Pharmacogenomics in Psoriasis Treatment: Comparison
Please note this is a comparison between Version 1 by Raffaella Cascella and Version 2 by Peter Tang.

Pharmacogenomic studies allowed the reasons behind the different responses to treatments to be understood. Its clinical utility, in fact, is demonstrated by the reduction in adverse drug reaction incidence and the improvement of drug efficacy. Pharmacogenomics is an important tool that is able to improve the drug therapy of different disorders.

  • psoriasis
  • psoriatic arthritis
  • biomarkers
  • pharmacogenomics
  • polymorphisms
  • drug
  • treatment

1. Introduction

The transition from reactive to proactive care has outlined new management strategies, which are oriented towards the maintenance of patient welfare. This healthcare approach includes the exploration of the human genome, with the aim of identifying different genetic variants (single-nucleotide variants, SNVs; copy number variations, CNVs; small insertions and deletions, INDELs) that are involved in diseases susceptibility, drug response degree, and adverse drug reactions (ADRs). In particular, the collection of these data can be employed for the development of personalized treatments, designed in relation to the patient’s genomic profile. To this purpose, pharmacogenomics is one of the personalized medicine tools, which plays an important role in the management of therapeutic treatments [1]. On the other hand, the implementation of pharmacogenomics is encouraged by the identification and validation of specific biomarkers that can be detected in different biological sources (blood, saliva, tissue). SNVs, CNVs, and INDELs can be recognized as pharmacogenomic biomarkers that are able to affect the efficacy and toxicity of drugs [2][3][2,3]. Moreover, pharmacogenomic biomarkers were utilized to develop several genetic tests, with the aim of predicting the response degree or ADRs to specific treatments. Their clinical utility has been widely shown by the reduction in ADR incidence and the improvement of drug efficacy [4][5][4,5]. To date, pharmacogenomics can be considered as a tool to improve the drug therapy of several diseases or viral infections, such as inflammatory bowel disease (IBD), cardiovascular disease (CD), cancer, psoriasis (Ps), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) [6][7][8][9][10][11][6,7,8,9,10,11].
In particular, Ps is a chronic immune-mediated inflammatory skin disease, with a world-wide prevalence of 2–3% according to the different ethnicities and geographical regions [12]. It is possible to distinguish several phenotypes of Ps, depending on the appearance of skin lesions. Indeed, cutaneous manifestations are numerous, with a vulgar form that is characterized by well-circumscribed erythematous plaques, covered by a squamous scale, preferentially located on the skin of extensor surfaces of the body [13]. The most common form is plaque Ps that affect approximately 90% of patients. Furthermore, approximately 20–30% of Ps patients develop psoriatic arthritis (PsA) during their lifetime [14].
Numerous comorbidities (Crohn’s disease, psychological/psychiatric disorders, and uveitis) have been associated with Ps, although metabolic syndrome (MS) represents the most common one. In fact, psoriatic subjects have an increased risk of developing cardio-metabolic diseases (CVD) underling the systemic features of Ps [15][16][15,16].
Ps severity is classified as mild, moderate, and severe, which is determined by the body surface area (BSA), psoriasis area and severity index (PASI), physician global assessment (PGA), and dermatology life quality index (DLQI) [16]. Ps is described as a multifactorial disorder, in which environmental and genetic/epigenetic factors are likely to influence the susceptibility to the disease. To date, the genetic contribution has been investigated, highlighting the existence of a large number of risk variants associated with the onset and/or progression of Ps [17][18][19][17,18,19].

2. Pharmacogenetics of Ps Treatments

2.1. Biological Drugs

Biopharmaceutical or biologics are drugs derived from biological sources (humans, animals, plants, microorganisms), which act on specific molecular pathways, in order to prevent or treat immune-mediated inflammatory disorders. The biologics utilized to treat Ps can be classified in two different groups, according to the therapeutic target, such as tumor necrosis factor (TNF) inhibitors and IL-23/IL-17 inhibitors [20][21][23,24].

2.1.1. Pharmacogenetics of Anti-Tumor Necrosis Factor Drugs

TNF plays a central role in the activation of several signaling pathways leading to the stimulation of cells involved in the inflammatory and immune response. In particular, TNF engages macrophages, T-cells, B-cells, pro-inflammatory cytokines (IL-1, IL-6), and chemokines (IL-8, RANTES). The TNF or TNF-α gene is located on the short arm of chromosome 6 (6p21.33), and encodes for a multifunctional pro-inflammatory cytokine as a member of the TNF superfamily. This cytokine, mainly secreted by macrophages, is involved in the regulation of a wide spectrum of biological processes, such as cell proliferation, differentiation, and lipid metabolism. Moreover, TNF is involved in the production of T-cells, which trigger the local proliferation of epidermal keratinocytes and, thereby, plays an essential role in the etiopathogenesis of psoriatic lesions [22][25].
Anti-TNF drugs are one of the treatment options for psoriatic patients, which are resistant to conventional systemic therapies. These therapeutic approaches have also shown good efficacy, even if 30–50% of psoriatic patients do not show enhancement of their health status [23][26]. Anti-TNF therapy may be responsible for severe adverse events, causing paradoxical psoriasiform reactions and changing the morphology of psoriatic lesions [24][27]. In addition, TNF-α inhibitors are used to treat patients affected by IBD. As reported, these patients have an increased risk of developing ADRs, due to overproduction of interferon-α by plasmacytoid dendritic cells, resulting in the activation and amplification of pathogenic T-cells [25][28].
The TNF-α inhibitors employed in Ps treatments are infliximab (INF), adalimumab (ADA), certolizumab (CTL), and etanercept (ETN). INF, ADA, and CTL are monoclonal antibodies against TNF-α, whereas ETN is a recombinant fusion protein [26][29]. ADA, INF, and CTL are indicated for the treatment of moderate-to-severe Ps. The efficacy of these monoclonal antibodies is influenced by different genetic variants located on the TNF-α gene [27][28][30,31]. To date, more than 200 genetic variants have been identified. In particular, the polymorphisms TNF-308 (A/G, rs1800629), TNF-238 (G/A, rs361525), and TNF-857 (C/T, rs1799724) have been extensively investigated, either as risk or pharmacogenetic biomarkers [28][31]. The role of these SNPs has been evaluated in a meta-analysis that examined psoriatic patients treated with ETN, ADA, and INF, showing controversial results [29][32]. In fact, the G allele of rs1800629 and the G allele of rs361525 were significantly associated (p = 0.000086 and p = 0.016, respectively) with a good response to anti-TNF drugs in European patients. However, the association of these genetic variants failed to be significant in the Asian cases. Furthermore, studies performed on rs1799724 reported that only European patients carrying the C allele showed a better response. Another genotyping study revealed that TNF-1031 (T/C, rs1799964), located on the promoting region of the TNF gene, is associated with a good response to anti-TNF drugs. In particular, patients with the TT genotype and treated with INF showed the highest response at 3 months and at 6 months after treatment. Moreover, the bioinformatic analysis reported that rs361525 and rs1800629 modify regulatory regions linked to specific biological process, such as epithelial–mesenchymal transition (EMT). EMT is involved in cell morphology changes. In fact, this mechanism allows a polarized epithelial cell to assume a mesenchymal cell phenotype, increasing its migratory capacity, invasiveness, and high resistance to apoptosis. This result suggests that EMT could be involved in epithelium changes in patients affected by Ps [30][33].

2.1.2. Pharmacogenetics of Cytokine Inhibitors

Cytokines are water-soluble extracellular polypeptides produced by different types of cells. The cytokine-targeted therapy for the treatment of Ps patients involves the administration of IL-17 inhibitors (secukinumab, SCK; ixekizumab, IXE; brodalumab, BDL) targeting the IL-17RA receptor. Other cytokine inhibitors utilized for the treatment of Ps are guselkumab (GSL), tildrakizumab (TDK), risankizumab (RSK), and ustekinumab (UTK). In particular, GSL, TDK, and RSK inhibit IL-23, or its receptor IL-23R. On the other hand, UTK is able to block the biological activities of IL-12. Furthermore, these drugs have a different effect on the outcomes in moderate-to-severe phenotypes, and this condition may be explained by the existence of genetic polymorphisms linked to the individual variability to a drug response. To this purpose, it has been estimated that 50–70% of psoriatic patients show different response degrees to anti-ILs drugs [31][35].
The IL-17A gene is a member of the IL-17 receptor family and encodes a pro-inflammatory cytokine. IL-17A is involved in the production of inflammatory molecules, chemokines, antimicrobial peptides, and remodeling proteins. Moreover, IL-17 has an impact on host defense, cell trafficking, immune modulation, and tissue repair, playing a crucial role in the activation of innate immune defenses. As extensively demonstrated, high levels of IL-17 are associated with several chronic inflammatory diseases, including rheumatoid arthritis, Ps, and multiple sclerosis [32][36]. IL-17 polymorphisms are associated with different response degrees to cytokine inhibitors. In particular, the heterozygous genotype CT of rs763780 (C/T) was correlated to a worse response to UTK [26][28][29,31]. A recent study described six SNPs that could alter the molecular processes (hyper-proliferation of keratinocytes, T-cell polarization, and EMT) involved in the pathophysiology of Ps [30][33]. IL-17RA (22q11.1) is mainly involved in the keratinocytes hyper-proliferation process, and the SNP rs4819958 (G/A) may modify the interaction with PAX1 and NR2F1.
SCK and IXE are fully human monoclonal antibodies that target IL-17A. IXE also binds to the heterodimer form of the protein (IL-17A/F). These drugs provide a fast initial response that is maintained over time, with high safety profile [33][34][37,38]. Moreover, due to the increased risk of fungal infection in IL-17 inhibitor-treated patients, a screening of the CLEC7A (12p13.2) gene should be included in the clinical algorithm, to stratify the target population. This gene encodes for Dectin-1, which is a natural killer (NK) cell receptor-like C-type lectin that is thought to be involved in innate immune responses to fungal pathogens. In particular, genetic variants in Dectin-1 could predispose to fungal infection, and concomitant use of the IL-17 inhibitor could increase this risk [35][36][39,40].
The majority of pharmacogenetic studies are focused on SCK [28][37][31,41]. Preliminary data reported that the presence of the HLA-C*06:02 allele may influence the effectiveness and safety of SCK [38][42]. However, this result was not confirmed, as SCK proved to be effective independently of the HLA-C genotype [39][40][43,44]. The research of pharmacogenetic biomarkers was performed in a multicenter study, focusing on IL-17A inhibitors (SCK and IXE). In particular, they analyzed the coding regions and untranslated regions (UTR) of IL-17A, identifying five SNPs (rs3748067, C/T; rs2275913, C/G/T; rs3819025, A/G; rs7747909, A/G and rs8193037, A/C/T) located in non-coding regions. As reported, these genetic variants did not act on the efficacy of these drugs after 12 weeks of treatment [41][45].

2.2. Small Molecules

Small-molecule inhibitors (SMIs) are new-generation drugs that find an excellent use, as they can easily enter cells thanks to their low molecular weight. In particular, treatments for Ps include the administration of oral SMIs, such as apremilast, dimethyl fumarate, and tofacitinib [41][45].

2.2.1. Phosphodiesterase-4 Inhibitor

Phosphodiesterases (PDEs) represent a large family of enzymes that regulate the intracellular levels of cyclic nucleotides. PDEs are able to terminate cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and cGMP. In particular, phosphodiesterase-4 (PDE-4) regulates the inflammatory response by degrading cAMP [18]. The cAMP-specific PDE-4 is highly expressed in the brain, cardiovascular tissues, smooth muscles, keratinocytes, and immune cells (T cells, monocytes, macrophages, neutrophils, dendritic cells, eosinophils) [42][48]. In the skin, PDE-4 is principally expressed in keratinocytes, neutrophils, Langerhans, and T cells, which contribute to the formation of the psoriatic plaque. The inhibition of PDE-4 can increase the intracellular level of cAMP, and subsequently modulate the inflammatory responses and maintain the immune system homeostasis [43][49]. Different PDEs (roflumilast, apremilast, and crisaborole) were approved for the treatment of inflammatory disorders or skin diseases.
Apremilast has been licensed by the US Food and Drug Administration (FDA) for the management of active PsA (21 March 2014) and moderate-to-severe plaque Ps (23 September 2014). Apremilast acts significantly on the inhibition of inflammatory responses. In fact, this small molecule reduces circulating levels of Th1 and Th17 pro-inflammatory mediators, and increases anti-inflammatory mediators. PDE-4 inhibition is able to increase intracellular cAMP levels and, consecutively, downregulate the inflammatory response, by modulating the expression of TNF-α, IL-23, IL-17, and other pro-inflammatory cytokines. Moreover, this drug induces the production of anti-inflammatory cytokines, including IL-10 [44][50]. Preclinical studies revealed that apremilast alleviated the epidermal thickness and abnormal proliferation, and reduced the expression of TNF-α, HLA-DR, and ICAM-1 in the lesions. Apremilast is absorbed from the gut and is mainly metabolized by CYP450 3A4. On the other hand, this drug may cause adverse reactions, such as headache, abdominal pain, depression, weight loss, nausea, diarrhea, vomiting, and nasopharyngitis.

2.2.2. Fumaric Acid Esters

Fumaric acid esters (FAEs) are lipophilic ester derivatives of fumaric acid, and are recommended by the European guidelines for the management of moderate-to-severe plaque Ps. Dimethyl fumarate (DMF) is an orally administered FAE, indicated for the treatment of plaque Ps in adults. DMF acts as an immunomodulatory agent, which inhibits NF-κB translocation [45][52]. In addition, this small molecule induces the reduction in inflammatory cytokine production, blocks the proliferation of keratinocytes, alters the expression of adhesion molecules, and decreases inflammatory infiltrate within psoriatic plaques [45][52]. This drug showed a good efficacy and tolerable safety profile. The most common adverse events (flushing and gastrointestinal disorders) occurred mainly during the first few weeks of treatment.

2.2.3. JAK Inhibitor

The novel class of drugs investigated for the treatment of different immune-mediated and inflammatory disorders are the Janus kinase (JAK) inhibitors. The JAK family includes JAK1, JAK2, JAK3, and TYK2 that transduce cytokine-mediated signals via the JAK-STAT pathway. This pathway plays an important role in the modulation of cytokines directly involved in the inflammation. Tofacitinib (TOF) is an oral JAK1 and JAK3 inhibitor that was firstly approved for the treatment of rheumatoid arthritis (November 2012). Afterwards, the FDA allowed the use of TOF to treat PsA (December 2017). Although TOF was effective for the treatment of moderate-to-severe plaque Ps, the FDA declined its approval because of the high incidence of ADRs [46][53]. The common side effects are upper respiratory tract infections, headache, diarrhea, and cold symptoms, such as a sore throat, or runny or stuffy nose. On the other hand, different research studies demonstrated that TOF affects the pathophysiological processes involved in Ps etiopathogenesis. In fact, this small molecule influences the dysregulation of keratinocytes, induces the reduction in inflammatory infiltrates, and normalizes the IL-23/Th17 axis. It is important to highlight that pharmacogenetic data concerning the differential response and ADRs risk in the treatment with TOF are not available.
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