Preventive Approach to Congenital Heart Block With Hydroxychloroquine

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.

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.