Biological agents in pregnancy and lactation – A rational approach

Biologicals in pregnancy

There is a shift from T helper (Th) 1 response to Th2 response in pregnancy. If pregnancy is associated with autoimmune or other inflammatory diseases, there is increased ratio of Th17 to T regulatory (Treg) cells, whereas reverse is true in normal healthy pregnancy.^[1] Pregnancy outcomes are generally poor in patients with severe psoriasis and other immunological diseases, thus justifying the use of biologicals in pregnancy in severe conditions. Most biologicals pass minimally through the placental barrier in the first two trimesters until active transport of immunoglobulins starts at the beginning of the third trimester, with the development of fetal Fc receptor on the placenta.^[2]

Biologicals in lactation

Overall, there is a limited information regarding their use; though few published case reports do not indicate any adverse effects on the lactating infant. Due to high molecular weights, they are secreted in breast milk to a very minuscule extent. However, during the first 3 days, the breast alveolar cells have wide gaps to allow immunoglobulins to pass through, and hence, it is prudent to avoid biologics in this interval. As these are protein molecules, these are likely to be destroyed by the acid and proteolytic enzymes in the infantile gut and even the minuscule amount secreted in breast milk may not be absorbed.^[3] Pharmaceutical industry with concerns of future liability issues aims at caution and excludes the use of biologics in pregnancy and lactation.

This article aims at dissecting the feasibility of biologicals in pregnancy and lactation for dermatological indications. The guidelines and recommendations are extrapolated from the data of use in other conditions such as inflammatory bowel disease and rheumatoid arthritis (RA) as there is no sufficient literature evidence for the use of biologicals in pregnancy for dermatological conditions. It is essential to remember that while treating a pregnant woman, the chief objective should be to control the disease while taking care to minimize maternal and fetal risk to side effects of medication. Benefit of treatment should always outweigh the risk.

Biologicals used in dermatology and their use in pregnancy and lactation has been tabulated in Table 1. (Biologicals such as alefacept and efalizumab which have been withdrawn are not being discussed here).

Tumor necrosis factor-alpha (TNF-α inhibitors)
Infliximab

This is a chimeric human – murine monoclonal antibody, which irreversibly binds to soluble as well as transmembrane forms of TNF–α, thereby blocking its action. It also depletes TNF-α producing cells by apoptosis induced by complement lysis and antibody-dependent cellular cytotoxicity.

Indications in dermatology include moderate-to-severe plaque psoriasis, psoriatic arthritis, pustular psoriasis, and erythrodermic psoriasis. Off-label uses include hidradenitis suppurativa, pyoderma gangrenosum, Behcet’s syndrome, vasculitis, graft versus host disease, systemic lupus erythematosus (SLE), sarcoidosis, and Sjogren’s syndrome.^[4] Mode of administration: 3, 5, or 10 mg/kg body weight intravenous infusion in 500 ml normal saline at 0, 2, and 6 weeks and thereafter, every 8 weeks.

Etanercept

Etanercept is a soluble TNF receptor, a dimeric fusion protein composed of extracellular ligand-binding portion of human p75 tumor necrosis receptor linked to Fc portion of human IgG1. It modulates all the biological responses of TNF. Chief indications are rheumatoid, juvenile idiopathic, and psoriatic arthritis, though it is also used in other conditions, similar to infliximab. Dosage is 50 mg subcutaneous (s/c) once or twice a week for 3 months.

Adalimumab

This is a fully human IgG1 monoclonal antibody against soluble as well as membrane bound TNF –α administered as initial 80 mg dose subcutaneously, thereafter 40 mg subcutaneously every 2 weeks. Indications in dermatology are similar to those of infliximab and are also used in alopecia areata, pemphigus, and multicentric reticulohistiocytosis.^[5]

Golimumab

Although it is available in India and is indicated in psoriasis and psoriatic arthritis, it has only limited use. It is given 50 mg s/c once a month.

Certolizumab

It is used in rheumatoid and psoriatic arthritis at a dose of 400 mg s/c initially, followed by 200 mg every 2 weeks, has been recently approved by FDA in pregnant and lactating mothers with pregnancy category B. In the CRIB study, certolizumab levels were below the lower limit of quantification in 13 of 15 infant blood samples at birth and in all samples at weeks 4 and 8. No anti-certolizumab antibodies were detected in mothers, umbilical cords, or infants.^[18] It was not detected in 134 of 137 breast milk samples from 19 lactating mothers, and all infants were normal.^[19] Although it is minimally excreted in breast milk, it is destroyed by the infant’s gut and absorption is unlikely. Although manufacturers recommend cessation of breastfeeding, most experts consider this to be probably safe in lactation.

Other biologicals

As pregnancy is commonly an exclusion criterion for clinical trials, there are no large properly conducted studies on newer biologicals. Data are usually extrapolated from animal studies, or from case reports, series, or retrospective studies. There are surveillance registries in some countries, but bias of preferentially reporting only adverse effects cannot be excluded.

Ustekinumab

This is a monoclonal antibody against interleukin (IL) 12 and 23, indicated in the treatment of resistant moderate to severe plaque psoriasis, active psoriatic arthritis, and Crohn’s disease. Dose is 45 mg s/c on day 0, at 4 weeks, subsequently every 12 weeks.

There are no adequate human studies for its use in pregnancy, though animal studies do not indicate any risk. It is preferable to avoid using in pregnancy as a precautionary measure.^[20]

There is limited published information on its use in lactation. It is only minimally detectable in breast milk, and absorption is unlikely as it is destroyed by the infant’s gastrointestinal tract. In the PIANO registry multicentric study, there were six women who breastfed infants while on ustekinumab. Among these six as well as others on different biologicals in mothers who were pregnant or lactating, there was no difference in infant growth, development, or infection rate as compared to infants of mothers who did not receive treatment.^[21] If ustekinumab is essential to the mother, it is not a reason to discontinue lactation but may be used with caution while nursing newborn or preterm infants.^[22]

Secukinumab

It is a recombinant high-affinity fully human monoclonal antibody of the IgG1/kappa isotype that selectively targets IL-17A, used in resistant moderate-to-severe plaque psoriasis and psoriatic arthritis at initial dose of 300 mg s/c weekly.^[23] As an IgG1 molecule, secukinumab could cross the placenta, but antibody transfer mostly occurs in the third trimester. Animal studies do not indicate harmful effects in pregnancy. It is pregnancy category B and may be used if benefits outweigh risks.

Of 292 pregnancies studied from the global safety database, there was no overall pattern of abnormality and secukinumab was not connected to any of the abortions or congenital malformations that occurred, which was in concordance with the normal rates of attrition.^[24] There is no clinical information on use in breastfeeding, though isolated cases report no side effects^[25] Being a large molecule, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant’s gastrointestinal tract. Secukinumab may be used with caution during breastfeeding, especially while nursing a newborn or preterm infant.^[26]

Ixekizumab

This is also a humanized monoclonal IgG antibody which binds to IL-17a receptor, thus inhibiting IL-17 activities, and is used in the treatment of moderate-to-severe chronic plaque psoriasis. It is administered as 160 mg s/c at the first visit, thereafter 80 mg s/c at fixed intervals.

Rituximab

Rituximab is a chimeric human monoclonal antibody against CD20 cell marker present on B-cells and causes depletion of B-cells in vivo; indications include large B-cell non-Hodgkin’s lymphoma (NHL), rheumatoid arthritis (RA), chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).^[28] The off-label use in dermatology includes autoimmune blistering disorders (pemphigus and its variants, mucous membrane pemphigoid, and epidermolysis bullosa acquisita), systemic lupus erythematosus (SLE), atopic dermatitis, vitiligo, graft versus host disease, dermatomyositis, and scleroderma.^[29]

There are two conventional protocols for the drug in adults – the RA protocol(the drug is given as an infusion of 1 gm every two weeks for two doses) and the lymphoma protocol(the drug is given at 375mg/m² body surface area doses every week for 4 weeks).

Omalizumab

Omalizumab is a recombinant, humanized, monoclonal antibody against immunoglobulin IgE which neutralizes IgE by binding to the same site on FcεR I. Initially used for the treatment of severe allergic asthma, it got FDA approval for treatment of chronic spontaneous urticaria in 2014.^[33] Off-label uses include atopic dermatitis, bullous and systemic mastocytosis, and bullous urticaria.^[34] Recommended dose and best response is seen with 300 mg subcutaneous injection once in 4 weeks. Some patients may respond to 150 mg once in 4 weeks.^[35]

Anakinra

This is a recombinant human IL-1 receptor antagonist (IL- 1Ra) used in diverse dermatological conditions such as psoriasis, atopic dermatitis, Schnitzler syndrome, pyoderma gangrenosum, pyogenic arthritis, pyoderma gangrenosum and acne syndrome, hidradenitis suppurativa, familial Mediterranean fever, and synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. Dosage is 100 mg s/c daily, drawbacks being the expense and increased propensity to allergies and infections. It is not widely used in India.

It is pregnancy category B, and excretion in breast milk is not determined. Natural IL-1Ra is present in human milk as an anti-inflammatory agent, but excretion of exogenous administration is not studied. Infants who have been breastfed by mothers on anakinra have not experienced any side effects. Hence, if maternal benefits outweigh risks, anakinra may be used in pregnancy as well as lactation.^[42]

Dupilumab

Dupilumab, a fully humanized monoclonal IgG4 antibody, acts as IL-4Ra, blocks IL-4/IL-13 signaling and thereby inhibits the Janus Kinase-Signal Transducer and Activation of Transcription pathway which leads to increased eosinophil recruitment and IgE production,^[43] and has got FDA approval for the treatment of atopic dermatitis. The recommended initial dose is 600 mg (two 300-mg injections in different injection sites) followed by 300 mg every other week, subcutaneously.^[44]