23 results on '"H. Leher"'
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2. Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors
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Karina Maslova, A. Praestgaard, H. Leher, Gerd R Burmester, Roy Fleischmann, and Mark C. Genovese
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Male ,medicine.medical_specialty ,Neutropenia ,Drug-Related Side Effects and Adverse Reactions ,Long Term Adverse Effects ,Antibodies, Monoclonal, Humanized ,Infections ,Placebo ,law.invention ,Arthritis, Rheumatoid ,Double-Blind Method ,Rheumatology ,Randomized controlled trial ,law ,Internal medicine ,Product Surveillance, Postmarketing ,Humans ,Medicine ,Pharmacology (medical) ,Adverse effect ,Dose-Response Relationship, Drug ,Drug Tapering ,business.industry ,Middle Aged ,medicine.disease ,Receptors, Interleukin-6 ,Discontinuation ,Sarilumab ,Treatment Outcome ,Antirheumatic Agents ,Rheumatoid arthritis ,Absolute neutrophil count ,Female ,Drug Monitoring ,business - Abstract
Objective The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis). Methods Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators’ judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive. Results Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years’ exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of 1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg. Conclusion In patients with RA refractory to TNFi, sarilumab’s long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years. Trial registration TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652.
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- 2021
3. OP0285 VOCLOSPORIN IS EFFECTIVE IN ACHIEVING PROTEINURIA TREATMENT TARGETS IN LUPUS NEPHRITIS DEFINED BY EULAR/ERA RECOMMENDATIONS
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H. J. Anders, R. Federico, S. Randhawa, and H. Leher
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundThe novel calcineurin inhibitor voclosporin was approved in 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunotherapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring.The Phase 2 AURA-LV and Phase 3 AURORA 1 studies demonstrated that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to significantly higher complete renal response rates in AURA-LV at 24 weeks (32.6% vs 19.3%; odds ratio [OR] 2.03; p=0.046) and in AURORA 1 at 52 weeks (40.8% vs 22.5%; OR 2.65; pObjectivesThe European League Against Rheumatism and European Renal Association (EULAR/ERA) published updated treatment recommendations for LN with targeted reductions in proteinuria over the course of the first year of therapeutic intervention.1 Here we report on a post-hoc analysis of pooled data from the similarly designed 48-week AURA-LV and 52-week AURORA 1 studies based on these updated response criteria.MethodsAURA-LV and AURORA 1 enrolled patients with biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Pooled data included 268 patients in the voclosporin (23.7 mg BID) group and 266 patients in the control group, with all patients receiving MMF (target dose 1 g BID) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). We assessed the following EULAR/ERA treatment targets: ≥25% reduction in urine protein creatinine ratio (UPCR) by 3 months, ≥50% reduction in UPCR by 6 months, UPCR ≤0.7 mg/mg by 12 months, and steroid dose ≤7.5 mg/day by 3, 6, and 12 months.ResultsWithin the first 3 months of treatment, 78.4% of patients in the voclosporin group and 62.4% of patients in the control group achieved ≥25% reduction in UPCR (odds ratio [OR] 2.25; 95% confidence interval [CI] 1.52, 3.33; p90%) of patients in both groups had achieved the recommended steroid dose, with 89.6% and 82.8% in the voclosporin and control groups, respectively, on the recommended dose at 12 months. The proportion of patients meeting all three UPCR targets during the one-year study period and having a steroid dose ≤7.5 mg/day at 12 months was 37.3% in the voclosporin group and 23.3% in the control group (OR 2.11; CI 1.43, 3.10; p=0.0001).ConclusionThe addition of voclosporin to a background regimen of MMF and low-dose steroids in patients with LN significantly increased the likelihood of achieving the 3-, 6-, and 12-month UPCR targets of therapy recommended by EULAR/ERA.References[1]Fanouriakis, A. et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann. Rheum. Dis. 79, 713–723 (2020).Figure 1.Integrated AURA-LV and AURORA 1 Analysis on the Achievement of UPCR Treatment Targets and Use of Low-Dose Steroids per EULAR/ERA Lupus Nephritis RecommendationsDisclosure of InterestsHans-Joachim Anders: None declared, Ray Federico Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Simrat Randhawa Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Henry Leher Shareholder of: Aurinia Pharmaceutical Inc., Employee of: Aurinia Pharmaceutical Inc.
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- 2022
4. POS0186 VOCLOSPORIN FOR LUPUS NEPHRITIS: RESULTS OF THE TWO-YEAR AURORA 2 CONTINUATION STUDY
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A. Saxena, Y. K. O. Teng, C. Collins, N. England, and H. Leher
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Rheumatology ,Immunology ,Immunology and Allergy ,General Biochemistry, Genetics and Molecular Biology - Abstract
BackgroundVoclosporin (VCS), a novel calcineurin inhibitor, was approved in the US in January 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunosuppressive therapy. The Phase 3 AURORA 1 study showed that the addition of VCS to mycophenolate mofetil (MMF) and low-dose steroids in patients with LN significantly increased rates of complete renal response at 52 weeks.ObjectivesHere we report the results of the completed continuation study, AURORA 2, which assessed the long-term safety and tolerability of VCS compared to placebo in patients with LN receiving treatment for an additional 24 months following completion of the AURORA 1 studyMethodsKey inclusion criteria for the parent AURORA 1 study included a diagnosis of biopsy-proven active LN (Class III, IV, or V ± III/IV), proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V) and estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2. Patients who completed AURORA 1 and who elected and were eligible to enter AURORA 2 continued on the same blinded therapy as at the end of AURORA 1 (either VCS or placebo twice daily in combination with MMF and low-dose steroids). Safety and tolerability were monitored, and eGFR, serum creatinine (SCr), and urine protein creatinine ratio (UPCR) were also assessed.ResultsIn total, 116 and 100 patients in the VCS and control arms enrolled in AURORA 2, with 92 (79.3%) and 73 (73.0%) patients in each respective arm receiving treatment to the end of AURORA 2. There were no unexpected safety signals in the VCS arm compared to control, with similar rates of serious adverse events reported in both arms (VCS [18.1%] vs. control [23.0%]; Table 1). Eight patients in each arm experienced serious adverse events of infection; serious coronavirus infections were observed in 2 patients in the voclosporin arm and 5 patients in the control arm. There were 4 and 2 adverse events by preferred term of renal impairment reported in the VCS and control arms, respectively, none of which were considered serious, and no reports of acute kidney injury by preferred term in either arm. There were no deaths in the VCS arm during AURORA 2; four deaths were reported in the control arm (pulmonary embolism [n=1], coronavirus infection [n=3]). Mean eGFR and SCr levels remained stable through the end of AURORA 2. The difference between the VCS and control arms in LS mean change from baseline in eGFR was 2.7 mL/min/1.73 m2 at 4 weeks following study drug discontinuation (Figure 1). The mean reductions in UPCR observed in patients treated with VCS in AURORA 1 were maintained in AURORA 2 with no increase in UPCR noted at the follow-up visit 4 weeks after study drug discontinuation.Table 1.Overall Summary of Adverse EventsControl(n=100)Voclosporin(n=116)n (%)n (%)Any AE80 (80.0)100 (86.2) Renal Impairment2 (2.0)4 (3.4) Acute Kidney Injury00Treatment-related AE21 (21.0)28 (24.1)Serious AE23 (23.0)21 (18.1)Serious Treatment-related AE2 (2.0)1 (0.9)AE Leading to Study Drug Discontinuation17 (17.0)11 (9.5)Death4 (4.0)0Treatment-related Death00Figure 1.LS Mean eGFR over TimeConclusionVoclosporin was well-tolerated over 3 years of treatment with no unexpected safety signals detected. Further, eGFR remained stable throughout the study period, and the significant and meaningful reductions in proteinuria achieved in AURORA 1 were maintained. These data provide evidence of a long-term treatment benefit of VCS in patients with LN.Includes adverse events starting on or after the first dose of study drug in AURORA 2 up to 30 days after the last dose and all events of death reported during study follow-up. Adverse events were aggregated by System Organ Class and Preferred Term and coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. AE, adverse event.Disclosure of InterestsAmit Saxena Speakers bureau: Aurinia Pharmaceuticals Inc., Consultant of: Aurinia Pharmaceuticals Inc., Y.K. Onno Teng Consultant of: Aurinia Pharmaceuticals Inc., Chris Collins Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals, Nicole England Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals, Henry Leher Shareholder of: Aurinia Pharmaceuticals, Employee of: Aurinia Pharmaceuticals
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- 2022
5. POS-227 LIPID PROFILES OF PATIENTS WITH LUPUS NEPHRITIS IN THE VOCLOSPORIN AURA-LV AND AURORA 1 CLINICAL TRIALS
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S. Ardoin, W. Smoyer, J.L. Cross, L. Hodge, and H. Leher
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Nephrology - Published
- 2022
6. FRI0092 LONG-TERM SAFETY AND EFFICACY OF SARILUMAB OVER 5 YEARS IN PATIENTS WITH RHEUMATOID ARTHRITIS REFRACTORY TO TUMOR NECROSIS FACTOR INHIBITORS
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Mark C. Genovese, A. Praestgaard, G.-R. Burmester, Roy Fleischmann, K. Maslova, and H. Leher
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education.field_of_study ,medicine.medical_specialty ,business.industry ,Immunology ,Population ,Neutropenia ,medicine.disease ,Placebo ,General Biochemistry, Genetics and Molecular Biology ,law.invention ,Discontinuation ,Sarilumab ,Rheumatology ,Randomized controlled trial ,Refractory ,law ,Rheumatoid arthritis ,Internal medicine ,medicine ,Immunology and Allergy ,education ,business - Abstract
Background:Sarilumab is a human IL-6 receptor (IL-6R) inhibitor approved for the treatment of adults with moderate to severely active rheumatoid arthritis (RA). In the TARGET study (NCT01709578), sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (DMARDs) significantly improved signs and symptoms of RA and physical function versus placebo in patients refractory to tumor necrosis factor (TNF) inhibitors.Objectives:Here we report the long-term safety and efficacy of subcutaneous (SC) sarilumab over 5 years in patients who continued treatment in the open-label extension study (OLE), EXTEND (NCT01146652).Methods:Patients who received double-blind placebo, sarilumab 150 mg, or sarilumab 200 mg every 2 weeks (q2w) in the 24-week randomized controlled trial (RCT) were eligible to receive open-label sarilumab 200 mg q2w in the OLE, with dose reduction to 150 mg q2w permitted to manage laboratory abnormalities or per investigator’s discretion. Safety outcomes are presented for the OLE population for the follow-up from RCT baseline through OLE cut-off date. Efficacy assessments included Clinical Disease Activity Index (CDAI) score and the proportion of responders (CDAI ≤10 and ≤2.8) over time.Results:Of the 546 patients randomized in the RCT, 454 (83%) entered and were treated with sarilumab 200 mg in the OLE (original placebo group n = 156; sarilumab 150 mg n = 145; sarilumab 200 mg n = 153). Demographics and disease characteristics at OLE baseline were similar across groups (mean age 53.2 years; 81% female; mean RA duration [SD] 11.8 years [8.9]). At the time of data cut-off (January 15, 2019), 199/546 (36%) patients had discontinued: 100 (18%), 68 (13%), and 27 (5%) due to treatment-emergent adverse events (AEs), other reasons, and lack of efficacy, respectively. Cumulative exposure to sarilumab through the RCT and OLE (n=521) was 1654.8 patient-years (PY), and 268 patients (51%) had ≥4 years’ exposure. The rates per 100 PY of AEs, serious AEs, AEs leading to discontinuation, and AEs leading to death were 160.4, 10.2, 8.1, and 0.3, respectively. The most common AEs were neutropenia and injection site erythema (15.3 and 11.9 per 100 PY). Absolute neutrophil count 3(Grade 3–4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48 (9.2%). Alanine aminotransferase >3× the upper limit of normal was observed in 46 patients (8.8%) and normalized on treatment in 25 (4.8%). Infections and serious infections occurred at rates of 57.8 and 3.9 per 100 PY, respectively. Clinical efficacy was sustained through 5 years of the OLE (Table). At OLE Week 240 (n = 95) mean change (SD) in CDAI from RCT baseline was −31.2 (14.6).Table .Proportion of responders*Original RCT groupPlacebo +DMARD(n=156)Sarilumab 150 mg +DMARD(n=145)Sarilumab 200 mg +DMARD(n=153)CDAI ≤2.8, n (%) OLE baseline21 (13)26 (18)23 (15) After 192 weeks’ follow-up17 (11)28 (19)28 (18)CDAI ≤10, n (%) OLE baseline62 (40)75 (52)76 (50) After 192 weeks’ follow-up57 (37)61 (42)66 (43)*Nonresponder imputationConclusion:The safety profile of sarilumab was consistent with results of Phase 3 trials, IL-6R inhibition, and SC administration, and no new safety signals were identified over 5 years of follow-up in patients with RA refractory to TNF inhibitors. Clinical efficacy was sustained through 5 years’ follow-up.Acknowledgments:Study funding and medical writing support (Joseph Hodgson, PhD, Adelphi Communications Ltd, Macclesfield, UK) provided by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. in accordance with GPP3 guidelines.Disclosure of Interests:Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Karina Maslova Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Amy Praestgaard Employee of: Sanofi Genzyme, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma
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- 2020
7. E064 The relationship between lipid profile changes and inflammation across the Phase 3 sarilumab rheumatoid arthritis (RA) development programme
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H. Leher, Miguel A. González-Gay, Christina Charles-Schoeman, Michael T. Nurmohamed, Hubert van Hoogstraten, Elaine Wilson, Gregory St John, Edward C. Keystone, and Toshio Kimura
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Sarilumab ,Rheumatology ,medicine.diagnostic_test ,business.industry ,Rheumatoid arthritis ,Immunology ,Medicine ,Pharmacology (medical) ,Inflammation ,medicine.symptom ,business ,medicine.disease ,Lipid profile - Published
- 2019
8. SAT0106 LONG-TERM SAFETY AND EFFICACY OF SARILUMAB OVER 5 YEARS IN PATIENTS WITH RHEUMATOID ARTHRITIS WITH 1 OR >1 PRIOR TUMOR NECROSIS FACTOR INHIBITOR FAILURES
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H. Leher, G.-R. Burmester, K. Maslova, A. Praestgaard, Roy Fleischmann, and Mark C. Genovese
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medicine.medical_specialty ,business.industry ,Immunology ,Placebo ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Discontinuation ,law.invention ,Sarilumab ,Rheumatology ,Randomized controlled trial ,law ,Internal medicine ,Rheumatoid arthritis ,Immunology and Allergy ,Medicine ,In patient ,Long term safety ,business ,Antirheumatic drugs - Abstract
Background:A proportion of adult patients with rheumatoid arthritis (RA) are refractory to tumor necrosis factor inhibitors (TNFi), and treatment with subsequent biologics is commonly associated with reduced response. Sarilumab is a human IL-6 receptor inhibitor approved for the treatment of adults with moderate to severely active RA. In the Phase 3 TARGET study (NCT01709578), significant improvements in the signs and symptoms of RA and physical function were shown with sarilumab plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) versus placebo in patients refractory to TNFi.Objectives:To investigate long-term safety and efficacy of subcutaneous sarilumab over 5 years in patients with 1 or >1 TNFi treatment failure prior to their enrollment in TARGET, who continued onto the open-label extension (OLE) study, EXTEND (NCT01146652).Methods:In the 24-week randomized controlled trial (RCT), patients received placebo, sarilumab 150 mg, or sarilumab 200 mg every 2 weeks (q2w), and were eligible to receive open-label sarilumab 200 mg q2w in the OLE. Dose reduction to 150 mg q2w was permitted per investigator’s discretion, or to manage laboratory abnormalities. Safety outcomes are presented for the entire follow-up period from RCT baseline through the OLE. Efficacy was assessed using Clinical Disease Activity Index (CDAI) score.Results:Of the 546 patients randomized in the RCT, 454 (83%) entered the OLE, of whom 339 had 1 TNFi failure and 115 had >1 TNFi failure. Patients with >1 TNFi failure were older and had a longer duration of RA than patients with 1 TNFi failure (mean age [SD] 55.3 [12.6] and 52.5 [11.9] years, mean RA duration [SD] 13.9 [9.1] and 11.1 [8.8] years, respectively). Kaplan–Meier estimates of the probability of continuation at 5 years were similar between groups: 48% and 54% for patients with >1 and 1 TNFi failure, respectively. At the time of data cut-off (January 15, 2019) 199/546 patients (36%) had discontinued through the RCT and OLE. The rates per 100 patient-years of treatment-emergent adverse events (AEs) and AEs leading to discontinuation for patients with >1 and 1 TNFi failure were 290.6 and 197.9, and 6.5 and 8.1, respectively. Clinical efficacy of sarilumab was sustained in the OLE through 5 years in both groups, regardless of initial treatment in the RCT (Table).TableMean CDAI and proportion of CDAI respondersTreatment allocation in 24-week RCTPlacebo+DMARDSarilumab 150 mg+DMARDSarilumab 200 mg+DMARD(n=156)(n=145)(n=153)TNFi failures1>11>11>1CDAI, mean (SD)RCT baseline43.7 (12.7)42.5 (10.3)42.0 (13.0)44.3 (13.5)42.1 (13.5)48.5 (13.0)Change after 216 weeks’ follow-up−30.9 (17.5)−32.6 (15.2)−33.3 (15.8)−33.1 (12.7)−30.3 (13.6)−36.0 (18.1)CDAI ≤10, n (%)*OLE baseline48 (42)14 (33)59 (53)16 (47)56 (49)20 (51)After 216 weeks’ follow-up24 (21)10 (24)29 (26)7 (21)29 (25)8 (21)*Nonresponder imputationConclusion:The long-term safety and efficacy of sarilumab were similar in patients with 1 or >1 prior TNFi failure over 5 years’ follow-up. Clinical efficacy could be sustained through 5 years of treatment.Acknowledgments:Study funding and medical writing support (Joseph Hodgson, PhD, Adelphi Communications Ltd, Macclesfield, UK) provided by Sanofi Genzyme (Cambridge, MA, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, NJ, USA) in accordance with GPP3 guidelines.Disclosure of Interests:Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Karina Maslova Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Amy Praestgaard Employee of: Sanofi Genzyme, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma
- Published
- 2020
9. THU0162 LIKELIHOOD OF CLINICAL WORSENING AMONG RHEUMATOID ARTHRITIS PATIENTS WHO ACHIEVED A PARTIAL RESPONSE TO ADALIMUMAB AND WERE SUBSEQUENTLY SWITCHED TO SARILUMAB
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K. Ford, H. Leher, Daniel Aletaha, Karthinathan Thangavelu, V.P. Bykerk, G.-R. Burmester, H. van Hoogstraten, and Jeffrey R. Curtis
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030203 arthritis & rheumatology ,0301 basic medicine ,medicine.medical_specialty ,Response to therapy ,business.industry ,Treatment switch ,Minimal clinically important difference ,Immunology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Safety profile ,Sarilumab ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Rheumatoid arthritis ,Partial response ,Internal medicine ,medicine ,Adalimumab ,Immunology and Allergy ,business ,medicine.drug - Abstract
Background:Rheumatoid arthritis (RA) patients who achieve a response to therapy but fail to reach low disease activity (LDA) or remission (partial responders) may decline treatment changes for fear of clinical worsening and losing their achieved response. Little is known about the likelihood of worsening after switching therapy in partial responders, and this limits patients’ ability to make informed treatment decisions.Objectives:This post hoc analysis of the open-label extension (OLE) of MONARCH (NCT02332590) assesses the effects of switching from adalimumab to sarilumab in patients with RA who achieved a partial response to adalimumab but not remission or LDA.Methods:MONARCH was a 24-week, head-to-head monotherapy trial comparing sarilumab with adalimumab. At study end, patients randomized to adalimumab were switched to sarilumab 200 mg q2w for the OLE. Partial responders to adalimumab were defined as patients who had improved more than the minimal clinically important difference (MCID) in the Clinical Disease Activity Index (CDAI) during MONARCH, but who continued to have moderate to high disease activity (CDAI >10) at OLE baseline (BL). MCID was defined as a CDAI decrease ≥12 from a BL CDAI >22 or ≥6 from a BL CDAI >10 to ≤22. Response following treatment switch was assessed by change in CDAI and other outcomes from OLE BL to OLE Week 24. The effect of switching was analyzed descriptively and categorized: worsening = CDAI increase ≥6; improvement = CDAI decrease ≥6; stable = CDAI absolute change Results:Of 369 patients enrolled in MONARCH, 320 (87%) entered the OLE; 155 were switched from adalimumab to sarilumab, and of these, 91 were partial responders, who had a mean (SE) CDAI at OLE BL of 19.56 (0.86). Mean (SE) improvement in CDAI from OLE BL to OLE Week 24 in these patients was 7.37 (1.10). At OLE Week 24, only 6% of adalimumab partial responders had worsened after switching to sarilumab, while 57% had improved; the remaining 37% maintained stable disease activity. Analyses of other efficacy measures—patient and physician global assessments, disease activity score 28-joint erythrocyte sedimentation rate, and swollen and tender joint counts—demonstrated similar results: improvement was seen in 27–78% and worsening in 2–17%. No new safety signals emerged during the OLE. The adverse event profile among patients switching from adalimumab to sarilumab was consistent with the established safety profile of sarilumab.Conclusion:Among adalimumab CDAI partial responders who switched to sarilumab, there was a low likelihood of clinical worsening, while more than half of such patients achieved clinically meaningful improvement. Similar results were observed for other efficacy measures. This small risk of worsening coupled with the substantial likelihood of improvement after switch may help alleviate patients’ concerns around loss of response and help inform shared decision-making.Acknowledgments:Study funding and medical writing support (Gregory Bezkorovainy, Adelphi Communications, New York) were provided by Sanofi Genzyme (Cambridge, USA) and Regeneron Pharmaceuticals, Inc. (Tarrytown, USA) in accordance with Good Publication Practice (GPP3) guidelines. Amy Praestgaard (Sanofi Genzyme employee) contributed to the statistical analysis for this abstract.Disclosure of Interests:Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Daniel Aletaha Grant/research support from: AbbVie, Novartis, Roche, Consultant of: AbbVie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi Genzyme, Speakers bureau: AbbVie, Celgene, Lilly, Merck, Novartis, Pfizer, Sanofi Genzyme, UCB, Gerd Rüdiger Burmester Consultant of: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Speakers bureau: AbbVie Inc, Eli Lilly, Gilead, Janssen, Merck, Roche, Pfizer, and UCB Pharma, Kerri Ford Shareholder of: Sanofi Genzyme, Employee of: Sanofi Genzyme, Hubert van Hoogstraten Shareholder of: Sanofi, Employee of: Sanofi, Henry Leher Shareholder of: Regeneron Pharmaceuticals, Inc., Employee of: Regeneron Pharmaceuticals, Inc., Karthinathan Thangavelu Shareholder of: Sanofi Genzyme, Employee of: EMD Serono, Sanofi Genzyme, Vivian Bykerk: None declared
- Published
- 2020
10. Inhibition of intraocular tumor growth by topical application of the angiostatic steroid anecortave acetate
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A F, Clark, J, Mellon, X Y, Li, D, Ma, H, Leher, R, Apte, H, Alizadeh, S, Hegde, A, McLenaghan, E, Mayhew, T J, D'Orazio, and J Y, Niederkorn
- Subjects
Uveal Neoplasms ,Mice ,Mice, Inbred BALB C ,Hydrocortisone ,Anterior Chamber ,Administration, Topical ,Melanoma, Experimental ,Tumor Cells, Cultured ,Animals ,Mice, Nude ,Female ,Cell Division ,Neoplasm Transplantation - Abstract
This study examined the effect of an angiostatic agent on the growth of a highly vascularized intraocular tumor.A murine uveal melanoma cell line (99E1) was transplanted intracamerally into athymic nude BALB/c mice. Mice were treated topically three times per day beginning on the day of tumor transplantation and continuing through day 28. Groups included (a) 1% anecortave acetate, (b) vehicle control, or (c) no treatment. Tumor growth was scored clinically according to the volume of anterior chamber occupied by tumor. Intraocular tumor weights were determined on days 10, 14, 21, and 28. The effect of the test agents on tumor cell proliferation was examined in vitro by [3H]thymidine incorporation.Tumors grew progressively in untreated mice and mice treated with the vehicle; tumors filled the entire eye by day 20 and frequently perforated the globe by day 21. By contrast, tumors treated with anecortave acetate grew significantly slower (P0.025) and did not perforate the eye. On days 21 and 28 the net tumor weight of the AL-3789-treated animals was 40% to 30% of controls (P0.05). Tumor inhibition was presumably due to the angiostatic properties of anecortave acetate because the compound did not affect tumor cell proliferation in vitro.The topical ocular administration of anecortave acetate restricted the growth of a highly vascularized angiogenic intraocular tumor.
- Published
- 1999
11. Systemic immune response to Acanthamoeba keratitis in the Chinese hamster
- Author
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Hassan Alizadeh, Jerry Y. Niederkorn, W. Taylor, H. Leher, Martine J. Jager, and F. Van Klink
- Subjects
Corneal Infection ,Antibodies, Protozoan ,Antigen-Presenting Cells ,chemical and pharmacologic phenomena ,Acanthamoeba ,Antigens, Protozoan ,Enzyme-Linked Immunosorbent Assay ,Microbiology ,Cornea ,Immune system ,Cricetulus ,Immunity ,Cell Movement ,Cricetinae ,medicine ,Immunology and Allergy ,Animals ,Hypersensitivity, Delayed ,Corneal epithelium ,Immunity, Cellular ,biology ,business.industry ,biology.organism_classification ,medicine.disease ,eye diseases ,Ophthalmology ,medicine.anatomical_structure ,Acanthamoeba keratitis ,Acanthamoeba Keratitis ,Immunoglobulin G ,Langerhans Cells ,Immunology ,Humoral immunity ,Antibody Formation ,biology.protein ,sense organs ,Antibody ,business - Abstract
Recrudescence is a common and troubling feature of Acanthamoeba keratitis and suggests that corneal infection with this organism fails to stimulate the systemic immune apparatus. The present study examined the cell-mediated and humoral immune responses to Acanthamoeba keratitis in the Chinese hamster. Corneal infection with A. castellanii failed to induce either delayed-type hypersensitivity (DTH) or serum IgG antibody against parasite antigens. The failure to induce cell-mediated and humoral immunity did not result in anergy or tolerance since subsequent intramuscular (i.m.) immunization with parasite antigens elicited robust DTH and IgG antibody responses. The inability of corneal infections to induce primary cell-mediated immune responses was due to the absence of resident antigen-presenting cells in the central cornea because induction of Langerhans cell (LC) migration into the central cornea prior to infection with Acanthamoeba promoted the development of parasite-specific DTH. Although the presence of resident LC did not promote the development of a primary humoral immune response, subsequent i.m. immunization elicited heightened parasite-specific IgG antibody production which was indicative of an anamnestic response. Collectively, the results indicate that in the absence of resident antigen-presenting cells, corneal infection with Acanthamoeba fails to stimulate primary cell-mediated or humoral immunity. Induction of peripheral LC into the central corneal epithelium promotes the development of parasite-specific DTH, but does not exacerbate corneal disease.
- Published
- 1998
12. Demographics, Comorbidities, and Biometric Characteristics of Infliximab-treated Patients with Crohnʼs Disease or Ulcerative Colitis in the Ambulatory Care Setting
- Author
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J Lofland, H Leher, C Carter, J McGinnis, C Gunnarsson, and A Ryan
- Subjects
medicine.medical_specialty ,Demographics ,business.industry ,Gastroenterology ,Disease ,medicine.disease ,Ulcerative colitis ,Infliximab ,Surgery ,Ambulatory care ,Internal medicine ,medicine ,Immunology and Allergy ,business ,medicine.drug - Published
- 2011
13. Efficacy of Voclosporin in Proliferative Lupus Nephritis with High Levels of Proteinuria.
- Author
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Menn-Josephy H, Hodge LS, Birardi V, and Leher H
- Subjects
- Adult, Humans, Immunosuppressive Agents adverse effects, Cyclosporine adverse effects, Mycophenolic Acid adverse effects, Proteinuria drug therapy, Proteinuria etiology, Glucocorticoids adverse effects, Treatment Outcome, Lupus Nephritis drug therapy, Lupus Nephritis complications
- Abstract
Background: In a phase 3 study of adults with active lupus nephritis, addition of voclosporin to mycophenolate mofetil (MMF) and low-dose glucocorticoids led to significant improvements in the proportion of participants achieving complete and partial renal response as well as sustained reduction in proteinuria. This analysis examined the efficacy and safety of voclosporin in a subgroup of the phase 3 study with proliferative lupus nephritis and high levels of proteinuria., Methods: Participants were randomized to oral voclosporin (23.7 mg twice daily) or placebo for 12 months; all participants received MMF and low-dose glucocorticoids. This analysis includes participants with class III or IV (±class V) lupus nephritis and baseline urine protein-creatinine ratio (UPCR) ≥3 g/g. Efficacy end points included complete renal response (UPCR ≤0.5 g/g with stable eGFR, low-dose glucocorticoids, and no rescue medication), partial renal response (≥50% reduction from baseline UPCR), and UPCR over time. Safety outcomes were also assessed., Results: A total of 148 participants were in the voclosporin ( n =76) and control ( n =72) arms. At 12 months, 34% and 11% of participants in the voclosporin and control arms, respectively, achieved a complete renal response (odds ratio, 4.43; 95% confidence interval [CI], 1.78 to >9.99; P = 0.001). A partial renal response was achieved by 65% of the voclosporin arm and 51% of the control arm at 12 months (odds ratio, 1.60; 95% CI, 0.8 to 3.20; P = 0.18). More voclosporin- than control-treated participants achieved UPCR ≤0.5 g/g (51% versus 26%), and voclosporin-treated participants met this end point significantly earlier (hazard ratio, 2.07; 95% CI, 1.19 to 3.60; P = 0.01). The incidence of adverse events was similar between the arms; mean eGFR values remained stable and within normal range in both arms., Conclusions: Addition of voclosporin to MMF and low-dose glucocorticoids resulted in a significantly higher proportion of participants with proliferative lupus nephritis achieving complete and partial renal responses as well as earlier reductions in proteinuria, with no evidence of worsening kidney function., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)
- Published
- 2024
- Full Text
- View/download PDF
14. Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors.
- Author
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Fleischmann R, Genovese MC, Maslova K, Leher H, Praestgaard A, and Burmester GR
- Subjects
- Antirheumatic Agents administration & dosage, Antirheumatic Agents adverse effects, Dose-Response Relationship, Drug, Double-Blind Method, Drug Monitoring methods, Drug Monitoring statistics & numerical data, Drug Tapering methods, Drug Tapering statistics & numerical data, Drug-Related Side Effects and Adverse Reactions diagnosis, Drug-Related Side Effects and Adverse Reactions epidemiology, Drug-Related Side Effects and Adverse Reactions etiology, Female, Humans, Male, Middle Aged, Product Surveillance, Postmarketing, Treatment Outcome, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Arthritis, Rheumatoid blood, Arthritis, Rheumatoid diagnosis, Arthritis, Rheumatoid drug therapy, Infections diagnosis, Infections epidemiology, Long Term Adverse Effects chemically induced, Long Term Adverse Effects diagnosis, Long Term Adverse Effects epidemiology, Neutropenia chemically induced, Neutropenia diagnosis, Neutropenia epidemiology, Receptors, Interleukin-6 antagonists & inhibitors
- Abstract
Objective: The objective of this study was to evaluate the long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFis)., Methods: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) who received double-blind placebo or sarilumab 150 or 200 mg every 2 weeks (q2w), plus conventional synthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200 mg q2w plus csDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150 mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratory abnormalities and clinical DASs. All statistics are descriptive., Results: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. The cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidence rates per 100 PY of AEs, and AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). An absolute neutrophil count of <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and similar for patients who either remained on 200 mg or reduced to 150 mg., Conclusion: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5 years., Trial Registration: TARGET, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01709578, NCT01709578; EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
15. Impact of persistence with infliximab on hospitalizations in ulcerative colitis.
- Author
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Carter CT, Leher H, Smith P, Smith DB, and Waters HC
- Subjects
- Adult, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents economics, Anti-Inflammatory Agents therapeutic use, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal economics, Colitis, Ulcerative economics, Cost-Benefit Analysis, Female, Gastrointestinal Agents administration & dosage, Gastrointestinal Agents economics, Gastrointestinal Agents therapeutic use, Hospitalization economics, Humans, Infliximab, Infusions, Intravenous, Insurance Claim Review, Length of Stay economics, Length of Stay statistics & numerical data, Male, Retrospective Studies, Treatment Outcome, United States, Antibodies, Monoclonal therapeutic use, Colitis, Ulcerative drug therapy, Hospitalization statistics & numerical data
- Abstract
Objectives: To assess infliximab infusion patterns in ulcerative colitis (UC) and assess the impact of persistence with infliximab maintenance therapy on UC-related hospitalizations, lengths of stay, and inpatient costs., Study Design: Retrospective analysis of medical claims for UC patients newly initiating infliximab treatment., Methods: Patients were aged >18 years and had 2 UC diagnosis codes, an infliximab index date between September 1, 2005, and January 31, 2008, and continuous enrollment for >12 months before and >14 months after the index date. Infliximab induction (first 56 days postindex) and maintenance (>56 days and <12 months postinduction) patterns were evaluated. Of patients with maintenance treatment, persistence was defined as a medication possession ratio (MPR) of >80%, and this group was compared with those without persistence (<80% MPR)., Results: Overall, 420 patients were included in the analysis; 84.3% (n = 354) continued to maintenance therapy. Maintenance infusion patterns were consistent with recommended prescribing information. A smaller proportion of patients with maintenance therapy persistence required hospitalization compared with patients without persistence (3.0% vs 20.4%; P <.001). Hospitalized patients with maintenance therapy persistence had significantly lower mean inpatient costs ($14,243 vs $32,745; P = .046), with a trend toward shorter mean lengths of stay (6.67 vs 9.71 days; P = .147) than patients without persistence., Conclusions: Infliximab maintenance therapy persistence in UC was associated with significantly fewer hospitalizations. Once hospitalized, patients with therapeutic persistence had significantly decreased inpatient costs.
- Published
- 2011
16. Role of tear anti-acanthamoeba IgA in Acanthamoeba keratitis.
- Author
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Niederkorn JY, Alizadeh H, Leher H, Apte S, El Agha S, Ling L, Hurt M, Howard K, Cavanagh HD, and McCulley JP
- Subjects
- Acanthamoeba Keratitis parasitology, Animals, Humans, Immunoglobulin G immunology, Reference Values, Acanthamoeba metabolism, Acanthamoeba Keratitis physiopathology, Antibodies, Protozoan metabolism, Immunoglobulin A immunology, Immunoglobulin A metabolism, Tears metabolism
- Published
- 2002
- Full Text
- View/download PDF
17. Exacerbation of Acanthamoeba keratitis in animals treated with anti-macrophage inflammatory protein 2 or antineutrophil antibodies.
- Author
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Hurt M, Apte S, Leher H, Howard K, Niederkorn J, and Alizadeh H
- Subjects
- Animals, Cell Movement, Chemokine CXCL2, Chemokines physiology, Complement System Proteins physiology, Cricetinae, Cricetulus, Immune Sera immunology, Mice, Peroxidase metabolism, Acanthamoeba Keratitis therapy, Antibodies therapeutic use, Chemokines antagonists & inhibitors, Neutrophils physiology
- Abstract
Neutrophils are thought to be involved in many infectious diseases and have been found in high numbers in the corneas of patients with Acanthamoeba keratitis. Using a Chinese hamster model of keratitis, conjunctival neutrophil migration was manipulated to determine the importance of neutrophils in this disease. Inhibition of neutrophil recruitment was achieved by subconjunctival injection with an antibody against macrophage inflammatory protein 2 (MIP-2), a powerful chemotactic factor for neutrophils which is secreted by the cornea. In other experiments, neutrophils were depleted by intraperitoneal injection of anti-Chinese hamster neutrophil antibody. The inhibition of neutrophils to the cornea resulted in an earlier onset and more severe infection compared to controls. Anti-MIP-2 antibody treatment produced an almost 35% reduction of myeloperoxidase activity in the cornea 6 days postinfection, while levels of endogenous MIP-2 secretion increased significantly. Recruitment of neutrophils into the cornea via intrastromal injections of recombinant MIP-2 generated an initially intense inflammation that resulted in the rapid resolution of the corneal infection. The profound exacerbation of Acanthamoeba keratitis seen when neutrophil migration was inhibited, combined with the rapid clearing of the disease in the presence of increased neutrophils, strongly suggests that neutrophils play an important role in combating Acanthamoeba infections in the cornea.
- Published
- 2001
- Full Text
- View/download PDF
18. Inhibition of intraocular tumor growth by topical application of the angiostatic steroid anecortave acetate.
- Author
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Clark AF, Mellon J, Li XY, Ma D, Leher H, Apte R, Alizadeh H, Hegde S, McLenaghan A, Mayhew E, D'Orazio TJ, and Niederkorn JY
- Subjects
- Administration, Topical, Animals, Anterior Chamber pathology, Cell Division drug effects, Female, Hydrocortisone administration & dosage, Hydrocortisone therapeutic use, Melanoma, Experimental blood supply, Melanoma, Experimental pathology, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Tumor Cells, Cultured, Uveal Neoplasms blood supply, Uveal Neoplasms pathology, Anterior Chamber drug effects, Hydrocortisone analogs & derivatives, Melanoma, Experimental drug therapy, Uveal Neoplasms drug therapy
- Abstract
Purpose: This study examined the effect of an angiostatic agent on the growth of a highly vascularized intraocular tumor., Methods: A murine uveal melanoma cell line (99E1) was transplanted intracamerally into athymic nude BALB/c mice. Mice were treated topically three times per day beginning on the day of tumor transplantation and continuing through day 28. Groups included (a) 1% anecortave acetate, (b) vehicle control, or (c) no treatment. Tumor growth was scored clinically according to the volume of anterior chamber occupied by tumor. Intraocular tumor weights were determined on days 10, 14, 21, and 28. The effect of the test agents on tumor cell proliferation was examined in vitro by [3H]thymidine incorporation., Results: Tumors grew progressively in untreated mice and mice treated with the vehicle; tumors filled the entire eye by day 20 and frequently perforated the globe by day 21. By contrast, tumors treated with anecortave acetate grew significantly slower (P < 0.025) and did not perforate the eye. On days 21 and 28 the net tumor weight of the AL-3789-treated animals was 40% to 30% of controls (P < 0.05). Tumor inhibition was presumably due to the angiostatic properties of anecortave acetate because the compound did not affect tumor cell proliferation in vitro., Conclusions: The topical ocular administration of anecortave acetate restricted the growth of a highly vascularized angiogenic intraocular tumor.
- Published
- 1999
19. Monoclonal IgA antibodies protect against Acanthamoeba keratitis.
- Author
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Leher H, Zaragoza F, Taherzadeh S, Alizadeh H, and Niederkorn JY
- Subjects
- Animals, Blotting, Western, Cell Adhesion immunology, Cell Line, Cricetinae, Cricetulus, Epithelium, Corneal parasitology, Immunization, Passive, Acanthamoeba immunology, Acanthamoeba Keratitis prevention & control, Antibodies, Monoclonal therapeutic use, Antibodies, Protozoan therapeutic use, Immunoglobulin A therapeutic use
- Abstract
Acanthamoeba keratitis is a rare, yet sight-threatening corneal infection. Ocular infection does not appear to induce protective immunity as repeated corneal infections occur in both humans and experimental animals. However, we have recently demonstrated that activation of the common mucosal immune system by oral immunization with Acanthamoeba antigens protects both Chinese hamsters and pigs against ocular infection with A. castellanii. Protection correlates closely with the appearance of anti- Acanthamoeba antibodies in the tears. To test the hypothesis that oral immunization induces specific protective IgA antibodies, two monoclonal IgA antibodies specific for Acanthamoeba antigens were generated. Both antibodies detected epitopes on the surface of fixed Acanthamoeba trophozoites. When delivered intraperitoneally, one monoclonal antibody (14E4) was detected in stool and tear samples. This clone also protected naive animals against ocular challenge with Acanthamoeba trophozoites (43% infection rate compared to a 91% infection rate in animals receiving control IgA). In vitro functional studies showed that neither antibody induced encystment or directly killed Acanthamoeba trophozoites. However, both monoclonal anti- Acanthamoeba IgA antibodies produced a three-fold inhibition in the adherence of trophozoites to corneal epithelial cells in vitro. These data show that monoclonal anti- Acanthamoeba IgA antibodies can protect against Acanthamoeba keratitis and suggest that this occurs by inhibiting adhesion of the parasite to the corneal epithelium., (Copyright 1999 Academic Press.)
- Published
- 1999
- Full Text
- View/download PDF
20. The pathogenesis of Acanthamoeba keratitis.
- Author
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Niederkorn JY, Alizadeh H, Leher H, and McCulley JP
- Subjects
- Acanthamoeba growth & development, Animals, Cornea pathology, Humans, Mice, Acanthamoeba pathogenicity, Acanthamoeba Keratitis parasitology, Acanthamoeba Keratitis pathology
- Abstract
Free-living amoebae of the genus Acanthamoeba produce a progressive, blinding infection of the corneal surface. The pathogenesis of Acanthamoeba keratitis involves parasite-mediated cytolysis and phagocytosis of corneal epithelial cells and induction of programmed cell death. Acanthamoeba spp. elaborate a variety of proteases which may facilitate cytolysis of the corneal epithelium, invasion of the extracellular matrix, and dissolution of the corneal stromal matrix.
- Published
- 1999
- Full Text
- View/download PDF
21. Impact of oral immunization with Acanthamoeba antigens on parasite adhesion and corneal infection.
- Author
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Leher H, Kinoshita K, Alizadeh H, Zaragoza FL, He Y, and Niederkorn J
- Subjects
- Acanthamoeba Keratitis immunology, Administration, Oral, Animals, Cricetinae, Cricetulus, Enzyme-Linked Immunosorbent Assay, Epithelium, Corneal parasitology, Humans, Immunity, Mucosal, Intestinal Mucosa immunology, Swine, Tissue Adhesions immunology, Acanthamoeba immunology, Acanthamoeba Keratitis prevention & control, Antigens, Protozoan immunology, Immunization methods, Immunoglobulin A, Secretory immunology, Tears immunology
- Abstract
Purpose: To determine whether oral immunization mitigates ongoing Acanthamoeba castellanii corneal infections in pigs., Methods: Pigs were orally immunized with aqueous Acanthamoeba antigen mixed with cholera toxin (Ac-CT) or with saline, before or after ocular infection with A. castellanii. Mucosal secretions (i.e., tears and enteric wash) were tested for Acanthamoeba-specific IgA by enzyme-linked immunosorbent assay. Enteric washes were used as a source of IgA in assays measuring the binding of trophozoites to Chinese hamster corneal epithelial (CHCE) cells., Results: Pigs immunized with Ac-CT before ocular challenge with A. castellanii had significant anti-Acanthamoeba IgA antibody titers in their tears and enteric washes and were protected against ocular infection. Enteric washes from orally immunized pigs inhibited trophozoite binding to CHCE cells in vitro by more than 75%. By contrast, pigs immunized after corneal infections had been established displayed keratitis of the same severity and duration as that in control pigs. However, 80% of the orally immunized animals were resistant to rechallenge with Acanthamoeba-laden contact lenses, whereas none of the control animals was resistant., Conclusions: Oral immunization with Ac-CT protects against Acanthamoeba keratitis when administered before corneal challenge. However, delaying oral immunization until after corneal disease is established fails to mitigate keratitis. The appearance of parasite-specific tear IgA correlates with protection and may act by preventing the parasite's binding to the corneal epithelium.
- Published
- 1998
22. Mannose induces the release of cytopathic factors from Acanthamoeba castellanii.
- Author
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Leher H, Silvany R, Alizadeh H, Huang J, and Niederkorn JY
- Subjects
- Acanthamoeba Keratitis metabolism, Animals, Cells, Cultured, Culture Media, Conditioned pharmacology, Cytotoxins isolation & purification, Epithelial Cells parasitology, Epithelium, Corneal parasitology, Galactose metabolism, Galactose pharmacology, Lactose metabolism, Lactose pharmacology, Mannose metabolism, Phenylmethylsulfonyl Fluoride pharmacology, Acanthamoeba metabolism, Acanthamoeba pathogenicity, Acanthamoeba Keratitis parasitology, Cytotoxins metabolism, Mannose pharmacology
- Abstract
Acanthamoeba keratitis is a chronic inflammatory disease of the cornea which is highly resistant to many antimicrobial agents. The pathogenic mechanisms of this disease are poorly understood. However, it is believed that the initial phases in the pathogenesis of Acanthamoeba keratitis involve parasite binding and lysis of the corneal epithelium. These processes were examined in vitro, using Acanthamoeba castellanii trophozoites. Parasites readily adhered to Chinese hamster corneal epithelial cells in vitro; however, parasite binding was strongly inhibited by mannose but not by lactose. Although mannose prevented trophozoite binding, it did not affect cytolysis of corneal epithelial cells. Moreover, mannose treatment induced trophozoites to release cytolytic factors that lysed corneal epithelial cells in vitro. These factors were uniquely induced by mannose because supernatants collected from either untreated trophozoites or trophozoites treated with other sugars failed to lyse corneal cells. The soluble factors were size fractionated in centrifugal concentrators and found to be > or = 100 kDa. Treatment of the supernatants with the serine protease inhibitor phenylmethylsulfonyl fluoride inhibited most, but not all, of the cytopathic activity. These data suggest that the binding of Acanthamoeba to mannosylated proteins on the corneal epithelium may exacerbate the pathogenic cascade by initiating the release of cytolytic factors.
- Published
- 1998
- Full Text
- View/download PDF
23. Systemic immune response to Acanthamoeba keratitis in the Chinese hamster.
- Author
-
Van Klink F, Leher H, Jager MJ, Alizadeh H, Taylor W, and Niederkorn JY
- Subjects
- Animals, Antibody Formation immunology, Antigen-Presenting Cells immunology, Antigens, Protozoan immunology, Cell Movement, Cornea parasitology, Cricetinae, Cricetulus, Enzyme-Linked Immunosorbent Assay, Hypersensitivity, Delayed immunology, Immunity, Cellular immunology, Immunoglobulin G analysis, Langerhans Cells immunology, Acanthamoeba immunology, Acanthamoeba Keratitis immunology, Antibodies, Protozoan analysis, Cornea immunology
- Abstract
Recrudescence is a common and troubling feature of Acanthamoeba keratitis and suggests that corneal infection with this organism fails to stimulate the systemic immune apparatus. The present study examined the cell-mediated and humoral immune responses to Acanthamoeba keratitis in the Chinese hamster. Corneal infection with A. castellanii failed to induce either delayed-type hypersensitivity (DTH) or serum IgG antibody against parasite antigens. The failure to induce cell-mediated and humoral immunity did not result in anergy or tolerance since subsequent intramuscular (i.m.) immunization with parasite antigens elicited robust DTH and IgG antibody responses. The inability of corneal infections to induce primary cell-mediated immune responses was due to the absence of resident antigen-presenting cells in the central cornea because induction of Langerhans cell (LC) migration into the central cornea prior to infection with Acanthamoeba promoted the development of parasite-specific DTH. Although the presence of resident LC did not promote the development of a primary humoral immune response, subsequent i.m. immunization elicited heightened parasite-specific IgG antibody production which was indicative of an anamnestic response. Collectively, the results indicate that in the absence of resident antigen-presenting cells, corneal infection with Acanthamoeba fails to stimulate primary cell-mediated or humoral immunity. Induction of peripheral LC into the central corneal epithelium promotes the development of parasite-specific DTH, but does not exacerbate corneal disease.
- Published
- 1997
- Full Text
- View/download PDF
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