The psoriasiform reaction pattern

Clinical variants

Several clinical variants of psoriasis have been recognized. Guttate psoriasis consists of 1- to 5-mm erythematous papules, which eventually develop a fine scale. It may be preceded by a streptococcal pharyngitis. Evidence of a preceding streptococcal infection is found in approximately two-thirds of cases of guttate psoriasis. T lymphocytes specific for group A streptococcal antigens have been isolated from lesions of guttate psoriasis. There is a predilection for the trunk, and it is more common in children. Clearing may occur spontaneously in weeks or months. Psoriasis begins as the guttate form in 15% or more of cases. It appears that a subset of patients with guttate psoriasis undergo complete or long-term remission, whereas another group has a chronic course, without remission and with progression to chronic plaque psoriasis. Among the former, there is an earlier age of onset with high ASO titers, whereas the latter tend to have a somewhat later age of onset and a family history of psoriasis. Erythrodermic psoriasis develops in approximately 2% of patients with psoriasis, and it accounts for 20% or more of erythrodermas. It is a severe form involving more than 90% of the skin with a high morbidity and an unpredictable course. A verrucous form of erythrodermic psoriasis has been described. Erythrodermic psoriasis may be precipitated by administration of systemic steroids, by the excess use of topical steroids, by radiological contrast media, or by a preceding illness; it may develop as a complication of phototherapy. Peripheral blood eosinophilia may be present in this form. Sebopsoriasis consists of yellowish-red, less well-marginated lesions, with variable degrees of scaling, often distributed in seborrheic regions of the body. Rare clinical variants include a nevoid form, sometimes along the lines of Blaschko, photosensitive psoriasis, inverse (flexural) psoriasis, follicular psoriasis, psoriasis spinulosa, psoriasis bullosa acquisita, congenital erythrodermic psoriasis, interdigital psoriasis, rupioid psoriasis, annular plaque-type psoriasis, annular verrucous psoriasis, verrucous (hypertrophic) psoriasis, erythema gyratum repens–like psoriasis, erythema annulare centrifugum-type psoriasis, and linear psoriasis, although the occurrence of a linear form of psoriasis is not accepted by some authorities. Linear psoriasis can be superimposed upon other forms of the disease and may reflect a clone of cells harboring a postzygotic mutation. Psoriasiform napkin dermatitis may also be a variant of psoriasis. 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.

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.

Genetics of psoriasis

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

Since 1994, many genetic loci (mainly on chromosomes 17q, 4q, 2p, 1q, and 6p) comprising at least nine genes have been under investigation. At least 19 different putative loci for genetic susceptibility to psoriasis have been reported. Recent studies suggest that there is a major susceptibility region for psoriasis on chromosome 6p21.3, near to HLA-C. It has been estimated that the proportion of genetic susceptibility attributable to this gene (PSORS1C3) is approximately 30%. Attempts to link this gene to the CDSN gene (corneodesmosin), also near to HLA-C, were initially unsuccessful. Both genes as well as the nearby HCR gene are now regarded as important psoriasis susceptibility genes in Chinese patients with psoriasis, although this has been questioned. The CDSN gene is associated with psoriasis vulgaris in Caucasian but not in Japanese populations. However, PSORS1 shows epistasis with genes at other locations, such as on 1p. PSORS1 contains several genes, some of which have an association with psoriasis. Another study of psoriasis in Chinese patients suggested that the MICA gene, another HLA-related gene on chromosome 6p21.3, may be a candidate gene. The ACE gene variants may confer susceptibility in some populations. The leptin gene did not appear to be involved in a Turkish population. Promoter region polymorphisms in the tumor necrosis factor α (TNF-α) gene have been associated with early-onset psoriasis in a Polish population but not in Japanese, Chinese, or Korean people. In contrast, IL12B gene polymorphisms, another cytokine gene, did confer a risk for psoriasis vulgaris in several different populations. Polymorphisms in the PTPN22 region are associated with psoriasis of early onset. Other proinflammatory genes have also been implicated. Recent studies have resulted in an increase in the number of candidate genes in psoriasis and psoriatic arthritis cohorts, which can be grouped into signaling networks affecting skin barrier function ( LCE3 , DEFB4 , and GJB2 ), innate immune responses involving nuclear factor κB ( NFKB ) and interferon signaling ( TNFAIP3 , TNIP1 , NFKBIA , REL , FBXL19 , TYK2 , and NOS2 ), and adaptive immune responses connected with CD8 ⁺ T cells and interleukin-23 and -17 (IL-23/IL-17)–mediated lymphocyte signaling ( HLA-C , IL12B , IL23R , IL23A , TRAF3IP2 , and ERAP1 ). A recent review of the complex subject of the genetics of psoriasis has been published.

Psoriasis is associated with HLA-Cw6, B13 and B17 on serology, and specifically with HLA-Cw*0602, HLA-DQA1*0104, and HLA-DRB1*0701 by polymerase chain reaction. An early study showed that all patients with guttate psoriasis carried the HLA-C allele, compared with 20% of the control population. This has not been confirmed by a subsequent study that concluded that the role of this allele in psoriasis has yet to be determined. In a recent report of severe erythrodermic psoriasis in twins, the major histocompatibility complex class I, Cw*06 was detected in both. It has been suggested that PSORS1 may indeed be the HLA-CW*06 allele encoding the HLA-CW6 molecule.

MicroRNAs (mi-RNAs) are implicated in the pathogenesis of psoriasis and also atopic eczema. Their effects may be mediated through a number of secondary pathways, including the TNF-α pathway. An imbalanced miRNA axis has been delineated in the pathogenesis of psoriasis, in which there is upregulation of miR-31/miR-203 and downregulation of hsa-miR99a/miR-125b.

Trigger factors

Specific factors may trigger the onset or exacerbation of psoriasis. Trauma, infections, and drugs are accepted triggers, whereas the roles of climate, hormonal factors, cigarette smoking, alcohol, mesotherapy, internal malignancy, and stress are sometimes disputed. Vitamin D has immunomodulatory effects on psoriasis. In a study of patients in the Mediterranean region it has been shown that, among psoriatic patients, insufficient intake of vitamin D is associated with a greater risk of dyslipidemia, metabolic syndrome, and cardiovascular comorbidity than is the case in normal controls who are also vitamin D deficient. Psoriasis may actually improve during pregnancy. It is often worse in the postpartum period. The development of lesions in response to trauma (Koebner reaction) is present in approximately one-third of cases. A link has been made between psoriasis and human papillomaviruses (HPVs) specifically associated with epidermodysplasia verruciformis, particularly the oncogenic HPV-5. The prevalence of HPV in hairs plucked from patients with psoriasis is increased in patients treated with psoralen-UV-A (PUVA). However, one study did not find a specific causal role for HPV-5 or HPV-36 in the pathogenesis of psoriasis. The role of Malassezia is more controversial. The improvement of scalp psoriasis treated with antifungal agents has suggested a role for Malassezia . Malassezia restricta is the predominant species in psoriatic scale. Malassezia globosa is also increased, but much less so. Cell wall–deficient bacterial infection may be a triggering factor through its effect on T-cell activation. Infection may precipitate guttate psoriasis. Drugs that precipitate or exacerbate psoriasis are listed in Table 5.1 . 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 because the histology shows lichenoid and spongiotic features. 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. They usually do not necessitate termination of efalizumab therapy and may optionally be treated with corticosteroids. A psoriasiform eruption, as opposed to true psoriasis, has been reported as a complication of several β-blocker drugs, and the related propafenone, with fluorescein sodium used in angiography, with the oral hypoglycemic agent glibenclamide, with icodextrin, and with terbinafine (discussed previously). The reactions caused by some of the β-blocker drugs have a lichenoid histology despite their clinical appearance. Psoriasis has also followed the use of stem cell transplantation.

Vascular changes

Because 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. Vascular changes in psoriasis include dilatation and tortuosity of vessels in the papillary dermis, as well as angiogenesis (neovascularization) 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 that may, in turn, facilitate the trafficking of T lymphocytes, of the T helper 1 (Th1) subclass, into the skin, thus maintaining the psoriatic plaque. Blood flow is increased in these plaques. The high endothelial venules play an important role in the cutaneous recruitment of circulating lymphocytes. Microvascular hyperpermeability is another feature of severe psoriasis. This appears to be mediated by circulating vascular endothelial growth factor (VEGF). Angiogenesis is stimulated by factors such as IL-8 and transforming growth factor α (TGF-α). 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. This study has not been confirmed. In short, it appears that dermal capillary changes alone are unlikely to be causal in psoriasis.

Lymphocytes and other inflammatory cells

Recruitment of lymphocytes to the papillary dermis is an important factor. This is aided by various chemoattractants such as platelet-activating factor and leukotriene B ₄ . Some of these lymphocytes are already activated before entering the skin, while still circulating in the bloodstream. 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. It appears that lymphocyte function–associated antigen type 1 (LFA-1), consisting of CD11a and CD18 subunits, 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. Furthermore, TNF-α may play an important role in induction of adhesion molecules on endothelial cells. Vascular adhesion protein 1 (VAP-1) is also overexpressed in psoriasis. Efalizumab, an anti-CD11a antibody, has been used to treat psoriasis (see later). 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. Chemotactic factors such as C5a anaphylatoxin are important in their recruitment.

Whereas the importance of T lymphocytes in the pathogenesis of psoriasis is accepted, there has been some dispute regarding the relative importance of CD4 ⁺ and CD8 ⁺ lymphocytes. The T cells in lesional dermis are predominantly CD4 ⁺ . Cells migrating into the epidermis are mostly CD8 ⁺ . Which type produces keratinocyte proliferation by the release of mediators (cytokines) is still disputed. Recent work indicates that CD4 ⁺ cells are most important in some tissues, but the CD4/CD8 ratio is reversed in the epidermis, synovial fluid, and entheses (connective tissues between tendon or ligament and bone), where CD8 ⁺ cells are more common. In fact, the classic microscopic changes of psoriasis are associated with CD3 ⁺ T-cell infiltrates and epidermotropism of CD8 ⁺ cells. Both now appear to be involved, but CD8 ⁺ cells are particularly important. CD8 ⁺ cells in the epidermis express the Vβ T-cell receptor subgroups Vβ3 and Vβ13.1. Another study has shown an increase in the Vβ2 receptor in skin-homing lymphocytes in psoriasis. In psoriasis, CD4 ⁺ CD25 ⁺ regulatory T cells are functionally deficient in suppressing effector T-cell proliferation.

Adhesion molecules and cytokines

Recent work has focused on a subset of γδ T cells that reside in the dermis. These cells are a major source of IL-17 in skin after IL-23 stimulation (see the following discussion) and are believed to play a role in the pathogenesis of psoriasis. As mentioned previously, leukocytes bind to endothelial cells in the papillary dermis, before their passage from the vessels. This process is under the control of adhesion molecules, which can be classified into three distinct groups:

• 1.

  The immunoglobulin gene superfamily, which includes ICAM-1 (CD54) and ICAM-2 and vascular cell adhesion molecule 1 (VCAM-1)

• 2.

  Integrins

• 3.

  Selectins (the most important of which is E-selectin)

One or more of these adhesion molecules lead to the selective adhesion of CD4, CD45RO helper T cells. 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. The expression of CDK5 is reduced in psoriasis. Various cytokines appear to induce the enhanced expression of these adhesion molecules in psoriasis; they include IL-1, IL-2, TNF-α, interferon-γ (IFN-γ), and IL-4. On the other hand, UV-B radiation reduces the adhesive interactions and expression of adhesion molecules, possibly explaining its mode of action in the treatment of psoriasis. Serum levels of soluble E-selectin correlate with the extent of psoriatic lesions.

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. Dendritic cells and macrophages also produce important cytokines, one of which is IL-12. IL-12 induces differentiation of naive CD4 T lymphocytes to 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. It also activates natural killer cells. IL-23, which is closely related to IL-12 in structure, stimulates a subset of CD4 ⁺ lymphocytes to produce IL-17. The importance of IL-17 has been emphasized in recent years, as it has become evident that Th17 cells play a significant role as proximal regulators of inflammation in psoriatic skin. IL-17A, the main effector cytokine of Th17 cells, induces the production of proinflammatory cytokines, predominantly by endothelial cells and macrophages, and other molecules to sustain chronic inflammation. Serum β-defensin 2 (BD-2) is an easily measurable biomarker of IL-17A activity. Not surprisingly, the inhibition of IL-17A has been considered a potential treatment approach for disrupting the cycle of psoriatic inflammation.

Therapy using an IL-12/IL-23 antibody has undergone clinical trials (see later). 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. In contrast, low levels of IL-10, an antiinflammatory cytokine, have been found in psoriatic lesions. The many functions of these various cytokines include stimulation of keratinocytes, vascular changes (discussed previously), control of lymphocyte trafficking (discussed previously), and stimulation of neutrophil chemotaxis. Exacerbations of psoriasis are preceded by a rapid increase in neutrophil chemotaxis. IL-8 is a cytokine with possibly more chemotactic activity than the various complement factors. Another is psoriasin (S100A7), a protein belonging to the calcium-binding S100 family. It is a potent inflammatory mediator. Two other members of this family, S100A8 and S100A9, are increased in psoriasis and contribute to the hyperproliferation of psoriatic skin. The importance of the cytokines in the pathogenesis is shown by the downregulatory effects of cyclosporine (ciclosporin) on cytokines and cytokine receptors in the treatment of psoriasis. The role of the various cytokines in psoriasis has been reviewed. They are summarized in Table 5.2 .

Epidermal interactions

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 later). 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. TNF-α also has a major role. Its release from cells is under the influence of TNF-α-converting enzyme (TACE). The success of the various TNF-α neutralizing modalities in the treatment of psoriasis has led to a reevaluation 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. This is supported by the finding of increased levels of perforin, the cytotoxic product of NK cells, in the epidermis of psoriatic plaques. Paradoxically, circulating NK cells are reduced in psoriasis. There is also an overexpression of the CXC chemokines, IL-8, and growth-regulated oncogene (GRO)/melanoma growth-stimulatory activity (GRO-α/MGSA). They are potent activators of neutrophils and lymphocytes but also stimulate proliferation of keratinocytes. These factors produce an alteration in the turnover time for the epidermis: 3 or 4 days in psoriasis compared with the usual 13 days in normal skin. It has been estimated that there is a 12-fold increase in the number of basal and suprabasal keratinocytes in cell cycling. TGF-β, which is elevated in psoriasis, is predominantly synthesized in subcorneal keratinocytes. It is a potent mitogen that can also stimulate angiogenesis. In contrast, TGF-β has an inhibitory effect on epithelial cell proliferation. Downregulation of its receptor in psoriatic epidermis has the effect of diminishing this inhibitory influence. Amphiregulin, a cytokine that acts as an epidermal growth factor, is also increased in psoriatic keratinocytes. 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. There is increased activation of the Src family of tyrosine kinases (SFKs) in psoriasis. They are important regulators of epidermal growth and differentiation. The existence of an increased number of epidermal growth factor receptors (EGF-Rs), resulting from their persistence at all levels of the epidermis instead of just the basal layer, may be just as important. 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. These activated antigen-presenting cells produce TNF-α in close proximity to these keratinocytes. 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. 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. Bcl-2 expression in lymphocytes is increased. Suppression of apoptosis also occurs in psoriasis. 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. Some of the therapies for psoriasis act by their increase in apoptosis. A senescence switch involving p16 may prevent malignant transformation of this upregulated epidermis. Also, methylation of the p16 ^INK4 gene promoter is found in psoriatic epidermis.

As a consequence of the hyperproliferation of keratinocytes, there is enhanced expression of keratins K6, K16, and K17 and reduced amounts of the keratins indicative of differentiation (K1, K2, and K10). K16 is also expressed in nonlesional psoriatic skin and may serve as a marker of preclinical psoriasis. It has been found that altered peptide ligands derived from keratin 17 are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro . This opens up another therapeutic option in the treatment of psoriasis. There is a unique subpopulation of cells in psoriatic epidermis that coexpress K6 and K10. There is also increased nuclear β-catenin in suprabasal cells, alterations in cell-surface glycoconjugates, 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. Tight junction components are also altered. It has also been suggested that basement membrane laminin could be important in driving psoriasis, at least in part through a T-cell–mediated immune response.

Microbial superantigens

The role of microbiological superantigens in the pathogenesis of psoriasis is gaining acceptance, although formal proof of a pathogenic role is still lacking. Superantigens are toxins of microbial origin that not only stimulate certain classes of T cells 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. 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. One study has confirmed that prior pharyngeal infection is a risk factor for guttate psoriasis. Peripheral blood lymphocytes from patients with psoriasis are generally hyporesponsive to streptococcal superantigens, but there is a subpopulation of CD4 ⁺ cells that produces IFN-γ in response to this antigen. Superantigens produced by Staphylococcus aureus may also be triggering factors. Malassezia furfur is also capable of exacerbating psoriasis. Patients with psoriasis harbor HPV-5 in a significant number of cases. 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. The high prevalence of cytomegalovirus antigenemia in psoriasis is possibly related to reactivation of the virus by elevated levels of TNF-α. Endogenous retroviral sequences are expressed in psoriasis. They are part of the normal human genome. Their possible role in the pathogenesis of psoriasis is currently being investigated. It has been suggested 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).

Other abnormalities

These disparate findings remain to be integrated into a unitarian theory of pathogenesis. It is possible that abnormalities in epidermal barrier function play a role in the pathogenesis of psoriasis, as is the case for a number of other disorders, such as Crohn's disease, that are considered “barrier organ disorders.” A number of highly conserved genes—particularly nucleotide-binding domain, leucine-rich containing (NLR), or CATTERPILLER genes—are associated with barrier organs such as skin and contribute to the defense against microbial pathogens; the discovery of defects in this system in psoriasis could lead to novel therapeutic approaches. Other findings in psoriasis that may play some role in the pathogenetic cascade include the increased expression of heat shock proteins by keratinocytes, an increase in reactive oxygen species, excessive activation of a phospholipase C/protein kinase C signal transduction system that stimulates keratinocyte proliferation, overexpression of serpin squamous cell carcinoma antigens in psoriatic skin, and increased lysophosphatidyl choline activity in lesional skin. This substance is a lysophospholipid that is chemotactic for monocytes and stimulates the expression of certain adhesion molecules—VCAM-1 and ICAM-1. The finding of immunoreactants in the stratum corneum and the dermis is not thought to be of major pathogenetic significance. There is an upregulation of the gap junction protein connexin 26 between keratinocytes of psoriasis. There is also an overexpression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and other related members of the ADAM family. Increased levels of kallikreins are also found in the stratum corneum and serum of patients with psoriasis. Telomerase activity is increased in peripheral blood mononuclear cells in psoriasis. The level correlates with disease severity. 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. 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. It is a potent elastase inhibitor that may protect the epidermis from the proteolytic activity of neutrophils. The epidermis is also protected against bacterial infections by the release of granulysin by lesional T cells and dendrocytes. 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. Increased serum cortisol levels are another possible mechanism by which stress influences psoriasis. Serotonin levels are also increased in the lesions of psoriasis.

Conclusions on the pathogenesis of psoriasis

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. All of these features are possibly the consequence of an autoreactive inflammatory process mediated by T lymphocytes of the Th1 subclass. This cytokine profile may be the result of local factors and not determined by a specific genotype.

Treatment of Psoriasis

Guttate psoriasis is managed with tar and UV-B therapy (with questionable efficacy), dithranol and topical corticosteroids with or without UV-B therapy, or calcipotriol (also a useful agent in other forms of psoriasis). Whereas antistreptococcal therapy is generally not effective in the management of guttate or plaque psoriasis, tonsillectomy may be beneficial in select patients who have recurrent streptococcal infections. Other therapies used in psoriasis include topical corticosteroids, most often used in tandem with other agents, calcineurin inhibitors, PUVA, narrowband UV-B, saltwater baths with UV-B irradiation (balneophototherapy), systemic retinoids, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine, sulfasalazine, efalizumab (a CD11a blocker), TNF-α antagonists etanercept, infliximab, and adalimumab, and alefacept, an agent that reduces CD45RO-positive T cells. Newer treatments include the recombinant IL-10 agent ilodecakin, ABT-874 (an IL-12/23 monoclonal antibody), botulinum toxin type A for flexural psoriasis, oral bexarotene, a synthetic retinoid X receptor, paclitaxel, everolimus, a rapamycin-derived macrolide, the thiazolidinediones, new-generation, all- trans retinoic acid metabolism blocking agents (RAMBAs), dimethylfumarate, teneligliptin and sitagliptin (members of a new class of antidiabetic agents with immunomodulating properties), and secukinumab, brodalumab, and ixekizumab (new biological agents that target IL-17).

Electron microscopy

There are numerous cytoplasmic organelles in the keratinocytes, reflecting their hyperactivity. These are decreased with treatment. Tonofilaments and desmosomes are reduced in number and size, and there is also a reduction in the number of keratohyaline granules. Vessels in the papillary dermis are dilated with abundant fenestrations. Neutrophils are said to be polar in shape with ruffled cell membranes.