Publications by authors named "Michael Maldonado"

25 Publications

  • Page 1 of 1

Urinary CD80 Discriminates Among Glomerular Disease Types and Reflects Disease Activity.

Kidney Int Rep 2020 Nov 14;5(11):2021-2031. Epub 2020 Aug 14.

Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Heterogeneity of nephrotic diseases and a lack of validated biomarkers limits interventions and reduces the ability to examine outcomes. Urinary CD80 is a potential biomarker for minimal change disease (MCD) steroid-sensitive nephrotic syndrome (NS). We investigated and validated a CD80 enzyme-linked immunosorbent assay (ELISA) in urine in a large cohort with a variety of nephrotic diseases.

Methods: A commercial CD80 ELISA was enhanced and analytically validated for urine. Patients were from Mayo Clinic (307) and Nephrotic Syndrome Study Network Consortium (NEPTUNE; 104) as follows: minimal change disease (MCD, 56), focal segmental glomerulosclerosis (FSGS, 92), lupus nephritis (LN, 25), IgA nephropathy (IgAN, 20), membranous nephropathy (MN, 49), autosomal dominant polycystic kidney disease (ADPKD, 10), diabetic nephropathy (DN; 106), pyuria (19), and controls (34). Analysis was by Kruskal-Wallis test, generalized estimating equation (GEE) models, and receiver operating characteristic (AUC) curve.

Results: Urinary CD80/creatinine values were highest in MCD compared to other glomerular diseases and were increased in DN with proteinuria >2 compared to controls (control = 36 ng/g; MCD = 139 ng/g,  < 0.01; LN = 90 ng/g,  < 0.12; FSGS = 66 ng/g,  = 0.18; DN = 63,  = 0.03; MN = 69 ng/g,  = 0.33; ng/g, 0.07; IgA = 19 ng/g,  = 0.09; ADPKD = 42,  = 0.36; and pyuria 31,  = 0.20; GEE, median, vs. control). In proteinuric patients, CD80 concentration appears to be independent of proteinuria levels, suggesting that it is unrelated to nonspecific passage across the glomeruli. CD80/creatinine values were higher in paired relapse versus remission cases of MCD and FSGS ( < 0.0001, GEE).

Conclusion: Using a validated ELISA, urinary CD80 levels discriminate MCD from other forms of NS (FSGS, DN, IgA, MN) and primary from secondary FSGS.
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http://dx.doi.org/10.1016/j.ekir.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609973PMC
November 2020

Efficacy of Abatacept and Adalimumab in Patients with Early Rheumatoid Arthritis With Multiple Poor Prognostic Factors: Post Hoc Analysis of a Randomized Controlled Clinical Trial (AMPLE).

Rheumatol Ther 2019 Dec 22;6(4):559-571. Epub 2019 Oct 22.

University of Colorado School of Medicine, Denver, CO, USA.

Introduction: Patients with rheumatoid arthritis (RA) with poor prognostic factors, such as seropositivity for anti-citrullinated protein antibodies and early erosions, may benefit from early intensive treatment. However, information to guide physicians on the best choice of therapy in these patients is limited. The objective of this study was to describe the efficacy of subcutaneous abatacept versus adalimumab over 2 years in patients with seropositive, erosive early RA in the AMPLE study.

Methods: This exploratory post hoc analysis compared clinical, functional and radiographic outcomes in two subsets of patients: patients with early RA (≤ 6 months' disease duration) who were seropositive for rheumatoid factor and/or anti-citrullinated protein antibodies and had > 1 radiographic erosion (Cohort 1); and patients with RA and absence of ≥ 1 of these inclusion criteria (Cohort    2).

Results: Of the 646 randomized patients, Cohort 1 included 38 patients receiving abatacept and 45 receiving adalimumab, and Cohort 2 included 280 patients receiving abatacept and 283 receiving adalimumab. Baseline demographics and disease characteristics were generally similar between treatment groups in both cohorts. Over 2 years, in Cohort 1, the adjusted mean change from baseline in the Disease Activity Score in 28 joints (using C-reactive protein) was numerically greater for abatacept than for adalimumab (mean difference at day 365 was 0.9, 95% confidence interval - 1.47 to - 0.33). Similar patterns of improvement were observed for other disease activity measures and physical function, but not for radiographic outcomes. No treatment-related differences were observed in Cohort 2.

Conclusion: This analysis indicates a trend towards improved disease activity and physical function with abatacept versus adalimumab in patients with seropositive, erosive early RA.

Trial Registration: ClinicalTrials.gov NCT00929864.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1007/s40744-019-00174-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858431PMC
December 2019

Relationship Between Middle Ear Volume and Long-term Audiological Outcomes in Congenital Aural Atresia Repair.

Otol Neurotol 2019 07;40(6):782-788

Department of Otolaryngology, University of Virginia, Charlottesville.

Objective: To assess the association of middle ear volume with long-term hearing outcomes in congenital aural atresia (CAA) repair.

Study Design: Retrospective chart and radiological review.

Setting: Single academic tertiary referral center.

Patients: Children and adults who underwent CAA repair between 1995 and 2016. Patients were divided into "best" and "worst" audiometric groups, based on stability of postoperative air conduction pure-tone average (AC PTA) results. Ten patients were included for study in the "best" group, and 12 in the "worst" group.

Intervention(s): CAA repair.

Main Outcome Measure(s): Long-term (> 1 yr) postoperative three-tone (500, 1000, 2000 Hz) AC PTA, speech reception threshold (SRT), air bone gap, and semiautomated calculated middle ear volume from preoperative computed tomography (CT) scans.

Results: Statistically significant differences were noted between "best" and "worst" groups in AC PTA, SRT, and air bone gap (p < 0.001). Mean middle ear volume in the "best" group was 434.6 mm (range 326.3-602.1 mm) and 339.5 mm (range 199.4-502.1 mm) in the "worst" group (p = 0.02). The majority in both groups were right ears (p = 0.38), and males outnumbered females in the "best" group (9 out of 10; p = 0.018). Preoperative Jahrsdoerfer grading scores were similar between groups (p = 0.31). Mean follow-up for the "best" and "worst" groups was approximately 3.5 and 4.5 yr, respectively.

Conclusions: For patients undergoing CAA repair, larger middle ear volume is associated with stable and better long-term audiometric outcomes.
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http://dx.doi.org/10.1097/MAO.0000000000002233DOI Listing
July 2019

Re-treatment with abatacept plus methotrexate for disease flare after complete treatment withdrawal in patients with early rheumatoid arthritis: 2-year results from the AVERT study.

RMD Open 2019 8;5(1):e000840. Epub 2019 Feb 8.

Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objectives: To complete reporting of outcomes after total withdrawal of all rheumatoid arthritis (RA) therapy and re-treatment after flare in Assessing Very Early Rheumatoid arthritis Treatment study (NCT01142726).

Methods: Patients with early RA were initially randomised to double-blind, weekly subcutaneous abatacept plus methotrexate, or abatacept or methotrexate monotherapy. At month 12, patients with Disease Activity Score (DAS)28 C reactive protein (CRP) <3.2 had all RA treatments rapidly withdrawn and were observed for ≤12 months or until flare. After ≥3 months' withdrawal, patients with protocol-defined RA flare received open-label abatacept plus methotrexate for 6 months (re-treatment).

Results: Proportion of patients in DAS28-CRP-defined remission remained numerically higher in original abatacept plus methotrexate and abatacept arms versus methotrexate arm up to day 253 of withdrawal. At the end of the withdrawal period, few patients remained in remission across all arms: 9/73 (12.3%), 7/50 (14.0%) and 6/53 (11.3%), respectively. For patients entering re-treatment, after 6 months' re-treatment, 95/124 (76.6%) and 78/124 (62.9%) patients achieved DAS28-CRP <3.2 and <2.6, respectively; mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index scores from re-treatment baseline were -2.87 and 0.76, respectively. Re-treatment was well tolerated; exposure-adjusted infection rates per 100 patient-years were lower with abatacept plus methotrexate during withdrawal (7.2) and re-treatment (17.2) versus initial treatment periods of months 0-6 (116.6) and 6-12 (64.6).

Conclusions: Most patients flared within 6 months of therapy withdrawal and few sustained major responses for 1 year. Re-treatment with abatacept plus methotrexate was effective and well tolerated in this controlled setting.
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http://dx.doi.org/10.1136/rmdopen-2018-000840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446179PMC
April 2020

Spinal Hematomas: What a Radiologist Needs to Know.

Radiographics 2018 Sep-Oct;38(5):1516-1535

From the Departments of Radiology and Medical Imaging (J.L.P., J.H.D., N.C.N., C.R.Q., M.T.P., N.F., M.D.M., C.A.S.) and Orthopedic Surgery (G.A.F., F.H.S.), University of Virginia, 1215 Lee St, Charlottesville, VA 22908.

Spinal hematomas are a frequent indication for radiologic evaluation and can be a diagnostic dilemma for many radiologists and surgeons. There are four types of spinal hematomas: epidural, subdural, subarachnoid, and intramedullary (spinal cord) hematomas. Because they differ by their location in relationship to the meningeal membranes and spinal cord, unique radiologic appearances can be recognized to distinguish these types of spinal hemorrhage. Anatomic knowledge of the spinal compartments is essential to the radiologist for confident imaging diagnosis of spinal hematomas and to specify correct locations. MRI is the modality of choice to diagnose the location of the hematoma, characterize important features such as age of the hemorrhage, and detect associated injury or disease. Each type of spinal hematoma has imaging patterns and characteristics that distinguish it from the others, as these specific spinal compartments displace and affect the adjacent anatomic structures. Early detection and accurate localization of spinal hematomas is critical for the surgeon to address the proper treatment and surgical decompression, when necessary, as neurologic deficits may otherwise become permanent. Online supplemental material is available for this article. RSNA, 2018.
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http://dx.doi.org/10.1148/rg.2018180099DOI Listing
December 2018

Isolated left upper eyelid ptosis with pansinusitis and contralateral otitis media in a 9-year-old boy.

Am J Ophthalmol Case Rep 2018 Sep 21;11:6-9. Epub 2018 Apr 21.

Department of Ophthalmology, University of Virginia, 1300 Jefferson Park Ave, Charlottesville, VA, 22908, USA.

Purpose: Upper eyelid ptosis has different etiologies in children and adults. In children, the common causes include orbital cellulitis, congenital ptosis, Cranial Nerve (CN) III palsy, and Horner's syndrome. The purpose of this report is to discuss an unusual presentation of ptosis.

Observations: We describe a case of a 9-year-old boy with left-sided ptosis with no apparent clinical signs of orbital or preseptal infection. Magnetic resonance imaging (MRI) revealed pansinusitis and contralateral otitis media with direct extension into the superior aspect of the left orbit affecting the levator palpebrae superioris muscle.

Conclusions And Importance: This finding on imaging disclosed the etiology of an otherwise unexplained case of upper lid ptosis.
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http://dx.doi.org/10.1016/j.ajoc.2018.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058058PMC
September 2018

Randomized Clinical Trial Design to Assess Abatacept in Resistant Nephrotic Syndrome.

Kidney Int Rep 2018 Jan 31;3(1):115-121. Epub 2017 Aug 31.

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, and Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA.

Introduction: Treatment-resistant nephrotic syndrome is a rare form of glomerular disease that occurs in children and adults. No Food and Drug Administration-approved treatments consistently achieve remission of proteinuria and preservation of kidney function. CD80 (B7-1) can be expressed on injured podocytes, and administration of abatacept (modified CTLA4-Ig based on a natural ligand to CD80) has been associated with sustained normalization of urinary protein excretion and maintenance of glomerular filtration rate in experimental and clinical settings.

Methods: In this report, we describe the rationale for and design of a randomized, placebo-controlled, clinical trial of abatacept in patients with treatment-resistant nephrotic syndrome caused by focal segmental glomerulosclerosis or minimal change disease. The design is a hybrid of a parallel-group and crossover design (switchover) with the primary objectives assessed in the first period of the study and the secondary objectives assessed using data from both periods. All participants will receive the active agent in 1 of the periods. The duration of treatment will be 4 months per period.

Results: The primary outcome will be improvement in nephrotic-range proteinuria to subnephrotic range, that is, reduction from baseline to 4 months in urine protein:creatinine ratio ≥ 50% and to a level < 3. The projected sample size is 90 patients, which has 80% power to detect a treatment difference of 28%.

Conclusion: This study advances efforts to validate CD80 as a therapeutic target for treatment-resistant nephrotic syndrome, and implements a precision medicine-based approach to this serious kidney condition in which the selection of a therapeutic agent is guided by the underlying disease mechanism operating in individual patients.
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http://dx.doi.org/10.1016/j.ekir.2017.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762951PMC
January 2018

Imaging of pediatric neurovascular emergencies.

Emerg Radiol 2018 Jun 11;25(3):227-234. Epub 2018 Jan 11.

Department of Neurology, Hunter Holmes McGuire VA Medical Center, Virginia Commonwealth University Medical Center, Richmond, VA, USA.

Pediatric strokes are rare but critical diagnoses to make in the emergency setting. They are associated with a set of pathologies that are not frequently encountered in the adult population. Some of these diseases have variable clinical presentations and imaging appearance depending on the age of onset and severity of the underlying pathologies. This article reviews the differential diagnoses and noninvasive imaging evaluation of pediatric cerebral ischemic and hemorrhagic diseases.
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http://dx.doi.org/10.1007/s10140-017-1576-5DOI Listing
June 2018

Identification of biomarkers of response to abatacept in patients with SLE using deconvolution of whole blood transcriptomic data from a phase IIb clinical trial.

Lupus Sci Med 2017 28;4(1):e000206. Epub 2017 Jul 28.

Clinical Biomarkers, Bristol-Myers Squibb, Princeton, New Jersey, USA.

Objective: To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment.

Methods: This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10 mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated. Efficacy data were re-analysed.

Results: Patient data (n=144: abatacept: n=98; placebo: n=46) were grouped into four main clusters (C) by predominant characteristic cells: C1-neutrophils; C2-cytotoxic T cells, B-cell receptor-ligated B cells, monocytes, IgG memory B cells, activated T helper cells; C3-plasma cells, activated dendritic cells, activated natural killer cells, neutrophils; C4-activated dendritic cells, cytotoxic T cells. C3 had the highest baseline total British Isles Lupus Assessment Group (BILAG) scores, highest antidouble-stranded DNA autoantibody levels and shortest time to flare (TTF), plus trends in favour of response to abatacept over placebo: adjusted mean difference in BILAG score over 1 year, -4.78 (95% CI -12.49 to 2.92); median TTF, 56 vs 6 days; greater normalisation of complement component 3 and 4 levels. Differential improvements with abatacept were not seen in other clusters, except for median TTF in C1 (201 vs 109 days).

Conclusions: Immune cell clustering segmented disease severity and responsiveness to abatacept. Definition of immune response cell types may inform design and interpretation of SLE trials and treatment decisions.

Trial Registration Number: NCT00119678; results.
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http://dx.doi.org/10.1136/lupus-2017-000206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704740PMC
July 2017

Reply.

Arthritis Rheumatol 2017 04 28;69(4):867-868. Epub 2017 Feb 28.

University of Colorado, Denver, CO.

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http://dx.doi.org/10.1002/art.40021DOI Listing
April 2017

Brief Report: Estimating Disease Activity Using Multi-Biomarker Disease Activity Scores in Rheumatoid Arthritis Patients Treated With Abatacept or Adalimumab.

Arthritis Rheumatol 2016 09;68(9):2083-9

University of Colorado, Denver.

Objective: To assess the ability of a multi-biomarker disease activity (MBDA) test (Vectra DA) to reflect clinical measures of disease activity in patients enrolled in the AMPLE (Abatacept Versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate) trial.

Methods: In the AMPLE trial, patients with active rheumatoid arthritis (RA) who were naive to biologic agents and had an inadequate response to methotrexate were randomized (1:1) to receive subcutaneous abatacept (125 mg every week) or subcutaneous adalimumab (40 mg every 2 weeks), with background methotrexate, for 2 years. The MBDA score was determined using serum samples collected at baseline, month 3, and years 1 and 2. The adjusted mean change from baseline in the MBDA score was compared between the abatacept and adalimumab treatment groups. Cross-tabulation was used to compare the MBDA score with the following clinical measures of disease activity: Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and Routine Assessment of Patient Index Data 3 (RAPID-3).

Results: In total, 318 patients were randomized to receive abatacept, and 328 were randomized to receive adalimumab; MBDA data were available for 259 and 265 patients, respectively. No association between the MBDA score and disease activity defined by the CDAI, SDAI, DAS28-CRP, or RAPID-3 in the abatacept and adalimumab treatment groups was observed.

Conclusion: The MBDA score did not reflect clinical disease activity in patients enrolled in AMPLE and should not be used to guide decision-making in the management of RA, particularly for patients who receive abatacept or adalimumab as the first biologic agent.
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http://dx.doi.org/10.1002/art.39714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099512PMC
September 2016

Reductions in disease activity in the AMPLE trial: clinical response by baseline disease duration.

RMD Open 2016 19;2(1):e000210. Epub 2016 Apr 19.

University of Texas Southwestern Medical Center , Dallas, Texas , USA.

Objectives: To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial.

Methods: Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated.

Results: A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures.

Conclusions: Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses.

Trial Registration Number: NCT00929864, Post-results.
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http://dx.doi.org/10.1136/rmdopen-2015-000210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838764PMC
April 2016

Patient-Reported Outcomes From a Two-Year Head-to-Head Comparison of Subcutaneous Abatacept and Adalimumab for Rheumatoid Arthritis.

Arthritis Care Res (Hoboken) 2016 07;68(7):907-13

University of California at Los Angeles.

Objective: To report 2-year patient-reported outcomes (PROs) from the head-to-head Abatacept versus Adalimumab Comparison in Biologic-Naive RA Subjects with Background Methotrexate (MTX) (AMPLE) trial.

Methods: AMPLE was a phase IIIb, randomized, investigator-blinded trial. Biologic-naive patients with rheumatoid arthritis (RA) and an inadequate response to MTX were randomized to subcutaneous (SC) abatacept (125 mg/week) or adalimumab (40 mg every 2 weeks) with background MTX. PROs (pain, fatigue, ability to perform work, and ability to perform daily activities) were compared up to year 2 for patients in each treatment group, as well as those who achieved low disease activity at both years 1 and 2 (responders) and those who did not (nonresponders).

Results: A total of 646 patients were randomized and treated with SC abatacept (n = 318) or adalimumab (n = 328). Baseline characteristics were balanced between the 2 treatment arms. Comparable improvements in PROs were observed in the abatacept and adalimumab groups over 2 years, with both groups achieving clinically meaningful improvements in PROs from baseline. At year 2, fatigue improved by 23.4 mm and 21.5 mm on a 100-mm visual analog scale with abatacept and adalimumab, respectively. Clinical responders achieved greater improvements in PROs than nonresponders.

Conclusion: In biologic-naive patients with active RA, despite prior MTX, treatment with SC abatacept or adalimumab with background MTX resulted in comparable improvements in PROs, which were highly correlated with physician-reported clinical response end points.
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http://dx.doi.org/10.1002/acr.22763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094537PMC
July 2016

Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial.

Ann Rheum Dis 2016 Apr 10;75(4):709-14. Epub 2015 Sep 10.

VA Palo Alto Health Care System and Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA.

Objectives: To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study.

Methods: In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations. Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates.

Results: Baseline characteristics were generally comparable across quartiles and treatment groups. In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients. At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group.

Conclusions: In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab. Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab.

Trial Registration Number: NCT00929864.
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http://dx.doi.org/10.1136/annrheumdis-2015-207942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819608PMC
April 2016

Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial.

Ann Rheum Dis 2014 Jan 20;73(1):86-94. Epub 2013 Aug 20.

Department of Rheumatology, University of Colorado, , Denver, Colorado, USA.

Objectives: To compare over 2 years the safety, efficacy and radiographic outcomes of subcutaneous abatacept versus adalimumab, in combination with methotrexate (MTX), in patients with rheumatoid arthritis (RA).

Methods: AMPLE is a phase IIIb, 2-year, randomised, investigator-blinded study with a 1-year primary endpoint. Biologic-naive patients with active RA and an inadequate response to MTX were randomised to 125 mg abatacept weekly or 40 mg adalimumab bi-weekly, both with a stable dose of MTX.

Results: Of 646 patients randomised, 79.2% abatacept and 74.7% adalimumab patients completed year 2. At year 2, efficacy outcomes, including radiographic, remained comparable between groups and with year 1 results. The American College Rheumatology 20, 50 and 70 responses at year 2 were 59.7%, 44.7% and 31.1% for abatacept and 60.1%, 46.6% and 29.3% for adalimumab. There were similar rates of adverse events (AEs) and serious adverse events (SAEs). More serious infections occurred with adalimumab (3.8% vs 5.8%) including two cases of tuberculosis with adalimumab. There were fewer discontinuations due to AEs (3.8% vs 9.5%), SAEs (1.6% vs 4.9%) and serious infections (0/12 vs 9/19 patients) in the abatacept group. Injection site reactions (ISRs) occurred less frequently with abatacept (4.1% vs 10.4%).

Conclusions: Through 2 years of blinded treatment in this first head-to-head study between biologic disease-modifying antirheumatic drugs in RA patients with an inadequate response to MTX, subcutaneous abatacept and adalimumab were similarly efficacious based on clinical, functional and radiographic outcomes. Overall, AE frequency was similar in both groups but there were less discontinuations due to AEs, SAEs, serious infections and fewer local ISRs with abatacept.
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http://dx.doi.org/10.1136/annrheumdis-2013-203843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888617PMC
January 2014

Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study.

Arthritis Rheum 2013 Jan;65(1):28-38

Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Objective: There is a need for comparative studies to provide evidence-based treatment guidance for biologic agents in rheumatoid arthritis (RA). Therefore, this study was undertaken as the first head-to-head comparison of subcutaneous (SC) abatacept and SC adalimumab, both administered along with background methotrexate (MTX), for the treatment of RA.

Methods: Patients with active RA who were naive to treatment with biologic agents and had an inadequate response to MTX were randomly assigned to receive 125 mg SC abatacept weekly or 40 mg SC adalimumab biweekly, both given in combination with MTX, in a 2-year study. The primary end point was treatment noninferiority, assessed according to the American College of Rheumatology 20% improvement response (ACR20) at 1 year.

Results: Of the 646 patients who were randomized and treated, 86.2% receiving SC abatacept and 82% receiving SC adalimumab completed 12 months of treatment. At 1 year, 64.8% of patients in the SC abatacept group and 63.4% in the SC adalimumab group demonstrated an ACR20 response; the estimated difference between groups was 1.8% (95% confidence interval -5.6%, 9.2%), thus demonstrating the noninferiority of abatacept compared to adalimumab. All efficacy measures showed similar results and kinetics of response between treatments. The rate of radiographic nonprogression (defined as a total modified Sharp/van der Heijde score [SHS] less than or equal to the smallest detectable change) was 84.8% for SC abatacept-treated patients and 88.6% for SC adalimumab-treated patients, while the mean change from baseline in the total SHS was 0.58 and 0.38, respectively. In the SC abatacept and SC adalimumab groups, the incidence of serious adverse events (SAEs) was 10.1% and 9.1%, respectively, and the rate of serious infections was 2.2% and 2.7%, respectively. In patients treated with SC abatacept, the frequency of discontinuations due to AEs was 3.5% and discontinuations due to SAEs was 1.3%, while in patients treated with SC adalimumab, the frequencies were 6.1% and 3%, respectively. Injection site reactions occurred in 3.8% of patients receiving SC abatacept compared to 9.1% of patients receiving SC adalimumab (P=0.006).

Conclusion: The results demonstrate that SC abatacept and SC adalimumab have comparable efficacy in patients with RA, as shown by similar kinetics of response and comparable inhibition of radiographic progression over 1 year of treatment. The safety was generally similar, other than the occurrence of significantly more local injection site reactions in patients treated with SC adalimumab.
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http://dx.doi.org/10.1002/art.37711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572583PMC
January 2013

Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice.

J Immunol 2012 Dec 29;189(11):5434-41. Epub 2012 Oct 29.

Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.
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http://dx.doi.org/10.4049/jimmunol.1201621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3507618PMC
December 2012

RANTES deficiency attenuates autoantibody-induced glomerulonephritis.

J Clin Immunol 2011 Feb 1;31(1):128-35. Epub 2010 Oct 1.

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Mail Code 8884, Y8.212, 5323 Harry Hines Boulevard, Dallas, TX 75390-8884, USA.

Experimental autoimmune nephritis in mice and spontaneous lupus nephritis are both associated with elevated expression of several chemokines in the kidneys. Nevertheless, the role that different chemokines play in mediating renal inflammation is far from complete. This study focuses on elucidating the functional role of RANTES, a chemokine that has been noted to be hyper-expressed within the kidneys, both in experimental renal disease as well as in spontaneous lupus nephritis. To elucidate if RANTES was essential for immune-mediated glomerulonephritis, DBA/1 mice that are highly sensitive to nephrotoxic serum nephritis were rendered RANTES-deficient and then tested for disease susceptibility. Nephritis-sensitive DBA/1 mice expressed more RANTES within the diseased kidneys. Compared to wild-type DBA/1 mice, RANTES-deficient DBA/1 mice developed significantly less proteinuria, azotemia, and renal inflammation, with reduced crescent formation and tubulo-interstitial nephritis. These findings indicate that RANTES ablation attenuates immune-mediated nephritis and suggest that this chemokine could be a potential therapeutic target in these diseases.
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http://dx.doi.org/10.1007/s10875-010-9470-xDOI Listing
February 2011

Animal models for SLE.

Curr Protoc Immunol 2003 Feb;Chapter 15:Unit 15.20

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Systemic lupus erythematosus (SLE) in humans is characterized by inflammatory lesions in skin, joints, kidneys, the central nervous system (CNS), and elsewhere. The clinical manifestations are accompanied by autoantibodies to diverse self antigens, mainly but not exclusively derived from the cell nucleus. Autoantibodies are generally believed to cause most of the tissue damage, although direct injury via cell-mediated immunity is also important. This unit describes protocols for the quantitation of SLE-associated autoantibody levels in mouse serum: detection of anti-chromatin antibodies, detection of anti-single and anti-double-stranded DNA antibodies, and detection of rheumatoid factor. Support protocols for preparing chicken chromatin and dsDNA are included. Also included is an immunoglobulin allotype-specific adaptation of the basic autoantibody ELISA which is useful for measuring antibody production in chimeric animals. The unit includes an ELISPOT protocol for quantitating cells producing anti-chromatin, as well as a method for genotyping mice for the faslpr and fasLgld mutations.
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http://dx.doi.org/10.1002/0471142735.im1520s52DOI Listing
February 2003

Decay-accelerating factor ameliorates systemic autoimmune disease in MRL/lpr mice via both complement-dependent and -independent mechanisms.

Am J Pathol 2007 Apr;170(4):1258-66

Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, 1254 BRBII/III, 421 Curie Blvd., Philadelphia, PA 19104, USA.

Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. Previous studies have established a significant protective activity of DAF in the MRL/lpr murine model of human systemic lupus erythematosus. To dissect the mechanism of protection by DAF in this disease model, we evaluated the effect of C3 gene ablation on disease development in MRL/lpr-Daf-1(-/-) mice. We found no significant difference in lymphadenopathy, splenomegaly, or anti-chromatin autoantibody titer between complement-sufficient and complement-deficient MRL/lpr-Daf-1(-/-) mice. On the other hand, complement deficiency strikingly reduced the incidence and severity of dermatitis in MRL/lpr-Daf-1(-/-) mice. To assess the contribution of DAF expression on lymphocytes versus local tissues in suppressing dermatitis, we generated BM chimeric mice between MRL/lpr-Daf-1(-/-) and MRL/lpr-Daf-1(+/+) mice. Compared with MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(-/-) controls, MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(+/+) chimeras developed significantly attenuated dermatitis, suggesting that the protective effect of DAF in suppressing dermatitis is primarily attributable to its local expression. We conclude that DAF works as a complement regulator in the skin to protect MRL/lpr mice from skin inflammation, whereas its inhibitory role in the induction phase of MRL/lpr autoimmunity is complement-independent. Together, these results reveal multiple mechanisms of action for DAF in ameliorating systemic autoimmunity.
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http://dx.doi.org/10.2353/ajpath.2007.060601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1829459PMC
April 2007

The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases.

Cell Mol Immunol 2006 Aug;3(4):255-61

Translational Medicine, Wyeth Research, Collegeville, PA 19426, USA.

Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases. In this review, we described the basic biochemistry and molecular biology of the ubiquitin-proteasome system, and its complex role in the development of inflammatory and autoimmune diseases. In addition, therapies and potential therapeutic targets related to the ubiquitin-proteasome system are discussed as well.
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August 2006

The role of host CD4 T cells in the pathogenesis of the chronic graft-versus-host model of systemic lupus erythematosus.

J Immunol 2005 Jun;174(12):7600-9

Department of Medicine, Division of Rheumatology, University of Pennsylvania, and Veterans Affairs Medical Center, Philadelphia, PA 19104, USA.

Systemic lupus erythematosus is characterized by production of autoantibodies and glomerulonephritis. The murine chronic graft-vs-host (cGVH) model of systemic lupus erythematosus is induced by allorecognition of foreign MHC class II determinants. Previous studies have shown that cGVH could not be induced in CD4 knockout (CD4KO) mice. We have further explored the role of host CD4 T cells in this model. Our studies now show that B cells in CD4KO mice have intrinsic defects that prevent them from responding to allohelp. In addition, B cells in CD4KO mice showed phenotypic differences compared with congeneic C57BL/6 B cells, indicating some degree of in vivo activation and increased numbers of cells bearing a marginal zone B cell phenotype. The transfer of syngeneic CD4 T cells at the time of initiation of cGVH did not correct these B cell abnormalities; however, if CD4 T cells were transferred during the development and maturation of B cells, then the B cells from CD4KO mice acquire the ability to respond in cGVH. These studies clearly indicate that B cells need to coexist with CD4 T cells early in their development to develop full susceptibility to alloactivation signals.
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http://dx.doi.org/10.4049/jimmunol.174.12.7600DOI Listing
June 2005

Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor.

Blood 2002 Dec 1;100(13):4544-9. Epub 2002 Aug 1.

Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

The role of complement in the pathogenesis of autoimmune hemolytic anemia (AIHA) has been controversial and may depend on a number of factors, including the affinity and isotype of the pathogenic antibodies involved. We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein, complement receptor 1-related gene/protein y (Crry), but not decay-accelerating factor (DAF), were spontaneously eliminated in vivo by complement. Here, by generating a mouse deficient in both DAF and Crry, we further delineated the roles of Crry and DAF in regulating alternative and classical pathway C3 activation. By using immunoglobulin-, Fcgamma receptor (FcgammaR)-, C3-, C4-, and C5-deficient mice, we also determined the mechanism by which membrane C3 regulator-deficient erythrocytes are cleared from the circulation. Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry-deficient erythrocytes. We conclude that (1) Crry plays a more dominant role than DAF in regulating the alternative pathway of complement, whereas DAF and Crry are equally effective in preventing antibody-induced runaway complement activation on mouse erythrocytes; (2) DAF/Crry-deficient erythrocytes are eliminated by the alternative pathway of complement via complement receptor-mediated erythrophagocytosis in the spleen; and (3) when opsonized with an immunoglobulin G2a (IgG2a) autoantibody, Crry/DAF-deficient erythrocytes are eliminated more rapidly by complement than by the Fc receptor pathway. These results shed new light on the relative activities of Crry and DAF and underscore the critical roles of membrane C3 regulators in preventing spontaneous and antibody-induced erythrocyte damage in vivo.
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http://dx.doi.org/10.1182/blood-2002-06-1875DOI Listing
December 2002

Deletion of decay-accelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice.

Am J Pathol 2002 Sep;161(3):1077-86

Department of Pharmacology, Center for Experimental Therapeutics, Philadelphia, Pennsylvania, USA.

Decay-accelerating factor (DAF, CD55) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. It is also a ligand for CD97, an activation-associated lymphocyte antigen with seven transmembrane domains. It is widely expressed on cells of both the hematopoietic and nonhematopoietic lineages. Although deficiency of DAF on human erythrocytes is associated with the hemolytic anemia syndrome paroxysmal nocturnal hemoglobinuria, the in vivo biology of DAF is still poorly understood. We addressed the in vivo function of DAF in a knockout mouse model and describe here that deletion of DAF exacerbates autoimmune disease development in MRL/lpr mice, a model for human systemic lupus erythematosus. Compared to DAF-sufficient littermate controls, DAF-deficient female MRL/lpr mice developed exacerbated lymphadenopathy and splenomegaly, higher serum anti-chromatin autoantibody levels, and aggravated dermatitis. Consistent with the phenotype of aggravated dermatitis in DAF-deficient mice, Northern and Western blots and immunofluorescence studies showed DAF to be expressed abundantly in the mouse skin, suggesting that it may play a particularly important role in this tissue. Histology and immunostaining demonstrated inflammatory infiltrate and focal C3 deposition in early skin lesions, mostly along the dermal-epidermal junction. These results reveal a protective function of DAF in the development of a systemic autoimmune syndrome and suggest that dysfunction or down-regulation of DAF may contribute to autoimmune disease pathogenesis and manifestation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867258PMC
http://dx.doi.org/10.1016/S0002-9440(10)64268-XDOI Listing
September 2002

Chronic graft-versus-host in Ig knockin transgenic mice abrogates B cell tolerance in anti-double-stranded DNA B cells.

J Immunol 2002 Apr;168(8):4142-53

Department of Medicine, Division of Rheumatology, Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.

Anti-dsDNA Abs are specific diagnostic markers of systemic lupus erythematosus, and are also implicated in kidney pathology. Anti-dsDNA B cells have been shown to be tolerized in nonautoimmune mice. The immunodysregulation that causes these cells to break tolerance is presumably part of the fundamental defects in systemic lupus erythematosus. To explore these mechanisms, we used the chronic graft-versus-host model mediated by MHC class II differences. Induction of chronic graft-vs-host in anti-DNA H chain knockin (3H9.KI) transgenic mice on a nonautoimmune background resulted in specific activation of anti-dsDNA B cells, as evidenced by high titers of soluble Ab in sera and a high frequency (70%) of anti-dsDNA B cell clones recovered as hybridomas. In addition, the lambda(+)-anti-dsDNA B cells developed increased expression of cell surface activation markers, and concentrated in the T cell area of the follicle with an Ab-forming cell-compatible phenotype. Genetic analysis of the hybridoma clones showed strong evidence of secondary rearrangements of the L chain associated with anti-dsDNA reactivity. Thus, our study indicates that alloreactive T cell help can break tolerance in a complex manner, involving several events.
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http://dx.doi.org/10.4049/jimmunol.168.8.4142DOI Listing
April 2002