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Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy

https://doi.org/10.1016/j.jaad.2006.01.038Get rights and content

Background

Psoriasis is a common dermatosis characterized by erythematous skin plaques and associated arthritis. Microvessels of the papillary dermis in psoriatic lesions are elongated, tortuous, and dilated, which contributes significantly to the proinflammatory response. Angiopoietin (Ang) 1 and 2 and their receptor, Tie2, are a family of growth factors recognized in inflammatory lesions to be critical for new blood vessel growth and maintenance, with recent studies suggesting tumor necrosis factor (TNF)-α-induced angiogenesis is in part mediated by the Tie2 receptor. The aim of this study was to evaluate the effect of anti-TNF-α therapy on angiogenic growth factor expression and on the cellular infiltrate in psoriatic lesional skin.

Methods

Sixteen patients with moderate to severe psoriasis and associated psoriatic arthritis (n = 13) received infliximab infusions (3-5 mg/kg) at baseline and at 2 and 6 weeks. Clinical assessments and skin biopsies were undertaken at baseline, and at 2 and 12 weeks. Ang 1, Ang 2, Tie2, and TNF-α messenger RNA expression were quantified by real-time polymerase chain reaction. Protein expression of vascular endothelial growth factor, Ang 2, Tie2, TNF-α, and the inflammatory infiltrate was determined using immunohistology. We conducted clinical assessments including Psoriasis Area and Severity Index, percentage body surface area, Arthritis Disease Activity Score, and Health Assessment Questionnaire.

Results

At baseline expression of Ang 1/2, vascular endothelial growth factor, Tie2, and TNF-α messenger RNA and protein were greater in preinvolved skin compared with uninvolved skin (P < .05). Infliximab produced a significant reduction in protein expression of Ang 2, vascular endothelial growth factor, and Tie2 (P < .001) along with a decrease in messenger RNA expression of Ang 1 (P < .045) and Tie2 (P < .021). This was paralleled by a significant reduction in the inflammatory infiltrate scores (P < .001) and platelet-endothelial cell adhesion molecule (CD31) expression (P = .001), suggesting deactivation of endothelial cell. There was a 93% mean reduction in Psoriasis Area and Severity Index (P = .001), and a significant reduction in Disease Activity Score 28 (P = .012) and mean Health Assessment Questionnaire scores by week 12.

Limitations

This study involves a small number of patients.

Conclusion

These results suggest infliximab is both effective and well tolerated in severe psoriasis, resulting in deactivation of endothelium and down-regulation of growth factor and cytokine expression, leading to a decrease in the cellular infiltrate and clinical improvement in psoriasis. Furthermore, the effect of infliximab on growth factor expression, in particular Tie2, supports previous in vitro work suggesting TNF-α may be a major regulator of the Ang/Tie2 pathway.

Section snippets

Patients and samples

Patients with moderate/severe psoriasis who had failed previous systemic therapy were recruited from our dermatology and rheumatology outpatient clinics. The study was approved by our local research and ethics committee and all clinical investigation was conducted according to the principles of the Declaration of Helsinki. After fully informed, written consent, patients underwent a full clinical assessment and skin biopsy before receiving anti-TNF-α therapy. Clinical assessments included

Patient demographics

Sixteen patients (13 male, 3 female) with moderate to severe psoriasis (median PASI 15.8) and previous failure to systemic therapy undergoing infliximab treatment were recruited; 13 had associated PsA. Of the 16 patients, 9 were taking concomitant systemic medication in the form of methotrexate (n = 4), cyclosporine (n = 2), and prednisolone (n = 3). The median age was 44 years (range 22-57), the median duration of psoriasis was 25 years, and PsA was 12.5 years. Fifteen patients completed the

Discussion

In this study a cohort of patients with moderate/severe psoriasis, many with an associated arthritis, who had failed systemic therapy, showed a dramatic clinical response to intravenous infliximab. PASI scores and BSA of psoriasis showed highly significant reductions as early as week 2 with further improvement at week 12. Patients with an associated arthritis also showed significant responses as measured by the joint DAS-28 and the HAQ functional assessment. Although the clinical efficacy of

References (50)

  • C.J. Oh et al.

    Treatment with anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions

    J Am Acad Dermatol

    (2000)
  • U. Chaudhari et al.

    Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial

    Lancet

    (2001)
  • P. Stordeur et al.

    Cytokine mRNA quantification by real-time PCR

    J Immunol Methods

    (2002)
  • V. Blaschke et al.

    Rapid quantitation of proinflammatory and chemoattractant cytokine expression in small tissue samples and monocyte-derived dendritic cells: validation of a new real-time RT-PCR technology

    J Immunol Methods

    (2000)
  • R.E. Schopf et al.

    Treatment of psoriasis with the chimeric monoclonal antibody against tumor necrosis factor alpha, infliximab

    J Am Acad Dermatol

    (2002)
  • A.B. Gottlieb et al.

    Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial

    J Am Acad Dermatol

    (2004)
  • A.B. Gottlieb et al.

    Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-alpha monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris

    J Am Acad Dermatol

    (2003)
  • F.J. Baert et al.

    Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis

    Gastroenterology

    (1999)
  • I. Kim et al.

    Tumor necrosis factor-alpha upregulates angiopoietin-2 in human umbilical vein endothelial cells

    Biochem Biophys Res Commun

    (2000)
  • D. Voskas et al.

    A cyclosporine-sensitive psoriasis-like disease produced in Tie2 transgenic mice

    Am J Pathol

    (2005)
  • J.P. Ortonne

    Recent developments in the understanding of the pathogenesis of psoriasis

    Br J Dermatol

    (1999)
  • E.M. Paleolog et al.

    Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis

    Arthritis Rheum

    (1998)
  • P.C. Brooks et al.

    Requirement of vascular integrin alpha v beta 3 for angiogenesis

    Science

    (1994)
  • D. Creamer et al.

    Altered vascular endothelium integrin expression in psoriasis

    Am J Pathol

    (1995)
  • B.J. Nickoloff et al.

    Aberrant production of interleukin-8 and thrombospondin-1 by psoriatic keratinocytes mediates angiogenesis

    Am J Pathol

    (1994)
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    Supported by a grant from the Health Research Board of Ireland.

    Conflicts of interest: None identified.

    Presented and published at the British Association of Dermatologists 2003 Annual Meeting in Brighton, United Kingdom [Presented July 1, 2003; published Br J Dermatol 2003;149(suppl):20] and American College of Rheumatologists 2003 Annual Meeting in Orlando, Florida [Presented October 23, 2003; published Arthritis Rheum 2003;48(Suppl):s168].

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