Research Letter
Narrowband ultraviolet B phototherapy in psoriasis reduces proinflammatory cytokine levels and improves vitiligo and neutrophilic asthma DOI: 10.1111/bjd.13988
Table 1 Values of exhaled breath condensate, induced sputum, fractional exhaled nitric oxide and spirometric data before and after psoriasis treatment in monozygotic twins 3 September 2013 (before psoriasis treatment)
5 December 2013 (after psoriasis treatment)
Twin 1
Twin 1 (treated)
DEAR EDITOR, Psoriasis, neutrophilic asthma and vitiligo vulgaris are three immune-mediated diseases in which raised serum levels of proinflammatory T helper (Th) 1/Th17 cytokines have been detected. Psoriasis is considered a systemic disease with several comorbidities, and the role of high levels of cytokines referable to Th1–Th17 patterns in the pathogenesis of these comorbidities remains to be clarified.1–3 Monozygotic twins, aged 69 years, affected by psoriasis and vitiligo were referred to the outpatient clinic of the internal medicine department of the University of Brescia, Brescia, Italy, because of poorly controlled asthma. Both twins had asthma, which had been treated with montelukast 10 mg daily, inhaled corticosteroid and a long-acting b2 agonist (fluticasone 250 lg/ formoterol 10 lg) twice daily in the preceding 6 months. Physical examination revealed high respiratory rates (22 and 26 breaths per min, respectively) with signs of accessory muscle use and, on auscultation, decreased breathing sounds with inspiratory and expiratory wheezing. Pulse oximetry was 94% and 92%, respectively, on room air. A chest radiograph of both twins showed bronchial thickening, hyperinflation and focal atelectasis consistent with asthma. Spirometry detected, respectively, a forced expiratory volume in the first second (FEV1) of 64% and 66% of the predicted volume, and a Tiffeneau index of 70% and 71% of the predicted value. The patients reported moderate limitations of daily activities and a mean of three asthma attacks weekly, suggesting the presence of severe uncontrolled asthma.3 In both twins a chest computer tomography scan was performed during inspiration, and demonstrated air trapping. Immunology examinations resulted in negative antinuclear antibody, extractable nuclear antigen and rheumatoid factor, no eosinophilia and normal total IgE, erythrocyte sedimentation rate, C-reactive protein and procalcitonin levels. Serum levels of interleukin (IL)-17, IL-1b, IL-6, IL-8, IL-12 and tumour necrosis factor (TNF)-a were higher than normal, whereas IL-4 was in the normal range (Table 1). Hence, sputum induction was performed to characterize asthma inflammatory phenotype showing a neutrophilic pattern. Afterwards, the twins underwent an exhaled breath condensate test, analysed with an enzyme-linked immunosorbent assay, which showed a lymphocyte Th1/Th17 cytokine
pattern (Table 1).4 After these assessments the dose of formoterol and fluticasone was doubled, and an anticholinergic (tiotropium bromide 18 lg) once daily was added. Associated
British Journal of Dermatology (2015) 173, pp1544–1545
© 2015 British Association of Dermatologists
1544
Twin 2
Cytokine serum levels (pg mL 1)a IL-17 (100–140) 200 180 150 IL-1b (0) 11 10 2 TNF-a (22–34) 60 72 37 IL-6 (05–160) 225 242 120 IL-12 (10–65) 80 85 55 IL-8 (24–35) 53 48 37 Exhaled breath condensate (pg mL 1) IL-17 157 161 56 IL-1b 83 79 26 TNF-a 134 131 81 IL-6 95 89 30 IL-12 62 66 21 IL-8 50 51 38 IL-4 17 12 16 Induced sputum (%) Macrophages 26 28 41 Neutrophils 71 68 56 Eosinophils 1 1 1 Lymphocytes 2 3 2 Epithelial cells 0 0 0 Fractional exhaled nitric oxide, ppb (mL s 1) 30 885 867 603 50 540 560 320 100 274 267 158 200 132 137 78 Spirometry (%) Prebronchodilator FEV1 64 66 81 FEV1/FVC 70 71 80 Postbronchodilator FEV1 64 67 89 FEV1/FVC 70 71 83
Twin 2 (untreated) 170 7 70 180 70 45 102 65 124 52 44 49 14 40 58 0 2 0 719 470 223 116
72 76 73 76
IL, interleukin; TNF, tumour necrosis factor; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity. aPredicted values are given in parentheses.
Research Letter 1545
with the asthma, the patients had severe psoriasis, with a Psoriasis Area Severity Index (PASI) score of 23 and 25, respectively. Body surface area score was 40 in both cases. In addition, patches of vitiligo occurred on the hands and feet in both twins. Only one twin consented to undergo a treatment cycle for psoriasis with narrowband ultraviolet B phototherapy three times a week, while the other refused all dermatological care. After 3 months, the twins were re-examined. The twin who underwent phototherapy presented a clear improvement of psoriasis, with a PASI of 12 and a partial follicular repigmentation of the patches of vitiligo. In the same patient we observed an improvement of laboratory parameters, including a reduction in the level of cytokines in the serum (Table 1). Moreover, this twin had controlled asthma without daily symptoms and/or daily life activity limitations, with a functional respiratory improvement (FEV1 81%; Tiffeneau index 80%). The other twin, who was treated with the same asthma therapy, showed only slight improvement in the limitations of daily activities and in the laboratory parameters of airway obstruction (FEV1 72%; Tiffeneau index 76%). Only the twin treated for both asthma and psoriasis achieved good control of the asthma, psoriasis and vitiligo, while the second twin experienced less improvement in the asthma, without any change in psoriasis and vitiligo. In addition, we showed that, at baseline, the median serum levels of TNF-a, IL-1, IL-6, IL-8, IL-17 and IL-12 were significantly higher in both patients compared with findings in normal controls, and that they decreased only in the twin who was successfully treated with phototherapy. Psoriasis, vitiligo and neutrophilic asthma are autoimmune skin diseases.1,2,5,6 In psoriatic skin, the production of Th1 and Th17 cytokines is upregulated,7 leading to raised serum levels that correlate with disease severity and extension.7,8 Vitiligo is also frequently associated with other autoimmune conditions (up to 23% of patients), including psoriasis in 8% of cases.2 In addition, in this study, levels of IL-17 were found to be increased both in serum and lesional skin, suggesting a pivotal pathogenetic role for this cytokine, which may favour the skewing of the immune response to Th1 and Th17 cells.5 Asthma is a wellknown chronic inflammatory airway disorder, and biological studies on the pathogenesis of asthma have shown (using bronchoalveolar lavage and induced sputum) that different cell populations are involved in different inflammatory phenotypes of asthma.3 In particular, in neutrophilic asthma, a prevalence of Th1 lymphocytes and interferon-c was found.6 In addition, the presence of Th17 cells and enhanced production of IL-17 have been directly documented in lung tissue,9 and a single nucleotide polymorphism in IL17A and IL17F was found to confer susceptibility for neutrophilic asthma.10 In conclusion, we speculate that in these three different manifestations of Th1/Th17 dysregulation, phototherapy
© 2015 British Association of Dermatologists
could improve the regulatory mechanisms that control both psoriasis and neutrophilic asthma, decreasing proinflammatory cytokine spillover from skin. Moreover, phototherapy can enhance the effects of asthma therapy, thus suggesting a pivotal role of Th1 and TH17 in developing neutrophilic systemic inflammation. 1
M. MALERBA1 Department of Internal Medicine, University of Brescia and AOU Spedali Civili, Brescia, G. DAMIANI1 Italy A. RADAELI2 2 Department of Emergency, AOU Spedali B. RAGNOLI2 Civili, Brescia, Italy A. OLIVINI1 3 Department of Dermatology, University P . G . C A L Z A V A R A - P I N T O N 3 of Brescia, Brescia, Italy E-mail: [email protected]
References 1 Nast A, Boehncke WH, Mrowietz U et al. S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012; 10(Suppl. 2):S1–95. 2 Sheth VM, Guo Y, Quareshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology 2013; 227:311– 15. 3 Global Initiative for Asthma. Global strategy for asthma management and prevention. Available at: www.ginasthma.org (last accessed 27 October 2015). 4 Horvath I, Hunt J, Barnes PJ et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005; 26:523–48. 5 Bassiouny DA, Shaker O. Role of interleukin-17 in the pathogenesis of vitiligo. Clin Exp Dermatol 2011; 36:292–7. 6 Kim YM, Kim YS, Jeon SG et al. Immunopathogenesis of allergic asthma: more than the Th2 hypothesis. Allergy Asthma Immunol Res 2013; 5:189–96. 7 Chiricozzi A, Guttman-Yassky E, Suarez-Fari~ nas M et al. Integrative responses to IL-17 and TNF-a in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 2011; 131:677–87. 8 Coimbra S, Oliveira H, Reis F et al. Interleukin (IL)-22, IL-17, IL23, IL-8, vascular endothelial growth factor and tumour necrosis factor-a levels in patients with psoriasis before, during and after psoralen-ultraviolet A and narrowband ultraviolet B therapy. Br J Dermatol 2010; 163:1282–90. 9 Pene J, Chevalier S, Preisser L et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008; 180:7423–30. 10 Maalmi H, Beraies A, Charad R et al. IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia. J Asthma 2014; 51:348–54.
Funding sources: none. Conflicts of interest: none declared.
British Journal of Dermatology (2015) 173, pp1544–1545
Narrowband ultraviolet B phototherapy in psoriasis reduces proinflammatory cytokine levels and improves vitiligo and neutrophilic asthma DOI: 10.1111/bjd.13988
Table 1 Values of exhaled breath condensate, induced sputum, fractional exhaled nitric oxide and spirometric data before and after psoriasis treatment in monozygotic twins 3 September 2013 (before psoriasis treatment)
5 December 2013 (after psoriasis treatment)
Twin 1
Twin 1 (treated)
DEAR EDITOR, Psoriasis, neutrophilic asthma and vitiligo vulgaris are three immune-mediated diseases in which raised serum levels of proinflammatory T helper (Th) 1/Th17 cytokines have been detected. Psoriasis is considered a systemic disease with several comorbidities, and the role of high levels of cytokines referable to Th1–Th17 patterns in the pathogenesis of these comorbidities remains to be clarified.1–3 Monozygotic twins, aged 69 years, affected by psoriasis and vitiligo were referred to the outpatient clinic of the internal medicine department of the University of Brescia, Brescia, Italy, because of poorly controlled asthma. Both twins had asthma, which had been treated with montelukast 10 mg daily, inhaled corticosteroid and a long-acting b2 agonist (fluticasone 250 lg/ formoterol 10 lg) twice daily in the preceding 6 months. Physical examination revealed high respiratory rates (22 and 26 breaths per min, respectively) with signs of accessory muscle use and, on auscultation, decreased breathing sounds with inspiratory and expiratory wheezing. Pulse oximetry was 94% and 92%, respectively, on room air. A chest radiograph of both twins showed bronchial thickening, hyperinflation and focal atelectasis consistent with asthma. Spirometry detected, respectively, a forced expiratory volume in the first second (FEV1) of 64% and 66% of the predicted volume, and a Tiffeneau index of 70% and 71% of the predicted value. The patients reported moderate limitations of daily activities and a mean of three asthma attacks weekly, suggesting the presence of severe uncontrolled asthma.3 In both twins a chest computer tomography scan was performed during inspiration, and demonstrated air trapping. Immunology examinations resulted in negative antinuclear antibody, extractable nuclear antigen and rheumatoid factor, no eosinophilia and normal total IgE, erythrocyte sedimentation rate, C-reactive protein and procalcitonin levels. Serum levels of interleukin (IL)-17, IL-1b, IL-6, IL-8, IL-12 and tumour necrosis factor (TNF)-a were higher than normal, whereas IL-4 was in the normal range (Table 1). Hence, sputum induction was performed to characterize asthma inflammatory phenotype showing a neutrophilic pattern. Afterwards, the twins underwent an exhaled breath condensate test, analysed with an enzyme-linked immunosorbent assay, which showed a lymphocyte Th1/Th17 cytokine
pattern (Table 1).4 After these assessments the dose of formoterol and fluticasone was doubled, and an anticholinergic (tiotropium bromide 18 lg) once daily was added. Associated
British Journal of Dermatology (2015) 173, pp1544–1545
© 2015 British Association of Dermatologists
1544
Twin 2
Cytokine serum levels (pg mL 1)a IL-17 (100–140) 200 180 150 IL-1b (0) 11 10 2 TNF-a (22–34) 60 72 37 IL-6 (05–160) 225 242 120 IL-12 (10–65) 80 85 55 IL-8 (24–35) 53 48 37 Exhaled breath condensate (pg mL 1) IL-17 157 161 56 IL-1b 83 79 26 TNF-a 134 131 81 IL-6 95 89 30 IL-12 62 66 21 IL-8 50 51 38 IL-4 17 12 16 Induced sputum (%) Macrophages 26 28 41 Neutrophils 71 68 56 Eosinophils 1 1 1 Lymphocytes 2 3 2 Epithelial cells 0 0 0 Fractional exhaled nitric oxide, ppb (mL s 1) 30 885 867 603 50 540 560 320 100 274 267 158 200 132 137 78 Spirometry (%) Prebronchodilator FEV1 64 66 81 FEV1/FVC 70 71 80 Postbronchodilator FEV1 64 67 89 FEV1/FVC 70 71 83
Twin 2 (untreated) 170 7 70 180 70 45 102 65 124 52 44 49 14 40 58 0 2 0 719 470 223 116
72 76 73 76
IL, interleukin; TNF, tumour necrosis factor; FEV1, forced expiratory volume in the first second; FVC, forced vital capacity. aPredicted values are given in parentheses.
Research Letter 1545
with the asthma, the patients had severe psoriasis, with a Psoriasis Area Severity Index (PASI) score of 23 and 25, respectively. Body surface area score was 40 in both cases. In addition, patches of vitiligo occurred on the hands and feet in both twins. Only one twin consented to undergo a treatment cycle for psoriasis with narrowband ultraviolet B phototherapy three times a week, while the other refused all dermatological care. After 3 months, the twins were re-examined. The twin who underwent phototherapy presented a clear improvement of psoriasis, with a PASI of 12 and a partial follicular repigmentation of the patches of vitiligo. In the same patient we observed an improvement of laboratory parameters, including a reduction in the level of cytokines in the serum (Table 1). Moreover, this twin had controlled asthma without daily symptoms and/or daily life activity limitations, with a functional respiratory improvement (FEV1 81%; Tiffeneau index 80%). The other twin, who was treated with the same asthma therapy, showed only slight improvement in the limitations of daily activities and in the laboratory parameters of airway obstruction (FEV1 72%; Tiffeneau index 76%). Only the twin treated for both asthma and psoriasis achieved good control of the asthma, psoriasis and vitiligo, while the second twin experienced less improvement in the asthma, without any change in psoriasis and vitiligo. In addition, we showed that, at baseline, the median serum levels of TNF-a, IL-1, IL-6, IL-8, IL-17 and IL-12 were significantly higher in both patients compared with findings in normal controls, and that they decreased only in the twin who was successfully treated with phototherapy. Psoriasis, vitiligo and neutrophilic asthma are autoimmune skin diseases.1,2,5,6 In psoriatic skin, the production of Th1 and Th17 cytokines is upregulated,7 leading to raised serum levels that correlate with disease severity and extension.7,8 Vitiligo is also frequently associated with other autoimmune conditions (up to 23% of patients), including psoriasis in 8% of cases.2 In addition, in this study, levels of IL-17 were found to be increased both in serum and lesional skin, suggesting a pivotal pathogenetic role for this cytokine, which may favour the skewing of the immune response to Th1 and Th17 cells.5 Asthma is a wellknown chronic inflammatory airway disorder, and biological studies on the pathogenesis of asthma have shown (using bronchoalveolar lavage and induced sputum) that different cell populations are involved in different inflammatory phenotypes of asthma.3 In particular, in neutrophilic asthma, a prevalence of Th1 lymphocytes and interferon-c was found.6 In addition, the presence of Th17 cells and enhanced production of IL-17 have been directly documented in lung tissue,9 and a single nucleotide polymorphism in IL17A and IL17F was found to confer susceptibility for neutrophilic asthma.10 In conclusion, we speculate that in these three different manifestations of Th1/Th17 dysregulation, phototherapy
© 2015 British Association of Dermatologists
could improve the regulatory mechanisms that control both psoriasis and neutrophilic asthma, decreasing proinflammatory cytokine spillover from skin. Moreover, phototherapy can enhance the effects of asthma therapy, thus suggesting a pivotal role of Th1 and TH17 in developing neutrophilic systemic inflammation. 1
M. MALERBA1 Department of Internal Medicine, University of Brescia and AOU Spedali Civili, Brescia, G. DAMIANI1 Italy A. RADAELI2 2 Department of Emergency, AOU Spedali B. RAGNOLI2 Civili, Brescia, Italy A. OLIVINI1 3 Department of Dermatology, University P . G . C A L Z A V A R A - P I N T O N 3 of Brescia, Brescia, Italy E-mail: [email protected]
References 1 Nast A, Boehncke WH, Mrowietz U et al. S3 – Guidelines on the treatment of psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012; 10(Suppl. 2):S1–95. 2 Sheth VM, Guo Y, Quareshi AA. Comorbidities associated with vitiligo: a ten-year retrospective study. Dermatology 2013; 227:311– 15. 3 Global Initiative for Asthma. Global strategy for asthma management and prevention. Available at: www.ginasthma.org (last accessed 27 October 2015). 4 Horvath I, Hunt J, Barnes PJ et al. Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 2005; 26:523–48. 5 Bassiouny DA, Shaker O. Role of interleukin-17 in the pathogenesis of vitiligo. Clin Exp Dermatol 2011; 36:292–7. 6 Kim YM, Kim YS, Jeon SG et al. Immunopathogenesis of allergic asthma: more than the Th2 hypothesis. Allergy Asthma Immunol Res 2013; 5:189–96. 7 Chiricozzi A, Guttman-Yassky E, Suarez-Fari~ nas M et al. Integrative responses to IL-17 and TNF-a in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 2011; 131:677–87. 8 Coimbra S, Oliveira H, Reis F et al. Interleukin (IL)-22, IL-17, IL23, IL-8, vascular endothelial growth factor and tumour necrosis factor-a levels in patients with psoriasis before, during and after psoralen-ultraviolet A and narrowband ultraviolet B therapy. Br J Dermatol 2010; 163:1282–90. 9 Pene J, Chevalier S, Preisser L et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008; 180:7423–30. 10 Maalmi H, Beraies A, Charad R et al. IL-17A and IL-17F genes variants and susceptibility to childhood asthma in Tunisia. J Asthma 2014; 51:348–54.
Funding sources: none. Conflicts of interest: none declared.
British Journal of Dermatology (2015) 173, pp1544–1545
