DDR
DRUG DEVELOPMENT RESEARCH 75 : S64–S66 (2014)
Clinical Overview
A Possible Role of Polycystic Ovary Syndrome for Pregnancy Complications in Women with Psoriasis Clara De Simone,1* Giacomo Caldarola,1 Marialuisa Corbeddu,1 Francesca Moro,2 Anna Tropea,2 Gaia Moretta,1 and Rosanna Apa2 1 Institute of Dermatology, Università Cattolica del Sacro Cuore (Catholic University of the Sacred Heart), 00168 Rome, Italy 2 Institute of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Psoriasis is a common, chronic, relapsing immune-mediated inflammatory disease (IMID) of the skin. IMIDs are multifactorial diseases characterized by common molecular pathways leading to a systemic inflammation. Patients with an IMID are also at higher risk of developing co-morbidities, such as adverse pregnancy outcomes, than the general population. A higher rate of pregnancy complications have been seen in inflammatory bowel disease and rheumatoid arthritis. The data for psoriasis are inconsistent but it appears that women with moderate-to-severe psoriasis may also have an increased risk of poor pregnancy outcomes. The cause of this association is unknown, although it may be related to elevated proinflammatory cytokines such as IL-6 and TNF-α, the high prevalence of comorbidities and other unhealthy behaviours, or the high prevalence of polycystic ovary syndrome (PCOS). In a recent study, PCOS prevalence in a psoriatic cohort (n = 51) was higher than in nonpsoriatic women (n = 102) (47% versus 11%), and women with PCOS and psoriasis had a greater probability of insulin resistance, hyperinsulinaemia, and dyslipidaemia as well as a more severe skin condition, than those with psoriasis alone. Further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular if these effects are mediated by concomitant PCOS. Drug Dev Res 75 : S64–S66, 2014. © 2014 Wiley Periodicals, Inc. Key words: psoriasis; comorbidities; pregnancy; complications; polycystic ovary syndrome
INTRODUCTION
Psoriasis is a common, chronic, relapsing skin disease, affecting approximately 2% of the world population [Christophers, 2001], which is classified now as an immune-mediated inflammatory disease (IMID). IMIDs are a group of multifactorial diseases characterized by common molecular pathways leading to a systemic state of inflammation, which can cause organ damage and increased morbidity and/or mortality. In fact, several epidemiological studies have shown that, in patients with IMIDs, including psoriasis, associated disorders may occur more frequently than expected. In particular, it is known that these patients are at © 2014 Wiley Periodicals, Inc.
higher risk of developing co-morbidities such as cardiovascular disease, metabolic syndrome, diabetes and Funding/support information: Authors did not receive any funding for this work. Conflict of Interest: Clara De Simone has received honoraria from Abbott. *Correspondence to: Clara De Simone, Institute of Dermatology, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Roma, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21199
PCOS, PREGNANCY, AND PSORIASIS
non-alcoholic fatty liver disease [Christophers, 2007; Miele et al., 2009; Davidovici et al., 2010] compared with to the general population. Moreover, IMIDs are also associated with adverse pregnancy outcomes. In fact, studies on women with inflammatory bowel disease have shown a higher incidence of adverse pregnancy outcomes in these patients. In particular, in 2007 a meta-analysis found that there was a 1.87-fold increase in the incidence of prematurity, a 2-fold increase in the incidence of low birth weight (LBW), a 2.37-fold increase in congenital abnormalities, and a 1.5-fold higher likelihood of having to undergo a caesarean section than normal controls [Cornish et al., 2007]. Women with rheumatoid arthritis also have a high prevalence of adverse birth outcomes, such as preterm birth (PTB), infants with a low Apgar score, small for gestational age (SGA) births, stillbirths, and infants with congenital abnormalities [Norgaard et al., 2010]. On the other hand, the data reported in psoriatic women are inconsistent. A 2007 study compared pregnancy rate and pregnancy outcomes among women with inflammatory skin disease and a non-skin disease group stating that age-standardized incidence rate ratios for pregnancies and spontaneous abortions were virtually the same. There was no evidence that the presence of a skin disease substantially altered the incidence of pregnancy outcomes in affected women [Seeger et al., 2007]. In disagreement with these findings, two recent studies have found that psoriatic women have an increase in odds of poor composite outcomes including PTB and LBW [Lima et al., 2012], whereas mild psoriasis was not associated with adverse birth outcomes [Yang et al., 2011]. Moreover, CohenBarak et al. found, in a multivariate analysis, that moderate-to-severe psoriasis was an independent risk factor for previous spontaneous abortions, induced abortions, premature rupture of membranes, and newborn macrosomia [Cohen-Barak et al., 2011], while Ben-David found an association with recurrent abortions (OR = 2.1), chronic hypertension (OR = 2.9) and the risk of caesarean delivery [Ben-David et al., 2008]. The cause of this association between IMIDs, in particular psoriasis, and adverse outcomes of pregnancy are unknown, although it is known that proinflammatory cytokines such as IL-6 and TNF-α, usually elevated in IMIDs, are also found to be increased either in the mother’s serum or in the cord blood in pregnancies of PTB or SGA [Sorokin et al., 2010; Amarilyo et al., 2011; Bastek et al., 2011]. Conversely, Bandoli et al. explained the increased risk for pregnancy complications in psoriatic women, as being due to a high prevalence of comorbidities and other unhealthy behaviours associated with this skin disease [Bandoli
S65
et al., 2010]. Indeed, pregnant psoriatic women are more likely to be overweight, smoke, have a diagnosis of depression and delay taking vitamins than non-psoriatic women, and these factors are all associated with an adverse pregnancy outcome. Another explanation for this association, in particular in psoriatic women, may be the high prevalence of polycystic ovary syndrome (PCOS) [Moro et al., 2013]. In fact, recently we conducted a study that showed that the prevalence of PCOS in the psoriatic cohort (n = 51) was remarkably greater (about 47%) than that seen in non-psoriatic women (n = 102) matched for age and body mass index; this was independent of some potential confounders, such as metabolic syndrome, hypertension and family history of early coronary disease. Moreover, women with comorbid PCOS and psoriasis had a greater probability of having insulin resistance, hyperinsulinaemia, low HDL-cholesterol, and high triglycerides, as well as a more severe skin condition than those with psoriasis alone. PCOS is a condition largely known to be associated with menstrual irregularity and infertility, but is also associated with several pregnancy and neonatal complications. Affected women, in fact, demonstrated a significantly higher risk of developing gestational diabetes, pregnancy-induced hypertension, pre-eclampsia and PTB, and their babies had a significantly higher risk of admission to a neonatal intensive care and a higher perinatal mortality [Boomsma et al., 2006]. It is noteworthy that none of above-mentioned studies evaluating pregnancy outcomes in psoriatic women considered the prevalence of PCOS in their sample of patients. Therefore, further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular to ascertain if these effects are mediated by comorbid PCOS. ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia. REFERENCES Amarilyo G, Oren A, Mimouni FB, Ochshorn Y, Deutsch V, Mandel D. 2011. Increased cord serum inflammatory markers in small-forgestational-age neonates. J Perinatol 31:30–32. Bandoli G, Johnson DL, Jones KL, Lopez Jiminez J, Salas E, Mirrasoul N, Chambers CD. 2010. Potentially modifiable risk factors for adverse pregnancy outcomes in women with psoriasis. Br J Dermatol 163:334–339. Bastek JA, Brown AG, Anton L, Srinivas SK, D’Addio A, Elovitz MA. 2011. Biomarkers of inflammation and placental dysfunction are associated with subsequent preterm birth. J Matern Fetal Neonatal Med 24:600–605.
Drug Dev. Res.
S66
DE SIMONE ET AL.
Ben-David G, Sheiner E, Hallak M, Levy A. 2008. Pregnancy outcome in women with psoriasis. J Reprod Med 53:183–187. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. 2006. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 12:673–683. Christophers E. 2001. Psoriasis—epidemiology spectrum. Clin Exp Dermatol 26:314–320.
and
clinical
Christophers E. 2007. Comorbidities in psoriasis. Clin Dermatol 25:529–534. Cohen-Barak E, Nachum Z, Rozenman D, Ziv M. 2011. Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol 25:1041–1047. Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, Tekkis PP. 2007. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 56:830–837.
Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, Grieco A. 2009. Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol 51:778–786. Moro F, De Simone C, Morciano A, Tropea A, Sagnella F, Palla C, Scarinci E, Teti A, Caldarola G, D’Agostino M, Mancuso S, Lanzone A, Apa R. 2013. Psoriatic patients have an increased risk of polycystic ovary syndrome: results of a cross-sectional analysis. Fertil Steril 99:936–942. Norgaard M, Larsson H, Pedersen L, Granath F, Askling J, Kieler H, Stephansson O. 2010. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med 268:329–337. Seeger JD, Lanza LL, West WA, Fernandez C, Rivero E. 2007. Pregnancy and pregnancy outcome among women with inflammatory skin diseases. Dermatology 214:32–39.
Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, Krueger JG. 2010. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 130:1785–1796.
Sorokin Y, Romero R, Mele L, Wapner RJ, Iams JD, Dudley DJ, Sibai B. 2010. Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth
DRUG DEVELOPMENT RESEARCH 75 : S64–S66 (2014)
Clinical Overview
A Possible Role of Polycystic Ovary Syndrome for Pregnancy Complications in Women with Psoriasis Clara De Simone,1* Giacomo Caldarola,1 Marialuisa Corbeddu,1 Francesca Moro,2 Anna Tropea,2 Gaia Moretta,1 and Rosanna Apa2 1 Institute of Dermatology, Università Cattolica del Sacro Cuore (Catholic University of the Sacred Heart), 00168 Rome, Italy 2 Institute of Obstetrics and Gynaecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics
Preclinical Research
Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics
Clinical Development Phases I-III Regulatory, Quality, Manufacturing
Postmarketing Phase IV
ABSTRACT Psoriasis is a common, chronic, relapsing immune-mediated inflammatory disease (IMID) of the skin. IMIDs are multifactorial diseases characterized by common molecular pathways leading to a systemic inflammation. Patients with an IMID are also at higher risk of developing co-morbidities, such as adverse pregnancy outcomes, than the general population. A higher rate of pregnancy complications have been seen in inflammatory bowel disease and rheumatoid arthritis. The data for psoriasis are inconsistent but it appears that women with moderate-to-severe psoriasis may also have an increased risk of poor pregnancy outcomes. The cause of this association is unknown, although it may be related to elevated proinflammatory cytokines such as IL-6 and TNF-α, the high prevalence of comorbidities and other unhealthy behaviours, or the high prevalence of polycystic ovary syndrome (PCOS). In a recent study, PCOS prevalence in a psoriatic cohort (n = 51) was higher than in nonpsoriatic women (n = 102) (47% versus 11%), and women with PCOS and psoriasis had a greater probability of insulin resistance, hyperinsulinaemia, and dyslipidaemia as well as a more severe skin condition, than those with psoriasis alone. Further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular if these effects are mediated by concomitant PCOS. Drug Dev Res 75 : S64–S66, 2014. © 2014 Wiley Periodicals, Inc. Key words: psoriasis; comorbidities; pregnancy; complications; polycystic ovary syndrome
INTRODUCTION
Psoriasis is a common, chronic, relapsing skin disease, affecting approximately 2% of the world population [Christophers, 2001], which is classified now as an immune-mediated inflammatory disease (IMID). IMIDs are a group of multifactorial diseases characterized by common molecular pathways leading to a systemic state of inflammation, which can cause organ damage and increased morbidity and/or mortality. In fact, several epidemiological studies have shown that, in patients with IMIDs, including psoriasis, associated disorders may occur more frequently than expected. In particular, it is known that these patients are at © 2014 Wiley Periodicals, Inc.
higher risk of developing co-morbidities such as cardiovascular disease, metabolic syndrome, diabetes and Funding/support information: Authors did not receive any funding for this work. Conflict of Interest: Clara De Simone has received honoraria from Abbott. *Correspondence to: Clara De Simone, Institute of Dermatology, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, 00168 Roma, Italy. E-mail: [email protected] Published online in Wiley Online Library (wileyonlinelibrary .com). DOI: 10.1002/ddr.21199
PCOS, PREGNANCY, AND PSORIASIS
non-alcoholic fatty liver disease [Christophers, 2007; Miele et al., 2009; Davidovici et al., 2010] compared with to the general population. Moreover, IMIDs are also associated with adverse pregnancy outcomes. In fact, studies on women with inflammatory bowel disease have shown a higher incidence of adverse pregnancy outcomes in these patients. In particular, in 2007 a meta-analysis found that there was a 1.87-fold increase in the incidence of prematurity, a 2-fold increase in the incidence of low birth weight (LBW), a 2.37-fold increase in congenital abnormalities, and a 1.5-fold higher likelihood of having to undergo a caesarean section than normal controls [Cornish et al., 2007]. Women with rheumatoid arthritis also have a high prevalence of adverse birth outcomes, such as preterm birth (PTB), infants with a low Apgar score, small for gestational age (SGA) births, stillbirths, and infants with congenital abnormalities [Norgaard et al., 2010]. On the other hand, the data reported in psoriatic women are inconsistent. A 2007 study compared pregnancy rate and pregnancy outcomes among women with inflammatory skin disease and a non-skin disease group stating that age-standardized incidence rate ratios for pregnancies and spontaneous abortions were virtually the same. There was no evidence that the presence of a skin disease substantially altered the incidence of pregnancy outcomes in affected women [Seeger et al., 2007]. In disagreement with these findings, two recent studies have found that psoriatic women have an increase in odds of poor composite outcomes including PTB and LBW [Lima et al., 2012], whereas mild psoriasis was not associated with adverse birth outcomes [Yang et al., 2011]. Moreover, CohenBarak et al. found, in a multivariate analysis, that moderate-to-severe psoriasis was an independent risk factor for previous spontaneous abortions, induced abortions, premature rupture of membranes, and newborn macrosomia [Cohen-Barak et al., 2011], while Ben-David found an association with recurrent abortions (OR = 2.1), chronic hypertension (OR = 2.9) and the risk of caesarean delivery [Ben-David et al., 2008]. The cause of this association between IMIDs, in particular psoriasis, and adverse outcomes of pregnancy are unknown, although it is known that proinflammatory cytokines such as IL-6 and TNF-α, usually elevated in IMIDs, are also found to be increased either in the mother’s serum or in the cord blood in pregnancies of PTB or SGA [Sorokin et al., 2010; Amarilyo et al., 2011; Bastek et al., 2011]. Conversely, Bandoli et al. explained the increased risk for pregnancy complications in psoriatic women, as being due to a high prevalence of comorbidities and other unhealthy behaviours associated with this skin disease [Bandoli
S65
et al., 2010]. Indeed, pregnant psoriatic women are more likely to be overweight, smoke, have a diagnosis of depression and delay taking vitamins than non-psoriatic women, and these factors are all associated with an adverse pregnancy outcome. Another explanation for this association, in particular in psoriatic women, may be the high prevalence of polycystic ovary syndrome (PCOS) [Moro et al., 2013]. In fact, recently we conducted a study that showed that the prevalence of PCOS in the psoriatic cohort (n = 51) was remarkably greater (about 47%) than that seen in non-psoriatic women (n = 102) matched for age and body mass index; this was independent of some potential confounders, such as metabolic syndrome, hypertension and family history of early coronary disease. Moreover, women with comorbid PCOS and psoriasis had a greater probability of having insulin resistance, hyperinsulinaemia, low HDL-cholesterol, and high triglycerides, as well as a more severe skin condition than those with psoriasis alone. PCOS is a condition largely known to be associated with menstrual irregularity and infertility, but is also associated with several pregnancy and neonatal complications. Affected women, in fact, demonstrated a significantly higher risk of developing gestational diabetes, pregnancy-induced hypertension, pre-eclampsia and PTB, and their babies had a significantly higher risk of admission to a neonatal intensive care and a higher perinatal mortality [Boomsma et al., 2006]. It is noteworthy that none of above-mentioned studies evaluating pregnancy outcomes in psoriatic women considered the prevalence of PCOS in their sample of patients. Therefore, further studies are necessary to clarify the impact of psoriasis on pregnancy and in particular to ascertain if these effects are mediated by comorbid PCOS. ACKNOWLEDGMENT
Editorial assistance was provided by Mary Hines on behalf of HPS—Health Publishing and Services Srl and funded by Pfizer Italia. REFERENCES Amarilyo G, Oren A, Mimouni FB, Ochshorn Y, Deutsch V, Mandel D. 2011. Increased cord serum inflammatory markers in small-forgestational-age neonates. J Perinatol 31:30–32. Bandoli G, Johnson DL, Jones KL, Lopez Jiminez J, Salas E, Mirrasoul N, Chambers CD. 2010. Potentially modifiable risk factors for adverse pregnancy outcomes in women with psoriasis. Br J Dermatol 163:334–339. Bastek JA, Brown AG, Anton L, Srinivas SK, D’Addio A, Elovitz MA. 2011. Biomarkers of inflammation and placental dysfunction are associated with subsequent preterm birth. J Matern Fetal Neonatal Med 24:600–605.
Drug Dev. Res.
S66
DE SIMONE ET AL.
Ben-David G, Sheiner E, Hallak M, Levy A. 2008. Pregnancy outcome in women with psoriasis. J Reprod Med 53:183–187. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. 2006. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 12:673–683. Christophers E. 2001. Psoriasis—epidemiology spectrum. Clin Exp Dermatol 26:314–320.
and
clinical
Christophers E. 2007. Comorbidities in psoriasis. Clin Dermatol 25:529–534. Cohen-Barak E, Nachum Z, Rozenman D, Ziv M. 2011. Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol 25:1041–1047. Cornish J, Tan E, Teare J, Teoh TG, Rai R, Clark SK, Tekkis PP. 2007. A meta-analysis on the influence of inflammatory bowel disease on pregnancy. Gut 56:830–837.
Miele L, Vallone S, Cefalo C, La Torre G, Di Stasi C, Vecchio FM, Grieco A. 2009. Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis. J Hepatol 51:778–786. Moro F, De Simone C, Morciano A, Tropea A, Sagnella F, Palla C, Scarinci E, Teti A, Caldarola G, D’Agostino M, Mancuso S, Lanzone A, Apa R. 2013. Psoriatic patients have an increased risk of polycystic ovary syndrome: results of a cross-sectional analysis. Fertil Steril 99:936–942. Norgaard M, Larsson H, Pedersen L, Granath F, Askling J, Kieler H, Stephansson O. 2010. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study. J Intern Med 268:329–337. Seeger JD, Lanza LL, West WA, Fernandez C, Rivero E. 2007. Pregnancy and pregnancy outcome among women with inflammatory skin diseases. Dermatology 214:32–39.
Davidovici BB, Sattar N, Prinz J, Puig L, Emery P, Barker JN, Krueger JG. 2010. Psoriasis and systemic inflammatory diseases: potential mechanistic links between skin disease and co-morbid conditions. J Invest Dermatol 130:1785–1796.
Sorokin Y, Romero R, Mele L, Wapner RJ, Iams JD, Dudley DJ, Sibai B. 2010. Maternal serum interleukin-6, C-reactive protein, and matrix metalloproteinase-9 concentrations as risk factors for preterm birth
