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SLE flares during and after pregnancy are mild and occur at similar rates [Meeting Abstract]
Davis-Porada, J; Stern, S; Guerra, M M; Laskin, C; Petri, M; Lockshin, M; Sammaritano, L R; Branch, D; Sawitzke, A D; Merrill, J T; Buyon, J P; Kim, M; Salmon, J E
Background/Purpose: Systemiclupus erythematosus (SLE) disproportionally affects women of childbearing age. Low disease activity for 6 months prior to conception leads to the best outcomes; however, there is little prospective data describing the relative frequency and predictors of flares during and after pregnancy under such conditions.
Method(s): Analyses used data from the PROMISSE study, a multicenter, prospective observational study (2003-2014) of 384 pregnant women meeting >=4 ACR SLE criteria. Subjects were enrolled <12 wks gestation and samples collected throughout pregnancy and post-partum. Exclusion criteria were multi-fetal pregnancy, active disease (prednisone >20 mg/ d), or renal disease (proteinuria >1 gm/24h, and creatinine > 1.2 mg/dL). Mild/moderate and severe flares were defined using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients, and post-partum flares in those with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent predictors of experiencing any type of flare during pregnancy and post-partum.
Result(s): Rates of Flare: 105 flares were recorded during pregnancy (3.8% 1st Trimester, 53.3% 2nd, 42.9% 3rd). Counting one flare per person, 100 of 384 patients (26%) flared at any point during pregnancy; 20.8% of patients had mild/ moderate flares and 6.25% had severe. 57 of 234 patients (24.4%) with a study visit 2-6 months post-partum flared; 22.7% had mild/moderate flares and 1.7% severe. Post-partum flares were mild, and 19 of 57 (33.3%) were treated; 13 with an increase in prednisone, 6 with NSAID or hydroxychloroquine, and 1 with mycophenolate mofetil. The rate of any type of flare was 0.39/person-year at any point during pregnancy and 0.84/person-year post-partum. The proportion of subjects who had any flares during and after pregnancy was similar, but the post-partum flares occurred over a shorter duration of follow-up. Correlates of Flare: Among baseline variables considered (Table) only age, ethnicity/race, low complement, and PGA were independently predictive of having any flare during pregnancy. Clinical features associated with adverse pregnancy outcome (platelet count, antihypertensive use, and LAC) were not predictive of flare. The mean time from the last visit during pregnancy to the post-partum visit was 20 weeks and ranged from 9 to 34 weeks. Neither baseline clinical variables nor clinical variables of the last visit during pregnancy were associated with occurrence of any post-partum flare.
Conclusion(s): Flares during pregnancy are correlated with clinical and serological activity during the first trimester. Flares during and after pregnancy are typically mild, infrequently require treatment, and occur at similar rates. (Table Presented)
EMBASE:626434775
ISSN: 2326-5205
CID: 3705022
Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks
Martínez-Bueno, Manuel; Oparina, Nina; Dozmorov, Mikhail G; Marion, Miranda C; Comeau, Mary E; Gilkeson, Gary; Kamen, Diane; Weisman, Michael; Salmon, Jane; McCune, Joseph W; Harley, John B; Kimberly, Robert; James, Judith A; Merrill, Joan; Montgomery, Courtney; Langefeld, Carl D; Alarcón-Riquelme, Marta E
BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combined with a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomic marks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways.
PMCID:6121630
PMID: 30096841
ISSN: 1422-0067
CID: 3688972
Missing outcomes in sle clinical trials: Impact on estimating treatment effects [Meeting Abstract]
Kim, M; Merrill, J T; Kalunian, K C; Hanrahan, L; Izmirly, P M
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
EMBASE:626516818
ISSN: 2053-8790
CID: 3729942
Economic evaluation of damage accrual in an international sle inception cohort [Meeting Abstract]
Clarke, A E; Bruce, I N; Urowitz, M B; Hanly, J G; Romero-Diaz, J; Gordon, C; Bae, S -C; Bernatsky, S; Wallace, D J; Merrill, J T; Isenberg, D A; Rahman, A; Ginzler, E M; Petri, M; Dooley, M A; Fortin, P; Gladman, D D; Sanchez-Guerrero, J; Steinsson, K; Ramsey-Goldman, R; Khamashta, M A; Aranow, C; Alarcon, G S; Manzi, S; Nived, O; Zoma, A A; Van, Vollenhoven R F; Ramos-Casals, M; Ruiz-Irastorza, G; Sam, Lim S; Kalunian, K C; Inanc, M; Kamen, D L; Peschken, C A; Jacobsen, S; Askanase, A; Pierre, Y S; Su, L; Farewell, V
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
EMBASE:626517014
ISSN: 2053-8790
CID: 3729952
A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus
Patel, Zubin; Lu, Xiaoming; Miller, Daniel; Forney, Carmy R; Lee, Joshua; Lynch, Arthur; Schroeder, Connor; Parks, Lois; Magnusen, Albert F; Chen, Xiaoting; Pujato, Mario; Maddox, Avery; Zoller, Erin E; Namjou, Bahram; Brunner, Hermine I; Henrickson, Michael; Huggins, Jennifer L; Williams, Adrienne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Glenn, Stuart B; Adler, Adam; Shen, Nan; Nath, Swapan K; Stevens, Anne M; Freedman, Barry I; Pons-Estel, Bernardo A; Tsao, Betty P; Jacob, Chaim O; Kamen, Diane L; Brown, Elizabeth E; Gilkeson, Gary S; Alarcón, Graciela S; Martin, Javier; Reveille, John D; Anaya, Juan-Manuel; James, Judith A; Sivils, Kathy L; Criswell, Lindsey A; Vilá, Luis M; Petri, Michelle; Scofield, R Hal; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Bang, So-Young; Lee, Hye-Soon; Bae, Sang-Cheol; Boackle, Susan A; Cunninghame Graham, Deborah; Vyse, Timothy J; Merrill, Joan T; Niewold, Timothy B; Ainsworth, Hannah C; Silverman, Earl D; Weisman, Michael H; Wallace, Daniel J; Raj, Prithvi; Guthridge, Joel M; Gaffney, Patrick M; Kelly, Jennifer A; Alarcón-Riquelme, Marta E; Langefeld, Carl D; Wakeland, Edward K; Kaufman, Kenneth M; Weirauch, Matthew T; Harley, John B; Kottyan, Leah C
Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.
PMCID:6005081
PMID: 29912393
ISSN: 1460-2083
CID: 3167622
Comparison of the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus to More Complex Disease Activity Instruments As Evaluated by Clinical Investigators or Real-World Clinicians
Askanase, Anca D; Nguyen, Samantha C; Costenbader, Karen; Lim, S Sam; Kamen, Diane; Aranow, Cynthia; Grossman, Jennifer; Kapoor, Teja M; Baker-Frost, DeAnna; Aberle, Teresa; Thanou-Stavraki, Aikaterini; Hanrahan, Leslie M; Kim, Mimi; Merrill, Joan T
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 (Ï = 0.58-0.88, P < 0.001). LFA-REAL scores produced correlation coefficients of Ï > 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.
PMID: 28992399
ISSN: 2151-4658
CID: 4874702
Brief Report: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multiple-Dose Study to Evaluate AMG 557 in Patients With Systemic Lupus Erythematosus and Active Lupus Arthritis
Cheng, Laurence E; Amoura, Zahir; Cheah, Benjamin; Hiepe, Falk; Sullivan, Barbara A; Zhou, Lei; Arnold, Gregory E; Tsuji, Wayne H; Merrill, Joan T; Chung, James B
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.
PMCID:6032945
PMID: 29513931
ISSN: 2326-5205
CID: 4874742
Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial
Merrill, Joan T; Shanahan, William R; Scheinberg, Morton; Kalunian, Kenneth C; Wofsy, David; Martin, Renee S
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.
PMID: 29563108
ISSN: 1468-2060
CID: 4874752
New Trials in Lupus and where Are we Going
Thanou, Aikaterini; Merrill, Joan T
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.
PMID: 29725880
ISSN: 1534-6307
CID: 4874762
Glucocorticoid use and factors associated with variability in this use in the Systemic Lupus International Collaborating Clinics Inception Cohort
Little, Jayne; Parker, Ben; Lunt, Mark; Hanly, John G; Urowitz, Murray B; Clarke, Ann E; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Bernatsky, Sasha; Wallace, Daniel J; Merrill, Joan T; Buyon, Jill; Isenberg, David A; Rahman, Anisur; Ginzler, Ellen M; Petri, Michelle; Dooley, Mary Anne; Fortin, Paul; Gladman, Dafna D; Steinsson, Kristjan; Ramsey-Goldman, Rosalind; Khamashta, Munther A; Aranow, Cynthia; Mackay, Meggan; Alarcón, Graciela S; Manzi, Susan; Nived, Ola; Jönsen, Andreas; Zoma, Asad A; van Vollenhoven, Ronald F; Ramos-Casals, Manuel; Ruiz-Irastorza, Guillermo; Sam Lim, Sung; Kalunian, Kenneth C; Inanc, Murat; Kamen, Diane L; Peschken, Christine A; Jacobsen, Soren; Askanase, Anca; Sanchez-Guerrero, Jorge; Bruce, Ian N
Objectives/UNASSIGNED:To describe glucocorticoid (GC) use in the SLICC inception cohort and to explore factors associated with GC use. In particular we aimed to assess temporal trends in GC use and to what extent physician-related factors may influence use. Methods/UNASSIGNED:Patients were recruited within 15 months of diagnosis of SLE from 33 centres between 1999 and 2011 and continue to be reviewed annually. Descriptive statistics were used to detail oral and parenteral GC use. Cross sectional and longitudinal analyses were performed to explore factors associated with GC use at enrolment and over time. Results/UNASSIGNED:We studied 1700 patients with a mean (s.d.) follow-up duration of 7.26 (3.82) years. Over the entire study period, 1365 (81.3%) patients received oral GCs and 447 (26.3%) received parenteral GCs at some point. GC use was strongly associated with treatment centre, age, race/ethnicity, sex, disease duration and disease activity. There was no change in the proportion of patients on GCs or the average doses of GC used over time according to year of diagnosis. Conclusion/UNASSIGNED:GCs remain a cornerstone in SLE management and there have been no significant changes in their use over the past 10-15 years. While patient and disease factors contribute to the variation in GC use, between-centre differences suggest that physician-related factors also contribute. Evidence-based treatment algorithms are needed to inform a more standardized approach to GC use in SLE.
PMCID:5888922
PMID: 29361147
ISSN: 1462-0332
CID: 3036612