HLA studies

Histocompatibility antigens (HLA) are surface antigens on human cells, and the corresponding chromosomal region is called the major histocompatibility complex (MHC). It is situated on the short arm (p) of chromosome 6. Psoriasis is associated with HLA-Cw6, with the presence of HLA-Cw6 conferring a relative risk of 13 for developing psoriasis in the Caucasian population and 25 in the Japanese.

HLA-Cw6 is strongly linked to the age of onset of psoriasis. In one series, HLA-Cw6 was expressed in 90% of the patients with early-onset psoriasis, in 50% of those with late-onset psoriasis, and only in 7% of a control population. A specific MHC class II antigen (DRB1*0701/2) also appeared to be associated with early-onset psoriasis, and the psoriasis-associated HLA alleles were often in an extended haplotype: Cw6-B57-DRB1*0701-DQA1*0201-DQB1*0303. Individuals carrying this haplotype were found to have a 26-fold increased risk of developing early-onset psoriasis . As a result, some clinicians have designated patients with early-onset psoriasis, a positive family history of psoriasis, and expression of HLA-Cw6 as having type I psoriasis and those with late-onset disease, no family history, and a lack of expression of HLA-Cw6 as having type II psoriasis . Other HLA alleles may be associated with different psoriasis variants and related conditions. For example, the HLA-B27 allele is a marker for sacroiliitis-associated psoriasis and reactive arthritis (see below).

Genome-wide association studies

Classic genome-wide linkage analysis has identified at least nine psoriasis susceptibility regions (PSORS1–9) in different chromosomal locations . By far the most important genetic region is PSORS1 (on chromosome 6p), which is estimated to account for up to 50% of psoriasis risk. PSORS1 contains genes such as HLA-C (with the HLA-Cw6 risk allele; see above) and corneodesmosin ( CDSN ). Due to high linkage disequilibrium in PSORS1 (i.e. genes within this region are inherited as a block), it has been challenging to determine which gene(s) within PSORS1 contribute to psoriasis pathogenesis. Use of genome-wide association studies (GWAS) has recently provided new insights into the genetic basis of psoriasis. In GWAS, hundreds of thousands of s ingle n ucleotide p olymorphisms (SNPs) across the entire human genome are examined in thousands of patients (see Ch. 54 ). Genes that have been associated with psoriasis through utilization of this and other methods are summarized in Table 8.1 .

Several conclusions regarding the genetic factors in psoriasis can be drawn from recent GWAS . First, most of the genes that have been implicated have immune-related functions, underscoring the importance of the innate and adaptive immune systems in the pathogenesis of psoriasis; in contrast, relatively few genes that encode skin-specific proteins have been associated with psoriasis. Second, thus far surprisingly few interactions among the genetic variants have been identified (with the exception of HLA-Cw6 and ERAP-1; see below). Third, associated genes encode proteins with roles in particular immunologic and signaling pathways, especially those involving tumor necrosis factor (TNF), NF-κB, interferons (IFN), and interleukin (IL)-23/Th17 cells (see Table 8.1 ) . Lastly, ERAP1 , which encodes an aminopeptidase involved in MHC class I antigen processing, interacts synergistically with the HLA-Cw6 risk allele, providing another argument for the role of an MHC-restricted antigen and its presentation through HLA-C in the pathogenesis of psoriasis .

Functional genomic studies

Microarray technology has been utilized to obtain a comprehensive picture of the genes expressed in psoriatic skin . More than 1300 genes were found to be differentially expressed when compared to normal human skin. This group of genes included known markers of psoriasis in the skin, but it also contained numerous genes not known to be expressed in the skin. These analyses confirmed (on a genomic scale) the involvement of T cells and dendritic cells (DCs) and also implicated a role for comorbidity-associated genes involved in atherosclerosis signaling and fatty acid metabolism.

Another important gene family differentially expressed in psoriatic epidermis encodes antimicrobial peptides. These peptides are expressed at high levels in psoriatic skin but at low levels in skin affected by atopic dermatitis .

Role of T cells and dendritic cells

A pathogenic role for antigen-presenting cells and T cells is strongly suggested by the association of psoriasis with particular MHC alleles, e.g. HLA-Cw6 , as well as (in individuals who carry such alleles) variants in ERAP1 , which encodes an aminopeptidase involved in antigen processing. The presence of specific T-cell subsets within the epidermis and dermis of lesional skin is well documented ( Fig. 8.1 ). Also, a number of compounds that affect T-cell function (e.g. by targeting the IL-2 receptor, CD2, CD11a and CD4) were found to result in clinical improvement of psoriasis . Another argument supporting involvement of the adaptive immune system is the disappearance or development of psoriasis following hematopoietic stem cell transplantation . In addition, analysis of lesional T cells has shown oligoclonality, indicating potential antigen-specific expansion of T-cell subpopulations, possibly triggered by exogenous microbial or viral antigens or cross-reacting autoantigens, e.g. keratins .

Immunopathogenesis of psoriasis.

The occurrence of triggering environmental factors in genetically predisposed individuals, carrying susceptibility alleles of psoriasis-associated genes, results in disease development. During the initiation phase, stressed keratinocytes can release self DNA and RNA, which form complexes with the cathelicidin LL37 that then induce interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs; recruited into the skin via fibroblast-released chemerin), thereby activating dermal DCs (dDCs). Keratinocyte-derived interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) also contribute to the activation of dDCs. Activated dDCs then migrate to the skin-draining lymph nodes to present an as-yet-unknown antigen (either of self or of microbial origin) to naive T cells and (via secretion of different types of cytokines such as IL-12 and IL-23 by DCs) promote their differentiation into T helper 1 (Th1), Th17, and Th22 cells. Th1 cells (expressing cutaneous lymphocyte antigen [CLA], CXC-chemokine receptor 3 [CXCR3], and CC-chemokine receptor 4 [CCR4]), Th17 cells (expressing CLA, CCR4, and CCR6), and Th22 cells (expressing CLA, CCR4 and CCR10) migrate via lymphatic and blood vessels into psoriatic dermis, attracted by the keratinocyte-derived chemokines CCL20, CXCL9–11, CCL17, and CCL27; this ultimately leads to the formation of a psoriatic plaque. Th1 cells release IFN-γ and TNF-α, which amplify the inflammatory cascade, acting on keratinocytes and dDCs. Th17 cells secrete IL-17A and IL-17F (and also IFN-γ and IL-22), which stimulate keratinocyte proliferation and the release of β-defensin 1/2, S100A7/8/9 and the neutrophil-recruiting chemokines CXCL1, CXCL3, CXCL5 and CXCL8. Neutrophils (N) infiltrate the stratum corneum and produce reactive oxygen species (ROS) and α-defensin with antimicrobial activity, as well as CXCL8, IL-6 and CCL20. Th22 cells secrete IL-22, which induces further release of keratinocyte-derived T-cell-recruiting chemokines. Moreover, inflammatory DCs (iDCs) produce IL-23, nitric oxide (NO) radicals and TNF-α, while natural killer T (NKT) cells release TNF-α and IFN-γ. Keratinocytes also release vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietin (Ang), thereby promoting neoangiogenesis. Macrophage (M)-derived chemokine CCL19 promotes clustering of Th cells expressing chemokine receptor CCR7 with DCs in the proximity of blood vessels, with further T-cell activation. At the dermal–epidermal junction, memory CD8 ⁺ cytotoxic T cells (Tc1) expressing very-late antigen-1 (VLA-1) bind to collagen IV, allowing entry into the epidermis and contributing to disease pathogenesis by releasing both Th1 and Th17 cytokines. Cross-talk between keratinocytes, producing TNF-α, IL-1β and transforming growth factor-β (TGF-β), and fibroblasts, which in turn release keratinocyte growth factor (KGF), epidermal growth factor (EGF) and TGF-β, and possibly Th22 cells releasing FGFs, contribute to tissue reorganization and deposition of extracellular matrix (e.g. collagen, proteoglycans). LC, Langerhans cell.

Courtesy, Dr Paola DiMeglio.

Animal models for psoriasis have also demonstrated the importance of T cells. In xenograft models in which uninvolved psoriatic skin was transplanted onto immunodeficient mice, donor immune cells (in particular resident T cells) were capable of expanding and inducing the complete lesional phenotype . Induction of psoriatic lesions in these models was also shown to be dependent on TNF-α and on IFN-α derived from plasmacytoid DCs (pDCs) . These experiments demonstrated that T cells can trigger psoriasis in a suitable patient-derived environment.

In humans, several cell types have been implicated in the initiation and maintenance of psoriatic lesions (see Fig. 8.1 ). Most of the epidermal T cells are CD8 ⁺ , whereas the dermal infiltrate is a mixture of CD4 ⁺ and CD8 ⁺ cells. The majority of the cells in both locations are memory T cells that express cutaneous lymphocyte antigen (CLA; the skin homing receptor) and chemokine receptors such as CCR4. Expression of α ₁ β ₁ integrin (VLA-1) on psoriatic T cells, which allows their interaction with basement membrane collagen IV, is key for the entrance of these cells into psoriatic epidermis and establishment of the psoriatic epithelial phenotype . Unconventional T cells also contribute to the pathogenesis of psoriasis via secretion of proinflammatory cytokines and chemokines. These include natural killer (NK) T cells, gamma delta (γδ) T cells, and innate lymphoid cells (ILCs) .

DCs are present in both uninvolved and lesional psoriatic skin, and because of their potent immunostimulatory capacity, they are likely to be involved in its pathogenesis. There is an increased number of dermal DCs in psoriatic skin, and they have an enhanced ability to activate T cells when compared to DCs from normal skin . DC phenotype and function are quite plastic, with the ability to differentiate into potent proinflammatory DCs that produce inducible nitric oxide synthase (iNOS) and TNF-α (referred to as TIP [ T NF/ i NOS- p roducing] DCs) . The role of DCs in psoriasis has been validated by the presence of a prominent genomic DC signature and the decrease of DCs during effective targeted therapy .

Based upon studies in humans and a xenograft model, another type of DC, the pDC, was shown to initiate psoriasis via the production of IFN-α . Complexes of self DNA or RNA (from keratinocytes) plus antimicrobial peptide LL37 trigger IFN-α release by pDCs via a Toll-like receptor 9 (TLR9)-dependent mechanism (see Fig. 8.1 ). This leads to a breaking of tolerance to self nucleic acids and potentially explains the start of the inflammatory cascade in psoriasis .

The presence of neutrophils in the epidermis, either in spongiform pustules of Kogoj or in microabscesses of Munro, is a typical histopathologic feature of psoriasis, especially acute or pustular forms. Neutrophils are typically prominent in active lesions and in the marginal zone of expanding plaques, but, in contrast to T cells, they are not a consistent feature of lesional skin. Although activated neutrophils could contribute to its pathogenesis, they are not considered to be the primary cause of psoriasis.

Prominent angiogenesis is observed within plaques of psoriasis. There is increased expression of vascular endothelial growth factor (VEGF) , and anti-VEGF therapy leads to improvement in mouse models of psoriatic inflammation .

Cytokines and chemokines

Psoriasis is considered to be a disease with prominent involvement of T-helper-cell subsets and their secreted cytokines . Increased amounts of Th1 cytokines (IFN-γ and IL-2) are observed, whereas levels of the anti-inflammatory cytokine IL-10 are reduced. Based on animal studies and measurements in lesional skin, IL-12, IL-23 and IL-15 are likely to contribute to the disease. The striking response of psoriasis to ustekinumab, a human monoclonal antibody against the p40 subunit of IL-12 and IL-23, provides additional evidence for the role of cytokines. It is thought that IL-23 (produced by DCs) stimulates Th17 cells to release IL-17 and IL-22; the concerted action of these cytokines leads to proliferation of keratinocytes and dermal inflammation (see Fig. 8.1 ) . Of note, circulating levels of IL-22 correlate with disease severity. It has also been proposed that there is a distinct subset of IL-22-producing T helper cells (Th22 cells) that contribute to the pathogenesis of psoriasis . The IL-17-producing T cells in psoriatic epidermis might have a cytotoxic phenotype, qualifying them as Tc17 cells .

IFN-γ is released by activated T cells and NK T cells within the epidermis, and it activates members of the STAT transcription factor family, which drive the expression of a large number of immune-related genes that have roles in psoriasis pathogenesis. The IFN-γ-activated pathway is a key feature of psoriasis and explains several phenotypic alterations such as vasodilation (by the induction of iNOS) and accumulation of T cells (via the expression of various chemokines).

The innate immune cytokines IL-1, IL-6 and TNF-α are upregulated in psoriatic skin. TNF-α is a particularly relevant cytokine and its importance is underscored by the therapeutic efficacy of TNF-α inhibitors (see Treatment ).

Chemokines are important mediators in the trafficking of leukocytes, and the increase in several chemokines and their cognate receptors within psoriatic lesions has been extensively documented. CXCL8 is thought to mediate the often-prominent infiltration by neutrophils. CCL17, CCL20, CCL27, and CXCL9–11 are implicated in attracting T cells to the psoriatic plaque. A pDC-attracting chemokine, chemerin, is increased in psoriatic skin and might contribute to the early recruitment of pDCs into psoriatic lesions .

Innate immunity and role of keratinocytes

In the skin, various cell types are involved in innate (non-adaptive) immune response pathways. These include DCs (myeloid DCs and pDCs), NK T cells, γδT cells, ILCs, and neutrophils (see above), as well as epidermal keratinocytes. For example, keratinocytes constitutively express antimicrobial proteins such as β-defensin-1 (hBD1) and secretory leukocyte protease inhibitor (SLPI), which have direct antimicrobial activity against a broad spectrum of pathogens. In addition, keratinocytes can be stimulated to express a wide variety of other inducible antimicrobials such as hBD2, the cathelicidin LL37, and SKALP/elafin . In addition to these effector molecules, keratinocytes express TLRs and secrete signaling molecules such as IL-1, IL-6, IL-8, and TNF-α. Interestingly, the antimicrobial effector protein hBD2 was also shown to have chemotactic activity via CCR6 and to bind to TLR4. Since most of these proteins are highly expressed in lesional psoriatic skin, it is likely that they are involved in the initiation or control of the inflammatory process; however, their precise roles remain to be determined.

Any model of the pathogenesis of psoriasis also has to account for the dramatically increased proliferation rate of keratinocytes. The cytokines and chemokines found in lesional skin are generally not mitogenic for keratinocytes. For example, IFN-γ, a prominent Th1 cytokine, is itself antiproliferative, but it was found to be a crucial factor in supernatants of lesion-derived T-cell clones that could drive keratinocyte stem cell proliferation .

Keratinocytes within psoriatic plaques express STAT3, suggesting that this transcription factor might be of pathogenetic importance. In a transgenic animal model, epidermal expression of STAT3 (in cooperation with T cells) was found to induce psoriasis-like lesions in mice . STAT3 induced the upregulation of a number of genes relevant for psoriasis, such as those encoding ICAM-1 and TGF-α; the latter has been shown to stimulate proliferation of keratinocytes in psoriasis via an autocrine loop. As STAT3 is activated by a variety of cytokines including IL-22 as well as IL-6, IL-20 and IFN-γ, this could represent a link between keratinocyte activation and immune cells in the development of the psoriatic lesion.

External triggering factors

The Koebner or isomorphic phenomenon, i.e. the elicitation of psoriatic lesions by injury to the skin, is observed in ~25% of patients with psoriasis. A particular patient may be “Koebner-negative” at one point in time and later become “Koebner-positive”. The Koebner phenomenon suggests that psoriasis is a generalized skin disease that can be triggered locally. Psoriatic lesions can also be induced by other forms of cutaneous injury, e.g. sunburn, morbilliform drug eruption, viral exanthem. The lag time between the trauma and the appearance of skin lesions is usually 2–6 weeks.

Systemic triggering factors

Generalized pustular psoriasis

In generalized pustular psoriasis, infiltration of neutrophils dominates the histologic picture, explaining the bright erythema and sterile pustules ( Fig. 8.8 ). It is an unusual manifestation of psoriasis, and triggering factors include pregnancy, rapid tapering of corticosteroids (or other systemic therapies), hypocalcemia, infections, and, in the case of the localized pattern, topical irritants. Generalized pustular psoriasis during pregnancy is also referred to as impetigo herpetiformis . Of note, the clinical presentation of several inherited autoinflammatory disorders (e.g. DIRA, DITRA, CARD14-mediated pustular psoriasis, ADAM17 deletion) resembles generalized pustular psoriasis (see Table 45.7 ) .

Generalized pustular psoriasis.

Broad areas of erythema with numerous pustules and the formation of lakes of pus.

Courtesy, Julie V Schaffer, MD.

Four distinct patterns of generalized pustular psoriasis can be seen:

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  von Zumbusch pattern . This is a generalized eruption starting abruptly with erythema and pustulation (see Fig. 8.8 ). The skin is painful during this phase, and the patient has a fever and feels ill. After several days, the pustules usually resolve and extensive scaling is observed. Sometimes, chronic plaques of psoriasis, if present, can resolve. In the original case report by von Zumbusch (1910), nine episodes of pustulation occurred over a period of 10 years.

  
  
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  Annular pattern . The eruption is characterized by annular lesions, consisting of erythema and scaling with pustulation at the advancing edge ( Fig. 8.9 ). The lesions enlarge by centrifugal expansion over a period of hours to days, while healing occurs centrally.

  
  

  
  

  
  

  

  
  

  
  

  Annular pustular psoriasis.

  
  

  A,B Multiple annular inflammatory plaques whose active borders are studded with pustules followed by desquamation. As these lesions enlarge, there is central clearing. The intensity of erythema can vary and the color is influenced by the skin phototype.

  
  

  A, Courtesy, Marieke M B Seyger, MD, PhD; B, Courtesy, Julie V Schaffer, MD.

  
  
  
  
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  Exanthematic type . This is an acute eruption of small pustules, abruptly appearing and disappearing over a few days. It usually follows an infection or may occur as a result of administration of specific medications, e.g. lithium. Systemic symptoms usually do not occur. There is overlap between this form of pustular psoriasis and pustular drug eruptions, also referred to as acute generalized exanthematous pustulosis (AGEP; see Ch. 21 ).

  
  
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  “Localized” pattern . Sometimes pustules appear within or at the edge of existing psoriatic plaques. This can be seen during the unstable phase of chronic plaque psoriasis and following the application of irritants, e.g. tars, anthralin.

Pustulosis of the palms and soles

Pustulosis of the palms and soles is characterized by “sterile” pustules of the palmoplantar surfaces admixed with yellow–brown macules ( Fig. 8.10 ); scaly erythematous plaques may also be seen. A minority of patients have chronic plaque psoriasis elsewhere. In contrast to the natural history of generalized pustular psoriasis, the pustules remain localized to the palmoplantar surfaces and the course of this disease is chronic. Focal infections and stress have been reported as triggering factors and smoking may aggravate the condition. Pustulosis of the palms and soles is one of the entities most commonly associated with sterile inflammatory bone lesions within the context of SAPHO syndrome, which consists of s ynovitis, a cne, p ustulosis, h yperostosis and o steitis. Several neutrophilic dermatoses are associated with SAPHO (see Table 26.18 ).

Pustulosis of the palms and soles.

Multiple sterile papules are admixed with yellow–brown macules on the palm.

Acrodermatitis continua of Hallopeau

This is a rare manifestation of psoriasis. Clinically, pustules are seen on the distal portions of the fingers ( Fig. 8.11 ) and sometimes the toes. Pustulation is often followed by scaling and crust formation. Pustules may also form in the nail bed (beneath the nail plate), and there may be shedding of nail plates. Transition into other forms of psoriasis can occur and acrodermatitis continua may be accompanied by annulus migrans of the tongue (see below).

Acrodermatitis continua of Hallopeau.

Erythema and slight scale of the distal digit, pustules within the nail bed, and partial shedding of the nail plate.

Scalp psoriasis

The scalp is one of the most common sites for psoriasis. Unless there is complete confluence, the individual lesions are discrete, in contrast to the less well-defined areas of involvement in seborrheic dermatitis. At times, however, it is not possible to distinguish seborrheic dermatitis from psoriasis, and the two disorders may coexist. The lesions of psoriasis often advance onto the periphery of the face, the retroauricular areas and the posterior upper neck ( Fig. 8.12 ). The scales sometimes have an asbestos-like appearance and can adhere to hair shafts in clumps (pityriasis amiantacea). Although pityriasis amiantacea can also be seen in patients with seborrheic dermatitis, secondarily infected atopic dermatitis and tinea capitis, psoriasis is the most common cause. Alopecia occasionally develops within involved areas, including in the setting of TNF inhibitor-induced psoriasis (see Ch. 69 ). In addition, patients with dermatomyositis involving the scalp may have lesions that resemble psoriasis.

Scalp psoriasis with extension onto the neck.

Note the involvement of the external auditory canal.

Flexural psoriasis

Flexural lesions are characterized by shiny, pink to red, sharply demarcated thin plaques ( Fig. 8.13 ). There is much less scale than in untreated chronic plaque psoriasis. Often a central fissure is seen. The most common sites of involvement are the retroauricular fold, intergluteal cleft, inguinal crease, axilla, and inframammary region. When flexural areas are the only sites of involvement, the term “inverse” psoriasis is sometimes used. Localized dermatophyte, candidal or bacterial infections can be a trigger for flexural psoriasis.

Inverse psoriasis.

Shiny erythematous plaques of the inframammary folds that lack scale.

Courtesy, Luis Requena, MD.

Oral mucosa

Migratory annular erythematous lesions with hydrated white scale (annulus migrans) have been observed in patients with acrodermatitis continua of Hallopeau and generalized pustular psoriasis. The most common location is the tongue, and the clinical (and histologic) appearance is similar to geographic tongue. Occasionally, lesions are observed on the buccal mucosa.

Nail psoriasis

Nail involvement has been reported in 10–80% of psoriatic patients, depending upon the series. The fingernails are more often affected than the toenails ( Fig. 8.14 ). In a survey from the Netherlands, 79% of patients reported involvement of their nails, with 52% experiencing associated pain and 14% major restrictions in daily life due to the nail changes. Patients with nail involvement appear to have an increased incidence of psoriatic arthritis.

Nail psoriasis.

Nail plate pitting, distal onycholysis, oil drop changes, and subungual and proximal hyperkeratosis are seen. There is also proximal nail-fold inflammation with loss of the cuticle, especially of the forefingers.

Courtesy, Marcel C Pasch, MD.

Psoriasis affects the nail matrix, nail bed, and hyponychium. Small parakeratotic foci in the proximal portion of the nail matrix lead to pits in the nails (see Ch. 71 ). Leukonychia and loss of transparency (less common findings) are due to involvement of the midportion of the matrix. If the entire nail matrix is involved, a whitish, crumbly, poorly adherent “nail” is seen. Psoriatic changes of the nail bed result in the “oil drop” or “salmon patch” phenomenon, which reflects exocytosis of leukocytes beneath the nail plate. Splinter hemorrhages are the result of increased capillary fragility, and subungual hyperkeratosis and distal onycholysis are due to parakeratosis of the distal nail bed. Vigorous removal of distal subungual debris may be an exacerbating factor.

Inflammatory linear verrucous epidermal nevus (ILVEN)

ILVEN is characterized by linear psoriasiform lesions (i.e. scaling and erythematous plaques) that follow the lines of Blaschko (see Ch. 62 ). Based upon its chronicity and resistance to therapy, ILVEN is thought to be an entity separate from linear psoriasis.

Reactive arthritis (formerly Reiter disease)

This syndrome features urethritis, arthritis, ocular findings and oral ulcers, in addition to psoriasiform skin lesions. The disorder is uncommon in children and occurs more frequently in men than in women. The urethritis may be mild or severe and accompanied by complications such as cystitis, cervicitis, and salpingitis. Chlamydia trachomatis is a major cause of urethritis and may trigger the entire syndrome, as may other infections such as shigellosis. Conjunctivitis is a common eye finding in affected patients, although iritis, uveitis with glaucoma, and keratitis may also occur. Polyarthritis and sacroiliitis are the most frequent joint manifestations. Cutaneous lesions occur in approximately 5% of reactive arthritis patients, with a predilection for the soles, extensor surfaces of the legs, penis, dorsal aspects of the hands, fingers, nails, and scalp ( Fig. 8.17 ). The lesions on the plantar surface usually have thick yellow scale and are often pustular (keratoderma blennorrhagicum). Psoriatic plaques on the penis are referred to as balanitis circinata.

Reactive arthritis (formerly Reiter disease).

A, B Plantar lesions of keratoderma blennorrhagicum. The amount of scale can vary and when sterile pustules form, they are often admixed with yellow–brown macules. C Papulosquamous lesions on the glans and shaft of the penis.

B, Courtesy, Eugene Mirrer, MD.

Reactive arthritis has a strong association with HLA-B27. Although the course is often self-limited, lasting weeks to months, some patients have disease that is chronic and disabling. Of note, HIV-infected patients can also develop this disorder and it may be severe.

Sneddon–Wilkinson disease (subcorneal pustular dermatosis)

This disorder is characterized by annular or polycyclic lesions, usually commencing in the flexures ( Fig. 8.18A ). Very superficial (subcorneal) sterile pustules are the hallmark of Sneddon–Wilkinson disease, hence its second name ( Fig. 8.18B ). There may be a gravity-induced demarcation in some vesiculopustules, with clear fluid superiorly and pus inferiorly. This disease has a cyclic course, i.e. as the pustules resolve they are replaced by superficial scaling and then new pustules form again. Some patients with Sneddon–Wilkinson disease have an associated IgA paraproteinemia. Its response to dapsone, combined with subcorneal pustules (in the absence of spongiform pustules), provide support for this condition being a disease entity distinct from pustular psoriasis, although some authors have questioned the existence of Sneddon–Wilkinson disease as a distinct entity. Of note, immunofluorescence studies are required to distinguish the subcorneal pustular dermatosis type of IgA pemphigus from Sneddon–Wilkinson disease.

Sneddon–Wilkinson disease.

A Annular and polycyclic plaques in the axilla with small pustules, erosions and scale in the border. B Numerous, fragile, subcorneal pustules arising within a background of erythema. There is dependent pooling of the pustular contents in some of the larger lesions. There is significant overlap with pustular psoriasis.

B, Courtesy, Department of Dermatology, Medical University of Graz.

Associations with skin diseases

There is a pronounced under-representation of allergic skin diseases in psoriatic patients as compared to age-matched controls without psoriasis. The frequencies of atopic dermatitis, asthma, urticaria and allergic contact dermatitis have been found to be lower in psoriatic patients. For example, in one study atopic dermatitis was seen ~50 times less often in psoriatic compared with non-psoriatic patients . An obvious explanation is the immunologic difference between these two conditions, with a predominantly Th1 response in psoriasis and a predominantly Th2 response in atopic dermatitis. However, in patients with psoriasis in atypical locations and/or treatment-resistant lesions, the possibility of allergic contact dermatitis as a triggering factor needs to be considered.

A bi-directional relationship exists between lichen simplex chronicus (LSC) and psoriasis. If a psoriatic lesion is pruritic, superimposed LSC may develop and the surface becomes shiny with increased skin markings. Because the LSC itself is pruritic, the resultant rubbing may worsen the psoriasis (Koebner phenomenon). The patient then enters a vicious cycle. Therapeutic regimens must address both disorders.

Seborrheic dermatitis is characterized by pink to red patches with yellowish, sometimes greasy, scales (see Ch. 13 ). The sites of predilection are the scalp, central face, ears, presternal area, and intertriginous zones. As the clinical features of psoriasis and seborrheic dermatitis can be seen in the same patient, some authors use the term “sebopsoriasis”, especially when diagnostic lesions of psoriasis are not present elsewhere.

Infections

In contrast to atopic dermatitis, psoriatic lesions are seldomly impetiginized, i.e. secondarily infected by bacteria. One explanation for this resistance to secondary bacterial infections is increased production of skin-derived antimicrobial peptides, e.g. defensins, SKALP/elafin (see Pathogenesis ).

The prevalence of onychomycosis, due to Candida species or dermatophytes, is increased in psoriatic patients (average, ~18%), compared to control groups . In flexural psoriasis, concomitant Candida infections are frequently observed and have been incriminated as a local triggering factor.

Cancer

Patients with psoriasis may have a slightly higher incidence rate of all malignancies compared to the general population . With the exception of a significantly higher rate of nonmelanoma skin cancer in those who had received phototherapy (type not specified), differences in rates were minimal when various systemic therapies were compared . It has been shown that psoriatic patients who have had >200 PUVA treatments are at increased risk for the development of skin cancers, especially squamous cell carcinomas (SCCs). Of note, the use of cyclosporine in patients previously treated with PUVA significantly increases the number and rate of appearance of SCCs. Lastly, there is controversy as to whether PUVA-treated patients have an increased risk of cutaneous melanoma.

Association with internal diseases (including comorbidities)

Cardiovascular diseases , e.g. myocardial infarctions, peripheral arterial disease, cerebrovascular accidents, are more common in patients with severe psoriasis. The latter is associated with a threefold increased risk for myocardial infarction and a 3.5–4.4-year reduction in life expectancy. This is largely due to an increased risk for having metabolic syndrome (see Table 53.5 ) . In patients with psoriatic arthritis, serum levels of C-reactive protein (CRP) have been reported to be elevated (as compared to healthy controls), and elevated CRP levels represent a risk factor for the development of cardiovascular disease. It has also been shown that TNF-α and IL-6 can target adipocytes and induce dyslipidemia. It has not yet been shown convincingly that treatment with methotrexate and/or TNF-α inhibitors reduces the risk of atherosclerotic cardiovascular disease. Patients with psoriasis may also be at increased risk for the development of venous thromboembolism.

Non-alcoholic steatohepatitis , characterized by fatty infiltration, periportal inflammation and focal necrosis, is more commonly observed in patients with psoriasis. In a study of 142 adults with psoriasis, non-alcoholic fatty liver disease was detected in 59%, and it correlated with the presence of obesity, hyperlipidemia, the metabolic syndrome, an AST : ALT ratio >1, and psoriatic arthritis . Chronic administration of methotrexate is associated with a significant risk for hepatic damage in patients with psoriasis, whereas similar methotrexate dosages in patients with rheumatoid arthritis do not pose such hepatotoxic potential. Although the reason for this difference is not known, several possible explanations have been put forward, including a genetic predisposition, increased alcohol consumption by psoriasis patients, and a higher incidence of non-alcoholic fatty liver disease.

Crohn disease, ulcerative colitis, and psoriasis share an association with sacroiliitis and HLA-B27 positivity. In genome-wide association studies of Crohn disease and psoriasis, shared susceptibility loci were identified . Additional disorders that share susceptibility genes with psoriasis are listed in Table 8.1 . Lastly, in a population-based cohort study, an association between psoriasis and kidney disease was suggested .