Faculty Bibliography

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

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

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