Faculty Bibliography

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

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

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.

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:The spectrum of antinuclear antibodies (ANA) is changing to include both nuclear staining as well as cytoplasmic and mitotic cell patterns (CMPs) and accordingly a change in terminology to anti-cellular antibodies. This study examined the prevalence of indirect immunofluorescence (IIF) anti-cellular antibody staining using the Systemic Lupus International Collaborating Clinics inception cohort. METHODS:Anti-cellular antibodies were detected by IIF on HEp-2000 substrate utilizing the baseline serum. Three serological subsets were examined: 1) ANA-positive (presence of either nuclear or mixed nuclear/CMP staining), 2) anti-cellular antibody-negative (absence of any intracellular staining), and 3) isolated CMP staining. The odds of being anti-cellular antibody-negative versus ANA or isolated CMP-positive was assessed by multivariable analysis. RESULTS:1137 patients were included; 1049/1137 (92.3%) were ANA-positive, 71/1137 (6.2%) were anti-cellular antibody-negative, and 17/1137 (1.5%) had isolated CMP. The isolated CMP group did not differ from the ANA-positive or anti-cellular antibody-negative group in clinical, demographic or serologic features. Patients who were older (OR 1.02 [95% CI: 1.00, 1.04]), of Caucasian race/ethnicity (OR 3.53 [95% CI: 1.77, 7.03]), or on high dose glucocorticoids at or prior to enrolment (OR 2.39 [95% CI: 1.39, 4.12]) were more likely to be anti-cellular antibody-negative. Patients on immunosuppressants (OR 0.35 [95% CI: 0.19, 0.64]) or with anti-SSA/Ro60 (OR 0.41 [95% CI: 0.23, 0.74]) or anti-UI-RNP (OR 0.43 [95% CI: 0.20, 0.93]) were less likely to be anti-cellular antibody-negative. CONCLUSIONS:In newly diagnosed SLE, 6.2% of patients were anti-cellular antibody-negative and 1.5% had isolated CMP. The prevalence of anti-cellular antibody-negative SLE will likely decrease as emerging nomenclature guidelines recommend that non-nuclear patterns should also be reported as a positive ANA.

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.

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.

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.

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.