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Use of anti-tumor necrosis factor agents: A possible therapy for vitiligo
Medical Hypotheses 72 (2009) 546–547
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Use of anti-tumor necrosis factor agents: A possible therapy for vitiligo Yajie Lv 1, Qiang Li 1, Lei Wang, Tianwen Gao * Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
a r t i c l e
i n f o
Article history: Received 5 December 2008 Accepted 10 December 2008
s u m m a r y Vitiligo is a depigmenting skin disorder resulting from the loss of melanocytes in the epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses have been frequently observed in vitiligo patients. Moreover, some vitiligo patients show higher lesion levels of tumor necrosis factor (TNF)-a. TNF-a is an important pleiotropic cytokine that exerts potent pro-inflammatory effects. There is growing evidence that TNF-a plays an important role in the pathomechanism process of some autoimmunity diseases, including ankylosing spondylitis (AS). Treated with anti-TNF agents infliximab, with the improvement of AS, a patient’s vitiligo lesions also faded out. Therefore, we hypothesized that TNF-a play an important role in vitiligo. On the one hand, TNF-a destroys melanocytes through induction of various apoptotic pathways. On the other hand, TNF-a inhibits melanocyte stem cells differentiation. Anti-TNF therapy may be an effective treatment for vitiligo. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Vitiligo is an acquired skin disorder of depigmentation, resulting from the destruction of melanocytes in the epidermis. The incidence of vitiligo is 0.5–2% worldwide, and no predilection exists for sex or race. These studies in the literature suggested a number of possible mechanisms in regard to vitiligo’s development [1]. Although the cause of vitiligo remains obscure, autoimmunity hypothesis has been now recognized as one of the most influential pathogenic mechanisms [2]. TNF-a is a pleiotropic cytokine and has numerous effects on the immune response, driving activation and recruitment of other inflammatory cells, amplifying production of IL-1, IL-6, and IL-8, and activating nuclear transcription factors such as NF-kB to propagate and maintain an inflammatory response [3]. It is produced by many different cell types, including activated T cells, keratinocytes, structural cells including fibroblasts, adipocytes and smooth muscle cells. It is clear that higher expression of TNF-a plays a central role in the pathogenesis of a number of autoimmune diseases. The hypothesis As TNF-a plays an important role in regulating apoptosis in many cell types including T lymphocytes, and abnormal expression of TNF-a has been observed in vitiligo, we hypothesized that TNF-a plays an important role in vitiligo. On the one hand, TNF-a destroys melanocytes through induction of various apoptotic pathways. On the other hand, TNF-a inhibits melanocyte stem cells differentia* Corresponding author. Tel./fax: +86 29 84775401. E-mail address: [email protected] (T. Gao). 1 These authors contributed equally to this work. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.12.033
tion. Anti-TNF therapy may be an effective treatment for vitiligo. Here, we provide evidence to support the hypothesis. Evidence of TNF-a in vitiligo TNF-a is a major mediator of inflammation and, when overexpressed, can give rise to chronic inflammatory and autoimmune diseases. Over the last few years, evidence suggests TNF-a plays an important role in apoptosis through activation of the receptor-mediated apoptosis pathway in numerous cell types [8]. It is worth mentioning that TNF-a is a paracrine inhibitor of stem cells [9]. Vitiligo is often associated with other disorders that have an autoimmune origin, including AS, Graves’ disease and Hashimoto’s thyroiditis [5]. In a retrospective review, Sandhu et al. [7] found that some psoriasis patients also had vitiligo. As we all know, TNF-a has direct effects on the pathogenesis of these diseases. Autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. Briefly, the discovery strongly suggests a role for cellular immunity in vitiligo [6]. Moreover, some studies provided evidence that in vitiligo skin a significantly higher expression of TNF-a was detected, compared with perilesional, non-lesional and healthy skin [4]. Thus, it seems that TNF-a is a key step in the development of vitiligo. Previous studies indicated that not only T cells but also keratinocytes and fibroblasts changed the level of TNF-a around melanocytes. It seems that the leukasmus was the result that melanocytes disappear was caused by TNF-a through induction of various apoptotic pathways and together with inhibition of melanocyte stem cells differentiation. TNF-a also plays a key role in the pathogenesis of vitiligo.
Y. Lv et al. / Medical Hypotheses 72 (2009) 546–547
547
Associations between anti-TNF therapy and vitiligo
References
Skurkovich was the first to talk about the theory that anti-cytokine therapy in the treatment of autoimmune and cytokine-disturbance diseases [10,11]. Now, this theory is widely used in many autoimmune diseases treatment. Inhibitor of TNF-a infliximab (a chimeric monoclonal anti-TNF antibody) has been approved by the US FDA as a therapy for patients with various autoimmune diseases, including rheumatoid arthritis, AS and psoriasis. It has been demonstrated that the TNF blockers are quite successful [12]. Data on possible association between vitiligo and anti-TNF agents are limited so far and therefore, not fully conclusive. Topical tacrolimus ointment [13], a potent immunosuppressive drug is an effective alternative therapy for vitiligo, particularly when the disease involves the head and neck. Posttreatment expression of some cytokines including TNF-a decreased in the depigmented and adjacent uninvolved skin. These data suggested that an imbalance in local cytokine expression, In particular, TNF-a might play a role in the pathogenesis of vitiligo. It further indirectly supports the hypothesis that suppression of TNF-a may be an effective treatment of vitiligo. Simon and Burgor-Vargas [14] described a patient with AS and vitiligo. The patient was treated with infliximab, which resulted in immediate improvement in clinical and laboratory measures. The vitiligo lesions gradually faded out. They suggested that TNF-a was involved in the pathogenesis of vitiligo and this drug was an effective treatment for vitiligo. Although there is only one case, the case inspired us that some patient’s vitiligo lesions resulted from TNF-a. Further, anti-TNF agents are effective therapies to these patients. If, as suggested here, TNF-a levels play a major role in pathomechanism process of vitiligo, in some cases, the anti-TNF agents would provide a further effective strategy. As there is little data on anti-TNF agents in vitiligo, in evaluation of our hypothesis we suggest that more experimental and clinical studies must be performed to evaluate the exact precise effects of anti-TNF agents in vitiligo.
[1] Dell’anna ML, Picardo M. A review and a new hypothesis for nonimmunological pathogenetic mechanisms in vitiligo. Pigment Cell Res 2006;19(5):406–11. [2] Kemp EH, Waterman EA, Weetman AP. Immunological pathomechanisms in vitiligo. Expert Rev Mol Med 2001;3(20):1–22. [3] Blanco P, Palucka AK, Pascual V, Banchereau J. Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev 2008;19(1):41–52. [4] Birol A, Kisa U, Kurtipek GS, Kara F, Kocak M, Erkek E, et al. Increased tumor necrosis factor alpha (TNF-a) and interleukin 1-a (IL1-a) levels in the lesional skin of patients with nonsegmental vitiligo. Int J Dermatol 2006;45(8): 992–3. [5] Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007;21(7):865–76. [6] Lambe T, Leung JC, Bouriez-Jones T, Silver K, Makinen K, Crockford TL, et al. CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas–Fas ligand interactions. J Immunol 2006;177(5):3055–62. [7] Sandhu K, Kaur I, Kumar B. Psoriasis and vitiligo. J Am Acad Dermatol 2004;51(1):149–50. [8] Gupta S, Gollapudi S. Molecular mechanisms of TNF-a-induced apoptosis in naive and memory T cell subsets. Autoimmun Rev 2006;5(4):264–8. [9] Dybedal I, Bryder D, Fossum A, Rusten LS, Jacobsen SE. Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells. Blood 2001;98(6):1782–91. [10] Skurkovich SV, Skurkovich B, Kelly JA. Anticytokine therapy – new approach to the treatment of autoimmune and cytokine-disturbance diseases. Med Hypotheses 2002;59(6):770–80. [11] Skurkovich S, Skurkovich B, Bellanti JA. A disturbance of interferon synthesis with the hyperproduction of unusual kinds of interferon can trigger autoimmune disease and play a pathogenetic role in AIDS: the removal of these interferons can be therapeutic. Med Hypotheses 1994;42(1):27–35. [12] Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-a agents. Ann NY Acad Sci 2005;105:1559–69. [13] Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metzger A. Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol 2004;51(1):52–61. [14] Simon JA, Burgos-Vargas R. Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab. Dermatology 2008;216(3):234–5.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Use of anti-tumor necrosis factor agents: A possible therapy for vitiligo Yajie Lv 1, Qiang Li 1, Lei Wang, Tianwen Gao * Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, China
a r t i c l e
i n f o
Article history: Received 5 December 2008 Accepted 10 December 2008
s u m m a r y Vitiligo is a depigmenting skin disorder resulting from the loss of melanocytes in the epidermis. Although the exact aetiology of vitiligo has not yet been established, the abnormal immune responses have been frequently observed in vitiligo patients. Moreover, some vitiligo patients show higher lesion levels of tumor necrosis factor (TNF)-a. TNF-a is an important pleiotropic cytokine that exerts potent pro-inflammatory effects. There is growing evidence that TNF-a plays an important role in the pathomechanism process of some autoimmunity diseases, including ankylosing spondylitis (AS). Treated with anti-TNF agents infliximab, with the improvement of AS, a patient’s vitiligo lesions also faded out. Therefore, we hypothesized that TNF-a play an important role in vitiligo. On the one hand, TNF-a destroys melanocytes through induction of various apoptotic pathways. On the other hand, TNF-a inhibits melanocyte stem cells differentiation. Anti-TNF therapy may be an effective treatment for vitiligo. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction Vitiligo is an acquired skin disorder of depigmentation, resulting from the destruction of melanocytes in the epidermis. The incidence of vitiligo is 0.5–2% worldwide, and no predilection exists for sex or race. These studies in the literature suggested a number of possible mechanisms in regard to vitiligo’s development [1]. Although the cause of vitiligo remains obscure, autoimmunity hypothesis has been now recognized as one of the most influential pathogenic mechanisms [2]. TNF-a is a pleiotropic cytokine and has numerous effects on the immune response, driving activation and recruitment of other inflammatory cells, amplifying production of IL-1, IL-6, and IL-8, and activating nuclear transcription factors such as NF-kB to propagate and maintain an inflammatory response [3]. It is produced by many different cell types, including activated T cells, keratinocytes, structural cells including fibroblasts, adipocytes and smooth muscle cells. It is clear that higher expression of TNF-a plays a central role in the pathogenesis of a number of autoimmune diseases. The hypothesis As TNF-a plays an important role in regulating apoptosis in many cell types including T lymphocytes, and abnormal expression of TNF-a has been observed in vitiligo, we hypothesized that TNF-a plays an important role in vitiligo. On the one hand, TNF-a destroys melanocytes through induction of various apoptotic pathways. On the other hand, TNF-a inhibits melanocyte stem cells differentia* Corresponding author. Tel./fax: +86 29 84775401. E-mail address: [email protected] (T. Gao). 1 These authors contributed equally to this work. 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.12.033
tion. Anti-TNF therapy may be an effective treatment for vitiligo. Here, we provide evidence to support the hypothesis. Evidence of TNF-a in vitiligo TNF-a is a major mediator of inflammation and, when overexpressed, can give rise to chronic inflammatory and autoimmune diseases. Over the last few years, evidence suggests TNF-a plays an important role in apoptosis through activation of the receptor-mediated apoptosis pathway in numerous cell types [8]. It is worth mentioning that TNF-a is a paracrine inhibitor of stem cells [9]. Vitiligo is often associated with other disorders that have an autoimmune origin, including AS, Graves’ disease and Hashimoto’s thyroiditis [5]. In a retrospective review, Sandhu et al. [7] found that some psoriasis patients also had vitiligo. As we all know, TNF-a has direct effects on the pathogenesis of these diseases. Autoreactive T cells that recognise pigment cell antigens have been detected in the sera of a significant proportion of vitiligo patients compared with healthy individuals. Briefly, the discovery strongly suggests a role for cellular immunity in vitiligo [6]. Moreover, some studies provided evidence that in vitiligo skin a significantly higher expression of TNF-a was detected, compared with perilesional, non-lesional and healthy skin [4]. Thus, it seems that TNF-a is a key step in the development of vitiligo. Previous studies indicated that not only T cells but also keratinocytes and fibroblasts changed the level of TNF-a around melanocytes. It seems that the leukasmus was the result that melanocytes disappear was caused by TNF-a through induction of various apoptotic pathways and together with inhibition of melanocyte stem cells differentiation. TNF-a also plays a key role in the pathogenesis of vitiligo.
Y. Lv et al. / Medical Hypotheses 72 (2009) 546–547
547
Associations between anti-TNF therapy and vitiligo
References
Skurkovich was the first to talk about the theory that anti-cytokine therapy in the treatment of autoimmune and cytokine-disturbance diseases [10,11]. Now, this theory is widely used in many autoimmune diseases treatment. Inhibitor of TNF-a infliximab (a chimeric monoclonal anti-TNF antibody) has been approved by the US FDA as a therapy for patients with various autoimmune diseases, including rheumatoid arthritis, AS and psoriasis. It has been demonstrated that the TNF blockers are quite successful [12]. Data on possible association between vitiligo and anti-TNF agents are limited so far and therefore, not fully conclusive. Topical tacrolimus ointment [13], a potent immunosuppressive drug is an effective alternative therapy for vitiligo, particularly when the disease involves the head and neck. Posttreatment expression of some cytokines including TNF-a decreased in the depigmented and adjacent uninvolved skin. These data suggested that an imbalance in local cytokine expression, In particular, TNF-a might play a role in the pathogenesis of vitiligo. It further indirectly supports the hypothesis that suppression of TNF-a may be an effective treatment of vitiligo. Simon and Burgor-Vargas [14] described a patient with AS and vitiligo. The patient was treated with infliximab, which resulted in immediate improvement in clinical and laboratory measures. The vitiligo lesions gradually faded out. They suggested that TNF-a was involved in the pathogenesis of vitiligo and this drug was an effective treatment for vitiligo. Although there is only one case, the case inspired us that some patient’s vitiligo lesions resulted from TNF-a. Further, anti-TNF agents are effective therapies to these patients. If, as suggested here, TNF-a levels play a major role in pathomechanism process of vitiligo, in some cases, the anti-TNF agents would provide a further effective strategy. As there is little data on anti-TNF agents in vitiligo, in evaluation of our hypothesis we suggest that more experimental and clinical studies must be performed to evaluate the exact precise effects of anti-TNF agents in vitiligo.
[1] Dell’anna ML, Picardo M. A review and a new hypothesis for nonimmunological pathogenetic mechanisms in vitiligo. Pigment Cell Res 2006;19(5):406–11. [2] Kemp EH, Waterman EA, Weetman AP. Immunological pathomechanisms in vitiligo. Expert Rev Mol Med 2001;3(20):1–22. [3] Blanco P, Palucka AK, Pascual V, Banchereau J. Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev 2008;19(1):41–52. [4] Birol A, Kisa U, Kurtipek GS, Kara F, Kocak M, Erkek E, et al. Increased tumor necrosis factor alpha (TNF-a) and interleukin 1-a (IL1-a) levels in the lesional skin of patients with nonsegmental vitiligo. Int J Dermatol 2006;45(8): 992–3. [5] Rezaei N, Gavalas NG, Weetman AP, Kemp EH. Autoimmunity as an aetiological factor in vitiligo. J Eur Acad Dermatol Venereol 2007;21(7):865–76. [6] Lambe T, Leung JC, Bouriez-Jones T, Silver K, Makinen K, Crockford TL, et al. CD4 T cell-dependent autoimmunity against a melanocyte neoantigen induces spontaneous vitiligo and depends upon Fas–Fas ligand interactions. J Immunol 2006;177(5):3055–62. [7] Sandhu K, Kaur I, Kumar B. Psoriasis and vitiligo. J Am Acad Dermatol 2004;51(1):149–50. [8] Gupta S, Gollapudi S. Molecular mechanisms of TNF-a-induced apoptosis in naive and memory T cell subsets. Autoimmun Rev 2006;5(4):264–8. [9] Dybedal I, Bryder D, Fossum A, Rusten LS, Jacobsen SE. Tumor necrosis factor (TNF)-mediated activation of the p55 TNF receptor negatively regulates maintenance of cycling reconstituting human hematopoietic stem cells. Blood 2001;98(6):1782–91. [10] Skurkovich SV, Skurkovich B, Kelly JA. Anticytokine therapy – new approach to the treatment of autoimmune and cytokine-disturbance diseases. Med Hypotheses 2002;59(6):770–80. [11] Skurkovich S, Skurkovich B, Bellanti JA. A disturbance of interferon synthesis with the hyperproduction of unusual kinds of interferon can trigger autoimmune disease and play a pathogenetic role in AIDS: the removal of these interferons can be therapeutic. Med Hypotheses 1994;42(1):27–35. [12] Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-a agents. Ann NY Acad Sci 2005;105:1559–69. [13] Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metzger A. Topical tacrolimus therapy for vitiligo: therapeutic responses and skin messenger RNA expression of proinflammatory cytokines. J Am Acad Dermatol 2004;51(1):52–61. [14] Simon JA, Burgos-Vargas R. Vitiligo improvement in a patient with ankylosing spondylitis treated with infliximab. Dermatology 2008;216(3):234–5.