Case and Review Dermatology 2015;231:103–104 DOI: 10.1159/000380880
Received: November 10, 2014 Accepted after revision: February 11, 2015 Published online: March 17, 2015
Pregnancy during Ustekinumab Treatment for Severe Psoriasis Katiucia Rocha Mariana Carolina Piccinin Luciana F. Kalache Adriane Reichert-Faria Caio César Silva de Castro Department of Dermatology, Hospital Santa Casa de Curitiba, Pontifícia Universidade Católica do Paraná – PUCPR, Curitiba, Brazil
Abstract We report the case of a 25-year-old patient who became pregnant during ustekinumab therapy. Treatment was suspended immediately after pregnancy had been confirmed. The patient had an uneventful pregnancy and her child is currently 14 months old, with adequate development to her age. Four reports of pregnancy during ustekinumab treatment have been reported and one resulted in mis© 2015 S. Karger AG, Basel carriage.
Introduction
Ustekinumab is a human monoclonal antibody, anti-interleukin 12 (anti-IL-12) and anti-IL-23. It is the most recent biologic agent approved in Brazil for the treatment of psoriasis. There are four reports describing pregnancy during ustekinumab treatment, one resulting in miscarriage and the others with normal gestational evolution [1–4]. Many women under treatment with biologic agents are of childbearing age, and previous studies have shown that these women have increased risks of adverse pregnancy outcomes and labor and/
or delivery complications compared to the general population [5, 6]. Biologics are relatively new agents, and although classified as class B drugs during pregnancy, they should be studied for their possible teratogenic and abortifacient effects. Case Report
A 25-year-old woman with severe plaque psoriasis since the age of 10 presented for a follow-up visit. Prior to this visit she was treated with topical corticosteroids, UVB phototherapy, photochemotherapy (PUVA) and methotrexate, which was suspended due to the high cumulative dose. Most recently, cyclosporine was used for 22 months with significant initial improvement when she reached PASI 2.9 (the previous PASI was 12). However, due to inadequate psoriasis control (PASI 20) despite dose increase (up to 3 mg/kg daily) and long-term use of cyclosporine, it was chosen to suspend it and start ustekinumab. After 5 months, her PASI decreased to 1.4 with no adverse events. Despite orientation regarding contraception, on the 8th month of therapy, the patient reported that she was pregnant (6 weeks). Her most recent dose of ustekinumab was 18 days before the estimated date of conception. Treatment was immediately suspended
© 2015 S. Karger AG, Basel 1018–8665/15/2312–0103$39.50/0 E-Mail [email protected] www.karger.com/drm
and emollients were prescribed. She was referred to a high-risk prenatal center. During pregnancy her psoriasis worsened considerably. Periodic obstetric evaluations revealed satisfactory fetal development. At 39 weeks, the patient delivered a healthy newborn with 3,665 g and 51 cm. Apgar score at 1 and 5 min was 5 and 8, respectively. Routine vaccination was performed in the delivery room, including hepatitis B and bacillus Calmette-Guérin (BCG). No neonatal abnormality was observed. Ustekinumab remained suspended during the lactation period and was resumed in April 2014, after the patient had ceased breastfeeding. The child had normal development at 14-month follow-up. The Denver test was applied and the child scored properly in all criteria, consistent with her age. Discussion
Treatment of pregnant women with psoriasis requires careful consideration of the benefits of therapy, safety and effective alternatives, and the possible risk to the fetus [6]. The obstetric literature mentions psoriasis as an independent risk factor for increased rates of pregnancy complications such as miscarriages, inability to conceive and premature birth [7]. It is known that
Katiucia da Rocha Department of Dermatology, Hospital Santa Casa de Curitiba Rua Sylvio Zeny, 64, #114, Portão Curitiba, Paraná (Brazil) E-Mail katiuciarocha @ hotmail.com
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/21/2015 6:37:47 PM
Key Words Psoriasis · Pregnancy · Ustekinumab
pregnancy is a particular immune status during the woman’s life. Many authors have described high levels of inflammatory cytokines such as tumor necrosis factor alpha, IL-6 and interferon-γ during this period. Pregnant psoriasis patients suffer from two types of pro-inflammatory forces: the skin affected by psoriasis and the pregnancy per se, which can impose adverse effects on the maternal placenta and thus lead to unfavorable outcomes [8]. Both moderate and severe psoriasis are associated with an increased prevalence of spontaneous abortions [7]. Gestational risk factors such as obesity, dyslipidemia, depression, diabetes and hypertension should be excluded, and the fact that these comorbidities are often associated with psoriasis may be a confounding bias in adverse pregnancy outcomes when patients are on biologic therapies [9]. Ustekinumab, a human monoclonal antibody, binds to the p40 subunit, which is shared by IL-12 and IL-23 and inhibits the action of these cytokines, which are involved in the pathogenesis of the disease [2]. Elevated levels of IL-12 are associated with impaired embryo implantation and fetuses small for gestational age [10, 11]. The transplacental transport of ustekinumab is minor until the end of the second quarter of pregnancy due to its large size characteristic of IgG. The administration
of high doses of ustekinumab to cynomolgus monkeys during pregnancy and lactation had no adverse effects on females or fetuses. In this animal model, abortion rates were the same with and without exposure to the drug [12]. According to medication characteristics, it is preferable to avoid ustekinumab during pregnancy, and women of childbearing age should use effective contraception during and up to 15 weeks after treatment [13]. It has been shown that ustekinumab is excreted in the milk of lactating monkeys. This finding has been generalized, and it is assumed that the drug is also excreted in human milk. The gastrointestinal absorption of ustekinumab is suspected to be minimal but unknown [2]. There are four reports regarding exposure to ustekinumab during pregnancy. The first one described a spontaneous abortion in a 35-year-old female psoriasis patient at the end of the first trimester [1]. The second reported exposure during the third trimester of pregnancy and the child had normal development up to 9 months, when she had her last update, based on the mother’s information [2]. More recently two additional reports were published, both with uncomplicated pregnancies [3, 4]. According to unpublished data from clinical studies until June 2010, 42 maternal exposures were identified during trials of ustekinumab, but only 10 had adequate results registered [14].
Our report describes a 14-month-old child with normal development where objective criteria of psychomotor evaluation (including fine and gross motor adaptive, language and personal social) were applied. Furthermore, the child received all vaccines recommended by the national immunization schedule, including BCG, and no complications have been registered up to now. A previous report of infliximab treatment for Crohn’s disease during pregnancy was associated with disseminated BCG in the child 6 weeks after vaccination [15]. Additional studies are needed to determine whether adverse gestational outcomes in psoriasis patients using biologics are related to the disease itself and associated comorbidities or are side effects from the therapy.
7 Ben-David G, Sheiner E, Hallak M, Levy A: Pregnancy outcome in women with psoriasis. J Reprod Med 2008;53:183–187. 8 Guven MA, Coskun A, Ertas IE, Aral M, Zencirci B, Oksuz H: Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens Pregnancy 2009; 28: 190– 200. 9 Cohen-Barak E, Nachum Z, Rozenman D, Ziv M: Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol 2011;25:1041–1047. 10 Lédée-Bataille N, Dubanchet S, CoulombL’hermine A, Durand-Gasselin I, Frydman R, Chaouat G: A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization. Fertil Steril 2004;81:59–65. 11 Description from FDA NDA review document, http://www.accessdata.fda.gov/drugsatfda_ docs/nda/2009/125261s000_OtherR.pdf.
12 Martin PL, Sachs C, Imai N, Tsusaki H, Oneda S, Jiao Q, Treacy G: Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23 p40 monoclonal antibody, during pregnancy and lactation. Birth Defects Res B Dev Reprod Toxicol 2010;89:351–363. 13 European Medicines Agency: Stelara, European Public Assessment Report. EPARs for authorised medicinal products for human use. 2009. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000958/human_ med_001065.jsp&mid=WC0b01ac 058001d124. 14 Data on File. Reports of pregnancy with ustekinumab: STE/Inj/DoF/Sep2010/ EMEA001. 2010, Janssen. 15 Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J: Case report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J Crohns Colitis 2010;4:603–605.
Acknowledgments
The authors wish to thank Dr. Felipe B. Cerci for his important contribution in providing language assistance during manuscript preparation. Disclosure Statement
The authors report no conflicts of interest.
1 Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D: Spontaneous abortion during ustekinumab therapy. J Dermatol Case Rep 2012;6:105–107. 2 Andrulonis R, Ferris LK: Treatment of severe psoriasis with ustekinumab during pregnancy. J Drugs Dermatol 2012;11:1240–1241. 3 Sheeran C, Nicolopoulos J: Pregnancy outcomes of two patients exposed to ustekinumab in the first trimester. Australas J Dermatol 2014;55:235–236. 4 Alsenaid A, Prinz JC: Inadvertent pregnancy during ustekinumab therapy in a patient with plaque psoriasis and impetigo herpetiformis. J Eur Acad Dermatol Venereol DOI: 10.1111/ jdv.12872. 5 Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL: Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–826. 6 Puig L, Barco D, Alomar A: Treatment of psoriasis with anti-TNF drugs during pregnancy: case report and review of the literature. Dermatology 2010;220:71–76.
104
Dermatology 2015;231:103–104 DOI: 10.1159/000380880
Rocha /Piccinin /Kalache /Reichert-Faria / Silva de Castro
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/21/2015 6:37:47 PM
References
Received: November 10, 2014 Accepted after revision: February 11, 2015 Published online: March 17, 2015
Pregnancy during Ustekinumab Treatment for Severe Psoriasis Katiucia Rocha Mariana Carolina Piccinin Luciana F. Kalache Adriane Reichert-Faria Caio César Silva de Castro Department of Dermatology, Hospital Santa Casa de Curitiba, Pontifícia Universidade Católica do Paraná – PUCPR, Curitiba, Brazil
Abstract We report the case of a 25-year-old patient who became pregnant during ustekinumab therapy. Treatment was suspended immediately after pregnancy had been confirmed. The patient had an uneventful pregnancy and her child is currently 14 months old, with adequate development to her age. Four reports of pregnancy during ustekinumab treatment have been reported and one resulted in mis© 2015 S. Karger AG, Basel carriage.
Introduction
Ustekinumab is a human monoclonal antibody, anti-interleukin 12 (anti-IL-12) and anti-IL-23. It is the most recent biologic agent approved in Brazil for the treatment of psoriasis. There are four reports describing pregnancy during ustekinumab treatment, one resulting in miscarriage and the others with normal gestational evolution [1–4]. Many women under treatment with biologic agents are of childbearing age, and previous studies have shown that these women have increased risks of adverse pregnancy outcomes and labor and/
or delivery complications compared to the general population [5, 6]. Biologics are relatively new agents, and although classified as class B drugs during pregnancy, they should be studied for their possible teratogenic and abortifacient effects. Case Report
A 25-year-old woman with severe plaque psoriasis since the age of 10 presented for a follow-up visit. Prior to this visit she was treated with topical corticosteroids, UVB phototherapy, photochemotherapy (PUVA) and methotrexate, which was suspended due to the high cumulative dose. Most recently, cyclosporine was used for 22 months with significant initial improvement when she reached PASI 2.9 (the previous PASI was 12). However, due to inadequate psoriasis control (PASI 20) despite dose increase (up to 3 mg/kg daily) and long-term use of cyclosporine, it was chosen to suspend it and start ustekinumab. After 5 months, her PASI decreased to 1.4 with no adverse events. Despite orientation regarding contraception, on the 8th month of therapy, the patient reported that she was pregnant (6 weeks). Her most recent dose of ustekinumab was 18 days before the estimated date of conception. Treatment was immediately suspended
© 2015 S. Karger AG, Basel 1018–8665/15/2312–0103$39.50/0 E-Mail [email protected] www.karger.com/drm
and emollients were prescribed. She was referred to a high-risk prenatal center. During pregnancy her psoriasis worsened considerably. Periodic obstetric evaluations revealed satisfactory fetal development. At 39 weeks, the patient delivered a healthy newborn with 3,665 g and 51 cm. Apgar score at 1 and 5 min was 5 and 8, respectively. Routine vaccination was performed in the delivery room, including hepatitis B and bacillus Calmette-Guérin (BCG). No neonatal abnormality was observed. Ustekinumab remained suspended during the lactation period and was resumed in April 2014, after the patient had ceased breastfeeding. The child had normal development at 14-month follow-up. The Denver test was applied and the child scored properly in all criteria, consistent with her age. Discussion
Treatment of pregnant women with psoriasis requires careful consideration of the benefits of therapy, safety and effective alternatives, and the possible risk to the fetus [6]. The obstetric literature mentions psoriasis as an independent risk factor for increased rates of pregnancy complications such as miscarriages, inability to conceive and premature birth [7]. It is known that
Katiucia da Rocha Department of Dermatology, Hospital Santa Casa de Curitiba Rua Sylvio Zeny, 64, #114, Portão Curitiba, Paraná (Brazil) E-Mail katiuciarocha @ hotmail.com
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/21/2015 6:37:47 PM
Key Words Psoriasis · Pregnancy · Ustekinumab
pregnancy is a particular immune status during the woman’s life. Many authors have described high levels of inflammatory cytokines such as tumor necrosis factor alpha, IL-6 and interferon-γ during this period. Pregnant psoriasis patients suffer from two types of pro-inflammatory forces: the skin affected by psoriasis and the pregnancy per se, which can impose adverse effects on the maternal placenta and thus lead to unfavorable outcomes [8]. Both moderate and severe psoriasis are associated with an increased prevalence of spontaneous abortions [7]. Gestational risk factors such as obesity, dyslipidemia, depression, diabetes and hypertension should be excluded, and the fact that these comorbidities are often associated with psoriasis may be a confounding bias in adverse pregnancy outcomes when patients are on biologic therapies [9]. Ustekinumab, a human monoclonal antibody, binds to the p40 subunit, which is shared by IL-12 and IL-23 and inhibits the action of these cytokines, which are involved in the pathogenesis of the disease [2]. Elevated levels of IL-12 are associated with impaired embryo implantation and fetuses small for gestational age [10, 11]. The transplacental transport of ustekinumab is minor until the end of the second quarter of pregnancy due to its large size characteristic of IgG. The administration
of high doses of ustekinumab to cynomolgus monkeys during pregnancy and lactation had no adverse effects on females or fetuses. In this animal model, abortion rates were the same with and without exposure to the drug [12]. According to medication characteristics, it is preferable to avoid ustekinumab during pregnancy, and women of childbearing age should use effective contraception during and up to 15 weeks after treatment [13]. It has been shown that ustekinumab is excreted in the milk of lactating monkeys. This finding has been generalized, and it is assumed that the drug is also excreted in human milk. The gastrointestinal absorption of ustekinumab is suspected to be minimal but unknown [2]. There are four reports regarding exposure to ustekinumab during pregnancy. The first one described a spontaneous abortion in a 35-year-old female psoriasis patient at the end of the first trimester [1]. The second reported exposure during the third trimester of pregnancy and the child had normal development up to 9 months, when she had her last update, based on the mother’s information [2]. More recently two additional reports were published, both with uncomplicated pregnancies [3, 4]. According to unpublished data from clinical studies until June 2010, 42 maternal exposures were identified during trials of ustekinumab, but only 10 had adequate results registered [14].
Our report describes a 14-month-old child with normal development where objective criteria of psychomotor evaluation (including fine and gross motor adaptive, language and personal social) were applied. Furthermore, the child received all vaccines recommended by the national immunization schedule, including BCG, and no complications have been registered up to now. A previous report of infliximab treatment for Crohn’s disease during pregnancy was associated with disseminated BCG in the child 6 weeks after vaccination [15]. Additional studies are needed to determine whether adverse gestational outcomes in psoriasis patients using biologics are related to the disease itself and associated comorbidities or are side effects from the therapy.
7 Ben-David G, Sheiner E, Hallak M, Levy A: Pregnancy outcome in women with psoriasis. J Reprod Med 2008;53:183–187. 8 Guven MA, Coskun A, Ertas IE, Aral M, Zencirci B, Oksuz H: Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine, folic acid and vitamin B12 levels with the severity of preeclampsia and fetal birth weight. Hypertens Pregnancy 2009; 28: 190– 200. 9 Cohen-Barak E, Nachum Z, Rozenman D, Ziv M: Pregnancy outcomes in women with moderate-to-severe psoriasis. J Eur Acad Dermatol Venereol 2011;25:1041–1047. 10 Lédée-Bataille N, Dubanchet S, CoulombL’hermine A, Durand-Gasselin I, Frydman R, Chaouat G: A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization. Fertil Steril 2004;81:59–65. 11 Description from FDA NDA review document, http://www.accessdata.fda.gov/drugsatfda_ docs/nda/2009/125261s000_OtherR.pdf.
12 Martin PL, Sachs C, Imai N, Tsusaki H, Oneda S, Jiao Q, Treacy G: Development in the cynomolgus macaque following administration of ustekinumab, a human anti-IL-12/23 p40 monoclonal antibody, during pregnancy and lactation. Birth Defects Res B Dev Reprod Toxicol 2010;89:351–363. 13 European Medicines Agency: Stelara, European Public Assessment Report. EPARs for authorised medicinal products for human use. 2009. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000958/human_ med_001065.jsp&mid=WC0b01ac 058001d124. 14 Data on File. Reports of pregnancy with ustekinumab: STE/Inj/DoF/Sep2010/ EMEA001. 2010, Janssen. 15 Cheent K, Nolan J, Shariq S, Kiho L, Pal A, Arnold J: Case report: Fatal case of disseminated BCG infection in an infant born to a mother taking infliximab for Crohn’s disease. J Crohns Colitis 2010;4:603–605.
Acknowledgments
The authors wish to thank Dr. Felipe B. Cerci for his important contribution in providing language assistance during manuscript preparation. Disclosure Statement
The authors report no conflicts of interest.
1 Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D: Spontaneous abortion during ustekinumab therapy. J Dermatol Case Rep 2012;6:105–107. 2 Andrulonis R, Ferris LK: Treatment of severe psoriasis with ustekinumab during pregnancy. J Drugs Dermatol 2012;11:1240–1241. 3 Sheeran C, Nicolopoulos J: Pregnancy outcomes of two patients exposed to ustekinumab in the first trimester. Australas J Dermatol 2014;55:235–236. 4 Alsenaid A, Prinz JC: Inadvertent pregnancy during ustekinumab therapy in a patient with plaque psoriasis and impetigo herpetiformis. J Eur Acad Dermatol Venereol DOI: 10.1111/ jdv.12872. 5 Verstappen SM, King Y, Watson KD, Symmons DP, Hyrich KL: Anti-TNF therapies and pregnancy: outcome of 130 pregnancies in the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011;70:823–826. 6 Puig L, Barco D, Alomar A: Treatment of psoriasis with anti-TNF drugs during pregnancy: case report and review of the literature. Dermatology 2010;220:71–76.
104
Dermatology 2015;231:103–104 DOI: 10.1159/000380880
Rocha /Piccinin /Kalache /Reichert-Faria / Silva de Castro
Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/21/2015 6:37:47 PM
References
