Psoriasis (2024)

Plaque-Type Psoriasis

Plaque-type psoriasis, occurring in 85%–90% of affected patients, is the most common form of psoriasis and is characterized by oval or irregularly shaped, red, sharply demarcated, raised plaques covered by silvery scales (Fig. 1A–C) (van de Kerkhof and Nestle 2012). Plaques occur mainly on the extensor surface of elbows and knees, on the scalp, and in the lower back, but can affect every area of the body, often with a symmetrical distribution. Size of the lesions can vary, from pinpoint to larger individual lesions or confluent areas leading to two clinical subphenotypes. The term large (>3 cm) plaque psoriasis describes thick (>0.75 cm), well-demarcated, red plaques with silvery scales. Small (<3 cm) plaque psoriasis presents with numerous lesions; the plaques are thinner (<0.75 cm), pinkish in color with a fine scale, and can be well-defined or merge with surrounding skin. A further classification takes into account the age of onset. Type I psoriasis has early onset (<40 yr), is often associated with familiar disease history and shows high association with the human leukocyte antigen (HLA)-Cw0602 allele, whereas type II psoriasis develops after the age of 40 (Henseler and Christophers 1985).

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Figure 1.

See Also

Kim Kardashian says going plant-based cured her psoriasisIs Psoriasis Hereditary?Psoriasis and Diet: How Foods Can Impact InflammationWhy Not Treating Psoriasis Affects More Than Your Skin

Clinical and histopathological features of psoriasis. (A–C) Clinical pictures of chronic plaque psoriasis. Note nail involvement in B. (D) Hematoxylin-stained section from a chronic psoriatic plaque. Typical histological features are visible: acanthosis, papillomatosis, parakeratosis, as well as Munro abscess in the stratum corneum. (E) Immunofluorescence staining of chronic psoriatic plaque showing skin infiltrating CD3⁺ T cells in green.

Psoriasis is a dynamic disease; morphological changes accompany the evolution of a newly formed lesion into an advanced plaque that can slowly enlarge (active lesions, sharing most of the histological features of newly formed lesions) or remain static (stable lesions, retaining the morphology of the advanced stage) (Griffiths et al. 2007). In the early stages of a newly developing plaque, the first changes occur in the uppermost layer of the dermis, the papillary dermis. Blood vessels become dilated and tortuous, with lymphocytes and neutrophils emerging from their lumen (“squirting” papilla) and reaching for the epidermis, which looks still quite normal at this stage. Shortly after, however, aberrant keratinocyte (KC) proliferation and migration begin, resulting in epidermal thickening, incomplete terminal differentiation with initial loss of the “stratum granulosum,” and the appearance of foci of parakeratosis, that is, the retention of the nucleus by corneocytes. In the advanced stage, fully flagged psoriasis hyperplasia is present with acanthosis, which is the thickening of the “stratum spinosum,” and papillomatosis, the elongation of the rete ridges extending downward between dermal papillae. Parakeratosis becomes confluent, the stratum granulosum is absent, lymphocytes, mainly CD8⁺ T cells, are interspersed between KCs, and neutrophils accumulate into the parakeratotic scales, forming Munro microabscesses (Fig. 1D,E). The dilated blood vessels extend high into papillae, accounting for pinpoint bleeding when a scale is removed, known as Auspitz sign. The dermis is heavily infiltrated by T cells and dendritic cells (DC). Lesions can spontaneously resolve, although rarely. Resolving lesions after therapy can be encased by a distinctive rim of blanching (Woronoff’s ring), predictive of clearing and histologically characterized by orthokeratosis, that is thickening of the stratum corneum without parakeratosis and restoration of the stratum granulosum.

Guttate Psoriasis

Guttate psoriasis, from the Latin “gutta” for tear drop, is characterized by multiple small scaly plaques usually occurring around the trunk and upper arms and thighs. The rash has often sudden onset, usually within 2–4 wk after a bacterial infection of the upper ways, notably streptococcal pharyngitis in children and young adults, and is therefore associated with type I psoriasis (Griffiths et al. 2007). Guttate psoriasis can either completely clear spontaneously or following topical treatment, become chronic, or worsen into the plaque type.

Generalized Pustular Psoriasis

GPP, also known as von Zumbush psoriasis, is a rare but potentially life-threatening disease characterized by episodic, widespread skin and systemic inflammation. Typical histological feature of GPP is the presence of prominent aggregates of neutrophils infiltrating the stratum spinosum (spongiform pustules of Kogoj) and giving rise to sterile cutaneous pustules (van de Kerkhof and Nestle 2012). The skin manifestations are associated with marked systemic features: high fever, fatigue, and neutrophils leukocytosis. Acute attacks often occur during pregnancy and may be triggered by infection, exposure to or withdrawal from drugs. GPP can be frequently associated with plaque-type psoriasis and/or palmoplantar pustular psoriasis. Although still classified as a variant of psoriasis, the striking clinical and histological features of GPP have long suggested that it is a disease of distinct etiology. Recent genetic data lend further support to this hypothesis with the identification of some cases of familial GPP in which the disease is inherited as an autosomal recessive trait with mutations in the IL36RN gene encoding the anti-inflammatory IL-36-receptor antagonist, IL-36Ra (Marrakchi et al. 2011; Onoufriadis et al. 2011). IL-36Ra blocks the proinflammatory cytokines IL-36α/β/γ; when IL36RN is mutated, IL-36 signaling is uncontrolled with enhanced production of further proinflammatory cytokines (Onoufriadis et al. 2011). However, IL36RN mutations only occur in a minority of patients (Setta-Kaffetzi et al. 2013), thus, more genes are likely involved. Interestingly, a de novo mutation in the epidermal NF-κB activator CARD14 (Jordan et al. 2012b) has been described to underlay a sporadic case of severe GPP, suggesting that KCs dysfunction is likely to play a predominant role in this disease phenotype.

Erythrodermic Psoriasis

Erythrodermic psoriasis, one of the rarest forms of psoriasis (1%–2.25% of patients with psoriasis), represents the most severe phenotype; it carries substantial morbidity and can be potentially life threatening (Boyd and Menter 1989). It is characterized by diffuse erythema, with or without scaling, involving >75% of the skin surface. If present, scales are only superficial and differ from the adherent scales of plaque psoriasis. Systemic manifestations such as hypothermia and limb edema might occur because of the generalized vasodilation underlying the erythema, as well as myalgia, fatigue, and fever. GPP may revert to erythrodermic psoriasis when pustule formation stops. Both administration and abrupt withdrawals of systemic corticosteroids or methotrexate, sunburn, and emotional stress have been suggested as possible triggering factors (Ayala 2007).

Table 1.

Psoriasis susceptibility genes identified by genome-wide association studies (GWASs)

Psoriasis Susceptibility Genes Identified by GWASs

Advances in high-throughput genotyping technologies and the completion of the genome-wide database of common genetic sequence variation (HapMap project) have paved the way to the identification of a number of psoriasis susceptibility genes by means of GWAS (Capon et al. 2008; de Cid et al. 2009; Nair et al. 2009; Zhang et al. 2009; Ellinghaus et al. 2010; Huffmeier et al. 2010; Strange et al. 2010; Stuart et al. 2010) and subsequent meta-analysis (Ellinghaus et al. 2012a; Tsoi et al. 2012). Collectively, these studies identified 36 independent psoriasis-associated regions within individuals of European ancestry (Tsoi et al. 2012), plus five more uniquely associated in the Chinese population (Sun et al. 2010).

The psoriasis genetic landscape (Table 1) emerging from these studies includes skin-specific genes and immune-related genes, with the latter belonging to either the innate or the adaptive immunity, as well as being at the interface between the two arms of the immune system. SNPs and copy number variation (de Cid et al. 2009; Tsoi et al. 2012) in genes of the late cornified envelope (LCE) family within the epidermal cell differentiation complex, a cluster of genes involved in skin barrier formation, support a critical role for skin-specific genes in psoriasis susceptibility. Moreover, there is genetic interaction (epistasis) between LCE deletions and HLA-C (Tsoi et al. 2012). A closer look at the immune genes reveals the critical contribution to disease susceptibility of four fundamental immunological processes and pathways: antigen presentation, NF-κB signaling, IL-23/IL-17 axis, and type I IFN pathway. The fundamental importance of antigen presentation in psoriasis is highlighted by several observations. First, the HLA-C association has the greatest statistical significance observed in GWAS studies (Tsoi et al. 2012). Second, HLA-C accounts for about 6% of the total genetic variance (Chen et al. 2011), which is at least 10-fold more than that explained by any other known psoriasis susceptibility locus (Tsoi et al. 2012). Third, epistasis is present between HLA-C and ERAP1 (Strange et al. 2010), which encodes for an aminopeptidase involved in the trimming of peptide antigens. Among genes of the innate immunity, more than half belong to the NF-κB pathway, which has a pivotal role in amplifying and sustaining chronic inflammation. Of particular interest are genes encoding for molecules regulating NF-κB activation downstream from TNF (TNFAIP3 and TNIP1) or downstream from IL-17 (TRAF3IP2). Two recent studies have identified and evaluated the functional consequences of rare and common gene variants (Jordan et al. 2012a; Tsoi et al. 2012) and missense mutations (Jordan et al. 2012b) in CARD14, an activator of NF-kB primarily expressed in skin epidermis, providing further evidence that intrinsic defects in KCs can promote psoriasis. Genes belonging to the type I IFN pathway (e.g., IL-28RA and RNF114) support clinical and experimental findings, indicating an important role for innate antiviral responses in psoriasis (Nestle et al. 2005). Finally, a sizeable number of genes, including IL-23, IL-12B, and IL-23R, belong to the IL-23/IL-17 pathway, whose critical involvement in psoriasis pathogenesis has been well documented by a wealth of studies showing a pivotal role for IL-23-induced and IL-17-mediated responses in psoriasis (Di Cesare et al. 2009). Moreover, the genetic association with IL-23R is one of the very few supported by functional evidence with reduced IL-17 responses in carriers of the protective Arg381Gln IL-23R allele (Di Meglio et al. 2011a, 2013).

Interestingly, some genes from the above pathways influence multiple phenotypic traits, in particular, other immune-mediated conditions such as Crohn’s disease (CD), celiac disease, and ankylosing spondylitis (Table 1) (Tsoi et al. 2012), thus confirming the presence of a shared genetic basis among immune-mediated inflammatory diseases. It has been noted that pleiotropism is more pronounced in genes of the evolutionary more recent adaptive immunity (e.g., IL-23R), whereas genes uniquely associated with psoriasis are mainly involved in innate immune responses (e.g., CARD14), in keeping with the diverse and well-conserved set of innate immune mechanisms exploited by the skin to maintain homeostasis. The signals identified in the European population collectively account for ∼20% of estimated psoriasis heritability (Tsoi et al. 2012); therefore, the search for psoriasis genes is yet to be completed. Moreover, the gene variants identified have modest-effect size and it has been hypothesized that rare variants with bigger effect may explain this “missing heritability” (Manolio et al. 2009). However, a recent study, which has resequenced 25 genes from 20 GWAS-identified risk loci overlapping between six common autoimmune disease including psoriasis, has shown that rare variants at known loci have a negligible role in common immune-mediated disease susceptibility, suggesting that the missing heritability likely results from the coexistence of many common variants of weak effect (Hunt et al. 2013).

Disease Initiation

One of the best-characterized initiation mechanisms, leading to dysregulated skin immune responses, involves KCs releasing the cationic antimicrobial peptide (AMP) LL-37 following physical trauma (Koebner phenomenon) or infection. LL-37 binds to self-DNA/RNA fragments (Lande et al. 2007; Ganguly et al. 2009) also released by damaged skin cells (Ganguly et al. 2009; Lin et al. 2011), forming LL-37/self-DNA/RNA complexes found in psoriasis lesions. These complexes activate TLR7/9-bearing pDC, a subset of circulatory DC normally absent in human healthy skin, but highly infiltrating developing psoriasis lesions (Nestle et al. 2005), to release type I IFN, which is thought to play important roles in the early phases of psoriasis development. In the AGR129 xenotransplantation model in which human nonlesional psoriatic skin is transplanted onto AGR129 mice lacking T/B cells and having severely impaired NK activity, type I IFN triggers activation and expansion of autoimmune T cells present in the transplant, leading to fully fledged psoriasis plaque formation (Nestle et al. 2005). Moreover, type I IFN, as well as proinflammatory cytokines released by activated KCs (IL-1β, IL-6, and TNF), can also mature and activate myeloid DC. Psoriatic skin lesions have a 30-fold increase in myeloid dermal dendritic cells (DDC) (Zaba et al. 2007) and, in addition to “classical” CD11c⁺CD1c⁺ DDC found in healthy skin, it harbors a distinct population of “inflammatory” CD1c^– DC (Zaba et al. 2009b) producing TNF, iNOS, IL-20, and IL-23 (Lee et al. 2004; Wang et al. 2006; Zaba et al. 2009a). The clinical benefit of anti-TNF agents strongly shows that elevated TNF levels in the skin are critical for the pathogenic interaction between DDC and T cells with TNF blockade-impairing DDC maturation and IL-23 production (Zaba et al. 2007). In keeping with their role as antigen presenting cells, mature DDC are thought to migrate to skin-draining lymph nodes to present an as-yet elusive antigen to naïve T cells. The presence of oligoclonal T cells in psoriatic lesions, identification of conserved clonal T-cell receptor (TCR) rearrangements in different patients, and presence of the same T-cell clone over time (Chang et al. 1994; Menssen et al. 1995; Prinz et al. 1999; Vollmer et al. 2001) imply the presence of a common antigen triggering the disease. LL-37/self-RNA complexes have been shown to activate TLR8-bearing myeloid DC and, thus, they could fulfill this role. In line with the association between psoriasis and streptococcal infection, molecular mimicry (Valdimarsson et al. 2009), with several streptococcal antigens such as M protein (which shares high similarity structure with certain human keratins), peptidoglycan, and CpG DNA, has been suggested as possible mechanism for specific T-cell activation (Cai et al. 2012), but conclusive evidence identifying psoriasis (auto)antigen(s) has yet to be provided.

Nevertheless, T cells are critical players in the initiation phase of disease and particularly important are those residing in the skin as tissue-resident memory T (T_RM) cells. T_RM are memory cells that do not circulate, but are strategically positioned as the first-line of defense in the tissue (Boyman et al. 2007; Clark 2010) and have been implicated in long-term peripheral immunity (Gebhardt et al. 2009; Jiang et al. 2012). Early evidence of their existence came from the AGR129 xenotransplantation model of human nonlesional psoriatic skin onto immunodeficient mice. In this model, development of fully fledged psoriatic lesions occurs in the absence of T-cell recruitment from blood (Boyman et al. 2004) and depends on the ability of locally activated skin T_RM cells, present in the initial graft, to migrate into the epidermis (Conrad et al. 2007).

Table 2.

Targeted therapies in psoriasis, either approved or under investigation as of July 2013

Anti-T-Cell Therapies

The first biologic to be approved was Alefacept in 2003, a lymphocyte function-associated antigen (LFA)-3/IgG1 fusion protein binding CD2 on T cells and, thus, selectively inducing apoptosis of CD2⁺ human memory-effector T cells in vivo (da Silva et al. 2002), although further studies suggested a broader immunomodulatory effect (Chamian et al. 2005; Haider et al. 2007). Clinical efficacy was shown in phase III studies with 40% of patients achieving a PASI75 response (75% reduction of the PASI) (Krueger et al. 2002) and more that 50% achieving PASI 50 (50% reduction of the PASI) (Lebwohl et al. 2003a).

A second anti-T-cell strategy was approved in 2003 and consisted of a humanized antibody (Efalizumab) binding and blocking CD11a, a key molecule for T-cell activation and migration through the circulation into the skin (Jullien et al. 2004).

Despite a good efficacy profile, efalizumab (Gordon et al. 2003; Lebwohl et al. 2003b; Leonardi et al. 2005, 2008a; Menter et al. 2005; Gottlieb et al. 2006; Papp et al. 2006) has been withdrawn from the market in 2009 because of three cases of progressive multifocal leukoencephalopathy (Tan and Koralnik 2010), highlighting the importance of carefully monitoring the long-term safety of immunomodulatory therapies.

Anticytokine Therapies

An alternative strategy to anti-T-cell targeting aims at interfering with the psoriasis cytokine network (Nickoloff 1991) by using anticytokine biologic drugs.

TNF blockade, using etanercept, a human p75 TNF receptor fusion protein (approved in 2004), infliximab, a humanized chimeric anti-TNF monoclonal antibody (approved in 2006), or adalimumab, a fully human monoclonal antibody (approved in 2008) is another effective therapeutic strategy. Etanercept efficacy have been shown in three phase III trials with about 50% of patients achieving PASI75 at week 12 in the high-dose group (Leonardi et al. 2003; Papp et al. 2005, 2011d; Tyring et al. 2006). TNF neutralization causes early down-modulation of myeloid cell-related genes, with decrease of Th17 cell products and downstream molecules in just 2 wk after commencing therapy (Gottlieb et al. 2005; Zaba et al. 2007; Johansen et al. 2010). Interestingly, only patients who downregulate the expression of Th17 pathway genes successfully respond to etanercept treatment (Zaba et al. 2007; Zaba et al. 2009c).

The latest biologic to be approved for psoriasis in 2009, ustekinumab, is a monoclonal antibody simultaneously blocking the heterodimeric proteins IL-12 and IL- 23 via its biding to the shared subunit p40. Its efficacy is quite high, with 67% of patients achieving PASI75 at 12 wk of treatment (Leonardi et al. 2008b; Papp et al. 2008).

Some serious adverse events, such as opportunistic infections and reactivation of latent tubercolosis, have been reported for these monoclonal antibodies (Sivamani et al. 2013). Long-term safety data (up to 4 and 5 yr treatment) are now available for etanercept and ustekinumab (Leonardi et al. 2003; Papp et al. 2005, 2012d, 2013a; Tyring et al. 2006), suggesting a safe use of these drugs.

A number of other biologic drugs is currently (mid-2013) being investigated in clinical trials. In line with the prominent role of IL-23/IL-17 axis in psoriasis, two antibodies (guselkumab [formerly CNTO1959] and MK-3222) targeting the specific IL-23p19 subunit are in phase II and III, respectively (Janssen 2013; Merck 2013a,b).

Monoclonal antibodies blocking either IL-17A (ixekizumab and secukinumab) (Leonardi et al. 2012; Papp et al. 2013b; Rich et al. 2013) or IL-17R brodalumab (Papp et al. 2012b) have shown striking efficacy in phase II clinical trials with >70% of patients achieving PASI75 and more than half receiving a remarkable PASI90. Although phase III clinical trials are currently ongoing (Amgen 2013a,b,c; Eli Lilly 2013a,c,d,e,f; Novartis 2013b), initial molecular data showed that the effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α is greater than in previous studies with anti-TNF therapy (Krueger et al. 2012).

Notwithstanding the efficacy of the biologic drug currently available in the clinic, at least one third of patients do not respond to biologic therapy (Gudjonsson et al. 2012) or lose initial responsiveness because of the development of antidrug antibodies (ADA), which causes decreased drug efficacy and/or induction of adverse events (Sathish et al. 2013; Vincent et al. 2013). Moreover, biologic drugs pose a considerable economical burden because of their costs (Poulin et al. 2009; Liu et al. 2012). Finally, a sizable number of patients with mild-to-moderate psoriasis still rely on traditional topical treatments.

Small Molecule Drugs

The aforementioned limitations of biologic drugs has led to other therapeutic options being explored, such as small molecule, that is, low molecular weight, organic compounds targeting key molecules involved in cellular signaling (Garcia-Perez et al. 2013) aimed at minimizing general immunosuppression.

Within this category, tofacitinib and apremilast are currently the molecules most advanced in the clinical development. Tofacitinib is an inhibitor of Janus kinases (JAK)1 and JAK3, key intracellular enzymes transducing cytokine-initiated signals, which showed efficacy both in the oral and topical formulation (Boy et al. 2009; Ports et al. 2013), with 66.7% of patients reaching PASI75 at 12 wk in a phase IIb trial (Papp et al. 2012c). These encouraging results are in agreement with the efficacy displayed by tofacitinib in phase III clinical trials in rheumatoid arthritis (RA) (Fleischmann et al. 2012; van Vollenhoven et al. 2012), which have led to its approval in the United States of America for the treatment of patients with moderate-to-severe RA who inadequately responded to metothrexate.

Apremilast is an inhibitor of phosphodiesterase 4, an enzyme involved in the breakdown of cAMP. Apremilast inhibitory activity increases cAMP levels, thus inhibiting the production on proinflammatory cytokines. Phase IIb data on efficacy (41% of patients achieving PASI75 at week 16), safety, and tolerability of apremilast in the treatment of psoriasis have been recently published, supporting the transition of this drug to the next level of clinical development (Papp et al. 2012a).

Even if their efficacy is, in some cases, far from that of biologic drugs, these molecules have a cheaper manufacturing process, can be administered orally or topically, and have shown a good safety profile so far, although long-term safety data are needed to confirm the initial studies. Thus, they could find their therapeutic niche in the treatment of less severe forms of psoriasis.

⁵John Updike (1932–2009), was a Pulitzer Prize-winning American writer who had psoriasis. His description of his lifelong personal journey with psoriasis is both touching and inspiring for whoever is engaged in psoriasis research (Updike 1976, 1985, 1989).

Editors: Anthony E. Oro and Fiona M. Watt

Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org

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