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Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials
Manzi, Susan; Sanchez-Guerrero, Jorge; Merrill, Joan T; Furie, Richard; Gladman, Dafna; Navarra, Sandra V; Ginzler, Ellen M; D'Cruz, David P; Doria, Andrea; Cooper, Simon; Zhong, Z John; Hough, Douglas; Freimuth, William; Petri, Michelle A
OBJECTIVE: To evaluate the effects of belimumab versus placebo, plus standard systemic lupus erythematosus (SLE) therapy, on organ domain-specific SLE disease activity. METHODS: Data obtained after 52 weeks of treatment from two phase III trials (BLISS-52 and BLISS-76) comparing belimumab 1 and 10 mg/kg versus placebo, plus standard therapy, in 1684 autoantibody-positive patients were analysed post hoc for changes in British Isles Lupus Assessment Group (BILAG) and Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) organ domain scores. RESULTS: At baseline, the domains involved in the majority of patients were musculoskeletal and mucocutaneous by both BILAG and SELENA-SLEDAI, and immunological by SELENA-SLEDAI. At 52 weeks, significantly more patients treated with belimumab versus placebo had improvement in BILAG musculoskeletal and mucocutaneous domains (1 and 10 mg/kg), and in SELENA-SLEDAI mucocutaneous (10 mg/kg), musculoskeletal (1 mg/kg) and immunological (1 and 10 mg/kg) domains. Improvement was also observed in other organ systems with a low prevalence (=16%) at baseline, including the SELENA-SLEDAI vasculitis and central nervous system domains. Significantly fewer patients treated with belimumab versus placebo had worsening in the BILAG haematological domain (1 mg/kg) and in the SELENA-SLEDAI immunological (10 mg/kg), haematological (10 mg/kg) and renal (1 mg/kg) domains. CONCLUSIONS: Belimumab treatment improved overall SLE disease activity in the most common musculoskeletal and mucocutaneous organ domains. Less worsening occurred in the haematological, immunological and renal domains.
PMCID:3465857
PMID: 22550315
ISSN: 0003-4967
CID: 986342
Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus
Adrianto, Indra; Wang, Shaofeng; Wiley, Graham B; Lessard, Christopher J; Kelly, Jennifer A; Adler, Adam J; Glenn, Stuart B; Williams, Adrienne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Wakeland, Benjamin E; Liang, Chaoying; Kaufman, Kenneth M; Guthridge, Joel M; Alarcon-Riquelme, Marta E; Alarcon, Graciela S; Anaya, Juan-Manuel; Bae, Sang-Cheol; Kim, Jae-Hoon; Joo, Young Bin; Boackle, Susan A; Brown, Elizabeth E; Petri, Michelle A; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Criswell, Lindsey A; Edberg, Jeffrey C; Freedman, Barry I; Gilkeson, Gary S; Jacob, Chaim O; James, Judith A; Kamen, Diane L; Kimberly, Robert P; Martin, Javier; Merrill, Joan T; Niewold, Timothy B; Pons-Estel, Bernardo A; Scofield, R Hal; Stevens, Anne M; Tsao, Betty P; Vyse, Timothy J; Langefeld, Carl D; Harley, John B; Wakeland, Edward K; Moser, Kathy L; Montgomery, Courtney G; Gaffney, Patrick M
OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-kappaB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-kappaB pathway. METHODS: We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. RESULTS: We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. CONCLUSION: Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.
PMCID:3485412
PMID: 22833143
ISSN: 0004-3591
CID: 986372
Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations
Sanchez, Elena; Rasmussen, Astrid; Riba, Laura; Acevedo-Vasquez, Eduardo; Kelly, Jennifer A; Langefeld, Carl D; Williams, Adrianne H; Ziegler, Julie T; Comeau, Mary E; Marion, Miranda C; Garcia-De La Torre, Ignacio; Maradiaga-Cecena, Marco A; Cardiel, Mario H; Esquivel-Valerio, Jorge A; Rodriguez-Amado, Jacqueline; Moctezuma, Jose Francisco; Miranda, Pedro; Perandones, Carlos E; Castel, Cecilia; Laborde, Hugo A; Alba, Paula; Musuruana, Jorge L; Goecke, I Annelise; Anaya, Juan-Manuel; Kaufman, Kenneth M; Adler, Adam; Glenn, Stuart B; Brown, Elizabeth E; Alarcon, Graciela S; Kimberly, Robert P; Edberg, Jeffrey C; Vila, Luis M; Criswell, Lindsey A; Gilkeson, Gary S; Niewold, Timothy B; Martin, Javier; Vyse, Timothy J; Boackle, Susan A; Ramsey-Goldman, Rosalind; Scofield, R Hal; Petri, Michelle; Merrill, Joan T; Reveille, John D; Tsao, Betty P; Orozco, Lorena; Baca, Vicente; Moser, Kathy L; Gaffney, Patrick M; James, Judith A; Harley, John B; Tusie-Luna, Teresa; Pons-Estel, Bernardo A; Jacob, Chaim O; Alarcon-Riquelme, Marta E
OBJECTIVE: American Indian-Europeans, Asians, and African Americans have an excess morbidity from systemic lupus erythematosus (SLE) and a higher prevalence of lupus nephritis than do Caucasians. The aim of this study was to analyze the relationship between genetic ancestry and sociodemographic characteristics and clinical features in a large cohort of American Indian-European SLE patients. METHODS: A total of 2,116 SLE patients of American Indian-European origin and 4,001 SLE patients of European descent for whom we had clinical data were included in the study. Genotyping of 253 continental ancestry-informative markers was performed on the Illumina platform. Structure and Admixture software were used to determine genetic ancestry proportions of each individual. Logistic regression was used to test the association between genetic ancestry and sociodemographic and clinical characteristics. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs). RESULTS: The average American Indian genetic ancestry of 2,116 SLE patients was 40.7%. American Indian genetic ancestry conferred increased risks of renal involvement (P < 0.0001, OR 3.50 [95% CI 2.63- 4.63]) and early age at onset (P < 0.0001). American Indian ancestry protected against photosensitivity (P < 0.0001, OR 0.58 [95% CI 0.44-0.76]), oral ulcers (P < 0.0001, OR 0.55 [95% CI 0.42-0.72]), and serositis (P < 0.0001, OR 0.56 [95% CI 0.41-0.75]) after adjustment for age, sex, and age at onset. However, age and sex had stronger effects than genetic ancestry on malar rash, discoid rash, arthritis, and neurologic involvement. CONCLUSION: In general, American Indian genetic ancestry correlates with lower sociodemographic status and increases the risk of developing renal involvement and SLE at an earlier age.
PMCID:3485439
PMID: 22886787
ISSN: 0004-3591
CID: 986382
Apolipoprotein L1 Risk Variants Underlie Racial Disparities in Lupus Nephritis-Induced End-Stage Renal Disease [Meeting Abstract]
Kimberly, Robert P; Freedman, Barry I; Langfeld, Carl D; Absher, Devin; Andringa, Kelly K; Birmingham, Daniel; Brown, Elizabeth E; Comeau, Mary E; Costenbader, Karen H; Criswell, Lindsey A; Edberg, Jeffrey C; Harley, John B; James, Judith A; Kamen, Diane L; Merrill, Joan T; Niewold, Timothy B; Patel, Neha; Petri, Michelle A; Ramsey-Goldman, Rosalind; Salmon, Jane E; Segal, Mark; Sivils, Kathy Moser; Tsao, Betty P; Julian, Bruce A; Lupus Nephritis-ESRD Consortium
ISI:000309748301266
ISSN: 0004-3591
CID: 2629332
Preferential Association of Complement Receptor 2 Variants with Anti-dsDNA Autoantibodies in Systemic Lupus Erythematosus. [Meeting Abstract]
Giles, Brendan M; Zhao, Jian; Lough, Kara M; Gaffney, Patrick M; Alarcon-Riquelme, Marta E; Brown, Elizabeth E; Criswell, Lindsey A; Gilkeson, Gary S; Jacob, Chaim O; James, Judith A; Merrill, Joan T; Moser, Kathy L; Niewold, Timothy B; Scofield, RHal; Vyse, Timothy J; Harley, John B; Kaufman, Kenneth M; Kelly, Jennifer A; Langefeld, Carl D; Edberg, Jeffrey C; Kimberly, Robert P; Ulgiati, Daniela; Tsao, Betty P; Boackle, Susan A; LLAS2; BIOLUPUS; PROFILE
ISI:000309748305203
ISSN: 0004-3591
CID: 2629392
Directed Intuitive Assessment of Lupus (the DIAL system for real world clinics) Correlates Well with BILAG and SLEDAI [Meeting Abstract]
Askanase, Anca D.; Shum, Katrina M.; Kamp, Stan; Carthen, Fredonna C.; Aberle, Teresa J.; Merrill, J. T.
ISI:000309748303139
ISSN: 0004-3591
CID: 184122
Abnormal Serologies in the Absence of Clinical Activity Do Not Predict New or Recurrent Lupus Nephritis During Pregnancy [Meeting Abstract]
Buyon, Jill; Aslam, Aanam; Guerra, Marta M.; Lockshin, Michael D.; Laskin, Carl A.; Branch, Ware; Sammaritano, Lisa R.; Petri, Michelle; Merrill, Joan T.; Sawitzke, Allen D.; Salmon, Jane E.
ISI:000309748303371
ISSN: 0004-3591
CID: 184152
Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus
Merrill, Joan T; Ginzler, Ellen M; Wallace, Daniel J; McKay, James D; Lisse, Jeffrey R; Aranow, Cynthia; Wellborne, Frank R; Burnette, Michael; Condemi, John; Zhong, Z John; Pineda, Lilia; Klein, Jerry; Freimuth, William W
OBJECTIVE: To evaluate the safety profile of long-term belimumab therapy combined with standard therapy for systemic lupus erythematosus (SLE) in patients with active disease. METHODS: Patients who were randomized to receive intravenous placebo or belimumab 1, 4, or 10 mg/kg, plus standard therapy, and completed the initial 52-week double-blind treatment period were then allowed to enter a 24-week open-label extension phase. During the extension period, patients in the belimumab group either received the same dose or were switched to 10 mg/kg and patients in the placebo group were switched to belimumab 10 mg/kg. Patients who achieved a satisfactory response during the 24-week extension period were allowed to participate in the long-term continuation study of monthly belimumab 10 mg/kg. Adverse events (AEs) and abnormal laboratory results were analyzed per 100 patient-years in 1-year intervals. RESULTS: Of the 364 patients who completed the 52-week double-blind treatment period, 345 entered the 24-week extension, and 296 continued treatment with belimumab in the long-term continuation study. Safety data through 4 years of belimumab exposure (1,165 cumulative patient-years) are reported. Incidence rates of AEs, severe/serious AEs, infusion reactions, infections, malignancies, grades 3/4 laboratory abnormalities, and discontinuations due to AEs were stable or declined during 4-year belimumab exposure. The most common AEs included arthralgia, upper respiratory tract infection, headache, fatigue, and nausea. Serious infusion reactions were rare: only 1 occurred during the 4-year followup period. Rates of serious infection decreased from 5.9/100 patient-years to 3.4/100 patient-years, and no specific type of infection predominated. CONCLUSION: Belimumab added to standard therapy was generally well-tolerated over the 4-year treatment period in patients with SLE, which suggests that belimumab can be administered long term with an acceptable safety profile.
PMID: 22674457
ISSN: 0004-3591
CID: 986362
Seizure disorders in systemic lupus erythematosus results from an international, prospective, inception cohort study
Hanly, John G; Urowitz, Murray B; Su, Li; Gordon, Caroline; Bae, Sang-Cheol; Sanchez-Guerrero, Jorge; Romero-Diaz, Juanita; Wallace, Daniel J; Clarke, Ann E; Ginzler, Em; Merrill, Joan T; Isenberg, David A; Rahman, Anisur; Petri, M; Fortin, Paul R; Gladman, Dd; Bruce, Ian N; Steinsson, Kristjan; Dooley, Ma; Khamashta, Munther A; Alarcon, Graciela S; Fessler, Barri J; Ramsey-Goldman, Rosalind; Manzi, Susan; Zoma, Asad A; Sturfelt, Gunnar K; Nived, Ola; Aranow, Cynthia; Mackay, Meggan; Ramos-Casals, Manuel; van Vollenhoven, Rf; Kalunian, Kenneth C; Ruiz-Irastorza, Guillermo; Lim, Sam; Kamen, Diane L; Peschken, Christine A; Inanc, Murat; Theriault, Chris; Thompson, Kara; Farewell, Vernon
OBJECTIVE: The aim of this study was to describe the frequency, attribution, outcome and predictors of seizures in systemic lupus erythematosus (SLE). METHODS: The Systemic Lupus International Collaborating Clinics, or SLICC, performed a prospective inception cohort study. Demographic variables, global SLE disease activity (SLE Disease Activity Index 2000), cumulative organ damage (SLICC/American College of Rheumatology Damage Index (SDI)) and neuropsychiatric events were recorded at enrolment and annually. Lupus anticoagulant, anticardiolipin, anti-beta(2) glycoprotein-I, antiribosomal P and anti-NR2 glutamate receptor antibodies were measured at enrolment. Physician outcomes of seizures were recorded. Patient outcomes were derived from the SF-36 (36-Item Short Form Health Survey) mental component summary and physical component summary scores. Statistical analyses included Cox and linear regressions. RESULTS: The cohort was 89.4% female with a mean follow-up of 3.5+/-2.9 years. Of 1631 patients, 75 (4.6%) had >/=1 seizure, the majority around the time of SLE diagnosis. Multivariate analysis indicated a higher risk of seizures with African race/ethnicity (HR (CI): 1.97 (1.07 to 3.63); p=0.03) and lower education status (1.97 (1.21 to 3.19); p<0.01). Higher damage scores (without neuropsychiatric variables) were associated with an increased risk of subsequent seizures (SDI=1:3.93 (1.46 to 10.55); SDI=2 or 3:1.57 (0.32 to 7.65); SDI>/=4:7.86 (0.89 to 69.06); p=0.03). There was an association with disease activity but not with autoantibodies. Seizures attributed to SLE frequently resolved (59/78 (76%)) in the absence of antiseizure drugs. There was no significant impact on the mental component summary or physical component summary scores. Antimalarial drugs in the absence of immunosuppressive agents were associated with reduced seizure risk (0.07 (0.01 to 0.66); p=0.03). CONCLUSION: Seizures occurred close to SLE diagnosis, in patients with African race/ethnicity, lower educational status and cumulative organ damage. Most seizures resolved without a negative impact on health-related quality of life. Antimalarial drugs were associated with a protective effect.
PMCID:4656036
PMID: 22492779
ISSN: 0003-4967
CID: 986322
Derivation and validation of systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus
Petri, M; Orbai, AM; Alarcon, GS; Gordon, C; Merrill, JT; Fortin, PR; Bruce, IN; Isenberg, D; Wallace, DJ; Nived, O; Sturfelt, G; Ramsey-Goldman, R; Bae, SC; Hanly, JG; Sanchez-Guerrero, J; Clarke, A; Aranow, C; Manzi, S; Urowitz, M; Gladman, D; Kalunian, K; Costner, M; Werth, VP; Zoma, A; Bernatsky, S; Ruiz-Irastorza, G; Khamashta, MA; Jacobsen, S; Buyon, JP; Maddison, P; Dooley, MA; Vollenhoven, RF; Ginzler, E; Stoll, T; Peschken, C; Jorizzo, JL; Callen, JP; Lim, SS; Fessler, BJ; Inanc, M; Kamen, DL; Rahman, A; Steinsson, K; Franks, AG Jr; Sigler, L; Hameed, S; Fang, H; Pham, N; Brey, R; Weisman, MH; McGwin, G Jr; Magder, LS
OBJECTIVE.: The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology. METHODS.: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls. RESULTS.: Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001). CONCLUSIONS.: The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification. (c) 2012 American College of Rheumatology.
PMCID:3409311
PMID: 22553077
ISSN: 0004-3591
CID: 167761