Faculty Bibliography

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

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.

Background/Purpose : Given the heterogeneity of systemic lupus erythematosus (SLE), the effect of any intervention is expected to vary. The ability to identify those most and least likely to benefit from a treatment would improve the interpretability of trial outcomes and advance medical care. Conventional subgroup analyses suffer from low power, can encompass only a few variables at a time, and require a priori specification of cut-points for continuous variables. We explored the utility of a machine learning-based algorithm for discovering in a SLE trial the subgroups in which adding experimental therapy to standard of care considerably enhances or diminishes response compared to placebo (PBO). Methods : A two-step virtual twin (VT) method was applied to combined data from the BLISS-52 (N=865) and BLISS-76 (N=819) trials. A random forest algorithm was first used to estimate for each patient, given baseline characteristics, the probabilities of SRI-4 response to belimumab and PBO. A regression tree was then constructed to partition the study population into distinct subgroups and identify those in which the estimated difference in these response probabilities is much greater or smaller than the treatment effect in the overall population. Two separate VT analyses were conducted of the 10 mg/kg and 1 mg/kg belimumab doses compared to PBO. Cross-validation was used to assess the method ' s performance. Results : In the combined BLISS trials, response rates to the primary endpoint (SRI-4) were 51% in those receiving 10 mg/kg belimumab, 46% (1 mg/kg), and 39% (PBO). VT analysis of 10 mg/kg vs. PBO found a 23% belimumab response advantage over PBO in patients with SLEDAI >= 7 & steroid dose >= 4 mg/d & low C4 & no BILAG A at baseline , vs 12% in the total population. In contrast, the estimated response difference in those entering with SLEDAI < 7 & normal C4 was 5% lower on 10 mg/kg than PBO. In analysis of 1 mg/kg vs. PBO, two subgroups showed enhanced belimumab effect: SLEDAI >= 8 & steroid dose >= 19 mg/d and SLEDAI >= 8 & steroid dose < 19 mg/d & BLyS >= 1.9 ng/mL ; average estimated between-treatment response differences were 18% and 14%, respectively, compared to 7% in the overall population. But in patients with SLEDAI < 8 & steroid dose < 16 mg/d & age < 43 , the 1 mg/kg belimumab response rate was estimated to be 7% lower. Cross-validation indicated the accuracy of the VT method to identify subgroups exceeded 70%. Conclusion : Enhanced belimumab response was associated with low C4 and higher disease activity, steroid dose, and BLyS levels, as in prior studies. However, the VT method identified alternative cutpoints for continuous variables and additional features predicting non-response. SLEDAI >= 7 or 8 was most predictive of response to treatment. Thus, lower response difference is identified in patients who are potentially too ill (BILAG A severity) or not ill enough (minimal disease criteria) to benefit from adding belimumab. The 1 mg/kg belimumab effect was enhanced only in those on high baseline steroid doses. The VT and other machine learning techniques are promising for subgroup discovery in SLE trials as more sophisticated biomarkers, especially potent but less common indicators, become available

Background/Purpose : Many studies of cancer risk in SLE are limited by small sample size or use of administrative data, which rely on billing code diagnoses instead of clinical data. No studies to date focused on incident SLE. We studied cancer risk in the largest-ever cohort of clinically confirmed incident SLE patients. Methods : Patients meeting ACR criteria for new-onset SLE (within 15 months of diagnosis) were enrolled into the SLICC Inception Cohort, across 32 centres. Patients are followed yearly using a standard protocol, with detailed data collection including SLE Disease Activity Index-2000 (SLEDAI-2K) and damage, and drugs in the past year. New cancer diagnoses are recorded by the examining physician at the annual study visit, and confirmed with chart review including pathology reports. Multivariate proportional hazard regression was performed, using baseline variables for demographics (age at SLE onset, sex, race/ethnicity), and time-dependent variables for drugs (corticosteroids, anti-malarial drugs, immunosup-pressive drugs), smoking, and SLEDAI-2K. As well as cancer over-all, we evaluated risk factors for the most common cancer types. Results : Of 1848 new-onset SLE patients enrolled between 1999-2011, 1668 had at least one follow-up; these were the sample for the current analysis. End date was the first of death, last visit, or end of study interval for this analysis (Aug. 2015). Baseline demographics are shown in Table 1. Over 14,215 years (mean 8.5 years) there were 60 cancers (incidence 4. 2 events per 1,000 patient-years). This included 12 breast cancers, 9 non-melanoma skin, 7 lung, 6 hematological, 5 melanoma, 5 prostate, 3 cervical, 3 renal, 2 gastric, 2 head and neck, 2 thyroid, and one each rectal, sarcoma, thymoma, and uterine. Almost half of the cancer cases (including all of the lung cancers) were associated with baseline smoking, versus only one-third of those patients who did not develop cancer. Univariate analyses of all cancer types suggested a higher risk of cancer among patients of white race/ethnicity and among those with the highest quartile of disease activity at cohort entry. However, the multivariate proportional hazard regression indicated that among SLE patients, the over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In those analyses, the effect of race/ethnicity was not clearly evident, and the point estimate for highest quartile of disease activity actually reversed to suggest a nonsignificant trend towards lower cancer risk. In the multivariate analyses specifically for breast cancer, age at SLE diagnoses remained a risk factor, and antimalarials were associated with a decreased risk. This effect of anti-malarials was not clearly seen for any other cancer type. For non-melanoma skin cancer, both age at SLE diagnosis and cyclophosphamide were strongly linked with risk. Conclusion : This is the first large, multicentre cohort study to clearly show how different cancer types in SLE are associated with specific risk factors. Additional follow-up may allow additional determination of the possible effects of disease activity and drugs on cancer subtypes

Background/Purpose : Measuring improvement or worsening is problematic in lupus trials. The British Isles Lupus Assessment Group (BILAG) index often fails to capture sustained decrease in disease activity when the change levels off. The SLE Disease Activity Index (SLEDAI) is inflexible if improvement does not meet a low threshold definition. False positive or negative flares create additional problems. Mild/moderate worsening on the SLEDAI Flare Index (SFI) can be due to insignificant changes. According to an older BILAG flare definition ( >/= 2 new B or 1 new A), which is still commonly used, a false flare occurs if previously improving disease stabilizes, while true worsening is frequently missed when organ scores remain unchanged. A newer BILAG flare definition addresses most of these issues, but fails to account for > 1 feature flaring in a single organ or to allow a moderately severe flare in only 1 organ to rate more than mild. Given the pitfalls of glossary-based measures, we sought the advice of the clinician in determining changes in disease severity. Methods : A simple algorithm for clinician ' s global impression of change (CGIC) was tested during a phase 2 trial of the B Cell modulator, Xmab5871. investigators were asked to rate disease progress at each visit as no change or insignificant change (NC) significant partial improvement (PI), major or complete improvement (MI), significant moderate worsening (MW), or severe worsening (SW). Discrepancies between the CGIC and other instruments were brought to the investigators' attention, but it was emphasized that the clinician ' s opinion could conflict with the technical scoring. Results were collected in an online database along with the BILAG, SLEDAI, PGA and SFI results. Results : Of 104 randomized patients, data from 102 were available from 2-11 visits. The results of the trial have been reported elsewhere; briefly, the primary endpoint, maintenance of improvement, was met by 42% of XmAb5871-treated patients vs 28.6% of the placebo (PBO) group (p=0.18) and time to flare was longer in the XmAb5871 group (p=0.025). Using the CGIC, clinicians rated 445 visits as NC, 148 PI, 64 MI, 84 MW and 8 SW. CGIC was tested as a gold standard for the comparison of other measures of change that are used in SLE trials. Results of this study are summarized in Tables 1 and 2. Conclusion : Clinician ' s opinion, recorded using CGIC, is better reflected by changes of BILAG and PGA than it is by the SLEDAI, which offers fewer gradations of scoring. More patients were free of flare using the CGIC compared to other instruments. In the double-blind trial of Xmab5871 the increased CGIC threshold for defining worsening disease impacted results for patients receiving active treatment more than PBO, suggesting the utility of CGIC as a gold standard for clinical significance

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.

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4⁺ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

OBJECTIVE:Investigate long-term safety and efficacy of intravenous (IV) belimumab plus standard systemic lupus erythematosus (SLE) therapy (SoC) in active, autoantibody-positive SLE. METHODS:This was a multicenter, open-label, continuation study of IV belimumab given every four weeks with SoC in patients with SLE who completed a Phase II, double-blind study. Adverse events (AEs) and laboratory data were monitored from the first belimumab dose (in either study) until 24 weeks after the final dose. Efficacy assessments (every 16 weeks) included SLE Responder Index (SRI), flares and corticosteroid use (every 4 weeks). RESULTS:Of 476 patients in the parent study, 298 (62.6%) entered the continuation study; 96 (32.2%) remained in the study. Patients received belimumab for up to 13 years (median [range] 3334.0 [260, 4332] days; total belimumab exposure 2294 patient-years; median [range] number of infusions 115.5 [7, 155]). The percentage of patients with AEs each year remained stable or decreased. The majority of patients maintained normal IgG levels and the rate of infections remained stable. The percentage of patients who achieved an SRI response increased from 32.8% (Year 1) to 75.6% of those remaining on treatment at Year 12. Corticosteroid dose decreased for patients receiving >7.5 mg/day at baseline. CONCLUSIONS:This study reports the longest duration of belimumab treatment in clinical trials. Belimumab was well tolerated with no new safety concerns, and efficacy was maintained in patients who continued the study. For patients who initially respond to belimumab, the treatment continues to be well tolerated and provides long-term disease control.

OBJECTIVE:To evaluate the properties of a frailty index (FI), constructed using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort, as a novel health measure in SLE. METHODS:For this secondary analysis, the baseline visit was defined as the first study visit at which both organ damage (SLICC/ACR Damage Index [SDI]) and health-related quality of life (Short-Form 36 [SF-36]) were assessed. The SLICC-FI was constructed using baseline data. The SLICC-FI comprises 48 health deficits, including items related to organ damage, disease activity, comorbidities, and functional status. Content, construct, and criterion validity of the SLICC-FI were assessed. Multivariable Cox regression was used to estimate the association between baseline SLICC-FI values and mortality risk, adjusting for demographic and clinical factors. RESULTS:The 1683 SLE patients in the baseline dataset were 89% female with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months. At baseline, the mean (SD) SLICC-FI score was 0.17 (0.08) with a range from 0 to 0.51. Baseline SLICC-FI values exhibited the expected measurement properties and were weakly correlated with baseline SDI scores (r=0.262; p<0.0001). Higher baseline SLICC-FI values (per 0.05 increment) were associated with increased mortality risk (Hazard Ratio 1.59; 95%CI 1.35-1.87), after adjusting for age, sex, steroid use, ethnicity/region, and baseline SDI scores. CONCLUSION/CONCLUSIONS:The SLICC-FI demonstrates internal validity as a health measure in SLE and predicts future mortality risk. The SLICC-FI is potentially valuable for quantifying vulnerability among patients with SLE, and adds to existing prognostic scores.