Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics:A retrospective comparative study in EudraVigilance

AIM: To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP) MATERIAL AND METHODS: A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologics (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment). RESULTS: ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus null in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. CONCLUSION: No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n= 64), anakinra (n= 20), belimumab (n= 93), ixekizumab (n= 29), rituximab (n=57), secukinumab (n= 128), tocilizumab (n= 124) and ustekinumab (n= 215). Regarding observed CCAs in the vedolizumab group (n= 113) no firm conclusions can be made based on available information

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease

OBJECTIVES: While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns. METHODS: Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant pairs (n=53). RESULTS: 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid. CONCLUSION: These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns

Safety of biologics during pregnancy in women with immune-mediated inflammatory diseases

The aim of this dissertation is to fill in the knowledge gaps on the use of biologics during pregnancy in women suffering from immune-mediated autoimmune diseases (IMIDs). To address this aim we used different information sources: for retrospective studies data was assembled from European Medicines Agency’s (EMA) EudraVigilance database; for prospective studies, patients were included from the Preconceptional Counselling in Active Rheumatoid Arthritis (PreCARA) cohort at Erasmus Medical Center in Rotterdam, the Netherlands

Dilemma of belimumab therapy (dis)continuation during pregnancy: Results of a retrospective study in eudravigilance

Introduction: The first biologic authorized for systemic lupus erythematosus (SLE) up to this date, belimumab, is currently not recommended for use during pregnancy due to lack of data. Provided that the health of the child begins with the health of the mother, pregnant patients face the dilemma of cessation or continuation of belimumab. If belimumab is stopped, there will be a risk of SLE flare and its consequences for the mother and the foetus. Continuation is also not optimal because of the lack of knowledge on safety for use during pregnancy. Aim: To compare the reported foetal outcomes in SLE patients who stopped scheduled belimumab within the first trimester (group A) and those who continued scheduled belimumab during the first trimester or thereafter (group B). Material and method: All belimumab-exposed pregnancy-related reports were extracted from the EudraVigilance (EV) database until March 11th, 2021. After case review, repeated cases, uninformative reports, non-medical elective abortions and foetal chromosomal abnormalities were excluded. Included pregnancies were divided into two groups (group A and B, as described above). Foetal outcomes were divided into live birth or foetal death (due to miscarriage or stillbirth) and were compared between both groups. Furthermore, neonatal outcomes, such as reporting rates of preterm birth, low birth weight and major congenital malformations were compared. Results: No statistical difference in foetal death was observed between group A and B (reported numbers (%) = 32 (46.4) and 11 (52.4), respectively). Odds ratio (OR, [95% Confidence Intervals (CIs)]) of foetal death in group B compared to group A was 1.27 [0.48, 3.32]. Reporting rates of preterm birth and low birth weight were higher – though not statistically different – in group A. Conclusion: The positive results of our study are supportive for the continuation of belimumab during pregnancy. Since the analysis is based on spontaneous reports/retrospective data, additional studies are needed to confirm the results

Analysing cord blood levels of TNF inhibitors to validate the EULAR points to consider for TNF inhibitor use during pregnancy

BACKGROUND: To minimise placental transfer of tumour necrosis factor inhibitors (TNFi), the European League Against Rheumatism (EULAR) created points to consider (PtC) for the use of TNFi during pregnancy. We are the first to validate the EULAR-PtC by analysing TNFi concentrations in cord blood. METHODS: Patients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis Study. TNFi was stopped at the time points recommended by the EULAR. Maternal blood and cord blood were collected and analysed for the concentration of TNFi. RESULTS: 111 patients were eligible for the analysis. Median stop time points were gestational age (GA) 37.0 weeks for certolizumab pegol, GA 25.0 weeks for etanercept, GA 19.0 weeks for adalimumab and GA 18.4 weeks for infliximab. Certolizumab pegol (n=68) was detectable in 5.9% of cord blood samples, with a median concentration of 0.3 µg/mL (IQR: 0.2-1.3) and a median cord/maternal concentration ratio of 0.010. Etanercept (n=30) was not detected in any cord blood samples. Adalimumab (n=25) was detectable in 48.0% of cord blood samples, with a median concentration of 0.5 µg/mL (IQR: 0.2-0.7) and a median concentration ratio of 0.062 (IQR: 0.018-0.15). Infliximab (n=14) was detectable in 57.1% of cord blood samples, with a median concentration of 0.4 µg/mL (IQR: 0.1-1.2) and a median concentration ratio of 0.012 (IQR: 0.006-0.081). CONCLUSION: Compliance with the EULAR-PtC results in absence or low levels of TNFi in cord blood

Supplemental Material - Dilemma of belimumab therapy (dis)continuation during pregnancy: Results of a retrospective study in eudravigilance

Supplemental Material for Dilemma of belimumab therapy (dis)continuation during pregnancy: Results of a retrospective study in eudravigilance by Nafise Ghalandari, Hubertina JMJ Crijns, Radboud JEM Dolhain, Johanna MW Hazes and Eugene P van Puijenbroek in Lupus</p

Active counselling and well-controlled disease result in a higher percentage of women with rheumatoid arthritis that breast feed: Results from the PreCARA study

Objectives Previous research has demonstrated that patients with rheumatoid arthritis (RA) are less likely to breast feed their offspring. Treatment options for RA during lactation have expanded and the importance of counselling is recognised. The aim of the current research was to study breast feeding among women with RA who benefit from these developments. Methods Patients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis (PreCARA) cohort. Patients were treated according to a modified treat-to-target approach aimed at remission and received pregnancy counselling, including counselling on breast feeding. Postpartum visits were scheduled at 4-6, 12 and 26 weeks post partum. Prevalence of breast feeding at each postpartum visit was compared with a historical reference cohort (Pregnancy-induced Amelioration of Rheumatoid Arthritis cohort) and the general population. Results Data on 171 pregnancies were available for the current analysis. 120 (70.2%) patients with RA initiated breast feeding. 103/171 (60.2%), 68/171 (39.8%) and 45/171 (26.3%) patients with RA breast fed their offspring at 4-6, 12 and 26 weeks post partum, respectively. These percentages were higher at all postpartum visits compared with the historical reference cohort (p<0.001). In comparison with the general population, the rates were similar at each time point. Conclusion Patients with RA in the PreCARA cohort were more likely to breast feed their offspring compared with patients with RA in the historical reference cohort. The breastfeeding rates observed were similar to breastfeeding rates among women in the general population. The increase in breast feeding among patients with RA may be due to the extension of lactation-compatible medication and pregnancy counselling

Reported congenital malformations after exposure to non-tumour necrosis factor inhibitor biologics: A retrospective comparative study in EudraVigilance

Aims To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitor biologics (non-TNFi biologics) compared to certolizumab pegol (CZP). Methods A retrospective comparative study was conducted in the EudraVigilance (EV) database. A safe biologic (CZP) was considered as the reference group. Odds ratios (ORs) for CMs were calculated for each non-TNFi biologic (including abatacept, anakinra, belimumab, ixekizumab, rituximab, secukinumab, tocilizumab, ustekinumab and vedolizumab), versus CZP (quantitative assessment). Then, CM patterns were reviewed in consultation with a clinical geneticist (qualitative assessment). Results ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Except for vedolizumab, no specific CM patterns were observed for the included non-TNFi biologics. Three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus none in CZP and other investigated non-TNFi biologics). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. Conclusion No special safety signal was identified regarding the occurrence of CMs after exposure to abatacept (n = 64), anakinra (n = 20), belimumab (n = 93), ixekizumab (n = 29), rituximab (n = 57), secukinumab (n = 128), tocilizumab (n = 124) and ustekinumab (n = 215). Regarding observed CCAs in the vedolizumab group (n = 113), no firm conclusions can be made based on available information

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease.

OBJECTIVES: While protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In this pilot study, we explored whether treatment with tumour necrosis factor alpha inhibitors (TNFis) in pregnant patients with rheumatic disease interferes with Tdap vaccine responses and affects maternal anti-pertussis IgG antibody levels in newborns. METHODS: Patients were included by a rheumatologist during pregnancy in case they received maternal Tdap vaccination in the late-second or early-third trimester of pregnancy. Blood samples were obtained from mothers during the first pregnancy trimester, 3 months after delivery and from the umbilical cord. IgG antibody levels against Tdap-included antigens were measured using a bead-based multiplex immunoassay. Findings on patients exposed to TNFis were compared with those from TNFi-unexposed patients and with data from a historical comparator study among healthy Tdap vaccinated mother-infant pairs (n=53). RESULTS: 66 patients (46 exposed and 20 unexposed to TNFIs) were enrolled. No major differences in IgG antibody levels were observed between TNFi-exposed and unexposed mothers before maternal Tdap vaccination and 3 months after delivery. In cord sera, however, antibody levels against pertussis toxin were significantly lower after TNFi-treatment (35.94 IU/mL, 95% CI 20.68 to 62.45) compared with no TNFi-treatment of mothers with rheumatic disease (94.61 IU/mL, 95% CI 48.89 to 183.07) and lower compared with a cohort of healthy mothers (125.12 IU/mL, 95% CI 90.75 to 172.50). We observed similar differences for filamentous haemagglutinin, pertactin, tetanus toxoid and diphtheria toxoid.CONCLUSION: These preliminary data indicate no major differences in IgG antibody levels on maternal Tdap vaccination in pregnant women with or without immune-modulating treatment, although our findings suggest that TNFis during pregnancy induce lower maternal anti-pertussis-specific protective antibody levels in newborns.</p