Biologics and novel small molecule treatments, reproduction and psoriasis

Author: Dr Charlotte L Thomas, MBChB MA (Oxon) MRCP Dermatology Research Fellow, Skin and Cancer Foundation Australia; Dr.Monisha Gupta, MD, FACD, Dermatologist, Sydney, Australia; Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, August 2015.


Biologics and novel small molecule treatments, reproduction and psoriasis - codes and concepts
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Introduction

Psoriasis is a common scaly skin condition. If you are pregnant or planning pregnancy and have psoriasis, seek your doctor's advice. This is particularly important if you are on systemic therapy for psoriasis. This article discusses the use of biologic and novel small molecule treatments for psoriasis such as apremilast, in women during their reproductive time of life.

Note:

  • Psoriasis affects many young people, so the need to plan for pregnancies in psoriasis is common.
  • Several biologic and small molecule agents are licensed for the treatment of psoriasis (2015).
  • Safety information for biologics in reproduction (from conception to pregnancy and breast-feeding) is limited.
  • Clinical trials of biologic medications exclude pregnant patients and those planning pregnancies, so evidence for safety comes largely from patient registries and case reports.

How does pregnancy affect psoriasis and its treatment?

Active psoriasis is characterised by inflammation throughout the body. The risk to the unborn baby from uncontrolled inflammation must be weighed up against the risk from medication.

  • Psoriasis is unpredictable in pregnancy. Most women experience an improvement during pregnancy with a flare after the birth of their baby, but psoriasis in some women worsens during pregnancy.
  • Psoriasis does not affect the chances of conceiving.
  • Active or untreated psoriasis can be associated with premature birth, low birth-weight babies and miscarriage.

Other health conditions associated with psoriasis may also complicate pregnancy:

  • Metabolic syndrome (obesity, high cholesterol, high blood pressure and impaired processing of sugars) is associated with premature birth, low birth-weight babies and the birth of large babies (with subsequent delivery complications).
  • Depression is linked to low birth-weight babies.
  • High maternal intake of alcohol can lead to fetal alcohol syndrome

Safety of medicines in pregnancy

All medications are categorised by their safety in pregnancy and the risk of harm to the unborn baby. The Australian Drug Evaluation Committee’s categorisation of medicines in pregnancy is summarised in Table 1.

Table 1: Categorisation of medicines in pregnancy
CategoryDescription
A Drugs which have been taken by large numbers of pregnant women, without any proven increase of malformations or any other harmful effects on the fetus.
B1 Drugs that have been taken by only a limited number of pregnant women, without an increase in the frequency of malformation or harmful effects on the fetus.
Studies in animals have not shown evidence of an increased occurrence of fetal damage.
B2 Drugs which have only been taken by a limited number of pregnant women, without an increase in the frequency of malformation or other harmful effects on the human fetus.
Studies in animals are inadequate or lacking, but show no increased occurrence of fetal damage.
B3 Drugs which have only been taken by a limited number of pregnant women, without an increase in the frequency of malformation or other harmful effects on the human fetus.
Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
C Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonates without causing malformations. These effects may be reversible.
D Drugs which have caused are expected to have caused an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects
X Drugs which are so high risk for causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy.

How safe are biologics and small molecule drugs in pregnancy?

Evidence regarding the use of biologic and small molecule medications in pregnancy and when planning a pregnancy is summarised in Table 2.

Table 2. Biologic and small molecules for the treatment of psoriasis
Medication (trade name)Pregnancy categoryMechanism and routeHalf life5 half lives* (days)
Biologic agents
Infliximab
(Remicade®)
C Anti-TNFα
  • Chimeric human-murine IgG monoclonal antibody
  • Intravenous
10 days 50
Adalimumab
(Humira®)
C Anti-TNFα
  • Human recombinant IgG monoclonal antibody
  • Subcutaneous
14 days 70
Etanercept
(Enbrel®)
B2 Anti-TNFα
  • Human recombinant TNF-α receptor fusion protein
  • Subcutaneous
3 days 15
Ustekinumab
(Stelara®)
B1 Anti-IL-12/IL-23
  • Human IgG monoclonal antibody
  • Subcutaneous
21 days 105
Secukinumab
(Cosentyx®)
C Anti-IL17A
  • Human IgG monoclonal antibody
  • Subcutaneous
27 days 135
Small molecule inhibitor
Apremilast
(Otezla®)
B3 Anti-PD4
  • Small molecule inhibitor of enzyme
  • Oral
9 hours 2

*In general, drugs are eliminated from the body after 5 drug half-lives.
TNF: tumour necrosis factor
IL: Interleukin
PD: phosphodiesterase

Is fertility affected by these agents?

  • It is not known if male and female fertility is affected by biologic medications, as studies assessing fertility have not been performed in humans with psoriasis.
  • High levels of TNFα in men can reduce sperm function; anti-TNFα medication can improve sperm function.
  • Anti-TNFα medications in arthritis does not appear to adversely affect sperm function or quality.
  • Individual reports indicate there is no delay in conception for men and women treated with biologics.
  • Less is known about the effects of ustekinumab, secukinumab and apremilast on fertility in humans, as they are relatively new compared to anti-TNFα medications.

Conclusions:

  • A conservative approach is to stop biologic and small molecule medications in women at least 5 half-lives prior to conception (see Table 2).
  • Anti-TNFα medications can be used safely in potential fathers.

Are these medications harmful during pregnancy?

Biologics and small molecule medications are not routinely recommended in pregnancy because they have not been studied sufficiently; they should only be considered when the potential benefit outweighs the risk. Therefore, contraceptive measures are recommended during biologic and apremilast treatment and for at least 5 half-lives afterwards.

  • Because TNFα inhibitors have been used for more than 10 years to treat inflammatory bowel disease and arthritis, there is more experience in pregnancy with these medications compared to the newer agents.
  • Apremilast was not teratogenic in animal studies.
  • The frequency of congenital malformations is no higher in women treated with biologic medications than in the general population.
  • Immunoglobulin G type (IgG) antibodies cross the placenta during the third trimester (week 24–36 of pregnancy), when biologic medications may reach and affect a developing fetus.
  • If treatment is continued during pregnancy, it is best to stop biologics and apremilast before week 23 of gestation.

Conclusions:

  • No biologic agent is recommended during pregnancy .
  • Psoriasis can be treated during pregnancy with topical agents, UVB phototherapy and oral ciclosporin.
  • Biologics may be considered during pregnancy if the risk of treatment is less than the risk of withholding treatment.
  • The mother’s psychological and physical wellbeing is of central importance.
  • If biologics are continued during pregnancy, the mother should be told that the baby’s immune system may be suppressed during the first months of life.

Should live vaccines be avoided?

Babies whose mothers are treated with a biologic may be at higher risk of infection. It is very important that live vaccinations (live polio, chickenpox/varicella, yellow fever) are avoided in these young infants. See Immunisation in immunosuppressed dermatology patients.

  • Infliximab: avoid live vaccines in infants for at least 6 months from birth.
  • Adalimumab: avoid live vaccines in infants for 5 months after the mother’s last dose.
  • Etanercept: avoid live vaccines in infants for 16 weeks after the mother’s last dose.
  • Ustekinumab: there are no recommendations about live vaccination for an exposed infant
  • Secukinumab: avoid live vaccines in infants for 16 weeks after the mother’s last dose.
  • Apremilast: there are no recommendations about live vaccination for an exposed infant

Can biologics be used during breast-feeding?

It is unknown if biologics are excreted in breast milk or whether they are absorbed by the infant through their gut.

  • Etanercept has been detected in the breast milk of treated mothers at low levels but has not been detected in infant blood.
  • Apremilast has been detected in the milk of treated animals.
  • Infants breast-feeding from mothers taking biologics have not experienced any untoward events.
  • The drug half-life (table 2) must be taken into account when deciding how long after the last dose to introduce breast-feeding.

Conclusions:

  • Biologics and apremilast are not recommended in breastfeeding mothers.
  • The choice of discontinuing breast feeding or the medication should take into account the importance of continuing the drug to the mother and the benefits of breast-feeding to the mother and child.
New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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