Psoriasis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Sch?n and Boehncke (May 5 issue)1 did not comment on the important relationship between psychological stress and psoriasis. People affected with psoriasis may have substantial stress from the manifestations of the disease as well as a high prevalence of anxiety, depression, and anger; however, stressful life events can initiate or exacerbate psoriasis in as many as 60 percent of cases.2
Endogenous corticosteroids released during psychological stress may increase vascular permeability and modulate leukocyte trafficking between the blood and other immune compartments, and norepinephrine may enhance the inflammatory process through an adjuvant effect on the functions of skin dendritic cells.3 Psychological stress has a detrimental effect on treatment outcome and has impaired the clearance of psoriasis in patients treated with psoralen plus ultraviolet A.4 Unfortunately, there is little agreement between physicians and patients with psoriasis regarding the role of significant psychological distress, and this may prevent the identification of patients who can benefit from adjunctive psychological treatment.5
Miguel G. Madariaga, M.D.
University of Nebraska Medical Center
Omaha, NE 68131
migmad@worldnet.att.net
References
Sch?n MP, Boehncke W-H. Psoriasis. N Engl J Med 2005;352:1899-1912.
Choi J, Koo JY. Quality of life issues in psoriasis. J Am Acad Dermatol 2003;49:S57-S61.
Saint-Mezard P, Chavagnac C, Bosset S, et al. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol 2003;171:4073-4080.
Fortune DG, Richards HL, Kirby B, et al. Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy. Arch Dermatol 2003;139:752-756.
Richards HL, Fortune DG, Weidmann A, Sweeney SK, Griffiths CE. Detection of psychological distress in patients with psoriasis: low consensus between dermatologist and patient. Br J Dermatol 2004;151:1227-1233.
To the Editor: The authors of the review of psoriasis missed an opportunity to present the reader with a balanced overview of risk factors and treatment options. Several nongenetic risk factors for psoriasis have been identified, including smoking and a high body-mass index.1 These factors are ignored in the review, which emphasizes drugs and infections. However, in our view, no single, well-designed study provides risk estimates for drug use in patients with psoriasis, and no convincing evidence supports the notion that beta-blockers trigger psoriasis. With the exception of guttate psoriasis, there is limited evidence that infections may trigger or exacerbate plaque psoriasis. Whereas the development of biologic agents is currently based on short-term, placebo-controlled, randomized studies,2 older, "traditional" medications are not sufficiently considered, perhaps because funding from pharmaceutical companies to study older drugs is lacking.3 Indeed, the first short-term, comparative, randomized trial of methotrexate in comparison with cyclosporine was published only in 2003.4 Public expectations with regard to new drugs are increasingly high, and studies in which newer agents are compared with existing options for the treatment of psoriasis are urgently needed.
Luigi Naldi, M.D.
Ospedali Riuniti
24128 Bergamo, Italy
luigi.naldi@gised.it
Liliane Chatenoud, M.D.
Istituto di Ricerche Farmacologiche M. Negri
20157 Milan, Italy
References
Naldi L. Epidemiology of psoriasis. Curr Drug Targets Inflamm Allergy 2004;3:121-128.
Stern RS. A promising step forward in psoriasis therapy. JAMA 2003;290:3133-3135.
Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J Invest Dermatol 2003;120:738-741.
Heydendael VMR, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-665.
To the Editor: The review article on psoriasis highlighted the T-cell–mediated pathogenic process. Certain T cells with immunoregulatory functions control immunopathogenetic processes,1 and autoimmune disease develops as a consequence of abnormality in this T-cell population. CD4+ cells that express CD25 are referred to as regulatory T cells, and in humans, these cells express the forkhead transcription factor FOX33. Sakaguchi and Sakaguchi showed that congenitally T-cell–deficient athymic (nu/nu) nude mice or euthymic mice in which T cells were depleted by thymectomy and irradiation and that underwent syngeneic thymic engraftment can spontaneously develop organ-specific and systemic autoimmune disease.2
Dermal injection of activated T cells from patients with psoriasis has induced psoriasis-like changes in human skin samples transplanted onto SCID (severe combined immunodeficiency) mice,3 and T-cell clones had the capacity for keratinocytic proliferation in uninvolved skin from patients with psoriasis.4 Psoriatic CD4+CD25high, CTLA4+ (cytotoxic T-lymphocyte–associated antigen 4–expressing), FOXP3high regulatory T cells have impaired inhibitory functions and are anergic to CD3+CD28 T-cell–receptor stimulation.5 This loss in activity to polyclonal stimulation means that these cells cannot resist further inflammatory insults. Novel therapies to correct the regulatory T-cell defect could prove to be useful therapeutic interventions in the future.
Sujoy Khan, M.B., B.S., M.R.C.P.
St. Bartholomew's Hospital
London EC1A 7BE, United Kingdom
sujoy.khan@bartsandthelondon.nhs.uk
References
Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816-822.
Sakaguchi S, Sakaguchi N. Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J Exp Med 1990;172:537-545.
Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98:1878-1887.
Prinz JC, Gross B, Vollmer S, et al. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol 1994;24:593-598.
Sugiyama H, Gyulai R, Toichi E, et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164-173.
The authors reply: Although there is broad consensus about a genetic predisposition and a primary role of immune or autoimmune reactions in the pathogenesis of psoriasis, numerous extrinsic and intrinsic factors modulate the accrual of psoriasis. These factors include a mutual influence between psoriasis itself and psychosocial characteristics, a notion that is increasingly covered in the literature, including our review. According to the Medical Outcomes Study 36-item Short-Form General Health Survey, psoriasis yielded scores similar to those associated with other severe diseases, such as depression, cancer, and diabetes, whose impact on quality of life remains undisputed. In addition, stress-reducing strategies may improve the efficacy of antipsoriatic therapies.1
Specific education programs for patients with psoriasis, such as those implemented by the German Dermatological Society, are based on psychosocial cofactors. Other factors that have an effect on psoriasis activity include the interdependency among inflammation, stress, and insulin resistance.2 A possible link between the known increased risk of occlusive vascular disease and the thrombocyte activation driven by psoriasis has been proposed.3 There is also a well-established link between systemic drugs such as beta-adrenergic blockers and the onset or exacerbation, or both, of psoriasis. Indeed, the first documentation of circumstantial evidence of this connection dates back more than three decades, to the period shortly after beta-blockers were introduced into clinical practice, and has been confirmed by numerous studies4 — although, of course, ethical considerations preclude prospective studies.
Complete coverage of treatment options for psoriasis warrants a comprehensive review in its own right, and high public expectations with regard to new drugs, such as biologic agents developed for the treatment of psoriasis, may not always be met. The rather restrictive European label for biologic agents as "second-line" therapies may, therefore, be a wise approach until comparative data are available. Given their specificity, new biologic agents fit into and corroborate current pathogenic concepts, which are the focus of our review. The major advantages of biologic agents may be that they have little end-organ toxicity and cause no drug interactions — advantages that potentially circumvent some of the contraindications that restrict the use of "conventional" therapies. Studies of some of the new biologic agents demonstrate that selectively targeting certain T-cell subsets can alleviate a complex disease such as psoriasis. This finding is consonant with the critical role even of subsets of regulatory T cells that govern the tissue-selective migration of immune cells, their pathogenic function in chronic skin inflammation, or both.5 Thus, it is indeed conceivable that correcting the functions of certain subsets of regulatory T cells will be beneficial in psoriasis despite a lack of experimental support as yet for this hypothesis.
Michael P. Sch?n, M.D.
University of Würzburg
97078 Würzburg, Germany
michael.schoen@virchow.uni-wuerzburg.de
W.-Henning Boehncke, M.D.
Johann Wolfgang Goethe University
60590 Frankfurt, Germany
Since publication of his article, Dr. Sch?n reports having received lecture fees from Wyeth.
References
Zachariae R, Oster H, Bjerring P, Kragballe K. Effects of psychologic intervention in psoriasis: a preliminary report. J Am Acad Dermatol 1996;34:1008-1015.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111-1119.
Ludwig RJ, Schultz JE, Boehncke WH, et al. Activated, not resting, platelets increase leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules. J Invest Dermatol 2004;122:830-836.
Gold MH, Holy AK, Roenigk HH Jr. Beta-blocking drugs and psoriasis: a review of cutaneous side effects and retrospective analysis of their effects on psoriasis. J Am Acad Dermatol 1988;19:837-841.
Siegmund K, Feuerer M, Siewert C, et al. Migration matters: regulatory T cell compartmentalization determines suppressive activity in vivo. Blood (in press).
Endogenous corticosteroids released during psychological stress may increase vascular permeability and modulate leukocyte trafficking between the blood and other immune compartments, and norepinephrine may enhance the inflammatory process through an adjuvant effect on the functions of skin dendritic cells.3 Psychological stress has a detrimental effect on treatment outcome and has impaired the clearance of psoriasis in patients treated with psoralen plus ultraviolet A.4 Unfortunately, there is little agreement between physicians and patients with psoriasis regarding the role of significant psychological distress, and this may prevent the identification of patients who can benefit from adjunctive psychological treatment.5
Miguel G. Madariaga, M.D.
University of Nebraska Medical Center
Omaha, NE 68131
migmad@worldnet.att.net
References
Sch?n MP, Boehncke W-H. Psoriasis. N Engl J Med 2005;352:1899-1912.
Choi J, Koo JY. Quality of life issues in psoriasis. J Am Acad Dermatol 2003;49:S57-S61.
Saint-Mezard P, Chavagnac C, Bosset S, et al. Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo. J Immunol 2003;171:4073-4080.
Fortune DG, Richards HL, Kirby B, et al. Psychological distress impairs clearance of psoriasis in patients treated with photochemotherapy. Arch Dermatol 2003;139:752-756.
Richards HL, Fortune DG, Weidmann A, Sweeney SK, Griffiths CE. Detection of psychological distress in patients with psoriasis: low consensus between dermatologist and patient. Br J Dermatol 2004;151:1227-1233.
To the Editor: The authors of the review of psoriasis missed an opportunity to present the reader with a balanced overview of risk factors and treatment options. Several nongenetic risk factors for psoriasis have been identified, including smoking and a high body-mass index.1 These factors are ignored in the review, which emphasizes drugs and infections. However, in our view, no single, well-designed study provides risk estimates for drug use in patients with psoriasis, and no convincing evidence supports the notion that beta-blockers trigger psoriasis. With the exception of guttate psoriasis, there is limited evidence that infections may trigger or exacerbate plaque psoriasis. Whereas the development of biologic agents is currently based on short-term, placebo-controlled, randomized studies,2 older, "traditional" medications are not sufficiently considered, perhaps because funding from pharmaceutical companies to study older drugs is lacking.3 Indeed, the first short-term, comparative, randomized trial of methotrexate in comparison with cyclosporine was published only in 2003.4 Public expectations with regard to new drugs are increasingly high, and studies in which newer agents are compared with existing options for the treatment of psoriasis are urgently needed.
Luigi Naldi, M.D.
Ospedali Riuniti
24128 Bergamo, Italy
luigi.naldi@gised.it
Liliane Chatenoud, M.D.
Istituto di Ricerche Farmacologiche M. Negri
20157 Milan, Italy
References
Naldi L. Epidemiology of psoriasis. Curr Drug Targets Inflamm Allergy 2004;3:121-128.
Stern RS. A promising step forward in psoriasis therapy. JAMA 2003;290:3133-3135.
Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis 1977-2000: the EDEN survey. J Invest Dermatol 2003;120:738-741.
Heydendael VMR, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-665.
To the Editor: The review article on psoriasis highlighted the T-cell–mediated pathogenic process. Certain T cells with immunoregulatory functions control immunopathogenetic processes,1 and autoimmune disease develops as a consequence of abnormality in this T-cell population. CD4+ cells that express CD25 are referred to as regulatory T cells, and in humans, these cells express the forkhead transcription factor FOX33. Sakaguchi and Sakaguchi showed that congenitally T-cell–deficient athymic (nu/nu) nude mice or euthymic mice in which T cells were depleted by thymectomy and irradiation and that underwent syngeneic thymic engraftment can spontaneously develop organ-specific and systemic autoimmune disease.2
Dermal injection of activated T cells from patients with psoriasis has induced psoriasis-like changes in human skin samples transplanted onto SCID (severe combined immunodeficiency) mice,3 and T-cell clones had the capacity for keratinocytic proliferation in uninvolved skin from patients with psoriasis.4 Psoriatic CD4+CD25high, CTLA4+ (cytotoxic T-lymphocyte–associated antigen 4–expressing), FOXP3high regulatory T cells have impaired inhibitory functions and are anergic to CD3+CD28 T-cell–receptor stimulation.5 This loss in activity to polyclonal stimulation means that these cells cannot resist further inflammatory insults. Novel therapies to correct the regulatory T-cell defect could prove to be useful therapeutic interventions in the future.
Sujoy Khan, M.B., B.S., M.R.C.P.
St. Bartholomew's Hospital
London EC1A 7BE, United Kingdom
sujoy.khan@bartsandthelondon.nhs.uk
References
Maloy KJ, Powrie F. Regulatory T cells in the control of immune pathology. Nat Immunol 2001;2:816-822.
Sakaguchi S, Sakaguchi N. Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease. J Exp Med 1990;172:537-545.
Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98:1878-1887.
Prinz JC, Gross B, Vollmer S, et al. T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products. Eur J Immunol 1994;24:593-598.
Sugiyama H, Gyulai R, Toichi E, et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J Immunol 2005;174:164-173.
The authors reply: Although there is broad consensus about a genetic predisposition and a primary role of immune or autoimmune reactions in the pathogenesis of psoriasis, numerous extrinsic and intrinsic factors modulate the accrual of psoriasis. These factors include a mutual influence between psoriasis itself and psychosocial characteristics, a notion that is increasingly covered in the literature, including our review. According to the Medical Outcomes Study 36-item Short-Form General Health Survey, psoriasis yielded scores similar to those associated with other severe diseases, such as depression, cancer, and diabetes, whose impact on quality of life remains undisputed. In addition, stress-reducing strategies may improve the efficacy of antipsoriatic therapies.1
Specific education programs for patients with psoriasis, such as those implemented by the German Dermatological Society, are based on psychosocial cofactors. Other factors that have an effect on psoriasis activity include the interdependency among inflammation, stress, and insulin resistance.2 A possible link between the known increased risk of occlusive vascular disease and the thrombocyte activation driven by psoriasis has been proposed.3 There is also a well-established link between systemic drugs such as beta-adrenergic blockers and the onset or exacerbation, or both, of psoriasis. Indeed, the first documentation of circumstantial evidence of this connection dates back more than three decades, to the period shortly after beta-blockers were introduced into clinical practice, and has been confirmed by numerous studies4 — although, of course, ethical considerations preclude prospective studies.
Complete coverage of treatment options for psoriasis warrants a comprehensive review in its own right, and high public expectations with regard to new drugs, such as biologic agents developed for the treatment of psoriasis, may not always be met. The rather restrictive European label for biologic agents as "second-line" therapies may, therefore, be a wise approach until comparative data are available. Given their specificity, new biologic agents fit into and corroborate current pathogenic concepts, which are the focus of our review. The major advantages of biologic agents may be that they have little end-organ toxicity and cause no drug interactions — advantages that potentially circumvent some of the contraindications that restrict the use of "conventional" therapies. Studies of some of the new biologic agents demonstrate that selectively targeting certain T-cell subsets can alleviate a complex disease such as psoriasis. This finding is consonant with the critical role even of subsets of regulatory T cells that govern the tissue-selective migration of immune cells, their pathogenic function in chronic skin inflammation, or both.5 Thus, it is indeed conceivable that correcting the functions of certain subsets of regulatory T cells will be beneficial in psoriasis despite a lack of experimental support as yet for this hypothesis.
Michael P. Sch?n, M.D.
University of Würzburg
97078 Würzburg, Germany
michael.schoen@virchow.uni-wuerzburg.de
W.-Henning Boehncke, M.D.
Johann Wolfgang Goethe University
60590 Frankfurt, Germany
Since publication of his article, Dr. Sch?n reports having received lecture fees from Wyeth.
References
Zachariae R, Oster H, Bjerring P, Kragballe K. Effects of psychologic intervention in psoriasis: a preliminary report. J Am Acad Dermatol 1996;34:1008-1015.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111-1119.
Ludwig RJ, Schultz JE, Boehncke WH, et al. Activated, not resting, platelets increase leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules. J Invest Dermatol 2004;122:830-836.
Gold MH, Holy AK, Roenigk HH Jr. Beta-blocking drugs and psoriasis: a review of cutaneous side effects and retrospective analysis of their effects on psoriasis. J Am Acad Dermatol 1988;19:837-841.
Siegmund K, Feuerer M, Siewert C, et al. Migration matters: regulatory T cell compartmentalization determines suppressive activity in vivo. Blood (in press).