Psoriasis pathogenesis and the development of novel targeted immune therapies

doi:10.1016/j.jaci.2017.07.004

Journal of Allergy and Clinical Immunology

Volume 140, Issue 3, September 2017, Pages 645-653

https://doi.org/10.1016/j.jaci.2017.07.004 Get rights and content

Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.

Section snippets

Psoriasis as a T cell–mediated autoimmune condition

The requirement of the immune response for the development of psoriasis was suggested by early observations that characteristic skin lesions contained increased numbers of inflammatory cellular infiltrates.9, 10 Additionally, patients with psoriasis undergoing bone marrow transplantations¹¹ or treatment with immunosuppressive agents, such as cyclosporine12, 13 and methotrexate,¹⁴ experienced dramatic improvements in their inflammatory skin lesions. Subsequent experiments found that the

The pivotal role of IL-17 in updated disease models of psoriasis

For many years, psoriasis was primarily characterized as a T_H1-driven disease based on increased production of IFN-γ by CD4⁺ T cells found in psoriatic tissues compared with low production of cytokines that define the T_H2 T-cell subset (ie, IL-4, IL-5, and IL-13). However, with the characterization of a novel T_H17 cell subset discovered in the experimental autoimmune encephalomyelitis mouse model commonly used to study multiple sclerosis,⁴² the field of dermatology research experienced a major

TNF antagonists

TNF is a potent proinflammatory cytokine made by a variety of immune cells found in the skin, including T cells, keratinocytes, DCs, and macrophages. Its upregulation in the skin of patients with psoriasis has been well characterized.59, 60 The clinical efficacy of multiple TNF antagonists (eg, adalimumab, etanercept, and infliximab) underscore the importance of this cytokine in the promotion and maintenance of psoriatic skin lesions, although the percentage of patients experiencing dramatic

Recently approved and novel therapeutic agents for psoriasis

The discovery of the T17 cell population and elucidation of the broad effects of the IL-23/T17 cell signaling axis on keratinocytes and infiltrating immune cells in the skin has largely shaped the current disease model of psoriasis. Therefore psoriatic disease is best understood as a patterned response to chronic activation of the IL-23/T17 cell pathway. For this reason, current therapeutic strategies are now focused on the development of novel agents that disrupt IL-23 or IL-17 cytokine

Conclusions and future directions

The success of the IL-17 and IL-23 antagonists for the treatment of psoriatic disease has resulted in a modification of the primary clinical outcome being used in clinical trials. The treatment target has been moving to increased clearing of disease, such that PASI90 and PASI100 responses are now considered better targets than the PASI75 response. Still, the mere existence of patients with psoriasis whose symptoms do not improve with IL-17 or IL-23 blockade highlights the complexity of this

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Cang-ai volatile oil ameliorates imiquimod-induced psoriatic skin lesions by suppressing the ILC3s
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The effect of CAVO on the expression of IL-6 and IL-1β was assessed in TNF-α-induced HaCaT cells using enzyme-linked immunosorbent assay (ELISA). Mice were given imiquimod (IMQ) and administered orally with different CAVO doses (0.03 and 0.06 g/kg) for 5 days. The levels of inflammatory cytokines related to group-3 innate lymphoid cells (ILC3s) in the skin were assessed using hematoxylin and eosin (H&E) staining, ELISA, and western blotting (WB). The frequency of ILC3s in mice splenocytes and skin cells was evaluated using flow cytometry.
The results demonstrated that CAVO decreased the expression of IL-6 and IL-1β in TNF-α- induced HaCaT cells. CAVO significantly reduced the severity of psoriatic symptoms in IMQ-induced mice. The expression of inflammatory cytokines in the skin, such as IL-1β, IL-6, IL-8, IL-22, IL-23, and IL-17 A were decreased, whereas IL-10 levels were increased. The mRNA expressions of TNF-α, IL-23 A, IL-23 R, IL-22, IL-17 A, and RORγt were down-regulated in skin tissues. CAVO also decreased the levels of NF-κB, STAT3, and JAK2 proteins.
CAVO potentially inhibits ILC3s activation to relieve IMQ-induced psoriasis in mice. These effects might be attributed to inhibiting the activation of NF-κB, STAT3, and JAK2 signaling pathways.
Novel anti-psoriasis agent-associated cardiotoxicity, analysis of the FDA adverse event reporting system (FAERS)
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Psoriasis is a chronic skin condition characterized by hyperproliferation of epidermal keratinocytes, resulting in erythematous and scaling lesions. The US Food and Drug Administration (FDA) has approved nine biologic agents to address the burden of psoriasis, but their cardiovascular risks remain poorly studied.
This retrospective pharmacovigilance study utilized the FDA Adverse Event Reporting System (FAERS) database to analyze adverse events associated with newly approved therapeutic agents for psoriasis. We employed disproportionally signal analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval.
Among the vast FAERS database, which contained >25 million adverse events, a total of 334,399 events were associated with newly approved therapeutic agents for psoriasis. Cardiac adverse events accounted for 3852 cases, including pericarditis, atrial fibrillation, and coronary artery disease. Secukinumab had the highest number of reported adverse events, followed by brodalumab, while tildrakizumab had the lowest. Coronary artery disease was the most reported adverse event (1438 cases), followed by pericarditis (572 cases) and atrial fibrillation (384 cases). Secukinumab had the highest incidence of coronary artery disease, pericarditis, and atrial fibrillation. Risankizumab was significantly associated with an increased risk of coronary artery disease and atrial fibrillation, while tildrakizumab and Ixekizumab were associated with atrial fibrillation. Secukinumab was associated with an elevated risk of pericarditis.
The study uncovers the cardiovascular adverse effects related to biologic agents used in psoriasis treatment. These findings emphasize the importance of monitoring and evaluating the cardiovascular safety profiles of biological agents used in psoriasis treatment.
Small-molecule agents for treating skin diseases
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Skin diseases are a class of common and frequently occurring diseases that significantly impact daily lives. Currently, the limited effective therapeutic drugs are far from meeting the clinical needs; most drugs typically only provide symptomatic relief rather than a cure. Developing small-molecule drugs with improved efficacy holds paramount importance for treating skin diseases. This review aimed to systematically introduce the pathogenesis of common skin diseases in daily life, list related drugs applied in the clinic, and summarize the clinical research status of candidate drugs and the latest research progress of candidate compounds in the drug discovery stage. Also, it statistically analyzed the number of publications and global attention trends for the involved skin diseases. This review might provide practical information for researchers engaged in dermatological drugs and further increase research attention to this disease area.
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Psychological stress is a crucial factor in the development of many skin diseases, and the stigma caused by skin disorders may further increase the psychological burden, forming a vicious cycle of psychological stress leading to skin diseases. Therefore, understanding the relationship between stress and skin diseases is necessary. The skin, as the vital interface with the external environment, possesses its own complex immune system, and the neuroendocrine system plays a central role in the stress response of the body. Stress-induced alterations in the immune system can also disrupt the delicate balance of immune cells and inflammatory mediators in the skin, leading to immune dysregulation and increased susceptibility to various skin diseases. Stress can also affect the skin barrier function, impair wound healing, and promote the release of pro-inflammatory cytokines, thereby exacerbating existing skin diseases such as psoriasis, atopic dermatitis, acne, and urticaria. In the present review, we explored the intricate relationship between stress and skin diseases from a neuroendocrine-immune interaction perspective. We explored the occurrence and development of skin diseases in the context of stress, the stress models for skin diseases, the impact of stress on skin function and diseases, and relevant epidemiological studies and clinical trials. Understanding the relationship between stress and skin diseases from a neuroendocrine-immune interaction perspective provides a comprehensive framework for targeted interventions and new insights into the diagnosis and treatment of skin diseases.
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: J.E.H. is supported in part by Rockefeller University CTSA award grant no. KL2TR001865 from the National Center for Advancing Translational Sciences (NCATS)/National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. J.E.H. and J.G.K. are supported in part by grant no. UL1TR001866 from the NCATS/NIH CTSA program.

: Disclosure of potential conflict of interest: J. G. Krueger has received personal fees from Novartis, Pfizer, Lilly, Boehringer, BiogenIdec, Janssen, AbbVie, Escalier, Acros, Roche, Valeant, Allergan, and Aurigene and has received grants paid to his institution from Novartis, Pfizer, Amgen, Boehringer, Innovaderm, BMS, EMD Serono, AbbVie, Paraxel, Leo Pharma, Vitae, Kineta, Regeneron, and Novan. The rest of the authors declare that they have no relevant conflicts of interest.

: Terms in boldface and italics are defined in the glossary on page 646.

^∗: These authors contributed equally to this work.

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Reviews and feature articlePsoriasis pathogenesis and the development of novel targeted immune therapies

Section snippets

Psoriasis as a T cell–mediated autoimmune condition

The pivotal role of IL-17 in updated disease models of psoriasis

TNF antagonists

Recently approved and novel therapeutic agents for psoriasis

Conclusions and future directions

J Am Acad Dermatol

Rheum Dis Clin North Am

J Am Acad Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

J Biol Chem

Matrix Biol

J Biol Chem

J Neurol Sci

Dermatol Clin

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Invest Dermatol

J Am Acad Dermatol

J Am Acad Dermatol

Lancet

Lancet

J Allergy Clin Immunol

J Allergy Clin Immunol

J Am Acad Dermatol

J Am Acad Dermatol

J Allergy Clin Immunol

Psoriasis

N Engl J Med

Economic burden of psoriasis in the United States: a systematic review

JAMA Dermatol

The risk of mortality in patients with psoriasis: results from a population-based study

Arch Dermatol

Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin

Arch Dermatol Res

Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies

Arch Dermatol Res

Clearance of severe psoriasis after allogenic bone marrow transplantation

BMJ

Cyclosporine improves psoriasis in a double-blind study

JAMA

Clearance of psoriasis with low dose cyclosporin

Br Med J (Clin Res Ed)

Systemic corticosteroids and folic acid antagonists in the treatment of generalized pustular psoriasis. Evaluation and prognosis based on the study of 104 cases

Br J Dermatol

CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes

Proc Natl Acad Sci U S A

Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis

Nat Med

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

J Clin Invest

Development and use of alefacept to treat psoriasis

J Am Acad Dermatol

A novel targeted T-cell modulator, efalizumab, for plaque psoriasis

N Engl J Med

Natural history of psoriasis in 61 twin pairs

Arch Dermatol

Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution

Acta Derm Venereol

Psoriasis and HLA-Cw6

Br J Dermatol

Reviews and feature article
Psoriasis pathogenesis and the development of novel targeted immune therapies