Psoriatic Arthritis

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis and characterized by stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments and tendons (dactylitis and enthesitis).57 Studies have confirmed that increased levels of proinflammatory mediators are found in psoriatic lesions and the synovium of patients with PsA.40, 41 The proinflammatory mediators, whose possible involvement in PsA is being investigated, are released by a variety of cell types, including innate immune cells, adaptive immune cells, and resident nonimmune cells.58

In psoriatic arthritis, abnormal levels of multiple proinflammatory and anti-inflammatory mediators have been observed in:

  • B cells64
  • Chondrocytes65
  • Synovial cells44

Intracellular cAMP is degraded by the enzyme PDE4, which leads to the increased production of proinflammatory mediators and decreased production of anti-inflammatory mediators.3, 4, 5, 6 Once an immune cell has been activated, it releases proinflammatory mediators that can then activate other immune cells and promote cell proliferation, thus recruiting more immune cells to the site of disease.31 In psoriatic disease, this process does not resolve; instead, it disrupts immune homeostasis, thus creating a chronic cycle of inflammation.54

PDE4 plays an important role in the regulation of the pro- and anti-inflammatory mediators that are involved in psoriatic arthritis. Dysregulation of the production of pro- and anti-inflammatory mediators in joint-resident cells in the synovium could account for the characteristic swelling and tenderness of PsA.44

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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.

B cells (or B lymphocyte)

One of the 2 major types of lymphocytes. B cells express but do not release surface immunoglobulins. B cells are the precursors of plasma cells, which are active in the formation and secretion of antibodies.

Intracellular

Within a cell or 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

Psoriatic Arthritis

A form of polyarthritis (ie, affecting more than one joint) that occurs in patients with psoriasis; the arthritis resembles rheumatoid arthritis but is seronegative for rheumatoid factor and often involves the digits.

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References:

  1. 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.
  2. 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.
  3. 5 Essayan DM, Huang SK, Kagey‑Sobotka A, Lichtenstein LM. Effects of nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors on antigen‑induced cytokine gene expression in peripheral blood mononuclear cells. Am J Respir Cell Mol Biol. 1995;13:692‑702.
  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. 31 Johnson‑Huang LM, McNutt NS, Krueger JG, Lowes MA. Cytokine‑producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol. 2009;29:247‑256.
  6. 40 Boniface K, Guignouard E, Pedretti N, et al. A role for T cell‑derived interleukin 22 in psoriatic skin inflammation. Clin Exp Immunol. 2007;150:407‑415.
  7. 41 van Kuijk AW, Reinders‑Blankert P, Smeets TJ, Dijkmans BA, Tak PP. Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment. Ann Rheum Dis. 2006;65:1551‑1557.
  8. 44 Ritchlin C, Haas‑Smith SA, Hicks D, Cappuccio J, Osterland CK, Looney RJ. Patterns of cytokine production in psoriatic synovium. J Rheumatol. 1998;25:1544‑1552.
  9. 54 Mease PJ. Psoriatic arthritis ‑ update on pathophysiology, assessment, and management. Bull NYU Hosp Jt Dis. 2010;68:191‑198.
  10. 57 Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol. 2008;58:851‑864.
  11. 58 König A, Krenn V, Gillitzer R, et al. Inflammatory infiltrate and interleukin‑8 expression in the synovium of psoriatic arthritis‑‑an immunohistochemical and mRNA analysis. Rheumatol Int. 1997;17:159‑168.
  12. 64 Zarrabeitia MT, Farinas MC, Rodriguez‑Valverde V, Riancho JA, Llaca HF. T and B cell function in psoriasis and psoriatic arthropathy. Allergol Immunopathol (Madr ). 1989;17:155‑159.
  13. 65 Röhner E, Matziolis G, Perka C, et al. Inflammatory synovial fluid microenvironment drives primary human chondrocytes to actively take part in inflammatory joint diseases. Immunol Res. 2012;52(3):169-175.