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1. Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Author

Zayat, Ahmed, Machado, Ana Rita, Cuervo, Andrea, Mahto, Arti, Cubuk, Cankut, Rawlings, Charlotte, Mosanya, Chijioke, Buckley, Chris, Holroyd, Chris, Maskall, Debbie, Carlucci, Francesco, Thorborn, Georgina, Tan, Gina, Lliso-Ribera, Gloria, Rizvi, Hasan, Peel, Joanna, Fonseca, João Eurico, Isaacs, John, Ramírez, Julio, Meric de Bellefon, Laurent, Fossati-Jimak, Liliane, Githinji, Mary, Congia, Mattia, Millar, Neal, Purkayastha, Nirupam, Celis, Raquel, Seth, Rakhi, Hands-Greenwood, Rebecca, Landewé, Robert, Perniola, Simone, Alivernini, Stefano, Marcia, Stefano, Marini, Stefano, Kelly, Stephen, Romão, Vasco, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Warren, Louise, Jaworska, Edyta, Bombardieri, Michele, Lewis, Myles J, Humby, Frances, Pratt, Arthur G, Filer, Andrew, Gendi, Nagui, Cauli, Alberto, Choy, Ernest, McInnes, Iain, Durez, Patrick, Edwards, Christopher J, Buch, Maya H, Gremese, Elisa, Taylor, Peter C, Ng, Nora, Cañete, Juan D, Raizada, Sabrina, McKay, Neil D, Jadon, Deepak, Sainaghi, Pier Paolo, Stratton, Richard, Ehrenstein, Michael R, Ho, Pauline, Pereira, Joaquim P, Dasgupta, Bhaskar, Gorman, Claire, Galloway, James, Chinoy, Hector, van der Heijde, Désirée, Sasieni, Peter, Barton, Anne, and Pitzalis, Costantino

Published
2023
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2. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E. A., Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R., Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E., Hudson, Briana M., Warren, Sarah E., McKeigue, Paul M., Humby, Frances, Bombardieri, Michele, Barnes, Michael R., Lewis, Myles J., and Pitzalis, Costantino

Published
2022
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3. Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Author

Rivellese, Felice, primary, Nerviani, Alessandra, additional, Giorli, Giovanni, additional, Warren, Louise, additional, Jaworska, Edyta, additional, Bombardieri, Michele, additional, Lewis, Myles J, additional, Humby, Frances, additional, Pratt, Arthur G, additional, Filer, Andrew, additional, Gendi, Nagui, additional, Cauli, Alberto, additional, Choy, Ernest, additional, McInnes, Iain, additional, Durez, Patrick, additional, Edwards, Christopher J, additional, Buch, Maya H, additional, Gremese, Elisa, additional, Taylor, Peter C, additional, Ng, Nora, additional, Cañete, Juan D, additional, Raizada, Sabrina, additional, McKay, Neil D, additional, Jadon, Deepak, additional, Sainaghi, Pier Paolo, additional, Stratton, Richard, additional, Ehrenstein, Michael R, additional, Ho, Pauline, additional, Pereira, Joaquim P, additional, Dasgupta, Bhaskar, additional, Gorman, Claire, additional, Galloway, James, additional, Chinoy, Hector, additional, van der Heijde, Désirée, additional, Sasieni, Peter, additional, Barton, Anne, additional, Pitzalis, Costantino, additional, Zayat, Ahmed, additional, Machado, Ana Rita, additional, Cuervo, Andrea, additional, Mahto, Arti, additional, Cubuk, Cankut, additional, Rawlings, Charlotte, additional, Mosanya, Chijioke, additional, Buckley, Chris, additional, Holroyd, Chris, additional, Maskall, Debbie, additional, Carlucci, Francesco, additional, Thorborn, Georgina, additional, Tan, Gina, additional, Lliso-Ribera, Gloria, additional, Rizvi, Hasan, additional, Peel, Joanna, additional, Fonseca, João Eurico, additional, Isaacs, John, additional, Ramírez, Julio, additional, Meric de Bellefon, Laurent, additional, Fossati-Jimak, Liliane, additional, Githinji, Mary, additional, Congia, Mattia, additional, Millar, Neal, additional, Purkayastha, Nirupam, additional, Celis, Raquel, additional, Seth, Rakhi, additional, Hands-Greenwood, Rebecca, additional, Landewé, Robert, additional, Perniola, Simone, additional, Alivernini, Stefano, additional, Marcia, Stefano, additional, Marini, Stefano, additional, Kelly, Stephen, additional, and Romão, Vasco, additional

Published
2023
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6. Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Author

Humby, Frances, primary, Durez, Patrick, additional, Buch, Maya H, additional, Lewis, Myles J, additional, Bombardieri, Michele, additional, John, Christopher, additional, Rizvi, Hasan, additional, Warren, Louise, additional, Peel, Joanna, additional, Fossati-Jimack, Liliane, additional, Hands, Rebecca E, additional, Giorli, Giovanni, additional, Rivellese, Felice, additional, Cañete, Juan D, additional, Taylor, Peter C, additional, Sasieni, Peter, additional, Fonseca, João E, additional, Choy, Ernest, additional, and Pitzalis, Costantino, additional

Published
2022
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7. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, R4RA collaborative group, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, and R4RA collaborative group

Abstract

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Published
2022

8. Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Bombardieri, Michele, John, Christopher, Rizvi, Hasan, Warren, Louise, Peel, Joanna, Fossati-Jimack, Liliane, Hands, Rebecca E, Giorli, Giovanni, Rivellese, Felice, Cañete, Juan D, Taylor, Peter C, Sasieni, Peter, Fonseca, João E, Choy, Ernest, Pitzalis, Costantino, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Bombardieri, Michele, John, Christopher, Rizvi, Hasan, Warren, Louise, Peel, Joanna, Fossati-Jimack, Liliane, Hands, Rebecca E, Giorli, Giovanni, Rivellese, Felice, Cañete, Juan D, Taylor, Peter C, Sasieni, Peter, Fonseca, João E, Choy, Ernest, and Pitzalis, Costantino

Abstract

Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells).

Published
2022

9. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Author

Rivellese, Felice, Surace, Anna E A, Goldmann, Katriona, Sciacca, Elisabetta, Çubuk, Cankut, Giorli, Giovanni, John, Christopher R, Nerviani, Alessandra, Fossati-Jimack, Liliane, Thorborn, Georgina, Ahmed, Manzoor, Prediletto, Edoardo, Church, Sarah E, Hudson, Briana M, Warren, Sarah E, McKeigue, Paul M, Humby, Frances, Bombardieri, Michele, Barnes, Michael R, Lewis, Myles J, Pitzalis, Costantino, R4RA collaborative group, Taylor, PC, group, R4RA collaborative, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie

Subjects
Arthritis, Rheumatoid, Antirheumatic Agents, Biopsy, Antibodies, Monoclonal, Humans, General Medicine, Antibodies, Monoclonal, Humanized, Rituximab, General Biochemistry, Genetics and Molecular Biology, Biomarkers
Abstract

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.

Published
2021

10. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Rizvi, Hasan, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Mahto, Arti, Montecucco, Carlomaurizio, Lauwerys, Bernard, Ng, Nora, Ho, Pauline, Bombardieri, Michele, Romão, Vasco C, Verschueren, Patrick, Kelly, Stephen, Sainaghi, Pier Paolo, Gendi, Nagui, Dasgupta, Bhaskar, Cauli, Alberto, Reynolds, Piero, Cañete, Juan D, Moots, Robert, Taylor, Peter C, Edwards, Christopher J, Isaacs, John, Sasieni, Peter, Choy, Ernest, Pitzalis, Costantino, R4RA collaborative group, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Humby, Frances, Durez, Patrick, Buch, Maya H, Lewis, Myles J, Rizvi, Hasan, Rivellese, Felice, Nerviani, Alessandra, Giorli, Giovanni, Mahto, Arti, Montecucco, Carlomaurizio, Lauwerys, Bernard, Ng, Nora, Ho, Pauline, Bombardieri, Michele, Romão, Vasco C, Verschueren, Patrick, Kelly, Stephen, Sainaghi, Pier Paolo, Gendi, Nagui, Dasgupta, Bhaskar, Cauli, Alberto, Reynolds, Piero, Cañete, Juan D, Moots, Robert, Taylor, Peter C, Edwards, Christopher J, Isaacs, John, Sasieni, Peter, Choy, Ernest, Pitzalis, Costantino, and R4RA collaborative group

Abstract

Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab o

Published
2021

11. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial

Author

Humby, Frances, primary, Durez, Patrick, additional, Buch, Maya H, additional, Lewis, Myles J, additional, Rizvi, Hasan, additional, Rivellese, Felice, additional, Nerviani, Alessandra, additional, Giorli, Giovanni, additional, Mahto, Arti, additional, Montecucco, Carlomaurizio, additional, Lauwerys, Bernard, additional, Ng, Nora, additional, Ho, Pauline, additional, Bombardieri, Michele, additional, Romão, Vasco C, additional, Verschueren, Patrick, additional, Kelly, Stephen, additional, Sainaghi, Pier Paolo, additional, Gendi, Nagui, additional, Dasgupta, Bhaskar, additional, Cauli, Alberto, additional, Reynolds, Piero, additional, Cañete, Juan D, additional, Moots, Robert, additional, Taylor, Peter C, additional, Edwards, Christopher J, additional, Isaacs, John, additional, Sasieni, Peter, additional, Choy, Ernest, additional, Pitzalis, Costantino, additional, Thompson, Charlotte, additional, Bugatti, Serena, additional, Bellan, Mattia, additional, Congia, Mattia, additional, Holroyd, Christopher, additional, Pratt, Arthur, additional, Cabral da Fonseca, João Eurico, additional, White, Laura, additional, Warren, Louise, additional, Peel, Joanna, additional, Hands, Rebecca, additional, Fossati-Jimack, Liliane, additional, Hadfield, Gaye, additional, Thorborn, Georgina, additional, Ramirez, Julio, additional, and Celis, Raquel, additional

Published
2021
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13. The Global Prevalence of Strongyloides stercoralis Infection

Author

Buonfrate, Dora, primary, Bisanzio, Donal, additional, Giorli, Giovanni, additional, Odermatt, Peter, additional, Fürst, Thomas, additional, Greenaway, Christina, additional, French, Michael, additional, Reithinger, Richard, additional, Gobbi, Federico, additional, Montresor, Antonio, additional, and Bisoffi, Zeno, additional

Published
2020
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15. A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNFα-Blockade in Rheumatoid Arthritis Patients

Author

Nerviani, Alessandra, primary, Di Cicco, Maria, additional, Mahto, Arti, additional, Lliso-Ribera, Gloria, additional, Rivellese, Felice, additional, Thorborn, Georgina, additional, Hands, Rebecca, additional, Bellan, Mattia, additional, Mauro, Daniele, additional, Boutet, Marie-Astrid, additional, Giorli, Giovanni, additional, Lewis, Myles, additional, Kelly, Stephen, additional, Bombardieri, Michele, additional, Humby, Frances, additional, and Pitzalis, Costantino, additional

Published
2020
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16. O07 Randomised, open labelled clinical trial to investigate synovial mechanisms determining response: resistance to rituximab versus tocilizumab in RA patients failing TNF inhibitor therapy

Author

Humby, Frances C, primary, Lewis, Myles, primary, Durez, Patrick, primary, Buch, Maya H, primary, Bombardieri, Michele, primary, Rizvi, Hasan, primary, Rivellese, Felice, primary, Fossati, Liliane, primary, Hands, Rebecca, primary, Giorli, Giovanni, primary, John, Chris, primary, Mahto, Arti, primary, Kelly, Stephen, primary, Nerviani, Alessandra, primary, Montecucco, Carlomaurizio, primary, Lauwerys, Bernard, primary, Ng, Nora, primary, Thornborn, Georgina, primary, Romao, Vasco C, primary, Ho, Pauline, primary, Verschueren, Patrick, primary, Sainaghi, Pier Paolo, primary, Bellan, Mattia, primary, Bugatti, Serena, primary, Pratt, Arthur G, primary, Holyroyd, Christopher, primary, Congia, Mattia, primary, Thompson, Charlie, primary, Gendi, Nagui, primary, Dasgupta, Bhaskar, primary, Cauli, Alberto, primary, Reynolds, Piero, primary, Cañete, Juan, primary, Moots, Robert J, primary, Taylor, Peter C, primary, Edwards, Christopher, primary, Isaacs, John, primary, Sasieni, Peter, primary, Fonseca, João Eurico, primary, Choy, Ernest, primary, and Pitzalis, Costantino, primary

Published
2020
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21. THU0058 B CELL SYNOVITIS AND CLINICAL PHENOTYPES IN RHEUMATOID ARTHRITIS AT DIFFERENT DISEASE STAGES

Author

Rivellese, Felice, primary, Humby, Frances, additional, Bugatti, Serena, additional, Fossati-Jimack, Liliane, additional, Rizvi, Hasan, additional, Lucchesi, Davide, additional, Ribera, Gloria Lliso, additional, Nerviani, Alessandra, additional, Hands, Rebecca, additional, Giorli, Giovanni, additional, Frias, Barbara, additional, Jaworska, Edyta, additional, Goldmann, Katriona, additional, Lewis, Myles, additional, Manzo, Antonio, additional, Bombardieri, Michele, additional, and Pitzalis, Costantino, additional

Published
2019
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23. Tropheryma whipplei intestinal colonization in Italian and migrant population: a retrospective observational study

Author

Beltrame, Anna, primary, Ragusa, Andrea, additional, Perandin, Francesca, additional, Formenti, Fabio, additional, Fenollar, Florence, additional, Edouard, Sophie, additional, Laroche, Maureen, additional, Zavarise, Giorgio, additional, Doro, Francesco, additional, Giorli, Giovanni, additional, Raoult, Didier, additional, and Bisoffi, Zeno, additional

Published
2019
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24. Efficacy of ivermectin to control Strongyloides stercoralis infection in sheltered dogs

Author

Paradies, Paola, primary, Buonfrate, Dora, additional, Iatta, Roberta, additional, Iarussi, Fabrizio, additional, Giorli, Giovanni, additional, Palmieri, Vincenzo Ostilio, additional, Sasanelli, Mariateresa, additional, Perandin, Francesca, additional, Šlapeta, Jan, additional, Capogna, Antonio, additional, Otranto, Domenico, additional, and Bisoffi, Zeno, additional

Published
2019
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31. Tropheryma whippleiintestinal colonization in Italian and migrant population: a retrospective observational study

Author

Beltrame, Anna, Ragusa, Andrea, Perandin, Francesca, Formenti, Fabio, Fenollar, Florence, Edouard, Sophie, Laroche, Maureen, Zavarise, Giorgio, Doro, Francesco, Giorli, Giovanni, Raoult, Didier, and Bisoffi, Zeno

Abstract

Aim: To obtain the first molecular epidemiological survey of Tropheryma whippleiintestinal colonization in Italy. Materials & methods:Retrospective, observational study to assess the prevalence of T. whipplei, the causative agent of Whipple's disease, in stool samples (real-time PCR) of patients attending the Center for Tropical Diseases (Italy) and risk factors associated. Results:Overall prevalence was 6.9 (85/1240). The younger age group showed a significantly higher rate than older age group (12.7 vs 5.9, p  0.002). The prevalence was 4.9 for Italians and 9.3 for migrants (p  0.003). Among the latter, children less than 10 years had higher prevalence than older ones (17.3 vs 7.3, p  0.003). The young age, male gender and Giardia duodenalisand Entamoeba histolyticacoinfection were risk factors. Conclusion:Our study confirms an increased risk of acquiring T. whippleiinfection during childhood, under poor sanitary conditions.

Published
2019
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32. Occurrence, diagnosis and follow-up of canine strongyloidiosis in naturally infected shelter dogs.

Author

Iatta, Roberta, Buonfrate, Dora, Paradies, Paola, Cavalera, Maria Alfonsa, Capogna, Antonio, Iarussi, Fabrizio, Šlapeta, Jan, Giorli, Giovanni, Trerotoli, Paolo, Bisoffi, Zeno, and Otranto, Domenico

Subjects
PARASITIC diseases, POLYMERASE chain reaction, SEROLOGY, NEMATODES, MEDICINE
Abstract

Strongyloidiosis by Strongyloides stercoralis is a disease of increasing interest in human and animal medicine. The scientific knowledge on canine strongyloidiosis is hindered by the poor diagnostics available. To assess the most sensitive and specific diagnostic method, feces and blood from 100 shelter dogs were screened for S. stercoralis by coprological, molecular and serological tests. Thirty-six dogs (36%) scored positive to S. stercoralis by coprology (22.3% to Baermann) and/or 30% to real time-polymerase chain reaction (rt-PCR). According to two composite reference standards (CRS) based on all coprological methods and rt-PCR (first CRS) or in combination with serology (second CRS), the most sensitive test was IFAT (93.8%; CI 82.8–98.7), followed by rt-PCR (80.6%; 95% CI 64–91.8) and Baermann (60.6%; 95% CI 42.1–77.1). The inconsistent shedding of L1 during the 4-week follow-up in infected dogs suggests the importance of multiple faecal collections for a reliable diagnosis. A combination of serological and coprological tests is recommended for the surveillance and diagnosis of S. stercoralis infection in dogs. [ABSTRACT FROM AUTHOR]

Published
2019
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33. Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

Author

Humby F, Durez P, Buch MH, Lewis MJ, Bombardieri M, John C, Rizvi H, Warren L, Peel J, Fossati-Jimack L, Hands RE, Giorli G, Rivellese F, Cañete JD, Taylor PC, Sasieni P, Fonseca JE, Choy E, and Pitzalis C

Abstract

Background: Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20 + /B cells)., Design: The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor., Participants: Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population., Main Outcome Measures: The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of < 10.1, defined for simplicity as CDAI major treatment response (CDAI-MTR). Secondary outcomes included the assessment of CDAI response in the B-cell-rich cohort, in which the non-inferiority of rituximab compared with tocilizumab was evaluated. Safety data up to week 48 are reported., Results: In total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population ( n  = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group., Conclusion: To our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility., Trial Registration: Current Controlled Trials ISRCTN97443826., Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation ; Vol. 9, No. 7. See the NIHR Journals Library website for further project information., (Copyright © Queen’s Printer and Controller of HMSO 2022. This work was produced by Humby et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health and Care Research, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.)

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2022
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