Clinica Chimica Acta 429 (2014) 212–214
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Effect of treatment on prolactin levels in patients with psoriasis vulgaris
Dear Editor Psoriasis vulgaris, a prototypical Th-1, Th-17, and Th-22 mediated inflammatory disease and is presently classified as an immune mediated inflammatory disease associated with systemic inflammation resulting in increased risk for associated comorbidities [1]. Prolactin, a neuropeptide secreted by the anterior pituitary gland, has been integrated in a multiconcentration neuroendocrine-immune communication along the “brain-skin axis” acting as neuroendocrine modulator of both skin epidermal growth and the skin immune system [2]. Prolactin has been shown to enhance Th1 and Th17 responses thereby implicating its role in the pathogenesis of psoriasis [3]. Stress, an important triggering and exacerbating factor for psoriasis may represent a link between prolactin and its pathogenesis in psoriasis [3]. Although there are studies evaluating the concentrations of circulating prolactin in psoriasis, most of them are inconclusive and there is dearth of studies evaluating its response to anti-psoriatic treatment. Hence, we undertook this study to assess the effect of treatment (both topical and systemic therapy with methotrexate) on prolactin levels in patients with psoriasis vulgaris. This was a hospital-based, prospective cohort study on 60 patients with psoriasis vulgaris with or without psoriatic arthritis and 60 ageand gender-matched healthy controls. This study was approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry, India, and written informed consent was obtained from all study subjects prior to participation. This study was conducted according to the Helsinki Declaration of 1975, as revised in 1983. Patients with psoriasis vulgaris (International Psoriasis Council Consensus Classification of psoriasis vulgaris) [4] and psoriatic arthritis (as diagnosed by CASPAR criteria) [5], attending the dermatology outpatient department of our institute were included as cases in our study. Age- and gender-matched healthy volunteers were recruited as controls. The exclusion criteria for cases and controls were the following: Patients on any medication for the last month prior to inclusion, patients on other systemic therapy for psoriasis other than methotrexate, age b 18 y, pregnancy, malignancies, hepatic and renal disease, diabetes mellitus, morbid obesity (N 30 kg/m2), cardiovascular disease, infectious diseases and other inflammatory skin diseases. In all patients with psoriasis vulgaris, a detailed history with treatment details was taken followed by clinical examination and anthropometric measurements and was recorded in a predesigned proforma. The disease severity was assessed by PASI (Psoriasis Area Severity Index) scoring. [6] The concentrations of prolactin were estimated at baseline and at 12 weeks after treatment. For controls, anthropometric measurements were done and single blood sample was collected at time of recruitment for assay of prolactin concentrations. Five milliliters of venous blood was drawn after a fasting period of 12 h at 8 AM. Serum was separated and stored at − 80 °C for further 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.021
analysis of prolactin. Prolactin (DS-EIA-Prolactin) levels were estimated by commercially available ELISA kit. On follow-up at 12 weeks after initiation of therapy, 5 ml fasting blood sample was collected only in cases for reassessment of prolactin levels. All these assays were done in duplicate and their means were computed to increase the reliability of the measurements. Data processing and statistical analyses were performed using SPSS ver 20. The normality of data was assessed using the Kolmogorov and Smirnov method. The data are expressed as means ± SD. As the distribution of baseline prolactin concentrations between cases and controls was non-Gaussian, the Mann–Whitney U test was used to assess the significance of differences between cases and controls. For assessing the significance of differences between prolactin and PASI between pre and post treatment groups, Wilcoxon signed rank test was used as this data was non-Gaussian. Prolactin was correlated with disease severity (PASI), using Spearman's rank correlation test. Analysis was carried out at 5% concentration of significance and a p b 0.05 was considered as statistically significant. Sixty patients with chronic plaque psoriasis had mean disease duration of 40.65 ± 43.49 months and a mean PASI of 12.96 ± 9.38 at baseline. Seventeen patients had co-existing psoriatic arthritis. Forty-one patients were started on systemic therapy with methotrexate (mean PASI 16.57 ± 9.25) at a dose of 0.4 mg/kg body weight/week and the rest 19 patients were given topical therapy (mean PASI 5.17 ± 2.14) with tars and emollients. At the end of 12 weeks, 20 patients were lost to follow up and the concentrations of the study parameters post treatment were assessed in only 40 patients. The mean PASI after 12 weeks of treatment was 3.33 ± 2.04. At baseline, prolactin levels were significantly higher in patients with psoriasis (32.79 ± 18.72 ng/ml), when compared to controls (15.83 ± 7.29 ng/ml) (p b0.0001). Men and women with psoriasis showed significant elevation in prolactin, as compared with control men and women (Fig. 1A). Baseline prolactin demonstrated a significant positive correlation with the severity of psoriasis (r = 0.894, p b 0.0001). Out of the 40 psoriatic patients who were followed up at 12 weeks, 11 had received topical therapy with tars and emollients and the rest 29 patients had received systemic therapy with methotrexate. After 12 weeks of therapy (both topical and systemic), there was a significant reduction in PASI and prolactin levels. (Fig. 1B) The improvement was more with systemic therapy, compared to topical therapy. Prolactin, secreted by the anterior pituitary has been implicated as an important immuno-modulator and has been found to exert a proliferative effect in cultured human keratinocytes via specific receptors [3]. It is a member of the type I cytokine superfamily causing proliferation of lymphocytes during immune responses. It enhances proliferation of IFN-γ production in T cells or NK cells, potentiating IFN-γ induced CXC chemokine production in keratinocytes which, in turn, generates abundant infiltrates of Th1 cells. Prolactin induces CCL20 secretion from epidermal keratinocytes in psoriatic lesions, which recruit Th17 cells that release interleukin-17 (IL-17). Prolactin and IL-17 cooperate in a positive feedback loop to increase CCL20 secretion. This process may aggravate the Th17-mediated inflammation in psoriatic lesions [7].
Letter to the Editor
213
Fig. 1. A. Comparison of prolactin levels at baseline between males and females in cases and controls. B. Effect of topical and systemic therapy on prolactin levels and PASI.
From 30 psoriasis patients, Kato et al. [2] observed significantly high levels of prolactin among patients compared to controls, with significant decrease among patients after treatment. A significant positive correlation was found between serum prolactin and PASI, both before and after treatment with methotrexate. Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) correlated with PASI and prolactin concentrations before and after therapy. El-Khateeb et al. [7] evaluated 15 psoriasis patients and found significantly high levels of prolactin in lesional skin compared to non-lesional psoriasis skin, serum of psoriasis patients, control skin and control serum. The concentrations showed no correlation with disease severity. They concluded that locally produced prolactin might be implicated in the etiopathogenesis of psoriasis.
In our study, we observed significantly higher levels of prolactin in patients with psoriasis when compared to controls and these levels correlated positively with the disease severity. Prolactin levels were significantly lowered after 12 weeks of therapy with both topical as well as with systemic therapy with methotrexate and the improvement was more with systemic therapy compared to topical therapy. We observed that the improvement in PASI observed clinically was translated as an improvement in the prolactin levels. However, Gorpelioglu et al. [8] in 39 patients with psoriasis found no significant difference in prolactin levels between cases and controls and no correlation between prolactin levels and PASI. The results of the various studies are conflicting owing to the differences in the treatment
214
Letter to the Editor
modalities used. In our study, both topical therapy and systemic therapy with methotrexate have been proven to be beneficial in improving the prolactin levels by decreasing the inflammation. Our study suggests that methotrexate is the best modality of therapy producing a reduction in PASI and prolactin concentrations in our study. The limitations of our study include the following: relatively smaller sample size and shorter period of follow up and high dropout rate. Another major limitation was that correlation of prolactin concentrations with emotional disturbances, using a psychological questionnaire in the patients with psoriasis was not done. Future studies on a larger sample size involving psoriasis patients belonging to all spectrums and receiving different modalities of treatment with a longer period of follow up are required to validate the results of our study. Prolactin can play a role in the pathogenesis of psoriasis as a neuroendocrine modulator of both skin epithelial growth and the skin immune system [3,7,9]. Our results indicate that prolactin levels are significantly higher in patients with psoriasis when compared to that in controls, which correlate with disease severity. In addition, treatment of psoriasis significantly lowers the prolactin levels. These observations indicate that prolactin seems to have a role in the pathogenesis of psoriasis and prolactin may be a novel future therapeutic target in psoriasis especially in refractory cases. As psoriasis is often triggered or exacerbated by psychoemotional stress, prolactin may represent a link between psoriasis and stress, and elevated levels can be cause and/or a consequence of psoriasis pathology. Elevated levels of prolactin could be attributed to either the increased stress-induced pituitary secretion of prolactin or to the overproduction in the affected skin. [3,7,9] The exact source of this increase still remains to be established. More studies at both clinical, and basic research concentration are warranted to form a basis on which a comprehensive therapeutic strategy for psoriasis can be devised. Funding The present study was funded by the Intramural Research Grant of the Jawaharlal Institute of Postgraduate Medical Education and Research [JIPMER], Puducherry, India. Conflict of interest The authors report no conflict of interest. References [1] Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 2010;130:1785–96.
[2] Kanda N, Shibata S, Tada Y, Nashiro K, Tamaki K, Watanabe S. Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes. Eur J Immunol 2009;39(4):996–1006. [3] Kato AM, Gheida SF, El-Bendary AS, Badawy AA, El-Fakharany RE. Serum level of prolactin in psoriatic patients. Egypt Dermatol Online J 2012;8(2):1–12. [4] Griffiths CE, Christophers E, Barker JN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol 2007;156:258–62. [5] Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665–73. [6] Langley RG. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. J Am Acad Dermatol 2004;51:563–9. [7] El-Khateeb EA, Zuel-Fakkar NM, Eid SM, Abdul-Wahab SE. Prolactin level is significantly elevated in lesional skin of patients with psoriasis. Int J Dermatol 2011;50:693–6. [8] Gorpelioglu C, Gungor E, Alli N. Is prolactin involved in etiopathogenesis of psoriasis. J Eur Acad Dermatol Venereol 2008;22:1135–6. [9] Foitzik K, Langan EA, Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone. J Invest Dermatol 2009;129:1071–87.
S. Rathika Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Medha Rajappa* Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Laxmisha Chandrashekar Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Malathi Munisamy Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Devinder Mohan Thappa Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India ⁎Corresponding author at: Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry-605006, India. Tel.: +91 948 639 8875; fax: +91 413 227 2067. E-mail address: [email protected]. 28 October 2013
Contents lists available at ScienceDirect
Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Letter to the Editor Effect of treatment on prolactin levels in patients with psoriasis vulgaris
Dear Editor Psoriasis vulgaris, a prototypical Th-1, Th-17, and Th-22 mediated inflammatory disease and is presently classified as an immune mediated inflammatory disease associated with systemic inflammation resulting in increased risk for associated comorbidities [1]. Prolactin, a neuropeptide secreted by the anterior pituitary gland, has been integrated in a multiconcentration neuroendocrine-immune communication along the “brain-skin axis” acting as neuroendocrine modulator of both skin epidermal growth and the skin immune system [2]. Prolactin has been shown to enhance Th1 and Th17 responses thereby implicating its role in the pathogenesis of psoriasis [3]. Stress, an important triggering and exacerbating factor for psoriasis may represent a link between prolactin and its pathogenesis in psoriasis [3]. Although there are studies evaluating the concentrations of circulating prolactin in psoriasis, most of them are inconclusive and there is dearth of studies evaluating its response to anti-psoriatic treatment. Hence, we undertook this study to assess the effect of treatment (both topical and systemic therapy with methotrexate) on prolactin levels in patients with psoriasis vulgaris. This was a hospital-based, prospective cohort study on 60 patients with psoriasis vulgaris with or without psoriatic arthritis and 60 ageand gender-matched healthy controls. This study was approved by the Institute Ethics Committee (Human Studies), JIPMER, Puducherry, India, and written informed consent was obtained from all study subjects prior to participation. This study was conducted according to the Helsinki Declaration of 1975, as revised in 1983. Patients with psoriasis vulgaris (International Psoriasis Council Consensus Classification of psoriasis vulgaris) [4] and psoriatic arthritis (as diagnosed by CASPAR criteria) [5], attending the dermatology outpatient department of our institute were included as cases in our study. Age- and gender-matched healthy volunteers were recruited as controls. The exclusion criteria for cases and controls were the following: Patients on any medication for the last month prior to inclusion, patients on other systemic therapy for psoriasis other than methotrexate, age b 18 y, pregnancy, malignancies, hepatic and renal disease, diabetes mellitus, morbid obesity (N 30 kg/m2), cardiovascular disease, infectious diseases and other inflammatory skin diseases. In all patients with psoriasis vulgaris, a detailed history with treatment details was taken followed by clinical examination and anthropometric measurements and was recorded in a predesigned proforma. The disease severity was assessed by PASI (Psoriasis Area Severity Index) scoring. [6] The concentrations of prolactin were estimated at baseline and at 12 weeks after treatment. For controls, anthropometric measurements were done and single blood sample was collected at time of recruitment for assay of prolactin concentrations. Five milliliters of venous blood was drawn after a fasting period of 12 h at 8 AM. Serum was separated and stored at − 80 °C for further 0009-8981/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.cca.2013.12.021
analysis of prolactin. Prolactin (DS-EIA-Prolactin) levels were estimated by commercially available ELISA kit. On follow-up at 12 weeks after initiation of therapy, 5 ml fasting blood sample was collected only in cases for reassessment of prolactin levels. All these assays were done in duplicate and their means were computed to increase the reliability of the measurements. Data processing and statistical analyses were performed using SPSS ver 20. The normality of data was assessed using the Kolmogorov and Smirnov method. The data are expressed as means ± SD. As the distribution of baseline prolactin concentrations between cases and controls was non-Gaussian, the Mann–Whitney U test was used to assess the significance of differences between cases and controls. For assessing the significance of differences between prolactin and PASI between pre and post treatment groups, Wilcoxon signed rank test was used as this data was non-Gaussian. Prolactin was correlated with disease severity (PASI), using Spearman's rank correlation test. Analysis was carried out at 5% concentration of significance and a p b 0.05 was considered as statistically significant. Sixty patients with chronic plaque psoriasis had mean disease duration of 40.65 ± 43.49 months and a mean PASI of 12.96 ± 9.38 at baseline. Seventeen patients had co-existing psoriatic arthritis. Forty-one patients were started on systemic therapy with methotrexate (mean PASI 16.57 ± 9.25) at a dose of 0.4 mg/kg body weight/week and the rest 19 patients were given topical therapy (mean PASI 5.17 ± 2.14) with tars and emollients. At the end of 12 weeks, 20 patients were lost to follow up and the concentrations of the study parameters post treatment were assessed in only 40 patients. The mean PASI after 12 weeks of treatment was 3.33 ± 2.04. At baseline, prolactin levels were significantly higher in patients with psoriasis (32.79 ± 18.72 ng/ml), when compared to controls (15.83 ± 7.29 ng/ml) (p b0.0001). Men and women with psoriasis showed significant elevation in prolactin, as compared with control men and women (Fig. 1A). Baseline prolactin demonstrated a significant positive correlation with the severity of psoriasis (r = 0.894, p b 0.0001). Out of the 40 psoriatic patients who were followed up at 12 weeks, 11 had received topical therapy with tars and emollients and the rest 29 patients had received systemic therapy with methotrexate. After 12 weeks of therapy (both topical and systemic), there was a significant reduction in PASI and prolactin levels. (Fig. 1B) The improvement was more with systemic therapy, compared to topical therapy. Prolactin, secreted by the anterior pituitary has been implicated as an important immuno-modulator and has been found to exert a proliferative effect in cultured human keratinocytes via specific receptors [3]. It is a member of the type I cytokine superfamily causing proliferation of lymphocytes during immune responses. It enhances proliferation of IFN-γ production in T cells or NK cells, potentiating IFN-γ induced CXC chemokine production in keratinocytes which, in turn, generates abundant infiltrates of Th1 cells. Prolactin induces CCL20 secretion from epidermal keratinocytes in psoriatic lesions, which recruit Th17 cells that release interleukin-17 (IL-17). Prolactin and IL-17 cooperate in a positive feedback loop to increase CCL20 secretion. This process may aggravate the Th17-mediated inflammation in psoriatic lesions [7].
Letter to the Editor
213
Fig. 1. A. Comparison of prolactin levels at baseline between males and females in cases and controls. B. Effect of topical and systemic therapy on prolactin levels and PASI.
From 30 psoriasis patients, Kato et al. [2] observed significantly high levels of prolactin among patients compared to controls, with significant decrease among patients after treatment. A significant positive correlation was found between serum prolactin and PASI, both before and after treatment with methotrexate. Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA) correlated with PASI and prolactin concentrations before and after therapy. El-Khateeb et al. [7] evaluated 15 psoriasis patients and found significantly high levels of prolactin in lesional skin compared to non-lesional psoriasis skin, serum of psoriasis patients, control skin and control serum. The concentrations showed no correlation with disease severity. They concluded that locally produced prolactin might be implicated in the etiopathogenesis of psoriasis.
In our study, we observed significantly higher levels of prolactin in patients with psoriasis when compared to controls and these levels correlated positively with the disease severity. Prolactin levels were significantly lowered after 12 weeks of therapy with both topical as well as with systemic therapy with methotrexate and the improvement was more with systemic therapy compared to topical therapy. We observed that the improvement in PASI observed clinically was translated as an improvement in the prolactin levels. However, Gorpelioglu et al. [8] in 39 patients with psoriasis found no significant difference in prolactin levels between cases and controls and no correlation between prolactin levels and PASI. The results of the various studies are conflicting owing to the differences in the treatment
214
Letter to the Editor
modalities used. In our study, both topical therapy and systemic therapy with methotrexate have been proven to be beneficial in improving the prolactin levels by decreasing the inflammation. Our study suggests that methotrexate is the best modality of therapy producing a reduction in PASI and prolactin concentrations in our study. The limitations of our study include the following: relatively smaller sample size and shorter period of follow up and high dropout rate. Another major limitation was that correlation of prolactin concentrations with emotional disturbances, using a psychological questionnaire in the patients with psoriasis was not done. Future studies on a larger sample size involving psoriasis patients belonging to all spectrums and receiving different modalities of treatment with a longer period of follow up are required to validate the results of our study. Prolactin can play a role in the pathogenesis of psoriasis as a neuroendocrine modulator of both skin epithelial growth and the skin immune system [3,7,9]. Our results indicate that prolactin levels are significantly higher in patients with psoriasis when compared to that in controls, which correlate with disease severity. In addition, treatment of psoriasis significantly lowers the prolactin levels. These observations indicate that prolactin seems to have a role in the pathogenesis of psoriasis and prolactin may be a novel future therapeutic target in psoriasis especially in refractory cases. As psoriasis is often triggered or exacerbated by psychoemotional stress, prolactin may represent a link between psoriasis and stress, and elevated levels can be cause and/or a consequence of psoriasis pathology. Elevated levels of prolactin could be attributed to either the increased stress-induced pituitary secretion of prolactin or to the overproduction in the affected skin. [3,7,9] The exact source of this increase still remains to be established. More studies at both clinical, and basic research concentration are warranted to form a basis on which a comprehensive therapeutic strategy for psoriasis can be devised. Funding The present study was funded by the Intramural Research Grant of the Jawaharlal Institute of Postgraduate Medical Education and Research [JIPMER], Puducherry, India. Conflict of interest The authors report no conflict of interest. References [1] Davidovici BB, Sattar N, Prinz J, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 2010;130:1785–96.
[2] Kanda N, Shibata S, Tada Y, Nashiro K, Tamaki K, Watanabe S. Prolactin enhances basal and IL-17-induced CCL20 production by human keratinocytes. Eur J Immunol 2009;39(4):996–1006. [3] Kato AM, Gheida SF, El-Bendary AS, Badawy AA, El-Fakharany RE. Serum level of prolactin in psoriatic patients. Egypt Dermatol Online J 2012;8(2):1–12. [4] Griffiths CE, Christophers E, Barker JN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol 2007;156:258–62. [5] Taylor W, Gladman D, Helliwell P, et al. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665–73. [6] Langley RG. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. J Am Acad Dermatol 2004;51:563–9. [7] El-Khateeb EA, Zuel-Fakkar NM, Eid SM, Abdul-Wahab SE. Prolactin level is significantly elevated in lesional skin of patients with psoriasis. Int J Dermatol 2011;50:693–6. [8] Gorpelioglu C, Gungor E, Alli N. Is prolactin involved in etiopathogenesis of psoriasis. J Eur Acad Dermatol Venereol 2008;22:1135–6. [9] Foitzik K, Langan EA, Paus R. Prolactin and the skin: a dermatological perspective on an ancient pleiotropic peptide hormone. J Invest Dermatol 2009;129:1071–87.
S. Rathika Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Medha Rajappa* Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Laxmisha Chandrashekar Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Malathi Munisamy Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India Devinder Mohan Thappa Department of Dermatology, Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India ⁎Corresponding author at: Department of Biochemistry, Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Puducherry-605006, India. Tel.: +91 948 639 8875; fax: +91 413 227 2067. E-mail address: [email protected]. 28 October 2013
