Faculty Bibliography

BACKGROUND: A recent case-control study suggested a benefit of hydroxychloroquine (HCQ) in lowering the risk of cardiac manifestations of neonatal lupus (cardiac-NL) in pregnancies of anti-SSA/Ro-positive patients with systemic lupus erythematosus. A historical cohort assembled from 3 international databases was used to evaluate whether HCQ reduces the nearly 10-fold increase in risk of recurrence of cardiac-NL independently of maternal health status. METHODS AND RESULTS: Two hundred fifty-seven pregnancies of anti-SSA/Ro-positive mothers (40 exposed and 217 unexposed to HCQ) subsequent to the birth of a child with cardiac-NL were identified from 3 databases (United States, England, and France). Exposure was defined as the sustained use of HCQ throughout pregnancy with initiation before 10 weeks of gestation. The recurrence rate of cardiac-NL in fetuses exposed to HCQ was 7.5% (3 of 40) compared with 21.2% (46 of 217) in the unexposed group (P=0.050). Although there were no deaths in the exposed group, the overall case fatality rate of the cardiac-NL fetuses in the unexposed group was 21.7%. In a multivariable analysis that adjusted for database source, maternal race/ethnicity, and anti-SSB/La status, HCQ use remained significantly associated with a decreased risk of cardiac-NL (odds ratio, 0.23; 95% confidence interval, 0.06-0.92; P=0.037). Similar results were obtained with propensity score analysis, an alternative approach to adjust for possible confounding by indication. CONCLUSION: Aggregate data from a multinational effort show that in mothers at high risk of having a child with cardiac-NL, the use of HCQ may protect against recurrence of disease in a subsequent pregnancy.

OBJECTIVE.: The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology. METHODS.: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls. RESULTS.: Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001). CONCLUSIONS.: The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification. (c) 2012 American College of Rheumatology.

Congenital complete heart block associated with transplacental passage of maternal autoantibodies reactive with SSA/Ro and SSB/La is a rare disease with significant fetal, neonatal, and childhood morbidity and mortality. We present the case of dichorionic, diamniotic twins (female twin A and male twin B) exposed to maternal Ro and La autoantibodies with different disease expression. Twin A (female) had Mobitz type I second degree atrioventricular (AV) block (Wenckebach); twin B (male) had normal sinus rhythm. Both twins had structurally normal hearts but demonstrated echocardiographic evidence of endocardial fibroelastosis (EFE). Following maternal dexamethasone 4 mg once daily, twin A reverted to sinus rhythm in utero; twin B remained in sinus rhythm throughout pregnancy. Echocardiograms after delivery demonstrated resolution of EFE in both fetuses, and EKGs confirmed sinus rhythm. However, at five months of age, Holter monitor demonstrated first degree AV block and intermittent Wenckebach in twin A. Twin B remains in sinus rhythm. This case is one of only three in the literature that describes Mobitz type I second degree atrioventricular block presenting in fetuses exposed to maternal SSA and SSB autoantibodies and is the first case that we have seen reported in twins. Importantly, this case also adds to the growing body of literature describing EFE as a presentation of neonatal lupus with or without conduction system abnormalities, emphasizes the spectrum of cardiac conduction abnormalities in neonatal lupus syndrome, and raises interesting questions about discordant disease expression in twins.

Objective. The autopsy and clinical information on children dying with anti-SSA/Ro-associated cardiac manifestations of neonatal lupus (cardiac NL) were examined to identify patterns of disease, gain insight into pathogenesis and enhance the search for biomarkers and preventive therapies.Methods. A retrospective analysis evaluating reports from 18 autopsies of cardiac NL cases and clinical data from the Research Registry for Neonatal Lupus was performed.Results. Of the 18 cases with autopsies, 15 had advanced heart block, including 3 who died in the second trimester, 9 in the third trimester and 3 post-natally. Three others died of cardiomyopathy without advanced block, including two dying pre-natally and one after birth. Pathological findings included fibrosis/calcification of the atrioventricular (AV) node, sinoatrial (SA) node and bundle of His, endocardial fibroelastosis (EFE), papillary muscle fibrosis, valvular disease, calcification of the atrial septum and mononuclear pancarditis. There was no association of pathology with the timing of death except that in the third-trimester deaths more valvular disease and/or extensive conduction system abnormalities were observed. Clinical rhythm did not always correlate with pathology of the conduction system, and the pre-mortem echocardiograms did not consistently detect the extent of pathology.Conclusion. Fibrosis of the AV node/distal conduction system is the most characteristic histopathological finding. Fibrosis of the SA node and bundle of His, EFE and valve damage are also part of the anti-Ro spectrum of injury. Discordance between echocardiograms and pathology findings should prompt the search for more sensitive methods to accurately study the phenotype of antibody damage.

OBJECTIVE: Membrane endothelial protein C receptor (mEPCR) is highly expressed in peritubular capillaries of kidneys from patients with active and poorly responsive lupus nephritis (LN). We investigated the hypothesis that changes in the microvasculature are widespread with extension to the dermal vasculature. METHODS: Skin biopsies from uninvolved skin (buttocks) were performed in 27 patients with LN and 5 healthy controls. Sections were stained with specific antibodies reactive with mEPCR, adiponectin, intercellular adhesion molecule-1 (ICAM-1), and CD31; then assessed by enumeration of stained blood vessels (percentage positive blood vessels) blinded to knowledge of clinical information. RESULTS: There was a significant increase in the prevalence of blood vessels that stained for mEPCR and ICAM-1 in patients compared to controls [94% vs 59% (p = 0.045) and 81% vs 67% (p = 0.037), respectively]. Adiponectin staining and CD31 staining were similar between the groups (45% vs 43% and 98% vs 92%). Dermal staining for mEPCR was greater in patients with proliferative glomerulonephritis than in those with membranous disease (96% vs 60%; p = 0.029). A composite of poor prognostic renal markers and death was significantly associated with greater expression of mEPCR staining. CONCLUSION: These data are consistent with the notion that in patients with LN, activation of the microvasculature extends beyond the clinically targeted organ. The insidious expression of this widespread vasculopathy may be a contributor to longterm comorbidities.

Within the last decade the prevalence of adult patients living with congenital heart disease equals that seen in children. This expanding population poses a challenge to clinical cardiologists who will be caring for patients with the clinical manifestations of this condition. Neonatal lupus is a model of passively acquired autoimmunity and is responsible for the majority of clinical cases of congenital heart block (CHB). This review will focus on the presentation, pathophysiology, and the long-term follow-up of CHB associated with neonatal lupus, and discuss important diagnostic tests, familial implications, and pacemaker issues associated with the care of an adult with CHB.

OBJECTIVE: Neonatal lupus (NL) occurs in fetuses exposed to maternal anti-SSA/Ro and/or anti-SSB/La antibodies, although the mothers themselves may not manifest any clinical disease. A focus on transmission of risk factors for NL from maternal grandparents to mothers of children with NL may yield dividends toward understanding the aggregation of autoantibodies and genetic factors in affected families. This study was perforned to determine the role of maternal grandparents in the development of the autoimmune phenotype of mothers of children with NL. METHODS: Fifty-one mothers of children with cardiac and/or cutaneous NL, 48 maternal grandmothers, and 35 maternal grandfathers in the Research Registry for Neonatal Lupus were interrogated for clinical symptoms by questionnaire and underwent laboratory assessments, including determination of anti-SSA/Ro and anti-SSB/La antibody status (by enzyme-linked immunosorbent assay) and genotype at rs1800629 (TNFalpha) and rs7775397 (C6orf10) (allelic discrimination). The transmission disequilibrium test (TDT) was computed to test for nonrandom transmission from maternal grandparents to mothers of children with NL. RESULTS: The common phenotypic feature in mothers of children with NL was the autoantibody and not the clinical profile; 7 had lupus, 14 had Sjogren's syndrome, 7 had both, and 23 were asymptomatic. Mothers of children with NL were significantly enriched for the risk alleles at both TNFalpha and C6orf10. The grandparents of children with NL carried minimal burden for autoimmune disease or abnormal antibody production and were not enriched in the genetic risk factors. However, the TDT analysis showed significant excess transmission of the risk alleles at both TNFalpha (odds ratio [OR] 6.67, P = 3.93 x 10(-4) ) and C6orf10 (OR 35.0, P = 3.74 x 10(-5) ) to mothers of children with NL. CONCLUSION: Mothers of children with NL are enriched for the TNFalpha and C6orf10 risk alleles, which are preferentially inherited from the asymptomatic maternal grandparents. These findings support the hypothesis that the development of NL and genetic etiology are multigenerational.

OBJECTIVE: Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in approximately 18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB. METHODS: We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies. RESULTS: Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P<0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied. CONCLUSION: This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.

The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio = 0.61; p = 0.052) and lowered mean +/- SD annualized A flare rates (0.86 +/- 1.47 vs. 1.41 +/- 2.14; p = 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p = 0.027). Prednisone rescue for A flares was similar in rituximab- (24%) and placebo-treated (14%) patients (p = 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares.

The Lupus Foundation of America (LFA) convened an international working group to obtain a consensus definition of disease flare in lupus. With help from the Paediatric Rheumatology International Trials Organization (PRINTO), two web-based Delphi surveys of physicians were conducted. Subsequently, the LFA held a second consensus conference followed by a third Delphi survey to reach a community-wide agreement for flare definition. Sixty-nine of the 120 (57.5%) polled physicians responded to the first survey. Fifty-nine of the responses were available to draft 12 preliminary statements, which were circulated in the second survey. Eighty-seven of 118 (74%) physicians completed the second survey, with an agreement of 70% for 9/12 (75%) statements. During the second conference, three alternative flare definitions were consolidated and sent back to the international community. One hundred and sixteen of 146 (79.5%) responded, with agreement by 71/116 (61%) for the following definition: 'A flare is a measurable increase in disease activity in one or more organ systems involving new or worse clinical signs and symptoms and/or laboratory measurements. It must be considered clinically significant by the assessor and usually there would be at least consideration of a change or an increase in treatment.' The LFA proposes this definition for lupus flare on the basis of its high face validity