Preventive Approach to Congenital Heart Block With Hydroxychloroquine
Condition: Congenital Heart Block; Neonatal Lupus; Autoantibody-Associated Heart Block
MeSH terms: Heart Block
Study type: Interventional
Phase: Phase 2

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. This heart problem is referred to as
      congenital heart block (the most serious being third degree complete block) and represents
      damage thought to be caused by these autoantibodies. The heart beats abnormally slowly and
      almost all children require permanent pacemakers before the age of 20. Importantly, 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. The study uses a Simon's 2-Stage design, and plans to enroll 19 patients in Stage 1
      and 35 patients in Stage 2 if Stage 1 is successful. Patients can already be on
      hydroxychloroquine or will be started as soon as pregnancy is confirmed. The hope is that
      fewer than 3 cases of heart block will occur in Stage 1, and fewer than 6 cases will occur
      out of all 54 patients if Stage 2 is reached. 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.
    

Detailed description: 
      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. Despite the attempt
      of large multicenter studies to forestall disease by serial in utero monitoring, irreversible
      block and extensive myocardial injury have been documented within 7 days of a normal rhythm
      and PR interval. CHB is associated with a substantial mortality and morbidity. Two recent
      prospective studies (20 mothers from U.S. and 15 from Europe) utilizing an identical protocol
      of IVIG at replacement doses demonstrated 1) this intervention does not prevent the
      recurrence of CHB 2) the recurrence rate of 17-18% is robust 3) recruitment of patients is
      feasible. During the time period of the IVIG trials, 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 study is to: 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. Despite the rarity of disease and the requirement of a previous
      CHB child, based on the US Research Registry for Neonatal Lupus, this proposal is feasible.
      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 (IFNƒÑƒnsignatures, 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.
    

Intervention name(s): Hydroxychloroquine
Intervention type(s): Drug
Intervention description(s): Nineteen women meeting eligibility criteria will receive 400mg per day of HCQ beginning as soon as pregnancy is established and informed consent obtained. Mothers already on HCQ will remain on 400mg, or escalate to 400mg if on 200mg. Hydroxychloroquine is taken in 200mg pill form - 400mg = 2 200mg pills.
Other intervention name(s): Plaquenil
Intervention MeSH terms: Hydroxychloroquine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: hydroxychloroquine; Plaquenil; congenital heart block; neonatal lupus; systemic lupus erythematosus; Sjogren's syndrome; autoantibodies; SSA/Ro; SSB/La; autoimmunity; pregnancy; immunoglobulin