Faculty Bibliography

OBJECTIVES/OBJECTIVE:In a multi-ethnic/racial, prospective SLE inception cohort, to determine the frequency, clinical characteristics, associations and outcomes in different types of peripheral nervous system (PNS) disease. METHODS:Patients were evaluated annually for 19 neuropsychiatric (NP) events including seven types of PNS disease. SLE disease activity, organ damage, autoantibodies, patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. RESULTS:Of 1,827 SLE patients, 88.8% were female, 48.8% Caucasian. The mean±SD age was 35.1±13.3 years, disease duration at enrollment 5.6±4.2 months and follow-up 7.6±4.6 years. There were 161 PNS events in 139/1,827 (7.6%) patients. The predominant events were peripheral neuropathy [66/161 (41.0%)], mononeuropathy [44/161 (27.3%)] and cranial neuropathy [39/161 (24.2%)] and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with prior history of neuropathy, older age at SLE diagnosis, higher SLEDAI-2K scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower SF-36 physical and mental component summary scores versus patients without NP events. By physician assessment, the majority of neuropathies resolved or improved over time and this was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. CONCLUSION/CONCLUSIONS:PNS disease is an important component of total NPSLE and has a significant negative impact on health related quality of life. The outcome is favourable for most patients, but we noted several factors associated with longer time to resolution. This article is protected by copyright. All rights reserved.

OBJECTIVE:To construct a frailty index (FI) as a measure of vulnerability to adverse outcomes among patients with SLE, using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. METHODS:The SLICC inception cohort consists of recently diagnosed SLE patients followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of a frailty index. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC frailty index (SLICC-FI). The prevalence of frailty in the baseline dataset was evaluated using established cut points for FI values. RESULTS:The 1683 SLE patients (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0%-29.2%) of patients were classified as frail, based on SLICC-FI values greater than 0.21. CONCLUSION/CONCLUSIONS:The SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of SLE patients, frailty was common. The SLICC-FI may be a useful tool for identifying SLE patients who are most vulnerable to adverse outcomes but validation of this index is required prior to its use.

BACKGROUND/PURPOSE/OBJECTIVE:The LFA REAL™ is a measurement system for evaluating lupus disease activity from both clinician and patient perspectives. Patients' viewpoints are captured using a patient-reported outcome (PRO) questionnaire. A series of visual analog scales are designed to rate disease severity and progress over the past 4 weeks. Brief instructions guide the patient to distinguish between active, potentially reversible symptoms and chronic pain or discomfort that are more likely due to damage. Beyond its simplicity and efficiency, the PRO can provide versatile assessments from a global, organ-based, and symptom-specific level. This paper describes the patient-centered approach used to evaluate the content validity of the LFA-REAL PRO. METHODS:The PRO was developed in accordance with FDA guidance. A two-phase qualitative study was performed with 25 lupus patients, 10 who participated in concept elicitation (Phase 1) and 15 in cognitive debriefing interviews (Phase 2). Qualitative data were analyzed using ATLAS.ti software v7.5. Upon completion of the interviews, participants completed the draft PRO and additional measures to characterize the sample. RESULTS:The mean age of participants was 45.6 and 88% were female, as expected in a lupus population. The mean SF-36 physical component score was 29.8 and the mean mental component score was 46.4. Phase 1 elicited symptom saturation and mapping of the draft PRO. Fatigue was reported by 100% of patients, highlighting its importance as a measurable domain. Additionally, 100% of patients spontaneously mentioned arthritis, which may be more important to this group than previously estimated, substantiating the approach of this PRO to break down components of arthritis into joint pain, stiffness, and swelling. Shortness of breath and fever were reported more frequently than expected. Phase 2 data demonstrated that participants found the instrument easy to use and offered recommendations to improve clarity, leading to adjustments in wording and formatting. CONCLUSIONS:Results suggest that the LFA-REAL PRO has content validity and, with some modifications suggested by participants, is ready for quantitative validation, including tests of reliability, validity, responsiveness to change, and performance relative to other PROs used in lupus trials. After validation, the LFA-REAL system is intended for use in clinical practice and research.

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.

OBJECTIVES:To assess the prevalence of combined hormonal contraceptives (CHCs) in reproductive-age women with SLE with and without possible contraindications and to determine factors associated with their use in the presence of possible contraindications. METHODS:This observational cohort study included premenopausal women ages 18-45 years enrolled in the SLICC Registry ⩽15 months after SLE onset, with annual assessments spanning 2000-2017. World Health Organization Category 3 or 4 contraindications to CHCs (e.g. hypertension, aPL) were assessed at each study visit. High disease activity (SLEDAI score >12 or use of >0.5 mg/kg/day of prednisone) was considered a relative contraindication. RESULTS:A total of 927 SLE women contributed 6315 visits, of which 3811 (60%) occurred in the presence of one or more possible contraindication to CHCs. Women used CHCs during 512 (8%) visits, of which 281 (55%) took place in the setting of one or more possible contraindication. The most frequently observed contraindications were aPL (52%), hypertension (34%) and migraine with aura (22%). Women with one or more contraindication were slightly less likely to be taking CHCs [7% of visits (95% CI 7, 8)] than women with no contraindications [9% (95% CI 8, 10)]. CONCLUSION:CHC use was low compared with general population estimates (>35%) and more than half of CHC users had at least one possible contraindication. Many yet unmeasured factors, including patient preferences, may have contributed to these observations. Further work should also aim to clarify outcomes associated with this exposure.

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.

Systemic lupus erythematosus (SLE) flares elicit progressive organ damage, leading to disability and early mortality. This study evaluated clinical and immunologic factors associated with impending flare in the Biomarkers of Lupus Disease study. Autoantibodies and 32 soluble mediators were measured by multiplex assays, immune pathway activation by gene expression module scores, and immune cell subset frequencies and activation states by flow cytometry. After providing baseline samples, participants received transient steroids to suppress disease and were followed until flare. Flare occurred early (within 60 days of baseline) in 21 participants and late (90-165 days) in 13. At baseline, compared to the late flare group, the early flare group had differential gene expression in monocyte, T cell, interferon, and inflammation modules, as well as significantly higher frequencies of activated (aCD11b⁺) neutrophils and monocytes, and activated (CD86^hi) naïve B cells. Random forest models showed three subgroups of early flare patients, distinguished by greater baseline frequencies of aCD11b⁺ monocytes, or CD86^hi naïve B cells, or both. Increases in these cell populations were the most accurate biomarkers for early flare in this study. These results suggest that SLE flares may arise from an overlapping spectrum of lymphoid and myeloid mechanisms in different patients.

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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.