Faculty Bibliography

INTRODUCTION/BACKGROUND:Autoimmune hepatitis (AIH) is a cause of chronic liver disease. It is usually suspected based on clinical presentation and laboratory findings, but the diagnosis relies on the presence of specific autoantibodies and characteristic histology. Other unexplained findings should always prompt investigation for coexisting syndromes. CASE PRESENTATION/METHODS:The patient is a 60-year-old Hispanic female with a history of mild asthma presented with exertional and pleuritic chest pain with weight loss, arthralgia, subjective fever, and night sweats for the last 3 months. Given the nonspecific nature of the presentation, further workup was pursued. Laboratory results indicated pancytopenia, elevated INR, and positive autoimmune panel including ANA, anti-chromatin, anti-histone, and rheumatoid factor as well as abnormal C3 and C4. Subsequent liver biopsy with interface hepatitis lead to a diagnosis of AIH with concurrent systemic lupus erythematosus suspected. CONCLUSION/CONCLUSIONS:The diagnostic work up for AIH is multimodal and aims to differentiate other etiologies such as congestive hepatopathy, iron overload, viral hepatitis, and other autoimmune liver diseases. In this particular case, unusual clinical and laboratory findings led to diagnosis of the overlap syndrome. Treatment for both was necessary to prevent further progression of disease.

Background There are no longitudinal studies regarding thelong term cardiac health of children with cardiac manifestations of neonatal lupus (NL). This study was performed toevaluate risk factors for morbidity and provide evidence-basedguidance regarding the course of cardiac NL.Methods Echocardiograms throughout life were evaluated in240 individuals born with cardiac NL from the ResearchRegistry for Neonatal Lupus: 142 were available from ages 0 1 years, 174 from ages 1 17 years, and 65>17 years. A composite adverse outcome defined as qualitatively decreased leftventricular (LV) function or concurrent use of cardiac medications was assessed. Aortic dilation (root or ascendingaorta z-score >2.0) was also recorded. Analyses were performed to associate the composite adverse outcome and aorticdilation with maternal medications, pacing, and fetal diseasestatus, including a severity score based on mortality risk factors such as lower fetal heart rate and extranodal disease.Results The composite adverse outcome for cardiac dysfunctionwas identified in 21.1% of echos in children ages 0 1, 13.2% ages1 17% and 29.2% ages>17. In 89 children in which echos wereavailable at ages 0 1 and 1 17, 6/16 with dysfunction at ages 0 1were also affected at ages 1 17, while 10 reverted to normal.Among those without dysfunction at age 0 1, 8/90 developednew worsening of cardiac function during age 1 17. In 35 caseswith echos at ages 1 17 and >17, 3/3 cases with dysfunction atage 1 17 were also affected at >17, and 2/32 developed new dysfunction in adulthood. Cardiac dysfunction was significantly associated with number of years paced at all ages (p<0.001, 0.001,<0.001). A lower fetal ventricular heart rate at the first time ofheart block detection was associated with cardiac dysfunction age0 1 and >17 (p=0.048, 0.005 respectively) and lowest heart ratein utero associated with dysfunction at age <1 and 1 17(p<0.001, 0.015). Fetal extranodal cardiac disease was associatedwith dysfunction in ages1 17 and >17 (p=0.026, 0.023). Higherfetal severity score associated with postnatal dysfunction in ages0 1 and 1 17 groups (p=0.013, 0.001). Aortic dilation waspresent in 13.4% at ages 0 1% and 14.9% at ages 1 17, butat >17, dilation only occurred in 9.2%. There was no associationof postnatal cardiac dysfunction or aortic dilation with maternalmedication use, maternal rheumatic disease, fetal age at heartblock detection or gestational age of birth.Conclusions Cardiac dysfunction in the first year normalizesby later childhood in the majority of cases, possibly due tothe short term effects of cardiac pacing or resolution ofinflammation with the clearance of maternal autoantibodies.However, new onset dysfunction can occur after the first yearof life. Aortic dilation can continue for longer periods, butmay decrease in frequency with age. Nevertheless, cardiac dysfunction is present in roughly 30%, and in adulthood thereare associations with fetal extranodal disease and heart rate atdetection. Patients who develop morbidity in utero may havesubclinical damage or be more susceptible to future insultsthat manifest later in life, which can be exacerbated by prolonged pacing. Close monitoring and aggressive treatment ofearly extranodal disease in cardiac NL may have long termbenefit in preventing subsequent morbidity

Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted with many clinical trial investigators, biopharmaceutical developers and stakeholders from government and voluntary sectors. This paper examines the available evidence that supports workable trial designs and proposes approaches to improve the odds of completing interpretable treatment development programs for lupus.

PURPOSE OF REVIEW: To provide new insights into pathogenesis, prevention and management of cardiac manifestations of neonatal lupus (cardiac neonatal lupus) and issues pertinent to all anti-SSA/Ro positive individuals of childbearing age. RECENT FINDINGS: Antibody specificity with high risk for cardiac neonatal lupus remains elusive, but high titers of Ro60, Ro52 or Ro52p200 antibodies appear to be required. Varying antibody specificities to the p200 region of Ro52 can induce first-degree block in a rodent model. In consideration of the contribution of macrophages to inflammation and fibrosis in cardiac neonatal lupus, hydroxychloroquine (HCQ) is being considered as preventive therapy. Cord blood biomarkers support the association of fetal reactive inflammatory and fibrotic components with the development and morbidity of cardiac neonatal lupus. Data from U.S. and French registries do not provide evidence that the prompt use of fluorinated steroids in cases of isolated block significantly alters fetal/neonatal morbidity or mortality. SUMMARY: The search for a high-risk cardiac neonatal lupus antibody profile remains, but high-titer antibodies to Ro60 and R052 are a consistent finding, and this may guide the need for fetal echocardiographic surveillance. The uniform use of fluorinated steroids to prevent progression of cardiac neonatal lupus or reduce mortality does not appear justified. HCQ, based on diminishing an inflammatory component of cardiac neonatal lupus, is under consideration as a potential preventive approach.

While the relationship between maternal connective tissue diseases and neonatal rashes was described in the 1960s and congenital heart block in the 1970s, the "culprit" antibody reactivity to the SSA/Ro-SSB/La ribonucleoprotein complex was not identified until the 1980s. However, studies have shown that approximately 10-15% of cases of congenital heart block are not exposed to anti-SSA/Ro-SSB/La. Whether those cases represent a different disease entity or whether another antibody is associated has yet to be determined. Moreover, the cutaneous manifestations of neonatal lupus have also been identified in infants exposed only to anti-U1RNP antibodies. In this review, we describe what we believe to be the first case of congenital heart block exposed to maternal anti-U1RNP antibodies absent anti-SSA/Ro-SSB/La. The clinical and pathologic characteristics of this fetus are compared to those typically seen associated with SSA/Ro and SSB/La. Current guidelines for fetal surveillance are reviewed and the potential impact conferred by this case is evaluated.