Faculty Bibliography

Background/Purpose : Based on encouraging bench to bedside results including experimental evidence supporting Toll-like receptor signaling in the pathogenesis of CHB, a case control study demonstrating CHB risk reduction in hydroxychoroquine (HCQ) exposed fetuses of anti-Ro positive SLE women, and a historical cohort study supporting a reduction in recurrence rate, an open label single arm Phase 2 clinical trial was initiated to evaluate whether HCQ reduces the CHB recurrence rate (pi) below the historical recurrence rate of 18%. Methods : A two-stage trial design (N=19 first stage; N=54 second stage) using Simon's optimal approach was employed to allow for early stopping due to absence of treatment efficacy. The null hypothesis, H 0 :pi <= 18%, would be rejected and HCQ considered efficacious at the end of the trial if <= 5 of 54 mothers with anti-Ro and a previous CHB child had a subsequent child with 2 nd or 3 rd degree block (primary outcome). The protocol required HCQ initiation or maintenance at 400mg by 10 wks gestation. Mothers underwent serial echocardiograms, with bloods drawn each trimester and delivery for cord blood to measure antibody and HCQ levels. Results : Sixty five mothers (all with previous CHB child and anti-Ro52 or Ro60 > 1,000 EU; 47.9% with anti-La; 71.4% White; 47.6% SLE and/or SS; 42.9% started HCQ solely for CHB prevention; 41% prior CHB child died, 3.2% had > 1 CHB child) signed consent. Ten were considered screen failures (2 miscarriages < 12 wks, 7 wherein dating of conception placed HCQ initiation at > 10 wks, 1 given dexamethasone (dex) 1mg at 10 wks) and 1 was lost to follow up before delivery leaving 54 pregnancies evaluable with serial fetal echos and birth or one yr EKG or echo results known. In Stage I, 2/19 fetuses had CHB, and the study proceeded to Stage II. By intention to treat analysis, 4/54 pregnancies resulted in CHB (7.4%; p = 0.02 for H 0 ), all at 19-20 wks. Three presented with 2 nd degree block, one reverted to NSR at birth following dex and two progressed to 3 rd degree despite dex and IVIG (one electively terminated). One presenting with 1 st degree was treated with dex prophylactically (eliminating this case from evaluating HCQ exposure alone), progressed to 2 nd but reverted to NSR at birth. At 2 yrs, the 2 in NSR had intermittent 2 nd degree on Holter monitor. In 8 mothers potentially confounding medications, IVIG and/or dex, were prescribed after enrollment for lupus flare, cardiac concerns apart from advanced block (APCs, echo brightness, 1 st degree block), and/or physician decision to consider additional prophylaxis. To evaluate HCQ alone, 9 additional mothers were enrolled, one whose fetus developed 3 rd degree block at 19 wks. Including only pregnancies exposed to HCQ alone prior to confirmed 2 nd or 3 rd degree block, 4/54 developed CHB (7.4%; p = 0.02). In total 5/63 pregnancies (7.9%) resulted in advanced block. HCQ levels in the second trimester confirmed a 98% adherence rate. Anti-Ro levels remained > 1,000 EU (considered vulnerable for CHB) throughout pregnancy. No CHB developed in any of the 7 mothers screened out because of low dose or delayed start of HCQ. Conclusion : These prospective data from a single-arm clinical trial support that HCQ significantly reduces the recurrence of CHB below the historical rate

Background/Purpose : Cell-bound complement activation products (CB-CAPs) are stable forms of classical complement activation ex-vivo, with high sensitivity and specificity for systemic lupus erythematosus (SLE). We sought to compare the performance of CB-CAPs to the gold standard low complement C3 or C4 in distinguishing SLE from other rheumatic diseases and healthy individuals. Methods : Multiple academic centers in the United States contributed to the adult ( >= 18 years) cross sectional cohort (n=1200) consisting of SLE (n=450), healthy individuals (n=252), and other rheumatic diseases (n=450; 189 RA, 88 Sjogren ' s, 90 fibromyalgia, and 83 other connective tissue diseases). Abnormal CB-CAPs status (erythrocyte bound C4d [EC4d] and/or B-Lymphocyte bound C4d [BC4d] >99th percentile of normal healthy group) was determined using flow cytometry. Serum low C3 (< 81 mg/dl) and low C4 (< 12.9 mg/dl) levels was determined using immunoturbidimetry. Performance of the markers, either alone or in combination, to distinguish SLE from other rheumatic diseases and healthy controls were established using sensitivity, specificity, odds ratio (OR) and area under the curve (AUC) of the receiver operating characteristic curve (ROC). Youden Index (Sensitivity+Specificity-100) and Akaike information criteria (AIC) were also calculated. The combination of 4 complement marker abnormalities was also evaluated using logistic regression and composite score cumulating the presence of these abnormalities was calculated. Results : Abnormal CB-CAPs status yielded 62% sensitivity with 88% specificity in distinguishing SLE from the group with other diseases (Table). Youden index was 0.492+/-0.027. Low C3/C4 status yielded 38% sensitivity and 93% specificity in distinguishing SLE from the group with other diseases. Youden index for low C3/C4 (0.313+/-0.025) was signifi-cantly lower than the index associated with abnormal CB-CAPs status (p< 0.01). Specificity of low C3/C4 and abnormal CB-CAPs in distinguishing SLE from healthy individuals was 93% and 99%, respectively. AUC was significantly higher with BC4d (0.718) than with EC4d (0.675; p< 0.01), low C3 (0.620; p< 0.01), low C4 (0.618; p< 0.01) and low C3 and/or C4 status (0.656; p< 0.01). Average (SEM) composite score cumulating all 4 abnormalities (range 0-4) was higher in SLE (1.47+/-0.06) than disease control group (0.21+/-0.02) (p< 0.01) and healthy individuals (0.01+/-0.02) (p< 0.01). The cumulative complement scoring system yielded higher AUC (0.812), higher OR (36.0 CI95%: 18.8-69.0), lower AIC (1037) than low C3/C4 or abnormal CB-CAPS; score greater than 1 abnormality yielded 45% sensitivity and 98% specificity. Conclusion : Our data suggest that the combination of CB-CAPs with low complement have superior diagnostic performance in SLE than either abnormality alone

Background/Purpose : Anifrolumab is a fully human, IgG1kappa monoclonal antibody that binds to the type I IFN receptor and inhibits activity of all type I IFNs. 1 In the MUSE phase 2b randomized controlled trial (Study 1013, NCT01438489), anifrolumab demonstrated an acceptable safety profile and efficacy on a range of clinical endpoints in patients with moderate to severe SLE. An open-label extension (OLE) of Study 1013 (Study 1145, NCT01753193) evaluated longterm safety and tolerability of anifrolumab. Methods : Study 1145 was a 3-year, multinational OLE in adults with moderate to severe SLE (per ACR classification criteria, assessed in Study 1013) who completed randomized treatment with anifrolumab 1000 or 300 mg or placebo in Study 1013 to Day 337 with follow-up to Day 422. All patients in Study 1145 initially received IV anifrolumab 1000 mg every 4 weeks (Q4W). After data from Study 1013 showed the 300-mg dose had a better benefit/risk profile, the dosage in Study 1145 was amended to 300 mg Q4W. Patients received anifrolumab Q4W over 156 weeks with 85 days of follow-up. The primary objective was to evaluate long-term safety/tolerability. Efficacy, pharmacodynamics, and health-related quality of life (HRQoL) were exploratory objectives. Safety was assessed at every visit; SLEDAI-2K and SLICC Damage Index were measured every 3 and 6 months, respectively. Results : Of 305 randomized patients in Study 1013, 218 (71.5%) at 59 sites participated in Study 1145; 66/218 (30.3%) received placebo in Study 1013. Of 218 patients in Study 1145, 139 (63.8%) completed 3 years of treatment. The most common reason for treatment discontinuation was patient withdrawal (31/218, 14.2%). Treatment was discontinued due to adverse events (AEs) for 15/218 patients (6.9%). During Year 1, 152/218 patients (69.7%) had >=1 AE ( Table ). Over the full study period, the rate of serious AEs was 8.56 per 100 patient-years (PY); the most common serious AEs were SLE flares and pneumonia (each 0.70 per 100 PY). The most common AE of special interest was herpes zoster (1.92 per 100 PY). There was 1 death due to pneumonia. Two of 218 patients were anti-drug antibody positive at any time during treatment (both persistently positive). Sustained improvement of the SLEDAI-2K was observed through the end of treatment (mean change -2.1 [SD=3.5] from baseline to Week 160; Figure 1 ). Short Form 36 Health Survey physical and mental component scores showed similar patterns of sustained improvement. SLICC Damage Index generally remained stable over time (mean change 0.1 [SD=0.6] from baseline to Week 168). Neutralization of type I IFN gene signature (IFNGS) expression was rapid and sustained in patients with high baseline IFNGS ( Figure 2 ). C3, C4, and anti-dsDNA showed numeric trends toward sustained improvement. Conclusion : Long-term anifrolumab treatment for up to 3 years was generally safe and well tolerated. The safety profile was consistent with the 52-week Study 1013. Disease activity, HRQoL, and SLE-related serology showed sustained improvement

BACKGROUND:Osteoporosis (OP) results in weak bone and can ultimately lead to fracture. Drugs such as glucocorticoids can also induce OP (glucocorticoid-induced osteoporosis [GIO]). Bone marrow adipose tissue composition and quantity may play a role in OP pathophysiology, but has not been thoroughly studied in GIO compared to primary OP. PURPOSE/HYPOTHESIS/UNASSIGNED:Chemical shift-encoded (CSE) MRI allows detection of subregional differences in bone marrow adipose tissue composition and quantity in the proximal femur of GIO compared to OP subjects and has high agreement with the reference standard of magnetic resonance spectroscopy (MRS). STUDY TYPE/METHODS:Prospective. SUBJECTS/METHODS:In all, 18 OP and 13 GIO subjects. FIELDS STRENGTH/UNASSIGNED:3T. SEQUENCE/UNASSIGNED:Multiple gradient-echo, stimulated echo acquisition mode (STEAM). ASSESSMENT/RESULTS:Subjects underwent CSE-MRI in the proximal femurs, and for each parametric map regions of interest (ROIs) were assessed in the femoral head (fHEAD), femoral neck (fNECK), Ward's triangle (fTRIANGLE), and the greater trochanter (GTROCH). In addition, we compared CSE-MRI against the reference standard of MRS performed in the femoral neck and Ward's triangle. STATISTICAL TESTS/UNASSIGNED:Differences between OP/GIO were investigated using the Mann-Whitney nonparametric test. Bland-Altman methodology was used to assess measurement agreement between CSE-MRI and MRS. RESULTS: DATA CONCLUSION/UNASSIGNED:3T CSE-MRI may allow reliable assessment of subregional bone marrow adipose tissue (bMAT) quantity and composition in the proximal femur in a clinically reasonable scan time. Glucocorticoids may alter the lipid profile of bMAT and potentially result in reduced bone quality. LEVEL OF EVIDENCE/METHODS:2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.

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.