99–101 While the majority of CD4 T cells are Th1, about 20% of them produce IL-17 (Th17) and ∼15% produce IL-22 (Th22).98 Similarly, CD8+ epidermal T cells producing IFN-γ (Tc1), IL-17 (Tc17), and IL-22 (Tc22) are found in psoriasis.98 These T-cell subsets have considerable functional plasticity and conversions of Tc17 to Tc1102 and Th17 to Th1103–105 have been described. In mice most Th17 cells also elaborate IL-22, which mediates dermal inflammation and epidermal hyperplasia after intracutaneous injection of IL-23.106 However, in humans, this overlap is much less pronounced, with largely distinct populations of Th17 and Th22 cells.98,107–109

Regulatory T cells suppress immune responses in an antigen-specific fashion, and are responsible not only for downregulating successful responses to pathogens but also for the maintenance of immunologic tolerance.110 Several different populations of regulatory T cells (T-regs) exist but the best characterized one is the CD4+ CD25+ subset.111 A recent study of this subset in psoriasis demonstrated impaired inhibitory function and failure to suppress effector T-cell proliferation,112 possibly due to a tissue environment rich in IL-6 produced by endothelial, dendritic, and Th17 cells.113

Natural killer T cells (NKT cells) are a heterogeneous subpopulation of T lymphocytes defined by coexpression of the T-cell receptor (TCR) and natural killer (NK) lineage markers such as CD16, CD56, CD57, CD94, and CD161. Unlike conventional T cells, NKT cells recognize glycolipid antigens in the context of the MHC Class I-like antigen-presenting molecule CD1d. NKT cells constitute only a small fraction of lymphocytes. Nevertheless, their ability to rapidly secrete large amounts of cytokines, including IFN-γ, IL-4, IL-2, IL-5, IL-10, IL-13, IL-17, and TNF-α, positions them as potentially important regulators of T-cell differentiation at sites of inflammation. While NKT cells are increased in psoriatic lesions relative to uninvolved or normal skin, their precise role in psoriasis remains unclear.114

Natural Killer Cells

Like NKT cells, NK cells are major producers of IFN-γ and serve as a bridge between innate and acquired immunity. Unlike NKT cells, NK cells do not express the T-cell receptor. NK cells are present in psoriasis,115,116 and can trigger the formation of psoriasis lesions in a xenograft model system.117 NK cells are regulated in part by killer immunoglobulin-like receptors (KIRs), which recognize HLA-C and other MHC Class I molecules. KIRs are a family of ∼15 closely linked genes located on chromosome 19q13.4,118 some of which stimulate and others of which inhibit NK cell activation. KIR genes have been associated with psoriasis119–121 and psoriatic arthritis.122,123 It has been proposed that susceptibility to psoriatic arthritis is determined by the overall balance of activating and inhibitory genotypes.121,124 Although it is attractive to speculate that the association of psoriasis with HLA-Cw6 might reflect a KIR-mediated dysregulation of NK cells, it is known that a number of other HLA-C protein alleles recognize the same inhibitory receptor (KIR2DL1), including HLA-Cw2, HLA-Cw4, HLA-Cw5, HLA-Cw15, and HLA-Cw17. Thus, it is not straightforward to explain the action of HLA-Cw6 in psoriasis on the basis of KIR recognition alone.

Dendritic Cells

Treatments directed primarily against key costimulatory molecules expressed by “professional” antigen-presenting DCs markedly improve psoriasis.79 This suggests that T cells in psoriatic lesions are in constant communication with DCs, which have a role in both the priming of adaptive immune responses and the induction of self-tolerance125 (see Chapter 10). Several subsets of DCs have been defined, and many of these are found in markedly increased numbers within psoriatic lesions.125–128 Although DCs are believed to be central to the pathogenesis of psoriasis, the specific role of each subset is still somewhat unclear.

Langerhans Cells

Usually defined by a Langerin+, CD1a+ surface phenotype, Langerhans cells (LCs) are considered to be immature DCs (iDCs). LCs have a well-defined role as antigen-presenting cells (APCs) in contact dermatitis,129 but their role in psoriasis is currently somewhat unclear. While the density of LC is decreased in lesional psoriasis in terms of cells per unit area,126,130 the number of LC per unit length of epidermis is similar in normal, uninvolved, and lesional skin.128 DCs lacking the characteristic Birbeck granule but positive for the maturation molecule DC-LAMP found in the dermis of psoriatic lesions could be derived from epidermal or dermal iDC.131 Recently, LC have been shown to preferentially drive Th22 differentiation, relative to dermal DC.132 Interestingly, migration of LCs in response to inflammatory cytokines is markedly impaired in uninvolved psoriatic epidermis relative to normal skin,133 especially in type I (early onset) psoriasis.134

Dermal Dendritic Cells

Dermal DCs do not express activation markers in resting normal skin and in that context can be considered as another type of iDC that is similar to myeloid iDCs found in other tissues.128,135 Immunophenotyping studies have revealed that the population of dermal DCs is quite complex, and that psoriasis lesions demonstrate a marked increase in the number and maturation state of dermal DC.126,136,137 Identified initially by strong expression of MHC Class II and/or factor XIIIa,138 it is now appreciated that factor XIIIa+ cells are macrophages rather than DCs, and that the most reliable marker for myeloid-derived dermal DC is CD11c.139 There appears to be three types of myeloid-derived (CD11c+) DCs in psoriasis lesions.128,139,140 The first is the population of “resident” dermal DCs that are also seen in normal skin. These CD11c+/CD1c+ DC account for about 10%–15% of DCs in psoriasis lesions. These cells are relatively more mature than inflammatory DCs (see Section “Inflammatory Dendritic Epidermal Cells”), but less so than fully mature DCs. The second population comprises mature DCs that are marked by DC-LAMP or CD83. The DC-LAMP+ DCs form large aggregates with T cells in the dermis, whereas the CD83+ DCs are more diffuse. It has been suggested that fully mature DCs may be the sustaining force for chronic T-cell activation in skin and the characteristics of these cells are very similar to those in lymph nodes.128,139–141 The third population of myeloid DCs are the inflammatory DCs, which are CD11c+/CD1c−, and are less mature than the resident CD1c+ subset. These cells make IL-23 and probably help drive Th17 differentiation.142 About 80%–90% of DCs in psoriasis lesions are these relatively immature, inflammatory DCs and, interestingly, the total number of these cells can exceed the number of T cells in lesions. A subset of these inflammatory DC express high levels of TNF-α and iNOS, and by analogy to similar if not identical cells in mice, have been called “TIP-DC” (for TNF-α and iNOS-producing DC). Consistent with our recent genetic findings,64 TIP-DCs are increased up to 30-fold in psoriatic lesions.128 There appears to be substantial plasticity in this population of cells, as the cytokine milieu in atopic dermatitis promotes the emergence of dermal DC that chemotactically attract a different subset of T cells than those found in psoriasis.143

Inflammatory Dendritic Epidermal Cells

Thought to be either monocyte-derived iDCs,144 or a variant of inflammatory myeloid DC that migrate into the epidermis,145 inflammatory dendritic epidermal cells (IDECs) are distinguished from LCs by the lack of Birbeck granules and lower expression of CD1a. Unlike LCs, IDECs are nearly absent in normal skin, and their numbers are markedly increased in the epidermis of active psoriasis lesions, as well as a large number of other inflammatory dermatoses.126,130

Plasmacytoid Dendritic Cells

Plasmacytoid DCs (pDCs) are inefficient presenters of antigens to T cells. However, they regulate inflammation and link innate with adaptive immunity, producing large amounts of IFN-α when activated146 (see Chapter 10). Absent from normal skin, pDCs are significantly increased in both uninvolved and involved psoriatic skin, but activated only in involved skin.126,147 Interestingly, inhibition of pDCs was shown to prevent development of psoriasis in a mouse xenograft model.147 Conversely, imiquimod, which has been reported to exacerbate psoriasis,148 likely acts through this type I IFN system by binding to Toll-like receptor 7 on pDCs.149 Although IFN-α appears to have a role in psoriatic lesional development and exacerbations,147 its role in stable chronic plaque psoriasis has been questioned.150

Mast Cells

Mast cells have long been observed in initial and developing psoriasis lesions,67 with prominent mast cell degranulation in both eruptive psoriasis72 and in lesions reappearing after discontinuation of topical corticosteroid suppression.74 Interestingly, skin-derived mast cell release of preformed and newly synthesized mediators is potently suppressed byCsA and tacrolimus,151 suggesting that the antipsoriatic effects of these compounds could be mediated by mast cells as well as T cells. Recently, mast cells have been shown to be a major source of IL-17 production in both rheumatoid arthritis synovium152 and in psoriatic lesions.153

Macrophages

Macrophages are prominent in initial and developing psoriasis lesions.67 CD163 has recently been shown to be a reliable marker for skin-derived macrophages,139 and as mentioned earlier, these cells also express Factor XIIIa.154 A population of CD11c−, CD1a+, CD68+ macrophages is found scattered just under the basement membrane, subadjacent to proliferating keratinocytes expressing the macrophage chemokine MCP-1 (CCL2).155–157 These phagocytically active cells could be involved in generating fenestrations (holes) in the epidermal basement membrane.158 Recent studies in two different mouse models of psoriasis, one dependent on and the other independent of T cells, showed that selective elimination of macrophages led to prompt improvement of lesions. These findings suggest that macrophages may play a key role in the pathogenesis of psoriasis, at least in part via production of tumor necrosis factor (TNF)-α, iNOS, and IL-23.154,159–161

Neutrophils

Although neutrophils are commonly seen in the upper epidermis of psoriatic lesions, they appear late during the development of lesions, their number is quite variable, and their role in the pathogenesis of psoriasis is unclear. Studies in one of the same mouse models used to implicate macrophages indicate that neutrophils are probably unnecessary for lesional development.161

Keratinocytes

As detailed below, keratinocytes are a major producer of proinflammatory cytokines, chemokines, and growth factors,162 as well as other inflammatory mediators such as eicosanoids163 and mediators of innate immunity such as cathelicidins, defensins, and S100 proteins.164 Psoriatic keratinocytes are engaged in an alternative pathway of keratinocyte differentiation called regenerative maturation.165 Regenerative maturation is activated in response to immunologic stimulation in psoriasis,166 but the mechanism by which this occurs is presently unknown.

Other Cell Types

Other cell types, such as endothelial cells and fibroblasts, are also likely to be participants in the pathogenic process. Endothelial cells are strongly activated in developing and mature lesions of psoriasis67,71 and in addition to delivering a tenfold increase in blood flow to the lesion, they play a major role in controlling the flux of leukocytes and serum proteins into psoriatic tissue.167–169 Fibroblasts support keratinocyte proliferation in a paracrine manner,170 and this process is exaggerated in psoriasis.171 Fibroblasts produce many chemotactic factors and support the migration of T cells out of psoriatic lesions.172 Thus, fibroblasts may also be intimately involved in psoriasis by directing the localization of T cells.

Signaling Molecules in Psoriasis

Cytokines and Chemokines

The cytokine network in psoriasis is extremely complex, involving the actions and interactions of multiple cytokines, chemokines, and growth factors, and their receptors in addition to other mediators produced by multiple cell types. Combinations of cytokines and growth factors can result in effects that are not seen when these factors are studied individually. For example, T-cell clones isolated from psoriatic skin lesions are able to promote keratinocyte proliferation in an IFN-γ-dependent manner,173,174 but by itself, IFN-γ has an antiproliferative effect on cultured keratinocytes.175

The most prominent cytokines currently thought to be involved in the pathogenesis of psoriasis are summarized in Fig. 18-3. Besides IFN-γ,96,176 a plethora of cytokines and chemokines are upregulated in psoriasis, including the cytokines TNF-α,177 IL-2,95 IL-6,178 IL-8,179 IL-15,180 IL-17,181 IL-18,182 IL-19, IL-20, IL-22,183 IL-21,184 IL-23,97,100,101 and the chemokines MIG/CXCL9, IP-10/CXCL10, I-TAC/CXCL11, and MIP-3α/CCL20.7,185 More complex abnormalities have been observed for other immunomodulatory cytokines and their receptors, including IL-1 and TGF-β.186–188 IL-23 is currently believed to play a central role in the pathogenesis of psoriasis through its role in maintaining and expanding specific subsets of CD4+ T cells characterized by production of IL-17 (Th17)189 and IL-22 (Th22).106 IFN-γ plays a role in amplifying this process by stimulating antigen-presenting cells to produce more IL-23.190 The entry of activated, cytokine secreting, CD8+ T cells into the epidermis promotes epidermal hyperplasia191 and activation of keratinocyte innate defense response with resulting production of antimicrobial peptides, cytokines, chemokines, and growth factors (see Fig. 18-3). The other major cytokine producers in psoriatic lesions are DC and macrophages,154 with additional contributions from mast cells, neutrophils, and endothelial cells. Overall, this creates a highly complex network of inflammatory signals between the main cellular participants.

Innate Immune Mediators

In addition to cytokines and chemokines, several mediators of innate immunity are abnormally expressed in psoriasis.164 Prominent among the innate immune mediators are the antimicrobial peptides human β-defensin-2 (hBD-2) and cathelicidin (LL-37), both of which are much more highly overexpressed in psoriasis than in atopic dermatitis.192,193 Notably, expression of HBD-2 and LL-37 is increased in response to proinflammatory and type I cytokines (TNF-γ, IL-1, and IFN-γ) and suppressed by type II cytokines (IL-4, IL-10, and IL-13).194 These differences in antimicrobial peptide expression help to explain why approximately 30% of patients with atopic dermatitis have bacterial or viral infections, as opposed to only 7% of psoriasis patients, even though both conditions have a defective skin barrier.195 They may also explain why psoriasis patients, though frequently colonized with Staphylococcus aureus, are not markedly improved by antibiotic treatment, whereas atopic dermatitis patients often obtain dramatic benefit from antibiotic therapy. The S100 proteins are a large family of dimeric low-molecular-weight proteins that bind calcium and other divalent cations. S100A2, S100A7 (psoriasin), and the S100A8/A9 heterodimer (calprotectin) are markedly overexpressed in psoriasis lesions.196 These proteins exert chemotactic and antimicrobial activity, the latter through sequestration of zinc ions,197,198 and have been shown to function as TLR4 ligands on CD8+ T cells, upregulating IL-17 expression and inducing autoimmunity.199 Nitric oxide is produced in large amounts by DCs in psoriasis, triggering multiple signal transduction events.137 Finally, the complement component C5a is a potent chemoattractant for neutrophils and may contribute to the accumulation of neutrophils in the stratum corneum of psoriasis.200 Interestingly, it is also the most potent chemoattractant for DCs in psoriatic scale extracts.201 Many of these mediators are regulated in response to Toll-like receptors, providing a mechanism whereby the innate immune system can rapidly recognize a wide variety of pathogens according to their pathogen-associated molecular patterns202 (see Chapter 10).

Eicosanoids

The role of eicosanoids in psoriasis remains unclear.203 Levels of free arachidonic acid, leukotriene B4, 12-hydroxyeicosatetraenoic acid, and 15-hydroxyeicosatetraenoic acid are markedly increased in lesional skin, whereas levels of prostaglandins E and F2α are increased less than twofold.

Growth Factors

Multiple growth factors are overexpressed in psoriasis.204 Members of the epidermal growth factor (EGF) family induce their own production in keratinocytes, including transforming growth factor-α, amphiregulin (AREG), and heparin-binding EGF-like growth factor.205 Studies in xenografted mice found a reduction in epidermal hyperplasia after antibody-mediated neutralization of AREG.206 Activation of the EGF receptor stimulates keratinocyte production of vascular endothelial growth factor (VEGF),167 perhaps accounting for the long-standing observation that the angiogenic properties of normal and psoriatic skin associate with the epidermis.207 Nerve growth factor (NGF) is also overexpressed by keratinocytes in psoriatic skin, and NGF receptors are increased in the peripheral nerves of lesional skin. Psoriasis has been shown to clear in denervated skin,208 and psoriasis improved after NGF blockade in xenografted mice.209 Moreover, direct connections have been documented between terminal nerve fibers and DCs in the skin, and neuropeptides have been shown to modulate DC function.210 Paracrine growth factors produced outside the epidermal compartment may also play an important role in stimulating epidermal hyperplasia in psoriasis, including insulin-like growth factor-1211 and keratinocyte growth factor.212

Proteases and Their Inhibitors

The psoriatic lesion is characterized by marked overexpression of multiple classes of proteinases by both keratinocytes and leukocytes. Metalloproteinases release TNF-α, several EGF-like growth factors, and many other cytokines and growth factors from their membrane-anchored precursors.213 Leukocyte-derived elastase has also been implicated in the release of EGF-like growth factors.214 Serine proteases directly activate protease-activated receptors.215 Each of these mechanisms may contribute to stimulation of keratinocyte proliferation. The protease inhibitors elafin, serpinB3, and serpinB13 (hurpin) are among the most markedly overexpressed genes in psoriatic lesions,216,217 suggesting that homeostatic mechanisms are strongly engaged in an effort to regulate the proteolytic environment of psoriatic lesions.

Integrins

Several observations suggest an early role for α5 integrins and their ligand fibronectin in psoriasis. Fibronectin is increased in psoriatic epidermis,218 and it has been suggested that fibronectin gains access to the epidermis via fenestrations in the epidermal basement membrane.219 Fibronectin receptors (α5 integrins) are only weakly expressed in normal skin, but are strongly expressed in uninvolved as well as involved psoriatic skin,219 and fibronectin selectively increases the proliferation of keratinocytes cultured from uninvolved psoriatic skin.219 Receptors for collagen and laminin-5 (α2β1 and α3β1 integrins, respectively) are confined to the basal layer of normal skin but are strongly expressed in suprabasal keratinocytes as part of the regenerative maturation program.220 Interestingly, forced expression of β1 integrins in the suprabasal compartment results in epidermal hyperplasia.221 Finally, the entry and retention of CD8+ T cells into the epidermis requires binding of type IV collagen by α1β1 integrin and binding of E-cadherin by αEβ7 integrin, respectively.191,222

Signal Transduction

As would be expected given this plethora of intercellular signaling alterations, multiple signal transduction mechanisms are dysregulated in psoriatic epidermis, including receptor tyrosine kinase, mitogen-activated protein kinase, Akt, STAT, Src family kinase, Wnt,223 and NF-κB pathways. These abnormalities affect immunocyte activation and trafficking as well as keratinocyte responses of proliferation, differentiation, and survival. As described below, many of the susceptibility variants associated with psoriasis have a role in regulating these signaling pathways, particularly the NF-κB pathway.34,64 This is a challenging area of research, as signal transduction experiments are typically conducted on cell lines in culture, whereas the phenotype of psoriasis requires intercellular interactions and differentiation conditions that can only be obtained in vivo. Animal models are helping to define signal transduction abnormalities at a functional level. Space does not allow detailed consideration of these pathways in psoriasis, nor of the animal models being used to study them. Interested readers are referred to several reviews for details.50,188,224–226

Psoriasis: Integrating Genetics and Immunology

HLA-Cw6

(Fig. 18-4). As has been made clear by detailed fine mapping, genetic linkage, and association studies, HLA-C is by far the major genetic risk factor for psoriasis.30,34,35,38,57 Because it presents antigens to CD8+ T cells, HLA-Cw6 is an excellent candidate for functional involvement in psoriasis. Psoriasis has long been known to be triggered by streptococcal pharyngitis, and is the only infection that has been shown to trigger psoriasis in a prospective cohort study.227 Because tonsillar T cells are cutaneous lymphoid antigen (CLA)-positive and recognize activated skin endothelium228 they can traffic into the skin, explaining why the same CLA-positive T-cell clones are found in the tonsils and in the lesional skin of psoriatic patients.229 CD8+ T cells comprise at least 80% of the T cells in the epidermis of psoriatic lesions,230 and epidermal invasion correlates with lesional development.94,231,232 CD8+ T cells selectively traffic to the epidermis because they express integrin α1β1 (also known as VLA-1), which binds to type IV basement membrane collagen,191 as well as integrin αEβ7, which binds to keratinocyte E-cadherin.222 Once in the epidermis, CD8+ T cells “interrogate” peptides bound to HLA-Cw6 on the surface of dendritic APCs and/or keratinocytes. In normal immune responses, CD4+ T cells provide critical help in processing and presentation of intracellular viral components and tumor antigens, in a process called cross-priming. While CD4+ and CD8+ memory T cells can traffic between the skin and lymph nodes and blood, increasing evidence suggest that they spend most of their time in the skin itself.233 This may help to account for the characteristic distribution of psoriatic plaques, which tend to recur in the same places after therapeutic or spontaneous improvement.

As mentioned earlier, there is a very strong association between HLA-Cw6 and guttate psoriasis. This form of psoriasis is often self-limiting5,234 but can progress to chronic plaque psoriasis, which has a fluctuating inflammatory course in the absence of ongoing streptococcal infection. The transition from guttate to chronic plaque psoriasis likely reflects a transition from a self-limited cutaneous immune reaction triggered by streptococci encountered in the tonsils during a guttate flare, to a persistent and inappropriate immune reaction directed against host proteins in chronic plaque disease.235 The mechanisms by which normal immunologic tolerance of self-proteins is broken during this transition remain to be elucidated.

Autoantigens and Guttate Flare

 What Happens during a Guttate Flare?

 What Is (Are) the Psoriasis Autoantigen(s)?

 How Antigen-Specific Is T-Cell Activation in Psoriasis?

 Cross-Priming in Psoriasis: Why Is It Important?

Non-MHC Genes

(Fig. 18-5). As reviewed earlier, in the online edition, the advent of GWAS has identified an increasing number of convincing genetic association signals for psoriasis outside the MHC (Table 18-1). The genes contained within these associated regions fit very well with our current concepts of psoriasis pathogenesis. This integration is further reinforced by the pronounced clinical responsiveness of psoriasis to biological agents that specifically target the genetically implicated pathways. Most of the non-MHC associations identified thus far fall into four interconnected functional axes: (1) IFN-γ/IL-23/IL-17 signaling, (2) NF-κB signaling, (3) inflammatory DC function, and (4) keratinocyte differentiation. While the actual functional genetic variations that are ultimately responsible for these associations remain to be determined, these discoveries provide a rationale for biological and therapeutic dissection of the implicated pathways.

IFN-γ/Il-23/Il-17 Signaling

Three strong regions of association map near genes involved in IL-23 signaling: (1) IL12B (encoding the p40 subunit of IL-23 and IL-12), (2) IL23A (encoding the p19 subunit of IL-23), and (3) IL23R (encoding a subunit of the IL-23 receptor).34,60,61 These associations are further supported by the impressive efficacy of biologics targeting the p40 subunit common to IL-12 and IL-23,268 along with the fact that IL12B and IL23A are markedly overexpressed in psoriatic lesions, whereas IL12A is not.269 IL-23 signaling promotes cellular immune responses by promoting the survival and expansion of a subset of IL-17-expressing T cells that protects epithelia against microbial pathogens.270 Given the similarities between skin and gut as epithelial tissues, it is notable that inflammatory bowel disease (IBD) is clinically associated with psoriasis271 and the same genetic variation in IL23R that increases risk for both diseases.272 Ankylosing spondylitis (AS) is another HLA-Class I-associated autoimmune disorder that is clinically associated with IBD273 and genetically associated with IL23R.274 Psoriatic arthritis (PsA) shares a number of clinical similarities with AS, and is genetically associated with IL12B, IL23A, and IL23R34,275,276 (see Chapter 19).

IFN-γ is a major product of activated Th1 cells that stimulates DC to produce IL-23.190 Several psoriasis susceptibility loci contain genes involved in interferon signaling (IFIH1, IL28R, and TYK2)61 Together with IL-1, IL-23 promotes the survival and proliferation of IL-17-expressing T cells (Th17), thereby explaining why Th1 and Th17 are colocalized in psoriasis lesions and in many other sites of inflammation.190 Given the well-known reciprocal relationship between Th1 and Th2 differentiation, it is notable that another psoriasis susceptibility region contains the IL4 and IL13 genes.34,63 In addition to biasing T-cell differentiation away from Th1 and toward Th2, IL-4 inhibits Th17 cell development.277 Both IL-4 and IL-13 are expressed at high levels in atopic dermatitis, but only at very low levels in psoriasis.278 Moreover, treatment of psoriasis with IL-4 resulted in significant clinical improvement,279 accompanied by reduced expression of IL-23 (but not of IL-12) and reduced numbers of Th17 cells.280 The fact that significant genetic signals at both ends of this polarizing spectrum (IL-23, on the one hand, and IL-4/IL-13, on the other), with IFN-γ positioned between them, suggests that Th1-Th2-Th17 balance is a key functional and genetic determinant of psoriasis.

NF-κB Signaling

At least five psoriasis-associated genomic regions contain genes involved with controlling signaling through the transcription factor NF-κB: (1) TNFAIP3, (2) TNIP1, (3) NFKBIA, (4) FBXL19, and (5) TRAF3IP2.34,58,59,61,64 TNF-α is a major activator of NF-κB signaling, and these associations are clinically reinforced by the dramatic therapeutic response of psoriasis to anti-TNF biologicals (see Section “Treatment”). TNFAIP3 and TNIP1, respectively encode A20 and ABIN-1, which interact with each other to regulate the ubiquitin-mediated destruction of IKKγ/NEMO, a central nexus of NF-κB signaling.281 TNFAIP3 is genetically associated with rheumatoid arthritis (RA),282,283 and both TNFAIP3 and TNIP1 are associated with systemic lupus erythematosus (SLE).284–287 The polymorphisms implicated in RA and SLE show no association with psoriasis, suggesting that each of these common autoimmune diseases is driven by a different variant of the TNFAIP3 gene. Interestingly, in mice, Tnfaip3 is associated with atherosclerosis,288 which is now known to be a major comorbidity of psoriasis.289 NFKBIA encodes IκBα, which inhibits NF-κB signaling by sequestering it in the cytoplasm. FBXL19 and TRAF3IP2 are significantly more strongly associated with PsA than with purely cutaneous psoriasis.58,64 FBXL19 is structurally related to FBXL11, an F-box family member recently shown to inhibit NF-κB activity by lysine demethylation.290 FBXL11 contains domains known to be required for demethylase activity, but FBLX19 does not.291 Thus, FBXL19 might act as a dominant negative inhibitor of demethylase activity, thereby serving to activate NF-κB. TRAF3IP2 encodes Act1, a ubiquitin ligase that interacts with TRAF (tumor necrosis factor receptor-associated factors) proteins and the IKK complex to activate NF-κB. Interestingly, Act1 is a key component of IL-17-mediated signaling through the IL-17 receptor, allowing the incorporation of TRAF6 into the IL-17 receptor signaling complex, with consequent activation of NF-κB.292 Thus, Act1 may serve as a key link between the IFN-γ/IL-23/IL-17 axis on the one hand, and the NF-κB axis on the other.

Inflammatory DC Function

Beyond the major role of HLA-Cw6 described earlier, it is noteworthy that two other regions of association contain genes whose products function in antigen presentation: (1) PSMA6, which encodes a proteosomal subunit involved in MHC Class I antigen processing,64 and (2) ERAP1, an IFN-γ-inducible aminopeptidase that trims peptides for optimal binding to the MHC Class I peptide groove. As noted above, inflammatory DC produce large amounts of TNF-α and nitric oxide in addition to their well-recognized functions in antigen presentation. Thus, it seems more than coincidental that another novel region of association contains NOS2, which encodes iNOS, the enzyme responsible for nitric oxide production by DC. Reflective of the massive increase in inflammatory dermal dendritic cells characteristic of psoriasis lesions, NOS2 is markedly overexpressed in lesional skin.64 In addition to iNOS, these inflammatory DC produce large amounts of TNF-α, which synergizes strongly with IL-17 to induce a marked increase expression of innate inflammatory mediators such as hBD2 by keratinocytes.58

Keratinocyte Differentiation

Given that hyperproliferation and altered differentiation of keratinocytes figure prominently in psoriasis pathophysiology, it is perhaps surprising that relatively few of the psoriasis-associated regions highlight genes that function primarily in keratinocytes. The most well-established association is an insertion–deletion polymorphism of the late cornified envelope genes LCE3B and LCE3C, which was independently discovered in European65 and Chinese57 populations. Located in the EDC, these genes are expressed very late during keratinocyte terminal differentiation293 and are markedly overexpressed in psoriasis,294 wound healing, and epidermal stress.65,293 Another reported genetic association involving keratinocytes involves increased DEFB4 copy number.66 Whether or not this association is ultimately confirmed, it is notable that DEFB4 is one of the most highly overexpressed genes in psoriatic lesions.295 Finally, TRAF3IP2 is known to function in epidermal cells, as shRNA-mediated knockdown of TRAF3IP2 abrogates the TNF-α + IL-17-mediated upregulation of DEFB4 in human keratinocytes.58

Figure 18-6 is an algorithm showing clinical findings and treatment for psoriasis.

History

It is useful to determine the age at onset and the presence or absence of a family history of psoriasis, as younger age of onset and positive family history have been associated with more widespread and recurrent disease.6,21 In addition, the physician should inquire about the prior course of the disease, as major differences exist between “acute” and “chronic” disease. In the latter form, lesions may persist unchanged for months or even years, whereas acute disease shows sudden outbreak of lesions within a short time (days). Likewise, patients have great variability in regard to relapses. Some patients have frequent relapses occurring weekly or monthly, whereas others have more stable disease with only occasional recurrence. The frequently relapsing patients tend to develop more severe disease with rapidly enlarging lesions covering significant portions of the body surface296 and may require more rigorous treatment compared to those with more stable disease. Certain medications may worsen psoriasis (see Section “Treatment”). The physician should also inquire about joint complaints. Although osteoarthritis is extremely common and can coexist with psoriasis, a history of onset of joint symptoms before the fourth decade and/or a history of warm, swollen joints should raise the suspicion of psoriatic arthritis (see Chapter 19).

Cutaneous Lesions297

The classic lesion of psoriasis is a well-demarcated, raised, red plaque with a white scaly surface (Fig. 18-7). Lesions can vary in size from pinpoint papules to plaques that cover large areas of the body. Under the scale, the skin has a glossy homogeneous erythema, and bleeding points appear when the scale is removed, traumatizing the dilated capillaries below (the Auspitz sign) (Fig. 18-8).297 Psoriasis tends to be a symmetric eruption, and symmetry is a helpful feature in establishing a diagnosis. Unilateral involvement can occur, however. The psoriatic phenotype may present a changing spectrum of disease expression even within the same patient.

Koebner phenomenon (also known as the isomorphic response) is the traumatic induction of psoriasis on nonlesional skin; it occurs more frequently during flares of disease and is an all-or-none phenomenon (i.e., if psoriasis occurs at one site of injury it will occur at all sites of injury) (Fig. 18-9). The Koebner reaction usually occurs 7–14 days after injury, and approximately 25% of patients may have a history of trauma-related Koebner phenomenon at some point in their lives.298 Estimates of lifetime prevalence rise as high as 76% when factors such as infection, emotional stress, and drug reactions are included.4 The Koebner phenomenon is not specific for psoriasis but can be helpful in making the diagnosis when present.

Clinical Patterns of Skin Presentation297

Psoriasis Vulgaris, Chronic Stationary Psoriasis, Plaque-Type Psoriasis

Psoriasis vulgaris is the most common form of psoriasis, seen in approximately 90% of patients. Red, scaly, symmetrically distributed plaques are characteristically localized to the extensor aspects of the extremities, particularly the elbows and knees, along with scalp, lower lumbosacral, buttocks, and genital involvement (see Fig. 18-7). Other sites of predilection include the umbilicus and the intergluteal cleft. The extent of involvement varies widely from patient to patient. There is constant production of large amounts of scale with little alteration in shape or distribution of individual plaques. Single small lesions may become confluent, forming plaques in which the borders resemble a land map (psoriasis geographica). Lesions may extend laterally and become circinate because of the confluence of several plaques (psoriasis gyrata). Occasionally, there is partial central clearing, resulting in ring-like lesions (annular psoriasis) (Fig. 18-10). This is usually associated with lesional clearing and portends a good prognosis. Other clinical variants of plaque psoriasis have been described depending on the morphology of the lesions; particularly those associated with gross hyperkeratosis (see Fig. 18-10). Rupioid psoriasis refers to lesions in the shape of a cone or limpet. Ostraceous psoriasis, an infrequently used term, refers to a ring-like, hyperkeratotic concave lesion, resembling an oyster shell. Finally, elephantine psoriasis is an uncommon form characterized by thickly scaling, large plaques, usually on the lower extremities. A hypopigmented ring (Woronoff ring) surrounding individual psoriatic lesions may occasionally be seen and is usually associated with treatment, most commonly UV radiation or topical corticosteroids (see Fig. 18-10C). The pathogenesis is not well understood but may result from inhibition of prostaglandin synthesis.299

Guttate (Eruptive) Psoriasis

Guttate psoriasis (from the Latin gutta, meaning “a drop”) is characterized by eruption of small (0.5–1.5 cm in diameter) papules over the upper trunk and proximal extremities (Fig. 18-11). It typically manifests at an early age and as such is found frequently in young adults. This form of psoriasis has the strongest association to HLA-Cw6,26 and streptococcal throat infection frequently precedes or is concomitant with the onset or flare of guttate psoriasis.300 However, antibiotic treatment has not been shown to be beneficial or to shorten the disease course.301 Patients with a history of chronic plaque psoriasis may develop guttate lesions, with or without worsening of their chronic plaques.

Small Plaque Psoriasis

Small plaque psoriasis resembles guttate psoriasis clinically, but can be distinguished by its onset in older patients, by its chronicity, and by having somewhat larger lesions (typically 1–2 cm) that are thicker and scalier than in guttate disease. It is said to be a common adult-onset presentation of psoriasis in Korea and other Asian countries.141

Inverse (Flexural) Psoriasis

Psoriasis lesions may be localized in the major skin folds, such as the axillae, the genito-crural region, and the neck. Scaling is usually minimal or absent, and the lesions show a glossy sharply demarcated erythema, which is often localized to areas of skin-to-skin contact (Fig. 18-12). Sweating is impaired in affected areas.302

Erythrodermic Psoriasis

(See also Chapter 23). Psoriatic erythroderma represents the generalized form of the disease that affects all body sites, including the face, hands, feet, nails, trunk, and extremities (Fig. 18-13). Although all the symptoms of psoriasis are present, erythema is the most prominent feature, and scaling is different compared with chronic stationary psoriasis. Instead of thick, adherent, white scale there is superficial scaling. Patients with erythrodermic psoriasis lose excessive heat because of generalized vasodilatation, and this may cause hypothermia. Patients may shiver in an attempt to raise their body temperature. Psoriatic skin is often hypohidrotic due to occlusion of the sweat ducts,303 and there is an attendant risk of hyperthermia in warm climates. Lower extremity edema is common secondary to vasodilatation and loss of protein from the blood vessels into the tissues. High-output cardiac failure and impaired hepatic and renal function may also occur. Psoriatic erythroderma has a variable presentation, but two forms are thought to exist.304 In the first form, chronic plaque psoriasis may worsen to involve most or all of the skin surface, and patients remain relatively responsive to therapy. In the second form, generalized erythroderma may present suddenly and unexpectedly or result from nontolerated external treatment (e.g., UVB, anthralin), thus representing a generalized Koebner reaction. Generalized pustular psoriasis [see Section “Generalized Pustular Psoriasis (von Zumbusch)”] may revert to erythroderma with diminished or absent pustule formation. Occasional diagnostic problems may arise in differentiating psoriatic erythroderma from other causes (see Chapter 23).

Pustular Psoriasis

Several clinical variants of pustular psoriasis exist: generalized pustular psoriasis (von Zumbusch type), annular pustular psoriasis, impetigo herpetiformis, and two variants of localized pustular psoriasis—(1) pustulosis palmaris et plantaris and (2) acrodermatitis continua of Hallopeau. In children, pustular psoriasis can be complicated by sterile, lytic lesions of bones305,306 and can be a manifestation of the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis).307

Generalized Pustular Psoriasis (Von Zumbusch)

Generalized pustular psoriasis (von Zumbusch) is a distinctive acute variant of psoriasis. It is usually preceded by other forms of the disease. Attacks are characterized by fever that lasts several days and a sudden generalized eruption of sterile pustules 2–3 mm in diameter (Fig. 18-14). The pustules are disseminated over the trunk and extremities, including the nail beds, palms, and soles. The pustules usually arise on highly erythematous skin, first as patches (Fig. 18-14C) and then becoming confluent as the disease becomes more severe. With prolonged disease, the fingertips may become atrophic. The erythema that surrounds the pustules often spreads and becomes confluent, leading to erythroderma. Characteristically, the disease occurs in waves of fevers and pustules. The etiology of generalized psoriasis von Zumbusch type is unknown. Various provoking agents include infections, irritating topical treatment (Koebner phenomenon), and withdrawal of oral corticosteroids.308 This form of psoriasis is usually associated with prominent systemic signs and can potentially have life-threatening complications such as hypocalcemia,309 bacterial superinfection, sepsis, and dehydration.310 Severe pustular psoriasis can be difficult to control and requires a potent treatment regimen with rapid onset of action to avoid life-threatening complications. Drugs commonly used include etretinate, methotrexate (MTX), cyclosporine, infliximab,311,312 or oral corticosteroids (see Section “Treatment”).313 Cases of acute respiratory distress syndrome associated with generalized pustular psoriasis have been reported.314 Two recent reports have identified recessive loss-of function mutations in the IL36RN gene encoding IL-36 receptor antagonist (IL-36ra) in patients with generalized pustular psoriasis. Consistent with the prominent inflammation associated with generalized pustular psoriasis, IL-36ra is an anti-inflammatory cytokine that inhibits signaling by three related IL-1 like proteins (IL-36alpha, beta, and gamma).315,316

Exanthematic Pustular Psoriasis

Exanthematic pustular psoriasis tends to occur after a viral infection and consists of widespread pustules with generalized plaque psoriasis. However, unlike the von Zumbusch pattern, there are no constitutional symptoms, and the disorder tends not to recur.297 There is an overlap between this form of pustular psoriasis and acute generalized exanthematous pustulosis, a type of drug eruption.

Annular Pustular Psoriasis

Annular pustular psoriasis is a rare variant of pustular psoriasis. It usually presents in an annular or circinate form. Lesions may appear at the onset of pustular psoriasis, with a tendency to spread and form enlarged rings, or they may develop during the course of generalized pustular psoriasis. The characteristic features are pustules on a ring-like erythema that sometimes resembles erythema annulare centrifugum. Identical lesions are found in patients with impetigo herpetiformis, an entity defined by some as a variant of pustular psoriasis occurring in pregnancy.317 Onset in pregnancy is usually early in the third trimester and persists until delivery.318 It tends to develop earlier in subsequent pregnancies. Impetigo herpetiformis is often associated with hypocalcemia.309,319 There is usually no personal or family history of psoriasis.320

Localized Pustular Psoriasis Variants

Localized pustular psoriasis variants, including pustulosis palmaris et plantaris and acrodermatitis continua (of Hallopeau), are discussed in Chapter 21.

Sebopsoriasis

A common clinical entity, sebopsoriasis presents with erythematous plaques with greasy scales localized to seborrheic areas (scalp, glabella, nasolabial folds, perioral and presternal areas, and intertriginous areas). In the absence of typical findings of psoriasis elsewhere, distinction from seborrheic dermatitis is difficult. Sebopsoriasis may represent a modification of seborrheic dermatitis by the genetic background of psoriasis and is relatively resistant to treatment. Although an etiologic role of Pityrosporum remains unproven, antifungal agents may be useful.321

Napkin Psoriasis

Napkin psoriasis usually begins between the ages of 3 and 6 months and first appears in the diaper (napkin) areas as a confluent red area (see Fig. 18-12B) with appearance a few days later of small red papules on the trunk that may also involve the limbs. These papules have the typical white scales of psoriasis. The face may also be involved with red scaly eruption. Unlike other forms of psoriasis, the rash responds readily to treatment and tends to disappear after the age of 1 year.

Linear Psoriasis

Linear psoriasis is a very rare form. The psoriatic lesion presents as linear lesion most commonly on the limbs but may also be limited to a dermatome on the trunk. This may be an underlying nevus, possibly an inflammatory linear verrucous epidermal nevus (ILVEN), as these lesions resemble linear psoriasis both clinically and histologically. The existence of a linear form of psoriasis distinct from ILVEN is controversial.322

Related Physical Findings

Nail Changes in Psoriasis

(See also Chapter 89). Nail changes are frequent in psoriasis, being found in up to 40% of patients,21 and are rare in the absence of skin disease elsewhere. Nail involvement increases with age, with duration and extent of disease, and with the presence of psoriatic arthritis. Several distinct changes have been described and can be grouped according to the portion of the nail that is affected (Table 18-2).323

Nail pitting is one of the commonest features of psoriasis, involving the fingers more often than the toes (Fig. 18-15). Pits range from 0.5 to 2.0 mm in size and can be single or multiple. The proximal nail matrix forms the dorsal (superficial) portion of the nail plate, and psoriatic involvement of this region results in pitting due to defective keratinization. Other alterations in the nail matrix resulting in deformity of the nail plate (onychodystrophy) include leukonychia, crumbling nail, and red spots in the lunula. Onychodystrophy has a stronger association with psoriatic arthritis than other nail changes.21 Oil spots and salmon patches are translucent, yellow–red discolorations observed beneath the nail plate often extending distally toward the hyponychium, due to psoriasiform hyperplasia, parakeratosis, microvascular changes, and trapping of neutrophils in the nail bed.324,325 Unlike pitting, which is also seen in alopecia areata and other disorders, oil spotting is considered to be nearly specific for psoriasis. Splinter hemorrhages result from capillary bleeding underneath the thin suprapapillary plate of the psoriatic nail bed. Subungual hyperkeratosis is due to hyperkeratosis of the nail bed and is often accompanied by onycholysis (separation of the nail plate from the nail bed), which usually involves the distal aspect of the nail. Anonychia is total loss of the nail plate. Although nail changes are rarely seen in the localized pustular variant of pustulosis palmaris et plantaris, anonychia can be seen in other forms of pustular psoriasis.

Geographic Tongue

(See also Chapter 76). Geographic tongue, also known as benign migratory glossitis or glossitis areata migrans, is an idiopathic inflammatory disorder resulting in the local loss of filiform papillae. The condition usually presents as asymptomatic erythematous patches with serpiginous borders, resembling a map. These lesions characteristically have a migratory nature. Geographic tongue has been postulated to be an oral variant of psoriasis, as these lesions show several histologic features of psoriasis, including acanthosis, clubbing of the rete ridges, focal parakeratosis, and neutrophilic infiltrate. In addition, the prevalence of geographic tongue is increased in psoriatic patients.326 However, geographic tongue is a relatively common condition and is seen in many nonpsoriatic individuals, so its relationship to psoriasis needs further clarification.

Psoriatic Arthritis

Arthritis is a common extracutaneous manifestation of psoriasis seen in up to 40% of patients. It has a strong genetic component, and several overlapping subtypes exist. This condition is discussed in Chapter 19.

Laboratory Tests

Although histopathologic examination is rarely necessary to make the diagnosis, it can be helpful in difficult cases. The histopathologic findings of guttate and chronic plaque psoriasis have already been described (see Section “Development of Lesions”). In early lesions of pustular psoriasis, the epidermis is usually only slightly acanthotic, whereas psoriasiform hyperplasia is seen in older and persistent lesions. Neutrophils migrate from dilated vessels in the upper dermis into the epidermis where they aggregate beneath the stratum corneum and in the upper Malpighian layer to form the spongiform pustules of Kogoj.

Other laboratory abnormalities in psoriasis are usually not specific and may not be found in all patients. In severe psoriasis vulgaris, generalized pustular psoriasis, and erythroderma, a negative nitrogen balance can be detected, manifested by a decrease of serum albumin.327

Psoriasis patients manifest altered lipid profiles, even at the onset of their skin disease.328 Patients had 15% higher levels of high-density lipoproteins, and their cholesterol–triglyceride ratio for very low-density lipoprotein particles was 19% higher. Furthermore, plasma apolipoprotein-A1 concentrations were 11% higher in psoriasis patients. Whether these differences in lipid profile can explain or are contributing to an increased incidence of cardiovascular events in psoriasis remains to be seen.

Serum uric acid is elevated in up to 50% of patients and is mainly correlated with the extent of lesions and the activity of disease. There is an increased risk of developing gouty arthritis. Serum uric acid levels usually normalize after therapy.

Markers of systemic inflammation can be increased, including C-reactive protein, α2-macroglobulin, and erythrocyte sedimentation rate. However, such elevations are rare in chronic plaque psoriasis uncomplicated by arthritis. Increased serum immunoglobulin (Ig) A levels and IgA immune complexes, as well as secondary amyloidosis, have also been observed in psoriasis, and the latter carries a poor prognosis.329

Special Tests

Immunostaining techniques, fluorescence-activated cell sorting of dissociated cell suspensions, and assessment of T-cell receptor gene rearrangements have been of major importance in elucidating the pathogenesis of psoriasis and in characterizing the response to antipsoriatic therapies but are generally not required for diagnosis or management.

(Box 18-1)

Patients with psoriasis have an increased morbidity and mortality from cardiovascular events, particularly those with severe and long duration of psoriasis skin disease.330,331 Risk of myocardial infarction is particularly elevated in younger patients with severe psoriasis.289 In a recent study of 1.3 million German health care recipients, metabolic syndrome was 2.9-fold more frequent among psoriatic patients, and the most common diagnoses were hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidemia (29.9% vs. 17.1%). The frequencies of rheumatoid arthritis [prevalence ratio (PR) 3.8], Crohn's disease (PR 2.1), and ulcerative colitis (PR 2.0) were also increased.2 Psoriasis remained associated with after controlling for age, sex, smoking status, obesity, diabetes, and NSAID use.332 Psoriasis patients have also been shown to have increased relative risk of both Hodgkin lymphoma and cutaneous T-cell lymphoma, especially in patients with more severe disease.333

Psoriasis is emotionally disabling, carrying with it significant psychosocial difficulties. Emotional difficulties arise from concerns about appearance, resulting in lowered self-esteem, social rejection, guilt, embarrassment, emptiness, sexual problems, and impairment of professional ability.334 The presence of pruritus and pain can aggravate these symptoms. Psychological aspects can modify the course of illness; in particular, feeling stigmatized can lead to treatment noncompliance and worsening of psoriasis.335 Likewise, psychological stress can also lead to depression and anxiety.336 The prevalence of suicidal ideation and depression in patients with psoriasis is higher than that reported in other medical conditions and the general population.337 Thus, although the disease is not threatening to life itself, psoriasis can very significantly impair quality of life.338 A comparative study reported reduction in physical and mental functioning comparable with that seen in cancer, arthritis, hypertension, heart disease, diabetes, and depression.339 According to a recent survey, 79% of patients with severe psoriasis reported a negative impact on their lives.340

Natural History297

Guttate psoriasis is often a self-limited disease, lasting from 12 to 16 weeks without treatment.297 It has been estimated that one-third to two-thirds of these patients later develop the chronic plaque type of psoriasis.5,234 In contrast, chronic plaque psoriasis is in most cases a lifelong disease, manifesting at unpredictable intervals. Spontaneous remissions, lasting for variable periods of time, may occur in the course of psoriasis in up to 50% of patients. The duration of remission ranges from 1 year to several decades. In two separate studies, remission ranged from 17% to 55%. In another study of patients followed for 21 years, 71% had persistent lesions, 13% were free of the disease, and 16% had intermittent lesions.297 The cause of spontaneous remission is unknown, but could reflect successful generation of self-tolerance under the model of immunologic self-reactivity discussed earlier (see Section “Psoriasis as an Autoimmune Disease”).

Erythrodermic and generalized pustular psoriasis have a poorer prognosis, with the disease tending to be severe and persistent.297

Modifying Factors

Obesity

It has been demonstrated that obese individuals are more likely to present with severe psoriasis (defined as >20% body surface area involvement).341 However, obesity does not appear to have a role in defining the onset of psoriasis.341

Smoking

Smoking (more than 20 cigarettes daily) has also been associated with more than a twofold increased risk of severe psoriasis.342 Unlike obesity, smoking appears to have a role in the onset of psoriasis.341 Recently, a gene–environment interaction has been identified between low activity of the cytochrome P450 gene CYP1A1 and smoking in psoriasis.343

Infection

An association between streptococcal throat infection and guttate psoriasis has been repeatedly confirmed.300,343 Streptococcal throat infections have also been demonstrated to exacerbate preexisting chronic plaque psoriasis.227

Severe exacerbation of psoriasis can be a manifestation of human immunodeficiency virus (HIV) infection.345 Like psoriasis in general, HIV-associated psoriasis has a strong association with HLA-Cw6.345 Interestingly, the prevalence of psoriasis in HIV infection is no higher than in the general population (1%–2% of patients),346,347 indicating that this infection is not a trigger for psoriasis but rather a modifying agent. Psoriasis is increasingly more severe with progression of immunodeficiency but can remit in the terminal phase.348,349 This paradoxical exacerbation of psoriasis may be due to loss of regulatory T cells and increased activity of the CD8 T-cell subset.300 Psoriasis exacerbation in HIV disease may be effectively treated with antiretroviral therapy.350 Psoriasis has also been associated with hepatitis C infection.351

Drugs

Medications that exacerbate psoriasis include antimalarials, β blockers, lithium, nonsteroidal anti-inflammatory drugs, IFNs-α and -γ, imiquimod, angiotensin-converting enzyme inhibitors, and gemfibrozil.352 Imiquimod acts on pDCs and stimulates IFN-α production,147 which then strengthens both innate and Th1 immune responses. Exacerbations and onset of psoriasis have been described in patients receiving TNF inhibitor therapy. The majority of these cases are palmoplantar pustulosis, but about one-third develop chronic plaque psoriasis.353 Lithium has been proposed to cause exacerbation by interfering with calcium release within keratinocytes, whereas β blockers are thought to interfere with intracellular cyclic adenosine monophosphate levels.352 The mechanisms by which the remaining medications exacerbate psoriasis are largely unknown. Patients with active or unstable psoriasis should receive advice when traveling to countries where antimalarial prophylaxis is needed.

General Considerations

A broad spectrum of antipsoriatic treatments, both topical and systemic, is available for the management of psoriasis. As detailed in Tables 18-3, 18-4, 18-5, and 18-6, it is notable that most if not all of these treatments are immunomodulatory. When choosing a treatment regimen (see Fig. 18-6) it is important to reconcile the extent and the measurable severity of the disease with the patient's own perception of his or her disease. In this context, it is notable that a recent study found that 40% of patients felt frustrated with the ineffectiveness of their current therapies, and 32% reported that treatment was not aggressive enough.350 As psoriasis is a chronic condition, it is important to know the safety of a treatment during long-term use. In most treatments, the duration of a treatment is restricted because of the cumulative toxicity potential of an individual treatment, and, in some instances, treatment efficacy may diminish with time (tachyphylaxis). Some treatments, such as calcipotriol, MTX, and acitretin, can be regarded as appropriate for continuous use.354 These treatments maintain efficacy and have low cumulative toxicity potential. In contrast, topical corticosteroids, dithranol, tar, photo(chemo) therapy, and cyclosporine are not indicated for continuous chronic use, and combinatorial or rotational treatments354 are suggested. However, patients with stable chronic plaque psoriasis who respond well to local treatments may not require a change of treatment.354 In cases of itchy/pruritic psoriasis, treatments with an irritative potential, such as dithranol, vitamin D3 analogs, and photo(chemo) therapy, should be used cautiously, whereas treatments with potent anti-inflammatory effects, such as topical corticosteroids, are more appropriate.354

In patients with erythrodermic and pustular psoriasis, treatments with an irritant potential should be avoided, and acitretin, MTX, or short-course cyclosporine are the treatments of first choice.354 See Boxes 18-2 and 18-3 for special considerations in the treatment of women of child-bearing potential and pregnancy and children.

Topical Treatments

(See Table 18-3.)355,356

Most cases of psoriasis are treated topically. As topical treatments are often cosmetically unacceptable and time-consuming to use, noncompliance is on the order of 40%.357 In most cases, ointment formulations are more effective than creams but are less cosmetically acceptable. For many patients, it is worth prescribing both cream and ointment formulations; cream for use in the morning and ointment for nighttime.358 Topical agents are also used adjunctively for resistant lesions in patients with more extensive psoriasis and who are concurrently being treated with either UV light or systemic agents.359 It is worth noting that around 400 g of a topical agent is required to cover the entire body surface of an average-sized adult when used twice daily for 1 week.360

Corticosteroids

Glucocorticoids exert many if not all of their myriad effects by stabilizing and causing nuclear translocation of glucocorticoid receptors, which are members of the nuclear hormone receptor superfamily. Topical glucocorticoids are commonly first-line therapy in mild to moderate psoriasis and in sites such as the flexures and genitalia, where other topical treatments can induce irritation. Improvement is usually achieved within 2–4 weeks, with maintenance treatment consisting of intermittent applications (often restricted to the weekends). Tachyphylaxis to treatment with topical corticosteroids is a well-established phenomenon in psoriasis.361 Long-term topical corticosteroids may cause skin atrophy, telangiectasia, striae (Fig. 18-16D) and adrenal suppression. Another concern is that when topical steroids are discontinued, patients may rebound, sometimes worse than it was prior to treatment.359 This class of agents is discussed in detail in Chapter 216.

Vitamin D3 and Analogs362

Vitamin D exerts its actions by binding to the vitamin D receptor, another member of the nuclear hormone receptor superfamily. Vitamin D3 acts to regulate cell growth, differentiation, and immune function, as well as calcium and phosphorous metabolism. Vitamin D has been shown to inhibit the proliferation of keratinocytes in culture and to modulate epidermal differentiation. Furthermore, vitamin D inhibits production of several proinflammatory cytokines by psoriatic T-cell clones, including IL-2 and IFN-γ.363

Analogs of vitamin D that have been used for the treatment of skin diseases are calcipotriene (also known as calcipotriol), tacalcitol, and maxacalcitol. In short-term studies, potent topical corticosteroids were found to be superior to calcipotriene. When compared with short-contact anthralin or 15% coal tar, calcipotriene was the more effective agent. The efficacy of calcipotriene is not reduced with long-term treatment.364 Calcipotriene applied twice daily is more effective than once-daily use. Hypercalcemia is the only major concern with the use of topical vitamin D preparations. When the amount used does not exceed the recommended 100 g/week, calcipotriene can be used with a great margin of safety.365 Vitamin D analogs are often used in combination with or in rotation with topical corticosteroids in an effort to maximize therapeutic effectiveness while minimizing steroid-related skin atrophy.

Anthralin (Dithranol)

Dithranol (1,8-dihydroxy-9-anthrone) is a naturally occurring substance found in the bark of the araroba tree in South America. It can also be synthesized from anthrone. Dithranol is made up in a cream, ointment, or paste. Dithranol is approved for the treatment of chronic plaque psoriasis. Its most common use has been in the treatment of psoriasis, particularly on plaques resistant to other therapies. It can be combined with UVB phototherapy with good results (the Ingram regimen). Most common side effects are irritant contact dermatitis and staining of clothing, skin, hair, and nails. Anthralin possesses antiproliferative activity on human keratinocytes along with potent anti-inflammatory effects. Classic anthralin therapy starts with low concentrations (0.05%–0.1%) incorporated in petrolatum or zinc paste and given once daily. To prevent autooxidation, salicylic acid (1%–2%) should be added. The concentration is increased weekly in individually adjusted increments up to 4% until the lesions resolve. Scalp psoriasis should be treated with great caution as anthralin can stain hair purple to green.

Coal Tar

The use of tar to treat skin diseases dates back nearly 2000 years. In 1925, Goeckerman introduced the use of crude coal tar and UV light for the treatment of psoriasis. Tar is the dry distillation product of organic matter heated in the absence of oxygen. Its mode of action is not understood, and, because of its inherent chemical complexity, tar is not pharmacologically standardized. It was recently suggested that carbazole, a coal-derived chemical, is the main active ingredient in tar.366 Tar appears to exert its action through suppression of DNA synthesis and consequent reduction of mitotic activity in the basal layer of the epidermis, and some components in tar appear to have anti-inflammatory activity. Coal tar, in concentrations up to 20% (5%–20%) can be compounded in creams, ointments, and pastes. It is often combined with salicylic acid (2%–5%), which by its keratolytic action leads to better absorption of the coal tar.297 Occasionally, patients become sensitive to the coal tar and develop allergic reactions. A folliculitis may occur after the use of coal tar. Furthermore, it has an unwelcome smell and appearance and can stain clothing and other items. Coal tar is carcinogenic.

Tazarotene

Tazarotene is a third-generation retinoid for topical use that reduces mainly scaling and plaque thickness, with limited effectiveness on erythema. It is thought to act by binding to retinoic acid receptors, but its molecular targets are unknown. It is available in 0.05% and 0.1% gels, and a cream formulation has been developed. When this drug is used as a monotherapy, a significant proportion of patients develop local irritation. This retinoid dermatitis is worse with the 0.1% formulation. Efficacy of this drug can be enhanced by combination with mid- to high-potency glucocorticoids or UVB phototherapy. When used in combination with phototherapy, it lowers the minimal erythema dose (MED) for both UVB and UVA. It has been recommended that UV doses be reduced by at least one-third if tazarotene is added in the middle of a course of phototherapy.367

Topical Calcineurin Inhibitors

(See Chapter 221.) Tacrolimus (FK-506) is a macrolide antibiotic, derived from the bacteria Streptomyces tsukubaensis that, by binding to immunophilin (FK506-binding protein), creates a complex that interacts and inhibits calcineurin, thus blocking both T-lymphocyte signal transduction and IL-2 transcription. Pimecrolimus is also a calcineurin inhibitor and works in a manner similar to tacrolimus and CsA.

In a study of 70 patients with chronic plaque psoriasis treated with topical tacrolimus, there was no improvement beyond that seen for placebo.368 However, for treatment of inverse and facial psoriasis, these agents appear to provide effective treatment.369,370 The main side effect of these medications is a burning sensation at application site. Anecdotal reports of lymph node or skin malignancy require further evaluation in controlled studies, and these drugs have a US Food and Drug Administration (FDA) “black-box warning.”

Salicylic Acid

(See also Chapter 222.) Salicylic acid is a topical keratolytic agent. Its mechanism of action includes reduction of keratinocyte adhesion and lowering the pH of the stratum corneum. This results in reduced scaling and softening of the plaques,371 thereby enhancing absorption of other agents. Therefore, salicylic acid is often combined with other topical therapies such as corticosteroids and coal tar. Topical salicylic acid decreases the efficacy of UVB phototherapy359 and systemic absorption can occur, particularly in patients with abnormal hepatic or renal function and when applied to more than 20% of the body surface area. No placebo-controlled studies have been performed to verify the efficacy and safety of salicylic acid as a monotherapy.359

Bland Emollients

Between treatment periods, skin care with emollients should be performed to avoid dryness. Emollients reduce scaling, may limit painful fissuring, and can help control pruritus. They are best applied immediately after bathing or showering. The addition of urea (up to 10%) is helpful to improve hydration of the skin and remove scaling of early lesions. The use of liberal bland emollients over a thin layer of topical prescription treatments improves hydration while minimizing treatment costs.

Phototherapy372

(See Table 18-4) (See Chapters 237 and 238.)

Phototherapy of psoriasis with artificial light sources dates back to 1925 when Goeckerman introduced a combination of topical crude coal tar and subsequent UV irradiation. In the 1970s, it was shown that broadband UVB radiation alone, if given in doses that produce a faint erythematous reaction, could clear the milder clinical forms of psoriasis. Major steps forward were the introduction of photochemotherapy with psoralen and UVA light (PUVA) in the 1970s and narrow band UVB (311–313 nm) in the 1980s.

The mechanism of action of phototherapy appears to involve selective depletion of T cells, predominantly those that reside in the epidermis.166,230 The mechanism of depletion appears to involve apoptosis373 and is accompanied by a shift from a Th1 immune response toward a Th2 response in the lesional skin.374

Ultraviolet B Light (290–320 nm)

The initial therapeutic UVB dose lies at 50%–75% of the MED. Treatments are given two to five times per week. As peak UVB erythema appears within 24 hours of exposure, increments can be performed at each successive treatment. The objective is to maintain a minimally perceptible erythema as a clinical indicator of optimal dosing. Treatments are given until total remission is reached or until no further improvement can be obtained with continued treatment. The main side effects of UVB phototherapy are summarized in Chapter 237.

Narrowband (312 nm) UVB (NBUVB) phototherapy is superior to conventional broadband UVB (290–320 nm) with respect to both clearing and remission times.375,376 Although early studies found NB-UVB to be as effective as psoralen and UVA light (PUVA),377,378 a recent controlled trial found that PUVA was more effective, albeit less convenient.379 On clearing, treatment is either discontinued or patients are subjected to maintenance therapy for 1 or 2 months. During this period, the frequency of UVB treatments is reduced while maintaining the last dose given at the time of clearing.372

Systemic drugs, such as retinoids, increase the efficacy of UVB light, particularly in patients with chronic and hyperkeratosis plaque-type psoriasis.380,381 Because they are known to inhibit carcinogenesis in experimental animals, retinoids may possibly reduce the carcinogenic potential of UVB phototherapy.

Psoralen and Ultraviolet A Light

(See Chapter 238.) PUVA is the combined use of psoralens (P) and long-wave ultraviolet A radiation (UVA). The combination of drug and radiation results in a therapeutic effect, which is not achieved by the single component alone. Remission is induced by repeated controlled phototoxic reactions. A detailed account of PUVA therapy and its short-term and long-term side effects is to be found in Chapter 238.

Excimer Laser362

(See Chapter 239.) Supraerythemogenic fluences of UVB and PUVA are known to result in faster clearing of psoriasis,383 however, the limiting factor for the use of such high fluences lies with the intolerance of the uninvolved surrounding skin as psoriatic lesions can often withstand much higher UV exposures.384 The monochromatic 308-nm excimer laser can deliver such supraerythemogenic doses of light (up to 6 MED, usually in the range of 2–6 MEDs) to lesional skin, however, only focally. The dosing is guided by the patients’ skin type and thickness of the plaque with subsequent doses based on the response to therapy or development of side effects.385 In a study on 124 patients, 72% of study subjects achieved at least 75% clearing in an average of 6.2 treatments delivered twice weekly.384 The role of this treatment seems to be indicated for patients with stable recalcitrant plaques particularly in the elbows and knee region.

Photodynamic Treatment386

(See Chapter 238.) Photodynamic therapy has been tried for several inflammatory dermatoses, including psoriasis. In a randomized study on the effect of topical aminolevulinic acid-based photodynamic therapy, 29 patients demonstrated unsatisfactory clinical response and frequent occurrence of pain during and after treatment, prompting the authors to declare this as an inadequate treatment option for psoriasis.

Climatic Therapy387

It is well known that going to a sunny climate can improve psoriasis, although a small proportion of patients actually deteriorate. Patients should be warned not to overexpose themselves in the first few days, as sunburn may actually progress to psoriasis (Koebner phenomenon). The best-studied effects are from the Dead Sea area, and those therapeutic effects may be attributed, at least partially, to the unique climatic characteristic of that location. As it is situated 400 m below sea level, the evaporation of the sea forms an aerosol that stays in the atmosphere above the sea and surrounding beaches. This aerosol screens out the majority of the UVB rays but not the UVA. This mixture of UV light appears to be sufficient to clear psoriasis but without sunburn. Thus, patients can stay on the shores of the Dead Sea for long periods of time with greatly reduced risk of sunburn. This treatment is carried out over a period of 3–4 weeks, and improvements comparable to NB-UVB or PUVA treatments are observed. The main disadvantages of this treatment are time and expense.

Systemic Oral Agents388–390

(See Table 18-5.)

Methotrexate

MTX is highly effective for chronic plaque psoriasis389 and is also indicated for the long-term management of severe forms of psoriasis, including psoriatic erythroderma and pustular psoriasis.388 For mechanisms of action, see Chapters 227 and 233. When first used for the treatment of psoriasis, MTX was thought to act directly to inhibit epidermal hyperproliferation via inhibition of dihydrofolate reductase (DHFR). However, it was found to be effective at much lower doses (0.1–0.3 mg/kg weekly) in the management of psoriasis, psoriatic arthritis, and other inflammatory conditions such as rheumatoid arthritis. At these concentrations, MTX inhibits the in vitro proliferation of lymphocytes, but not proliferation of keratinocytes.391 It is now thought that the inhibition of DHFR is not the main mechanism of anti-inflammatory action of MTX, but rather the inhibition of an enzyme involved in purine metabolism [AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) transformylase]. This leads to accumulation of extracellular adenosine, which has potent anti-inflammatory activities, particularly for neutrophils.392 Consistent with a DHFR-independent mechanism of action, concomitant administration of folic acid (1–5 mg/day) reduces certain side effects, such as nausea and megaloblastic anemia, without diminishing the efficacy of antipsoriatic treatment.393 The cellular targets of MTX action in psoriasis are still under investigation, but its mechanism of action may involve modulation of adhesion molecules, such as intercellular adhesion molecule 1, rather than induction of lymphocyte apoptosis.394

The very long half-life of MTX may account for its efficacy after weekly administration and may also help to explain why its onset of action is rather slow (therapeutic effects usually require 4–8 weeks to become evident). MTX is renally excreted and should therefore not be administered to patients with impairment in renal function, as MTX side effects are generally dose-related. Short-term toxicity and long-term concerns are discussed in Chapter 227.

In the most recent guidelines395,396 it is suggested that patients be divided into two separate groups based on their risk factors for liver injury: the low-risk patients follow the American College of Rheumatology (ACR) guidelines and are not asked to undergo liver biopsy until they have reached a cumulative MTX dose of 3.5–4.0 g. In contrast, those patients with one or more risk factors continue to follow the previously published397 more stringent guidelines requiring baseline liver biopsy either before treatment or after 2–6 months of treatment, and then at each cumulative MTX dose of 1.0–1.5 g.395,398 The risk factors include current or past alcohol consumption, persistent abnormalities of liver function enzymes, personal, or family history of liver disease, exposure to hepatotoxic drugs or chemicals, diabetes mellitus, hyperlipidemia, and obesity.395

Some groups have recommended the use of amino terminal type III procollagen peptide (PIIINP) assay for screening of liver fibrosis.292 Specific guidelines have been developed for monitoring PIIINP levels in psoriatic patients,292 but the FDA has not yet approved the use of this assay for diagnostic use within the United States.

Another well-known side effect of MTX is myelosuppression, especially pancytopenia, which usually occurs in the setting of folate deficiency. Leucovorin calcium (folinic acid) is the only antidote for the hematologic toxicity of MTX. When an overdose is suspected, an immediate leucovorin dose of 20 mg should be given parenterally or orally, and subsequent doses should be given every 6 hours.399 Pneumonitis can develop, and mucosal and skin ulcerations have also been reported in patients treated with MTX.399,400

Discontinuation of MTX treatment is required in the event of hepatotoxicity, hematopoietic suppression, active infections, nausea, and pneumonitis. MTX is also teratogenic and should therefore not be prescribed for women who are pregnant or breastfeeding. Several classes of drugs, including nonsteroidal anti-inflammatory drugs and sulfonamides, may interact with MTX to increase toxicity.

Acitretin401

Acitretin is a second-generation, systemic retinoid that has been approved for the treatment of psoriasis since 1997 and is discussed in Chapter 228.

The clinical forms most responsive to etretinate or acitretin as monotherapy include generalized pustular and erythrodermic psoriasis. Acitretin induces clearance of psoriasis in a dose-dependent fashion. Overall, higher starting doses appeared to clear psoriasis faster.402 The mechanism of action of retinoids for psoriasis is not fully understood.

The optimal initial dose of acitretin for psoriasis is reported at 25 mg/day, with a maintenance dose of 20–50 mg/day. Adverse effects, such as hair loss and paronychia, occur more frequently with higher initial dose (i.e., ≥50 mg/day). Most patients relapse within 2 months after discontinuing etretinate or acitretin. Acitretin should be discontinued if liver dysfunction, hyperlipidemia, or diffuse idiopathic hyperostosis develops.

Cyclosporine A

Cyclosporine A (CsA) is a neutral cyclic undecapeptide derived from the fungus Tolypocladium inflatum Gams. Its mechanism of action and side effects are discussed in Chapter 233. The only formulation approved for treatment of psoriasis is available as an oral solution or in capsules. It is highly effective for cutaneous psoriasis and can also be effective for nail psoriasis (see Fig. 18-16B). CsA is particularly useful in patients who present with widespread, intensely inflammatory, or frankly erythrodermic psoriasis. Dosage ranges from 2 to 5 mg/kg/day.403 Because the nephrotoxic effects of CsA are largely irreversible, CsA treatment should be discontinued if kidney dysfunction and/or hypertension occur. CsA-induced hypertension may be treated with calcium antagonists such as nifedipine.404 The most common adverse effects noted in patients using CsA for short periods of time are neurologic, including tremors, headache, paresthesia, and/or hyperesthesia. Long-term treatment of psoriasis with low-dose CsA was found to increase risk of nonmelanoma skin cancers.405 However, unlike organ transplant patients treated with higher doses of CsA, there is little or no increased risk of lymphoma.

Fumaric Acid Esters

Fumaric acid was first reported in 1959 to be beneficial in the systemic treatment of psoriasis406 and is licensed in Germany for treatment of psoriasis. Because fumaric acid itself is poorly absorbed after oral intake, esters are used for treatment. The esters are almost completely absorbed in the small intestine, and dimethyl fumarate is rapidly hydrolyzed by esterases to monomethyl fumarate, which is regarded as the active metabolite. The mode of action of fumaric acid esters (FAEs) in the treatment of psoriasis is not fully understood, but experimental data point toward a skewing of the Th1-dominated T-cell response in psoriasis to a Th2-like pattern and inhibition of keratinocyte proliferation.406 Patients with severe concomitant disease, chronic disease of the gastrointestinal tract, chronic kidney disease, or with bone marrow disease leading to leukocytopenias or leukocyte dysfunction should not be treated. Likewise, pregnant or lactating women and patients with malignant disease (including positive history of malignancy) should be excluded from treatment. Prolonged therapy (up to 2 years) to prevent relapse in psoriasis patients with high disease activity is possible. Another therapeutic option is short-course intermittent therapy. FAEs are given until a major improvement is achieved and are then withdrawn. If a patient remains lesion-free during prolonged treatment, the FAE dose should be gradually decreased to reach the individual's threshold.406 Therapy with FAEs can be stopped abruptly. Rebound phenomena have not been observed.406

Sulfasalazine

Sulfasalazine is an uncommonly used systemic agent in the management of psoriasis. In the only prospective double-blind study on the efficacy of sulfasalazine in psoriasis, moderate effects were seen, with 41% of the patients showing marked improvement, 41% with moderate, and 18% with minimal improvement after 8 weeks of treatment.407

Systemic Steroids

(See Chapter 224.) In general, systemic steroids should not be used in the routine care of psoriasis. When systemic steroids are used, clearance of psoriasis is rapid, but the disease usually breaks through, requiring progressively higher doses to control symptoms. If withdrawal is attempted, the disease tends to relapse promptly and may rebound in the form of erythrodermic and pustular psoriasis.408 However, systemic steroids may have a role in the management of persistent, otherwise uncontrollable, erythroderma and in fulminant generalized pustular psoriasis (von Zumbusch type) if other drugs are ineffective.

Mycophenolate Mofetil

(See Chapter 233.) Mycophenolate mofetil is a prodrug of mycophenolic acid, an inhibitor of inosine-5′-monophosphate dehydrogenase. Mycophenolic acid depletes guanosine nucleotides preferentially in T and B lymphocytes and inhibits their proliferation, thereby suppressing cell-mediated immune responses and antibody formation. The drug is usually well tolerated with few side effects. Few studies have been done on this medication for psoriasis, but, in a prospective open-label trial on 23 patients with dosage between 2 and 3 g daily, a 24% reduction of the Psoriasis Area and Severity Index (PASI) was seen after 6 weeks, with 47% improvement at 12 weeks.409

6-Thioguanine

6-Thioguanine is a purine analog that has been highly effective for psoriasis.410 Apart from bone marrow suppression, gastrointestinal complaints including nausea and diarrhea can occur, and elevation of liver function tests is common.388 Isolated instances of hepatic veno-occlusive disease have been reported.411

Hydroxyurea

Hydroxyurea is an antimetabolite that has been shown to be effective as monotherapy, but nearly 50% of patients who achieve marked improvement develop bone marrow toxicity with leukopenia or thrombocytopenia. Megaloblastic anemia is also common but rarely requires treatment.388 Cutaneous reactions affect most patients treated with hydroxyurea, including leg ulcers, which are the most troublesome.412

Combination Treatments

(See Table 18-6.)

Combination treatment may increase efficacy and reduce side effects, and so may result in a more substantial improvement, or alternatively, may permit reduced doses to reach the same improvement as compared with monotherapy.354 Data on combination of biologics with other systemic or topical agents are not yet widely available, but some combinations commonly used in the treatment of inflammatory arthritides, such as a combination of MTX and anti-TNF agents,413 may be appropriate for treatment of recalcitrant psoriatic disease.

Biologic Treatments414–417

(See Table 18-7.) (See also Chapter 234.)

Based on the continuous progress in psoriasis research and advances in molecular biology, a new class of agents—targeted biologic therapies—has emerged.414,415 These agents are designed to block specific molecular steps important in the pathogenesis of psoriasis or have been transferred to the psoriasis arena after being developed for other inflammatory diseases. Currently, three types of biologics are approved or are in development for psoriasis: (1) recombinant human cytokines, (2) fusion proteins, and (3) monoclonal antibodies, which may be chimeric or humanized. Due to the risk of the development of antibodies to mouse sequences, humanized or fully human antibodies are preferred for clinical use.

Using internationally acknowledged safety and efficacy endpoints, the overall utility and benefit of biologics have been demonstrated based on the percentage of patients achieving at least a 50% improvement in PASI (PASI-50), a 75% improvement in PASI (PASI-75), the impact of treatment on quality of life, and safety and tolerability.417 In general, these agents have antipsoriatic activity roughly comparable to that of MTX and lack its risk of hepatotoxicity. However, they are far more expensive, carry risks of immunosuppression, infusion reactions, and antibody formation, and their long-term safety remains to be evaluated. In the opinion of the authors, use of biologic agents should be reserved for treatment of severe psoriasis that is either unresponsive to MTX or in patients for whom the use of MTX is contraindicated.

Alefacept

Alefacept is a human lymphocyte function-associated antigen (LFA)-3-IgG1 fusion protein designed to prevent the interaction between LFA-3 and CD2. The LFA-3-CD2 signal plays an important role in activation of T cells. The LFA-3 portion of alefacept binds to the CD2 receptor on T cells, blocking the interaction between LFA-3 and CD2, thus interfering with the activation of T cells, inducing apoptosis and modifying the inflammatory process. CD2 is upregulated on memory effector T cells, explaining the preferential depletion of these cells by alefacept.418 One-third to one-half of psoriatic patients do not respond to alefacept; the reasons for this remain unclear. However, evidence indicates that repeated administration of alefacept leads to improved response, and that responses to alefacept are durable.415

Efalizumab

Efalizumab (anti-CD11a) is a humanized monoclonal antibody developed for treatment of plaque psoriasis. It is directed against CD11a, the α subunit of LFA-1, and thus blocks the interaction of LFA-1 with its ligand intercellular adhesion molecule 1. This blockade inhibits T-cell activation, cutaneous T-cell trafficking, and T-cell adhesion to keratinocytes.419,420 Some patients have shown evidence of exacerbation of the disease at the end of the dosing period.421 This medication is not longer in clinical use as it was withdrawn from the market in 2009 after reports of an increased incidence of progressive multifocal leukoencephalopathy of approximately one in 500 treated patients.422

Tumor Necrosis Factor-α Antagonists

The clinical application of TNF antagonists in inflammatory diseases has exploded on the clinical realm in a manner reminiscent of the discovery of the activity of corticosteroids.423 TNF-α is a homotrimeric protein that exists in both transmembrane and soluble forms, the latter resulting from proteolytic cleavage and release. It is still unclear which form is more important in mediating its proinflammatory activities or the relative importance of the two p55- and p75-kd TNF-α-binding receptors.424

Currently, four anti-TNF biologics are available in the United States. Infliximab is a chimeric monoclonal antibody that has high specificity, affinity, and avidity for TNF-α. An example of an excellent treatment outcome with infliximab is shown in Fig. 18-16A. Etanercept is a human recombinant, soluble, TNF-α receptor-Fc IgG fusion protein that binds TNF-α and neutralizes its activity. Adalimumab and golimumab are fully human recombinant IgG1 monoclonal antibodies and specifically targets TNF-α. Currently golimumab is only FDA-approved for psoriatic arthritis. Clinical trials have shown that each of these agents is well tolerated and appears suitable for long-term use in chronic plaque psoriasis. However, like all the targeted biologic therapies, they carry risks of immunosuppression, and their long-term safety requires further study.

Clinical studies have found infliximab and adalimumab to be slightly more effective than etanercept in the treatment of psoriasis. It is likely that the differential effects of these agents are associated with selectivity in their ability to perturb these receptor ligand interactions. It is known that infliximab, adalimumab, golimumab, and etanercept bind TNF differently; infliximab and adalimumab bind to both soluble and membrane-bound TNF, whereas etanercept binds primarily to soluble TNF.425 Binding to membrane-bound TNF can induce a dose-dependent increase in apoptosis of T cells, but the relevance of this mechanism in psoriasis has not been evaluated.

Anti-p40 (IL-12/IL-23 Antagonist)

Ustekinumab is a human monoclonal antibody that binds the shared p40 subunit of IL-12 and IL-23 and prevents interaction with their receptors.426 This treatment blocks IL-12, which is critical for Th1 differentiation, but its inhibitory effect on IL-23 may be more important. As described earlier, IL-23 supports chronic inflammation mediated by Th1799–101 and Th22 cells.427 Clinical studies have found ustekinumab to be slightly more effective than etanercept in the treatment of psoriasis,428 but direct comparison to infliximab or adalimumab has not been reported.

Numerous new drugs are currently in clinical trials for treatment of psoriasis as outlined in a comprehensive review.429 As would be predicted from the immunological and genetic studies depicted in Figs. 18-3 and 18-5, a humanized monoclonal antibody directed against the IL-17 receptor appears to be highly effective in early clinical trials.430

Extensive guidelines are available for specific clinical scenarios, including severe scalp psoriasis,431 intertriginous psoriasis,432 concomitant hepatitis C or HIV infection,396,433 and in erythrodermic psoriasis.434

There is no known prevention for psoriasis.