Preventive Approach to Congenital Heart Block With Hydroxychloroquine
Condition: Congenital Heart Block; Neonatal Lupus; Autoantibody-Associated Heart Block
MeSH terms: Heart Block
Intervention: Hydroxychloroquine
Intervention description: 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.
Intervention MeSH terms: Hydroxychloroquine
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 74.0
Sex: Female
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: No
Keywords: hydroxychloroquine; Plaquenil; congenital heart block; neonatal lupus; systemic lupus erythematosus; Sjogren's syndrome; autoantibodies; SSA/Ro; SSB/La; autoimmunity; pregnancy; immunoglobulin

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Mothers must have anti-Ro and/or anti-La Ab documented in the NYU immunology
             laboratory (CLIA-approved), which utilizes an ELISA as well as reactivity on ELISA to
             at least one of three recombinant antigens (48La, 52Ro, 60Ro, JB laboratory).

          2. Mothers must have a previous child with cardiac NL, defined herein as: the presence of
             heart block (1st, 2nd, or 3rd degree) documented by electrocardiogram (EKG),
             echocardiogram, pacemaker, or statement in the medical record, and/or; presence of
             cardiac injury, which specifically includes autopsy evidence of a mononuclear
             infiltrate in the endocardium, myocardium, and pericardium and/or EFE on
             echocardiogram always associated with cardiac dysfunction. In PITCH, we included women
             with a prior child with rash; however, recent data generated from the RRNL suggest
             that recurrence of CHB following rash is 11%, not 18% [34]. Thus, inclusion of
             previous rash could lead to a falsely lowered recurrence rate, and will therefore be
             excluded.

          3. Intrauterine pregnancy ≤10 weeks.

          4. Mother may be taking ≤20 mg prednisone because, in our experience, CHB has developed
             in the presence of this dose.

          5. Mother may be asymptomatic, or have a rheumatic disease such as SLE or SS. Maternal
             health status has not been considered an influence on the development of CHB.

          6. Mother may or may not already be taking HCQ. This latter point was discussed with Dr.
             Nathalie Costedoat-Chalumeau, who has published extensively on measurement of HCQ.
             While it might be optimal for the mothers anticipating enrollment in the study to all
             have been on HCQ prior to conception, this is impractical. Some may never achieve
             pregnancy and not want to take HCQ unless they conceive (especially those
             asymptomatic). On the other hand, women with SLE are likely to already be on HCQ and
             it would limit enrollment to exclude these patients if all must initiate HCQ only at
             enrollment in the first trimester. Although the accepted dogma is that HCQ requires
             several months for maximal efficacy in treating rheumatic disease, it is unknown
             whether this would apply to transplacental passage or fetal levels (which are
             impossible to measure). Dr. Costedoat-Chalumeau suggests that HCQ is probably a three
             compartment model which includes the circulation, tissues and cells. In the
             circulation, the half life is approximately 7 days and in the tissues, it is 40 days.
             In Dr. Costedoat-Chalumeau's experience, steady state blood levels of HCQ are achieved
             in 4-6 weeks. Thus, dosing the mother no later than 10 weeks gestation should provide
             sufficient fetal exposure before the vulnerable period of CHB which is generally
             accepted to span 18-24 wks. Furthermore, the placenta has to be formed for HCQ to gain
             access to the fetus and it may be effective quickly for the biology we are
             considering.

        Exclusion Criteria:

          1. Mother does not have Ab to Ro or La.

          2. Identification of any of the following structural lesions considered causal for CHB,
             i.e., those that could account for block because of fibrous disruption between the
             atrium and AV node or due to absence of the penetrating bundles of the AV node:

               -  atrioventricular septal defects;

               -  b) single ventricle

               -  c) developmental tricuspid valve disease;

               -  d) L-transposition of the great arteries;

               -  e) heterotaxia.

          3. Mother is taking any glucocorticoids. Although unlikely to be preventative, the use of
             steroids may confound the interpretation of results. The final point of intense
             discussion centered around whether another exclusion should be the use of HCQ in the
             first pregnancy in which CHB occurred. While one could argue that in these mothers HCQ
             was not effective and perhaps will not be again, this assumption remains speculative
             and thus prior absence of efficacy of HCQ will not constitute an exclusion criteria.