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1. Treatment Persistence of Apremilast Among Patients with Psoriatic Arthritis

Author

Haddad A, Stein N, Lavi I, Shynkar L, Bergman I, Feldhamer I, Cohen AD, Saliba W, and Zisman D

Subjects
psoriatic arthritis, drug persistence, therapy, apremilast, Medicine (General), R5-920
Abstract

Amir Haddad,1 Nili Stein,2 Idit Lavi,2 Lisa Shynkar,3 Irina Bergman,3,4 Ilan Feldhamer,5 Arnon Dov Cohen,5,6 Walid Saliba,2,4 Devy Zisman1,4 1Rheumatology Unit, Carmel Medical Center, Haifa, Israel; 2Department of Epidemiology, Clalit Health Services, Haifa, Israel; 3Internal Medicine Department, Carmel Medical Centre, Haifa, Israel; 4Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 5Chief Physician’s Office, Central Headquarters, Clalit Health Services, Tel Aviv, Israel; 6Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheba, IsraelCorrespondence: Amir Haddad, Rheumatology Unit, Carmel Medical Centre, 7 Michal Street, Haifa, Israel, Tel +972-4-8250486, Email Haddadamir@yahoo.com; Amirha3@clalit.org.ilIntroduction: Persistence in drug therapy reflects treatment effectiveness and tolerability. We aim to estimate the persistence of apremilast prescribed to patients with psoriatic arthritis (PsA) and to identify characteristics associated with treatment discontinuation in a real-world setting.Methods: Patients with PsA treated with apremilast from January 2016 were identified from a large health database and followed until medication stop date (using 3-months grace period), death or the end of observation period (June 2021). Demographic data, Charlson comorbidity index and concomitant and previous use of conventional and biologic DMARDs were extracted. The reasons for drug discontinuation were manually retrieved from patient charts. Time to discontinuation was estimated using survival analysis using Kaplan–Meier functions.Results: Overall, 568 PsA patients treated with apremilast were identified. The mean age was 55.3± 14.0 years, of whom 332 (58.5%) were females, 38.4% were obese (BMI> 30), 75.2% had a Charlson comorbidity index> 1, 24.1% were on concomitant treatment with methotrexate and 72.4% were biologic naïve. The median persistent period was 6.1,95% CI (5.2– 6.9) months in which only 16.9% remained persistent on apremilast. No difference was found with regard to age, sex, socioeconomic status, ethnicity and obesity between patients who were persistent compared to patients who discontinued apremilast. Concomitant treatment with methotrexate and prior history of biologic therapy did not affect drug persistency (log rank P=0.957 and 0.082, respectively). Causes for treatment discontinuation were due to lack of skin efficacy in 19.4%, lack of joint efficacy in 33.3%, combined skin and joint inefficacy at 2.3% and due to side effects in 24.1%.Conclusion: In this large observational retrospective cohort of patients treated with apremilast, a relatively low drug persistence was observed with 6-month and 1-year survival rates of 50.3% and 31.3%, respectively. Treatment discontinuation was mainly due to joint inefficacy, advocating for more studies for proper patient selection to assure treatment effectiveness and persistency.Plain language summery: This research aims to explore the role of apremilast in the real-world treatment landscape of Psoriatic Arthritis (PsA). The existing literature offers limited and inconclusive data regarding the persistence of apremilast in real-world settings. The outcomes of this investigation hold the potential to enhance patient selection criteria and establish treatment efficacy. Our study revealed that within this extensive observational cohort, apremilast exhibited relatively low levels of drug persistence. Discontinuation of treatment primarily stemmed from joint inefficacy, side effects, and inadequate improvement in skin symptoms. Notably, patient demographics, socioeconomic status, obesity, and the Charlson comorbidity index displayed no significant influence on treatment discontinuation. Intriguingly, concurrent use of methotrexate and prior utilization of biologics did not impact drug persistence either. These findings emphasize the need for further research aimed at refining patient selection protocols to ensure both treatment efficacy and prolonged persistence.Keywords: psoriatic arthritis, drug persistence, therapy, apremilast

Published
2023

2. Treatment with Ixekizumab Following Secukinumab Failure in Patients with Psoriatic Arthritis: Real-Life Experience from a Resistant Population

Author

Berman J, Furer V, Berman M, Isakov O, Zisman D, Haddad A, and Elkayam O

Subjects
secukinumab, ixekizumab, arthritis, psoriatic, duration of therapy, antibodies, monoclonal, humanized, psoriasis, Medicine (General), R5-920
Abstract

Julia Berman,1,2,* Victoria Furer,2,3,* Mark Berman,2,3 Ofer Isakov,1,2 Devy Zisman,4,5 Amir Haddad,4 Ori Elkayam2,3 1Department of Medicine ‘T’, Sourasky Medical Center, Tel Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Rheumatology, Sourasky Medical Center, Tel Aviv, Israel; 4Rheumatology Unit, Carmel Medical Center, Haifa, Israel; 5The Ruth and Bruce Rappaport Faculty of Medicine,Technion, Haifa, Israel*These authors contributed equally to this workCorrespondence: Julia Berman Email juliab@tlvmc.gov.ilObjective: To assess the clinical response to ixekizumab following secukinumab failure in patients with psoriatic arthritis.Methods: A retrospective multi-center observational study included psoriatic arthritis (PsA) patients with a history of treatment with secukinumab, further treated with ixekizumab. Primary endpoint was primary response to treatment (drug survival > 6 months); secondary endpoints were changes in disease activity indices from initiation of ixekizumab to 6 and 12 months later and overall drug survival.Results: Of 23 PsA patients, 86% (n = 20) received more than two TNF inhibitors (TNFi). Median secukinumab treatment time was 15 months (IQR 10– 21.5 months). Subsequently, 19 patients (83%) had a primary response to ixekizumab. Overall treatment duration during follow-up period for primary responders was 14 months (IQR 10– 20.5). Reasons for ixekizumab cessation were worsening psoriasis (27%), peripheral arthritis (27%), both (47%), worsening of axial disease (13%), and adverse events (6%). Articular disease indices including Disease Activity Index for Psoriatic Arthritis (DAPSA), tender joints count (TJC) and Simplified Disease Activity Index (SDAI) were significantly lower at 6 and 12 months (DAPSA 1.5– 2 levels reduction; p = 0.018 and 1– 1.5 levels reduction; p = 0.031, respectively; TJC − 2.16 [− 4.0, − 0.3]; p = 0.025 and − 1.69 [− 3.09, − 0.28]; p = 0.022, respectively; SDAI − 10.13 [− 16.4, − 3.8], p = 0.003 and − 12.2 [− 17.1, − 7.2], p = 0.0002, respectively). PASI75 at 6 and 12 months was achieved by 63% and 57%, respectively, and PASI100 at 6 and 12 months by 31% and 21%, respectively.Conclusion: Patients with resistant PsA, including inadequate response to secukinumab, demonstrated a good response to ixekizumab, albeit limited on time. Within class switch from secukinumab to ixekizumab may be a plausible therapeutic option in PsA patients following secukinumab failure.Keywords: secukinumab, ixekizumab, arthritis, psoriatic, duration of therapy, antibodies, monoclonal, humanized, psoriasis

Published
2021

3. High Body Mass Index is Associated with Shorter Retention of Tumor Necrosis Factor-Alpha Blocker Treatment in Rheumatoid Arthritis

Author

Elalouf O, Lidar M, Reitblat T, Zisman D, Balbir-Gurman A, Hakakian O, Mashiach T, Almog R, and Elkayam O

Subjects
tnf alpha, biologics, bmi, obesity, survival, Medicine (General), R5-920
Abstract

Ofir Elalouf,1,2 Merav Lidar,2,3 Tatiana Reitblat,4 Devy Zisman,5 Alexandra Balbir-Gurman,6 Odelia Hakakian,1 Tanya Mashiach,7 Ronit Almog,7 Ori Elkayam1,2 1Department of Rheumatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Rheumatology Unit, The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ramat Gan, Israel; 4Rheumatology Unit, Barzilai Medical Center, Ashkelon, Israel; 5Department of Rheumatology, Carmel Medical Center, Haifa, Israel; 6Rheumatology Institute; 7Epidemiology and Biostatistics Unit, Rambam Health Care Campus, Haifa, IsraelCorrespondence: Ofir ElaloufDepartment of Rheumatology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv, IsraelTel +972524262682Fax +97235422904Email ofire@tlvmc.gov.ilPurpose: To evaluate the association between body mass index (BMI) and tumor necrosis factor α (TNF-α) blockers retention in patients with rheumatoid arthritis (RA).Patients and Methods: This prospective cohort study analyzed data about patients with RA who initiated TNF blockers from the Israeli registry of inflammatory diseases from 2011 to 2019. Patients were grouped by BMI: normal (BMI < 24.9 kg/m2), overweight (BMI 25– 29.9 kg/m2), obese (BMI 30– 34.9 kg/m2) and morbid obese (BMI ≥ 35 kg/m2). Treatment cessation due to inefficacy was defined as an “event” and therapy with a drug above 3 months was defined as a “course.” Kaplan–Meier survival curve was used to describe drug survival. Event-free survival was calculated using Cox regression with a hazard ratio and confidence interval of 95%.Results: The final analysis included 521 RA patients (80% females) treated with etanercept, infliximab, adalimumab or golimumab. Eight hundred and eighteen treatment initiations were included in the final analysis, 334 (41%) in the normal weight group, 261 (32%) in the overweight, 144 (17%) in the obese and 79 (10%) in the morbid obesity group. Three hundred and twenty-six (40%) treatment initiations were with etanercept, 215 (26%) with adalimumab 197 (24%) with infliximab, and 80 (10%) with golimumab. BMI was inversely associated with drug survival. Morbid obese patients were more likely to discontinue treatment compared with normal weight patients HR 2.28 (95% CI 1.67– 3.10, p< 0.01). This association remained significant for each drug type (except for golimumab) in a subgroup analysis. Adalimumab switch rate was higher compared to etanercept with HR =1.51 (95% CI 1.20– 1.91, p< 0.01), no other significant differences were noted between the other drugs.Conclusion: Morbid obese RA patients have lower TNF-α blocker retention compared to normal weight patients.Keywords: TNF alpha, biologics, BMI, obesity, survival

Published
2021

4. Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double‐Blind, Placebo‐Controlled Trials

Author

Clowse, Megan EB, Wallace, Daniel J, Furie, Richard A, Petri, Michelle A, Pike, Marilyn C, Leszczyński, Piotr, Neuwelt, C Michael, Hobbs, Kathryn, Keiserman, Mauro, Duca, Liliana, Kalunian, Kenneth C, Galateanu, Catrinel, Bongardt, Sabine, Stach, Christian, Beaudot, Carolyn, Kilgallen, Brian, Gordon, Caroline, Batalov, A, Bojinca, M, Djerassi, R, Duca, L, Horak, P, Kolarov, Z, Milasiene, R, Monova, D, Otsa, K, Pileckyte, M, Popova, T, Radulescu, F, Rashkov, R, Rednic, S, Repin, M, Stoilov, R, Tegzova, D, Vezikova, N, Vitek, P, Zainea, C, East, Far, Baek, H, Chen, Y, Chiu, Y, Cho, C, Chou, C, Choe, J, Huang, C, Kang, Y, Kang, S, Lai, N, Lee, S, Park, W, Shim, S, Suh, C, Yoo, W, Armengol, H Avila, Zapata, F Avila, Santiago, M Barreto, Cavalcanti, F, Chahade, W, Costallat, L, Keiserman, M, Alcala, J Orozco, Remus, C Ramos, Roimicher, L, Abu‐Shakra, M, Agarwal, V, Agmon‐Levin, N, Kadel, J, Levy, Y, Mevorach, D, Paran, D, Reitblat, T, Rosner, I, Shobha, V, Sthoeger, Z, Zisman, D, Ayesu, K, Berney, S, Box, J, Busch, H, Buyon, J, Carter, J, Chi, J, Clowse, M, Collins, R, Dao, K, Diab, I, Dikranian, A, El‐Shahawy, M, Gaylis, N, Grossman, J, Halpert, E, Huff, J, Jarjour, W, Kao, A, Katz, R, Kennedy, A, Khan, M, Kivitz, A, Kohen, M, and Lawrence‐Ford, T

Subjects
Autoimmune Disease, Clinical Trials and Supportive Activities, Clinical Research, Lupus, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Inflammatory and immune system, Adult, Antibodies, Monoclonal, Humanized, Double-Blind Method, Female, Humans, Lupus Erythematosus, Systemic, Male, Severity of Illness Index, Treatment Outcome, EMBODY Investigator Group, Clinical Sciences, Immunology, Public Health and Health Services, Arthritis & Rheumatology
Abstract

ObjectiveEpratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double-blind, placebo-controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).MethodsPatients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double-stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG-2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day). BILAG-2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12-week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG-based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG-2004 score, no worsening in the BILAG-2004 score, SLEDAI-2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders.ResultsIn the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified.ConclusionIn patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Published
2017

5. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling

Author

Burdick, M D, Murray, L A, Keane, M P, Xue, Y Y, Zisman, D A, Belperio, J A, and Strieter, R M

Subjects
angiogenesis, chemokines, fibrosis
Abstract

Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase 11 trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-incluced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR- CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary Collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-incluced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.

Published
2005

6. AB1293 OMICRON BREAKTHROUGH INFECTIONS AMONG RITUXIMAB AND NON-RITUXIMAB TREATED PATIENTS WITH AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES: A MULTICENTER CONTROLLED STUDY

Author

Furer, V., primary, Eviatar, T., additional, Zisman, D., additional, Peleg, H., additional, Paran, D., additional, Levartovsky, D., additional, Kaufman, I., additional, Broyde, A., additional, Polachek, A., additional, Feld, J., additional, Haddad, A., additional, Gazitt, T., additional, Elias, M., additional, Hijaze, N., additional, Friedlander, Y., additional, and Elkayam, O., additional

Published
2023
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10. OP0177 IMMUNOGENICITY INDUCED BY TWO AND THREE DOSES OF THE BNT162B2 mRNA VACCINE IN PATIENTS WITH AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES AND IMMUNOCOMPETENT CONTROLS: A LONGITUDINAL MULTI-CENTER STUDY

Author

Furer, V., primary, Eviatar, T., additional, Peleg, H., additional, Hagin, D., additional, Freund, T., additional, Levartovsky, D., additional, Paran, D., additional, Kaufman, I., additional, Broyde, A., additional, Polachek, A., additional, Elalouf, O., additional, Feld, J., additional, Haddad, A., additional, Gazitt, T., additional, Elias, M., additional, Hijaze, N., additional, Kharouf, F., additional, Gertel, S., additional, Nevo, S., additional, Pel, S., additional, Zisman, D., additional, and Elkayam, O., additional

Published
2022
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11. POS1244 THE EFFECT OF SECUKINUMAB ON THE HUMORAL RESPONSE FOLLOWING TWO AND THREE DOSES OF THE BNT162b2 mRNA VACCINE IN PATIENTS WITH SPONDYLOARTHRITIS

Author

Elkayam, O., primary, Eviatar, T., additional, Peleg, H., additional, Paran, D., additional, Levartovsky, D., additional, Kaufman, I., additional, Broyde, A., additional, Elalouf, O., additional, Polachek, A., additional, Feld, J., additional, Haddad, A., additional, Gazitt, T., additional, Elias, M., additional, Hijaze, N., additional, Aassi, M., additional, Quebe-Fehling, E., additional, Alarcon, I., additional, Pel, S., additional, Zisman, D., additional, and Furer, V., additional

Published
2022
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12. POS1254 RISK FACTORS FOR SEVERE COVID-19 INFECTION AMONG PATIENTS WITH AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES (AIRD) AND THE IMPACT OF VACCINATIONS - AN ISRAELI, MULTI-CENTER EXPERIENCE

Author

Kharouf, F., primary, Eviatar, T., additional, Braun, M., additional, Pokroy-Shapira, E., additional, Brodavka, M., additional, Agmon-Levin, N., additional, Toledano, K., additional, Oren, S., additional, Lidar, M., additional, Amit Vazina, M., additional, Sabbah, F., additional, Tavor, Y., additional, Breuer, G., additional, Zisman, D., additional, Markovits, D., additional, Dagan, A., additional, Bishara Garzuzi, R., additional, Shifman, O., additional, Giryes, S., additional, Elias, M., additional, Feld, J., additional, Reitblat, T., additional, Gazit, T., additional, Hadad, A., additional, Elkayam, O., additional, Paran, D., additional, Mevorach, D., additional, Balbir-Gurman, A., additional, and Braun-Moscovici, Y., additional

Published
2022
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20. LB0003 IMMUNOGENICITY AND SAFETY OF THE BNT162b2 mRNA COVID-19 VACCINE IN ADULT PATIENTS WITH AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES AND GENERAL POPULATION: A MULTICENTER STUDY

Author

Furer, V., primary, Eviatar, T., additional, Zisman, D., additional, Peleg, H., additional, Paran, D., additional, Levartovsky, D., additional, Zisapel, M., additional, Elalouf, O., additional, Kaufman, I., additional, Meidan, R., additional, Broyde, A., additional, Polachek, A., additional, Wollman, J., additional, Litinsky, I., additional, Meridor, K., additional, Nochomovitz, H., additional, Silberman, A., additional, Rosenberg, D., additional, Feld, J., additional, Haddad, A., additional, Gazitt, T., additional, Elias, M., additional, Higazi, N., additional, Kharouf, F., additional, Shefer, G., additional, Sharon, O., additional, Pel, S., additional, Nevo, S., additional, and Elkayam, O., additional

Published
2021
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21. POS1217 THE PATTERN OF COVID 19 PANDEMIC AMONG PATIENTS WITH AUTOIMMUNE INFLAMMATORY RHEUMATIC DISEASES (AIIRD)

Author

Kharouf, F., primary, Eviatar, T., additional, Braun, M., additional, Pokroy-Shapira, E., additional, Brodavka, M., additional, Agmon-Levin, N., additional, Toledano, K., additional, Oren, S., additional, Lidar, M., additional, Tavor, Y., additional, Amit Vazina, M., additional, Sabbah, F., additional, Breuer, G., additional, Dagan, A., additional, Zisman, D., additional, Markovits, D., additional, Reitblat, T., additional, Giryes, S., additional, Mevorach, D., additional, Paran, D., additional, Elkayam, O., additional, Balbir-Gurman, A., additional, and Braun-Moscovici, Y., additional

Published
2021
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27. The comparative responsiveness of Hospital Universitario Princesa Index and other composite indices for assessing rheumatoid arthritis activity

Author

Gonzalez-Alvaro, Isidoro, Castrejon, Isabel, Carmona, Loreto, Dougados, M., Huizinga, T., Abu Shakra, M., Alberts, A., Alperi Lopez, M., Amital, H., Aringer, M., Aslanidis, S., Berenbaum, F., Bijlsma, H., Blanco Garcia, F. J., Bliddal, H., Borofsky, M., Brocq, O., Buldakov, S., Cantini, F., Carreno Perez, L., Chahade, W., Ciconelli, R., Codreanu, C., Dahlqvist, S. R., Damjanov, N., Diamantopoulos, A., Dimdina, L., Dimic, A., Dorokhov, A., Dubikov, A., Fadienko, G., Fano, N., Ferreira, G., Gabrielli, A., Gaffney, K., Gaudin, P., Gerlag, D. M., Gerli, R., Goncalves, C. R., Hansen, M. S., Hanvivadhanakul, P., Hoili, C., Hou, A., Hunter, J., Ilic, T., Ionescu, R., Kaine, J., Kakurina, N., Kamalova, R., Kelly, T., Knyazeva, L., Krumina, L., Kurthen, R., Lagrone, R. P., Lapadula, G., Lavrentjevs, V, Lawson, J. G., Lazic, Z., Lejnieks, A., Levy, Y., Lexberg, A., Mader, R., Mariette, X., Markovits, D., Mola, Martin E., Maugars, Y., Guarch, Maymo J., Mazurov, V., I, Mikkelsen, K., Vergles, Morovic J., Nabizadeh, S., Nanagara, R., Nasonov, E. L., Sarabia, Navarro F., Neumann, T., Novak, S., Olech, E., Oza, M., Paran, D., Parsik, E., Pegram, S., Suarez, Pombo M., Popova, T., Puechal, X., Raja, N., Ridley, D., Rosner, I, Rubbert-Roth, A., Rudin, A., Saraux, A., Saulite-Kandevica, D., Settas, L., Sfikakis, P., Sheeran, T., Sizikov, A., Stamenkovic, D., Stefanovic, D., Stolow, J. B., Tan, A. L., Tebib, J., Tishler, M., Tony, H. P., Troum, O. M., Uaratanawong, S., Ucar Angulo, E., Valenzuela, G., van der Laken, K., Van Laar, J., van Riel, P. L. C. M., Vasilopoulos, D., Veldi, T., Vinogradova, I, Vosse, D., Wassenberg, S., Weidmann, C., Weitz, M., Wollenhaupt, J., Xavier, R., Yakupova, S., Zagar, I, Zavgorodnaja, T., Zemerova, E., Zisman, D., Zonova, E., Camona, Loreto, Abasolo Alcazar, L., Alegre de Miguel, C., Andreu Sanchez, J. L., Aragon Diez, A., Balsa Criado, A., Batlle Gualda, E., Belmonte Serrano, M. A., Beltran Audera, J., Beltran Fabregat, J., Bonilla Hernan, G., Caro Fernandez, N., Casado, E., Cebrian Mendez, L., Corteguera Coro, M., Cuadra Diaz, J. L., Cuesta, E., Fiter Areste, J., Freire Gonzalez, M., Galindo Izquierdo, M., Garcia Meijide, J. A., Garcia Gomez, M. C., Gimenez Ubeda, E., Gomez Centeno, E., Gomez Vaquero, C., Gonzalez Fernandez, M. J., Gonzalez Gomez, M. L., Gonzalez Hernandez, T., Gonzalez-Alvaro, I, Gonzalez-Montagut Gomez, C., Grandal Delgado, Y., Gratacos Masmitja, J., Hernandez del Rio, A., Instxaurbe, A. R., Irigoyen Oyarzabal, M., V, Jimenez Palop, M., Juan Mas, A., Judez Navarro, E., Larrosa Padro, M., Lopez Longo, F. J., Loza Santamaria, E., Maese Manzano, J., Manero Ruiz, F. J., Mateo Bernardo, I, Mayordomo Gonzalez, L., Mazzucheli, R., Medrano San Idelfonso, M., Naranjo Hernandez, A., Pecondon Espanol, A., Peiro Callizo, E., Quiros Donate, J., Ramos Lopez, P., Rivera Redondo, J., Rodriguez Gomez, M., Rodriguez Lopez, M., Rosello Pardo, R., Sampedro Alvarez, J., Sanmarti Sala, R., Rey Rey, Santos J., Tena Marsa, X., Tenorio Martin, M., Torres Martin, M. C., Urena Garnica, I, Valdazo de Diego, J. P., Valls, M., Villaverde Garcia, V., Zarco Montejo, P., Zubieta Tabernero, J., Balsa, Alejandro, Sanmarti, Raimon, Cabezas, J. A., Cantalejo, M., Chamizo, E., Ciruelo, E., Corrales, A., Cruz, A., Diaz, C., Fiter, J., Freire, M. M., Galindo, M., Garcia de Vicuna, M. R., Gelman, S. M., Gonzalez Crespo, R., Gonzalez Fernandez, C., Gracia, A., Granados, J., Guzman, M. A., Irigoyen, M., V, Juan, A., Juanola, X., Laiz, A., Manero, F. J., Martinez, A., Martinez, F., Mata, C., Maymo, J., Navarro, F. J., Peiro, E., Perez, F., Perez, G., Perez, M., Pujol, M., Quiros, J., Ribas, B., Riera, M., Rivera, J., Rodriguez, J. M., Rosello, R., Tenorio, M., Toyos, F. J., ACT-RAY Study Grp, PROAR Study Grp, EMECAR Study Grp, Interne Geneeskunde, MUMC+: MA Reumatologie (9), and RS: CAPHRI - R3 - Functioning, Participating and Rehabilitation

Subjects
Male, medicine.medical_specialty, Science, humanos, Severity of Illness Index, RECOMMENDATIONS, VALIDATION, VARIABLES, ensayos clínicos como asunto, Arthritis, Rheumatoid, Cohort Studies, Internal medicine, Linear regression, Severity of illness, medicine, Humans, índice de gravedad de la enfermedad, estudios de cohortes, mediana edad, Clinical Trials as Topic, DISEASE-ACTIVITY MEASURES, Multidisciplinary, SCORES, business.industry, Arthritis, resultado del tratamiento, modelos lineales, Secondary data, Gold standard (test), Middle Aged, medicine.disease, Clinical trial, Treatment Outcome, Rheumatoid arthritis, Antirheumatic Agents, Cohort, Linear Models, Medicine, Female, GENDER, business, antirreumáticos, artritis, Cohort study
Abstract

Objective To evaluate the responsiveness in terms of correlation of the Hospital Universitario La Princesa Index (HUPI) comparatively to the traditional composite indices used to assess disease activity in rheumatoid arthritis (RA), and to compare the performance of HUPI-based response criteria with that of the EULAR response criteria. Methods Secondary data analysis from the following studies: ACT-RAY (clinical trial), PROAR (early RA cohort) and EMECAR (pre-biologic era long term RA cohort). Responsiveness was evaluated by: 1) comparing change from baseline (Delta) of HUPI with Delta in other scores by calculating correlation coefficients; 2) calculating standardised effect sizes. The accuracy of response by HUPI and by EULAR criteria was analyzed using linear regressions in which the dependent variable was change in global assessment by physician (Delta GDA-Phy). Results Delta HUPI correlation with change in all other indices ranged from 0.387 to 0.791); HUPI's standardized effect size was larger than those from the other indices in each database used. In ACT-RAY, depending on visit, between 65 and 80% of patients were equally classified by HUPI and EULAR response criteria. However, HUPI criteria were slightly more stringent, with higher percentage of patients classified as non-responder, especially at early visits. HUPI response criteria showed a slightly higher accuracy than EULAR response criteria when using Delta GDA-Phy as gold standard. Conclusion HUPI shows good responsiveness in terms of correlation in each studied scenario (clinical trial, early RA cohort, and established RA cohort). Response criteria by HUPI seem more stringent than EULAR's., Our study was supported by grants RD16/0012/0011 and PI14/00442 from the Ministerio de Economia y Competitividad (Instituto de Salud Carlos III; Spain) and cofunded by the Fondo Europeo de Desarrollo Regional (FEDER). Data from ACT-RAY clinical trial were kindly provided by Hoffmann-La Roche Ltd. No financial support was received from Hoffmann-La Roche Ltd Data from EMECAR and PROAR cohorts were provided by the Spanish Society of Rheumatology. No financial support was received from the Spanish Society of Rheumatology. None of these institutions played any role in the analysis or interpretation of data, nor were they involved in the writing of the manuscript. Roche and Sociedad Espanola de Reumatologia were involved in the collection of data from ACT-RAY, and EMECAR and PROAR, respectively. However, these funders had no role in study design, analysis, decision to publish, or preparation of the manuscript.

Published
2019

34. Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double-Blind, Placebo-Controlled Trials

Author

Clowse, Megan E. B, Wallace, Daniel J., Furie, Richard A., Petri, Michelle A., Pike, Marilyn C., Leszczyński, Piotr, Neuwelt, C. Michael, Hobbs, Kathryn, Keiserman, Mauro, Duca, Liliana, Kalunian, Kenneth C., Galateanu, Catrinel, Bongardt, Sabine, Stach, Christian, Beaudot, Carolyn, Kilgallen, Brian, Gordon, Caroline, Batalov, A., Bojinca, M., Djerassi, R., Duca, L., Horak, P., Kolarov, Z., Milasiene, R., Monova, D., Otsa, K., Pileckyte, M., Popova, T., Radulescu, F., Rashkov, R., Rednic, S., Repin, M., Stoilov, R., Tegzova, D., Vezikova, N., Vitek, P., Zainea, C., East, Far, Baek, H., Chen, Y., Chiu, Y., Cho, C., Chou, C., Choe, J., Huang, C., Kang, Y., Kang, S., Lai, N., Lee, S., Park, W., Shim, S., Suh, C., Yoo, W., Armengol, H. Avila, Zapata, F. Avila, Santiago, M. Barreto, Cavalcanti, F., Chahade, W., Costallat, L., Keiserman, M., Alcala, J. Orozco, Remus, C. Ramos, Roimicher, L., Abu Shakra, M., Agarwal, V., Agmon Levin, N., Kadel, J., Levy, Y., Mevorach, D., Paran, D., Reitblat, T., Rosner, I., Shobha, V., Sthoeger, Z., Zisman, D., Ayesu, K., Berney, S., Box, J., Busch, H., Buyon, J., Carter, J., Chi, J., Clowse, M., Collins, R., Dao, K., Diab, I., Dikranian, A., El Shahawy, M., Gaylis, N., Grossman, J., Halpert, E., Huff, J., Jarjour, W., Kao, A., Katz, R., Kennedy, A., Khan, M., Kivitz, A., Kohen, M., Lawrence Ford, T., Lawson, J., Levesque, M., Lowenstein, M., Majjhoo, A., Mcarthur, R., Mclain, D., Merrill, J., Murillo, A., Neucks, S., Niemer, G., Noaiseh, G., Parker, C., Pantojas, C., Pattanaik, D., Petri, M., Pickrell, P., Reveille, J., Roman Miranda, A., Rothfield, N., Sankoorikal, A., Sayers, M., Singhal, A., Snyder, A., Striebich, C., Vo, Q., von Feldt, J., Wallace, D., Wasko, M., Young, C., Adelstein, S., Hall, S., Littlejohn, G., Nicholls, D., Suranyi, M., Amoura, Z., Bannert, B., Behrens, F., Perez, L. Carreno, Chakravarty, K., Gonzales, F. Diaz, Davies, K., Doria, Andrea, Emery, P., Fernández Nebro, A., Govoni, M., Hachulla, E., Hellmich, B., Houssiau, F., Malaise, M., Margaux, J., Maugars, Y., Muñoz Fernández, S., Navarro, F., Ordi Ros, J., Pellerito, R., Pena Sagredo, J., Roussou, E., Schmidt, R. E., Ucar Angulo, E., Viallard, J. F., Westhovens, R., Worm, M., Yee, C. S., Nayiager, S., Reuter, H., Spargo, C., Bazela, B., Brzosko, M., Chudzik, D., Gasztonyi, B., Geher, P., Ionescu, R., Jeka, S., Kemeny, L., Kiss, E., Kotyla, P., Kovacs, L., Kovalenko, V., Kucharz, E., Kwiatkowska, B., Leszczynski, P., Levchenko, E., Lysenko, G., Majdan, M., Mihailov, C., Nalotov, S., Nedelciu, M., Pavel, M., Raskina, T., Rebrov, B., Rezus, E., Semen, T., Smakotina, S., Stanislavchuk, M., Stanislav, M., Szombati, I., Szucs, G., Udrea, G., Zajdel, J., Zon Giebel, A., Bonfiglioli, R., Bustamante, R., Klumb, E., Ramirez, G. Medrano, Neiva, C., Olguin, M., Gonzaga, J. Reyes, Scotton, A., Ayala, S. Sicsik, Ximenes, A., Sharma, R., Srikantiah, C., Aelion, J., Aranow, C., Baker, M., Chadha, A., Chao, J., Chatham, W., Chow, A., Clay, C., Cohen Gadol, S., Conaway, D., Denburg, J., Escalante, A., Espinoza, L., Fiechtner, J., Fortin, I., Fraser, A., Furie, R., Gladman, D., Goddard, D., Goldberg, M., Gonzalez Rivera, R., Gorman, J., Griffin, R., Haaland, D., Halter, D., Hemaiden, A., Hobbs, K., Joshi, V., Lim, S., Kalunian, K., Karpouzas, G., Khraishi, M., Lafyatis, R., Lidman, R., Lue, C., Mohan, M., Mease, P., Mehta, C., Mizutani, W., Nami, A., Nascimento, J., Neuwelt, C., Pappas, J., Pope, J., Porges, A., Roane, G., Rosenberg, D., Ross, S., Saadeh, C., Scoville, C., Sherrer, Y., Solomon, M., Surbeck, W., Valenzuela, G., Waller, P., Alten, R., Baerwald, C., Bienvenu, B., Bombardieri, S., Braun, J., Dival, L., Espinosa, G., Fernandez, I. Figueroa, Gomez Reino, J., Gordon, C., Hiepe, F., Hopkinson, N., Isenberg, D., Jacobi, A., Jorgensen, C., Guern, V. Le, Paul, C., Pego Reigosa, J. M., Heredia, J. Rodriguez, Rubbert Roth, A., Sabbadini, M., Schroeder, J., Schwarting, A., Spieler, W., Valesini, G., Wollenhaupt, J., Mendoza, A. Zea, and Zouboulis, C.

Subjects
humanized, adult, rheumatology, monoclonal, antibodies, monoclonal, humanized, double-blind method, female, humans, lupus erythematosus, systemic, male, severity of illness index, treatment outcome, immunology and allergy, immunology, systemic, Antibodies, Monoclonal, Humanized, Systemic Lupus Erythematosus, NO, Immunology and Allergy, Rheumatology, Immunology, Lupus Erythematosus, Systemic, antibodies, lupus erythematosus
Abstract

Objective Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE). Methods Patients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti–double‐stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI‐2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG‐2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5–60 mg/day). BILAG‐2004 grade A scores in the renal and central nervous system domains were excluded. Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12‐week dosing cycle, for 4 cycles. Patients across all 3 treatment groups also continued with their standard therapy. The primary end point was the response rate at week 48 according to the BILAG‐based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG‐2004 score, no worsening in the BILAG‐2004 score, SLEDAI‐2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications. Patients who discontinued the study medication were classified as nonresponders. Results In the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study. There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%). No new safety signals were identified. Conclusion In patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Published
2017

36. Authors’ reply

Author

Furer, V, primary, Zisman, D, additional, Pokroy-Shapira, E, additional, Molad, Y, additional, Elkayam, O, additional, and Paran, D, additional

Published
2017
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37. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism

Author

Agnelli, G, Berkowitz, S, Bounameaux, H, Büller, Hr, Cohen, A, Gallus, A, Lensing, Aw, Misselwitz, F, Haskell, L, Prins, Mh, Raskob, G, Schellong, S, Bauersachs, R, van Bellen, B, Boda, Z, Borris, L, Brenner, B, Brighton, T, Chlumsky, J, Davidson, B, Decousus, H, Eriksson, H, Jacobson, B, Kakkar, A, Kwong, Yl, Lee, Lh, Meijer, K, van der Meer, J, Minar, E, Monreal, M, Piovella, F, Sandset, Pm, Smith, M, Tomkowski, W, Verhamme, P, Wang, Y, Wells, P, Brandjes, D, Mac Gillavry, M, Otten, Hm, Carlsson, A, Laporte, S, Schulman, S, Gent, M, Turpie, A, Martinelli, I, Segers, A, Muhlhofer, E, Tewes, M, Trajanovic, M, Muller, K, Kim, C, Gebel, M, Benson, A, Pap, Af, Godrie, J, Horvat Broecker, A, Spadari, G, Peters Wulf, C, Roig, J, Baker, R, Bianchi, A, Blombery, P, Campbell, P, Carroll, P, Geraghty, R, Chong, B, Ramanathan, S, Archis, C, Coughlin, P, Salem, H, Crispin, P, Dean, M, Soni, R, Denaro, C, Kubler, P, Coghlan, D, Gan, Te, Tran, H, Coleman, C, Jackson, D, Khalafallah, A, Leahy, M, Leyden, M, Leyden, D, Sturtz, C, Mccann, A, Gibbs, H, Mcrae, S, Richards, B, Ward, C, Curnow, J, Baghestanian, M, Erdogmus, B, Samaha, E, Nikoupayan Mofrad, M, Hirschl, M, Sturm, W, Kirchmair, R, Marschang, P, Drexel, H, Mathies, R, Pilger, E, Brodmann, M, Weltermann, A, Buche, M, Demelenne, J, Gustin, M, Hainaut, P, Pothen, L, de Leersnyder, J, Motte, S, Schroë, H, Sprynger, M, Peerlinck, K, Delcroix, M, Vermassen, F, Verstraeten, P, Smet, V, Vossaert, R, Panico, M, Costa, C, Blondal, J, Kovacs, M, Rodger, M, Carrier, M, Wong, T, Bi, J, Chen, Z, Chen, R, Jing, Zc, He, J, Liu, C, Liu, S, Long, S, Ma, Y, Shao, Y, Wang, C, Yang, Yh, Xie, C, Xu, J, Ying, K, Zhihong, L, Hola, D, Jirat, S, Vitovec, M, Kovářová, K, Gilík, J, Dosál, J, Mandakova, E, Matoška, P, Podpera, I, Podperova, M, Spacek, R, Urbanova, R, Tuxen, C, Sukles, K, Pietila, K, Vesanen, M, Achkar, A, Agraou, B, Aquilanti, S, Rifaï, A, Berremili, T, Brisot, D, Brousse, C, Tarodo, P, Bura, A, Amid Lacombe, C, Malloizel, J, Boulon, C, Alavoine, L, Crestani, B, Mismetti, P, Buchmuller, A, Accassat, S, Elias, A, Elias, M, Emmerich, J, Ferrari, E, Guérin, T, Beaka, P, Lacroix, P, Szwebel, Ta, Benhamou, Y, de Maistre, E, Falvo, N, Mahe, I, Meneveau, N, Schiele, F, Meyer, G, Sanchez, O, Planquette, B, Mottier, D, Le Moigne, E, Couturaud, F, Parent, F, Pernod, G, Imbert, B, Elkouri, D, Dary, M, Queguiner, A, Quere, I, Galanaud, Jp, Roy, Pm, de Boisjolly Bonnefoi JM, Schmidt, J, Breuil, N, Heuser, S, Sevestre, Ma, Simoneau, G, Bergmann, Jf, Stephan, D, Trinh Duc, A, Gaillardou, A, Grange, C, Fassier, T, Wahl, D, Baron Von Bilderling, P, Kuhlencordt, P, Beyer Westendorf, J, Halbritter, K, Werth, S, Diehm, C, Lawall, H, Eifrig, B, Espinola Klein, C, Weisser, G, Giannitsis, E, Haering, Hu, Hasslacher, C, Herrmann, T, Hoffmann, U, Czihal, M, Horacek, T, Ibe, M, Bauer, A, Kieback, A, Landgraf, H, Lindhoff Last, E, Malyar, N, Petermann, W, Potratz, J, Ranft, J, Röcken, M, Pomper, L, Frommhold, R, Schwaiblmair, M, Berghaus, T, Taute, B, Lau, Yk, Tse, E, Olah, Z, Farkas, K, Kolossváry, E, Gurzó, M, Kis, E, Kovács, A, Landi, A, Lupkovics, G, Pecsvarady, Z, Riba, M, Sipos, G, Parakh, R, Sembiring, R, Barton, J, Goldstein, L, Gavish, D, Hoffman, R, Hussein, O, Inbal, A, Lishner, M, Elis, A, Lugassy, G, Varon, D, Zeltser, D, Rogowski, O, Steinvil, A, Zisman, D, Ageno, W, Ambrosio, G, Cattaneo, M, D'Angelo, A, Ghirarduzzi, A, Lotti, M, Pierfranceschi, Mg, Lodigiani, C, Palareti, G, Barone, M, Beltrametti, C, Porreca, E, Prandoni, Paolo, Spiezia, L, Quintavalla, R, Cho, Wh, Ha, Jw, Kim, Hs, Park, K, Sime, I, Miliauskas, S, Petrauskiene, R, Sathar, J, Beeker, A, Ten Cate, H, De Groot, M, Kamphuisen, P, Douma, R, Kooy, Mv, Coenen, J, Mäkelburg, A, Knol, M, Tichelaar, V, Harper, P, Knottenbelt, E, Ockelford, P, Young, L, Royle, G, Simpson, D, Chunilal, S, Ghanima, W, Foyn, S, Tveit, A, Abola, Mt, Adamiec, R, Gorski, P, Kloczko, J, Lewczuk, J, Nowak, M, Musial, J, Wronski, J, Ng, Hj, Adler, D, Becker, Jh, Ellis, G, Isaacs, R, Bloy, B, Allie, R, Eckstein, F, van Rensburg JH, Schmidt, S, Siebert, H, Zyl, L, Carrera, M, Del Campo, F, Diego, I, Garcia Bragado, F, Jiménez, D, Sánchez Álvarez, J, Redondo, M, Roman Sanchez, P, Villalta, J, Villegas Scivetti, M, Jonson, T, Tygesen, H, Lapidus, L, Ottosson, E, Själander, A, Asmis, L, Banyai, M, Heidemann, M, Baumgartner, I, Righini, M, Frank, U, Hayoz, D, Periard, D, Chang, Wt, Chiu, K, Wang, Ky, Weng, Zc, Angchaisuksiri, P, Pothirat, C, Rojnuckarin, P, Solis, J, Hunt, B, Luckit, J, Albrecht, C, Banish, D, Feinbloom, D, Botnick, W, Chen, D, Dexter, J, Ettinger, N, Gleeson, J, Jaffer, A, Joseph, S, Kennedy, M, Krell, K, Lavender, R, Lyons, R, Moll, S, Nadar, V, Darrow, K, Hardman, V, Rathbun, S, Rehm, J, Rodriguez Cintron, W, Stevens, K, Wright, P, Ramaswamy, M., ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, Other departments, Epidemiologie, MUMC+: KIO Kemta (9), RS: CAPHRI School for Public Health and Primary Care, Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Department of Epidemiology (MHP), Maastricht University [Maastricht], Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Service d'angiologie et d'hémostase (MR), Hôpital Universitaire de Genève, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Centre d'Investigation Clinique (CIC - Brest), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Pulmonary Embolism, Male, Vitamin K, Administration, Oral, Pulmonary Embolism/drug therapy/mortality, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Rivaroxaban, Edoxaban, Recurrence, Hemorrhage/chemically induced, 030212 general & internal medicine, Vitamin K/antagonists & inhibitors, Enoxaparin/adverse effects/therapeutic use, MESH: Treatment Outcome, MESH: Aged, ddc:616, MESH: Middle Aged, Hazard ratio, General Medicine, MESH: Follow-Up Studies, Vitamin K antagonist, MESH: Thiophenes, Middle Aged, Thrombosis, Morpholines/adverse effects/therapeutic use, 3. Good health, Pulmonary embolism, MESH: International Normalized Ratio, Treatment Outcome, Anesthesia, MESH: Administration, Oral, Administration, Combination, Apixaban, Drug Therapy, Combination, Female, MESH: Hemorrhage, medicine.drug, Oral, MESH: Enoxaparin, medicine.drug_class, Morpholines, Anticoagulants/adverse effects/therapeutic use, MESH: Morpholines, Hemorrhage, Thiophenes, MESH: Anticoagulants, 03 medical and health sciences, Drug Therapy, medicine, Humans, International Normalized Ratio, Enoxaparin, MESH: Kaplan-Meier Estimate, Aged, MESH: Humans, business.industry, MESH: Vitamin K, Anticoagulants, medicine.disease, MESH: Male, MESH: Recurrence, Regimen, MESH: Drug Therapy, Combination, chemistry, Thiophenes/adverse effects/therapeutic use, business, Pulmonary Embolism, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; BACKGROUND: A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. METHODS: In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS: Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. CONCLUSIONS: A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).

Published
2012
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40. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial

Author

King TE Jr, Albera, C, Bradford, Wz, Costabel, U, Hormel, P, Lancaster, L, Noble, Pw, Sahn, Sa, Szwarcberg, J, Thomeer, M, Valeyre, D, du Bois RM, INSPIRE Study Group, Agostini, Carlo, Allen, J, Anzueto, A, Behr, J, Bonnet, R, Buhl, R, Burge, S, Chan, A, Chan, C, Chanez, P, Chapman, J, Cordier, J, Covelli, H, Crimi, N, de Andrade, J, Delaval, P, Dromer, C, Egan, J, Enelow, R, Ettinger, N, Flaherty, K, Floreani, A, Frankel, S, Frost, A, Gibson, K, Glassberg, M, Gottfried, M, Harari, S, Helmersen, D, Hollingsworth, H, Horton, M, Jennings, J, Kallay, M, Lasky, J, Lee, A, Leonard, C, Lorch, D, Lynch, J, Mageto, Y, Mette, S, Millar, A, Morell Brotad, F, Müller Quernheim, J, Nathan, S, Noth, I, Padilla, M, Poletti, V, Raghu, G, Richeldi, L, Robbins, M, Rolf, J, Roman, J, Rosen, G, Rottoli, P, Saltini, C, Schaberg, T, Schaumberg, T, Scholand, M, Schönfeld, N, Sharma, S, Simonelli, P, Steele, M, Sussman, R, Tino, G, Vogelmeier, C, Wallaert, B, Wells, A, Wencel, M, Wesselius, L, Whelan, T, Wilcox, P, Wolters, P, Xaubet, A, and Zisman, D.

Subjects
Male, medicine.medical_specialty, Settore MED/10 - Malattie dell'Apparato Respiratorio, Injections, Subcutaneous, Vital Capacity, Placebo-controlled study, Kaplan-Meier Estimate, Placebo, Severity of Illness Index, Drug Administration Schedule, Pulmonary function testing, Injections, Idiopathic pulmonary fibrosis, Interferon-gamma, Double-Blind Method, Internal medicine, Pulmonary fibrosis, medicine, Humans, Aged, Analysis of Variance, Disease Progression, Europe, Exercise Test, Female, Idiopathic Pulmonary Fibrosis, North America, Proportional Hazards Models, Pulmonary Diffusing Capacity, Recombinant Proteins, Survival Rate, Treatment Failure, Medicine (all), Survival rate, business.industry, Subcutaneous, Hazard ratio, General Medicine, Interim analysis, medicine.disease, Surgery, business
Abstract

Summary Background Idiopathic pulmonary fibrosis is a fatal disease for which no effective treatment exists. We assessed whether treatment with interferon gamma-1b improved survival compared with placebo in patients with idiopathic pulmonary fibrosis and mild-to-moderate impairment of pulmonary function. Methods 826 patients with idiopathic pulmonary fibrosis were enrolled from 81 centres in seven European countries, the USA, and Canada. Patients were randomly assigned (double-blind) in a 2:1 ratio to receive 200 μg interferon gamma-1b (n=551) or equivalent placebo (n=275) subcutaneously, three times per week. Eligible patients were aged 40–79 years, had been diagnosed in the past 48 months, had a forced vital capacity of 55–90% of the predicted value, and a haemoglobin-corrected carbon monoxide diffusing capacity of 35–90% of the predicted value. The primary endpoint was overall survival time from randomisation measured at the second interim analysis, when the proportion of deaths had reached 75% of those expected by the study conclusion. This study is registered with ClinicalTrials.gov, number NCT00075998. Findings At the second interim analysis, the hazard ratio for mortality in patients on interferon gamma-1b showed absence of minimum benefit compared with placebo (1·15, 95% CI 0·77–1·71, p=0·497), and indicated that the study should be stopped. After a median duration of 64 weeks (IQR 41–84) on treatment, 80 (15%) patients on interferon gamma-1b and 35 (13%) on placebo had died. Almost all patients reported at least one adverse event, and more patients on interferon gamma-1b group had constitutional signs and symptoms (influenza-like illness, fatigue, fever, and chills) than did those on placebo. Occurrence of serious adverse events (eg, pneumonia, respiratory failure) was similar for both treatment groups. Treatment adherence was good and few patients discontinued treatment prematurely in either group. Interpretation We cannot recommend treatment with interferon gamma-1b since the drug did not improve survival for patients with idiopathic pulmonary fibrosis, which refutes previous findings from subgroup analyses of survival in studies of patients with mild-to-moderate physiological impairment of pulmonary function. Funding InterMune.

Published
2009

46. Systemic lupus erythematosus exacerbation following cessation of belimumab treatment.

Author

Furer, V, Zisman, D, Pokroy-Shapira, E, Molad, Y, Elkayam, O, and Paran, D

Subjects
*SYSTEMIC lupus erythematosus, *AUTOIMMUNE diseases, *BELIMUMAB, *TALL-1 (Protein), *CEREBROSPINAL fluid, *THERAPEUTIC use of monoclonal antibodies, *IMMUNOSUPPRESSIVE agents, *BRAIN, *HEMOLYTIC anemia, *PNEUMONIA, *LUPUS nephritis, *DISEASE remission, *SEVERITY of illness index, *PASSIVE euthanasia, *DISEASE progression
Abstract

Objectives: Belimumab has recently been approved for the treatment of systemic lupus erythematosus (SLE) refractory to standard therapy. Following one case of an SLE flare after cessation of belimumab, we hypothesized that this might lead to a rebound phenomenon and possible exacerbation of SLE.Method: Members of the Israeli Society of Rheumatology were contacted by e-mail and asked to report cases of an SLE flare following cessation of belimumab treatment.Results: Three cases of SLE patients who experienced a severe SLE flare following cessation of belimumab therapy were reported. In all cases, belimumab was given as treatment for active mucocutaneous manifestations and/or polyarthritis with improvement in all three patients, one of whom achieved disease remission. In all three cases, patients experienced a severe flare in previously uninvolved major organ systems, including one case of class IV lupus nephritis accompanied by a new-onset severe headache with elevated cerebrospinal fluid (CSF) protein and white matter lesions on brain magnetic resonance imaging (MRI), one case of severe pneumonitis and haemolytic anaemia, and one case of a systemic flare, fatigue, arthritis, and severe abdominal pain.Conclusions: Belimumab therapy has been shown to be beneficial in the management of active SLE, mostly in patients with mucocutaneous and musculoskeletal manifestations. We suggest a possible rebound effect following cessation of belimumab that could be due to an increase in B-cell activating factor (BAFF) levels and lead to a disease flare. Future assessment of BAFF levels in patients stopping belimumab therapy and clinical correlation may support this hypothesis. Further studies are needed to confirm this observation. [ABSTRACT FROM AUTHOR]

Published
2016
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47. CXCR3 ligands are augmented during the pathogenesis of pulmonary sarcoidosis

Author

Busuttil, A., primary, Weigt, S. S., additional, Keane, M. P., additional, Xue, Y. Y., additional, Palchevskiy, V., additional, Burdick, M. D., additional, Huang, C., additional, Zisman, D. A., additional, Fishbein, M., additional, Lynch, J. P., additional, Strieter, R. M., additional, Elashoff, R. M., additional, and Belperio, J. A., additional

Published
2009
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