Daily Archives: November 23, 2022

Abstract

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

Keywords: psoriasis, inflammation, chronic skin disease

Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenic traits. The worldwide prevalence is about 2%, but varies according to regions [1]. It shows a lower prevalence in Asian and some African populations, and up to 11% in Caucasian and Scandinavian populations [2,3,4,5].

The dermatologic manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque-type psoriasis, and is the most prevalent type. The terms psoriasis and psoriasis vulgaris are used interchangeably in the scientific literature; nonetheless, there are important distinctions among the different clinical subtypes (See ).

Clinical manifestations of psoriasis. (A,B) Psoriasis vulgaris presents with erythematous scaly plaques on the trunk and extensor surfaces of the limbs. (C) Generalized pustular psoriasis. (D) Pustular psoriasis localized to the soles of the feet. This variant typically affects the palms of the hands as well; hence, psoriasis pustulosa palmoplantaris. (E,F) Inverse psoriasis affects the folds of the skin (i.e., axillary, intergluteal, inframammary, and genital involvement).

About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical manifestations are sharply demarcated, erythematous, pruritic plaques covered in silvery scales. The plaques can coalesce and cover large areas of skin. Common locations include the trunk, the extensor surfaces of the limbs, and the scalp [6,7].

Also called flexural psoriasis, inverse psoriasis affects intertriginous locations, and is characterized clinically by slightly erosive erythematous plaques and patches.

Guttate psoriasis is a variant with an acute onset of small erythematous plaques. It usually affects children or adolescents, and is often triggered by group-A streptococcal infections of tonsils. About one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life [8,9].

Pustular psoriasis is characterized by multiple, coalescing sterile pustules. Pustular psoriasis can be localized or generalized. Two distinct localized phenotypes have been described: psoriasis pustulosa palmoplantaris (PPP) and acrodermatitis continua of Hallopeau. Both of them affect the hands and feet; PPP is restricted to the palms and soles, and ACS is more distally located at the tips of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an acute and rapidly progressive course characterized by diffuse redness and subcorneal pustules, and is often accompanied by systemic symptoms [10].

Erythrodermic psoriasis is an acute condition in which over 90% of the total body surface is erythematous and inflamed. Erythroderma can develop on any kind of psoriasis type, and requires emergency treatment ().

Psoriasis typically affects the skin, but may also affect the joints, and has been associated with a number of diseases. Inflammation is not limited to the psoriatic skin, and has been shown to affect different organ systems. Thus, it has been postulated that psoriasis is a systemic entity rather than a solely dermatological disease. When compared to control subjects, psoriasis patients exhibit increased hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased body mass index. The metabolic syndrome, which comprises the aforementioned conditions in a single patient, was two times more frequent in psoriasis patients [11,12]. Coronary plaques are also twice as common in psoriasis patients when compared to control subjects [13]. Several large studies have shown a higher prevalence of diabetes and cardiovascular disease correlating with the severity of psoriasis [14,15,16,17,18]. There are divided opinions regarding the contribution of psoriasis as an independent cardiovascular risk factor [19,20]; however, the collective evidence supports that psoriasis independently increases risk for myocardial infarction, stroke, and death due to cardiovascular disease (CVD) [21,22,23,24,25,26,27,28]. In addition, the risk was found to apply also to patients with mild psoriasis to a lower extent [21,27].

Vascular inflammation assessed via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) found psoriasis duration to be a negative predicting factor. It was suggested that the cumulative effects of low-grade chronic inflammation might accelerate vascular disease development [29]. In a study by Metha et al., systemic and vascular inflammation in six patients with moderate to severe psoriasis was quantified by FDG-PET/CT. Inflammation foci were registered as expected in the skin, joints, and tendons. In addition, FDG uptake in the liver and aorta revealed subclinical systemic inflammation [30]. Furthermore, standardized uptake values were reduced in the liver, spleen, and aorta following treatment with ustekinumab {Kim, 2018 #359}. A new biomarker to assess CVD risk in psoriasis patients was proposed by nuclear magnetic resonance spectroscopy [31]. The signal originating from glycan N-acetylglucosamine residues called GlycA in psoriasis patients was associated with psoriasis severity and subclinical CVD, and was shown to be reduced in response to the effective treatment of psoriasis.

Psoriatic inflammation of the joints results in psoriatic arthritis (PsA). The skin manifestations generally precede PsA, which shares the inflammatory chronicity of psoriasis and requires systemic therapies due to a potential destructive progression. Psoriatic arthritis develops in up to 40% of psoriasis patients [32,33,34,35,36,37,38]; around 15% of psoriasis patients are thought to have undiagnosed PsA [39]. It presents clinically with dactylitis and enthesitis in oligoarticular or polyarticular patterns. The polyarticular variant is frequently associated with nail involvement [40]. Nails are specialized dermal appendages that can also be affected by psoriatic inflammation. Nail psoriasis is reported to affect more than half of psoriasis patients, and can present as the only psoriasis manifestation in 510% of patients [41]. The clinical presentation of nail psoriasis depends on the structure affected by the inflammatory process. Nail matrix involvement presents as pitting, leukonychia, and onychodystrophy, whereas inflammation of the nail bed presents as oil-drop discoloration, splinter hemorrhages, and onycholysis () [42]. Psoriatic nail involvement is associated with joint involvement, and up to 80% of patients with PsA have nail manifestations [43,44].

Onycholysis and oil drop changes on psoriatic nail involvement.

In addition to an increased risk for cardiometabolic disease, psoriasis has been associated with a higher prevalence of gastrointestinal and chronic kidney disease. Susceptibility loci shared between psoriasis and inflammatory bowel disease support this association in particular with regard to Crohns disease [45,46]. An association with mild liver disease, which correlates with imaging studies, has been reported [30,47]. Psoriasis might be a risk factor for chronic kidney disease and end-stage renal disease, independent of traditional risk factors (demographic, cardiovascular, or drug-related) [48].

Taken together, the different factors contributing to psoriasis as a systemic disease can have a dramatic effect on the quality of life of patients and their burden of disease. Psoriasis impairment to psychological quality of life is comparable to cancer, myocardial infarction, and depression [49]. The high burden of disease is thought to be owed to the symptoms of the disease, which include pain, pruritus, and bleeding, in addition to the aforementioned associated diseases [50]. The impact of psoriasis on psychological and mental health is currently an important consideration due to the implications of the disease on social well-being and treatment. Patients with psoriasis have an increased prevalence of depression and anxiety and suicidal ideation. Interestingly, psoriasis treatment leads to improvement in anxiety symptoms [51,52].

The hallmark of psoriasis is sustained inflammation that leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation. The histology of the psoriatic plaque shows acanthosis (epidermal hyperplasia), which overlies inflammatory infiltrates composed of dermal dendritic cells, macrophages, T cells, and neutrophils (). Neovascularization is also a prominent feature. The inflammatory pathways active in plaque psoriasis and the rest of the clinical variants overlap, but also display discrete differences that account for the different phenotype and treatment outcomes.

Histopathology of psoriasis. (A) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. (B) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutrophilic infiltrates, which cause pustule formation.

Disturbances in the innate and adaptive cutaneous immune responses are responsible for the development and sustainment of psoriatic inflammation [53,54]. An activation of the innate immune system driven by endogenous danger signals and cytokines characteristically coexists with an autoinflammatory perpetuation in some patients, and T cell-driven autoimmune reactions in others. Thus, psoriasis shows traits of an autoimmune disease on an (auto)inflammatory background [55], with both mechanisms overlapping and even potentiating one another.

The main clinical findings in psoriasis are evident at the outermost layer of the skin, which is made up of keratinocytes. However, the development of the psoriatic plaque is not restricted to inflammation in the epidermal layer, but rather is shaped by the interaction of keratinocytes with many different cell types (innate and adaptive immune cells, vasculature) spanning the dermal layer of the skin. The pathogenesis of psoriasis can be conceptualized into an initiation phase possibly triggered by trauma (Koebner phenomenon), infection, or drugs [53] and a maintenance phase characterized by a chronic clinical progression (see ).

The pathogenesis of psoriasis.

It is well known that dendritic cells play a major role in the initial stages of disease. Dendritic cells are professional antigen-presenting cells. However, their activation in psoriasis is not entirely clear. One of the proposed mechanisms involves the recognition of antimicrobial peptides (AMPs), which are secreted by keratinocytes in response to injury and are characteristically overexpressed in psoriatic skin. Among the most studied psoriasis-associated AMPs are LL37, -defensins, and S100 proteins [56]. LL37 or cathelicidin has been attributed a pathogenic role in psoriasis. It is released by damaged keratinocytes, and subsequently forms complexes with self-genetic material from other damaged cells. LL37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs) [57]. The activation of pDC is key in starting the development of the psoriatic plaque, and is characterized by the production of type I IFN (IFN- and IFN-). Type I IFN signaling promotes myeloid dendritic cells (mDC) phenotypic maturation, and has been implicated in Th1 and Th17 differentiation and function, including IFN- and interleukin (IL)-17 production, respectively [58,59,60].

Whilst LL37DNA complexes stimulate pDCs through TLR9, LL37 bound to RNA stimulates pDCs through TLR7. In addition, LL37RNA complexes act on mDCs via TLR8 [56,57]. Activated mDCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)-, IL-23, and IL-12, with the latter two modulating the differentiation and proliferation of Th17 and Th1 cell subsets, respectively. Furthermore, slan+ monocytes, which are important pro-inflammatory cells found in psoriasis skin lesions, respond to LL37RNA activation by secreting high amounts of TNF-, IL-12, and IL-23 [61].

The activation of the adaptive immune response via the distinct T cell subsets drives the maintenance phase of psoriatic inflammation [62]. Th17 cytokines, namely IL-17, IL-21, and IL-22 activate keratinocyte proliferation in the epidermis.

The inflammatory milieu activates keratinocyte proliferation via TNF-, IL-17, and IFN-. Keratinocytes are also activated by LL37 and DNA, and greatly increase the production of type I IFNs [57]. Furthermore, they participate actively in the inflammatory cascade through cytokine (IL-1, IL-6, and TNF-), chemokine, and AMP secretion.

A widely used psoriasis-like inflammation mouse model relies on the effect of the TLR7/8 agonist imiquimod, and is thus in support of the TLR7/8 disease initiation model. In addition, the response to imiquimod was blocked in mice deficient of IL-23 or IL-17R, which highlights the involvement of the IL-23/IL-17 axis in skin inflammation and psoriasis-like pathology [63].

The TNFIL-23Th17 inflammatory pathway characterizes plaque-type psoriasis. The IL-17 cytokine family is composed of six members: IL-17AF. They are produced by different cell types, and are important regulators of inflammatory responses [64]. So far, the clinically relevant signaling in psoriasis is mediated mostly by IL-17A and IL-17F; both act through the same receptor, but have different potencies. IL-17A exerts a stronger effect than IL-17F, and the IL-17A/IL-17F heterodimer has an intermediate effect. IL-17A binds to its trimeric receptor complex composed of two IL-17RA subunits and one IL-17RC subunit, resulting in the recruitment of the ACT1 adaptor protein. The interaction between ACT1 and the IL-17 receptor complex leads to the activation of a series of intracellular kinases including: extracellular signal-regulated kinase (ERK), p38 MAPK, TGF-beta-activated Kinase 1 (TAK1), I-kappa B kinase (IKK), and glycogen synthase kinase 3 beta (GSK-3 beta). These kinases enable NFB, AP-1, and C/EBP transcription of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Th1 and Th2 cytokines act through Janus kinase (JAK)-STAT signaling pathways, whereas Th17 responses are mediated by ACT1 and NFB [65]. Alternatively, T cells are able to produce IL-17A independently of the IL-23 stimulus [66].

Drugs targeting TNF, IL-23, and IL-17 and signaling pathways such as JAK/STAT are effective in the clinical management of plaque psoriasis. However, alternate inflammatory pathways may be valid for distinct psoriatic variants.

Whereas the TNFIL23Th17 axis plays a central role in T cell-mediated plaque psoriasis, the innate immune system appears to play a more prominent role in the pustular variants of psoriasis [55]. Different pathomechanisms are associated with distinct psoriasis subtypes.

In guttate psoriasis, streptococcal superantigens are thought to stimulate the expansion of T cells in the skin [67]. It was shown that there is a considerable sequence homology between streptococcal M proteins and human keratin 17 proteins. Molecular mimicry may play a role in patients with the major histocompatibility HLA-Cw6 allele, since CD8(+) T cell IFN- responses were elicited by K17 and M6 peptides in said patients [68,69].

Pustular psoriasis is characterized by the increased expression of IL-1, IL-36, and IL-36 transcripts, which have been found in pustular psoriasis compared to psoriasis vulgaris [70]. Nevertheless, IL-17 signaling is also involved in pustular psoriasis and patients with generalized pustular psoriasis without IL-36R mutations responded to anti-IL-17 treatments [71,72].

In nail psoriasis and psoriatic arthritis (PsA), an increased expression of TNF-, NFB, IL-6, and IL-8 in psoriasis-affected nails is consistent with the inflammatory markers found on lesional psoriatic skin [73]. The pathophysiology of PsA and psoriasis is shared as synovial tissue in psoriatic arthritis expresses pro-inflammatory cytokines: IL-1, IFN-, and TNF [74,75]. Infiltrating cells in psoriasis arthritis, tissues, and synovial fluid revealed large clonal expansions of CD8+ T cells. Joint pathology, specifically bone destruction, is partly mediated via IL-17A signaling, which induces the receptor activator of nuclear factor kappa b ligand (RANKL), and in turn activating osteoclasts. Pro-inflammatory cytokines IL-1 and TNF- act in synergy with the local milleu [76].

Psoriasis shows clear autoimmune-related pathomechanisms. This very important area of research will allow for a deeper understanding of to which extent autoantigen-specific T cells contribute to the development, chronification, and overall course of the disease.

LL37 is one of two well-studied T cell autoantigens in psoriasis. CD4+ and CD8+ T cells specific for LL37 were found in two-thirds of patients with moderate to severe plaque psoriasis in a study. LL37-specific T cells produce IFN-, and CD4+ T cells produce IL-17, IL-21, and IL-22 as well. LL37-specific T cells can be found in lesional skin or in the blood, where they correlate with disease activity [77]. CD8+ T cells activated through LL37 engage in epidermotropism, autoantigen recognition, and the further secretion of Th17 cytokines. The melanocytic protein ADAMTSL5 was found to be an HLA-C*06:02-restricted autoantigen recognized by an autoreactive CD8+ T cell TCR. This finding establishes melanocytes as autoimmune target cells, but does not exclude other cellular targets [78].

Other autoantigen candidates include lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D) and hair follicle-derived keratin 17 [79,80]. Interestingly, keratin 17 exposure only lead to CD8+ T cell proliferation in patients with the HLA-Cw*0602 allele (see above) [81].

Psoriasis has a genetic component that is supported by patterns of familial aggregation. First and second-degree relatives of psoriasis patients have an increased incidence of developing psoriasis, while monozygotic twins have a two to threefold increased risk compared to dizygotic twins [82,83]. Determining the precise effect of genetics in shaping innate and adaptive immune responses has proven problematic for psoriasis and other numerous immune-mediated diseases [84,85]. The genetic variants associated with psoriasis are involved in different biological processes, including immune functions such as antigen presentation, inflammation, and keratinocyte biology [55].

Genome-wide linkage studies of psoriasis-affected families have so far detected at least 60 chromosomal loci linked to psoriatic susceptibility [86,87,88]; the most prominent locus is PSORS1, which has been attributed up to 50% of the heritability of the disease [89]. PSORS1 is located on chromosome 6p21 within the major histocompatibility complex (MHC), which is specifically in the class I telomeric region of HLA-B, and spans an approximately 220 kb-long segment and corresponds to HLA-Cw6 (C*06:02). HLA-Cw6 is strongly linked to early and acute onset psoriasis [90,91]. The HLA-C*06:02 allele is present in more than 60% of patients, and increases the risk for psoriasis nine to 23-fold [92]. Nevertheless, no link between late-onset psoriasis or pustular psoriasis and PSORS1 could be established, possibly reflecting a genetically heterogenic background associated with different clinical phenotypes [93]. PSORS2 spans the CARD14 gene, while PSORS4 is located in the epidermal differentiation complex [94,95,96,97,98,99,100,101].

The results of numerous genome-wide association studies (GWAS) in psoriasis are consistent with the prominent role of PSORS1 as a risk factor, but have also revealed over 50 single-nucleotide polymorphisms (SNPs) to be associated to psoriasis [102,103,104]. Variants involving the adaptive and immune system are a constant result in these studies [53,103,105].

The immunogenetics of IL-23 are strongly associated with psoriasis. IL-23 is a dimer composed of a specific subunit, p19, and a p40 subunit, which is shared with IL-12. IL-23 signals through a heterodimeric receptor expressed by both innate and adaptive immune cells, which include Th17, natural killer T, T cells, and RORt+ innate lymphoid cells. The IL-23R signals through JAK2/TYK2 and STAT3 [106]. SNPs in the regions coding for the IL-23 cytokine (both the p40 and p19 subunit) as well as the IL-23R have been identified to convey psoriasis risk [107,108,109]. Furthermore, these variants have been found to be associated with Crohns disease, psoriatic arthritis, and ankylosing spondylitis [110] [74,75]. IL-23 drives the expansion of Th17 T cells that produce IL-17A/F, which is another set of cytokines whose role is pivotal in the pathogenesis of psoriasis. Monoclonal antibodies targeting both the common p40 and the specific p19 subunit of IL-23 have proven to have high clinical efficacy [109].

As mentioned above, STAT3 is found in downstream signaling by IL-23, and is therefore essential in T cell development and Th17 polarization. STAT3 has also been detected in psoriasis GWAS, and its variants are associated with psoriasis risk [107,111]. Furthermore, transcription factor Runx1 induces Th17 differentiation by interacting with RORt. Interestingly, the interaction of Runx1 with Foxp3 results in reduced IL-17 expression [112].

CARD14 mapping was shown to correspond to PSORS2. The CARD family encompasses scaffolding proteins that activate NF-kB. It was suggested that in psoriasis patients with respective CARD14 mutations, a triggering event can result in an aberrant NF-kB over activation [96]. CARD14 is expressed in keratinocytes and in psoriatic skin; it is upregulated in the suprabasal epidermal layers and downregulated in the basal layers. In healthy skin, CARD14 is mainly localized in the basal layer. Mutations in CARD14 have been shown to be associated with psoriasis, as well as with familial pityriasis rubra pilaris (PRP) [113].

The NF-kB signaling pathway is involved in the production of both IL-17 and TNF-, and thus participates in adaptive and innate immune responses [73]; it is upregulated in psoriatic lesions and is responsive to treatment [114]. Gene variations in NFKBIA, TNIP1, and TRAF3PI2 affecting NF-kB regulatory proteins have been linked to psoriasis via GWAS [102,115,116,117]. TRAF3PI2 codes for the ACT1 adaptor protein and the specific variant TRAF3IP2 p. Asp10Asn was associated to both psoriasis and psoriatic arthritis [117].

The different clinical psoriasis variants may have additional genetic modifiers. For instance, mutations in the antagonist to the IL-36 receptor (IL-36RN), belonging to the IL-1 pro-inflammatory cytokine family, have been linked to pustular psoriasis [118,119]. Recessive mutations in IL36RN, coding for the IL-36 receptor antagonist, have been associated with generalized pustular psoriasis (GPP). This mutation is also found in palmar plantar pustulosis and acrodermatitis continua of Hallopeau. Furthermore, in patients with pre-existing plaque-type psoriasis, the gain of function mutation in CARD14, p.Asp176His, was found to be a predisposing factor for developing GPP [120].

In addition to studies of genetic variants, the profiling of gene expression in psoriasis has aided in the understanding of the relevant pathophysiological pathways. Transcriptomic studies of psoriatic skin have revealed differentially expressed genes (DEGs) when compared to healthy skin, and also between lesional and nonlesional psoriatic skin [121,122]. Further underscoring their relevance in psoriasis pathogenesis, IL-17A genes were found to be upregulated in nonlesional psoriatic skin compared to healthy skin. This finding suggests that nonlesional psoriatic skin is also subclinically affected, and supports the concept of the widespread inflammation that is present in psoriasis [123]. In addition, data showing the upregulation of Th2 genes in nonlesional psoriatic skin may reflect the activation of T cell regulatory compensation mechanisms in an effort to override the inflammatory cascade [123]. Cross-disease transcriptomics have aided in differentiating nonspecific DEGs present in inflammatory skin conditions (such as atopic dermatitis and squamous cell carcinoma) from DEGs specific to psoriasis. The latter are induced by IL-17A and are expressed by keratinocytes [124].

Despite solid evidence of genetic relevance in the pathogenesis of psoriasis, no single genetic variant seems to be sufficient to account on its own for the development of disease. Hence, a multifactorial setting including multiple genetic mutations and environmental factors, which have been attributed up to 30% of disease risk, ought to be considered [125].

The quest for the missing heritability associated with psoriasis candidate genes has fueled the search for epigenetic modifications. Epigenetic mechanisms modify gene expression without changing the genomic sequence; some examples include: long noncoding RNA (lncRNA), microRNA (miRNA) silencing, and cytosine and guanine (CpG) methylation.

lncRNA are at least 200 nucleotides long, and are not transcribed to protein. At least 971 lncRNAs have been found to be differentially expressed in psoriatic plaques compared to normal skin [126,127,128,129,130,131]. Thereof, three differentially expressed lncRNAs in proximity to known psoriasis susceptibility loci at CARD14, LCE3B/LCE3C, and IL-23R, and are thought to modulate their function [127].

miRNAs are small, evolutionarily conserved, noncoding RNAs that base pair with complementary sequences within mRNA molecules, and regulate gene expression at the posttranscriptional level, usually downregulating expression. Most of the studies of miRNAs in association with psoriasis address the plaque-type variant (see ), and so far, more than 250 miRNAs are aberrantly expressed in psoriatic skin [132,133,134,135]. A prominent role has been attributed to miR-31, which is upregulated in psoriatic skin and regulates NF-B signaling as well as the leukocyte-attracting and endothelial cell-activating signals produced by keratinocytes [135]. miR-21 is an oncomiR with a role in inflammation, and has been found to be elevated in psoriatic skin. Increased miR-21 has been localized not only to the epidermis, but is also found in the dermal inflammatory infiltrates, and correlates with elevated TNF- mRNA expression [136]. miR-221 and miR-222 are among other upregulated miRNAs in psoriatic skin [132]. The aberrant expression of miR-21, miR-221, and miR-222 correlates with a downregulation of the tissue inhibitor of metalloprotease 3 (TIMP3) [137,138]. TIMP3 is a member of the matrix metalloprotease family with a wide range of functions. Increased levels of said miRs are thought to result in unopposed matrix metalloprotease activity, leading to inflammation (partly via TNF--mediated signaling) and epidermal proliferation [138]. miR-210 was found to be highly expressed in psoriasis patients, and induced Th17 and Th1 differentiation while inhibiting Th2 differentiation through STAT6 and LYN repression [139].

MicroRNAs (miRNAs) increased in psoriasis.

Serum levels of miR-33, miR-126, and miR-143, among others, have been proposed as potential biomarkers of disease [140,141]. However, the studies have so far failed to consistently present elevations of a single miRNA in psoriatic patients. Thus, alterations of miRNA expression are better interpreted in the context of miRNA profiles, which have been reported to shift following psoriasis treatments [132]. Thus, miRNA expression profiles could potentially be used to predict response to treatment and personalize therapies.

DNA methylation is another epigenetic mechanism that can alter gene expression in a transient or heritable fashion, and primarily involves the covalent modification of cytosine and guanine (CpG) sequences. CpG methylation is usually repressive unless it inhibits transcriptional repressors, in which case it results in gene activation. Around 1100 differentially methylated CpG sites were detected between psoriatic and control skin. Of these sites, 12 corresponded to genes regulating epidermal differentiation, and were upregulated due to a lower methylation pattern. Said changes in DNA methylation reverted to baseline under anti-TNF- treatment, indicating that CpG methylation in psoriasis is dynamic [148,149]. Further research will shed light on the functional relevance of epigenetic regulation in psoriasis.

The skin microbiome exerts an active role in immune regulation and pathogen defense by stimulating the production of antibacterial peptides and through biofilm formation. A differential colonizing microbiota in comparison to healthy skin has been found in several dermatologic diseases, including atopic dermatitis, psoriasis, and acne vulgaris [150,151]. It is hypothesized that an aberrant immune activation triggered by skin microbiota is involved in the pathogenesis of autoimmune diseases. For instance, there is growing evidence that the steady-state microbiome plays a role in autoimmune diseases such as in inflammatory bowel disease [152].

The overall microbial diversity is increased in the psoriatic plaque [151]. However, an increase in Firmicutes and Actinobacteria phyla were found in psoriatic plaques () [153]. Proteobacteria were found to be higher in healthy skin when compared to psoriatic patients [153,154]. Nevertheless, Proteobacteria were found to be increased in the trunk skin biopsies of psoriatic lesions [151]. A combined increase in Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus was found in psoriatic skin; however, in another study, Staphylococci were significantly lower in psoriatic skin compared to healthy controls [151,154].

Psoriasis microbiome. increased. > higher than.

Certain fungi such as Malassezia and Candida albicans, and viruses such as the human papilloma virus have been associated with psoriasis [155]. So far, Malassezia proved to be the most abundant fungus in psoriatic and healthy skin. Nevertheless, the colonization level of Malassezia in psoriasis patients was lower than that in healthy controls [156]. Further studies are required to explain the role of the microbiome signature and the dynamics among different commensal and pathogenic phyla [157].

Psoriasis is a chronic relapsing disease, which often necessitates a long-term therapy. The choice of therapy for psoriasis is determined by disease severity, comorbidities, and access to health care. Psoriatic patients are frequently categorized into two groups: mild or moderate to severe psoriasis, depending on the clinical severity of the lesions, the percentage of affected body surface area, and patient quality of life [159]. Clinical disease severity and response to treatment can be graded through a number of different scores. The PASI score has been extensively used in clinical trials, especially those pertaining to the development of the biologic drugs, and will be used throughout this review.

Mild to moderate psoriasis can be treated topically with a combination of glucocorticoids, vitamin D analogues, and phototherapy. Moderate to severe psoriasis often requires systemic treatment. The presence of comorbidities such as psoriasis arthritis is also highly relevant in treatment selection. In this review, we will address the systemic therapies as small-molecule (traditional and new) and biologic drugs.

A number of case reports and case series have suggested that tonsillectomy has a therapeutic effect in patients with guttate psoriasis and plaque psoriasis [69,160,161]. A systematic review concluded that the evidence is insufficient to make general therapeutic recommendations for tonsillectomy, except for selected patients with recalcitrant psoriasis, which is clearly associated to tonsillitis [162]. A recent study stated that HLA-Cw*0602 homozygosity in patients with plaque psoriasis may predict a favorable outcome to tonsillectomy [163]. To date, a single randomized, controlled clinical trial showed that tonsillectomy produced a significant improvement in patients with plaque psoriasis in a two-year follow-up timespan [164]. Furthermore, the same cohort was evaluated to assess the impact of the clinical improvement after tonsillectomy on quality of life. The study reported a 50% improvement in health-related quality of life, and a mean 59% improvement in psoriasis-induced stress. Tonsillectomy was considered worthwhile by 87% of patients who underwent the procedure [165].

In the past years, an accelerated development in psoriasis therapies has resulted in advanced targeted biological drugs. Methotrexate (MTX), cyclosporin A, and retinoids are traditional systemic treatment options for psoriasis. All of the former are oral drugs with the exception of MTX, which is also available for subcutaneous administration. They will be briefly discussed in this review (see ). The section ends with an overview on dimethyl fumarate and apremilast, which are newer drugs that have been approved for psoriasis.

Drugs available for psoriasis therapy.

MTX is a folic acid analogue that inhibits DNA synthesis by blocking thymidine and purine biosynthesis. The initial recommended dose of 7.510 mg/weekly may be increased to a maximum of 25 mg/weekly [166,167]. A recent retrospective study reported successful treatment response (defined by PASI decrease of 50% to 75% and absolute DLQI value) was reached by 33%, 47%, and 64% of patients at three, six, and 12 months, respectively [168]. There is conflicting evidence regarding MTX effectiveness on psoriatic arthritis. A recent publication reported 22.4% of patients achieved minimal arthritic disease activity, and 27.2% reached a PASI 75 at week 12 [169]. Furthermore, HLA-Cw6 has been suggested as a potential marker for patients who may benefit from MTX treatment [170]. The most common side effects include nausea, leucopenia, and liver transaminase elevation. Despite the potential side effects and its teratotoxicity, it remains a frequently used cost-effective first-line drug, and the close monitoring of liver function and full blood count make a long-term administration feasible.

Cyclosporine is a T cell-inhibiting immunosuppressant from the group of the calcineurin inhibitors. Cyclosporine is effective as a remission inducer in psoriasis and as maintenance therapy for up to two years [171]. Hypertension, renal toxicity, and non-melanoma skin cancer are significant potential side effects. Nephrotoxicity is related to the duration of treatment and the dose. Cyclosporine is employed as an intermittent short-term therapy. The dosage is 2.5 to 5.0 mg/kg of body weight for up to 10 to 16 weeks. Tapering of the drug is recommended to prevent relapse [171].

Retinoids are natural or synthetic vitamin A-related molecules. Acitretin is the retinoid used in the treatment of psoriasis. It affects transcriptional processes by acting through nuclear receptors and normalizes keratinocyte proliferation and differentiation [172,173]. A multicenter, randomized study reported 22.2% and 44.4% of patients reaching PASI 75 and PASI 50 at 24 weeks [174]. Acitretin is initially administered at 0.30.5 mg/kg of body weight per day. The maximum dosage is 1 mg/kg body weight/daily. Cheilitis is the most common side effect appearing dose dependently in all patients. Other adverse effects include conjunctivitis, effluvium, hepatitis, and teratogenicity.

Fumaric acid esters (FAEs) are small molecules with immunomodulatory and anti-inflammatory properties [175,176]. The exact mechanism of action has not been cleared, but is thought to involve an interaction with glutathione, which among other mechanisms, inhibits the transcriptional activity of NF-B [177,178]. FAEs were initially available as a mix of dimethyl fumarate and monoethyl fumarate (DMF/MEF), the former being the main active compound in the formulation. DMF has been reported to decrease the migratory capacity of slan+ monocytes, and also inhibited the induction of Th1/Th17 responses [178]. DMF/MEF was approved in 1994 in Germany for the treatment of severe plaque psoriasis, and in 2008, the indication was expanded for moderate psoriasis [179]. This licensing was exclusive to Germany, where it remains a first-line drug; nevertheless, DMF/MEF was used as off-label treatment in other European countries [180,181,182,183]. A new FAE formulation containing exclusively the main active metabolite DMF became available in 2017, and was approved for psoriasis treatment in the European Union, Iceland, and Norway [184]. Although there are no studies comparing DMF/MEF directly to biologics, several studies document its efficacy [185,186,187,188,189]. A marked improvement is also seen in patients with psoriatic arthritis and nail psoriasis. The most common side effects are gastrointestinal symptoms and flushing, which are generally mild in severity, resolve over time, and are dose related [184]. In addition, FAEs may decrease lymphocyte and leukocyte counts. Therefore, it is recommended to perform a complete blood count before treatment initiation and monthly for DMF/MEF or every three months for DMF [184].

Apremilast, a phosphodiesterase-4 inhibitor, inhibits the hydrolyzation of the second messenger cAMP. This leads to the reduced expression of pro-inflammatory cytokines TNF-, IFN0, and IL-12, and increased levels of IL-10. Apremilast was shown to have broad anti-inflammatory effects on keratinocytes, fibroblasts, and endothelial cells [190]. We studied apremilast in the context of slan+ cells, which is a frequent dermal inflammatory dendritic cell type derived from blood circulating slan+ nonclassical monocytes. Here, apremilast strongly reduced TNF- and IL-12 production, but increased IL-23 secretion and IL-17 production in T cells stimulated by apremilast-treated slan+ monocytes [191]. These dual effects on slan+ antigen-presenting cells may constrain therapeutic responses. No routine monitoring of hematologic parameters is required for apremilast, which is a major advantage compared to the other small molecule drugs. Apremilast showed a 33.1% PASI 75 response at week 16. It is also effective for palmoplantar, scalp psoriasis, and nail psoriasis in addition to psoriatic arthritis [192,193,194]. The most common adverse events affected the gastrointestinal tract (nausea and diarrhea) and the upper respiratory tract (infections and nasopharyngitis). These effects were mild in nature and self-resolving over time.

The traditional systemic drugs are immunomodulators, which except for apremilast require close clinical monitoring due to the common side effects involving mainly the kidney and the liver. Methotrexate and cyclosporine are the only systemic therapies for psoriasis included in the World Health Organization (WHO) Model List of Essential Medicines, albeit for the indications of joint disease for the former and immunosuppression for the latter. The potential side effects of FAE and apremilast are usually not life-threatening, but might be sufficient to warrant discontinuation.

In the context of psoriasis treatment, current use of the term biologics refers to complex engineered molecules including monoclonal antibodies and receptor fusion proteins. Biologics are different from the above-described systemic therapies in that they target specific inflammatory pathways and are administered subcutaneously (s.c.) (or intravenously i.e., infliximab) on different weekly schedules. Biologics presently target two pathways crucial in the development and chronicity of the psoriatic plaque: the IL-23/Th17 axis and TNF--signaling (see ).

TNF- inhibitors have been available for over a decade. They are considered the first-generation biologics, and are effective for plaque psoriasis and psoriatic arthritis. TNF- inhibitors are still the standard used to evaluate drug efficacy in psoriasis clinical research. There are currently four drugs in this category: etanercept, infliximab, adalimumab, and certolizumab.

Etanercept is unique in the biologics category in that it is not a monoclonal antibody, but rather a recombinant human fusion protein. The receptor portion for the TNF- ligand is fused to the Fc portion of an IgG1 antibody. It was the first TNF- inhibitor approved by the United States Food and Drug Administration (FDA) for psoriasis. Infliximab is a chimeric monoclonal IgG1 antibody, and adalimumab is a fully human monoclonal IgG1 antibody. They neutralize TNF- activity by binding to its soluble and membrane-bound form. These drugs are particularly employed to treat psoriatic arthritis, and show a similar efficacy. In the treatment of psoriasis, they show different PASI 75 response rates: 52% for etanercept, 59% for adalimumab, and 80% for infliximab. Infliximab shows superiority in terms of efficacy when compared to the other TNF- inhibitors, and when compared with ustekinumab, it showed a similar performance [195]. The chimeric nature of infliximab might contribute to a higher immunogenic potential of the drug, which in turn might influence drug survival. Certolizumab pegol is a pegylated Fab fragment of a humanized monoclonal antibody against TNF-. PEGylation is the covalent conjugation of proteins with polyethylene glycol (PEG), and is attributed a number of biopharmaceutical improvements, including increased half-life and reduced immunogenicity [196]. The initial indication for treating Crohns disease was extended to psoriatic arthritis and recently to plaque psoriasis. Certolizumab has shown an 83% PASI 75 response. Unlike other anti-TNF- agents, it has no Fc domain, and is thus not actively transported across the placenta. Thus, certolizumab pegol is approved for use during pregnancy and breastfeeding.

As previously mentioned, IL-23 drives the expansion of Th17 cells whose inflammatory effects are in turn mediated by IL-17A, IL-17F, and IL-22.

IL-23 is a dimer composed of p40 and p19. The first biologic to be approved for psoriasis vulgaris after the TNF- inhibitors was ustekinumab, which is a monoclonal antibody directed against the p40 subunit. P40 is not exclusive to IL-23, but rather is shared with IL-12. IL-12 is a dimer consisting of p40 and p35, and is involved in the differentiation of nave T cells into Th1 cells. By targeting p40, ustekinumab blocks two different T-cell activating mechanisms, namely Th1 and Th17 selection. Ustekinumab is also effective for the treatment of PsA and Chrons disease. It is available in two dosages, 45 mg and 90 mg, depending on a threshold body weight of 100 kg. Ustekinumab has extensive safety data, few side effects, good clinical efficacy, and long treatment drug survival was reported. At 90 mg, ustekinumab showed a PASI 75 response in 72.4% and in 61.2% at 45 mg [197]. Studies using real-life data compared ustekinumab with the anti-TNF- drugs, and ustekinumab was found to have a significant longer drug survival [198,199,200]. Frequent adverse events include nasopharyngitis, upper respiratory tract infections, fatigue, and headache. Among the serious adverse events listed in the label of ustekinumab are infections. Tuberculosis (TB) has only been reported in two psoriasis patients receiving ustekinumab [201,202]. The clinical efficacy of ustekinumab and the further clarification of its mechanism of action highlighted the crucial role of IL-23 in shaping the Th17 response. On the other hand, Th1 signaling is important for the response against bacterial and viral pathogens, and a study showed IL-12 signaling to have a protective effect in a model of imiquimod psoriasis-like inflammation [203]. This rationale fueled the development of drugs targeting p19, which is the IL-23-exclusive subunit. This more specific molecular targeting approach has also achieved successful clinical outcomes. Three fully human monoclonal antibodies with p19 specificity are available: guselkumab, tildrakizumab, and risankizumab. Guselkumab is licensed for psoriasis, and showed clinical superiority when compared to adalimumab, with 85.1% of patients reaching a PASI 75, and 73.3% receiving a PASI 90 response at week 16 [204,205]. Patients receiving tildrakizumab showed a 74% PASI 75, and 52% PASI 90 at week 16. Tildrakizumab was compared to etanercept, and was more likely to reach PASI 75 at weeks 16 and 28 [206,207]. Risankizumab showed the following PASI responses at week 12: 88% PASI 75, 81% PASI 90, and 48% PASI 100. Patients were followed for 48 weeks after the last injection at week 16, and one-fourth of them showed a maintained PASI 100 [208]. Whether IL-23 inhibition has the potential to modify the course of the disease after subsequent drug retrieval is currently under study.

So far, three human monoclonal antibodies targeting IL-17 are available. Secukinumab and ixekizumab block IL-17A; whereas brodalumab is directed against the IL-17 receptor A. IL-17-targeted biologics are fast acting, showing significant differences from placebo within the first week of treatment. Secukinumab was the first IL-17A inhibitor approved for psoriasis in 2015. A year later, the approval extended to include PsA and ankylosing spondylitis. At week 12, 81.6% of patients on secukinumab reached a PASI 75 response, and 28.6% reached a PASI 100 response [209]. At week 52, over 80% maintained PASI 75. Secukinumab showed a rapid onset of action, reflecting a significant likelihood of achieving PASI 75 as early as the first week of treatment when compared to ustekinumab, and surpassed the latter in clinical superiority at week 16 and 52 [210,211].

Ixekizumab also showed a significantly rapid onset of action in the first week when compared to placebo: a 50% PASI 75 response at week four, and 50% PASI 90 by week eight. At week 12, response rates were 89.1% for PASI 75 and 35.3% for PASI 100 [212]. Secukinumab and ixekizumab have proven effective for scalp and nail psoriasis, which are two clinical variants that are resistant to conventional topical therapies.

Brodalumab is a human monoclonal antibody that targets the IL-17 receptor type A, thus inhibiting the biological activity of IL-17A, IL-17F, interleukin-17A/F, and interleukin-17E (also called interleukin-25). Brodalumab showed an 83.3% PASI 75, 70.3% PASI 90, and 41.9% PASI 100 response rate at week 12, and a satisfactory safety profile [213,214]. After the discontinuation of treatment with secukinumab, 21% of patients maintained their response after one year and 10% after two years [215]. This finding suggests that targeting IL-17 signaling exerts some disease-modifying effect that might reestablish the homeostasis of the inflammatory pathways in a subset of psoriasis patients. Frequent adverse effects under IL-17 blockade include nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Furthermore, IL-17 signaling is critical for the acute defense against extracellular bacterial and fungal infections. Candida infections are more frequent in patients receiving anti-IL17 biologics secukinumab and ixekizumab compared to etanercept [209]. Nonetheless, candida infections were not severe, and did not warrant treatment interruption. The risk of tuberculosis reactivation is considered small under biologic therapies other than anti-TNF- [216]. Anti-IL-17 biologics should not be used in psoriasis patients also suffering from Chrons disease.

The introduction of biosimilars for different diseases is revolutionizing the pharmaceutical arsenal at hand. As patents for many biologics face expiration, biosimilar versions of these drugs are being developed, or are already entering the market. A biosimilar is a biological product that must fulfill two requirements: it must be highly similar to an approved biologic product and have no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Guidelines for the development and approval of biosimilars have been issued by the European Medicines Agency, the FDA, and the World Health Organization. There are currently eight adalimumab biosimilars, four infliximab biosimilars, and two etanercept biosimilars approved in Europe. By lowering the costs of systemic treatment for psoriasis patients, biosimilars may also increase access to biologics.

Tofacitinib is an oral Janus kinase (JAK) inhibitor currently approved for the treatment of rheumatoid arthritis (RA) and PsA. Tofacitinib showed a 59% PASI 75 and 39% PASI 90 response rate at week 16, and was also effective for nail psoriasis; however, its development for psoriasis was halted for reasons unrelated to safety. Upadacitinib is another JAK inhibitor currently undergoing phase III clinical trials for the treatment of psoriatic arthritis. Piclidenoson, an adenosine A3 receptor inhibitor, serlopitant, a neurokinin-1 receptor antagonist, and RORt inhibitors are each being tested as oral treatments for psoriasis [217]. Two different biologics targeting IL-17 and one targeting IL-23 are being currently tested. In addition, there are currently 13 registered phase III clinical trials testing biosimilars for adalimumab (eight), infliximab (three), and etanercept (two).

See original here:
Psoriasis Pathogenesis and Treatment - PMC - PubMed Central (PMC)

J Clin Aesthet Dermatol. 2010 Jan; 3(1): 3238.

Understanding Pathophysiology and Clinical Relevance

aDermatology Research Fellow, Mohave Skin & Cancer Clinics, Las Vegas, Nevada

bDermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada, and Director of Dermatology Research, Mohave Skin & Cancer Clinics, Las Vegas, Nevada

aDermatology Research Fellow, Mohave Skin & Cancer Clinics, Las Vegas, Nevada

bDermatology Residency Director, Valley Hospital Medical Center, Las Vegas, Nevada, and Director of Dermatology Research, Mohave Skin & Cancer Clinics, Las Vegas, Nevada

DISCLOSURE: The authors report no relevant conflicts of interest.

Psoriasis is a commonly encountered dermatosis with a variety of internal and external paradoxical factors contributing to the clinical course of the disease. There are several drugs described in the literature that have been associated with the initiation, exacerbation, and aggravation of psoriasis. Understanding the pathophysiology can provide clues to treatment and management of drug-induced and drug-aggravated psoriasis, which may be indistinguishable from idiopathic psoriasis. The clinical manifestations of drug-associated psoriasis can range from plaque-type psoriasis to severe erythroderma, thus warranting astute and sustained clinical observation.

Psoriasis is a chronic, immune-mediated, inflammatory condition seen frequently in the clinical practice with a reported prevalence of 0.6 to 4.8 percent in the general population.1,2 Some factors known to trigger psoriasis include smoking, alcohol consumption, body mass index (BMI), trauma, infection, endocrine disorders, drugs, and acute withdrawal of systemic or potent topical corticosteroids.1 Analysis of comedication in a study of 1,203 psoriasis patients revealed 23.2 percent of patients were taking more than three systemic medications, and of these patients, 11.1 percent were taking more than 10 medications.3 Further analysis demonstrated that comorbid cardiac and metabolic disorders are common in these individuals with a high prevalence of hypertension (28.2%), diabetes (10.5%), and dyslipidemia (12.5%).3 With this in mind, many psoriasis patients can be on multi-drug regimens; therefore, careful analysis of medications that can exacerbate the disease is prudent. Drugs reported to be associated with exacerbation/induction of psoriasis are based mostly on case reports, with no definitive cause-and-effect links between these drugs and onset of psoriasis.

Drugs have several ways in which they can affect the diathesis of psoriasis including 1) precipitation of psoriasis de novo in predisposed and nonpredisposed individuals; 2) exacerbation of pre-existing psoriatic lesions; 3) induction of lesions in clinically normal skin in patients with psoriasis; and 4) development of treatment-resistant psoriasis.4 The clinical presentation of drug-provoked psoriasis spans the spectrum of generalized plaque psoriasis, palmoplantar pustulosis, and erythroderma.4 The nails and scalp can also be involved, thus making the distinction of drug-associated psoriasis a clinically difficult diagnosis.4 In addition, the mechanism of action can also involve both immunological and nonimmunological pathways.5 Therapeutic agents can also be categorized as having a causal relationship to psoriasis, with considerable but insufficient data supporting induction of psoriasis, or occasionally an association with psoriasis.4 Drugs that appear to have a strong causal relationship to psoriasis are beta-blockers, lithium, synthetic antimalarials, nonsteroidal anti-inflammatory drugs (NSAIDs), and tetracyclines, which will be discussed in this review.4

Psoriasiform drug eruption is a broad term referring to a heterogeneous group of disorders that clinically and/or histologically simulate psoriasis at some point during the course of the disease.6 A psoriasiform eruption is used also to describe a histological reaction pattern, which exhibits presence of cellular infiltration, papillomatosis, and epidermal hyperplasia with elongation of rete ridges.6 Hypergranulosis and parakeratosis may also be observed in selected cases.710 This type of eruption can also be seen with seborrheic dermatitis, pityriasis rubra pilaris, secondary syphilis, pityriasis rosea, mycosis fungoides, drugs, and some malignancies.6 These psoriasiform reactions are elicited by inflammatory events that cause dysregulation of cytokines, growth factors, and abnormal keratinocyte proliferation.6 Depending on the disorder, the lesions may vary in size, shape, extent and type of scaling, and anatomic distribution.6

Drug-provoked psoriasis can be divided into two categories (). The first category, drug-induced psoriasis, is where discontinuation of the causative drug stops the further progression of the disease. The second category, drug-aggravated psoriasis, is where the disease progresses even after the discontinuation of the offending drug.4 True drug-induced psoriasis tends to occur in a de-novo fashion in patients with no family or previous history of psoriasis.5 The clinical presentation of these lesions may often mimic the pustular variant of psoriasis, often with no nail involvement or associated arthritis.5 Furthermore, there is an absence of Munro microabscesses, few macrophages, and sparse vascular changes noted histologically.5 Drug-aggravated psoriasis exhibits a propensity to occur in patients with a history of psoriasis or with a genetic predisposition for the disease. Patients can have exacerbation of pre-existing psoriatic lesions or develop new lesions in previously uninvolved skin. Histological examination reveals features that are more characteristic of psoriasis vulgaris.11

Drug-provoked psoriasis: Subtypes4

Beta blockers are a very popular class of drugs used to treat both cardiovascular and noncardiovascular diseases, including hypertension, ischemic heart disease, arrhythmias, heart failure, hyperthyroidism, glaucoma, and anxiety disorders.11 They exert their action by blockade of either 1 receptors (cardioselective) or 2 receptors (noncardioselective), hence their classification. 2-adrenergic receptors are found predominantly on epidermal keratinocytes and on the surface of macrophages.11 Several theories have been proposed regarding the pathogenesis of beta blocker-induced psoriasis. These include a delayed-type hypersensitivity reaction, immunological mechanisms including impaired lymphocyte transformation, or alterations in the cyclic adenosine monophosphate (cAMP) pathway.1214 Cyclic adenosine monophosphate is an intracellular messenger that is responsible for the stimulation of proteins for cellular differentiation and inhibition of proliferation.11 The most reliable proposition is that blockade of epidermal 2 receptors leads to a decrease in intraepidermal cAMP causing keratinocyte hyperproliferation.4 Biopsy specimens from eruptions caused by 1 blockers (metoprolol and atenolol) are characterized by excessive degranulation of neutrophils in the dermis.15 Nonselective beta blockers (propranolol, nadolol, and sotalol) were marked by excessive release of proteolytic enzymes from macrophages.15 Both groups of beta blockers exhibit excessive release of enzymes by lymphocytes, neutrophils, and macrophages, and it is believed that this event is responsible for the presence of hyperproliferation and psoriasiform change. It has also been reported that beta blockers increase phosphorylation in T cells in psoriasis, which may be relevant to intracellular levels of calcium.16 The blockade of these receptors has been implicated in the pathogenesis of drug-provoked psoriasis in both groups of beta blockers.11

Clinical manifestations of beta-blocker-provoked psoriasis. In the past, beta blockers have been known to cause drug-induced/exacerbation of psoriasis, psoriasiform dermatitis, eczematous eruptions, and lichenoid changes.8 Psoriasiform eruptions are the most common cutaneous consequence of beta-blocker therapy, seen more frequently in patients with no past or family history of psoriasis.4,17 Clinical improvement after withdrawal of the implicated drug is the distinguishing feature in many cases suggesting drug-induced psoriasis.4 In a case-controlled and case-crossover study of 110 patients who were hospitalized for extensive psoriasis vulgaris, beta blockers were considered a major factor in triggering or aggravating psoriasis.1820 Practolol is the prototype cardioselective beta blocker, which is no longer available due to the high incidence of cutaneous side effects reported, including psoriasiform eruptions and exacerbations of pre-existing psoriasis.12 Transformation of plaque-type psoriasis into pustular psoriasis with pindolol has also been observed.21 In addition, atenolol has been reported to precipitate psoriasiform pustulosis.22 Topical application of timolol in the treatment of open-angle glaucoma has been reported to induce psoriasis and to transform psoriasis vulgaris into psoriatic erythroderma through the passage into the systemic circulation via the conjunctiva.23,24

Both psoriasiform eruption and drug-induced/aggravated psoriasis from beta-blocker therapy usually appear at 1 to 18 months after initiation of therapy.15 In psoriasiform eruptions, lesions clear after several weeks of discontinuing the medication.15 In addition, re-exposure with oral challenge results in recurrence within a few days.15 Many believe that psoriasiform eruptions from beta blockers are not true representations of psoriasis, partly due to histological features and partly due to clinical presentations exhibiting lesions that are less red, thick, or scaly than classic lesions of psoriasis, and usually with absence of knee and elbow involvement.15 In contrast, beta-blocker-provoked psoriasis improves upon discontinuation of medication, but usually does not completely resolve.11 In regard to beta-blocker-induced, de-novo pustular psoriasis, the duration is much shorter.4 Reasons for these variations remain a mystery and may be due to genetic, environmental, or racial backgrounds.

Management of beta-blocker-provoked psoriasis. Cross reactivity between both groups of beta blockers have led many researchers to believe that the mechanism of action is directly via the skin.5 This has been demonstrated with the observation that switching from one beta blocker to another results in re-introduction of psoriasiform skin lesions.5 However, researchers have found that the cumulative drug exposure to beta blockers is not a substantial risk factor for development of psoriasiform lesions.25 In psoriasiform eruptions, discontinuation alone can cause rapid regression of the disease.4 If psoriasis is present only in localized areas, emollients alone can be helpful.4 Exacerbation of psoriasis by beta blockers can be persistent and resistant to therapy unless they are discontinued.4 Management of drug-provoked psoriasis necessitates the use of conventional therapeutic agents that include topical and systemic agents used in the treatment of psoriasis vulgaris.4 Treatment of erythroderma resulting from beta-blocker therapy should be targeted at decreasing transepidermal fluid loss.26 Hospitalization is required to monitor hypovolemia and hemodynamic instability that requires aggressive fluid resuscitation.26 These cases should be treated aggressively with systemic and topical agents in concordance with discontinuation of the offending drug.26

Lithium is a metal ion that has been used extensively in the treatment of manic-depressive disorder since the 1970s.11 Although utilization of lithium is not as widespread as in the past, it is commonly prescribed. The first association of lithium with psoriasis was reported in 1972, and since then there have been several reports of lithium-induced psoriasis described in individuals with no personal or family history.11 Toxic effects of lithium on organs other than the skin are dose related, with adverse events involving the thyroid, kidneys, central nervous system, and gastrointestinal tract.11 Psoriasiform eruptions are the most common cutaneous side effects, reported to occur in 3.4 to 45 percent of patients treated with lithium.27

Pathogenesis of lithium-provoked psoriasis. There are several theories purported to explain the pathogenesis of lithium-provoked psoriasis. Induction and aggravation of psoriasis through cAMP are now being refuted by some investigators.16 In the past, researchers theorized that the decrease in cAMP from lithium treatment caused low intracellular levels of calcium, leading to a lack of differentiation, increased proliferation of keratinocytes, and enhanced chemotaxis and phagocytic activity of polymorphonuclear leukocytes.28,29 Past studies have shown that the short-term use of lithium leads to diminution of intracellular cAMP, but long-term lithium treatment causes just the opposite response through a compensatory mechanism.30,31 The current belief is that lithium causes depletion of inositol monophosphatase resulting in alterations in calcium homeostasis and seritonergic function.5,3234 Inositol is an intracellular second messenger system linked to neurotransmitters affecting cell function, growth, and differentiation.5 The association between the blockade of the phosphatidyl inositol pathway and lithium-provoked psoriasis is through the release and depletion of intracellular calcium.5 Low intracellular calcium levels cause increased proliferation of keratinocytes and affect terminal differentiation.11 Lithium inhibits the enzyme inositol monophosphatase, necessary for the recycling of inositol.11 The inhibition of the intracellular release of calcium appears to be the mechanism in which lithium provokes the development of a psoriasiform eruption.35 The support for the inositol depletion hypothesis comes from the clinical observation that inositol supplementation can reverse the exacerbation of lithium-provoked psoriasis.16 In addition, studies have shown that lithium increases the production of interleukin-2 (IL-2), tumor necrosis factor- (TNF-), and interferon-gamma in psoriatic keratinocytes.11 The dysregulation in the production of these cytokines has been linked to the induction of psoriatic lesions.11 Lithium also increases intracellular tyrosine phosphorylation in psoriatic T cells but not in control T cells, with a possible implication to psoriasis lesion development.16

Clinical manifestation of lithium-provoked psoriasis. Reports of lithium-provoked psoriasis in the literature include new onset of pustular psoriasis, palmoplantar pustulosis, erythroderma, psoriasiform dermatitis, psoriatic arthropathy, and psoriasis involving the nail and scalp.36 The most common presentation of lithium-provoked psoriasis is the classic plaque-type lesions.5 Clinically and histologically, there is little difference between psoriasis vulgaris and lithium-provoked psoriasis.37 In addition, elevated plasma concentrations of lithium have been found in patients with psoriasis who have never been treated with lithium compounds, suggesting a possible environmental factor.38 There may be inherent factors that influence the induction or aggravation of psoriasis with lithium.11 When plaque-type psoriasis develops with lithium therapy, it may take longer to resolve compared to pustular psoriasis.37 It has been suggested that exacerbation of pre-existing psoriasis is more common than induction of new psoriatic lesions.3940 While in some patients, there is a definite temporal relationship between aggravation of psoriasis with the initiation of lithium and improvement with discontinuation of the drug, this is not always the case.27,41 The refractory period for the development of psoriatic lesions after the initiation of lithium treatment is variable and ranges from a few weeks to several months.36 There have also been reports suggesting that production of psoriatic lesions can be temporally related to the improvement in mood symptoms due to cellular saturation with lithium ions.36

Management of lithium-provoked psoriasis. Supplementation with inositol in dietary consumption has sparked an interest in the treatment of psoriasis associated with lithium therapy. Peripheral inositols received in the form of dietary consumption do not cross the blood-brain barrier and therefore do not alter lithium effects on mood stabilization.42 Studies have shown that patients with psoriasis on lithium therapy experience significant improvement after 6g of daily inositol supplementation by mouth with dramatic improvement within 48 to 72 hours.43 A double-blind, randomized, placebo-controlled, crossover trial showed that inositol supplementation significantly improved the Psoriasis Area and Severity Index (PASI) scores in psoriasis patients on lithium compared to placebo.5 In another double-blind, placebo-controlled trial, 4 to 6g/day of omega-3 fatty acid was found to be very useful in clearing acute lithium-induced psoriasis.44 In addition, there has also been success with TNF- inhibitors, such as etanercept, in the treatment of severe, recalcitrant, lithium-provoked psoriasis.4445 However, there are new reports suggesting the onset or exacerbation of psoriasis with TNF- inhibitors possibly through elevation of cytokines or due to increased susceptibility to infections.46 In evaluating lithium-provoked psoriasis, the role of stress and other psychological factors, as well as current medications, must be evaluated. Lithium-provoked psoriasis can be controlled with conventional treatments, such as topical corticosteroids, keratolytics, vitamin D analogues, oral retinoids, psoralen plus ultraviolet A (PUVA) therapy, and methotrexate.36 Psoriatic lesions generally disappear within a few months after discontinuation of lithium treatment.36 In some cases, patients can develop treatment-resistant psoriasis, which may warrant discontinuation of lithium with change to another mood-stabilizing agent (under close supervision of a psychiatrist) depending on the severity of cutaneous involvement.40,47,48 Reduction in dosage of lithium is an additional option for treatment-resistant cases.36 Yet, lithium-provoked psoriasis has been reported to occur at varying therapeutic levels and is not believed to be dose related.49 It is advised that not all patients with psoriasis will have a flare-up with the initiation of lithium therapy, and psoriasis is not considered a contraindication to lithium use.50

The synthetic oral antimalarial (AM) agents are 4-aminoquinolone compounds that have been used in the prophylaxis and treatment of malaria and several dermatological disorders for many years.11 The most commonly used oral AMs are chloroquine and hydroxychloroquine.11 The exacerbation and induction of psoriasis during treatment with AMs has been widely acknowledged.4 One mode of action of AMs is through the inhibition of transglutaminase in the skin, which is thought to influence cellular proliferation.11 The inhibition of this enzyme can induce de-novo pustular psoriasis, which is notably uncommon compared to aggravation of pre-existing psoriasis.51 Some patients may have minimal presence of pre-existing psoriatic lesions without being aware that these minor skin changes constitute psoriasis.11 It has been shown that patients with psoriatic skin lesions after use of AMs had exacerbation of their psoriasis in 31 percent of cases.52 The same study also reported the induction of psoriasis and pustular psoriasis during chloroquine therapy.53,54 In another group, 42 percent (20/48) of American soldiers with psoriasis given chloroquine for the prophylaxis of malaria had exacerbation of psoriasis, which was treatment resistant.55 Exacerbation of psoriasis has been reported with chloroquine treatment for psoriatic arthritis.5657 Psoriatic skin lesions most often occur with a latency of 2 to 12 weeks (average of 3 weeks) after starting AMs, with some patients exhibiting durations longer than 40.5 weeks, especially in cases of pustular eruptions occurring in those with pre-existing psoriasis.4 Clinicians may be faced with a difficult decision in patients with simultaneous collagen vascular disease, such as progressive discoid or subacute cutaneous lupus erythematosus and psoriasis.4 Resolution of psoriatic lesions usually occurs within one month of discontinuing the AM agent.11 The use of chloroquine and hydroxychloroquine in patients with psoriasis is considered by some to be a contraindication.11

A relationship between systemic antibiotics and drug-provoked psoriasis remains controversial. The tetracyclines are one group of antibiotics that have been described in association with psoriasis with no definitive latency period.58 Tetracyclines may theoretically provoke psoriasis through reduction of intracellular cAMP and by the interaction with arachidonic acid and its metabolites.59 It has been theorized that tetracyclines accumulate in higher concentrations in psoriatic lesions compared to uninvolved skin.60 Some tetracyclines may cause photosensitization, which may result in predisposed patients with psoriasis to experience exacerbation through the Koebner phenomenon secondary to phototoxicity.6163 In one study, investigators reported that 4.11 percent (19/462) of patients experienced exacerbation of psoriasis as a consequence of tetracycline use.4 It has also been suggested that tetracyclines should be avoided in patients with clinical evidence of psoriasis, as well as in healthy individuals with a genetic predisposition for psoriasis, such as in those with a positive family history or with HLA-B13, B17, and B27 genotypes.4 The validity, practicality, and clinical relevance of these suggestions remain uncertain.

Reports suggest that exacerbation of psoriasis by penicillin derivatives is rare and may actually represent acute generalized exanthematous pustulosis and not true drug-provoked psoriasis.6566 Macrolides and penicillin derivatives were associated with psoriasis in one multivariate case-control model in patients less than 50 years of age.64 Whether the actual drug intake or the infection itself is the inciting agent is still uncertain.4 Therefore, clinicians should keep in mind that antibiotics may have been given as a treatment for presumed streptococcal infection, a known trigger of psoriasis development or exacerbation.64

NSAIDs are a class of medications used for treatment of pain and arthritides. NSAIDs are frequently used by patients who have psoriasis as well as psoriatic arthritis. NSAIDs are available by prescription and over the counter. NSAIDs inhibit the metabolism of arachidonic acid by the cyclo-oxygenase (COX) pathway leading to accumulation of leukotrienes, which has been postulated to aggravate psoriasis.11 According to one study, both topical and systemic NSAIDs were the most common cause of both exacerbation and induction of psoriasis.11 Of the NSAIDs, naproxen was the most common culprit.67 Six patients had exacerbation of psoriasis after taking oral NSAIDs in a large study of 462 patients.68 In another study, topical 1% indomethacin cream exacerbated psoriasis in 14 of 20 patients with known disease.69 In case-controlled and case-crossover studies, there have been adverse side effects of NSAIDs reported in patients with psoriasis, particularly with proprionic acid derivatives.69 The effects of NSAIDs have a short latency period (1.6 weeks on average) without significant variations between the different subsets of drug-provoked psoriasis.4 Considering that patients with psoriasis can have associated arthropathies, it is important for clinicians to recognize NSAIDs as potential exacerbators of psoriasis. Nevertheless, in some patients, exacerbation of psoriasis and arthritis may coincidently occur simultaneously with the use of NSAIDs.

Angiotensin-converting enzyme inhibitors (ACEI) are widely used to control hypertension. In an analysis of case-controlled and case-crossover studies, ACEIs were associated with psoriasis in patients greater than 50 years of age.64 Although there are no current studies confirming a causal relationship between the two, ACEIs are considered to be possible triggering/exacerbating agents of psoriasis.64 Recent studies suggest that patients with a history of familial psoriasis and a specific ACE genotype exhibiting low ACE activity are more susceptible to developing psoriasis after initiation of therapy.70

Drugs with considerable data in the induction/ exacerbation of psoriasis include interferons, terbinafine, and benzodiazepines.64,69 There have also been reports of generalized pustular psoriasis in association with phenylbutazone.4 Other miscellaneous drugs with a reported association with psoriasis include digoxin, clonidine, amiodarone, quinidine, gold, TNF-alpha inhibitors, imiquimod, fluoxetine, cimetidine, and gemfibrozil.11 With an ever-expanding list of medications, investigators have suggested using the Adverse Drug Reactions Probability Scale in assessing the relationship between drugs and adverse reactions if a clinician is faced with a difficult decision in high-risk psoriasis patients on multidrug regimens.71

Several drugs have been associated with drug-provoked psoriasis (). Understanding the pathogenesis of drug-provoked psoriasis not only helps to achieve a greater appreciation of the disease process, but is also useful in providing guidance for treatment methodologies. In certain cases of drug-provoked psoriasis, lesions may become resistant to treatment and hence early recognition and management can help avoid issues of nonadherence. In general, most drugs tend to exacerbate psoriasis rather than induce it.11 In cases where psoriasis is induced, one should question if this is truly a first-time occurrence or if previous subclinical signs may have gone undetected. Why provocation of psoriasis occurs in some individuals and not others who are exposed to a specific drug remains unclear. The absence of additional triggering factors should always be ruled out first. Patients should be encouraged to avoid alcohol, excessive sun exposure, smoking, and stressfactors that can all affect the clinical course of the disease. Management of drug-provoked psoriasis includes detailed personal, social, and family history. Provocation testing is also an option if a definitive relationship cannot be established. Drugs that are considered to have a strong potential risk factor for psoriasis development should be avoided after weighing the risk and benefits of the agent.64 Fortunately, there are only a few drugs that demonstrate a well-documented, direct, causal relationship with the development of psoriasis or psoriasiform eruptions, and alternative therapeutic options are frequently available.

Drug-provoked psoriasis: Reported agents

3. Zahl V, Gerdes S, Mrowietz U. Co-medication in patients with severe psoriasis: first results of a retrospective analysis in 1203 hospitalized patients in Germany. Presented at: the 4th International Congress-The Royal College of Physicians; December 13, 2005; London, England.

58. Botev-Slatkov N, Tsankov N, Tonev S, et al. Drug therapy deteriorates the course of psoriasis. Presented at: 17th World Congress of Dermatology, Part II; West Berlin: Springer; 1987:216.

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Drug-Provoked Psoriasis: Is It Drug Induced or Drug Aggravated?