Preventive Approach to Congenital Heart Block with
Hydroxychloroquine (PATCH Study) NOW ENROLLING

SUMMARY: Women with antibodies to proteins called SSA/Ro and or SSB/La face a 2% chance of having a child with a life threatening heart condition regardless of whether they have very active lupus, are in remission, or have only vague symptoms.

Women who have had one child with heart block have a ten-fold higher risk of having another child with the same heart condition. Unfortunately, even close monitoring by special techniques during pregnancy does not reverse complete heart block once it is observed. Thus, treatments aimed at prevention are critical.

This study will evaluate for the first time whether hydroxychloroquine, a drug used by many patients with SLE, prevents the development of this heart condition. Data from laboratory experiments suggests that this drug, which crosses the placenta, may decrease the inflammation initiated by the passage of anti-Ro antibodies to the fetus.

Patients who wish to enroll may already be on hydroxychloroquine or will be started as soon as pregnancy is confirmed. The hope is that less than 3 cases of heart block will occur out of 19 participants. The results of this study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy.

If you are interested in participating in this study or simply want more information, please contact Tishaun Middleton at: tishaun.middleton@nyumc.org or call 646-501-0578.

ABSTRACT: One of the strongest clinical associations with autoantibodies directed to components of the Ro/La ribonucleoprotein complex is the development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2% of primigravid mothers with these reactivities. The risk is 10-fold higher in women who have had a previously affected child. Basic science exploring the pathogenesis of disease supported the notion that Toll Like Receptor (TLR) signaling following ligation of ssRNA (hY3) complexed to the Ro protein contributes to fibrosis. This observation led to in vitro studies addressing inhibition of endosomal acidification by chloroquine and subsequent translation to patients by evaluating the use of hydroxychloroquine (HCQ) in an extensive retrospective chart review. The combined data suggest efficacy of HCQ. Accordingly, the goal of this one year study is: To determine whether hydroxychloroquine use during pregnancy prevents CHB in a high risk population. The trial is open-label and employs the Simon’s 2-stage optimal design to allow for early stopping due to absence of treatment efficacy. The first stage requires 19 subjects which are expected to be enrolled in the next year. If 3 or more mothers have a child with 2nd or 3rd degree CHB, the study is terminated after the first stage. If this does not occur, funds will be sought to enroll an additional 35 mothers in the second stage for a total of 54 subjects. Treatment will be considered efficacious if fewer than 6 mothers of 54 have a child with advanced CHB. With this design, the study has 90% power to conclude that hydroxychloroquine 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%. Serial echocardiograms (monitor PR interval) and blood drawing (IFNα signatures, antibody titers) will be included in the protocol. The results of this study are expected to become an integral part of the counseling of women with anti-SSA/Ro-SSB/La antibodies who are considering pregnancy.

Long-Term Outcome and Associated Prognostic Factors in Autoimmune Associated Congenital Heart Block and Endocardial Fibroelastosis (Long Term Follow-Up)

OBJECTIVES: 1. To document long term cardiac, rheumatic, and developmental outcomes in NL children and their anti-Ro exposed unaffected siblings. 2. To identify risk factors predictive of long term morbidity in cardiac NL, asses if neonatal pacemakers predispose to early heart failure. 3. To evaluate the frequency of associated clinical outcomes and conditions potentially related to cardiac disease in affected children, unaffected siblings, and friend controls.

METHODS: The U.S. based Research Registry for Neonatal Lupus (RRNL), in which 490 anti-Ro/La positive mothers and their 1140 children are enrolled, will allow us to accomplish the stated aims. As minimal follow-up information is available, an intense outreach will be initiated among enrollees and their physicians. Questionnaires, phone interviews, and extensive review of medical records will be used to provide information on symptoms/diagnoses, cardiac events, and detailed pacemaker information of children enrolled in the registry. Data will be evaluated for demographic and fetal echocardiographic risk factors for these outcomes.

By leveraging the unparalleled resources of the RRNL to document outcomes and identify risk factors associated with mortality/morbidity, it is anticipated that this study will provide evidence based advice to parents of affected children as well as clarify targets for potential treatment in this very serious condition.

If you would like more information regarding this study, please contact Tishaun Middleton at: tishaun.middleton@nyumc.org or call 646-501-0578.

Genome-wide association study of cardiac manifestations of neonatal lupus identifies candidate loci at 6p21 and 21q22

Clancy RM, Marion MC, Kaufman KM, Ramos PS, Adler A; Slegen, Harley JB, Langefeld CD, Buyon JP.

Department of Medicine, New York University Langone School of Medicine, Wake Forest University Health Sciences.

Abstract

OBJECTIVE: Cardiac manifestations of neonatal lupus (NL) comprising atrioventricular conduction defects and cardiomyopathy, occur in fetuses exposed to anti-SSA/Ro antibodies, and carry substantial mortality. There is strong evidence of a genetic contribution to the risk.

METHODS: Cardiac- NL children of European ancestry (n=116) were genotyped using the Illumina 370K SNP platform and merged with 3351 controls.

RESULTS: The seventeen most significant associations with cardiac NL reside in the HLA region. The region near the MICB gene shows the strongest variant (rs3099844, pdom = 4.52 x 10(-10), OR=3.34 (2.29-4.89)), followed by a missense variant within C6orf10 (rs7775397, pdom =1.35x10(-9), OR=3.30), which lies between NOTCH4 and BTNL2, and several SNPs near the TNFalpha gene (rs2857595, padd =1.96x10(-9), OR=2.37; rs2230365, padd =1.00x10(-3), OR=0.46; rs3128982, padd = 6.40 x 10(-6), OR=1.86). Outside HLA, an association was detected at 21q22, upstream from the transcriptional regulator ERG (rs743446, p=5.45x10(-6), OR=2.40). HLA notwithstanding, no individual locus previously implicated in autoimmune diseases achieved genome-wide significance.

CONCLUSION: These results suggest that variation near genes related to inflammatory and apoptotic responses may promote cardiac injury initiated by passively acquired autoantibodies.

PMID: 20662065

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If you are interested in participating in this study or simply want more information, please contact Tishaun Middleton at: tishaun.middleton@nyumc.org or call 646-501-0578

Preventive IVIG Therapy for Congenital Heart Block (PITCH Study)
Sponsored through peer reviewed grant from the Alliance for Lupus Research

PITCH study has concluded and is closed to enrollment.

Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter, prospective, open-label clinical trial.

Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, Cummiskey K, Dooley MA,
Foley J, Graves C, Hendershott C, Kates R, Komissarova EV, Miller M, Paré E, Phoon CK,
Prosen T, Reisner D, Ruderman E, Samuels P, Yu JK, Kim MY, Buyon JP.

New York Medical College, Valhalla, NY, USA.

Abstract

OBJECTIVE: The recurrence rate of anti-SSA/Ro-associated congenital heart block (CHB) is 17%. Sustained reversal of third-degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.

METHODS: A multicenter, prospective, open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included the presence of anti-SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with < or = 20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second-degree or third-degree CHB.

RESULTS: Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.

CONCLUSION: This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

PMID: 20391423

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For more information, please contact:

Jill P. Buyon, M.D., Rheumatologist
212-263-0746
jill.buyon@nyumc.org

Deborah M. Friedman, M.D., Pediatric Cardiologist
914-594-4370

deborah_friedman@nymc.edu

Thank you for your cooperation, and we look forward to hearing from you.

Jill P. Buyon, M.D.
Deborah M. Friedman, M.D.


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