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Elevated Regulatory Mediators and Interferon Gamma Associated Responses, but Not Interferon Alpha, BLyS or IP-10, Accompany High-Titer Anti-Ro Autoantibodies in Asymptomatic Mothers of Children with Neonatal Lupus. [Meeting Abstract]

Izmirly, Peter M; Clancy, Robert M; Munroe, Melissa; Rasmussen, Sara; Saxena, Amit; Scher, Jose U; Thanou, Aikaterini; Kamp, Stan; Merrill, Joan T; Buyon, Jill P; James, Judith
ISI:000344384903229
ISSN: 2326-5205
CID: 1444042

Pro-inflammatory adaptive cytokines and shed tumor necrosis factor receptors are elevated preceding systemic lupus erythematosus disease flare

Munroe, Melissa E; Vista, Evan S; Guthridge, Joel M; Thompson, Linda F; Merrill, Joan T; James, Judith A
Objective. Systemic lupus erythematosus (SLE) is a multifaceted disease characterized by immune dysregulation and unpredictable disease activity. This study evaluated changes in plasma concentrations of soluble mediators preceding clinically-defined disease flares. Methods. Soluble mediators (n=52) were examined, including cytokines, chemokines, and soluble receptors, using validated multiplex bead-based or enzyme-linked immunosorbent assays in plasma from European American SLE patients who developed disease flare 6 or 12 weeks after baseline assessment were compared to 28 matched SLE patients without impending flare and 28 matched healthy controls (n=84). For a subset, mediators within samples preceding SLE disease flare and during a clinically stable period from the same individual were compared. Results. Compared to clinically stable patients, patients with impending flare had significant (p
PMCID:4128244
PMID: 24578190
ISSN: 2326-5205
CID: 986592

American College of Rheumatology Criteria at Inception, and Accrual over 5 Years in the SLICC Inception Cohort

Urowitz, Murray B; Gladman, Dafna D; Ibanez, Dominique; Sanchez-Guerrero, Jorge; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Clarke, Anne E; Bernatsky, Sasha; Fortin, Paul R; Hanly, John G; Isenberg, David; Rahman, Anisur; Wallace, Daniel J; Ginzler, Ellen; Petri, Michelle; Bruce, Ian N; Merrill, Joan T; Nived, Ola; Sturfelt, Gunnar; Dooley, Mary Anne; Alarcon, Graciela S; Fessler, Barri; Steinsson, Kristjan; Ramsey-Goldman, Rosalind; Zoma, Asad; Khamashta, Munther; Manzi, Susan; van Vollenhoven, Ronald; Ramos-Casals, Manuel; Aranow, Cynthia; Stoll, Thomas
OBJECTIVE: To determine the frequency of each American College of Rheumatology (ACR) criterion met at time of enrollment, and the increase in each of the criteria over 5 years. METHODS: In 2000 the Systemic Lupus International Collaborating Clinics (SLICC) recruited an international inception cohort of patients with systemic lupus erythematosus (SLE; >/= 4 ACR criteria) who were followed at yearly intervals according to a standard protocol. Descriptive statistics were used to assess the total and cumulative number of ACR criteria met at each visit. Regression models were done to compare the increase of individual and cumulative criteria as a function of race/ethnicity group, and sex. RESULTS: In all, 768 patients have been followed for a minimum of 5 years. Overall, 59.1% of the patients had an increase in the number of ACR criteria they met over the 5-year period. The mean number of ACR criteria met at enrollment was 5.04 +/- 1.13 and at year 5 was 6.03 +/- 1.42. At enrollment, nonwhite patients had a higher number of ACR criteria (5.19 +/- 1.23) than white patients. The total number of criteria increased in both white and nonwhite ethnicities, but increased more among whites. Males had a slightly lower number of criteria at enrollment compared to females and males accrued fewer criteria at 5 years. CONCLUSION: In this international inception cohort of SLE patients with at least 4 ACR criteria at entry, there was an accumulation of ACR criteria over the following 5 years. The distribution of criteria both at inception and over 5 years is affected by sex and ethnicity.
PMID: 24692526
ISSN: 0315-162x
CID: 986602

Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription

Guthridge, Joel M; Lu, Rufei; Sun, Harry; Sun, Celi; Wiley, Graham B; Dominguez, Nicolas; Macwana, Susan R; Lessard, Christopher J; Kim-Howard, Xana; Cobb, Beth L; Kaufman, Kenneth M; Kelly, Jennifer A; Langefeld, Carl D; Adler, Adam J; Harley, Isaac T W; Merrill, Joan T; Gilkeson, Gary S; Kamen, Diane L; Niewold, Timothy B; Brown, Elizabeth E; Edberg, Jeffery C; Petri, Michelle A; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Kimberly, Robert P; Freedman, Barry I; Stevens, Anne M; Boackle, Susan A; Criswell, Lindsey A; Vyse, Tim J; Behrens, Timothy W; Jacob, Chaim O; Alarcon-Riquelme, Marta E; Sivils, Kathy L; Choi, Jiyoung; Joo, Young Bin; Bang, So-Young; Lee, Hye-Soon; Bae, Sang-Cheol; Shen, Nan; Qian, Xiaoxia; Tsao, Betty P; Scofield, R Hal; Harley, John B; Webb, Carol F; Wakeland, Edward K; James, Judith A; Nath, Swapan K; Graham, Robert R; Gaffney, Patrick M
Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.
PMCID:3980411
PMID: 24702955
ISSN: 0002-9297
CID: 986622

Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus

Ginzler, Ellen M; Wallace, Daniel J; Merrill, Joan T; Furie, Richard A; Stohl, William; Chatham, W Winn; Weinstein, Arthur; McKay, James D; McCune, W Joseph; Zhong, Z John; Freimuth, William W; Petri, Michelle A
OBJECTIVE: To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing). METHODS: Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study. RESULTS: Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%-9% during years 2-7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%-60% from baseline over 2-7 years with belimumab. Corticosteroid use decreased over time with >/= 50-55% reduction in median dose during years 5-7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment. CONCLUSION: Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362].
PMID: 24187095
ISSN: 0315-162x
CID: 970392

End-stage renal disease in African Americans with lupus nephritis is associated with APOL1

Freedman, Barry I; Langefeld, Carl D; Andringa, Kelly K; Croker, Jennifer A; Williams, Adrienne H; Garner, Neva E; Birmingham, Daniel J; Hebert, Lee A; Hicks, Pamela J; Segal, Mark S; Edberg, Jeffrey C; Brown, Elizabeth E; Alarcon, Graciela S; Costenbader, Karen H; Comeau, Mary E; Criswell, Lindsey A; Harley, John B; James, Judith A; Kamen, Diane L; Lim, S Sam; Merrill, Joan T; Sivils, Kathy L; Niewold, Timothy B; Patel, Neha M; Petri, Michelle; Ramsey-Goldman, Rosalind; Reveille, John D; Salmon, Jane E; Tsao, Betty P; Gibson, Keisha L; Byers, Joyce R; Vinnikova, Anna K; Lea, Janice P; Julian, Bruce A; Kimberly, Robert P
OBJECTIVE: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. METHODS: APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. RESULTS: Ninety percent of the SLE patients were female. The mean +/- SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 +/- 10.9 years versus 39.5 +/- 12.2 years). The mean +/- SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 +/- 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 x 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 x 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was approximately 2 years earlier among individuals with APOL1 risk genotypes (P = 0.01). CONCLUSION: APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
PMCID:4002759
PMID: 24504811
ISSN: 2326-5205
CID: 986582

Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study

Furie, Richard; Nicholls, Kathy; Cheng, Tien-Tsai; Houssiau, Frederic; Burgos-Vargas, Ruben; Chen, Shun-Le; Hillson, Jan L; Meadows-Shropshire, Stephanie; Kinaszczuk, Michael; Merrill, Joan T
OBJECTIVE: To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids. METHODS: This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period. RESULTS: There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an approximately 20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment. CONCLUSION: Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.
PMID: 24504810
ISSN: 2326-5205
CID: 986572

Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys

Thanou, Aikaterini; Merrill, Joan T
Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.
PMID: 24100460
ISSN: 1759-4790
CID: 986542

Which outcome measures in SLE clinical trials best reflect medical judgment?

Thanou, Aikaterini; Chakravarty, Eliza; James, Judith A; Merrill, Joan T
OBJECTIVES/OBJECTIVE:TO COMPARE TWO MEASURES OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) RESPONSE: the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Responder Index (SRI) against a clinician's assessment of improvement. METHODS:Ninety-one lupus patients were identified with two visits at which Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and BILAG had been scored and with active disease (SLEDAI≥6) at the first visit. A physician rated the disease activity at the second visit as clinically significant improvement, no change or worsening. SRI and BICLA were scored both with and without the medication criteria often used in trials to restrict response definitions. RESULTS:68 patients were considered improved, 17 same and 6 worse at follow-up. SRI versus BICLA, performed without considering medication changes, captured physician-rated improvement with 85% vs 76% sensitivity and 74% vs 78% specificity. With medication limits both instruments had 37% sensitivity and 96% specificity for physician-assessed improvement. Seven patients considered improved by the clinician met the BICLA but not the SRI definition of improvement by failing to achieve a four-point improvement in SLEDAI. 13 clinician-rated responders met SRI but not BICLA by improving in less than all organs. CONCLUSIONS:Shortfalls of SRI and BICLA may be due to BICLA only requiring partial improvement but in all organs versus SRI requiring full improvement in some manifestation(s) and not all organs. SRI and BICLA with medication restrictions are less likely to denote response when the physician disagrees and could provide stringent proof of efficacy in appropriately powered clinical trials.
PMCID:4225744
PMID: 25396057
ISSN: 2053-8790
CID: 4874522

Headache in systemic lupus erythematosus: results from a prospective, international inception cohort study

Hanly, John G; Urowitz, Murray B; O'Keeffe, Aidan G; Gordon, Caroline; Bae, Sang-Cheol; Sanchez-Guerrero, Jorge; Romero-Diaz, Juanita; Clarke, Ann E; Bernatsky, Sasha; Wallace, Daniel J; Ginzler, Ellen M; Isenberg, David A; Rahman, Anisur; Merrill, Joan T; Petri, Michelle; Fortin, Paul R; Gladman, Dafna D; Fessler, Barri J; Alarcon, Graciela S; Bruce, Ian N; Dooley, Mary Anne; Steinsson, Kristjan; Khamashta, Munther A; Ramsey-Goldman, Rosalind; Manzi, Susan; Sturfelt, Gunnar K; Nived, Ola; Zoma, Asad A; van Vollenhoven, Ronald F; Ramos-Casals, Manuel; Aranow, Cynthia; Mackay, Meggan; Ruiz-Irastorza, Guillermo; Kalunian, Kenneth C; Lim, S Sam; Inanc, Murat; Kamen, Diane L; Peschken, Christine A; Jacobsen, Soren; Theriault, Chris; Thompson, Kara; Farewell, Vernon
OBJECTIVE: To examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). METHODS: A disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. RESULTS: Among the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean +/- SD age was 34.6 +/- 13.4 years, duration of disease was 5.6 +/- 5.2 months, and length of followup was 3.8 +/- 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean +/- SD 42.5 +/- 12.2 versus 47.8 +/- 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 +/- 11.0 in those with headache versus 42.6 +/- 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. CONCLUSION: Headache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies.
PMID: 24166793
ISSN: 0004-3591
CID: 986562