Current and potential immune therapies and vaccines in the management of psoriasis

Abstract

Psoriasis is a chronic, immune skin disease associated with significant morbidity. Development of psoriasis is influenced by numerous genes, one allele is HLA-CW*0602. Other genes and single nucleotide polymorphisms affect immunologic pathways and antimicrobial peptide synthesis. Dendritic cells initiate psoriasis by activating T-cells toward a Th1 and Th17 response, with increased cytokines including TNF-α, IL-6, -12, -17, -22, and -23. IL-22 appears to promote keratinocyte dedifferentiation and increased antimicrobial peptide synthesis while TNF-α and IL-17 induce leukocyte localization within the psoriatic plaque. These recent insights identifying key cytokine pathways have led to the development of inhibitors with significant efficacy in the treatment of psoriasis. While a strategy for vaccine modulation of the immune response in psoriasis is in progress, with new technology they may provide a cost-effective long-term treatment that may induce tolerance or targeted self-inhibition for patients with autoimmune disorders, such as psoriasis.

Keywords: :

• IL-17
• IL-22
• IL-23
• TNF-α
• biologic therapies
• cytokine inhibitors
• immunotherapy
• interleukins
• psoriasis
• vaccines

Impact of Psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by thick, erythematous, scaly, plaques with preferential involvement of extensor extremities, which in some patients can be generalized to affect greater than 90% of the skin. Because psoriasis affects patients appearance, social stigmatization and sexual dysfunction are impacted,¹ and unfortunately, such patients have increased rates of depression and suicide.^2,3 There is a substantial psychologic burden from psoriasis, and patients commonly note flares associated with stress.⁴ The inflammation extends beyond the skin and joints and it is now accepted that the risk of cardiovascular disease is increased.⁵ Psoriasis is a highly prevalent condition with around 2–3% of the US and UK populace affected.^6,7 In addition, psoriatic arthritis may affect around 11% of patients with psoriasis.⁸

Patients with severe psoriasis may find employment prospects more challenging and patients with more severe disease have been found to have less income compared with patients with mild disease.⁹ Economic total and out-of-pocket costs, and time lost from work due to psoriasis symptoms also increase based on severity.¹⁰ The incremental cost associated with the diagnosis of psoriasis, not including out-of-pocket expenses or loss of productivity, was estimated to be $1500 per patient in the United States.¹¹ The estimated cost to the entire US health system is estimated at over $1.3 billion.¹² The impact of psoriasis is substantial with skin, psychosocial, arthritic, and cardiovascular implications.

Genetic Basis of Psoriasis

In the recent years, major strides have been made in elucidating the genetic basis of psoriasis, with 36 genes linked to the development of psoriasis.¹³ The exact inheritance is complex and clinical phenotype depends on variables from the environment, genetics, and adaptive and innate immunity.¹⁴ Results from twin studies show a concordance rate for monozygotic twins between 35–70% and there is a 2-fold increased risk of psoriasis in monozygotic twins compared with dizygotic twins.^15,16 Other family analyses demonstrated a 10-fold increased risk ratio for developing the disease in first-degree relatives of patients with juvenile-onset psoriasis.¹⁷ The strong association of HLA type, observed over 40 y ago, suggested 2 different psoriasis patterns: type I with more severe disease, family history, and expression of HLA-CW*0602; and type II with less severe disease and less genetic predisposistion.^17,18 The extended haplotype of this HLA association showed a 26-fold increased risk of developing early onset psoriasis.¹⁹ However, tight linkage disequilibrium made it uncertain whether the most strongly associated risk factor was HLA-CW*0602 or a colocalized gene.²⁰ This region was therefore called PSORS1 until more accurate sequence specific locus could be identified. Studies continued to be conducted implicating the primary association with psoriasis to the HLA-CW*0602 locus on chromosome 6p21 with a 16-fold increased risk of developing the disease compared with the general population.²¹ However, it was not until 2006 that the problem of linkage disequilibrium was elucidated and researchers confirmed that this HLA type was indeed the primary gene associated with the PSORS1 locus predisposing to psoriasis.^22,23

As psoriasis is a clinically heterogeneous disease with several distinct subtypes- chronic plaque type, pustular, inverse, guttate, and palmoplantar, each may have a different genetic predispositions. While the genetic region of the guttate form has been found to be associated with the PSORS1 region, the palmoplantar form of psoriasis has been shown to be distinct.²⁴

With the advent of the ability to rapidly sequence the genome, numerous new genes and single nucleotide polymorphisms associated with psoriasis have been discovered.^13,25,26 Most of these genes encode proteins such as those involved in skin barrier function, antimicrobial peptides (AMP), and immunologic signaling pathways including IL-23, TNF-α, NFκB, and interferons (IFN).^26-28 One susceptibility gene, endoplasmic reticulum aminopeptidase 1 (ERAP1), encodes a peptidase that cleaves proteins that are then displayed on MHC class I proteins, and is only associated with psoriasis if the HLA-Cw6 risk allele is present.²⁹ These GWAS studies have also identified another gene that is located within the PSORS1 region that is independently associated with psoriasis, and encodes for an integrated human endogeneous retrovirus K (HERV-K) dUTPase.^30,31 Although little is known about the regulation and pattern of expression of this retrovirus gene in psoriasis, similar to many other susceptibility genes, it does appear to have immunogenic properties.^31,32

Vast strides have been made in the field of the genetics of psoriasis and GWAS has allowed for identification of additional new genes linked to the susceptibility of psoriasis.¹³ These genes appear to function primarily within immunologic pathways, skin barrier function, and AMPs.¹³

Role of Dendritic Cells

The rapid production of thick adherent scales from keratinocytes in psoriasis suggested that the pathogenesis of psoriasis was fundamentally initiated by hyperproliferation of keratinocytes, but studies using a mouse xenotransplanation model demonstrated that human peripheral blood cells were necessary for recreating psoriasis histopathology in transplanted normal skin from a psoriasis patient, indicating the primary driver of psoriasis to have an immune basis.³³ This concept has been supported by the transfer of psoriasis from human donors to previously psoriasis-free recipients in the process of blood and marrow transplantation.³⁴

Dendritic cells (DC) are professional antigen presenting cells that play an important role in immune regulation and function to connect innate and adaptive immunity. Several types of dendritic cells have been identified based on surface markers, including Langerhans cells in the epidermis, plasmacytoid dendritic cells, and dermal DC, with both a resident and inflammatory phenotype. These subsets have been reviewed in relation to psoriasis by Zaba et al.³⁵ The plasmacytoid and dermal DC are believed to be integral in the immunopathogenesis of psoriasis. Plasmacytoid DC, normally part of the host anti-viral response, can produce a large amount of interferon-α (IFN-α) to initiate the immune cascade, followed by differentiation to myeloid DC, and stimulate naïve T cells into Th1 and Th17 polarized effector T cells (Fig. 1).^36,37 Evidence suggests plasmacytoid DC are initially recruited to the psoriatic skin by fibroblast, endothelial cell, and mast cell-released chemerin that is expressed in the perilesional psoriasis skin.³⁸ Chemerin functions as an AMP.³⁹ Plasmacytoid DC are then triggered to produce IFN-α by self-DNA/RNA from damaged keratinocytes coupled with the AMP, LL37, which activates Toll-like receptor (TLR)7/Toll-like receptor(TLR)9.^37,40,41 The inflammatory cytokines released by plasmacytoid DC can then activate or induce monocyte differentiation to dermal myeloid DC that are important in the chronic phase of the disease.^36,42 Heat shock proteins(HSP) may also play a role based on increased expression in patients with guttate psoriasis.⁴³ HSP60 has been shown to induce TNF-α, IL-12, IL-15, and IL-23 from macrophage cell lines and dendritic cells.^44,45 These proteins and others may interact with DC through TLRs. Inflammatory DC of chronic psoriasis skin show differential TLR activation such as TLR1, and 2, in addition to upregulation of TNF-α signaling, and inducible nitric oxide synthetase (iNOS) pathways.^46,47

Figure 1. Development of psoriasis plaque. An initial insult activates TLR-pathways in plasmocytoid DC. Dermal DC differentiate and are activated and secrete cytokines IL-12, TNF-α, TGF-β, and IL-6 that stimulate naïve T-cell to mobilize transcription factors that induces genes to polarize T cells into Th1 and Th17 subtypes, with suppression of Tregs. The corresponding cytokines, IL-17A, IL-17F, and IL-22 from Th17 T cells stimulate keratinocyte proliferation and result in the skin microenvironment with leukocyte infiltration, keratinocyte dedifferentiation, and increased AMP to form the clinical phenotype of a scaly lesion of psoriasis.

TLRs function as pattern recognition receptors of the innate immune system, are present on dendritic cells, and likely are the initial receptor that becomes activated in psoriasis, leading to activation of plasmacytoid DC through TLR7 and 9 and expression of high levels of interferon.^37,40 Synthetic stimulation of TLR7, by imiquimod also produces high levels of interferon and can induce clinical progression of psoriasis.⁴⁸ TLR8 and self-complexed RNA may also be involved in DC stimulation.⁴¹ Dendritic cells have also been shown to be activated via TLR2, by the HERV-K dUTPase that is associated with genetic susceptibility to psoriasis.^32,46

After the initial appearance, established psoriasis plaques have an increased population of DC with the potential to activate T-cells and polarize cytokine expression characteristic of psoriasis, TNF-α, and IL-17.^36,49 DC also play a role in the initial activation and proliferation of the Th17 helper cells and potentially γ/δ T-cells that express IL-17.⁵⁰ Dendritic cells appear to be the link between AMPs, skin damage, and the initiation of the cytokine cascade that activates T-cells resulting in the Th1 and Th17 response of psoriasis.

Cytokine Expression and T-Cells in Psoriasis

Psoriasis is a chronic autoimmune disease associated with the activation of an inappropriate cytokine cascade in the skin that propagates inflammation. In psoriasis, the plasmacytoid DC normally critical in anti-viral responses appear to initiate the imbalance with high levels of IFN-α production before differentiating into tissue resident or dermal DC.^37,42 IL-20, IL-23, iNOS, and other inflammatory products are produced by these dermal DC, of which IL-23 correlates well with the development of the psoriatic plaque.^51-53 TNF-α, which is also critical in the development of the psoriasis phenotype, is secreted from resident dermal DC and activates the resident T-cells.^54,55

Early studies into T-cell function in the immune response revealed 2 major phenotypic subsets based on cytokine expression: Th1 cytokine expression including IL-2, IFN-γ, IL-12, and TNF-α regulated by the transcription factor T-bet; and Th2 cytokine expression including IL-4, IL-5, IL-10, and IL13 regulated by the transcription factor GATA3.^56,57 This paradigm provided the conceptual framework for understanding the immune response, Th1 regulating cell mediated immunity and Th2 regulating humoral immunity. With the clinical efficacy of therapeutic agents such as cyclosporine in psoriasis, a pivotal role of T-cells in the psoriasis pathogenesis was demonstrated.^58,59 Furthermore, from analysis of the cytokine pattern detected in psoriasis with an increase in TNF-α, and IFN-γ, this was initially classified as a strongly Th1 dependent disease.

With continued research into T-cell function, the Th1/Th2 model was revised to include the role of additional T-cell subsets that have distinct functional properties to more accurately account for the murine disease model Experimental Autoimmune Encephalitis (EAE), used in studying Th1 mediated neurologic disease. In studies to explore the specific role of Th1 cytokines, it was observed that knockout of IL-12 receptor subunit, IL-12R-β2, worsened EAE rather than prevented the disease as was expected for a Th1 dominant disease.⁶⁰ On the other hand, the absence of the IL-12p40 subunit led to resistance in EAE and suggested the role of T cells regulated by IL-23 in EAE.⁶¹ Thus this observation supported the role of additional signaling pathways in T cell regulation and led to the discovery of the role of IL-17 in immune regulation and the identification of the Th17 cell subset, that is mediated by the transcription factor RORγt or ROR-C and gene RORC.^62,63 Since the identification of this additional T cell subset, it has now been shown that Th17 cells are critical in the pathogenesis of psoriasis.^54,64,65

In the presence of polarizing cytokines, CD4+ T-cell subsets, are stimulated to differentiate into effector subsets that play a role in psoriasis, such as Th1, Th17, Th22, and regulatory T-cells (Tregs).^49,66-68 Beyond the Th1/Th2 dichotomy of T-cell subsets, the previous beliefs of a stable phenotype regulated by specific transcription factors that orchestrate terminal differentiation in T-cell development has also been subjected to reanalysis. There is evidence from recent results to suggest that there is plasticity in the polarity of T-cell phenotypes, and that under certain conditions, cytokines have the ability to modulate gene expression of T-cell subset specific transcription factors and stimulate expression of genes of other T-cell subsets.^69,70

With regard to the key pathogenic cells important in psoriasis, emerging evidence has helped to highlight the role of different T cell subsets in human psoriasis. Th1 T-cells have been implicated in the pathogenesis with the ability to secrete TNF-α, but are not sufficient alone. Th17 cells, which were initially described in 2005,^71,72 are characterized by IL-17A and IL-17F cytokine production and normally stimulate neutrophils in the immune response to several microorganisms.^71,73 The cytokine subtypes IL17A, C, and F have been shown to be strikingly elevated in lesional psoriasis skin.⁷⁴ Upstream cytokines that allow Th17 differentiation include TGF-β, IL-6, and IL-21.^75,76 TGF-β upregulates the gene expression of ROR-C, a nuclear hormone transcription factor that is a marker of human Th17 cells. Activation of STAT3, a transcription factor activated by IL-6 receptor ligation is also important in differentiation of the Th17 phenotype. IL-23 is also increased in psoriatic plaques and promotes the expansion and survival of Th17 cells.^52,77,78

IL-17A and IL-17F directly affect gene regulation in keratinocytes involved in the innate immune response.^79-82 These cytokines also stimulate the expression of CCL20 which binds to CCR6 present on Th17 cells to promote leukocyte infiltration of the affected tissue,^72,83,84 Combined with TNF-α, it produces a synergistic inflammatory effect on the keratinocytes.⁸⁵ IL-22, expressed by both Th17 and Th22 cells, promotes abnormal differentiation of keratinocytes, AMP response, and hyperproliferation of the keratinocytes.^86-89

Regulatory T cells (Tregs) are a subset of T cells that act as brakes to downregulate the immune responses and these cells also have a role in psoriasis. These cells can be further subdivided into natural and induced Tregs. The former are derived directly from the thymus, while the latter arise as a response to inflammatory process or diseases. The cells were characterized initially by surface marker CD4+CD25+, but the identification of the transcription factor Foxp3 lead to a more specific marker to follow the Treg population.^90,91 Mice having mutations in Foxp3 typically demonstrate the scurfy phenotype, characterized by lymphoproliferation and robust inflammatory process involving the skin. In humans with Foxp3 mutations, a condition known as immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) manifests at an early age and is characterized by numerous autoimmune diseases.^92,93 The intracellular nature of Foxp3 has led to a search for specific surface markers to facilitate the study of Tregs, and markers such as high expression of CD25 (IL2Rα) and LRRC32 (GARP) as well as the low expression or absence of CD127 (IL-Rα) have all been proposed as markers to improve identification of potent Tregs.^94-96

The function of Tregs is important in immunoregulation and loss of activity or cell number can lead to a dysregulated inflammatory response. Indeed, decreased Tregs have been demonstrated in autoimmune diseases such as diabetes,⁹⁵ and dysfunction has been described in psoriasis, autoimmune hepatitis, Crohn disease, diabetes, and autoimmune thyroid disease.^97-101 Until recently, it was unclear as to how exactly Treg dysfunction contributed to psoriasis, beyond being less capable of inhibiting the growth of potentially autoimmune T cells. Studies by Sugiyama et al. demonstrated that psoriatic Tregs could not suppress the growth of lymphocytes in a mixed lymphocyte assay as well as a comparable number or Tregs derived from normal individuals.⁹⁸ However recent studies have now linked dysfunctional Tregs directly to the production of IL-17 via their differentiation into Th17 cells.¹⁰² In addition, elevated IL-6 produced by dermal DC and endothelial cells in psoriatic lesions has been shown in a murine model to reverse Treg suppressive activity resulting in loss of inhibition of cellular differentiation to the IL-17 pathway.¹⁰³

Highlighting the altered role of Tregs in autoimmune disease, in rheumatoid arthritis (RA), which is associated with decreased Treg function and increased TNF-α, treatment with anti-TNF therapy can restore Treg function.^104,105

It was recently shown that elevated IL-6 produced by CD11c+ dermal dendritic cells and CD31+ endothelial cells in psoriatic lesions in a murine model can reduce Treg suppressive activity via STAT3 phosphorylation in Tregs and also effector T (Teff) cells, resulting in bias toward Th17 differentiation.¹⁰³ This failed to show a direct link between Tregs and Th17 cell development in patients with psoriasis. Under certain situations, Tregs may actually change into IL-17 producing Tregs.¹⁰² Increased numbers of these IL-17 producing Tregs were seen in psoriatic lesions, thereby giving credence to the idea that such cells can become Th17 cells.¹⁰² In addition, increases in the level of the transcription factor RORC, induced by inflammatory cytokines such as IL-1β, IL-23, IL-2, and Il-15, in psoriatic Tregs, along with stimulation and costimulation via the TCR and CD28, resulted in a decrease in Foxp3 and a corresponding decrease in Treg activity.^102,106 IL-17 production was inversely correlated with this finding.^102,106

There is now marked evidence for a direct linkage between dysfunctional Tregs and the development of pathogenic Th17 cells in psoriasis.¹⁰⁶ Further studies into precisely how these IL-17 producing Tregs differentiate into the pathogenic Th17 cells will likely aid our understanding of how to better regulate the immune system in patients with psoriasis.

Viral Role in Psoriasis

Human endogenous retroviruses (HERVs) are a family of retroviruses incorporated previously into the human genome during the course of evolution. The retroviral sequences constitute 8% of human DNA.¹⁰⁷ These endogenous retroviruses integrated throughout the human DNA and can be detected at sites of long-terminal repeats (LTRs). Over millions of years, mutations have accumulated in these genes, but transcription is still maintained in up to 1/3 ofknown sequences and encode products that have been inactivated functionally by point and frame shift mutations.¹⁰⁸ Human endogenous retrovirus K (HERV-K) is the youngest of the family of endogenous retroviruses and the only one with open reading frames for all genes to encode the major proteins. Like other ERVs, it is named for the tRNA specificity of the primer binding site to initiate reverse transcription, hence HERV-K family uses lysine.¹⁰⁹

Virus transcription has been specifically detected among HERV-W, K, and E families in psoriatic skin while it is rarely detected in atopic dermatitis and normal skin samples.¹¹⁰ HERV-E glycoprotein envelope has been visualized via immunohistochemistry in both psoriatic and atopic skin, although only rarely in normal skin.¹¹¹ mRNA encoding for a putative deoxyuridine triphosphate nucleotidohydrolase (dUTPase) encoded by HERV-K has been demonstrated in peripheral blood mononuclear cells and skin in psoriasis patients.³⁰ This HERV-K dUTPase gene, although closely linked and just telomeric to the HLA-C allele, is independently associated with psoriasis.³¹ There is a significant humoral response to the HERV-K dUTPase in patients with psoriasis when compared with controls³¹ and the HERV-K dUTPase product induces a pro-inflammatory Th1and Th17 cytokine environment through interactions with TLR2 on dendritic cells and a lesser extent keratinocytes in vitro.³² Multiple questions concerning the possible role(s) of these viruses in psoriasis persists but the genetic association in conjunction with the relevant cytokine response remain intriguing for the HERV-K encoded dUTPase. Additional research is needed concerning the prevalence, expression, and role in psoriasis of this dUTPase. Eventually this product may become a target in the management of psoriasis.

Targeted Pathways in the Treatment of Psoriasis

Advances in understanding the molecular and cellular pathways in psoriasis have led to the development of highly targeted therapies for the treatment of psoriasis. There are currently 5 available TNF-α inhibitors, of which 3 (etanercept, infliximab, and adalimumab) are FDA approved in the treatment of psoriasis.¹¹² All 3 bind to either membrane bound and/or soluble TNF-α. Etanercept is a recombinant human TNF-α receptor protein (p75) fused with the Fc portion of immunoglobulin IgG1. Infliximab is a chimeric antibody generated with human and murine sequences in the hypervariable region recognizing TNF-α. Adalimumab is a fully human monoclonal antibody(mAb). Certolizumab pegol, which is pegylated for increased half-life, and golimumab are human TNF-α MAbs with FDA approval for the treatment of psoriatic arthritis, but also have clinical efficacy in cutaneous psoriasis.^113,114 All of the biologic monoclonal antibodies inhibit the inflammatory cascade by binding and preventing TNF-α from activating TNF receptors. Downstream effects from this inhibition include decreased IL-1, -8, -23, and iNOS, with a decrease in dermal DC resulting in blockage of the signaling for downstream Th17 induced infiltration and Th22 induced acanthosis.^53,85,115 While the class as a whole is highly effective, (Table 1), there are some differences with infliximab having the most efficacy based on clinical response as measured by the psoriasis activity severity index (PASI). PASI is a validated scoring system for psoriasis that incorporates morphologic features of psoriasis lesions such as the thickness, degree of redness and severity of scaliness in addition to extent of involvement.¹¹⁶ The PASI scale ranges from 1 to 72. Moderate to severe psoriasis have a PASI score that is typically greater than 12. However, infliximab has the highest rate of discontinuation due to serious events, particularly infusion reactions.¹¹⁷

Table 1. Summary of FDA approved and selected late stage development treatments for psoriasis

Drug	Target	Type	FDA Approval for psoriasis	PASI-75% Week 12	Serious adverse events	Psoriatic arthritis	Phase 2/3 trial feference
Etanercept	TNF-Α	Fusion Protein	2004	34–49* High doses	CHF DIL DMS IN TBR	FDA Approved	152
Infliximab	TNF-Α	Chimeric	2006	75* Week 10	CHF DIL DMS IN IR TBR	FDA Approved	153
Adalimumab	TNF-Α	Fully human	2008	71* Week 16	CHF DIL DMS IN TBR	FDA Approved	154
Ustekinumab	p40 of IL12, 23	Fully human	2009	66–67	IN ?MI ?RPLS ?TBR	FDA Approved	155
Secukinumab	IL-17A	Fully Human		57–82* High Doses Only	IN LFT NP		128
Ixekizumab	IL-17A	Humanized		76–82* High Doses Only	IN LFT NP		127
Brodalumab	IL-17A Receptor	Fully Human		67–82* High Doses Only	IN NP		126
Fexakizumab	IL-22	Humanized		Unpublished	Unpublished
Tofacitinib	JAK3	Small molecule		66* High Dose Only	AN HLD		131

Currently available biologic therapies and late stage development of treatments for psoriasis. mAb, monoclonal antibody; Adverse Events: AN, anemia, CHF, congestive heart failure exacerbation, DIL, drug induced lupus, DMS, demyelinating syndrome; IN, infection; IR, infusion reaction; HLD, hyperlipidemia, TBR, tuberculosis reactivation; MI, myocardial infarction; RPLS, reversible posterior leukencephalopathy syndrome; LFT, liver function test elevation; NP, neutropenia. *Indicates deviation of study if primary end point was not at 12 wk or if multiple doses were used the higher dosing regimens are reported.

Ustekinumab, a MAb against the shared protein subunit of IL-12 and IL-23 receptor known as p40, blocks IL-12-driven differentiation of naïve T cells to a Th1 phenotype and IL-23-driven survival signal to the Th17 phenotype.^118,119 Targeting IL-12 and IL-23 is an upstream method of blocking Th17 activity, and results in significant clinical improvement.¹²⁰ A similar antibody molecule, briakinumab is not currently being pursued for FDA approval after an increased number of cardiovascular events was seen in trials.¹²¹ However, it is unclear whether this represents more than sampling error. Overall, it does not appear to be a class risk against the IL-12/23 pathway based on the analysis of the 3 y safety data of ustekinumab having a similar risk of cardiovascular events compared with expected frequencies, no skewing toward a Th2 response (asthma exacerbation), and no increased salmonella infections.^122-124 Another option in IL-23 inhibition is targeting the opposing subunit of the molecule, the p19 subunit. Two such MAbs, CNTO1959 and SCH 900222, are currently undergoing clinical trials.¹²⁵

Targeting the Th-17 pathway from at a step that is further downstream, IL-17 directed biologics are the most recent agents and are currently in late-phase clinical development. IL17 is produced by Th17 cells which are activated by a cytokine mileu that includes IL-23.⁷⁸ There are several MAbs that target the IL-17 pathway in clinical studies. Brodalumab is an anti-IL-17 receptor MAb, and secukinumab and ixekizumab are MAbs to IL-17A.^125-127 Preliminary reports show these drugs have extensive efficacy, and appear to have better efficacy than the TNF-antagonists currently available in the treatment of psoriasis.^65,126-128 However, phase 3 studies and long-term safety studies will be needed to ensure long-term efficacy and safety of this class of medications.

Janus-associated kinase (JAK) –and Signal Transducer and Activator of Transcription (STAT) proteins are involved in signal transduction from various cytokines involved in psoriasis, including IL6, IL-12, and IL-23.^125,129,130 Inhibiting the activation of JAK/STATs may alter signals needed in the differentiation of Th-17 T cells. Therefore targeting this intracellular signal transduction pathway offers the advantage of a small molecule that can be given as an oral therapy as oppose to subcutaneous injections. There are 4 subtypes of JAK/STAT molecules that contribute to different pathways. that can be inhibited. JAK3 is specific to immune cells, and targeting this kinase may theoretically have a better therapeutic index. Preliminary trials of both topical and systemic JAK inhibitors have been promising, especially an oral JAK1/3 inhibitor called tofacitinib.^129,131,132 Several clinical trials are ongoing with regards to small molecule inhibitors of JAKs and the resultant cytokine signaling.¹²⁵ The STAT pathway may also be a future target but it does not possess enzymatic activity and is not as easily targeted. However, STAT3 inhibitors have been developed and may eventually be translated to studies for the treatment of psoriasis.^133,134

Another small molecule therapy that is in advanced trials for psoriasis is apremilast. This molecule targets phosphodiesterase-4 that is the primary phosphodiesterase in leukocytes. Blockage of this enzyme decreases cAMP in these cells and prevents activation including cytokine production of IL-12, -23, and TNF-α.¹³⁵ Apremilast has completed phase III studies and has shown efficacy for therapy of both psoriasis and psoriatic arthritis.^136-138

Finally, fezakinumab (ILV-094), a MAb directed against IL-22, which is upregulated in response to IL-17, is currently undergoing clinical trials.¹²⁵ The inhibition of IL-22 would be suspected to block the final step of stimulation of the keratinocytes causing hyperproliferation and increased antimicrobial peptide synthesis.⁸⁷ Additional small molecules and biologics that are in early stages of development have recently been reviewed.¹³⁹

Potential for Vaccine and Immunotherapy in Psoriasis

Several groups have published on potential and early phase clinical studies on the use of vaccines in psoriasis, first using Mycobacterium vaccae after observation of improvement in psoriasis during treatment of leprosy. In a preliminary study, a formulation of heat-killed, deglycolipidated, delipidated M. vaccae underwent rigid trials and an IND application was filed with the FDA for further testing. With intradermal injections, 3 wk apart, 65% of patients developed marked improvement in the PASI score at 12 wk after injection, although no placebo evaluation was performed.¹⁴⁰ An early comparison randomized patients to heat-killed M. vaccae vs. tetanus toxoid showed a decreased in PASI from baseline in intradermal injections although the placebo group decreased similarly.¹⁴¹ The results of this trial was compromised by high levels of drop-out, responder bias, and comparison to baseline rather than the placebo tetanus toxoid.¹⁴¹ The most rigidly conducted phase 2 study comparison testing of the same M. vaccae formulation ended disappointingly after subjecting patients to a high dose, low dose, and placebo immunotherapy injection 3 wk apart and did not demonstrate a PASI-75 improvement different between groups, with the highest response of 18% seen in the placebo group.¹⁴² The same vaccine did not show a benefit in psoriatic arthritis.¹⁴³ Two recent studies, one placebo controlled, have evaluated the use of Mycobacterium w, another non-pathogenic, rapid growing mycobacterial strain in psoriasis and these studies suggested potential benefit with some improvement, but unfortunately the studies lacked rigorous methodology and intergroup comparisons.^144,145

Another group has published on the use of a live attenuated varicella zoster virus strain for treatment of psoriasis, again after empiric improvement in a patient with severe psoriasis after infection with the live virus. This study was not double blind but did show improvement in comparison with a saline placebo while patients were on cyclosporine.¹⁴⁶

A third potential microbial based vaccination strategy developed in the third world was empirically developed based on improvement in psoriasis patients vaccinated for leishmania. A study of 2770 participants demonstrated up to 68% of patients treated with a leishmania AS100 vaccine achieved a PASI-75 response.¹⁴⁷ However, this study suffered from non-rigorous planning, inclusion, lack of clarity in reporting concommitant medications, baseline, and completion data between study groups. A secondary analysis of these patients found miraculous improvement using a non-validated arthritis scoring system by tender joint counts with this vaccine.¹⁴⁸ Both of these studies present an extensive quantity of data in a large number of patients, but serious methodologic flaws, lack of clarity of data, inclusion criteria, lack of placebo control, and lack of prospective nature make the results suspect.

The mechanism for the efficacy of the mycobacterium vaccae is unclear. However, a possible reason is that patients with psoriasis have an associated reduced T cell responsiveness to mycobacterium antigens.¹⁴⁹ Furthermore, dendritic cells and macrophages have been shown to be increased in the skin of patients with psoriasis underoing M. vaccae therapy, with an increased production of IL-10.¹⁴³ Since IL-10 is an immunosuppressing cytokine, stimulating immunity to mycobacterium with increased IL-10 may alter the immune balance to favor psoriasis clearance.¹⁵⁰

Lastly, a non-microbial based vaccination strategy has been performed in targeting soluble receptors such as TNF-α by conjugating human cytokines to an immunogenic virus like particle.¹⁵¹ However, this is in very early stages of development. This approach, while potentially long-lasting, will require careful experimental design and titration to reduce excessive TNF-α responsible for clinical disease. It also must be monitored to ensure that that immune suppression does not result in insufficient TNF-α needed for intact immune functions against mycobacterium and other bacterial infections.

Overall, vaccines studies that have been conducted have suffered from serious methodologic flaws and have been primarily pursued in third world countries. The most rigorous studies have not shown any benefit in psoriasis.^142,143 The most promising development may be immunization against human soluble receptors that are involved in psoriatic diathesis such as TNF-α, IL-12, -17, -22, and -23, however, this technology is far from ready for human use. The selection of cytokines to target may be based on the clinical experience with MAbs to these cytokine pathways. Ideally, cytokines that are highly specific for psoriasis, validated from clinical experience with MAbs against these cytokines would serve as early targets for vaccine development.

Summary

Psoriasis is a prevalent, chronic, and potentially incapacitating disease. Remarkable strides have been made in uncovering the immune pathways dysregulated in psoriasis, such as a Th1 and Th17 pathways. These discoveries have allowed for the development of highly targeted treatments with unparalleled efficacy. However, numerous challenges remain including how to maintain response in long-term treatment with biologic agents, how to ensure cost-effective treatments to all patients, and ensuring the long-term safety of these treatments. While vaccines are far from clinical use, they may eventually provide a “cure” to psoriasis by introducing tolerance or targeted self-inhibition to the immune system of the psoriasis patient with resolution of the maladaptive Th17 response.

AMP	=	anti-microbial peptide
DC	=	dendritic cell
ERV	=	endogeneous retrovirus
GWAS	=	genome wide association study
HLA	=	human leukocyte antigen
HERV-K	=	human endogeneous retrovirus K
HSP	=	heat shock protein
IFN	=	interferon
IL	=	interleukin
iNOS	=	inducible nitric oxide synthetase
JAK	=	Janus kinase
LTR	=	long terminal repeat
Mab	=	monoclonal antibody
PASI	=	psoriasis area and severity index
STAT	=	signal transducer and activator of transcription
Teff	=	T-effector cell
Th1	=	T-helper 1 cell
Th17	=	T-helper 17 cell
Th22	=	T-helper 22 cell
TLR	=	toll-like receptor
TNF-α	=	tumor necrosis factor α
Treg	=	regulatory T-cell

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Financial Disclosure

H.K.W. honoraria from Amgen. In addition, he is an investigator for Amgen, Janssen, Abbvie, and Celgene. All other authors report no conflicts of interest.

Funding

National Psoriasis Foundation grants to M.E.A., B.H.K., and H.K.W.

Acknowledgments

The authors would like to acknowledge the support of the National Psoriasis Foundation Grants to M.E.A., B.H.K., and H.K.W.

10.4161/hv.27532