Am J Clin Dermatol DOI 10.1007/s40257-015-0137-5

REVIEW ARTICLE

Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments Nannie Bangsgaard1 • Christina Rørbye2 • Lone Skov1

Ó Springer International Publishing Switzerland 2015

Abstract Psoriasis is a chronic inflammatory disease with a well-documented negative effect on the quality of life of affected patients. Psoriasis often occurs in the reproductive years, during which the issue of pregnancy needs to be addressed. The course of psoriasis during pregnancy is unpredictable, and many patients face the challenge of needing treatment during pregnancy. In this review we provide an overview of the key considerations for managing psoriasis in pregnant women, covering the potential effects of active psoriasis and co-morbid conditions on the health of the mother and fetus, as well as the effects of psoriasis treatment options on the developing fetus. Although there are no robust data on the safety of systemic treatment of pregnant women, increasing evidence regarding the safety of cyclosporine (ciclosporin) treatment as well as anti-tumor necrosis factor-a is available and should be considered in pregnant women with moderate to severe psoriasis unresponsive to local corticosteroids and UVB light treatment.

& Nannie Bangsgaard [email protected] 1

Herlev and Gentofte Hospital, University of Copenhagen, Kildega˚rdsvej 28, 2900 Hellerup, Denmark

2

Department of Obstetrics and Gynecology, Hvidovre Hospital, University of Copenhagen, 2650 Hvidovre, Denmark

Key Points The course of psoriasis during pregnancy is unpredictable. Local corticosteroids and UVB can be used during pregnancy. In severe psoriasis, cyclosporine (ciclosporin) or tumor necrosis factor-a inhibitors should be considered.

1 Introduction Psoriasis is a chronic inflammatory skin disease that affects 2–3 % of the population, men and women equally [1, 2]. The majority of patients have onset of disease before the age of 40 years, which coincides with the reproductive years [1]. The severity of psoriasis varies considerably, with the majority being mild disease. However, for those who have moderate to severe psoriasis, with widespread scaly and sometimes itchy plaques, an impaired quality of life similar to patients with other chronic diseases is well-documented [3–6]. In addition, patients with psoriasis have been shown to have anxiety and depression more often than others [7, 8]. The course of psoriasis during pregnancy is unpredictable. Some women experience improvement, some steady state, yet others exacerbation. For many women, treatment will be required during pregnancy. However, treating pregnant women with psoriasis is a challenge, as the well-being of the mother as well as the fetus needs to be considered. In order to prescribe the right treatment, the clinician must take into account to what extent the mother

N. Bangsgaard et al. Table 1 US FDA pregnancy categories of treatments of psoriasis [10] Category

Description

Topical

Systemic

A

Adequate and well-controlled human studies fail to show a fetal risk

None

None

B

Animal studies fail to show a fetal risk, and there are no human studies

None

TNF-a inhibitors, Ustekinumab

C

Animal studies show a fetal risk, and there are no adequate human studies

Corticosteroids, calcipotriene, calcineurin inhibitors

Cyclosporine (ciclosporin), corticosteroids

D

There is evidence of fetal risk, but the benefits may outweigh the risk

None

None

X

There is evidence of fetal risk, and the risks clearly outweigh any possible benefits

Tazarotene

Acitretin, methotrexate

TNF-a tumor necrosis factor-a

is affected by the disease during pregnancy and if better disease control is possible without affecting the fetus in an undesired way. Congenital malformation or birth defects affect about 3 % of childbirths nationwide in the USA [9]. This is due to teratogenic exposure that is due, besides prescription medication, to over-the-counter medications, maternal infections, and environmental and genetic factors. However, teratogenesis is often difficult to prove. An increase in a specific anomaly or group of anomalies must be documented for a specific agent. The US FDA classifies drugs into five categories to describe their teratogenicity (A, B, C, D, and X; see Table 1) to inform clinicians and pregnant women of the available data on teratogenic risks associated with prescription drugs. However, the categories are not meant to provide estimates of teratogenic risk and the labeling system by FDA is undergoing revision. The pregnancy categories, A, B, C, D, and X are expected to be removed and replaced by a labeling system containing a summary of the risks of using a drug during pregnancy and lactation and a discussion of the data supporting that summary. These changes are expected to give greater clarity and help healthcare providers to make prescribing decisions and counsel women about the use of drugs during pregnancy [10]. Due to obvious ethical reasons, there are no large randomized studies on treatments for psoriasis during pregnancy. Data are based on animal studies, case reports, retrospective studies, and a few cohort studies. In this review, we provide an overview of the evidence on pregnancy outcomes in psoriasis patients and the safety of the systemic and topical treatments available.

2 Pregnancy Outcomes with Psoriasis Moderate to severe psoriasis is characterized not only by a cutaneous disease, but also by a systemic inflammatory milieu that holds close resemblance to the inflammation

seen in other chronic inflammatory diseases, such as inflammatory bowel diseases and rheumatoid arthritis (RA) [11, 12]. These diseases have been associated with preterm birth and low birth weight [13–15]. In pregnancies resulting in low birth weight or preterm birth, pro-inflammatory cytokines such as interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-a have been demonstrated in cord blood [16–18], and are known to be elevated in active psoriasis [19]. Moderate to severe psoriasis would therefore be expected to influence pregnancy outcomes. Indeed, this has been demonstrated: in a nationwide population-based study of 1463 women, Yang et al. [20] found that women with severe psoriasis had an increased risk of low birth weight and Cohen-Barak et al. [21] and Ben-David et al. [22] have found an increased risk of spontaneous abortion in women with moderate to severe psoriasis; however, these latter two studies were based on small numbers (only ten and 35 women with psoriasis were included, respectively). Other results are found for mild psoriasis. In the study by Yang et al. [20], mild psoriasis was not associated with an excess risk of adverse birth outcomes. In a large Danish prospective cohort study of 100,418 pregnancies with a prevalence of psoriasis of 3 %, mild to moderate psoriasis was not found to be a risk factor for fetal death after the first trimester or for prolonged time to pregnancy [23]. This is also in line with Lima et al. [24], who found no increased risk of spontaneous abortions in pregnant women with psoriasis. Psoriasis has been associated with several co-morbidities that are known risk factors for adverse pregnancy outcomes, such as metabolic syndrome, diabetes mellitus, cardiovascular disease, and other inflammatory diseases including inflammatory bowel disease, RA, and psoriatic arthritis [25–28]. In a prospective cohort of pregnant women, Bandoli et al. [29] found that women with psoriasis were more likely to be overweight/obese prior to pregnancy, smoke, or have a diagnosis of depression, and were less likely to have been taking vitamin supplements

Treatment of Psoriasis During Pregnancy

prior to pregnancy [29]. These co-morbidities could potentially contribute to a higher risk of adverse pregnancy outcomes and need to be addressed in a clinical setting.

3 Topical Therapies

treated parentally with calcipotriene [43]. Topical use of calcipotriene is systemically absorbed, but the recommended dosage, less than 100 g/week of calcipotriene 0.005 %, has been shown not to disturb calcium homeostasis [44]. Topical use of the recommended dosage is considered safe; however, due to lack of safety data in humans, topical calcipotriene is assigned FDA pregnancy category C.

3.1 Corticosteroids Along with emollients, topical corticosteroids are considered to be first-line treatment in patients with psoriasis. However, topical corticosteroids have resulted in fetal growth restriction in animals [30, 31]. Topical corticosteroids are therefore classified by the FDA as category C. Many studies have investigated the risk of oral cleft associated with early use of topical corticosteroids, but have found no association [32–37].The use of topical corticosteroids during pregnancy has also been investigated in large population-based case–control studies and a Cochrane review [38–41]. No increased risk of low birth weight, congenital anomalies, including oral cleft or preterm delivery have been shown in infants of women treated with mild to moderate topical corticosteroids during pregnancy. However, concern has been raised about the use of potent topical corticosteroids during pregnancy. Chi et al. have conducted two studies [39, 40] that, consistent with previous studies, found no association of maternal exposure to topical corticosteroids with preterm delivery and fetal death; however, an exploratory analysis showed that exposure to very potent topical corticosteroids during pregnancy was associated with fetal growth restriction, with a dose-dependent relationship and a significantly increased risk of low birth weight when the dispensed amount of potent or very potent topical corticosteroids exceeded 300 g during the whole pregnancy (adjusted relative risk 7.74 [95 % CI 1.49–40.11]; P = 0.02 [41]). This could be due to the severity of the underlying maternal disease rather than the treatment, but warrants a cautious approach that recommends the preferable use of mild to moderate topical corticosteroids and potent corticosteroids only in limited amounts during pregnancy. 3.2 Calcipotriene (Calcipotriol) No studies on the teratogen effects of calcipotriene (calcipotriol) in human beings have been published. In an animal study, subcutaneous administration of non-toxic doses did not show adverse effects [42], but in another animal study, an increase in the incidence of skeletal abnormalities, and incomplete ossification of pubic bones and forelimb phalanges was seen in the offspring of rabbits

3.3 Calcineurin Inhibitors Calcineurin inhibitors are sometimes used in the treatment of psoriasis, especially on small areas of sensitive skin such as the face and genitals. There are no safety data on the topical use of calcineurin inhibitors during human pregnancy, but there are prospective studies, case series, and case reports on the use of oral calcineurin inhibitors in pregnant women after organ transplantation. Pregnancy in organ-transplanted women is associated with a high level of complications. Jain et al. [45] reported on 27 pregnancies and found a surprisingly low incidence of maternal complications and, consistent with other studies [46, 47], an incidence of preterm delivery and low birth weight similar to those described in other immunosuppressive agents. Due to the molecular size of calcineurin inhibitors, topical use results in poor systemic absorption [48] and is hence expected to be safe during pregnancy; however, due to the lack of human data the FDA has assigned it a pregnancy category C and topical corticosteroids are preferred. 3.4 Tazarotene Tazarotene is a topical retinoid. There are no published animal or human studies on the safety of tazarotene use during pregnancy. The manufacturer has conducted multiple animal studies [49] showing teratogenic effects of both topical and oral tazarotene use in pregnant rats and rabbits. Based on this, the FDA has assigned tazarotene pregnancy category X, although the topical retinoids adapalene and tretinoin are category C. The systemic absorption and bioavailability of topical tazarotene is low (1–5 %) [50] and the teratogenic effect is expected to be much smaller than when given orally. Eight pregnant women treated with tazarotene have been reported to give birth to healthy babies [51]. 3.5 Coal Tar Coal tar has been found to be teratogenic in animal studies [52]. Topical use of coal tar can lead to systemic absorption of polycyclic aromatic hydrocarbon, which is potentially

N. Bangsgaard et al.

mutagenic; polycyclic aromatic hydrocarbons have been found in the urine of patients treated for psoriasis in several studies [53, 54]. There are, however, no reports of adverse pregnancy outcomes in coal tar-treated women and it is unknown whether coal tar is teratogenic in humans [55]. Although there are no indications of teratogenic effects in humans, it is recommended that the use of coal tar be avoided during pregnancy. Coal tar has no FDA pregnancy category.

4 Phototherapy 4.1 UVB/Narrowband UVB Although data are limited, UVB and narrowband UVB treatments are considered safe in pregnant women. UVB does not penetrate the superficial layer of the skin and almost all pregnant women are exposed to UVB in daylight to some extent. In a large study of pregnant women with outdoor occupations exposed to UVB, no association with preterm birth, congenital malformations, or low birth weight was found [56]. One study of 15,402 pregnant women showed a greater risk for pre-eclampsia in those who conceived in summer [57]. This was argued to be due to heat, and it is thus advisable to avoid high doses of heat during UVB treatment. Folic acid levels have been shown to decrease with UVB treatment [58, 59], which could predispose to neural tube defects. Although other studies have not been able to reproduce this [60] and the issue is still debated, supplementation of folic acid in women considering pregnancy or in the first trimester is important [61]. Climatherapy has not been evaluated but is considered safe in pregnant women, with the same heat avoidance precaution as with UVB treatment. Phototherapy may exacerbate melasma and proper facial shielding during UVB treatment is advisable. UVB does not hold a FDA pregnancy category. 4.2 Psoralen Plus UVA (PUVA) Psoralen, which has theoretical mutagenic and teratogenic effects, is given orally to patients in conjunction with UVA (psoralen plus UVA; PUVA) to increase skin reactivity to UVA. In the presence of UVA, psoralen binds with DNA, inhibiting DNA synthesis and cell division [62]; however, PUVA has not been shown to be unsafe. In a study of 504 infants born to mothers treated with PUVA, no increase in congenital malformations was seen [63]. Due to the theoretical risk of mutagenicity and teratogenicity, it is recommended that PUVA be avoided during pregnancy and PUVA therefore holds a FDA pregnancy category C status.

5 Systemic Therapy 5.1 Acitretin Acitretin is a synthetic retinoid that is known to be highly teratogenic in animal studies [64]. Exposure during pregnancy is associated with a high risk of fetal malformation, involving craniofacial, cardiac, thymic, and central nervous system structures [65–67]. Based on this, acitretin is given FDA pregnancy category X, and is contraindicated in pregnant women. The elimination half-life of acitretin is 33–96 h; however, acitretin has the potential to re-esterify to etretinate with a much longer elimination half-life of up to 150 weeks [68–70], which requires the use of contraception for 2–3 years after cessation of acitretin. It is therefore recommended that acitretin is completely avoided in women with childbearing potential. 5.2 Methotrexate Methotrexate is a known teratogen and mutagen, with a well-documented association with miscarriage and numerous congenital malformations [71–75]. A specific pattern of malformations has been characterized in the aminopterin/methotrexate syndrome, consisting of intrauterine growth retardation, severe lack of ossification of the calvarium, hypoplastic supraorbital ridges, small low-set ears, micrognathia, limb abnormalities, and developmental delays [76, 77]. Studies have suggested a critical dose of above 10 mg/week and a critical time of 6–8 weeks after conception for the development of this syndrome [78]. Due to these studies, some authors are open to the idea of methotrexate use below 10 mg/week outside of the critical period during pregnancy. There are, however, reports of malformations outside the critical period and with a lower dose than 10 mg/week [79], and therefore a cautious approach is still warranted. Methotrexate is given FDA pregnancy category X, its use in pregnancy is contraindicated, and discontinuation of methotrexate is recommended 3 months prior to conception. 5.3 Cyclosporine (Ciclosporin) There are reports of around 1000 pregnancies among women treated with cyclosporine (ciclosporin) during pregnancy that consistently show that the risk of fetal loss and congenital anomalies are similar to the general population, but that the rate of prematurity and low birth weight are significantly increased [80–87]. However, there are very limited data on patients with psoriasis [88]. The majority of reports are from transplant recipients, who are treated with higher doses than psoriasis patients and who

Treatment of Psoriasis During Pregnancy

have serious medical problems. Pregnancy in transplant recipients is complicated and it can be debated whether the prematurity and low birth weight seen are due to cyclosporine or due to the underlying health status of the patient. The FDA has classified cyclosporine as pregnancy category C. 5.4 Corticosteroids Apart from treating pustular psoriasis, systemic corticosteroids are seldom used to treat psoriasis. Data are available from mothers with asthma treated with systemic corticosteroids during pregnancy. In large population studies, systemic corticosteroids given in the first trimester have been associated with a threefold increased risk of cleft lip [37]. However, the absolute risk is still low at three in 1000 births. Several studies, including a large prospective study, have found a significant increase in low birth weight when a systemic corticosteroid is given in the third trimester. One Canadian study found the use of corticosteroids during pregnancy to be associated with an increased risk of asthma in infants [89]. Other studies, including a large nationwide Danish study including 877,778 pregnancies, did not support a causal relationship between maternal use of corticosteroids during pregnancy and an increased risk of asthma in offspring [90]. The FDA has categorized systemic corticosteroids as pregnancy category C. Systemic corticosteroids should be avoided in the first trimester and be given cautiously in low doses during the second and third trimesters.

6 Biologics 6.1 Tumor Necrosis Factor-a Inhibitors The preclinical safety data of TNFa inhibitors registered for use in the treatment of psoriasis, including infliximab, etanercept, and adalimumab, have not raised any concerns about their use in pregnancy [91–93]. Available postmarketing clinical data are from pregnant women with Crohn’s disease, colitis ulcerosa, or RA and are based on case reports as well as larger studies [94–101]. In a large multicenter retrospective cohort study [94] and a large prospective long-term safety registry study of TNF-a inhibitor treatment in inflammatory bowel disease, antiTNF-a treatment was not associated with an unfavorable pregnancy outcome in terms of congenital malformations, preterm delivery, low birth weight, or miscarriage. Similarly, a large retrospective study of 146 patients treated with infliximab for RA or Crohn’s disease showed incidence rates of malformations, preterm birth, and stillbirths similar to the general population [95]. In one registry study,

anti-TNF-a treatment for RA at the time of conception showed a higher rate of spontaneous abortion [96]. This could, however, be due to high disease severity as well as concurrent methotrexate treatment. In 2006, a review of the FDA Adverse Events Reporting Database raised concern about the use of TNF-a inhibitor treatment in pregnancy as a specific group of anomalies consistent with VATER (Vertebrae, Anus, Trachea, Esophagus, and Renal anomalies) syndrome was found [102]. However, the solidness of the study and the interpretation of the data have been questioned [103] and the distribution of specific congenital malformations was later noted to be similar to that of the general population through the European Surveillance of Congenital Anomalies database. Anti-TNF-a inhibitors cross the placenta in the third trimester of pregnancy and can be found in cord blood [104, 105]. The placental transfer is a concern as it leaves the newborn child immunosuppressed for several months. In one case, a child of an infliximab-treated mother died after receiving routine BCG (Bacillus Calmette-Gue´rin) vaccination at the age of 3 months [106]. Live vaccines need to be avoided for at least 6 months. All TNF-a inhibitors hold FDA pregnancy class B. 6.2 Ustekinumab Two fetal development studies of ustekinumab conducted in cynomolgus macaques have revealed no evidence of maternal toxicity, embryotoxicity, or teratogenicity [107]. There are very limited data on the safety of ustekinumab treatment during pregnancy. The literature only holds case reports [108–111], all resulting in healthy babies. One report has pooled data from 4 years of clinical trials with 31 pregnancies, with no incidence of fetal malformations or death [111]. The FDA has assigned ustekinumab pregnancy category B, similar to anti-TNF-a; however, due to the lack of evidence, its use is not recommended. 6.3 New Biological Therapies Advances in our understanding of the cytokine network in psoriasis have led to the development of new biological therapies, targeting cytokines specifically upregulated in psoriasis. These include the IL-17 antagonists brodalumab and ixekizumab and the recently approved anti-IL17A secukinumab, which has shown a dramatic effect on psoriasis. Apremilast and tofacitinib are two new oral smallmolecule phosphodiesterase-4 and JAK (Janus kinase) inhibitors, respectively, that show promising results. There are no data on the treatment safety during pregnancy with these new biologics and so the treatments should be avoided during pregnancy.

N. Bangsgaard et al.

7 Conclusion Treating pregnant women with a chronic disease is a challenge as there is the welfare of both the fetus and the mother to consider. Dermatologists may have relatively little experience with issues of pregnancy and childbirth and may choose a conservative treatment approach in fear of causing harm to the fetus. It is, however, important to recognize the need for disease control for the mother. Psoriasis is much more than a skin disease. Moderate to severe psoriasis is associated with systemic inflammation similar to inflammatory bowel diseases and RA and has been shown, in line with these diseases, to carry an increased risk of adverse pregnancy outcomes, low birth weight, and preterm birth. Whether or not this increased risk can be modulated by aggressively controlling the disease with systemic treatment is unknown, but needs to be kept in mind when balancing the benefits and risks of treatment in pregnant women with psoriasis. Most data on systemic treatments during pregnancy come from gastroenterology and rheumatology. It is important to recognize that in inflammatory bowel disease and RA, the indication for treatment is not only to relieve the patient of pain and discomfort but also to minimize the risk of disease progression and functional limitations. This is not a consideration in psoriasis, unless the patient has psoriatic arthritis, and it is therefore reasonable to adopt a more conservative approach when the use of systemic antiinflammatory medications to treat psoriasis during pregnancy is considered. Moderate to severe psoriasis is, however, known to have a considerable impact on patients’ quality of life and, although it has never been investigated, there is no reason to believe that this will change during pregnancy. It could be argued that treating the mother’s psoriasis to achieve a better quality of life is important for a good pregnancy, for the mother as well as the fetus. The evidence of treatment safety in pregnant women with psoriasis is rather poor, and is based on case reports and retrospective studies rather than randomized trials. Many of the treatments available have, however, been on the market for many years, and accumulating evidence of their safety in pregnant women is readily available. The Medical Board of the American National Psoriasis Foundation recently published guidelines for the treatment of pregnant women with psoriasis and, reviewing the recent literature, there seems to be overall agreement on these [112] (see Fig. 1). According to these guidelines, the firstline treatment is emollients and low- to moderate-potency topical corticosteroids that have been proven to be safe to use in an adequate amount. Second-line treatment is phototherapy, UVB, or narrowband UVB with a focus on overheating and folate supplementation. However, while

1st Line treatment Emollients mild to moderate topical steroid

2nd Line treatment UVB, narrow band UVB

3rd Line treatment Cyclosporine, anti-TNFα

Fig. 1 Guidelines according to the Medical Board of the American National Psoriasis Foundation. TNF-a tumor necrosis factor-a

most patients with mild to moderate psoriasis will respond to it, this line of treatment will be inadequate for patients with moderate to severe psoriasis who are already taking systemic medications. Methotrexate and acitretin are contraindicated in pregnant women. The available systemic treatments that can be considered as a third-line treatment are cyclosporine and anti-TNF-a. Cyclosporine has been shown to be safe in the transplantation population, although it is associated with low birth weight, which is a concern with moderate to severe psoriasis. Whether or not disease control with systemic treatment will alter this risk is unknown. Anti-TNF-a has shown good safety data in rheumatology and gastroenterology and there is a growing consensus that antiTNF-a use in pregnancy carries a low risk. The primary concern is the immune status of the child, with high levels of anti-TNF-a in the blood at birth. However, this has not been associated with an increased risk of neonatal infection, but live virus vaccinations need to be avoided for at least 6 months. As anti-TNF-a crosses the placenta in the late second and third trimesters, some authors recommend discontinuation of anti-TNF-a at week 28–30 in order to reduce the risk. Etanercept has a shorter half-life and less placental transfer than infliximab and adalimumab, which is an obvious advantage when used in pregnant women. Ustekinumab, apremilast, tofacitinib, and secukinumab cannot be recommended due to lack of evidence. The issue of pregnancy needs to be addressed when treating women with psoriasis in their reproductive years. The patient may be reluctant to plan pregnancy due to incorrect ideas of what this will do to her disease and fear of treatment withdrawal. Patients should be counseled in advance on what to expect regarding the treatment options available to them and be advised on lifestyle changes, if necessary. The clinician, in agreement with the patient,

Treatment of Psoriasis During Pregnancy

needs to balance the risks from therapy versus the harmful effects of psoriasis and its associated co-morbidities.

15.

Compliance with ethical standards L. Skov has received consultancy and/or speaker honoraria from Abbott, Pfizer, Janssen-Cilag, MSD, and Leo Pharma, and is a member of the advisory Boards of MSD, Novartis, Eli Lilly, Abbvie, Celgene, Amgen, and Janssen-Cilag. L. Skov has also received grants from Pfizer, Abbvie, Novartis, and Leo Pharma, but not in relation to this study.

16.

17.

N. Bangsgaard and C. Rørbye have no conflict of interests. No funding was received to assist with the preparation of this manuscript.

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Treating Psoriasis During Pregnancy: Safety and Efficacy of Treatments.

Psoriasis is a chronic inflammatory disease with a well-documented negative effect on the quality of life of affected patients. Psoriasis often occurs...
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