Jeremy Strain, BSc1; Maria Leis, BA2; Kyle O. Lee, BMBS, MPH, CCFP3; Patrick Fleming, MD, MSc, FRCPC, FCDA4
1Northern Ontario School of Medicine, Thunder Bay, ON, Canada
2Faculty of Medicine, University of Toronto, Toronto, ON, Canada
3Department of Family & Community Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada
4Division of Dermatology, University of Toronto, Toronto, ON, Canada
Conflict of interest:
Jeremy Strain has no conflicts of interest to disclose. Maria Leis has no conflicts of interest to disclose. Kyle O. Lee has received honoraria and/or consulting fees and/or advisory board fees for Bausch Health, Eli Lilly, Eisai, Elvium, and Pfizer for work unrelated to this manuscript. Patrick Fleming has received honoraria and/or consulting fees and/or advisory board fees for AbbVie, Altius, Aralez, Bausch Health, Cipher, Galderma, Eli Lilly, UCB, Novartis, Pfizer, and Sanofi-Genzyme for work unrelated to this manuscript.
Psoriasis is a chronic, immune-mediated skin condition which commonly affects women of childbearing age. Certolizumab pegol (CZP) is an anti-tumor necrosis factor-alpha (anti-TNFα) agent that has demonstrated long-term safety and efficacy in treating moderate-to-severe plaque psoriasis. Previously, there has been limited safety data surrounding its use in pregnancy. The objective of this article is to review pivotal clinical trial data for CZP and explore safety considerations for this agent in pregnancy. This review demonstrates that CZP offers a safe and effective treatment option for women during childbearing years based on pharmacokinetics and available safety data. The observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.
psoriasis, certolizumab, Cimzia, biologics, anti-TNF agents, pregnancy, obstetrics
Plaque psoriasis is a chronic inflammatory immune-mediated skin disorder associated with genetic and environmental factors. The global prevalence of psoriasis is approximately 2% with some regional variation.1,2 Although psoriasis primarily affects the skin, it also has widespread systemic effects including psoriatic arthritis, depression, and cardiovascular disease.2
Over the past two decades our understanding of the pathogenesis of psoriasis has been largely elucidated. Research has demonstrated that the disease is primarily driven through a mediated pathogenic T-cell pathway. Specifically, high levels of interleukin (IL)-23/T-helper type 17 T-cell are thought to stimulate release of IL-17.3 IL-17 upregulation in turn leads to a “feed forward” cycle, including inflammatory responses in keratinocytes which further drive the development of psoriatic plaques by inducing characteristic changes such as epidermal hyperplasia and cell proliferation and leukocyte recruitment.3
TNFα is a pro-inflammatory cytokine further implicated in the immunopathogenesis of psoriasis.3 The upregulation of TNFα leads to increased production of IL-23, further stimulating the psoriatic pathway. Additionally, TNFα works synergistically with IL-17 to upregulate transcription of many pro-inflammatory genes. Increased understanding of these inflammatory pathways has led to the advent of biologic therapies, including TNFα inhibitors, which have revolutionized the treatment of psoriasis.3
Although advances in our understanding of the disease pathogenesis have spawned the development of targeted biologic therapies, research is limited on the use of these medications in specific subpopulations. Considering that psoriasis often affects women of childbearing age, effective and safe treatment options during pregnancy are an important consideration.4 The objective of this article is to review pivotal clinical trial data for certolizumab pegol (CZP), a PEGylated anti-TNFα biologic agent, and explore safety considerations for this treatment option in pregnancy.
Certolizumab Pegol and Early Clinical Trials
CZP (Cimzia®) is a recombinant humanized monoclonal anti- TNFα antibody approved to treat plaque psoriasis, psoriatic arthritis, Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis, and axial spondyloarthritis. CZP contains the antigen-binding fragment (Fab) of an immunoglobulin G (IgG) antibody and lacks the fragment crystallizable (Fc) region.5 A single cysteine residue allows the Fab portion to be conjugated with polyethylene glycol (PEG) to form CZP, increasing its halflife to 14 days while maintaining its ability to avidly bind TNFα.5
Two phase III double-blind randomized placebo-controlled studies (CIMPASI-1 and CIMPASI-2) using CZP for moderate-severe plaque psoriasis found biweekly doses of either 200 mg or 400 mg led to significantly improved responses of the Psoriasis Area and Severity Index (PASI) PASI-75, PASI-90, and Physician’s Global Assessment (PGA) 0/1, when compared to placebo.6 The pooled data from CIMPASI-1 and CIMPASI-2 show that after 16 weeks, CZP 200 mg q2w resulted in PASI-75 of 76.7% (P<0.0001), PGA 0/1 of 56.8% (P<0.0001), and PASI-90 of 45.9% (P<0.0001), while CZP 400 mg q2w showed PASI-75 of 82% (P<0.0001), PGA 0/1 of 65.3% (P<0.0001), and PASI-90 of 52.2% (P<0.0001) (supplemental Table 1).6 A similar study (CIMPACT) compared its use to etanercept, also a TNFα inhibitor, with CZP 200 mg q2w showing a PASI-75 of 61.3%, with 8% higher when compared to etanercept (P<0.1523).7 Similarly, CZP 400 mg q2w showed a PASI-75 responder rate of 66.7%, with 13.4% higher responder rate when compared to etanercept (P<0.0152) (supplemental Table 2), with efficacy either comparable or superior to etanercept in psoriasis.7 However, pregnant and breastfeeding patients were excluded in these initial studies.6,7
|Endpoint||Pooled Data (CIMPASI-1 & CIMPASI-2)|
|Placebo||CZP 200 mg q2w||CZP 400 mg q2w|
|Primary Endpoint – Week 16|
|PASI-75 responder rate (%)||9.9||76.7||82|
|PGA 0/1 responder rate (%)||2.7||56.8||65.3|
|Secondary Endpoint – Week 16|
|PASI-90 responder rate (%)||2.5||45.9||52.2|
|Secondary Endpoint – Week 48|
|PASI-75 responder rate (%) (95% CI)||NA||70.7(60.6 to 80.7)||83.6(75.9 to 91.3)|
|PGA 0/1 responder rate (%) (95% CI)||NA||61.0(50.3 to 71.8)||68.9(58.7 to 79.1)|
|Supplemental Table 1: Pooled data for CIMPASI-1 and CIMPASI-2 summarizing PASI, PGA 0/1, PASI-75, and PASI-90 values, along with respective P-values.6 CI = confidence interval|
|CZP 200 mg q2w||CZP 400 mg q2w||Etanercept|
|Secondary Endpoint vs. Etanercept – Week 12|
|PASI-75 responder rate (%)||61.3||66.7||53.3|
|Difference in responder rate, estimate (95% CI)||8.0 (–2.9 to 18.9)||13.4 (2.7 to 24.1)|
|Supplemental Table 2: Data from the CIMPACT study summarizing PASI, PGA 0/1, PASI-75, and PASI-90 values, along with respective P-values, when compared to etanercept7|
Certolizumab Pegol in Pregnancy
Psoriasis commonly affects women during childbearing years, making safe and effective treatment in this population important.4,8,9 Up to 32% of women may have worsening or ongoing high disease activity during pregnancy,10 with increased psoriatic disease linked to adverse outcomes such as low birth weight, preterm delivery, preeclampsia, small for gestational age and fetal loss.4 Following, control of psoriatic disease during pregnancy leads to improved pregnancy outcomes, such as reducing preterm delivery, fetal loss, and low birth rates.4 Disease control prior to pregnancy and into the postpartum period are also important to maternal and fetal outcomes.10
Most anti-TNF agents (infliximab, adalimumab, golimumab, etanercept) have a classical IgG structure with an Fc region which can attach to the neonatal Fc receptor for IgG (FcRn) and cross the placenta.11 In particular, circulating maternal IgG antibodies are actively transported across the placenta in the second half of pregnancy, facilitated by FcRn11 Importantly, IgG levels at term in the newborn are higher than maternal levels, with a half-life approximately twice as long as that in the mother.11-13 Unlike other anti-TNF agents, CZP lacks the Fc-binding property. Results from CZP nonclinical and human placental perfusion data demonstrate that in fact CZP does not bind to FcRn, and consequently suggest that there is no active FcRn-mediated placental transport.5,14
Several studies have specifically examined the use of CZP during pregnancy. The CRIB study (n=16 mother-infant pairs) measured any potential placental transfer of CZP from mothers to infants at birth, along with concentrations of CZP in the plasma of mothers at delivery and umbilical cords at birth.15 Maternal CZP plasma levels at delivery were within the expected range (median = 24.4 μg/mL), and infant levels were below the lower limit of quantitation (0.032 μg/mL). Further, the investigators found that gestational age and weight at birth of all infants were within the expected range for healthy infants.15 Safety data was consistent with the known safety profile of CZP for mothers, and clinical events by infants did not show any patterns of clusters of events suggesting a specific adverse safety signal.15 The CRIB study provides evidence that levels of CZP are not present in sufficient amounts in infants to cause treatment emergent adverse effects.
Similarly, a recent pooled analysis of n=11,317 patients in clinical trials examined the long-term safety of CZP in rheumatoid arthritis, psoriatic arthritis, psoriasis and Crohn’s disease.16 With regards to its use during pregnancy, the study concluded there is no to minimal placental transfer from mothers to infants (suggesting a lack of in utero exposure during the third trimester), with the median Relative Infant Dose of CZP in breastmilk (0.125%) considered to be in the safe range for breastfeeding (<10%). The authors concluded that the safety profile of CZP is in line with that of other anti-TNF agents in all indications16
The CRADLE study (n=18 mothers, n=17 infants) examined the concentration of CZP in mature human breast milk, and assessed safety profiles in both mothers and infants.17 The study demonstrated almost all breast milk concentrations were less than two times the lower limit of quantification. Further, adverse events in mothers and infants were mostly mild to moderate in intensity (mothers: 3 mild, 6 moderate; infants: 6 mild, 2 moderate). No serious adverse events were reported in infants, and no hospitalizations or deaths in mothers or infants occurred.17 Overall, this study suggests very low to undetectable levels of CZP in breast milk, which corresponded with no increased risk for breastfeeding infants of mothers using CZP.
A recent review by Clowse and colleagues examined pregnancy outcomes, including major congenital malformations, in women receiving CZP, with a specific focus on the timing of exposure. This analysis represents the largest published cohort (n=538) of pregnant women with known outcomes exposed to CZP for the management of chronic inflammatory diseases.18 Results demonstrated that most maternally CZP-exposed pregnancies resulted in live births (Figure 1), with miscarriage, induced abortion and stillbirth representing trends similar to the general population (Figure 2). Timing-wise, maternal exposure to CZP occurred during at least the first trimester for 367 of the 452 prospective pregnancies (81.2%) and almost half of the pregnant women (44.5%) were exposed to CZP during all three trimesters. Eight major congenital malformations were observed (Table 1).18 Further, serious maternal infections occurred in 22 (4.2%) pregnancies, and among those which resulted in a live birth, maternal comorbidities were due to preeclampsia (5 patients, 1.1%) and gestational diabetes (6 patients, 1.3%).18 Overall, the results suggest there is no increased teratogenic effect of CZP compared to the general population, nor a greater incidence of fetal death. Maternal complications are similar to the general population. Important limitations include a lack of an untreated control group for comparison, lack of follow up for a third of cases, and numbers of pregnancy outcomes in patients receiving an anti-TNF therapy are relatively small for less common birth characteristics.
|1st Trimester||2nd Trimester||3rd Trimester|
|Congenital heart disease||Yes||Yes|
|Cerebral ventricle dilatation||Yes|
Table 1: Summary of congenital malformations in fetuses exposed to CZP. Data adapted from Clowse and colleagues, 2018.18
The above studies provide evidence that CZP use during the third trimester of pregnancy has low or undetectable levels of CZP in infants’ blood, low to undetectable levels of CZP are present in breastmilk, and observed occurrence of major congenital malformations and miscarriages is no greater than that of the general population in mothers using CZP. Considering these findings and the increasingly emergent use of anti-TNF biologics in pregnancy, a Canadian consensus paper on management of plaque psoriasis in women of child-bearing potential was recently published.19 A panel of nine Canadian dermatologists managing psoriasis reviewed the relevant literature, focusing on TNF-α inhibitors, IL-23 inhibitors, IL-12/23 inhibitors, and IL-17 inhibitors. With respect to CZP, three main conclusions were drawn. First, CZP is the only biologic demonstrating no active placental transport throughout pregnancy due to the lack of the Fc portion, and as such can be used throughout all three trimesters. Second, CZP is the only biologic for psoriasis for which infants exposed have no detectable drug levels. Third, CZP has the most evidence of all biologics reviewed suggesting no to minimal exposure for the fetus and infant.19 Taken together, these results provide evidence for the safety of CZP throughout all three trimesters of pregnancy and during the breastfeeding period.
Psoriasis is a common condition affecting women during childbearing years, with untreated disease contributing to adverse events for both the mother and infant. CZP appears to offer a safe and effective treatment for patients who are considering pregnancy, pregnant, or lactating based on its pharmacokinetics and available safety data. Importantly, the observed occurrence of major congenital malformations and miscarriages appears to be no greater than the background occurrence of those in the general population, and risks to the mother are minimal based on its known safety profile. The use of CZP for treatment of plaque psoriasis should be considered and discussed with patients considering childbearing or whom are currently pregnant or breastfeeding.
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- Boehncke W-H, Schön MP. Psoriasis. The Lancet. 2015 Sep 5;386(9997):983-94.
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- Weir N, Athwal D, Brown D, et al. A new generation of high-affinity humanized PEGylated Fab fragment anti-tumor necrosis factor-α monoclonal antibodies. Therapy. 2006 Jul;3(4):535-45.
- Gottlieb AB, Blauvelt A, Thaci D, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo- controlled studies (CIMPASI-1 and CIMPASI-2). J Am Acad Dermatol. 2018 Aug;79(2):302-14
- Lebwohl M, Blauvelt A, Paul C, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT). J Am Acad Dermatol. 2018 Aug;79(2):266-76.
- Brouwer J, Hazes JMW, Laven JSE, et al. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015 Oct;74(10):1836-41.
- Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res (Hoboken). 2015 Mar;67(3):313-25.
- Polachek A, Li S, Polachek IS, et al. Psoriatic arthritis disease activity during pregnancy and the first-year postpartum. Semin Arthritis Rheum. 2017 Jun;46(6):740-5.
- Malek A, Sager R, Schneider H. Transport of proteins across the human placenta. Am J Reprod Immunol. 1998 Nov;40(5):347-51.
- Hazes JMW, Coulie PG, Geenen V, et al. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use. Rheumatology. 2011 Nov 1;50(11):1955-68.
- Sarvas H, Seppälä I, Kurikka S, et al. Half-life of the maternal IgG1 allotype in infants. J Clin Immunol. 1993 Mar;13(2):145-51.
- Wakefield I, Stephens S, Foulkes R, et al. The use of surrogate antibodies to evaluate the developmental and reproductive toxicity potential of an anti-TNFα PEGylated Fab’ monoclonal antibody. Toxicol Sci. 2011 Jul;122(1):170-6.
- Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018 Feb;77(2):228-33.
- Curtis JR, Mariette X, Gaujoux-Viala C, et al. Long-term safety of certolizumab pegol in rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis and Crohn’s disease: a pooled analysis of 11 317 patients across clinical trials. RMD Open. 2019 May;5(1):e000942.
- Clowse ME, Förger F, Hwang C, et al. Minimal to no transfer of certolizumab pegol into breast milk: results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study. Ann Rheum Dis. 2017 Nov;76(11):1890-6.
- Clowse MEB, Scheuerle AE, Chambers C, et al. Pregnancy outcomes after exposure to certolizumab pegol: updated results from a pharmacovigilance safety database. Arthritis Rheumatol. 2018 Sep;70(9):1399-407.
- Yeung J, Gooderham MJ, Grewal P, et al. Management of plaque psoriasis with biologic therapies in women of child-bearing potential consensus paper. J Cutan Med Surg. 2020 Jul/Aug;24(1 suppl):3S-14S.
- Kirby RS. The prevalence of selected major birth defects in the United States. Semin Perinatol. 2017 Oct;41(6):338-44.