Faculty Bibliography

INTRODUCTION/BACKGROUND:Patients with systemic lupus erythematosus (SLE) face lifelong challenges from chronic and disabling symptoms. The toolkit for assessing patient progress lacks a simple, scalable index that includes both physician assessments and patient experiences. Clinician and patient reported outcomes (ClinROs and PROs) were developed in isolation and discrepancies in their results promote confusion. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REALâ„¢) was designed as a simple, versatile instrument of simple additive scales. Dual physician and patient components allow for a complete evaluation of disease activity. This report presents the early development of the LFA-REALâ„¢ PRO. METHODS:An initial focus group was conducted consisting of 10 SLE patients who ranked 32 areas of health and identified additional domains that are important to people with lupus. Subsequently, 19 domains were ranked by 100 consecutive patients with SLE from New York and Oklahoma City. RESULTS:The 10 focus group participants were female and had a mean age of 38.6. The dimensions they identified were generally in two categories: symptoms and impacts. The main symptoms were fatigue, joint and muscle pain, and general pain. The main impacts were sleep, drug side effects, and physical well-being. The 100 patients with SLE (90% female, mean age 37.5 years) ranked the 19 fields of health in order of importance. The top eight domains ranked were joint and muscle pain, fatigue, experience of quality of life, general pain, physical well-being, emotional well-being, organ involvement, and family life. Clinicians reviewed the data and decided on an instrument that would differentiate between lupus related symptoms and impact on quality of life as well as differentiate active symptoms from chronic damage. The disease activity instrument draft included all the identified symptoms: rash, joint symptoms (pains, stiffness, and swelling), muscle pain, fatigue, organ involvement symptoms (fever, chest pain, shortness of breath, leg swelling, and other), and hair loss. DISCUSSION/CONCLUSIONS:The PRO derived here is a composite disease activity instrument to accompany the physician reported assessment. The ClinRO and the PRO will provide the spectrum of lupus disease activity and bring the patient's experience and provide essential quantitative data to the evaluation of lupus in routine clinical care and clinical research.

In a series of 10-day campaigns in Ontario and Quebec, Canada, between 2005 and 2007, ozonesondes were launched twice daily in conjunction with continuous high-resolution wind-profiling radar measurements. Windprofilers can measure rapid changes in the height of the tropopause, and in some cases follow stratospheric intrusions. Observed stratospheric intrusions were studied with the aid of a Lagrangian particle dispersion model and the Canadian operational weather forecast system. Definite stratosphere-troposphere transport (STT) events occurred approximately every 2-3 days during the spring and summer campaigns, whereas during autumn and winter, the frequency was reduced to every 4-5 days. Although most events reached the lower troposphere, only three events appear to have significantly contributed to ozone amounts in the surface boundary layer. Detailed calculations find that STT, while highly variable, is responsible for an average, over the seven campaigns, of 3.1% of boundary layer ozone (1.2 ppb), but 13% (5.4 ppb) in the lower troposphere and 34% (22 ppb) in the middle and upper troposphere, where these layers are defined as 0-1 km, 1-3 km, and 3-8 km respectively. Estimates based on counting laminae in ozonesonde profiles, with judicious choices of ozone and relative humidity thresholds, compare moderately well, on average, with these values. The lamina detection algorithm is then applied to a large dataset from four summer ozonesonde campaigns at 18 North American sites between 2006 and 2011. The results show some site-to-site and year-to-year variability, but stratospheric ozone contributions average 4.6% (boundary layer), 15% (lower troposphere) and 26% (middle/upper troposphere). Calculations were also performed based on the TOST global 3D trajectory-mapped ozone data product. Maps of STT in the same three layers of the troposphere suggest that the STT ozone flux is greater over the North American continent than Europe, and much greater in winter and spring than in summer or fall. When averaged over all seasons, magnitudes over North America show similar ratios between levels to the previous calculations, but are overall 3-4 times smaller. This may be because of limitations (trajectory length and vertical resolution) to the current TOST-based calculation.

OBJECTIVES/OBJECTIVE:To determine, in a multi-ethnic/racial, prospective SLE inception cohort, the frequency, attribution, clinical and autoantibody associations with lupus psychosis and the short and long-term outcome as assessed by physicians and patients. METHODS:Patients were evaluated annually for 19 neuropsychiatric (NP) events including psychosis. SLE disease activity 2000, SLICC/ACR damage index and SF-36 scores were collected. Time to event and linear regressions were used as appropriate. RESULTS:Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration 5.6±4.2 months and follow-up 7.4±4.5 years. There were 31 psychotic events in 28/1,826 (1.53%) patients and most [(26/28; 93%)] had a single event. In the majority of patients [20/25; (80%)] and events [28/31; (90%)] psychosis was attributed to SLE, usually within 3 years of SLE diagnosis. Positive associations [hazard ratio and 95% confidence interval [HR (95%CI)] with lupus psychosis were prior SLE NP events [3.59, (1.16, 11.14), male sex [3.0, (1.20, 7.50)], younger age at SLE diagnosis [(per 10 years younger), 1.45 (1.01, 2.07)] and African ancestry [4.59 (1.79, 11.76)]. By physician assessment most psychotic events resolved by the second annual visit following onset, in parallel with an improvement in patient reported SF-36 summary and subscale scores. CONCLUSION/CONCLUSIONS:Psychosis is an infrequent manifestation of NPSLE. Generally, it occurs early after SLE onset and has a significant negative impact on health status. As determined by patient and physician report, the short and long term outlook is good for most patients, though careful follow-up is required.

OBJECTIVES/OBJECTIVE:Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients. METHODS:Circulating antibodies to specific periodontal bacteria have been used as surrogate markers to determine an ongoing bacterial burden, or as indicators of past exposure to the bacteria. Banked serum samples from SLE patients in the Oklahoma Lupus Cohort were used to measure antibody titres against periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Treponema denticola) and commensals (Capnocytophaga ochracea, and Streptococcus gordonii) by ELISA. Correlations between anti-bacterial antibodies and different clinicalparameters of SLE including, autoantibodies (anti-dsDNA, anti-SmRNP, anti-SSA/Ro and anti-SSB/La), complement, and disease activity (SLEDAI and BILAG) were studied. RESULTS:SLE patients had varying amounts of antibodies to different oral bacteria. The antibody titres against A. actinomycetemcomitans, P. gingivalis, T. denticola, and C. ochracea were higher in patients positive for anti-dsDNA antibodies, and they showed significant correlations with anti-dsDNA titres and reduced levels of complement. Among the periodontal pathogens, only antibodies to A. actinomycetemcomitans were associated with higher disease activity. CONCLUSIONS:Our results suggest that exposure to specific pathogenic periodontal bacteria influences disease activity in SLE patients. These findings provide a rationale for assessing and improving periodontal health in SLE patients, as an adjunct to lupus therapies.

Objective/UNASSIGNED:Existing methods for grading lupus flares or improvement require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analysed the performance of the SELENA SLEDAI Physician's Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) as measures of improvement or worsening in SLE. Methods/UNASSIGNED:We evaluated the agreement between prospectively collected measures of lupus disease activity [SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index 2004 (BILAG 2004), Cutaneous Lupus Area and Severity Index (CLASI), SSPGA and LFA-REAL] and response [(SLE Responder Index (SRI)-4 and BILAG-Based Combined Lupus Assessment (BICLA)] in a clinical trial. Results/UNASSIGNED:Fifty patients (47 females, mean age 45 (±11.6) years) were assessed at 528 consecutive visits (average 10.6 (±4.1) visits/patient). Changes in disease activity compared with baseline were examined in 478 visit pairs. SSPGA and LFA-REAL correlated with each other (r=0.936), and with SLEDAI and BILAG (SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REAL: r=0.778 (SLEDAI), r=0.813 (BILAG); all p<0.0001). Changes (∆) in SSPGA and LFA-REAL compared with screening correlated with each other (r=0.857) and with changes in SLEDAI and BILAG (∆SSPGA: r=0.678 (∆SLEDAI), r=0.624 (∆BILAG); ∆LFA-REAL: r=0.686 (∆SLEDAI) and 0.700 (∆BILAG); all p<0.0001). Changes in SSPGA and LFA-REAL strongly correlated with SRI-4 and BICLA by receiver operating characteristic analysis (p<0.0001 for all). Additionally, LFA-REAL correlated to individual BILAG organ scores (musculoskeletal: r=0.842, mucocutaneous: r=0.826 (p<0.0001 for both)). Conclusion/UNASSIGNED:SSPGA and LFA-REAL are reliable surrogates of common SLE trial end points and could be used as continuous or dichotomous response measures. Additionally, LFA-REAL can provide individualised scoring at the symptom or organ level. Trial registration number/UNASSIGNED:NCT02270957.

Objective/UNASSIGNED:A common problem in clinical trials is missing data due to participant dropout and loss to follow-up, an issue which continues to receive considerable attention in the clinical research community. Our objective was to examine and compare current and alternative methods for handling missing data in SLE trials with a particular focus on multiple imputation, a flexible technique that has been applied in different disease settings but not to address missing data in the primary outcome of an SLE trial. Methods/UNASSIGNED:Data on 279 patients with SLE randomised to standard of care (SoC) and also receiving mycophenolate mofetil (MMF), azathioprine or methotrexate were obtained from the Lupus Foundation of America-Collective Data Analysis Initiative Database. Complete case analysis (CC), last observation carried forward (LOCF), non-responder imputation (NRI) and multiple imputation (MI) were applied to handle missing data in an analysis to assess differences in SLE Responder Index-5 (SRI-5) response rates at 52 weeks between patients on SoC treated with MMF versus other immunosuppressants (non-MMF). Results/UNASSIGNED:The rates of missing data were 32% in the MMF and 23% in the non-MMF groups. As expected, the NRI missing data approach yielded the lowest estimated response rates. The smallest and least significant estimates of differences between groups were observed with LOCF, and precision was lowest with the CC method. Estimated between-group differences were magnified with the MI approach, and imputing SRI-5 directly versus deriving SRI-5 after separately imputing its individual components yielded similar results. Conclusion/UNASSIGNED:The potential advantages of applying MI to address missing data in an SLE trial include reduced bias when estimating treatment effects, and measures of precision that properly reflect uncertainty in the imputations. However, results can vary depending on the imputation model used, and the underlying assumptions should be plausible. Sensitivity analysis should be conducted to demonstrate robustness of results, especially when missing data proportions are high.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population. In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans. We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles. We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles. Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02. We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665. The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR. The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR. Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

OBJECTIVE:To determine the frequency, associations and outcomes of cerebrovascular events (CerVEs) in a multi-ethnic/racial, prospective, SLE disease inception cohort. METHODS:Patients were assessed annually for 19 neuropsychiatric (NP) events including 5 types of CerVEs: (i) Stroke; (ii) Transient ischemia; (iii) Chronic multifocal ischemia; (iv) Subarachnoid/intracranial hemorrhage; (v) Sinus thrombosis. Global disease activity (SLEDAI-2K), SLICC/ACR damage index (SDI) and SF-36 scores were collected. Time to event, linear and logistic regressions and multi-state models were used as appropriate. RESULTS:Of 1,826 SLE patients, 88.8% were female, 48.8% Caucasian, mean±SD age 35.1±13.3 years, disease duration 5.6±4.2 months and follow-up 6.6±4.1 years. CerVEs were the fourth most frequent NP event: 82/1,826 (4.5%) patients had 109 events, 103/109 (94.5%) were attributed to SLE and 44/109 (40.4%) were identified at enrollment. The predominant events were stroke [60/109 (55.0%)] and transient ischemia [28/109 (25.7%)]. CerVEs were associated with other NP events attributed to SLE (HR (95% CI): (3.16; 1.73-5.75) (p<0.001), non-SLE NP (2.60; 1.49-4.51) (p<0.001), African ancestry at US SLICC sites (2.04; 1.01-4.13) (p=0.047) and organ damage (p=0.041). Lupus anticoagulant increased the risk of first stroke and sinus thrombosis [2.23 (1.11, 4.45) p=.024] and TIA [3.01 (1.15, 7.90) p=0.025]. Physician assessment indicated resolution or improvement in the majority but patients reported sustained reduction in SF-36 summary and subscale scores following CerVEs (P<0.0001). CONCLUSION/CONCLUSIONS:CerVEs, the fourth most frequent NP event in SLE, are usually attributable to lupus. In contrast to good physician reported outcomes, patients report a sustained reduction in health-related quality of life following CerVEs.