Main Potential Cytokine Targets in Psoriasis: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Aina Akmal Mohd Noor.

Psoriasis is an autoimmune disease mediated by disturbed T cells and other immune cells, and is defined by deep-red, well-demarcated skin lesions. Using biologics to target specific immune components, such as upregulated cytokines secreted by activated immune cells, is the most advanced therapy for psoriasis to date.

  • psoriasis
  • cytokines
  • inhibitors
  • biologics
  • autoimmunity
  • immune cells

1. Pathogenesis of Psoriasis

The sustained inflammation that leads to uncontrolled keratinocyte proliferation and faulty differentiation are the hallmarks of psoriasis. Multiple triggers could be from exogenous sources, for instance, infection, skin trauma, smoking habits, drugs, infections and occupational hazards [5]. A strong familial hereditary association of psoriasis-susceptible loci 

The sustained inflammation that leads to uncontrolled keratinocyte proliferation and faulty differentiation are the hallmarks of psoriasis. Multiple triggers could be from exogenous sources, for instance, infection, skin trauma, smoking habits, drugs, infections and occupational hazards [1]. A strong familial hereditary association of psoriasis-susceptible loci 

PSORS is also a cause of severe psoriasis development which can be detected at an early age [23,24]. If the disease is considered to be acquired, it might be from certain intrinsic conditions, such as hypertension, diabetes mellitus and predisposing metabolic syndrome [5,25].

 is also a cause of severe psoriasis development which can be detected at an early age [2][3]. If the disease is considered to be acquired, it might be from certain intrinsic conditions, such as hypertension, diabetes mellitus and predisposing metabolic syndrome [1][4].

Indeed, the complete pathogenesis of psoriasis remains ambiguous, and the “Psoriatic Universe” is still indefinite and waiting to be fully explored [26][5]. The development of psoriasis can be divided into four main phases: triggered initiation, responsive innate immune response, stimulated adaptive immune response and excessive epidermal proliferation (Figure 1). It is highly suggested that nucleic acid complexes, such as AMP chains of cathelicidin LL-37 within the upper layer of the skin, stimulate plasmacytoid dendritic cells (pDCs) during the early onset of psoriasis. Plasmacytoid DCs produce cytokines such as IFN-γ, TNF-α, IL-12 and IL-23 to communicate with myeloid dendritic cells (mDCs). These cytokines then signal CD4+ and CD8+ T cells to undergo clonal expansion and produce IL-17 and IL-22. CD8+ T cells migrate and connect with the MHC I receptors of the keratinocytes to assemble chemoattractants and innate immune mediators [27][6]. Moreover, mDCs also stimulate the differentiation of T helper (Th)1, Th22 and Th17 cells. Th1 cells secrete IFN-γ, TNF-α and IL-2 which promotes the inflammatory factors by signaling keratinocytes and DCs. Conversely, Th22 cells produce IL-22, which is responsible for triggering keratinocyte-derived T cell-recruiting chemokines and gives rise to the changed dermal phenotype, comprising epidermal hyperplasia, acanthosis and parakeratosis. Th17 cells that are stimulated by IL-1, IL-23, IL-12 and TNF-α release IL-17 once they undergo migration towards the dermis [28,29][7][8]. The released IL-17 then signals the keratinocytes to express TNF-α and CC chemokine ligands (CCL20). The combination of IL-17 and TNF-α can assemble neutrophils and create Munro’s microabscesses. Neutrophils can undergo degranulation and produce granular compounds, such as neutrophil elastase (NE), proteinase 3, LL-37, reactive oxygen species (ROS), α-defensin with antimicrobial characteristics and lipocalin, as well as C-X-C-motif ligand (CXCL)8, IL-6 and CCL20 [30][9].
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Figure 1. The summarized pathogenesis of psoriasis. Upon triggers, pDCs receive the signal via TLR8 and present the antigens to mDCs. mDCs activate Th1 and Th22 cells to release cytokines to generate hyperproliferative keratinocytes in the epidermis region. mDCs also present cytokines to Th17 cells to initiate keratinocyte hyperproliferation and the assembling of neutrophils to create Munro’s microabscesses. It is thought that once neutrophils undergo degranulation, this produces granular compounds, such as LL-37 and proteinase 3, which create an information loop to be detected again by pDCs. The cycle repeats. (AMP: antimicrobial proteins; PSORS: psoriasis susceptibility loci).

2. Psoriasis and Cytokines as Biologics Target

The currently available treatments for psoriasis are topical application, systemic therapy and biologics. Topical application is the only preferred treatment for mild psoriatic lesions and best acts on the surface of the lesioned sites in the short term. Hence, the epidermis layer in which keratinocytes become hyperproliferative can be softened and reduce the uncomfortable signs, especially during flare-ups, which include itchy, tingling and burning sensations [5,31][1][10].
In tackling the recurrent flaring episodes, particularly in moderate to severe forms, some patients choose systemic therapy, especially when they are unable to respond well to topical application. However, the long-term administration of systemic therapy results in low acceptance and potential multiorgan failure, as well as probable skin carcinogenesis [5,32][1][11]. For example, methotrexate disturbs DNA synthesis, replication and reconstruction. Some systemic therapies, for instance, acitretin and cyclosporin, lead to the abnormality of liver function and subsequent dyslipidemia, hyperkalemia, hyperuricemia and hypomagnesemia [33][12].
Biologics are considered to be the most advanced treatment strategy with minimum risks. It is very beneficial for moderate-to-severe psoriasis patients since this drug can selectively inhibit and/or dissolve targeted cytokines, hence reducing further inflammatory pathways [34,35][13][14]. Biologics are made of large and complex elements of combined monoclonal antibodies (mAb) with receptor fusion proteins which function to target immune mediators specifically [33][12]. They can specifically block any designated cytokines and their receptors from regulating the downstream signalling pathways [36][15].
The exploration of the usage of biologics has become worldwide after the discovery of the first successful introduction of alefacept, a type of biologic, in psoriasis [37][16]. This is the first instance of biologics in psoriasis using the dimeric fusion of the extracellular section of the human leukocyte function antigen-3 (LFA-3) and the Fc section of immunoglobulin (Ig) G1, which was approved by the US Food and Administration (FDA) in 2004 [38][17]. Alefacept is a non-cytokine-blocking agent since it is designed to target the interaction of T cells by blocking LFA-3 signalling on CD2, thus deactivating the stimulation [38,39,40][17][18][19]. However, it is indicated that alefacept produces non-neutralizing antibodies [41][20] and side effects [42][21]. Hence, further research later yearned to focus more on cytokine inhibitors instead [42][21].
Cytokines play a massive role in orchestrating and assembling the immune cells in psoriasis; thus, this could be the most suitable target to be used as a promising treatment [18][22]. The discovery of an effective novel biologic gives new insights into how beneficial it is to target important immune components, such as cytokines, in alleviating psoriasis exasperation. Hence, it can support other advanced methods, such as the quantification of numerous cytokines receptors using both mRNA and cDNA microarrays [43,44][23][24]. Thus, it is crucial to inhibit cytokine signaling if that is the attempted exit strategy for psoriasis. Herein, the information of the main cytokine inhibition targets, along with potential cytokines and their mechanism of action in psoriasis, are discussed. A literature search was conducted in PubMed, Scopus, ScienceDirect and Google Scholar using the search terms “psoriasis” AND “biologics” AND (“cytokines” OR “treatment” OR “pathogenesis” OR “pro-inflammatory” OR “topical” OR “systematic” OR “inhibitors” OR “TNF-α” OR “infliximab” OR “etanercept” OR “adalimumab” OR “certolizumab” OR “pegol” OR “IL-17” OR “secukinumab” OR “ixekizumab” OR “brodalumab” OR “IL-23” OR “tildrakizumab” OR “guselkumab” OR “risankizumab” OR “IL-12/23” OR “ustekinumab” OR “IFN” or “interferon” OR “IL-1” OR “IL-36” OR “IL-6” OR “IL-8” OR “IL-21” OR “IL-17/23” OR “IL-22”).

3. Main Potential Cytokine Targets in Psoriasis

Herein, the profiles of the main cytokines that play a major role in psoriasis are summarized and discussed.

3.1. TNF-α Inhibitors

TNF-α is a proinflammatory cytokine secreted by DCs, T cells, macrophages and non-immune cells, such as fibroblasts; therefore, its selection in the revolution of inhibitor drugs is promising [44][24]. TNF-α acts as the main mediator during the initiation phase of classical psoriasis and can sustain the disease over the long term [45,46,47][25][26][27]. It interposes inflammatory cascades, promotes cell growth, neovascularization and apoptosis and regulates the aggregation of other immune cells to the site of the lesions [12][28]. TNF-α plays an important role in suppressing the regulatory T cells, preventing them from allowing the subsequent hyperproliferation of pathogenic T cells and IL-17-producing cells. As a result, IL-17 is unable to stimulate CD8+ T cells; instead, it is downregulated [48,49][29][30]. Hence, the serum level of TNF-α in psoriatic patients is highly elevated with a positive correlation with the PASI score. Since TNF-α is also considered to be the central cytokine in this autoimmune disease, it can give predictions of the exacerbation susceptibility of psoriasis. Psoriasis can, indeed, be inherited and run down the family tree; hence, by tracing TNFA genes on the short arm of chromosome 6, which comprises −238G > A, −380G > A and −875C > T, genetic polymorphism as the predisposing factor could give early insights and help to identify drug targets [50,51][31][32]. Studies have reported that these polymorphisms contribute to more than 50% of prevalence cases in psoriasis [43,44,52,53][23][24][33][34]. Moreover, TNF-α, as the homotrimer cytokine, is associated with altering the cell cycle, especially in keratinocytes and hair follicles in psoriasis [54][35]. Collectively, these findings suggest that TNF-α is, indeed, a good candidate with which to establish a specific treatment regime for psoriasis.
During the early onset of psoriasis, DCs release TNF-α along with other cytokines, such as IL-23, to signal for the assembling of CD4+ and CD8+ T cells. Eventually, T cells migrate to the upper layer of the skin, which is near the epidermis region [55][36]. Since this disease involves the concurrent activity of multiple cytokines, TNF-α works best when combined with IL-17A and IL-17C [30,56][9][37]. The combination produces a preferable synergistic induction to generate chains of T cell expression [12][28]. For instance, TNF-α steadily integrates with IL-17A mRNA to upregulate IL-17A signalling and simultaneously initiates the overexpression of IL-17R on keratinocytes, causing them to become hyperproliferative [30,57][9][38]. TNF-α can also trigger DCs to release IL-23, stimulating Th17 cells. Concomitantly, keratinocytes are triggered by both TNF-α and cytokines from stimulated Th17 cells, causing them to undergo proliferation and produce chemokines [58][39].
In conjunction, anti-TNF-α biologics, such as etanercept, infliximab, adalimumab and golimumab, as illustrated in Figure 2, function to target and prevent the TNF-α in the inflammatory environment from stimulating other immune components. The function of TNF-α inhibitors differs from their respective molecular structure [59][40]. For example, etanercept is a type of psoriasis biologic that is made up of a large dimeric protein fusion of the extracellular region of TNFR2 fused with the Fc section of the humanized IgG1 mAb. It can capture the soluble and non-membrane-bound circulatory TNF-α, preventing it from binding to its receptors or TNF-α trimers, regardless of a weak binding [60,61][41][42]. It has been reported that etanercept is well tolerable in psoriasis patients, including pediatric and geriatric groups, for up to four years of treatment [62][43].
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Figure 2. TNF-α inhibitors. Infliximab and adalimumab depict almost similar molecular structures with different Fv regions. Etanercept has specialized extracellular portions of human TNFR2. Certolizumab pegol is the most unique, as its Fc region is replaced with PEG molecules to lengthen its half-life.
Meanwhile, infliximab and adalimumab share almost the same structures but have different constituents. Infliximab is chimeric, with 75% of it made up of a human IgG1 original section and 25% made up of a murine-derived antigen-binding variable section [63][44]. It is highly specific, whereby it can only neutralize the biological activity of TNF-α compared to TNF-β, although these two cytokines exhibit quite similar molecular structures [64][45]. Infliximab binds with a high affinity towards the circulating and transmembrane-bound TNF-α. Therefore, TNF-α will be inhibited from binding to its receptors and cellular lysis, which generates TNF-α, will also be prevented [65,66][46][47]. It can be concluded that infliximab can suppress any TNF-α-mediated connecting cascades of cellular proliferation and programmed cell death [67][48]. A collective of evidence stated that psoriasis patients who received a long-term subcutaneous injection of infliximab in their treatment regime experienced improved skin lesions and other related health conditions, such as psoriasis arthritis [68][49].
Although the molecular structures of adalimumab are almost similar to infliximab, it is not structurally chimeric, since it is made up of fully IgG1 human mAb, similar to golimumab [65,69][46][50]. Adalimumab is suitable for moderate-to-severe psoriasis patients in long-term treatment [70][51]. Its mechanism of action is also similar to infliximab. Nevertheless, infliximab is superior to adalimumab, since adalimumab is not highly specific when compared to the other two. This is due to the various binding affinities of adalimumab towards different antibody-antigen interfaces, whereby the force is lower than infliximab [65][46]. Blocking the free-bound and trans-membranous TNF-α in psoriasis from binding to a TNFR2 receptor can neutralize this overproduced cytokine. Hence, the downstream TNF-α signalling pathways that play a role in exacerbating psoriasis can be inhibited/blocked [51][32].
Meanwhile, on a side note, golimumab is better to administer in psoriatic arthritis patients instead of other psoriasis types [71][52]. Since golimumab has a high affinity and specificity towards TNF-α, it works well in blocking TNF-α from interacting with its receptor, hence neutralizing its downstream bioactivity. These bioactivities include neutralizing TNF-α-induced cell surface expression to block the adhesion activities of E-selectin, vascular cells and human endothelial cells [72][53]. To achieve 50% neutralization, golimumab requires less concentration when compared to infliximab and adalimumab, a property which is similar to etanercept. Golimumab is not exclusively used for psoriasis; however, it is the only FDA-approved psoriasis arthritis and rheumatoid arthritis drug/treatment [73][54].
In addition, among these listed TNF-α inhibitors, infliximab is the most efficient drug/inhibitor compared to adalimumab, golimumab and etanercept, given its high affinity and a PASI score that decreases by at least 75% after its administration [74][55]. Inhibiting the overproduced TNF-α in severe cases of psoriasis using different inhibitors opens many discussions relating to how different clinical efficacies can result in its improved biological activities. These drugs stated herein are only the primary example, since their usage is quite common.
Another TNF-α-blocking agent which has recently been discussed and explored is certolizumab pegol. It is an Fc-free with polyethylene glycol (PEG) biologic with chemical structures that are often described as peculiar since it has no Fc region. Due to its uniqueness, it disables the binding with the neonatal Fc receptor for IgG (FcRn) and, hence, minimizes the placental transfer from mother to the fetus [75][56]. Moreover, the PEG structure allows certolizumab pegol to undergo PEGylation to lengthen its half-life by up to 14 days [76][57]. Certolizumab pegol is not intensively discussed concerning psoriasis since it is commonly administered for rheumatoid arthritis [77][58]. This biologic is FDA-approved for psoriatic arthritis; hence, it is still yet to be exclusive solely for psoriasis. Nevertheless, this drug potentiates an excellent efficacy in improving psoriasis and has an acceptable safety profile [78][59].

3.2. IL-17 Inhibitors

IL-17 is also a promising inhibitory target in psoriasis. This inflammatory cytokine is generally involved in inflammatory cascades and reconstructing the outer cellular barrier. IL-17 is rather unique since it has multiple significant families which share homology properties, such as almost similar molecular structures [79,80][60][61]. To date, the most explored IL-17 additional families are IL-17A, IL-7B, IL-17C, IL-17D, IL-17E and IL-17F [81,82,83,84][62][63][64][65]. A previous study has shown that some of these cytokines undergo a prominent, differed expression in skin-manifested diseases, including psoriasis. In psoriasis, with the presence of IL-6 and transforming growth factor-β, CD4+ T cells will undergo differentiation into Th17. This event will lead to the secretion of proinflammatory cytokines, including IL-17 [85][66]. In a general understanding pertaining to psoriasis, IL-17 leads to the elevated expression of proinflammatory factors as well as promoting NF-κB and mitogen-activated protein kinase (MAPK) pathways [86][67]. IL-17 is also the key mediator in neovascularization, endothelial irregularities and coagulation, which leads to thrombosis, as well as arterial hypertension. This is one of the reasons why psoriasis is often correlated with cardiac dysfunctionality [87,88][68][69].
Among these listed additional families, IL-17A stands out the most as playing the central role in autoimmune diseases, followed by IL-17C and IL-17F [89,90][70][71]. By referring and comparing them to IL-17A in terms of the proteomic degree of conservation, wit can be fiound that IL-17F has the most similarities at 55%, while IL-17E depicts the least similarities at 16% [91][72]. Nevertheless, in regard to autoimmunity and chronic inflammatory diseases, IL-17A, IL-17C and IL-17F act as the key mediators in manipulating the pathway cellular machinery [79,90,92,93][60][71][73][74].
In psoriasis, IL-17A directly enhances keratinocyte gene expression, such as that of cathelicidin (LL-37) antimicrobial peptides [94][75], via its target receptors, IL-17RA and IL-17RC [95][76]. During the early onset of psoriasis, LL-37 initiates the immune pathway, which eventually activates T cell-expressing IL-17A subsets, such as Th17 cells. These Th17 cells release several cytokines, including IL-17A and IL-17F, as the inflammatory biomarkers to quickly render keratinocyte hyperproliferative [96,97][77][78]. The released IL-17A further aggregates neutrophils and simultaneously inhibits the apoptosis mechanism of neutrophils and elicits neovascularization by assisting the angiogenesis pathway [98,99][79][80]. Since IL-17A has a rather stabilized mRNA, it can also work synergistically with TNF-α to exacerbate cytokine storming and the overexpression of keratinocytes [30,100][9][81]. The investigation of serum IL-17A in psoriasis patients revealed the increment of IL-17A, indicating a more highly lesioned microenvironment [101,102,103,104,105][82][83][84][85][86].
IL-17A is the pillar foundation of other additional IL-17 families as it is the main key effector cytokine in regard to IL-17. IL-17F shares half of its homologous form with IL-17A, although IL-17A is thought to be more potent than IL-17F [95,106][76][87]. The latest findings relating to IL-17F in psoriasis depict a quite ambiguous role, but show that it still may be the effector of IL-6 production, which is the pro-inflammatory cytokine entailing inflammation [107][88]. IL-17F-altered expression leads to intensified psoriatic skin inflammation, as proven in both preclinical and clinical findings [19,108,109,110][89][90][91][92].
On another note, IL-17C, which is a rather more newly discovered IL-17 family mostly affecting keratinocytes, is 23% homologous with IL-17A and can connect to its own [80,110][61][92]. Structurally, the composition of the IL-17C receptor includes IL-17RE, which has the highest level of specificity of those specialized to IL-17C [56][37]. In a preclinical investigation of psoriasis, IL-17C was found to be highly upregulated and was suspected to largely contribute to the formation of psoriatic dermatitis in mice [104][85]. Some clinical findings suggested that IL-17C intensifies the plaque formation on psoriatic skin biopsies, whereby IL-17C is overexpressed up to 125 times more than IL-17A [56,110,111,112][37][92][93][94]. Herein, the discussion is focused on IL-17A, IL-17C and IL-17F, since these families mediate autoimmunity the best, albeit in the presence of other additional families. In addition to IL-17A being the main driver in mediating inflammation, this cytokine is locally overproduced at the psoriatic lesioned area; hence, tackling it in order to neutralize or stop its overproduction is a great idea to ameliorate painful flaring patches [113][95]. This discovery opens up numerous discussions on the inhibition of IL-17 as one of the strategies for alleviating psoriasis inflammation with biologic drugs.
Secukinumab is a type of biologic drug, approved by the FDA in 2015, constructed from a recombinant human mAb of IgG1, and which can selectively bind to IL-17A and IL-17F [114][96]. This drug is suitable to treat moderate-to-severe plaque psoriasis, hypertrophic palmoplantar psoriasis, generalized pustular psoriasis and active psoriatic arthritis in adult patients [115][97]. When all conditions (no hypersensitivity contracted, pass the tuberculosis initial evaluation and not taking live vaccine injections) are met, secukinumab serves as the first-line biologic therapy when patients experience intolerability and are approaching the possibility of multi-organ failure after systemic therapy administration [116][98]. The mechanism of action of secukinumab in psoriasis focuses on targeting the IL-17A released from Th17 to block it from binding with IL-17R. Thus, antimicrobial peptides and the subsequently released cytokines, such as IL-17A and IL-17F, can also be reduced and blocked [117][99]. The successful blocking of IL-17A from proceeding with the signaling cascade leads to benefits, such as lowering keratinocyte hyperproliferation, preventing T cells infiltration and halting the overexpression of pathogenic genes [116][98]. The administration of secukinumab has shown success in some large randomized, double-blind and placebo-controlled trials. Patients receiving this biologic give positive clinical feedback, especially in relation to relieving palmoplantar and nail psoriasis, as well as plaque psoriasis. Despite potential drawbacks, such as headaches and upper respiratory tract infections, which are are inevitable, psoriatic patients are mostly well adapted to secukinumab administration [114][96].
Meanwhile, ixekizumab is another IL-17 inhibitory biologic drug. It is a humanized mAb IgG4 with a high affinity to specifically bind to IL-17A [118][100]. It has been approved by the FDA in 2016 for the treatment of moderate-to-severe plaque psoriasis in adults, and has recently been used as a treatment for psoriatic arthritis as well [119][101]. The mechanism of action of ixekizumab is similar to that of secukinumab, which involves targeting IL-17A in psoriasis pathogenesis. Some studies have suggested that ixekizumab is more efficient than etanercept in downregulating cytokine chaos in psoriasis after just two weeks of administration [94,120][75][102]. Indeed, the quality of life in psoriatic patients receiving ixekizumab has been reported to be positive after a good assessment on the Dermatology Life Quality Index (DLQI) simultaneously with an improved PASI score, including the clearing of lesions within one year of the study being conducted [121][103].
Another IL-17 inhibitor joining the mainstream biologic treatment strategy of psoriasis is brodalumab. Brodalumab is a recombinant, fully humanized mAb IgG2 that was approved by the FDA in 2017 for the treatment of psoriasis vulgaris and pustular psoriasis [122][104]. This biologic is an interesting one, since it is the first IL-17 inhibitor drug that blocks and neutralizes IL-17 receptors due to its high affinity instead of the IL-17 cytokine itself [123][105]. After administration, brodalumab binds to IL-17A and IL-17C receptors, IL-17RA and IL-17RC. This action concomitantly blocks IL-17 from binding, thus downregulating psoriatic inflammation, such as lesioned skin transcriptome, and neutralizes associated gene expression. Hence, chemokine and IL-23 production are halted to further reduce psoriatic inflammation [124,125][106][107]. Such an impactful mechanism of action in blocking IL-17 by blocking IL-17 inhibitors brings benefits to psoriasis patients, including reduced inflammation of lesions and direct improvement in cardiovascular diseases [121,126][103][108].

3.3. IL-23 Inhibitors

The IL-23 structure has two main subunits, which are p19 and p40, which are specific to IL-23 and IL-12/IL-23, respectively. IL-23 is primarily produced by DCs and macrophages, while its receptors are commonly expressed on T cells, NK cells, neutrophils, macrophages and mast cells. With the presence of TNF-α, IFN-γ and other transcription factors, IL-23 can further enhance its regulation via the TLR signaling pathway [127][109]. In terms of its mechanism of action, IL-23 firstly binds to its receptor to form an IL-23/IL-23R complex. This can initiate Th17, Th22, CD4+, CD8+ and γδ T cells to produce pro-inflammatory cytokines, such as IL-17 and IL-22, which play roles in inflammatory pathways and neovascularization [124,128][106][110]. If IL-17A is absent in the event, IL-23 will stimulate keratinocytes, making them become hyperproliferative. Other mechanisms of IL-23 include triggering the proliferation of macrophages to generate more TNF-α and amplifying IL-23R expression to form a self-amplifying loop [128,129][110][111]. These events, in which IL-23 is overexpressed, are devastating in immune-mediated diseases, such as psoriasis, especially since there is evidence of upregulated IL-23 in psoriatic lesions [128,130][110][112]. Therefore, IL-23 does play a significant role in the pathogenesis of psoriasis from the early onset to its sustenance mechanisms [122,131][104][113]. The advanced technology of using biologics in inhibiting IL-23 in psoriasis has succeeded, giving promising results [132][114].
Tildrakizumab is a fully human mAb of IgG1 kappa suitable for adults who have moderate-to-severe psoriasis. It was approved by the FDA in 2018 and has a high affinity for selecting the p19 subunit of IL-23 [133][115]. Due to this characteristic, tildrakizumab will bind to this subunit, causing the later event of cytokine signaling to be prohibited. Hence, other downstream pro-inflammatory mediators will also be halted [134][116]. Tildrakizumab is more effective than TNF-α inhibitors, such as etanercept, as it is proven to achieve PASI 75 on the 12th week of administration [135][117].
Tildrakizumab’s mechanism of action is similar to other IL-23 inhibitors, such as guselkumab and risankizumab. Both biologics are a fully human mAb of IgG1, approved by the FDA for moderate-to-severe plaque psoriasis in adult patients [122,136][104][118]. These drugs are considered in mainstream biologics, since they are proven to lower the overexpressed IL-6, IL-17A, IL-17F and IL-22 as early as four weeks before the administration. This is concurrent with the reduced discomfort signs and symptoms of psoriasis as well [137][119].

3.4. IL-12/23 Inhibitors

IL-12 belongs to the heterodimeric cytokine IL-6 superfamily and has a structural β-chain subunit of p40 similar to IL-23; the only difference is in its α-chain, which commonly comprises a p35 instead [138][120]. Commonly, IL-12 is produced by DCs, macrophages, monocytes and B cells. In terms of biological activities, IL-12 and IL-23 primarily contribute to the expansion of Th1 and Th17 cells, respectively. In psoriasis, the common p40 subunit is the succeeding key that binds to its receptor to form its complex formation. Early investigations in both preclinical and clinical studies have shown that the p40 subunit of these pro-inflammatory cytokines is overexpressed [129,139][111][121]. This is necessary for the subsequent immunoregulation for recruiting pro-inflammatory Th1 and Th17 cells and triggering the release of their associated pro-stimulatory cytokines [140][122].
Most CD4+ T cells express IL-12 and its subunits, such as IL-12Rβ2 and IL-12p40, which further initiate the differentiation of T cells via Toll-like receptor signaling. This event will consequently overproduce IFN-γ [141][123]. Meanwhile, IL-23 can bind to IL-23R to initiate the secretion of multiple cytokines, such as IL-17, IL-22, IL-26, IFN-γ and TNF-α, as well as CCL20 [142][124]. Through the combination of the signal transducer and activator of transcription (STAT)3 and RAR-related orphan receptor gamma (RORγt) working together, IL-23 and IL-23R can transactivate to harmonize a positive feed-forward loop to reinforce IL-23R, IL-17 and IL-22 expressions. Eventually, the Th17 phenotype can achieve its stabilization, which is required for sustaining cytokine secretion, including IL-17 for keratinocyte hyperproliferation [142,143][124][125]. All these events are aggravated by the p40 subunit of both IL-12 and IL-23. Thus, p40 serves as the most favored target to inhibit the downregulation of the overall biological activities of IL-12 and IL-23, especially in psoriasis [140,142,143][122][124][125].
Ustekinumab is the only sole prime IL-12/23 inhibitor to date. It is a humanized mAb IgG1κ, and can bind to the p40 subunit of both IL-12 and IL-23 and disturb the downstream immunoregulation. It is suitable to administer to moderate-to-severe psoriasis patients due to its efficacy profiling [140,144][122][126]. The efficacy of ustekinumab in psoriasis can be seen by comparing mRNA expression alteration using microarray analysis. Concurrent with more than 75% PASI score amelioration, this IL-12/23p40 inhibitor caused a significant difference in approximately 5000 of the genes modulated. As a result, TNF-α is suppressed due to the successful blocking of IL-12/23, which provides subsequent IL-17-associated gene downregulation. In comparison with etanercept, ustekinumab excels in suppressing multivariate psoriasis-associated genes and cytokines such as IL-1, IL-22, IFN-γ and IL-17. Although it is unfortunate to learn that ustekinumab does not have enough data to support long-term usage, this dual-functioning inhibitor is proven to enhance the quality of life in psoriatic patients [145,146,147][127][128][129]. The cytokine inhibitors used in psoriasis treatment are summarized in Table 1, and the simplified mode of action of all inhibitors are illustrated in Figure 3.
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Figure 3. Cytokine inhibitors and their respective blocking interests based on the postulated psoriasis pathogenesis. The overexpressed cytokines released by respective cells can be blocked, and this can downregulate the further inflammatory pathway.
Table 1.
 Summary of cytokine inhibitors used in psoriasis treatment.
Cytokine Targets Biologic Drug Name (Brand) Year of FDA Approval for Psoriasis Treatment Molecular Structure Mode of Action Possible Side Effects References
TNF-α Infliximab (Remicade®) 2006 Human-mouse chimeric combination of mAb IgG1 Inhibit circulating and transmembrane-bound TNF-α Upper respiratory tract infection, hepatotoxicity, tuberculosis risk, worsening psoriasis [63,65,66][44][46][47]
Etanercept (Enbrel®) 2004 Extracellular region of TNFR2 fusion with humanized mAb IgG1 Inhibit soluble and non-membrane-bound circulatory TNF-α from binding to TNFR2 receptor Upper and lower respiratory tract infections, rhinitis, pharyngitis, tuberculosis risk [60,61][41][42]
Adalimumab (Humira®) 2008 Humanized mAb IgG1 Inhibit circulating and transmembrane-bound TNF-α Upper respiratory tract infection, sinusitis, urinary tract infection [64,69][45][50]
Golimumab (Simponi®) Not applicable * Humanized mAb IgG1κ Inhibit circulating and transmembrane-bound TNF-α Recurring psoriasis flare [72][53]
Certolizumab pegol (Cimzia®) Not applicable * Humanized Fab subunit to mAb fusion, with Fc-free PEGylation and no Fc region Inhibit circulating and transmembrane-bound TNF-α Urinary tract infections, gastroenteritis, nasopharyngitis, headache, pruritus, tuberculosis risk [75][56]
IL-17 Secukinumab (Cosentyx®) 2015 Humanized mAb IgG1 Inhibit IL-17A and IL-17F Nasopharyngitis, diarrhea, mucocutaneous candidiasis, upper respiratory tract infection, neutropenia [114,117][96][99]
Ixekizumab (Taltz®) 2016 Humanized mAb IgG4 Inhibit IL-17A Candidiasis, irritable bowel syndrome, neutropenia [118][100]
Brodalumab (Siliq®) 2017 Humanized mAb IgG2 Block IL-17A and IL-17C receptors Arthralgia, headaches, fatigue [122,124,125][104][106][107]
IL-23 Tildrakizumab (Ilumya®) 2018 Humanized mAb IgG1κ Inhibit IL-23 alpha subunit; p19 subunit Inflammatory bowel syndrome, acute myocardial infarction [122,136][104][118]
Guselkumab (Tremfya®) 2017 Humanized mAb IgG1λ Inhibit IL-23 alpha subunit; p19 subunit Upper respiratory tract, nasopharyngitis, headaches, infection [122,136][104][118]
Risankizumab (Skyrizi®) 2019 Humanized mAb IgG1 Inhibit IL-23A Nasopharyngitis, upper respiratory tract infection, headache, arthralgia, back

pain, diarrhea		 [122,136][104][118]
IL-12/23 Ustekinumab (Stelara®) 2009 Humanized mAb IgG1 Simultaneously inhibit p40 subunit of IL-12 and IL-23 Tuberculosis risk [140,145][122][127]
* FDA approved for psoriasis arthritis only.

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