Faculty Bibliography

Background: The recurrence rate of anti-SSA/Ro associated congenital heart block (CHB) is 17%. Reversal of 3^rd degree block has never been achieved. Prophylactic IVIG was considered based on two presumed mechanisms of efficacy, a) saturation of FcRn to accelerate maternal IgG catabolism and decrease placental transport b) elevation of macrophage FcRIIB expression to attenuate inflammatory fetal responses. Purpose: To evaluate IVIG efficacy and safety as a preventive therapy for CHB. Methods: A multicenter open-label study based on Simon's 2-stage optimal design was initiated. Enrollment criteria included: maternal anti-SSA/Ro antibody, a previous child with CHB/rash, nd or 3^rd degree CHB in three fetuses. Results: Twenty mothers were enrolled. Sixteen children had normal PR intervals throughout the study and no manifestations of neonatal lupus. One child developed a transient rash consistent with neonatal lupus and had normal PR intervals during pregnancy and normal EKG at birth. However, the pre-determined stopping rule was reached. CHB was detected in three fetuses, at 19, 20 and 25 weeks; none followed an abnormal PR interval. One of these mothers had two previous children with CHB. Antibody titers assessed before every IVIG infusion, and at 28 wks, 34 wks and delivery were compared with values obtained at baseline. No significant changes in maternal antibody titers to SSA/Ro, SSB/La, or Ro52 were detected over the course of therapy or at delivery (P>0.05 for all comparisons). There were no changes in maternal blood pressure, severe headaches, rashes, fever or any other adverse effects related to the infusions. Neonatal weight, height, and head circumference were derived from gestational age -specific growth curves to correct for prematurity when necessary. Four (21%) of the newborns, two with CHB and two healthy, were small for gestational age (<10th centile) and 3 healthy babies (16%) were born prematurely (<37 weeks of gestation). Conclusion: IVIG at doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers. Having established safety with this protocol and feasibility of patient enrollment, subsequent studies should address the efficacy of IVIG at higher doses to exploit an anti-inflammatory effect

OBJECTIVES: Reactivation of Mycobacterium tuberculosis (TB) is a significant problem with all available tumor necrosis factor (TNF) antagonists when used to treat rheumatoid arthritis (RA), psoriatic arthritis, psoriasis and other inflammatory diseases. Concerns have been raised regarding the appropriate management of patients with latent TB (LTB) exposure (or active TB infection) before initiating TNF antagonists since the safety data of combined therapy with two potentially hepatotoxic medications, methotrexate (MTX) and isoniazid (INH), is lacking. The goal of this study was to investigate the toxicity of MTX and INH therapy in RA patients before initiating TNF antagonists. METHODS: To investigate the toxicity of MTX and INH therapy in RA patients we performed a retrospective chart review of patients seen at the Bellevue Hospital Arthritis Clinic in New York City between 2002-2006. Forty-four patients who were concomitantly treated with both drugs were included. The primary outcome investigated was increase in liver function tests (LFT). RESULTS: Transient increases in LFT were seen in 11% of patients, but in no case was this more than twice the upper limit of normal values. All abnormal LFT resolved spontaneously without intervention. In addition, no patient has developed signs or symptoms of TB reactivation. CONCLUSION: The use of INH for LTB was well tolerated in RA patients on a background regimen of MTX. While the risks and benefits of all therapy must always be considered, in our experience the additive risk of INH to MTX in terms of hepatotoxicity was low. Nonetheless it is prudent to follow LFT closely on patients taking this combination

Neonatal lupus has become an important model of passively acquired autoimmunity since the seminal observation in the late 1970s that sera from nearly all mothers of children with isolated congenital heart block (CHB) contain specific autoantibodies

OBJECTIVE: Identification of isolated congenital heart block (CHB) predicts, with near certainty, the presence of maternal anti-SSA/Ro antibodies; however, the 2% incidence of CHB in first offspring of anti-SSA/Ro+ mothers, 20% recurrence in subsequent pregnancies, and discordance in identical twins suggest that an environmental factor amplifies the effect of the antibody. Accordingly, this study was carried out to explore the hypothesis that hypoxia potentiates a profibrosing phenotype of the fetal cardiac fibroblast. METHODS: Evidence of an effect of hypoxia was sought by immunohistologic evaluation of CHB-affected fetal heart tissue and by determination of erythropoietin levels in cord blood. The in vitro effect of hypoxia on gene expression and phenotype in fibroblasts derived from fetal hearts and lungs was investigated by Affymetrix arrays, quantitative polymerase chain reaction (PCR), immunofluorescence, and immunoblotting. RESULTS: In vivo hypoxic exposure was supported by the prominent intracellular fibroblast expression of hypoxia-inducible factor 1alpha in conduction tissue from 2 fetuses in whom CHB led to death. The possibility that hypoxia was sustained was suggested by significantly elevated erythropoietin levels in cord blood from CHB-affected, as compared with unaffected, anti-SSA/Ro-exposed neonates. In vitro exposure of cardiac fibroblasts to hypoxia resulted in transdifferentiation to myofibroblasts (a scarring phenotype), as demonstrated on immunoblots and immunofluorescence by increased expression of smooth muscle actin (SMA), an effect not seen in lung fibroblasts. Hypoxia-exposed cardiac fibroblasts expressed adrenomedullin at 4-fold increased levels, as determined by Affymetrix array, quantitative PCR, and immunofluorescence, thus focusing attention on cAMP as a modulator of fibrosis. MDL12,330A, an adenylate cyclase inhibitor that lowers the levels of cAMP, increased expression of fibrosis-related proteins (mammalian target of rapamycin, SMA, plasminogen activator inhibitor type 1, and type I collagen), while the cAMP activator forskolin attenuated transforming growth factor beta-elicited fibrosing end points in the cardiac fibroblasts. CONCLUSION: These findings provide evidence that hypoxia may amplify the injurious effects of anti-SSA/Ro antibodies. Modulation of cAMP may be a key component in the scarring phenotype. Further assessment of the susceptibility of cardiac fibroblasts to cAMP modulation offers a new research direction in CHB