Faculty Bibliography

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: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:To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS:Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS:The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION:Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.

OBJECTIVE:Lupus disease measures such as the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group (BILAG) index are challenging to interpret. The Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) is intended to provide an efficient application of anchored visual analog scores, each representing the individual severity of active symptoms, with the sum of individual scores deriving an overall disease activity assessment. Our objective was to compare the performance of LFA-REAL to systemic lupus erythematosus disease activity assessments and compare scores between trained lupus clinical investigators and clinicians. METHODS:Investigators scored the SLEDAI, BILAG, physician's global assessment (PGA), and LFA-REAL, while the clinicians scored the LFA-REAL. The level of agreement between physicians and instruments was determined. RESULTS:The study included 99 patients (93% women, 31% white, mean ± SD ages 43.4 ± 13.2 years). At the first visit, the mean ± SD SLEDAI score was 5.5 ± 4.5, BILAG score 6.7 ± 7.8, and PGA score 33.6 ± 24.5. The mean ± SD investigator LFA-REAL score was 46.2 ± 42.9, and clinician LFA-REAL score 56.1 ± 53.6. At the second visit, the mean ± SD investigator LFA-REAL score was 41.3 ± 36.7, and clinician LFA-REAL score 48.3 ± 42.6. Total LFA-REAL scores correlated positively with PGA, SLEDAI, and BILAG (ρ = 0.58-0.88, P < 0.001). LFA-REAL scores produced correlation coefficients of ρ > 0.7 for musculoskeletal, mucocutaneous, and renal BILAG domains. The intraclass correlation coefficient between the LFA-REAL scores of investigators and clinicians was 0.79 for visit 1 (P < 0.001) and 0.86 for visit 2 (P < 0.001). CONCLUSION:The LFA-REAL provides a reliable surrogate for more complicated disease activity measures when used by lupus clinical investigators or clinicians.

BACKGROUND:Targeted inhibitors of B-cell activating factor (BAFF) have been evaluated in phase III trials in over 4000 patients with systemic lupus erythematosus (SLE). Post hoc analyses of these studies identify greater treatment effect in patients entering with higher disease activity, greater corticosteroid doses, anti double-stranded DNA (dsDNA) and low complement C3 or C4. OBJECTIVES:To evaluate the efficacy and safety of blisibimod, a BAFF inhibitor, in a population of patients with SLE enriched for high disease activity. METHODS:442 patients with SLE with antinuclear antibodies or anti-dsDNA and Safety of Estrogen in Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥10 on standard-of-care medications were randomised to receive weekly subcutaneous blisibimod (200 mg) or placebo. Corticosteroid taper was encouraged from week 8. The primary end point was the week 52 SLE Responder Index-6 (SRI-6). RESULTS:The SRI-6 primary end point was not met. There was a statistically significant steroid-sparing effect, and significantly more blisibimod-treated subjects achieved corticosteroid taper. Increased blisibimod treatment effect on SRI-6 was observed in subjects who achieved a concomitant decrease in corticosteroid dose from baseline. In subjects with baseline urinary protein:creatinine ratio (UPCR) ≥56.5 mg/mmol, significantly higher proportions of blisibimod subjects achieved >50% reduction in UPCR and/or UPCR <56.5 mg/mmol. Reductions in SLE autoantibodies and B cells, and increases in complement C3 and C4 were observed with blisibimod.Blisibimod was well-tolerated. The most common adverse events were upper respiratory tract infection, urinary tract infection, injection site erythema/reaction and diarrhoea. CONCLUSIONS:Although the SRI-6 end point was not met, blisibimod was associated with successful steroid reduction, decreased proteinuria and biomarker responses. TRIAL REGISTRATION NUMBER:NCT01395745.

OBJECTIVE:To evaluate the safety and potential efficacy of AMG 557, a fully human antibody directed against the inducible T cell costimulator ligand (ICOSL) in patients with systemic lupus erythematosus (SLE) with arthritis. METHODS:In this phase Ib, randomized, double-blind, placebo-controlled study, patients received AMG 557 210 mg (n = 10) or placebo (n = 10) weekly for 3 weeks, then every other week for 10 additional doses. The corticosteroid dosage was tapered to ≤7.5 mg/day by day 85, and immunosuppressants were discontinued by day 29. Primary end points on day 169 were safety, immunogenicity, the Lupus Arthritis Response Index (LARI; defined by a reduction in the tender and swollen joint counts), ≥1-letter improvement in the musculoskeletal domain of the British Isles Lupus Assessment Group (BILAG) index, and medication discontinuation. The secondary/exploratory end points were changes in the tender and swollen joint counts, BILAG index scores (musculoskeletal, global), and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS:The incidence of adverse events, most of which were mild, was similar between groups. LARI responses occurred in 3 of 10 patients receiving AMG 557 and 1 of 10 patients receiving placebo (P = 0.58). More patients in the AMG 557 group achieved a ≥4-point improvement in the SLEDAI score on day 169 (7 of 10 patients) compared with the placebo group (2 of 10 patients) (P = 0.07). Patients treated with AMG 557 (versus placebo) had greater improvements from baseline in the global BILAG index scores (-36.3% versus -24.7%) and the SLEDAI score (-47.8% versus -10.7%) and in tender (-22.8% versus -13.5%) and swollen (-62.1% versus -7.8%) joint counts on day 169. CONCLUSION:AMG 557 showed safety and potential efficacy, supporting further evaluation of the clinical efficacy of ICOSL blockade in patients with SLE.

PURPOSE OF REVIEW:To review progress in the field of clinical trials for SLE. RECENT FINDINGS:Treatment development for SLE has been marked by failures of many later phase studies, representing billions of dollars of lost research and development funding. Recently, more successful Phase II trials have tested reductions in background medications, novel stringent endpoints, and identification of informative immunologic subsets to achieve greater treatment effects. A large number of agents with promising novel biologic mechanisms have continued to enter clinical development, and momentum is building to capitalize on newer strategies for trial designs. Widespread SLE drug development is proceeding despite setbacks and controversies. Approaches focusing on patients with high disease activity, reduction of background polypharmacy, or increased endpoint stringency provide strategies that might improve interpretation of trial results. Pharmacodynamics of immune-modulation is a field in its infancy, but ripe for development.

OBJECTIVE:To evaluate the efficacy and safety of atacicept, an antagonist of B lymphocyte stimulator/APRIL-mediated B cell activation, in patients with systemic lupus erythematosus (SLE). METHODS:ADDRESS II is a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study evaluating the safety and efficacy of atacicept in patients with SLE (ClinicalTrials.gov identifier NCT01972568). Patients with active, autoantibody-positive SLE receiving standard therapy were randomized (1:1:1) to receive atacicept (75 mg or 150 mg) or placebo for 24 weeks. The primary end point was the SLE responder index 4 (SRI-4) at week 24. RESULTS:The intent-to-treat (ITT) population included 306 patients. There was a trend toward an improved SRI-4 response rate with atacicept 75 mg (57.8%; adjusted odds ratio [OR] 1.78, P = 0.045) and 150 mg (53.8%; adjusted OR 1.56, P = 0.121) at week 24 as compared with placebo (44.0%) (primary analysis; using the screening visit as baseline). In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo. CONCLUSION:Atacicept treatment showed evidence of efficacy in SLE, particularly in HDA and serologically active patients. Reductions in disease activity and severe flare were observed with atacicept treatment, with an acceptable safety profile.

Background Little is known about the association of healthcare costs with damage accrual in SLE. We describe the costsassociated with damage progression using multi-statemodeling.Methods Patients fulfilling the revised ACR Classification Criteria for SLE from 32 centres in 11 countries were enrolledin the Systemic Lupus International Collaborating Clinics(SLICC) inception cohort within 15 months of diagnosis.Annual data on demographics, SLE disease activity (SLEDAI-2K), damage (SLICC/ACR Damage Index [SDI] if-6 monthsfrom diagnosis), hospitalizations, medications, dialysis, and utilization of selected medical/surgical procedures were collected.Annual health resource utilization was costed using 2017Canadian prices. Annual costs associated with SDI states wereobtained from multiple regressions adjusting for age, sex, race/ethnicity, and disease duration. As there were relatively fewtransitions to SDI states 5 11, these were merged into a singleSDI state. Five and 10 year cumulative costs were estimatedby multiplying annual costs associated with each SDI state bythe expected duration in each state, which was forecastedusing a multi-state model and longitudinal SDI data from theSLICC Inception Cohort (Bruce IN et al. Ann Rheum Dis2015;74:1706 13). Future costs were discounted at a yearlyrate of 3%.Results 1676 patients participated, 88.7% female, 49.2% Caucasian, mean age at diagnosis 34.6 years (SD 13.4), mean disease duration at enrollment 0.5 years (range 0 1.3 years), andmean follow up 7.8 years (range 0.6 16.9 years). Healthresource utilization and annual costs (after adjustment usingregression) were markedly higher in those with higher SDIs(SDI=0, annual costs $1847, 95% CI $1120 to $2574;SDI-5, annual costs $26 772, 95% CI $19 631 to $33 813).At SDI<=2, hospitalizations and medications accounted for97.1% of direct costs, whereas at SDI-3, dialysis was responsible for 55.0%.Five and 10 year cumulative costs stratified by baseline SDIwere calculated by multiplying the annual costs associatedwith each SDI by the expected duration in that state. Fiveand 10 year costs were greater in those with the highest SDIsat baseline (table 1).Conclusions Patients with the highest baseline SDIs incurannual costs and 10 year cumulative costs that are at least 10-fold higher than those with the lowest baseline SDI. By estimating the expected duration in each SDI state and incorporating annual costs, disease severity at presentation can beused to predict future healthcare costs, critical knowledge forcost-effectiveness evaluations of novel therapies

Background Missing data due to drop-out and loss to followup is a common problem in SLE trials. The usual approachesfor handling this issue include analyzing only subjects withcomplete data (complete case analysis; CC), last observationcarried forward (LOCF), or imputing non-responses for missing outcomes (non-responder imputation; NRI). However, thevalidity of these methods depends on strong assumptionsabout the missing data mechanism. Multiple imputation (MI)is a flexible model-based technique that accounts for uncertainty in the imputation process by generating several possiblevalues for the missing data, resulting in multiple completedata sets. These are analyzed separately and results are combined. MI is being used more widely in different disease settings but has not been applied to analyze the primaryoutcome in a SLE trial. We explored the use of MI to addressmissing data in the composite outcome, SLE Responder Index(SRI)-5, using data from patients assigned to standard of care(SoC) in a 52 week trial.Methods Data on 279 SLE patients randomized to SoC for 52weeks who were receiving mycophenolate mofetil (MMF), azathioprine, or methotrexate at entry were obtained from theLupus Foundation of America-Collective Data Analysis Initiative database. Multiple imputation using chained equationswas applied to handle missing data in an analysis to evaluatedifferences in SRI-5 response rates at 52 weeks betweenpatients on MMF and the other immunosuppressants (nonMMF). Three different imputation models were consideredthat included various combinations of longitudinal measures ofdisease activity (both composite and individual measures) andpatient characteristics. Results were compared to estimatesusing the CC, LOCF, and NRI.Results Missing data rates were 32% in the MMF and 23%in the non-MMF groups. As expected, the NRI missing dataapproach yielded the lowest response rates; the smallest andleast significant estimates of between group differences wereobserved with LOCF (table 1). Group differences were magnified with all three MI models compared to results of othermethods. Imputing SRI-5 directly (MI-1) versus the individualcomponents (MI-2) yielded nearly identical results.Conclusions Given the limitations of conventional approachesfor handling missing data, the MI method should also be considered in SLE trials. However, results can vary depending onthe imputation model that is used, and the assumptionsrequired for validity of this and other missing data methodsmust be justified. Sensitivity analysis using different approachesis important to demonstrate robustness of results especiallywhen missing data rates are non-negligible