Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Psoriasis: emerging therapeutic strategies

Key Points

  • Psoriasis is a common immune disorder whose major manifestation is in the skin. It most frequently begins in young adults, and is a lifelong condition.

  • The most common form of psoriasis — psoriasis vulgaris or plaque-type psoriasis — is characterized by the presence of red, raised scaly plaques that can cover any body surface.

  • Patients with limited disease can respond well to topical treatments, but established therapies for more severe disease, such as systemic immunosuppressive drugs and phototherapy, have several drawbacks, including inconvenience and/or toxicity, which means that treatments are used intermittently.

  • So, patients experience cycles of clearance with normal quality of life that alternate with active disease and poor quality of life. There is therefore a need for therapies that result in safe and effective long-term maintenance of disease clearance for patients with moderate-to-severe psoriasis.

  • Advances in the understanding of psoriasis in recent years have highlighted the importance of aberrant activation of and migration of T cells into the skin in the pathogenesis of the disease.

  • Several agents that target the molecules involved, such as tumour-necrosis factor-α, have been recently approved for the treatment of psoriasis, or are in clinical trials. Such agents have also proved valuable in understanding disease pathogenesis.

  • This article first reviews current knowledge on the pathogenesis of psoriasis, and then discusses clinical results with immunobiological agents that have been approved or that are in development. Finally, novel potential targets for the development of drugs to treat psoriasis are highlighted.

Abstract

Psoriasis is a chronic inflammatory skin disorder that is characterized by thickened, scaly plaques, and is estimated to affect 1–3% of the Caucasian population. Traditional treatments, although effective in patients with limited disease, have numerous shortcomings, including inconvenience and toxicity. These drawbacks mean that many patients experience cycles of disease clearance, in which normal quality of life alternates with active disease and poor quality of life. However, as this review discusses, recent advances have highlighted the key role of the immune system in the pathogenesis of psoriasis, and have provided new defined targets for therapeutic intervention, offering hope for safe and effective psoriasis treatment.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Immunopathogenesis of psoriasis: a selected view.
Figure 2: Known sites of action of psoriasis therapies.

Similar content being viewed by others

References

  1. Gottlieb, A. B. Novel immunotherapies for psoriasis: clinical research delivers new hope for patients and scientific advances. J. Invest. Dermatol. Symp. Proc. 9, 79–83 (2004).

    CAS  Google Scholar 

  2. Gottlieb, A. B. Psoriasis. Dis. Manag. Clin. Outcomes 1, 195–202 (1998).

    Google Scholar 

  3. Heydendael, V. M. R. et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N. Engl. J. Med. 349, 658–65 (2003).

    CAS  PubMed  Google Scholar 

  4. Rapp, S. R., Feldman, S. R., Exum, M. L., Fleischer, A. B. & Reboussin, D. M. Psoriasis causes as much disability as other major medical diseases. J. Am. Acad. Dermatol. 41, 401–407 (1999). This article documents the significant impact of psoriasis on mental and physical well-being.

    CAS  PubMed  Google Scholar 

  5. Krueger, G. et al. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation Patient-Membership Survey. Arch. Dermatol. 137, 280–284 (1998). This article emphasizes the role of quality of life in the assessment of disease severity and response to treatment.

    Google Scholar 

  6. de Korte, J., Sprangers, M. A. G., Mombers, F. M. C. & Bos, J. D. Quality of life in patients with psoriasis: a systemic literature review. J. Invest. Dermatol. Symp. Proc. 9, 140–147 (2004).

    Google Scholar 

  7. Brockbank, J. & Gladman, D. Diagnosis and management of psoriatic arthritis. Drugs 62, 2447–2457 (2002).

    CAS  PubMed  Google Scholar 

  8. Gottlieb, A. B. Psoriatic arthritis: a guide for dermatology nurses. Dermatol. Nursing 15, 107–118 (2003).

    Google Scholar 

  9. Farber, E. M., Nall, M. L. & Watson, W. Natural history of psoriasis in 61 twin pairs. Arch. Dermatol. 109, 207–211 (1974).

    CAS  PubMed  Google Scholar 

  10. Zhou, X. et al. Novel mechanisms of T-cell and dendritic cell activation revealed by profiling of psoriasis on the 63,100-element oligonucleotide array. Physiol. Genomics 13, 69–78 (2003). This article uses molecular genetic techniques to study the pathogenesis of psoriasis.

    CAS  PubMed  Google Scholar 

  11. Helms, C. et al. A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with increased susceptibility to psoriasis. Nature Genet. 35, 349–356 (2003).

    CAS  PubMed  Google Scholar 

  12. Ellis, C. N. et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N. Engl. J. Med. 324, 277–284 (1991). This is one of the most-cited multicentre trials demonstrating the efficacy of cyclosporine for treating psoriasis.

    CAS  PubMed  Google Scholar 

  13. Bos, J. D. The pathomechanisms of psoriasis: the skin immune system and cyclosporin. Br. J. Dermatol. 118, 141–155 (1988).

    CAS  PubMed  Google Scholar 

  14. Gottlieb, A. B. et al. Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J. Invest. Dermatol. 98, 302–309 (1992).

    CAS  PubMed  Google Scholar 

  15. Baker, B. S., Swain, A. F., Fry, L. & Valdimarsson, H. Epidermal T lymphocytes and HLA-DR expression in psoriasis. Br. J. Dermatol. 110, 555–564 (1984).

    CAS  PubMed  Google Scholar 

  16. Gottlieb, A. B. et al. Expression of HLA-DR molecules by keratinocytes and presence of Langerhans cells in the dermal infiltrate of active psoriatic plaques. J. Exp. Med. 164, 1013–1028 (1986). This article demonstrated increased numbers of activated T cells in psoriatic plaques.

    CAS  PubMed  Google Scholar 

  17. Gottlieb, A. B. & Krueger, J. G. in Psoriasis (ed. Dubertret, L.) 63–71 (ISED, Brescie, Italy, 1994).

    Google Scholar 

  18. Gottlieb, A. B. Immunopathology and immunomodulation. Med. Dermatol. 19, 649–657 (2001).

    CAS  Google Scholar 

  19. Gottlieb, A. B. Recombinantly engineered human proteins: transforming the treatment of psoriasis. Clin. Immunol. 105, 105–116 (2002).

    CAS  PubMed  Google Scholar 

  20. Wrone-Smith, T. & Nickoloff, B. J. Dermal injection of immunocytes induces psoriasis. J. Clin. lnvest. 98, 1878–1887 (1996). This paper describes one SCID mouse model of psoriasis.

    CAS  Google Scholar 

  21. Gilhar, A., David, M., Ullmann, Y., Berkutski, T. & Kalish, R. S. T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice. J. Invest. Dermatol. 109, 283–288 (1997). This paper describes one SCID mouse model of psoriasis.

    CAS  PubMed  Google Scholar 

  22. Gottlieb, S. L. et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nature Med. 1, 442–447 (1995). This paper demonstrated that T cells were primary pathogenic factors in the maintenance of psoriatic plaques and opened the field of biologicals in psoriasis treatment.

    CAS  PubMed  Google Scholar 

  23. Gottlieb, A. B., Bacha, P., Parker, K. & Strand, V. Use of the interleukin-2 fusion protein, DAB389IL-2, for the treatment of psoriasis. Dermatol. Ther. 5, 48–63 (1998).

    Google Scholar 

  24. Gottlieb, A. B. et al. Anti-CD4 monoclonal antibody treatment of moderate to severe psoriasis vulgaris: results of a pilot, multicenter, multiple dose, placebo-controlled study. J. Am. Acad. Dermatol. 43, 595–604 (2000).

    CAS  PubMed  Google Scholar 

  25. Gottlieb, A. B. et al. A multiple dose randomized double-blind pacebo-controlled study to determine the efficacy and safety of a humanized anti-CD4 monoclonal antibody in the treatment of moderate to severe chronic psoriasis vulgaris. J. Invest. Dermatol. 110, 678 (1998).

    Google Scholar 

  26. Khandke, L. et al. Cycloporine in psoriasis treatment: inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor-α/epidermal growth factor receptor pathways. Arch. Dermatol. 127, 1172–1179 (1991).

    CAS  PubMed  Google Scholar 

  27. Bachelez, H. et al. Treatment of recalcitrant plaque psoriasis with a humanized non-depleting antibody to CD4. J. Autoimmun. 11, 53–62 (1998).

    CAS  PubMed  Google Scholar 

  28. Austin, L. M., Coven, T. R., Bhardwaj, N., Steinman, R. & Krueger, J. G. Intraepidermal lymphocytes in psoriatic lesions are GMP-17 (TIA-1)+CD8+CD3+ CTLs as determined by phenotypic analysis. J. Cut. Pathol. 25, 79–88 (1998).

    CAS  Google Scholar 

  29. Weinshenker, B. G., Bass, B. H., Ebers, G. C. & Rice, G. P. A. Remission of psoriatic lesions with uromonab-CD3 (Orthoclone OKT3) treatment. J. Am. Acad. Dermatol. 20, 1132–1133 (1989).

    CAS  PubMed  Google Scholar 

  30. Krueger, J. The immunologic basis for the treatment of psoriasis with new biologic agents. J. Am. Acad. Dermatol. 46, 1–23 (2002).

    PubMed  Google Scholar 

  31. Weinstein, G. D. Methotrexate: diagnosis and treatment drugs five years later. Ann. Intern. Med. 86, 199–204 (1977).

    CAS  PubMed  Google Scholar 

  32. Bos, J. D., VanJoost, T., Powles, A. V., Meinardi, M. M. H. M. & Fry, L. Use of cyclosporin in psoriasis. Lancet 2, 1500–1502 (1989).

    CAS  PubMed  Google Scholar 

  33. Ellis, C. N. et al. Cyclosporine improves psoriasis in a double-blind study. JAMA 256, 3110–3116 (1986). This is one of the earlier multicentre trials of cyclosporine for psoriasis.

    CAS  PubMed  Google Scholar 

  34. Boyman, O. et al. Spontaneous development of psoriasis in a new animal model shows an essential rolse for resident T cells and tumor necrosis factor α. J. Exp. Med. 199, 731–736 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Conrad, C. et al. Crucial role for intraepidermal T cells expressing the collagen-binding integrin α1β1 in psoriasis. J. Invest. Dermatol. 122, A14–079 (2004).

    Google Scholar 

  36. Springer, T. A. et al. The lymphocyte function-associated LFA-1, CD2, and LFA-2 molecules: cell adhesion receptors of the immune system. Ann. Rev. Immunol. 5, 223–252 (1987).

    CAS  Google Scholar 

  37. Springer, T. A. Adhesions receptors of the immune system. Nature 346, 425–434 (1990).

    CAS  PubMed  Google Scholar 

  38. Biedermann, T., Rocken, M. & Carballido, J. M. TH1 and TH2 lymphocyte development and regulation of TH cell-mediated immune responses of the skin. J. Invest. Dermatol. Symp. Proc. 9, 5–14 (2004).

    CAS  Google Scholar 

  39. Ridge, J. P., DiRosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).

    CAS  PubMed  Google Scholar 

  40. Schoenberger, S. P., Toes, R. E. M., VanDerVoort, E. I. H., Offringa, R. & Melief, C. J. M. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998).

    CAS  PubMed  Google Scholar 

  41. Bennett, S. R. M. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–483 (1998).

    CAS  PubMed  Google Scholar 

  42. June, C. H., Ledbetter, J. A., Linsley, P. S. & Thompson, C. B. Role of the CD28 receptor in T-cell activation. Immunol. Today 11, 211–216 (1990).

    CAS  PubMed  Google Scholar 

  43. Abrams, J. R. et al. CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J. Clin. Invest. 103, 1243–1252 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Abrams, J. et al. Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J. Exp. Med. 192, 681–94 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Krueger, J. G. et al. Blockade of T-cell costimulation with CTLA4Ig (BMS-188667) reverses pathologic inflammation and keratinocyte activation in psoriatic plaques. J. Invest. Dermatol. 108, 555 (1997).

    Google Scholar 

  46. Lebwohl, M. et al. CTLA4Ig (BMS-188667)-mediated blockade of T cell costimulation in patients with psoriasis vulgaris. J. Invest. Dermatol. 108, 570 (1997).

    Google Scholar 

  47. Gottlieb, A. B. et al. Clinical and histologic response to single-dose treatment of moderate to severe psoriasis with an anti-CD80 monoclonal antibody. J. Am. Acad. Dermatol. 47, 692–700 (2002).

    PubMed  Google Scholar 

  48. Gottlieb, A. B. et al. Evaluation and safety and clinical activity of multiple doses of the anti-CD80 monoclonal antibody, galiximab, in patients with moderate to severe psoraisis. Clin. Immunol. 111, 28–37 (2004).

    CAS  PubMed  Google Scholar 

  49. Najarian, D. J. & Gottlieb, A. B. Connections between psoriasis and Crohn's disease. J. Am. Acad. Dermatol. 48, 805–821 (2003). This is a comprehensive review of the similarities between Crohn's disease and psoriasis.

    PubMed  Google Scholar 

  50. Chaudhari, U. et al. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357, 1842–1847 (2001). This is the first double-blind, placebo-controlled trial of TNF blockade monotherapy for psoriasis.

    CAS  PubMed  Google Scholar 

  51. Gottlieb, A. B. et al. Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor monoclonal antibody (Infliximab) treatment of moderate to severe psoriasis vulgaris. J. Am. Acad. Dermatol. 48, 68–75 (2003).

    PubMed  Google Scholar 

  52. Gottlieb, A. B. et al. Infliximab monotherapy provides rapid and sustained benefit for plaque-type psoriasis. J. Am. Acad. Dermatol. 48, 829–835 (2003).

    PubMed  Google Scholar 

  53. Leonardi, C., Gottlieb, A. & Zitnik, R. Efficacy and safety of ENBREL (etanercept) in patients with psoriasis: results of a phase III study. J. Invest. Dermatol. 121, 409 (2003).

    Google Scholar 

  54. Gottlieb, A. B. et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch. Dermatol. 139, 1627–1632 (2003). This is the Phase II study for etanercept monotherapy for psoriasis.

    CAS  PubMed  Google Scholar 

  55. Gottlieb, A. B. et al. Infliximab induction therapy in patients with severe plaque-type psoriasis: A randomized, double-blind, placbo-controlled trial. J. Am. Acad. Dermatol. (in the press)

  56. Nickoloff, B. J., Mitra, R. S., Elder, J. T., Fisher, G. J. & Voorhees, J. J. Decreased growth inhibition by recombinant γ-interferon is associated with increased transforming growth factor-α production in keratinocytes cultured from psoriatic lesions. Br. J. Dermatol. 121, 161–174 (1989).

    CAS  PubMed  Google Scholar 

  57. Grossman, R. M. et al. Interleukin-6 (IL-6) is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc. Natl Acad. Sci. USA 86, 6367–6371 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hancock, G. E., Kaplan, G. & Cohn, Z. A. Keratinocyte growth regulation by the products of immune cells. J. Exp. Med. 168, 1395–1402 (1988).

    CAS  PubMed  Google Scholar 

  59. Braunstein, S. et al. GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo. J. Invest. Dermatol. 103, 601–604 (1994).

    CAS  PubMed  Google Scholar 

  60. Rich, B. & Kupper, T. Cytokines: IL-20 — a new effector in skin inflammation. Curr. Biol. 11, R531–R534 (2001).

    CAS  PubMed  Google Scholar 

  61. Romer, J. et al. Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine a or calcipotriol. J. Invest. Dermatol. 121, 1306–1311 (2003).

    CAS  PubMed  Google Scholar 

  62. Heng, M., Kloss, S., Kuehn, C. & Chase, D. Significance and pathogenesis of basal keratinocyte herniations in psoriasis. J. Invest. Dermatol. 87, 362–366 (1986).

    CAS  PubMed  Google Scholar 

  63. Vaccaro, M. et al. The dermoepidermal junction in psoriatic skin as revealed by scanning electron microscopy. Arch. Dermatol. Res. 291, 396–369 (1999).

    CAS  PubMed  Google Scholar 

  64. Boehncke, W. -H., Wortmann, S., Kaufmann, R., Mielke, V. & Sterry, W. A subset of macrophages located along the basement membrane ('lining cells') is a characteristic histopathological feature of psoriasis. Am. J. Dermatopathol. 17, 139–144 (1995).

    CAS  PubMed  Google Scholar 

  65. Mansbridge, J. N. & Knapp, A. M. Changes in keratinocyte maturation during wound healing. J. Invest. Dermatol. 89, 253–263 (1987). This article describes the regenerative maturation phenotype.

    CAS  PubMed  Google Scholar 

  66. Smoller, B. A. et al. Recessive dystrophic epidermolysis bullosa skin displays a chronic growth-activated immunophenotype. Arch. Dermatol. 126, 78–83 (1990).

    CAS  PubMed  Google Scholar 

  67. Krueger, J. G., Gilleaudeau, P., Kikuchi, T. & Lee, E. Psoriasis-related subpopulations of memory CD4+ and CD8+ T cells are selectively reduced by Alefacept. J. Invest. Dermatol. 119, 345 (2002).

    Google Scholar 

  68. Wakita, H. & Takigawa, M. E-selectin and vascular cell adhesion molecule-1 are critical for initial trafficking of helper-inducer/memory T cells in psoriatic plaques. Arch. Dermatol 130, 457–463 (1994).

    CAS  PubMed  Google Scholar 

  69. daSilva, A. J. et al. Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2+ cells. J. Immunol. 168, 4462–4471 (2002).

    CAS  Google Scholar 

  70. Ellis, C. N., Krueger, G. G. & Group, A. C. S. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N. Engl. J. Med. 345, 248–255 (2001). This is the Phase II study of alefacept for psoriasis.

    CAS  PubMed  Google Scholar 

  71. Krueger, G. G. et al. Afefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy an dtolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J. Am. Acad. Dermatol. 47, 821–833 (2002).

    PubMed  Google Scholar 

  72. Lebwohl, M. et al. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch. Dermatol. 139, 719–727 (2003). This is the Phase III trial of intramuscular alefacept for psoriasis.

    CAS  PubMed  Google Scholar 

  73. Gottlieb, A. B. et al. CD4+ T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study. J. Am. Acad. Dermatol. 49, 816–825 (2003).

    PubMed  Google Scholar 

  74. Gottlieb, A. et al. Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis. J. Am. Acad. Dermatol. 42, 428–435 (2000). This is the first report of the efficacy of efalizumab in psoriasis.

    CAS  PubMed  Google Scholar 

  75. Kraan, M. C. et al. Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum. 46, 2776–2784 (2002). This is the first report of the efficacy of alefacept for psoriatic arthritis.

    CAS  PubMed  Google Scholar 

  76. Gottlieb, A. B. et al. Psoriasis as a model for T-cell-mediated disease: Immunobiologic and clinical effects of treatment with multiple doses of efalizumab, an anti-CD11a monoclonal antibody. Arch. Derm. 138, 591–600 (2002).

    CAS  PubMed  Google Scholar 

  77. Gottlieb, A. G. et al. Subcutaneously administered efalizumab (antiCD11a) improves signs and symptoms of moderate to severe plaque psoriasis. J. Cut. Med. Surg. 7, 198–207 (2003).

    Google Scholar 

  78. Lebwohl, M. et al. A Novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N. Engl J. Med. 349, 2004–2013 (2003). This is one of the Phase III trials of efalizumab for psoriasis.

    CAS  PubMed  Google Scholar 

  79. Papp, K., B., R. et al. The treatment of moderate to severe psoriasis with a new anti-CD11a monoclonal antibody. J. Am. Acad. Dermatol. 45, 665–674 (2001).

    CAS  PubMed  Google Scholar 

  80. Motensen, D. et al. The pharmacokinetics and pharmacodynamics of efalizumab following 12 weeks of subcutaneous treatment in subjects with moderate to severe plaque psoriasis in a phase I, open-label, multi–center study. J. Invest. Dermatol. 121, 379 (2003).

    Google Scholar 

  81. Chamian, F. et al. Presence of 'inflammatory' dendritic cells in psoriasis vulgaris lesions and modulation by efalizumab (anti-CD11a). J. Invest. Dermatol. 122, A41–A245 (2004).

    Google Scholar 

  82. Gordon, K. B. et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290, 3073–3080 (2004).

    Google Scholar 

  83. Gottlieb, A. B., Hamilton, T. K., Caro, I. & Gordon, K. B. Efficacy and safety outcomes of long-term efalizumab therapy in patients with moderate to severe plaque psoriasis: an update. J. Invest. Dermatol. 122, A57–A341 (2004).

    Google Scholar 

  84. Austin, L., Ozawa, M., Kikuchi, T. & Krueger, G. Intracellular TNF-α, IFN-γ, and IL-2 identify TC1 and TH1 effector populations in psoriasis vulgaris plaque lymphocytes: single–cell analysis by flow cytometry. J. Invest. Dermatol. 110, 649 (1998).

    Google Scholar 

  85. Ettehadi, P., Greaves, M. W., Wallach, D., Aderka, D. & Camp, R. D. R. Elevated tumour necrosis factor-α (TNF-α) biological activity in psoriatic skin lesions. Clin. Exp. Immunol. 96, 146–151 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ritchlin, C. T., Haas-Smith, S. A., Li, P., Hicks, D. G., Schwarz, E. M. Mechanisms of TNF-α- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J. Clin. Invest. 111, 821–831 (2003). This is a paper on the pathogenetic role of TNF in psoriatic arthritis.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Gottlieb, A. B. et al. Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-α monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris. J. Am. Acad. Dermatol. 48, 68–75 (2003).

    PubMed  Google Scholar 

  88. Nickoloff, B. J. The immunologic and genetic basis of psoriasis. Arch. Dermatol. 135, 1104–1110 (1999).

    CAS  PubMed  Google Scholar 

  89. Gottlieb, A. G. Clinical research helps elucidate the role of tumor necrosis factor-α in the pathogeesis of T1-mediated immune disorders: use of targeted immunotherapeutics as pathogenic probes. Lupus 12, 190–194 (2003).

    CAS  PubMed  Google Scholar 

  90. Weisfelner, M. E. & Gottlieb, A. B. The role of apoptosis in human epidermal keratinocytes. J. Drugs. Dermatol. 2, 385–391 (2003).

    PubMed  Google Scholar 

  91. Mease, P. J. et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356, 385–390 (2000). This is the first double-blind, placebo controlled report of TNF blockade in psoriatic arthritis.

    CAS  PubMed  Google Scholar 

  92. Konig, A. et al. Inflammatory infiltrate and interleukin-8 expression in the synovium of psoriatic arthritis — an immunohistochemical and mRNA analysis. Rheumatol. Int. 17, 159–168 (1997).

    CAS  PubMed  Google Scholar 

  93. Veale, D., Barnes, L., Rogers, S. & Fitz, G. O. Immunohistochemical markers for arthritis in psoriasis. Ann. Rheum. Dis. 53, 450–454 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Hohler, T. et al. A TNF-α promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis. J. Invest. Dermatol. 109, 562–565 (1997).

    CAS  PubMed  Google Scholar 

  95. VanDenBrande, J. M. H. et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's Disease. Gastroenterology 12, 1774–1785 (2003).

    Google Scholar 

  96. Scallon, B. et al. Binding and functional comjparisons of two types of tumor necrosis factor antagonists. J. Pharmacol. Exp. Ther. 301, 418–426 (2002).

    CAS  PubMed  Google Scholar 

  97. Scallon, B. J., Moore, M. A., Trinh, H., Knight, D. M. & Ghrayeb, J. Chimeric anti-TNF-α monoclonal anti-body cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine 7, 251–259 (1995).

    CAS  PubMed  Google Scholar 

  98. tenHove, T., vanMontfrans, C., Peppelenbosch, M. P. & vanDeventer, S. J. Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn's disease. Gut 50, 206–211 (2002).

    CAS  Google Scholar 

  99. Maini, R. et al. Infliximab (chimeric anti-tumour necrosis factor-α monoclonal antibody) versus placebo in theumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 354, 1932–1939 (1999). This is a Phase III trial of infliximab in rheumatoid arthritis.

    CAS  PubMed  Google Scholar 

  100. Targan, S. R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor-α for Crohn's disease. N. Engl. J. Med. 337, 1029–1035 (1997). This is a Phase III trial of infliximab in Crohn's disease.

    CAS  PubMed  Google Scholar 

  101. Present, D. H. et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N. Engl. J. Med. 340, 1398–1401 (1999).

    CAS  PubMed  Google Scholar 

  102. VanOosten, B. W. et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with monoclonal anti-tumor necrosis factor antibody CA2. Neurology 47, 1531–1534 (1996).

    CAS  Google Scholar 

  103. Oh, C. J., Das, K. M. & Gottlieb, A. B. Treatment with anti-tumor necrosis factor-α (TNF-α) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions. J. Am. Acad. Dermatol. 42, 829–830 (2000).

    CAS  PubMed  Google Scholar 

  104. Gottlieb, A. B. et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: A randomized, double-blind, placebo-controlled trial. J. Am. Acad. Dermatol. 51, 534–542 (2004).

    PubMed  Google Scholar 

  105. Antoni, C. et al. The Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT). Arthritis Rheum. 46, S381 (2002).

    Google Scholar 

  106. Antoni, C. et al. The one year results of the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. 48, S285 (2003).

    Google Scholar 

  107. Mease, P. et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and the effect on disease progression. Arthritis Rheum. 50, 2264–2272 (2004). This is the Phase III study of etanercept for psoriatic arthritis.

    CAS  PubMed  Google Scholar 

  108. Lovell, D. et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N. Engl J. Med. 342, 763–769 (2000).

    CAS  PubMed  Google Scholar 

  109. Moreland, I. W. et al. Longterm Safety and Efficacy of Etanercept in Patients with Rheumatoid Arthritis. J. Rheumatol. 28, 1238–1244 (2001).

    CAS  PubMed  Google Scholar 

  110. Davis, J. C. et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis. Arthritis Rheum. 48, 3230–3236 (2003).

    CAS  PubMed  Google Scholar 

  111. Leonardi, C. L. et al. Etanercept as monotherapy in patients with psoriasis. N. Engl. J. Med. 349, 2014–2022 (2003). This is the report of one of the Phase III trials of etanercept monotherapy for psoriasis.

    CAS  PubMed  Google Scholar 

  112. Gottlieb, A. B., Gordon, K. B., Wang, A. & Zitnik, R. Durability of treatment response following withdrawal from etanercept in psoriasis patients. J. Invest. Dermatol. 122, A51–306 (2004).

    Google Scholar 

  113. Gordon, K. B. et al. Efficacy of etanercept in an integrated multistudy database of patients with psoriasis. J. Invest. Dermatol. 122, A54–321 (2004).

    Google Scholar 

  114. Day, R. Adverse reactions to TNF-α inhibitors in rheumatoid arthritis. Lancet 359, 540–541 (2002).

    PubMed  Google Scholar 

  115. Keystone, E. et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy. Arthritis Rheum. 50, 1400–1411 (2004).

    CAS  PubMed  Google Scholar 

  116. Ellerin, T., Rubin, R. H. & Weinblatt, M. Infections and anti-tumor necrosis factor α therapy. Arthritis Rheum. 48, 3013–3022 (2003).

    CAS  PubMed  Google Scholar 

  117. Lee, E. et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199, 125–130 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kauffman, C. L. et al. Treatment of moderate-to-severe psoriasis with human monoclonal antibody to human IL-12. J. Invest. Dermatol. 121, 353 (2003).

    Google Scholar 

  119. Kauffman, C. L. et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J. Invest. Dermatol. 123, 1037–1044 (2004).

    CAS  PubMed  Google Scholar 

  120. Heufler, C., Koch, F. & Schuler, G. Granulocyte/macrophage colony-stimulating factor and interleukin 1 mediate the maturation of murine epidermal Langerhans cells into potent immunostimulatory dendritic cells. J. Exp. Med. 167, 700–705 (1988).

    CAS  PubMed  Google Scholar 

  121. Witmer-Pack, M. D., Olivier, W., Valinsky, J., Schuler, G. & Steinman, R. M. Granulocyte/macrophage colony-stimulating factor is essential for the viability and function of cultured murine epidermal Langerhans cells. J. Exp. Med. 166, 1484–1498 (1987).

    CAS  PubMed  Google Scholar 

  122. Kimber, I., Cumberbatch, M., Dearman, R. J., Bhushan, M. & Griffiths, C. E. M. Cytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization. Br. J. Dermatol. 142, 401–412 (2000).

    CAS  PubMed  Google Scholar 

  123. McInnes, I. B., Gracie, J. A. & Liew, F. Y. Interleukin-18: a novel cytokine in inflammatory rheumatic disease. Arthritis. Rheum. 44, 1481–1483 (2001).

    CAS  PubMed  Google Scholar 

  124. Ye, X. J., Tang, B., Kang, A. H., Myers, L. K. & Cremer, M. A. The roles of interleukin-18 in collagen-induced arthriis in the BB rat. Clin. Exp. Immunol. 136, 440–447 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Siegmund, B. et al. Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-γ and TNF-α production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 281, R1264–R1273 (2001).

    CAS  PubMed  Google Scholar 

  126. Jameson, S. C. Maintaining the norm: T-cell homeostasis. Nature Rev. Immunol. 2, 547–555 (2002).

    CAS  Google Scholar 

  127. Ruckert, R. et al. Inhibition of keratinocyte apoptosis by IL-15: a new parameter in the pathogenesis of psoriasis? J. Immunol. 165, 2240–2250 (2000).

    CAS  PubMed  Google Scholar 

  128. Schon, M. P., Zollner, T. M. & Henning Boehncke, W. The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J. Invest. Dermatol. 121, 951–962 (2003).

    PubMed  Google Scholar 

  129. Fuhlbrigge, R. C., Kieffer, J. D., Armerding, D. & Kupper, T. S. Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389, 978–981 (1997).

    CAS  PubMed  Google Scholar 

  130. Kupper, T. S. Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J. Clin. Invest. 86, 1783–1789 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Robert, C. & Kupper, T. S. Inflammatory skin diseases, T cells, and immune surveillance. Mech. Disease 341, 1817–1828 (1999).

    CAS  Google Scholar 

  132. Schon, M. P. et al. Efomycine M, a new specific inhibitor of selectin, impairs leukocyte adhesion and alleviates cutaneous inflammation. Nature Med. 8, 366–372 (2002).

    CAS  PubMed  Google Scholar 

  133. Ikegami-Kuzuhara, A. Y. T., Ohmoto, H. Inoue, Y., Saito, T. T. Therapeutic potential of a novel synthetic selectin blocker, J-R9188 in allergic dermatitis. J. Pharmacol. 134, 1498–1504 (2001).

    CAS  Google Scholar 

  134. Shand, A. F. A. Potential therapeutic role for cytokine or adhesion molecule manipulation in Crohn's disease in the shadow of infliximab? Int. J. Colorectal. Dis. 18, 1–11 (2003).

    PubMed  Google Scholar 

  135. Ghosh, S. et al. Natilizumab for active Crohn's disease. N. Engl. J. Med. 348, 24–32 (2003).

    CAS  PubMed  Google Scholar 

  136. De Boer, O. et al. Increased expression of adhesion receptors in both lesional and non-lesional psoriatic skin. Arch. Dermatol. Res. 286, 304–311 (1994).

    CAS  PubMed  Google Scholar 

  137. deBoer, O., Verhagen, C., Visser, A., Bos, J. & Das, P. Cellular interactions and adhesion molecules in psoriatic skin. Acta Derm. Venereol. Suppl. (Stockh.) 186, 15–18 (1994).

    CAS  Google Scholar 

  138. Griffiths, C. E. M., Voorhees, J. J. & Nickoloff, B. J. Characterization of intercellular adhesion molecule-1 and HLA-DR expression in normal and inflamed skin: modulation by recombinant γ interferon and tumor necrosis factor. J. Am. Acad. Dermatol. 20, 617–629 (1989).

    CAS  PubMed  Google Scholar 

  139. Lisby, S., Ralfkiaer, E., Rothlein, R. & Vejlsgaard, G. L. Intercellular adhesion molecule-I (ICAM-I) expression correlated to inflammation. Br. J. Dermatol. 120, 479–484 (1989).

    CAS  PubMed  Google Scholar 

  140. Onuma, S. Immunohistochemical studies of infiltrating cells in early and chronic lesions of psoriasis. J. Dermatol. 21, 223–232 (1994).

    CAS  PubMed  Google Scholar 

  141. Pauls, K. et al. Role of integrin αE(CD103)β7 for tissue-specific epidermal localization of CD8+ T lymphocytes. J. Invest. Dermatol. 117, 569–575 (2001).

    CAS  PubMed  Google Scholar 

  142. Teraki, Y. & Shiohara, T. Preferential expression of αEβ7 integrin (CD103) on CD8+ T cells in the psoriatic epidermis: regulation by interleukins 4 and 12 and transforming growth factor-β. J. Invest. Dermatol. 147, 1118–1126 (2002).

    CAS  Google Scholar 

  143. Nickoloff, B. J. Role of interferon-γ in cutaneous trafficking of lymphocytes with emphasis on molecular and cellular adhesion events. Arch. Dermatol. 124, 1835–1845 (1988).

    CAS  PubMed  Google Scholar 

  144. Rich, B. IL-7 promotes Th1 cell differentiation. J. Invest. Dermatol. 122, A124–753 (2004).

    Google Scholar 

  145. Ferenczi, K., Murphy, J., Krzysiek, R. & Kupper, T. S. CXCR6 and its logand are consecutively expressed in skin. J. Invest. Dermatol. 122, A130–777 (2004).

    Google Scholar 

  146. Xia, Y. P. et al. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102, 161–168 (2003).

    CAS  PubMed  Google Scholar 

  147. Detmar, M. Evidence for vascular endothelial growth factor (VEGF) as a modifier gene in psoriasis. J. Invest. Dermatol. 122, XIV–XV (2004).

    CAS  PubMed  Google Scholar 

  148. Young, H. S., Summers, A. M., Bhushan, M., Brenchley, P. E. C. & Griffiths, C. E. Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. J. Invest. Dermatol. 122, 209–215 (2004).

    CAS  PubMed  Google Scholar 

  149. Austin, L., Ozawa, M., Kikuchi, T., Walters, I. & Krueger, J. The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-γ, interleukin-2, and tumor necrosis factor-α, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J. Invest. Dermatol. 113, 752–759 (1999).

    CAS  PubMed  Google Scholar 

  150. Gottlieb, A. B., Luster, A. D., Posnett, D. N. & Carter, D. M. Detection of a γ-interferon-induced protein (IP-10) in psoriatic plaques. J. Exp. Med. 168, 941–948 (1988).

    CAS  PubMed  Google Scholar 

  151. Gottlieb, A. B. Immunologic mechanisms in psoriasis. J. Invest. Dermatol. 95, 18S–19S (1990).

    PubMed  Google Scholar 

  152. Livden, J. K., Nilsen, R., Bjerke, J. R. & Matre, R. In situ localization of interferons in psoriatic lesions. Arch. Dermatol. Res. 281, 392–397 (1989).

    CAS  PubMed  Google Scholar 

  153. Cooper, K. D. et al. Increased levels of an interleukin-1 inhibitor block interleukin-1 activity but not immunoreactivity of mRNA expression of interleukin-1β in psoriasis skin. J. Invest. Dermatol. 90, 552 (1988).

    Google Scholar 

  154. Matthews, S. J. & McCoy, C. Thalidomide: a review of approved and investigational uses. Clin.Ther. 25, 342–395 (2003).

    CAS  PubMed  Google Scholar 

  155. Kumar, S., Broehm, J. & Lee, J. C. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nature Rev. Drug Discov. 2, 717–726 (2003).

    CAS  Google Scholar 

  156. Thomas, P. IL-4-induced immune deviation as therapy of psoriasis. Arch. Derm. Res. 293, 30 (2001).

    Google Scholar 

  157. Asadullah, K. et al. IL-10 is a key cytokine in psoriasis. Proof of principle by IL-10 therapy: a new therapeutic approach. J. Clin. Invest. 101, 783–794 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Trepicchio, W. et al. IL-11 is an immune-modulatory cytokine which downregulates IL-12, Type 1 cytokines, and multiple inflammation-associated genes in patients with psoriasis. J. Invest. Dermatol. 112, 598 (1999).

    Google Scholar 

  159. Krueger, J. G. et al. Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis. J. Am. Acad. Dermatol. 43, 448–458 (2000).

    CAS  PubMed  Google Scholar 

  160. Altmeyer, P. et al. Antipsoriatic effect of fumaric acid derivatives. J. Am. Acad. Dermatol. 30, 977–981 (1994).

    CAS  PubMed  Google Scholar 

  161. Hoefnagel, J., Thio, H., Willemze, R. & Bavinck, J. Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis. Br. J. Dermatol. 149, 363–369 (2003).

    CAS  PubMed  Google Scholar 

  162. Hoxtermann, S., Nuchel, C. & Altmeyer, P. Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology 196, 223–230 (1998).

    CAS  PubMed  Google Scholar 

  163. Litjens, N. H. R. et al. Beneficial effects of fumarate therapy in psoriasis vulgaris patients coincide with downregulation of type 1 cytokines. Br. J. Dermatol. 148, 444–451 (2003).

    CAS  PubMed  Google Scholar 

  164. Loewe, R. et al. Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E Expression in an NF-κB-dependent manner. J. Invest. Dermatol. 117, 1363–1368 (2001).

    CAS  PubMed  Google Scholar 

  165. Mrowietz, U., Christophers, E. & Altmeyer, P. Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. Br. J. Dermatol. 138, 456–460 (1998).

    CAS  PubMed  Google Scholar 

  166. Ockenfels, H., Schultewolter, T., Ockenfels, G., Funk, R. & Goos, M. The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network. Br. J. Dermatol. 139, 390–395 (1998).

    CAS  PubMed  Google Scholar 

  167. Thio, H., van der Schroeff, J., Nugteren-Huying, W., & Vermeer, B. Long-term systemic therapy with dimethylfumarate and monoethylfumarate (Fumaderm) in psoriasis. J. Eur. Acad. Dermatol. Venereol. 4, 35–40 (1995).

    Google Scholar 

  168. Zhu, K. & Mrowietz, U. Inhibition of dendritic cell differentiation by fumaric acid esters. J. Invest. Dermatol. 116, 203–208 (2001).

    CAS  PubMed  Google Scholar 

  169. Treumer, F., Zhu, K., Glaser, R. & Mrowietz, U. Dimethylfumarate is a potent inducer of apoptosis in human T cells. J. Invest. Dermatol. 121, 1383–1388 (2003).

    CAS  PubMed  Google Scholar 

  170. Jones, E. L., Epinette, W. W., Hackney, V. C., Menendez, L. & Frost, P. Treatment of psoriasis with oral mycophenolic acid. J. Invest. Dermatol. 65, 537–542 (1975).

    CAS  PubMed  Google Scholar 

  171. Griffiths, D. L. & Gottlieb, A. Treatment with oral pimecrolimus significantly improves psoriasis with a clear dose–response effect. J. Invest. Dermatol. 121, 391 (2003).

    Google Scholar 

  172. Singh, F. & Weinberg, J. M. Oral tazarotene and oral pimecrolimus: novel oral therapies in development for psoriasis. J. Drugs Dermatol. 3, 141–143 (2004).

    PubMed  Google Scholar 

  173. Ihle, J. N. The Stat family in cytokine signaling. Curr. Opin. Cell. Biol. 13, 211–217 (2001).

    CAS  PubMed  Google Scholar 

  174. Manning, A. M. & Davis, R. J. Targeting JNK for therapeutic benefit: from junk to gold? Nature Rev. Drug Discov. 2, 554–565 (2003).

    CAS  Google Scholar 

  175. Karin, M., Yamamoto, Y., & Wang, Q. M. The IKKNF-kappaB system: a treasure trove for drug development. Nature Rev. Drug Discov. 3, 17–26 (2004).

    CAS  Google Scholar 

  176. Lu, I. et al. Modulation of epidermal differentiation, tissue inflammation, and T-lymphocyte infiltration in posoriatic plaques by topical calcitriol. J. Cutan. Pathol. 23, 419–434 (1996).

    CAS  PubMed  Google Scholar 

  177. Gottlieb, S. L. et al. Etretinate promotes keratinocyte terminal differentiation and reduces T-cell infiltration in psoriatic epidermis. J. Cutan. Pathol. 23, 404–418 (1996).

    CAS  PubMed  Google Scholar 

  178. Gottlieb, A. B., Chaudhari, U., Baker, D. G., Perate, M. & Dooley, L. T. The National Psoriasis Foundation Psoriasis Score (NPF-PS) system versus the Psoriasis Area Severity Index (PASI) and Physician's Global Assessment (PGA): a comparison. J. Drugs Dermatol. 3, 260–266 (2003).

    Google Scholar 

  179. Frederiksson, T. & Pettersson, U. Severe psoriasis oral therapy with a new retinoid. Dermatologica 157, 238–244 (1978).

    Google Scholar 

  180. Gladman, D. D. Effectiveness of psoriatic arthritis therapies. Sem. Arthritis Rheum. 33, 29–37 (2003).

    CAS  Google Scholar 

  181. Gladman, D. D. et al. Assessment of patients with psoriatic arthritis. A review of currently available measures. Arthritis Rheum. 50, 24–35 (2004).

    PubMed  Google Scholar 

  182. Abbas, A. K. & Lichtman, A. H. Cellular and Molecular Immunology 506–521 (Elsevier, Philadelphia, 2003).

    Google Scholar 

  183. Vallat, V. P. et al. PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J. Exp. Med. 180, 283–296 (1994).

    CAS  PubMed  Google Scholar 

  184. Ferenczi, K., Burack, L., Pope, M., Krueger, J. & Austin, L. CD69 HLA-DR and the IL-2R identify persistently activated T cells in psoriasis vulgaris lesional skin: blood and skin comparisons by flow cytometry. J. Autoimmun. 14, 63–78 (2000).

    CAS  PubMed  Google Scholar 

  185. Duncan, J. I. et al. Soluble IL-2 receptor and CD25 cells in psoriasis: effects of cyclosporin A and PUVA therapy. Clin. Exp. Immunol. 85, 293–296 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Krueger, J. G. et al. Successful ultraviolet B treatment of psoriasis is accompanied by a reversal of keratinocyte pathology and by selective depletion of intraepidermal T cells. J. Exp. Med. 182, 2057–2068 (1995).

    CAS  PubMed  Google Scholar 

  187. Hodak, E. et al. Climatotherapy at the Dead Sea is a remittive therapy for psoriasis: combined effects on epidermal and immunologic activation. J. Am. Acad. Dermatol. 49, 451–457 (2003).

    PubMed  Google Scholar 

  188. Nickoloff, B. & Griffiths, C. γ-Interferon induces different keratinocyte expression of HLA-DR, DQ and intercellular adhesion molecule-1 (ICAM-1) antigens. J. Invest. Dermatol. 90, 592 (1988).

    Google Scholar 

  189. Kupper, T. S. Immunologic targets in psoriasis. N. Engl J. Med. 349, 1987–1990 (2003).

    CAS  PubMed  Google Scholar 

  190. Gottlieb, A. B. Clinical research helps elucidate the role of tumor necrosis factor-α (TNF-α) in the pathogenesis of T1 mediated immune disorders: use of targeted immunotherapeutics as pathogenic probes. Lupus 12, 192–196 (2003).

    Google Scholar 

  191. Goebeler, M. et al. The C-X-C chemokine Mig is highly expressed in the papillae of psoriatic lesions. J. Pathol. 184, 89–95 (1998).

    CAS  PubMed  Google Scholar 

  192. Homey, B. et al. Up-regulation of macrophage inflammatory protein-3 α/CCL20 and CC chemokine receptor 6 in psoriasis. J. Immunol. 164, 6621–32 (2000).

    CAS  PubMed  Google Scholar 

  193. Das, P. et al. Differential expression of ICAM-1, E-selectin and VCAM-1 by endothelial cells in psoriasis and contact dermatitis. Acta Derm. Venereol. Suppl. (Stockh.) 186, 21–2 (1994).

    CAS  Google Scholar 

  194. Morganroth, G. S., Chan, L. S., Weinstein, G. D., Voorhees, J. J. & Cooper, K. D. Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells. J. Invest. Dermatol. 96, 333–340 (1991).

    CAS  PubMed  Google Scholar 

  195. Nickoloff, B. J. & Griffiths, C. E. M. Lymphocyte trafficking in psoriasis: a new perspective emphasizing the dermal dendrocyte with active dermal recruitment mediated via endothelial cells followed by intra-epidermal T-cell activation. J. Invest. Dermatol. 95, 35S–37S (1990).

    PubMed  Google Scholar 

  196. Gottlieb, A. B., Chang, C. K., Posnett, D. N., Fanelli, B. & Tam, J. P. Detection of transforming growth factor α in normal, malignant, and hyperproliferative human keratinocytes. J. Exp. Med. 167, 670–675 (1988).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded in part by grants from the David Ju Foundation and a Center of Excellence grant from the Federation of Clinical Immunology Societies (FOCIS).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

A.B.G. receives research funding from Amgen Inc.; Biogen Idec, Inc.; Centocor, Inc.; Genentech, Inc; WH Conzen Chair in Clinical Pharmacology; Abbott Labs; Ligand Pharmaceuticals Inc.; Beiersdorf, Inc.; Fujisawa Healthcare, Inc.; Merck, Inc.; Celgene Corp.; and Novartis AG.

A.B.G.'s Speakers' Bureau Memberships include Amgen Inc.; Biogen Idec, Inc.; Wyeth Pharmaceuticals; Centocor, Inc.; and Schering-Plough Corp.

A.B.G. currently has consulting agreements with Amgen Inc.; Biogen Idec, Inc; CellGate, Inc; Centocor, Inc.; Genentech, Inc; Novartis AG; QUATRx Pharmaceuticals Co.; Wyeth Pharmaceuticals, Schering-Plough Corp.; Eisai; Celgene Corp.; Bristol Myers Squibb Co.; Beiersdorf, Inc., Warner Chilcott, Abbott Labs., Kemia, Sankyo

Related links

Related links

DATABASES

Entrez Gene

CTLA4

ICAM1

iNOS

NF-κB

TNFα

VCAM1

VLA4

OMIM

Crohn's disease

psoriasis

psoriatic arthritis

rheumatoid arthritis

Glossary

TOPICAL THERAPY

Therapy applied to the skin.

PHOTOTHERAPY

Ultraviolet light irradiation therapy.

KERATINOCYTE

Keratinocytes are a type of cell found in the epidermis (the top layer of skin). Psoriasis is characterized by hyperproliferation of keratinocytes.

NATURAL KILLER CELLS

(NK cells). Lymphocytes that confer innate immunity. They were originally defined on the basis of their cytolytic activity against tumour targets, but it is now recognized that they serve a broader role in host defence against invading pathogens.

INTEGRIN

Integrins are a family of adhesion molecules that mediate cell–cell, cell–extracellular matrix and cell–pathogen interactions by binding to various ligands. Integrins are non-covalently associated α/β heterodimers.

MAJOR HISTOCOMPATIBILITY COMPLEX

A genetic region encoding proteins that are involved in antigen presentation to T cells. MHC class I molecules bound to antigen are most often recognized by the T-cell receptors of CD8+ T cells.

IMMUNOLOGICAL SYNAPSE

A large junctional structure that is formed at the cell surface between a T cell that is interacting with an antigen-presenting cell. Important molecules involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site.

MEMORY EFFECTOR T CELLS

Antigen-experienced T cells that have immediate effector capabilities and can efficiently migrate to peripheral sites of inflammation.

φX174

φX174 is an experimental immunogen (vaccine) used to assess immune integrity in humans

MUNRO'S ABSCESSES

Collections of neutrophils in the stratum corneum in psoriatic plaques.

SHARP SCORES

A radiographic score composite of joint-space narrowing and bone erosions in joints of the hand and wrist.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gottlieb, A. Psoriasis: emerging therapeutic strategies. Nat Rev Drug Discov 4, 19–34 (2005). https://doi.org/10.1038/nrd1607

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1607

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing