Psoriasis

Psoriasis (PsO) Is a Chronic Inflammatory Disease of the Skin

Inflammation is a tightly regulated, naturally occurring part of the body's protective response to injury or infection, intended to prevent damage to surrounding tissue. In response to inflammation, several mechanisms work to regulate this immune response. Thus, these regulatory mechanisms help to establish immune homeostasis.9

The most common form of psoriasis, plaque psoriasis, manifests as well-demarcated, raised, scaly, erythematous skin lesions.86 These lesions can appear anywhere on the body but are most commonly found on the scalp, elbows, nails, lower back, and knees.86, 87

Psoriasis plaque formation is thought to be caused by dysregulated immune activity within the skin.86, 88 This dysregulation can lead to an imbalance and overproduction of proinflammatory cytokines such as TNF-α, IL-17, and IL-23 from immune cells.68, 88 These cytokines promote chronic inflammation of the epidermis and induce keratinocyte hyperproliferation.87, 88, 89, 90, 91, 92 These changes result in redness, itching, epidermal thickening and scaly plaques.68, 84

What Is the Role of PDE4 in Psoriasis?

Current pre-clinical research supports the hypothesis that in patients with psoriasis, a dysregulated immune system is governed by the overproduction of proinflammatory cytokines, including TNF-α, IL-17, IL-23, and others.68, 88 PDE4 is an intracellular enzyme, located within immune cells, which plays an important role in modulating the overproduction of these proinflammatory cytokines.1, 3, 4 PDE4 is the predominant intracellular cAMP-degrading enzyme within a variety of inflammatory cells, including eosinophils, neutrophils, macrophages, T cells, and monocytes.1 PDE4 degrades cAMP into its inactive form AMP, thus allowing these immune cells to produce elevated levels of proinflammatory cytokines and decreased levels of anti-inflammatory cytokines.1, 3, 4, 6 Overproduction of proinflammatory cytokines is thought to drive the hyperproliferation and altered differentiation of keratinocytes. These changes can produce epidermal thickening and result in raised, red, scaly, and sometimes itchy psoriatic lesions (plaque psoriasis).68, 84

Associated Comorbidities

Associated Comorbidities

Psoriasis is associated with a number of serious comorbidities.

Take a closer look at comorbidities »

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Glossary:

Cyclic adenosine monophosphate (cAMP)

An activator of phosphorylase kinase and an effector of other enzymes, formed in muscle from ATP by adenylate cyclase and broken down to 5'‑AMP by a phosphodiesterase; the first known second messenger, it is a regulator of metabolism. A related compound (2',3') is also known.

Adenosine monophosphate (AMP), or adenylic acid

A condensation product of adenosine and phosphoric acid; a nucleotide found among the hydrolysis products of all nucleic acids. 3'‑Adenylic acid (adenosine 3'‑monophosphate) and 5'‑adenylic acid [adenosine 5'‑monophosphate (AMP)] differ in the place of attachment of the phosphoric acid to the D‑ribose; deoxyadenylic acid differs in having H instead of OH at the 2' position of D‑ribose.

Inflammation (or inflammatory response)

The general term for histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in affected blood vessels and adjacent tissue in response to injury or abnormal stimulation. The so‑called cardinal signs of rubor (redness), calor (heat), tumor (swelling), and dolor (pain) may or may not be present.

Inflammatory

Pertaining to, characterized by, causing, resulting from, or becoming affected by inflammation.

Interleukin (IL)

Any of a group of multifunctional cytokines synthesized by lymphocytes, monocytes, macrophages, and lymphoid and nonlymphoid cells.

Phosphodiesterase 4 (PDE4)

A key enzyme involved in the cytokine production of inflammatory cells. PDE4 is an intracellular enzyme that promotes inflammation by degrading intracellular levels of cyclic adenosine monophosphate (cAMP), a naturally occurring second messenger that helps maintain immune homeostasis by modulating the production of pro‑ and anti‑inflammatory mediators.

Psoriasis

A common dermatologic condition characterized by the eruption of circumscribed, discrete and confluent, reddish, silvery‑scaled maculopapules; the lesions occur predominantly on the elbows, knees, scalp, and trunk, and microscopically show characteristic parakeratosis and elongation of rete ridges with shortening of epidermal keratinocyte transit time due to decreased cyclic guanosine monophosphate

Tumor necrosis factor (TNF)

Any of several cytokines that function as cell‑associated or secreted proteins interacting with receptors of the tumor necrosis factor receptor (TNFR) family.

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References:

  1. 1 Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6:17‑26.
  2. 3 Souness JE, Griffin M, Maslen C, et al. Evidence that cyclic AMP phosphodiesterase inhibitors suppress TNF alpha generation from human monocytes by interacting with a 'low‑affinity' phosphodiesterase 4 conformer. Br J Pharmacol. 1996;118:649‑658.
  3. 4 Ma R, Yang BY, Wu CY. A selective phosphodiesterase 4 (PDE4) inhibitor Zl‑n‑91 suppresses IL‑17 production by human memory Th17 cells. Int Immunopharmacol. 2008;8:1408‑1417.
  4. 6 Oger S, Mehats C, Dallot E, Cabrol D, Leroy MJ. Evidence for a role of phosphodiesterase 4 in lipopolysaccharide‑stimulated prostaglandin E2 production and matrix metalloproteinase‑9 activity in human amniochorionic membranes. J Immunol. 2005;174:8082‑8089.
  5. 9 Van Parijs L, Abbas AK. Homeostasis and self‑tolerance in the immune system: turning lymphocytes off. Science. 1998;280:243‑248.
  6. 68 Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361:496‑509.
  7. 84 Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65(1):137-174
  8. 86 Mason AR, Mason J, Cork M, Dooley G, Hancock H. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2013;3:CD005028.
  9. 87 National Psoriasis Foundation. An Overview of Psoriasis and Psoriatic Arthritis. Portland, OR: National Psoriasis Foundation; 2009.
  10. 88 Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007;445(7130):866-873.
  11. 89 Schön MP, Boehncke WH. Psoriasis. N Engl J Med. 2005;352(18):1899-1912.
  12. 90 Perera GK, Di Meglio P, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385-422.
  13. 91 Balato A, Balato N, Megna M, Schiatarella M, Lembo S, Ayala F. Pathogenesis of psoriasis: the role of pro-inflammatory cytokines produced by keratinocytes. In: Soung J, Koo B, eds. Psoriasis. Rijeka, Croatia: InTech Europe; 2012.
  14. 92 Dogan S, Atakan N. Psoriasis: a disease of systemic inflammation with comorbidities. In: Lima H, ed. Psoriasis—Types, Causes and Medication. Rijeka, Croatia: InTech Europe; 2013.