Hydroxychloroquine under scrutiny for cardiac neonatal lupus prevention



NEW YORK – Positive signs from the nearly completed first stage of a prospective prevention trial for cardiac neonatal lupus are giving investigators hope that hydroxychloroquine can reduce the risk of fetal heart block if given during pregnancy to women with systemic lupus erythematosus who have previously had a child with the condition.

The first stage of the PATCH (Preventive Approach to Congenital Heart Block With Hydroxychloroquine) study has enrolled all of its intended 19 pregnant women with systemic lupus erythematosus (SLE) and anti-SSA/Ro and anti-SSB/La antibodies who had a previous child with cardiac neonatal lupus (CNL). So far, cardiac abnormalities have been found in only 1 of 17 completed pregnancies in women who began taking 400-mg hydroxychloroquine (HCQ) before 10 weeks’ gestation. The study will go on to a second stage if fewer than three cases of second- or third-degree heart block occur. Enrollment of an additional 35 women is planned for the second stage, Dr. Jill P. Buyon said at the New York University Seminar in Advanced Rheumatology. She is director of the New York University Lupus Center, a professor in the division of rheumatology at New York University, and the principal investigator of the open-label PATCH study.

HCQ treatment will be considered efficacious if fewer than 6 mothers of the 54 total have a child with advanced congenital heart block. With this design, the study has 90% power to conclude that HCQ is preventive if the true recurrence rate with the treatment is 5%. In addition, the probability of rejecting the treatment for further study is 95% if the true recurrence rate is 18%, according to Dr. Buyon and her colleagues.

Women in the trial are given weekly serial fetal echocardiograms and blood tests for potential biomarkers of efficacy and compliance. The results of the study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy, according to the investigators.

"We need prophylactic treatment for autoimmune-associated congenital heart block because of the significant morbidity and mortality. The fibrosis is immutable, and there is no sustained reversal of complete heart block," Dr. Buyon said at the meeting sponsored by NYU. In previous work, Dr. Buyon reported a 17.5% mortality rate of neonates with cardiac neonatal lupus (CNL), 30% in utero (Circulation 2011;124:1927-35).

Congenital atrioventricular block and cardiomyopathy are the two major manifestations of CNL. The risk of CNL is approximately 2% in women with SLE who have given birth to an unaffected child, but the recurrence rate is 17.4% in those who have previously given birth to a baby with CNL. Mechanistically, HCQ’s inhibitory effect on toll-like receptors is thought to interfere with the pathophysiologic cascade underlying CNL.

Research leading up to the PATCH study indicated that HCQ might reduce the risk of CNL by 65% when pregnant mothers with SLE took HCQ throughout their pregnancy, Dr. Buyon said.

She and her colleagues analyzed a historical cohort gathered from three international databases (the Research Registry for Neonatal Lupus, the PRIDE study, and the PROMISSE study). In total, 257 pregnancies of anti-SSA/Ro–positive mothers with SLE who had previously given birth to a child with CNL were identified. Forty of the women were exposed throughout their pregnancies (starting before 10 weeks of gestation) to HCQ and 217 were not exposed to HCQ during pregnancy (Circulation 2012;126:76-82).

Significantly more fetuses in the unexposed group developed CNL (46 [21%] of 217) than in the exposed group (3 [8%] of 40 fetuses) (P = .05). The overall case fatality rate of the CNL fetuses in the unexposed group was 22%, compared with no deaths in the exposed group. No reduction in CNL recurrence was found for prednisone, dexamethasone, or fluorinated steroids.

Dr. Buyon reported having no relevant financial disclosures.

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