Several clinical variants of psoriasis have been recognized. Guttate psoriasis consists of 1–5 mm erythematous papules, which eventually develop a fine scale. It may be preceded by a streptococcal pharyngitis.^{106.107.108. and 109.} Evidence of a preceding streptococcal infection is found in about two-thirds of cases of guttate psoriasis. ¹⁵ T lymphocytes specific for group A streptococcal antigens have been isolated from lesions of guttate psoriasis. ¹¹⁰ There is a predilection for the trunk and it is more common in children. ¹¹¹ Clearing may occur spontaneously in weeks or months. ¹⁵ Psoriasis begins as the guttate form in 15% or more of cases. ⁹⁹Erythrodermic psoriasis develops in approximately 2% of psoriatics and it accounts for 20% or more of erythrodermas.^{112.113.114. and 115.} It is a severe form involving more than 90% of the skin with a high morbidity and an unpredictable course. ¹⁵ Erythrodermic psoriasis may be precipitated by administration of systemic steroids, by the excess use of topical steroids, by radiologic contrast media, ¹¹⁶ or by a preceding illness; it may develop as a complication of phototherapy. ¹¹² Peripheral blood eosinophilia may be present in this form. ¹¹⁷Sebopsoriasis consists of yellowish-red, less well-marginated lesions, with variable degrees of scaling, often distributed in seborrheic regions of the body. ¹¹⁸ Rare clinical variants include a nevoid form,^{119. and 120.} sometimes along the lines of Blaschko, ¹²¹ photosensitive psoriasis, ¹²² inverse (flexural) psoriasis, ¹²³ follicular psoriasis,^{124. and 125.} psoriasis spinulosa,^{111. and 126.} psoriasis bullosa acquisita, ¹²⁷ congenital erythrodermic psoriasis, ¹²⁸ interdigital psoriasis, ¹²⁹ rupioid psoriasis, ¹³⁰ annular plaque-type psoriasis, ¹³¹ annular verrucous psoriasis, ¹³² verrucous (hypertrophic) psoriasis, ¹³³ erythema gyratum repens-like psoriasis, ¹³⁴ erythema annulare centrifugum-type psoriasis, ¹³⁵ and linear psoriasis,^{62.136.137.138. and 139.} although the occurrence of a linear form of psoriasis is not accepted by some authorities. Psoriasiform napkin dermatitis may also be a variant of psoriasis.^{96. and 140.} Pustular psoriasis is regarded as a discrete entity. Different forms of the disease may alter their morphology and become a different clinical type. This phenotype switching may be a consequence of alterations in interleukin pathways. ¹⁴¹

Cases reported as psoriasiform acral dermatitis are now thought to represent a variant of psoriasis in children and not a discrete entity. This variant is characterized by cutaneous involvement of the digits without nail dystrophy. ¹⁴²

There is a genetic proclivity to psoriasis, but no precise mode of inheritance is clear.^{87.143.144.145.146. and 147.} The pattern is polygenetic¹⁴⁸ rather than single-gene inheritance. A recessive mode of inheritance has been suggested in Swedish patients. ¹⁴⁹ Concordance in monozygotic twins varies from 35% to 70% or more.^{87. and 150.} It is 15–30% in dizygotic twins. ¹⁵¹ These statistics suggest that non-shared environmental influences also play a role. ¹⁵²

Since 1994, many genetic loci (mainly on chromosomes 17q, 4q, 2p, 1q, and 6p) comprising at last nine genes have been under investigation.^{7.153.154.155. and 156.} At least 19 different putative loci for genetic susceptibility to psoriasis have been reported.^{10. and 157.} More recent studies suggest that there is a major susceptibility region for psoriasis on chromosome 6p21.3, near to HLA-C.^{158.159.160.161.162.163. and 164.} It has been estimated that the proportion of genetic susceptibility attributable to this gene (PSORS1C3) is about 30%. ¹⁶⁵ Attempts to link this gene to the CDSN gene (corneodesmosin), also near to HLA-C, were initially unsuccessful. ¹⁴⁹ Both genes as well as the nearby HCR gene are now regarded as important psoriasis susceptibility genes in Chinese patients with psoriasis,^{166. and 167.} although this has been questioned in a recent paper. ¹⁵¹ The CDSN gene is associated with psoriasis vulgaris in Caucasian but not in Japanese populations. ¹⁶⁸ However, PSORS1 shows epistasis with genes at other locations, such as on 1p. ¹⁶⁹PSORS1 contains several genes, some of which have an association with psoriasis. ¹⁷⁰ Another study of psoriasis in Chinese has suggested that the MICA gene, another HLA-related gene on chromosome 6p21.3, may be a candidate gene. ¹⁷¹ The ACE gene variants may confer susceptibility in some populations.^{172. and 173.} The leptin gene did not appear to be involved in a Turkish population. ¹⁷⁴ Promoter region polymorphisms in the tumor necrosis factor-α gene have been associated with early-onset psoriasis in a Polish population, but not in Japanese, Chinese, or Korean people.^{175. and 176.} In contrast, IL-12B gene polymorphisms, another cytokine gene, did confer a risk for psoriasis vulgaris in several different populations.^{176. and 177.} Poly­morphisms in the PTPN22 region are associated with psoriasis of early onset. ¹⁷⁸ Other proinflammatory genes have also been implicated.^{179.180. and 181.}

Psoriasis is associated with HLA-Cw6, B13 and B17 on serology,^{87.182.183.184. and 185.} and more specifically with HLA-Cw*0602, HLA-DQA1*0104, and HLA-DRB1*0701 by PCR.^{161.186.187.188.189. and 190.} An early study showed that all patients with guttate psoriasis carried the HLA-C allele compared with 20% of the control population. ¹⁹¹ This has not been confirmed by a subsequent study which concluded that the role of this allele in psoriasis has yet to be determined. ¹⁹² It has been suggested that PSORS1 may indeed be the HLA-CW*06 allele encoding the HLA-CW6 molecule. ⁷

MicroRNAs are implicated in the pathogenesis of psoriasis and also atopic eczema. Its effect may be mediated through a number of secondary pathways, including the TNF-α pathway. ¹⁹³

Specific factors may trigger the onset or exacerbation of psoriasis. Trauma, infections,^{194. and 195.} and drugs are accepted triggers, while the roles of climate, hormonal factors, cigarette smoking,^{8.196. and 197.} alcohol, ¹⁹⁷ mesotherapy, ¹⁹⁸ internal malignancy,^{199. and 200.} and stress²⁰¹ are sometimes disputed. ⁸⁷ Psoriasis may actually improve during pregnancy.^{202. and 203.} It is often worse in the postpartum period.^{203. and 204.} The development of lesions in response to trauma (Koebner reaction) is present in approximately one-third of cases.^{205. and 206.} A link has been made between psoriasis and human papillomaviruses specifically associated with epidermodysplasia verruciformis, particularly the oncogenic HPV-5. ²⁰⁷ The prevalence of HPV in hairs plucked from patients with psoriasis is increased in patients treated with PUVA. ²⁰⁸ However, a more recent study did not find a specific causal role for HPV-5 or HPV-36 in the pathogenesis of psoriasis. ²⁰⁹ The role of Malassezia is more controversial. The improvement of scalp psoriasis treated with antifungal agents has suggested a role for Malassezia. M. restricta is the predominant species in psoriatic scale. M. globosa is also increased, but much less so. ²¹⁰ Infection may precipitate guttate psoriasis.^{106. and 211.} Various drugs may precipitate or exacerbate psoriasis,^{212. and 213.} particularly lithium;^{214.215. and 216.} other drugs include ecstasy, ²¹⁷ quinidine, ²¹⁸ clonidine, iodine, carbamazepine,^{219. and 220.} olanzapine, ²²¹ thalidomide, ²²² terbinafine,^{223. and 224.} indomethacin, ²¹⁸ rofecoxib, ²²⁵ celecoxib, ²²⁵ various beta-blocker drugs,^{226. and 227.} calcium channel blockers, ²²⁸ terfenadine, ²²⁹ urapidil (an α₁-adrenergic blocker), ²³⁰ isotretinoin, interferon-α,^{196. and 231.} interleukin-2, ²³² the interleukin-1 receptor antagonist anakinra, ²³³ the TNF-α agonists adalimumab and infliximab,^{234.235.236.237.238. and 239.} imiquimod,^{240.241.242. and 243.} antimalarials and, rarely, the non-steroidal anti-inflammatory drugs and the angiotensin-converting enzyme (ACE) inhibitors. ²⁴⁴ However, a recent population-based case-control study found no association between the use of beta-blockers and psoriasis. ²⁴⁵ The drugs that precipitate/exacerbate psoriasis are listed in Table 4.1. It has been suggested that the eruptions produced by TNF-α agonists may be a ‘new model of adverse drug reaction’ rather than true psoriasis, as the histology shows lichenoid and spongiotic features. ²⁴⁶ The eruption triggered by efalizumab, a human anti-CD11a monoclonal antibody used in the treatment of psoriasis, consists of new papular lesions that arise in previously unaffected areas. ²⁴⁷ They usually do not necessitate termination of efalizumab therapy and may optionally be treated with corticosteroids. ²⁴⁷ A psoriasiform eruption, as opposed to true psoriasis, has been reported as a complication of several beta-blocker drugs, ²⁴⁸ and the related propafenone, ²⁴⁹ with fluorescein sodium used in angiography, ²⁵⁰ with the oral hypoglycemic agent glibenclamide, ²⁵¹ with icodextrin, ²⁵² and with terbinafine (see above). ²⁵³ The reactions caused by some of the beta-blocker drugs have a lichenoid histology despite their clinical appearance. Psoriasis has also followed the use of stem cell transplantation.^{254. and 255.}

Psoriasis is a complex disease in which numerous abnormal findings have been reported.147. ^{and 256.} Despite this, the primary (initiating) alteration is unknown, but it appears that the molecular phenotype necessary for the clinical expression of psoriasis is present in all keratinocytes and includes a capacity for hyperproliferation and altered differentiation. Control of the expression of this phenotype involves the keratinocytes themselves, as well as cells of the immune system and various cytokines.^{257.258. and 259.} Many of the changes in these elements may be epiphenomena or secondary and tertiary events in the pathogenetic cascade. As mentioned already, the primary alteration is not known, although it may involve the signal-transducing system of epidermal keratinocytes or the transcription regulatory elements associated with one or more cytokines.^{260.261. and 262.} Stimulation of the immune system by superantigens has also been put forward as a primary event (see below). It is possible that different etiologies may initiate psoriasis in the genetically susceptible individual. Various aspects of the pathogenesis of psoriasis, particularly the immunopathogenesis, have recently been reviewed.^{170.263. and 264.}

As the earliest detectable morphological change in psoriasis involves blood vessels in the papillary dermis, some research has focused on their role in the pathogenetic cascade.^{265.266. and 267.} Vascular changes in psoriasis include dilatation and tortuosity of vessels in the papillary dermis, as well as angiogenesis (neovascularization) ²⁶⁸ and the formation of high endothelial venules, which are specialized postcapillary venules lined by tall columnar or cuboidal endothelial cells. These factors are important in expanding the size of the microcirculation which may, in turn, facilitate the trafficking of T lymphocytes, of the Th1 subclass, into the skin, ²⁶⁹ thus maintaining the psoriatic plaque. ²⁷⁰ Blood flow is increased in these plaques. ²⁷¹ The high endothelial venules play an important role in the cutaneous recruitment of circulating lymphocytes. ²⁷² Microvascular hyperpermeability is another feature of severe psoriasis. This appears to be mediated by circulating vascular endothelial growth factor (VEGF). ²⁷³ Angiogenesis is stimulated by factors such as interleukin-8 and transforming growth factor-α (TGF-α).^{265. and 274.} The presence of angiogenesis in psoriasis has been challenged. Using three-dimensional reconstructions, it has been suggested that downgrowths of the rete ridges include the vessels of the horizontal plexus giving the appearance of intrapapillary capillaries. ²⁷⁵ This study has not been confirmed. In short, it appears that dermal capillary changes alone are unlikely to be causal in psoriasis.^{267. and 270.}

Recruitment of lymphocytes to the papillary dermis is an important factor. ²⁷⁶ This is aided by various chemoattractants such as platelet-activating factor and leukotriene B₄. ²⁷⁷ Some of these lymphocytes are already activated before entering the skin, while still circulating in the bloodstream. ²⁷⁸ The lymphocytes bind to endothelial cells in venules in the papillary dermis as a consequence of the enhanced expression of various adhesion molecules by endothelial cells. ²⁷⁹ It appears that lymphocyte function-associated antigen type 1 (LFA-1), consisting of CD11a and CD18 subunits, ²⁸⁰ which acts as a ligand for intercellular adhesion molecule-1 (ICAM-1), and ICAM-1 itself play a major role in the adhesion of CD4⁺ T cells to endothelial cells. ²⁸¹ Furthermore, TNF-α may play an important role in induction of adhesion molecules on endothelial cells. ²⁸¹ Vascular adhesion protein-1 (VAP-1) is also overexpressed in psoriasis. ²⁸² Efalizumab, an anti-CD11a antibody, has been used to treat psoriasis (see below). Lymphocytes then diapedese transendothelially and pass through the vessel wall into the papillary dermis. Neutrophils will subsequently leave the vessels in a similar way and migrate into the stratum corneum. ²⁸³ Chemotactic factors such as C5a anaphylatoxin are important in their recruitment. ²⁸⁴

While the importance of T lymphocytes in the pathogenesis of psoriasis is accepted,^{285.286. and 287.} there has been some dispute over the relative importance of CD4⁺ and CD8⁺ lymphocytes. ²⁸⁸ The T cells in lesional dermis are predominantly CD4⁺. Cells migrating into the epidermis are mostly CD8⁺.^{170.289. and 290.} Which type produces keratinocyte proliferation by the release of mediators (cytokines) is still disputed. ²⁹¹ Both now appear to be involved, but CD8⁺ cells are particularly important.^{170.292.293. and 294.} CD8⁺ cells in the epidermis express the Vβ T-cell receptor subgroups Vβ3 and Vβ13.1. ²⁹⁵ Another study has shown an increase in the Vβ2 receptor in skin-homing lymphocytes in psoriasis. ²⁹⁶ In psoriasis CD4⁺CD25⁺ regulatory T cells are functionally deficient in suppressing effector T-cell proliferation. ²⁹⁷

As mentioned above, leukocytes bind to endothelial cells in the papillary dermis, prior to their passage from the vessels. This process is under the control of adhesion molecules, which can be classified into three distinct groups:

One or more of these adhesion molecules lead to the selective adhesion of CD4, CD45RO helper T cells. ²⁷⁷ Other categories of adhesion regulators, such as the proline-directed serine/threonine kinases, of which CDK5 is a member, exist. They appear to influence cadherins and integrins. ²⁹⁹ The expression of CDK5 is reduced in psoriasis. ²⁹⁹ Various cytokines appear to induce the enhanced expression of these adhesion molecules in psoriasis; they include interleukin-1 (IL-1), interleukin 2 (IL-2), TNF-α, interferon-γ (IFN-γ), and interleukin-4 (IL-4).^{276. and 300.} On the other hand, ultraviolet-B radiation reduces the adhesive interactions and expression of adhesion molecules, possibly explaining its mode of action in the treatment of psoriasis. ³⁰¹ Serum levels of soluble E-selectin correlate with the extent of psoriatic lesions. ³⁰²

There is a complex interplay between the various cytokines found in the skin in psoriasis; some cytokines have more than one action. They are produced mostly by lymphocytes, although keratinocytes release at least two.^{258.303. and 304.} Dendritic cells and macrophages also produce important cytokines. One of these is interleukin-12 (IL-12) which induces differentiation of naïve CD4 T lymphocytes to T-helper 1 (Th1) cells, which are key effector cells in the pathogenesis of psoriasis as a consequence of their production of various cytokines such as IFN-γ and IL-2.305. ^{and 306.} It also activates natural killer cells. ³⁰⁵ IL-23, which is closely related to IL-12 in structure, stimulates a subset of CD4⁺ lymphocytes to produce IL-17, which induces the production of further proinflammatory cytokines, predominantly by endothelial cells and macrophages.^{305. and 307.} Therapy using an IL-12/IL-23 antibody is currently undergoing clinical trials (see below). ³⁰⁵ Interleukin-18 (IL-18), a novel cytokine produced mainly by monocytes and macrophages but also synthesized by keratinocytes, plays an important role in the Th1 response by stimulating the production of IFN-γ and TNF. It is increased in the serum of patients with psoriasis. ³⁰⁸ In contrast, low levels of IL-10, an anti-inflammatory cytokine, have been found in psoriatic lesions.^{309. and 310.} The many functions of these various cytokines include stimulation of keratinocytes, ³¹¹ vascular changes (see above), control of lymphocyte trafficking (see above), and stimulation of neutrophil chemotaxis. Exacerbations of psoriasis are preceded by a rapid increase in neutrophil chemotaxis. Interleukin-8 (IL-8) is a cytokine with possibly more chemotactic activity than the various complement factors.^{312.313. and 314.} Another is psoriasin (S100A7), a protein belonging to the calcium-binding S100 family. It is a potent inflammatory mediator. ³¹⁵ Two other members of this family, S100A8 and S100A9, are increased in psoriasis and contribute to the hyperproliferation of psoriatic skin. ³¹⁶ The importance of the cytokines in the pathogenesis is shown by the down-regulatory effects of cyclosporine (ciclosporin) on cytokines and cytokine receptors in the treatment of psoriasis.^{317. and 318.} The role of the various cytokines in psoriasis has been reviewed. ³¹⁹ They are summarized in Table 4.2.

The final pathway in the pathogenesis of psoriasis involves the stimulation of keratinocytes by factors such as TNF-α, IL-6, IL-8, TGF-α, IFN-γ, granulocyte/macrophage colony stimulating factor, and the phospholipase C/protein kinase C signal transduction system (see below). IFN-γ, which plays an important role in the growth stimulation of keratinocyte stem cells in psoriasis, can be produced by mast cells as well as lymphocytes. ³²⁰ TNF-α also has a major role. Its release from cells is under the influence of TNF-α-converting enzyme (TACE). ³²¹ The success of the various TNF-α neutralizing modalities in the treatment of psoriasis has led to a re-evaluation of the role of TNF-α in the pathogenesis of psoriasis. It seems likely that dysregulation of innate immunity, involving natural killer (NK)-T cells, plays a role in the pathogenesis of psoriasis. ³²² This is supported by the finding of increased levels of perforin, the cytotoxic product of NK cells, in the epidermis of psoriatic plaques. ³²³ Paradoxically, circulating NK cells are reduced in psoriasis. ³²⁴ There is also an overexpression of the CXC chemokines, interleukin-8 (IL-8) and GRO/melanoma growth-stimulatory activity (GRO-α). ³²⁵ They are potent activators of neutrophils and lymphocytes but also stimulate proliferation of keratinocytes. ³²⁵ These factors produce an alteration in the turnover time for the epidermis: 3–4 days in psoriasis compared with the usual 13 days in normal skin. ³²⁶ It has been estimated that there is a 12-fold increase in the number of basal and suprabasal keratinocytes in cell cycling. ³²⁷ TGF-α, which is elevated in psoriasis, is predominantly synthesized in subcorneal keratinocytes. ³²⁸ It is a potent mitogen that can also stimulate angiogenesis. In contrast, TGF-β has an inhibitory effect on epithelial cell proliferation. Down-regulation of its receptor in psoriatic epidermis has the effect of diminishing this inhibitory influence. ³²⁹ Amphiregulin, a cytokine which acts as an epidermal growth factor, is also increased in psoriatic keratinocytes. ³³⁰ Transgenic mice engineered to overproduce amphiregulin develop a psoriasis-like phenotype, suggesting that a genetically transmitted alteration of amphiregulin synthesis may be a possible cause of the cascade of events in psoriasis. ³¹⁹ There is increased activation of the Src-family of tyrosine kinases (SFKs) in psoriasis.^{331. and 332.} They are important regulators of epidermal growth and differentiation. ³³¹ The existence of an increased number of epidermal growth factor receptors (EGF-R), resulting from their persistence at all levels of the epidermis instead of just the basal layer, may be just as important.^{327. and 333.} Antigen-presenting cells expressing the common heat shock protein receptor CD91 have been found juxtaposed to keratinocytes expressing HSP70, a ligand for CD91 in a mouse model of psoriasis.^{334. and 335.} These activated antigen-presenting cells produce TNF-α in close proximity to these keratinocytes. ³³⁴ T-cadherin, E-cadherin, P-cadherin, and protein kinase D expression all seem to play a part in the regulation of epidermal growth in psoriasis.^{336.337. and 338.} Associated with this hyperproliferation of keratinocytes is a mild increase in apoptosis, and a reduction in the number of Bcl-2-positive cells in the basal layer.^{339.340.341. and 342.} Bcl-2 expression in lymphocytes is increased. ³⁴³ Suppression of apoptosis also occurs in psoriasis. ³⁴⁴ Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is increased in psoriasis. It appears to be regulated by the transcriptional factor NF-κB. ³⁴⁵ Some of the therapies for psoriasis act by their increase in apoptosis. ³⁴⁶ A senescence switch involving p16 may prevent malignant transformation of this up-regulated epidermis. ³⁴⁷ Also methylation of the p16^INK4a gene promoter is found in psoriatic epidermis. ³⁴⁸

As a consequence of the hyperproliferation of keratinocytes, there is enhanced expression of keratins K6, K16, and K17, ³⁴⁹ and reduced amounts of the keratins indicative of differentiation (K1, K2, and K10). K16 is also expressed in non-lesional psoriatic skin and may serve as a marker of preclinical psoriasis. ³⁵⁰ It has been found recently that altered peptide ligands derived from keratin 17 are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro. ³⁵¹ This opens up another therapeutic option in the treatment of psoriasis. ³⁵¹ There is a unique subpopulation of cells in psoriatic epidermis that coexpress K6 and K10. ³⁵² There is also increased nuclear β-catenin in suprabasal cells, ³⁵³ alterations in cell-surface glycoconjugates, ³⁵⁴ and variations in the epidermal differentiation complex, a cluster of genes on chromosome 1q21 that fulfill important functions in the terminal differentiation in the human epidermis. ³⁵⁵ Tight junction components are also altered. ³⁵⁶

The role of microbiological superantigens in the pathogenesis of psoriasis is gaining acceptance, although formal proof of a pathogenic role is still lacking.^{357.358.359.360.361. and 362.} Superantigens are toxins of microbial origin that not only stimulate certain classes of T cells³⁶³ but also have the capability to interact directly (without prior processing) with MHC class II molecules: this leads to considerable T-cell activation and cytokine release. ³⁶⁴ Streptococcal antigens can function as superantigens and it is suggested that they may act as the initiating factor in some cases of guttate psoriasis, in part through superantigen-driven generation of Vβ-restricted CLA-positive skin homing lymphocytes.^{365.366. and 367.} A recent study has confirmed that prior pharyngeal infection is a risk factor for guttate psoriasis. ³⁶⁸ Peripheral blood lymphocytes from patients with psoriasis are generally hyporesponsive to streptococcal superantigens, ³⁶⁹ but there is a subpopulation of CD4⁺ cells that produces interferon-γ (IFN-γ) in response to this antigen.^{370. and 371.} Superantigens produced by Staphylococcus aureus may also be triggering factors.^{372. and 373.}Malassezia furfur is also capable of exacerbating psoriasis. ³⁷⁴ Patients with psoriasis harbor human papillomavirus type 5 (HPV-5) in a significant number of cases. ³⁷⁵ Antibodies to HPV-5, one of the types associated with epidermodysplasia verruciformis, appear to be generated in the epidermal repair process, but whether they contribute to a proliferation of keratinocytes in psoriasis is not known. ³⁷⁵ The high prevalence of cytomegalovirus antigenemia in psoriasis is possibly related to reactivation of the virus by elevated levels of tumor necrosis factor-α (TNF-α).^{376. and 377.} Endogenous retroviral sequences are expressed in psoriasis. ³⁷⁸ They are part of the normal human genome. Their possible role in the pathogenesis of psoriasis is currently being investigated.^{378. and 379.} It has been suggested recently that a broad range of viral and bacterial stimuli may stimulate psoriasis, not by acting on T cells directly but by stimulating plasmacytoid dendritic cells (myeloid-derived cells) to produce large amounts of type 1 interferons (IFN α/β).^{34. and 380.} These disparate findings remain to be integrated into a unitarian theory of pathogenesis.

Other findings in psoriasis that may play some role in the pathogenetic cascade include the increased expression of heat shock proteins by keratinocytes,^{381.382.383. and 384.} an increase in reactive oxygen species, ³⁸⁵ excessive activation of a phospholipase C/protein kinase C signal trans­duction system which stimulates keratinocyte proliferation,^{261.386. and 387.} overexpression of serpin squamous cell carcinoma antigens in psoriatic skin, ³⁸⁸ and increased lysophosphatidyl choline activity in lesional skin. This substance is a lysophospholipid which is chemotactic for monocytes and stimulates the expression of certain adhesion molecules – VCAM-1 and ICAM-1. ³⁸⁹ The finding of immunoreactants in the stratum corneum and the dermis is not thought to be of major pathogenetic significance. ³⁹⁰ There is an up-regulation of the gap junction protein connexin 26 between keratinocytes of psoriasis. ³⁹¹ There is also an overexpression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and other related members of the ADAM family.^{392.393. and 394.} Increased levels of kallikreins are also found in the stratum corneum and serum of patients with psoriasis. ³⁹⁵ Telomerase activity is increased in peripheral blood mononuclear cells in psoriasis. The level correlates with disease severity. ³⁹⁶ There is also increased expression of the natural killer cell inhibitory receptor CD94/NKG2A and CD158b on circulating and lesional T cells in psoriasis and this elevation correlates with disease severity. ³⁹⁷ The significance of these findings is uncertain. Increased levels of elafin, also termed skin-derived anti-leukoproteinase (SKALP), are found in subcorneal keratinocytes of psoriatic lesions. ³⁹⁸ It is a potent elastase inhibitor which may protect the epidermis from the proteolytic activity of neutrophils. ³⁹⁸ The epidermis is also protected against bacterial infections by the release of granulysin by lesional T cells and dendrocytes. ³⁹⁹ The exact role of neuropeptides (including substance P) remains to be clarified. They provide a possible explanation for the triggering action of stress in the exacerbation of psoriasis. ⁴⁰⁰ Increased serum cortisol levels are another possible mechanism by which stress influences psoriasis. ⁴⁰¹ Serotonin levels are also increased in the lesions of psoriasis. ⁴⁰²

In concluding this section, it should not be forgotten that psoriasis is characterized by erythematosquamous lesions. The erythematous nature of the lesions results from the dilatation and increase in vessels in the dermal papillae, which have a thin, overlying layer of epidermal keratinocytes. The clinical thickening of the lesions results from the psoriasiform epidermal hyperplasia brought about by increased mitotic activity in basal keratinocytes through the action of various cytokines with growth factor activity. The scale is composed of parakeratotic cells, resulting from increased transit time, and a focal admixture of neutrophils. ⁴⁰³ All of these features are possibly the consequence of an autoreactive inflammatory process mediated by T lymphocytes of the Th1 subclass.^{263. and 318.} This cytokine profile may be the result of local factors and not determined by a specific genotype. ⁴⁰⁴

In assessing the effects of treatment, there is a need to use appropriate, reproducible assessment criteria that can be compared with the results of other trials. The current benchmark is the PASI (Psoriasis Area and Severity Index), and reductions of 75% or more of this Index are regarded as a suitable response to a particular therapy. It has recently been suggested that a 50% reduction in the PASI is a meaningful response to any therapy. ⁴⁰⁵ Patient compliance is suboptimal in the treatment of psoriasis as treatments are generally prolonged and may have side effects. Up to 40% of patients at any point in time are not receiving any treatment for their condition. ⁴⁰⁶ A similar number do not use medications as directed. ⁴⁰⁷ Treatment also varies between different dermatologists. About 40% of patients receive topical therapy alone. ⁴⁰⁸ Clinical trials of various treatment schedules usually have a placebo group if they are not of a comparative nature. A study of these placebo groups has found that they generally do poorly, as might be expected. ⁴⁰⁹

The various therapies used in psoriasis target different components of the pathogenetic cascade, although some have an effect on more than one component. ⁴¹⁰

In the management of guttate psoriasis, there is little evidence of the efficacy of the standard treatment of this disease – tar and UVB phototherapy. ⁴¹¹ Dithranol and topical steroids with or without UVB phototherapy have also been used. The vitamin D3 analogue calcipotriol is sometimes effective. ⁴¹¹ There is no evidence that antistreptococcal interventions are effective in the management of guttate or chronic plaque psoriasis, ⁴¹² but tonsillectomy may be worthwhile in patients with recurrent streptococcal infections that seem to trigger or maintain their skin disease. ⁴¹³

Topical corticosteroids remain the most commonly prescribed therapy for psoriasis, but they are frequently used in tandem with other agents.^{414. and 415.} The use of anthralin and tar has declined with the increased availability of topical calcipotriol and tazarotene. ⁴¹⁴ A recent consensus conference on topical therapies for psoriasis concluded that there were inadequate studies to draw any conclusions regarding the efficacy, safety, and tolerability of tar and anthralin (dithranol). ⁴¹⁵ Calcipotriol ointment gives the same quality of life improvements as dithranol. ⁴¹⁶ Calcipotriol has proved effective when compared to all other topical treatments of psoriasis. ⁴¹⁶ It is safe provided no more than 100 g of formulation is used each week. ⁴¹⁶ When used with methylprednisolone it produces decreased p53 and Ki-67 expression in treated skin. ⁴¹⁷ A recent trial found that calcipotriene plus betamethasone dipropionate was more effective than either of the individual components alone. ⁴¹⁸ Calcitriol ointment may be used with the calcineurin inhibitor tacrolimus for psoriasis in sensitive areas such as the face and intertriginous areas. ⁴¹⁹ The two therapies have also been used to treat recalcitrant acrodermatitis continua of Hallopeau. ⁴²⁰ Tacrolimus and calcipotriol were found to be equally effective when compared with each other. ⁴²¹ Another trial found that tacrolimus was more effective than calcitriol. ⁴¹⁹ Topical calcitriol appears to target several different pathways in the pathogenetic cascade, producing decreased keratinocyte proliferation, normalized differentiation of keratinocytes, and decreased immune activation. It also normalizes the expression of adhesion molecules.^{422.423. and 424.} Pimecrolimus has been used with narrowband UVB to treat childhood psoriasis. ⁴²⁵ Zinc pyrithione is another topical therapy that can be used. ⁴²⁶ It produces apoptosis in treated keratinocytes.

A similar mechanism is thought to be responsible for the involution of psoriatic hyperplasia that follows PUVA, and narrowband UVB.^{427.428. and 429.} They also reduce the numbers of lymphocytes, macrophages and dendritic cells in treated skin, but PUVA is the only modality that decreases epidermal Langerhans cells. ⁴³⁰ Phototherapy also induces the enhanced expression of insulin-like growth factor-binding protein-7. ⁴³¹ Phototherapy remains the most commonly used therapy for widespread psoriasis but its use is declining because of its association with cutaneous malignancies. In chronic plaque psoriasis, PUVA achieves clearance in more patients with fewer treatment sessions and longer remissions than narrowband UVB. ⁴³² The latter therapy causes a reduction/depletion in epidermal CD4⁺ cells.^{433. and 434.} It may rarely cause a subepidermal blister. ⁴²⁹ A new UVB source generated by a 308 nm excimer laser produces significant T-cell depletion in the skin, increased apoptosis of keratinocytes and decreased Ki-67.^{435. and 436.} Results of this therapy seem promising. Results are enhanced by applying topical methoxypsoralen cream prior to the phototherapy. ⁴³⁷ The pulsed dye laser has limited use; it has met with some success. ⁴³⁸

Balneophototherapy, involving the use of saltwater baths followed by UVB irradiation, ⁴³⁹ is an attempt to reproduce the beneficial effects of Dead Sea climatotherapy.^{440. and 441.} This therapy has all the potential complications of ultraviolet exposure. It has been found that oral retinoids, when used with PUVA therapy, reduce the risk of squamous cell carcinoma but not basal cell carcinoma. ⁴⁴² Not unexpectedly, the melanocortin 1 receptor (MC1R) genotype influences the erythemal sensitivity of skin to PUVA. ⁴⁴³

A wide range of systemic medications are available for the treatment of psoriasis. The three most commonly used are retinoids, methotrexate, and cyclosporine. ⁴⁴⁴ They are approved by the FDA. Before discussing these systemic therapies, it should be emphasized that topical treatments will probably remain the mainstay of psoriasis therapy for most patients. ¹⁵⁷ Care should also be exercised in the use of various therapies in pregnant patients. This subject was reviewed recently. ⁴⁴⁵

Retinoids’ mechanism of action is by reducing the proliferation of keratinocytes, as well as having an inhibitory effect on tissue inflammation.^{446. and 447.} They have also been used to treat verrucous psoriasis. ⁴⁴⁸ Systemic retinoids combined with biological agents (see below) offer a promising method of managing refractory psoriasis. ³⁸⁰

Methotrexate is an effective therapy for moderate to severe psoriasis,^{449.450. and 451.} although there is a need to improve its safety profile by adhering to protocols for its use. ⁴⁵² It down-regulates the expression of some adhesion molecules and this may contribute to its therapeutic effects. ⁴⁴⁹ Long-term use of methotrexate is often discontinued because of its toxic effects, or the loss of a response to treatment. ⁴⁵³ Combining etanercept with methotrexate is reasonable when etanercept monotherapy produces insufficient improvement. ⁴⁵⁴ Vasculitis is a very rare complication of its use. ⁴⁵⁵

Cyclosporine is more effective than methotrexate from a short-term perspective. ⁴⁵⁶ It is safe in low doses. It affects several different steps in the cascade. Not only does it interfere with the expression of keratinocyte adhesion molecules, ⁴⁵⁷ but it also normalizes the basal lamina and the overexpression of cyclins.^{458.459. and 460.} It decreases the number of dermal dendrocytes⁴⁶¹ and inhibits IL-12 production by monocytes. ⁴⁶² There is an improved pattern of CK14 expression, and CK10 recovers to normal levels. ⁴⁶³

Other systemic drugs available include tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine,^{464. and 465.} and sulfasalazine. ⁴⁴⁴

Treatment options for severe psoriasis are either time-consuming (e.g. phototherapy) or have the potential for organ toxicity with chronic use. This applies to methotrexate, retinoids, and cyclosporine. ⁴⁶⁶ The newer immune-based (biological) therapies are becoming widely used for moderate to severe psoriasis, but they are expensive.^{467.468.469.470.471.472. and 473.} Patient satisfaction is high. ⁴⁷⁴ The tumor necrosis factor-α (TNF-α) antagonists have proved more effective than efalizumab, a CD11a blocker. ⁴⁷² Etanercept is usually favored over the other TNF-α antagonists, ⁴⁷² although increasing evidence suggests that infliximab is more efficacious and better tolerated (see below). Guidelines for the use of biological agents in the treatment of psoriasis have recently been published (2008). ⁴⁷⁵

TNF-α antagonists block an important inflammatory cytokine. TNF-α is increased as a consequence of the overexpression of proinflammatory type 1 (Th1) cytokines. ⁴⁷⁶ TNF-α up-regulates the expression of CTACK/CCL27, a cutaneous T-cell attracting chemokine. ⁴⁷⁷ As a consequence there is a decrease in skin-homing CD4⁺ and CD8⁺ lymphocytes. TNF-α antagonists impair dendritic cell function⁴⁷⁸ and decrease epidermal Langerhans cells. ⁴⁷⁹ They produce apoptosis of keratinocytes. ⁴⁸⁰ Infliximab down-regulates the inhibitor of apoptosis, survivin, in keratinocytes and endothelial cells. ⁴⁸¹ There are three main groups of TNF-α antagonists:

TNF-α antagonists are all effective in the treatment of psoriasis and psoriatic arthritis.^{485.486.487.488.489.490.491. and 492.} Sometimes dosage schedules need to be altered for an individual patient to control the disease or side effects of the therapy. ⁴⁹³ Some patients develop a flare of their psoriasis with the development of new lesions despite continued treatment.^{476.494.495. and 496.} Other cases may flare on cessation of treatment,^{476. and 496.} or recur several months after treatment has ceased.^{497.498. and 499.} They may be used in combination with systemic and topical medications when they confer an additional benefit. ⁴⁷⁶ One such combination that has been trialed is etanercept and acitretin. ⁵⁰⁰ The use of TNF-α antagonists allows tapering of methotrexate. ⁵⁰¹ They are better than methotrexate or a placebo, ⁵⁰² and improve quality of life.^{503. and 504.} A recent meta-analysis of published trials found that infliximab is the most efficacious agent for moderate-to-severe psoriasis, followed by adalimumab. ⁵⁰⁵ Another meta-analysis also found that infliximab was the most efficacious biological agent followed by etanercept, efalizumab, and alefacept. ⁵⁰⁶ Infliximab is also effective in treating psoriatic nail disease. ⁵⁰⁷ TNF-α antagonists may produce weight gain. ⁵⁰⁸ Patients should be screened for tuberculosis prior to commencing therapy because they suppress immunity.^{509. and 510.} A recent evidence-based assessment concluded that there is no strong evidence to support the performance of screening and monitoring tests when using systemic biological agents, despite earlier recommendations that they be carried out. ⁵¹¹ There may also be a need to consider available vaccinations. ⁵¹² Dose schedules may need to be altered in cases of obesity. ⁵¹³ Finally, mention should be made of a rare complication, demyelination. ⁵¹⁴

Monoclonal antibody to CD11a (efalizumab). Although this drug is not considered to be as effective as the TNF-α antagonists, several trials of this drug have produced good results.^{280.515.516.517.518. and 519.} It is given by subcutaneous injection. ⁴⁷⁶ There may be a rebound of psoriasis when the drug is ceased but this has been prevented by the use of cyclosporine. ⁴⁷⁶ Several patients who have been refractory to efalizumab have developed erythrodermic flares when switched to etanercept. ⁵²⁰ The drug interferes with T-cell activation and migration to the skin.^{521. and 522.}

Alefacept reduces the number of memory-effector (CD45RO⁺) T cells.^{409.523. and 524.} It has proved effective in several clinical trials.^{525. and 526.} Alefacept has been used specifically for scalp psoriasis⁵²⁷ and palmoplantar psoriasis. ⁵²⁸ Another drug designed to reduce the number of pathogenic T cells, an anti-CD4 antibody, has not produced significant improvement.529. ^{and 530.}

Newer treatments. Immune therapies based on new concepts of disease pathogenesis are now being trialed.^{531. and 532.} One of these drugs, ilodecakin, is a recombinant IL-10 which aims to down-regulate Th1 responses which are overexpressed in psoriasis. Only temporary improvement was achieved in one trial. ⁵³³ Further trials are needed with a recombinant IL-11. ⁴⁷⁶ ABT-874, an interleukin-12/23 monoclonal antibody, now undergoing phase II trials, has been highly effective and well tolerated.^{305. and 534.}

Newer non-immune therapies include botulinum toxin-type A, used to treat a small number of patients with flexural psoriasis, ¹²³ oral bexarotene, a synthetic retinoid X receptor, ⁵³⁵ paclitaxel, ⁵³⁶ everolimus, a rapamycin-derived macrolide, ⁵³⁷ the thiazolidinediones, used in the treatment of type 2 diabetes, and a new generation of all-trans retinoic acid metabolism blocking agents (RAMBA). In this latter group is an oral, anti-proliferative agent, known as R115866 (Rambazole); it shows promise. ⁵³⁸ Finally, circumin (the active component of the Indian spice turmeric) has been used as a complementary therapy for psoriasis, but in a formal study there was only a low response. ⁴⁶⁶

The treatment options for pustular psoriasis include phototherapy, photochemotherapy, retinoids, and immunosuppressive therapy. ⁶⁶³ Isotretinoin is comparable to etretinate in its effectiveness. Acitretin and narrowband UVB phototherapy have also been used. ⁶⁶⁴ It should be remembered that retinoids are teratogens and their use during pregnancy is contraindicated. Infliximab and etanercept can be used in refractory cases.^{665.666. and 667.} In impetigo herpetiformis, cyclosporine has produced good results. ⁶⁶⁸ This drug is associated with a higher risk of premature rupture of the membranes, but it is not thought to be teratogenic. ⁶⁶⁹ Cessation of cyclosporine has produced flares of the usual type of pustular psoriasis. ⁶⁷⁰ Often impetigo herpetiformis does not respond to oral corticosteroids. ⁶⁰³ Narrowband UVB and PUVA phototherapy, methotrexate, and oral retinoids have all been used. ⁶⁷¹Acrodermatitis continua is usually recalcitrant to treatment. ⁶⁷² Topical treatments have included corticosteroids, tar, dithranol, fluorouracil, calcipotriol, and topical tacrolimus 0.1% ointment. ⁶⁷³ Systemic therapy, with or without topical therapy, has included retinoids, methotrexate, cyclosporine, PUVA, colchicine, dapsone, corticosteroids, and oral propylthiouracil combined with methotrexate.^{668. and 673.}

Topical retinoids, either tazarotene gel or tretinoin 0.05% cream,^{723. and 752.} and topical corticosteroids⁷⁴² are the treatment of choice for localized disease. Topical calcipotriol and tar have also been used. Oral retinoids may be beneficial for more widespread disease.^{703.732.741. and 753.} The side effects of oral retinoids can warrant discontinuation of this therapy in children. ⁷⁰³ Other treatment modalities that have been used include vitamin D analogues, cyclosporine, ⁷¹³ methotrexate, azathioprine, and narrowband UVB. Intravenous immunoglobulin, ⁷⁵⁴ infliximab,^{753.755. and 756.} extracorporeal photochemotherapy, ⁷¹⁹ and etanercept alone or in combination with oral acitretin⁷⁵⁷ have been used for cases refractory to other treatments. Etanercept is not currently approved by the FDA for this purpose. ⁷⁵⁷