Preventive IVIG Therapy for Congenital Heart Block

Perhaps the strongest clinical association with autoantibodies against SSA/Ro-SSB/La is the
development of congenital heart block (CHB) in an offspring, an alarming prospect facing 2%
of primigravid mothers with these antibodies. Recurrence rates approach 20%. Disease can
progress rapidly, with advanced block and life-threatening cardiomyopathy observed less than
2 weeks from normal sinus rhythm. Once 3rd degree (complete) block is identified, reversal
has never been achieved, despite dexamethasone. This makes biologic sense since the signature
lesion is fibrosis of the atrioventricular node. Thus, strategies aimed at preventing disease
assume high priority. Although disease expression in the fetus requires additional factors to
amplify the cascade to fibrosis, maternal anti-Ro/La antibodies are necessary. Accordingly,
eliminating fetal exposure to these antibodies is a sound and important approach. Intravenous
immune globulin (IVIG) is particularly exciting in its potential not only to lower maternal
antibody levels (which is not accomplished with glucocorticoids or immunosuppression), but
actually to influence effector mechanisms in the fetus itself. Aim 1 is a clinical trial to
assess the efficacy of IVIG in preventing CHB. Proof of efficacy is challenging since CHB
occurs in only 2% of first pregnancies of anti-Ro/La+ women. However, given the 10-fold
higher risk of CHB in a pregnancy after the birth of child with neonatal lupus (NL), mothers
with previous NL-affected children are the target population for study. Sample size
calculations employ Simon's 2-stage optimal design. Based on a 2-sided significance level of
0.05, a power of 90% to show reduction of risk to 5% given the prediction that 18% of
untreated subjects will get some degree of CHB, Stage 1 will enroll 19 women who have had a
previous child with CHB or NL rash, to receive IVIG (400 mg/kg IVIG every 3 weeks for a total
of 5 treatments) from weeks 12 through 24 of gestation. If fewer than 3 mothers have children
with 2nd or 3rd degree block, then an additional 35 mothers will be enrolled in Stage 2
(total = 54 subjects). IVIG will be considered efficacious and worthy of further study if
fewer than 6 of 54 subjects have a child with advanced CHB. Secondary outcomes include 1st
degree block, myocardial injury absent conduction defects, and isolated endocardial
fibroelastosis as assessed by serial fetal echocardiograms and EKG at birth.

Aim 2 will address: a) the effect of IVIG on antibody titer and subclass; b) genetic
polymorphisms in Fc gamma receptor (FcgR) and platelet-activating factor acetylhydrolase and
their potential association with response to IVIG; c) whether a decrease in anti-La
antibodies positively correlates with the level of anti-La antiidiotypic antibodies; d)
whether IVIG blocks expression of activation markers on human macrophages after challenge
with opsonized apoptotic cardiocytes and whether this positively correlates with increased
expression of the inhibitory Fc receptor, FcgRIIb.

In sum, IVIG is a promising agent that may have effects at several levels of the pathologic
cascade to antibody-mediated CHB.

Inclusion Criteria:

- Mother must currently have an intrauterine pregnancy of less than 12 weeks.

- Mother must have antibodies to SSA/Ro and/or SSB/La (will be confirmed in the clinical
immunology laboratory at the Principal Investigator's institution, the NYU-Hospital
for Joint Diseases).

- Mother can be asymptomatic or have any rheumatic disease (such as lupus, Sjogren
syndrome or other).

- Mother must have had a previous child with one of the following: (a) congenital heart
block (any degree) documented by EKG if live birth and/or echocardiogram if fetal
demise; (b) characteristic neonatal lupus rash confirmed by photograph revealing
annular lesions (evaluated by the PI), dermatology note, and/or biopsy; (c) congenital
heart block and rash.

- Mother may be taking 20 mg prednisone per day or less.

Exclusion Criteria:

- Mother does not have antibodies to either SSA/Ro or SSB/La.

- Mother is taking greater than 20 mg prednisone per day.

- Mother has any condition that would contraindicate the use of IVIG: (a) prior serious
reaction to IVIG infusion; (b) known IgA deficiency; (c) intolerance of volume load,
e.g., congestive heart failure; (d) nephrotic syndrome.

- Identification in the fetus of any of the following structural lesions considered
causal for congenital heart block: (a) atrioventricular septal defects; (b) single
ventricle; (c) developmental tricuspid valve disease; (d) L-transposition of the great
arteries; (e) heterotaxia.