Non–TNF-Targeted Biologic Vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients with Insufficient Response to A

ROC “BIOTHERAPY ROTATION OR CHANGE AFTER FIRST ANTI-TNF TREATMENT FAILURE FOR RHEUMATOID ARTHRITIS”

PHRC national 2009, HUS n°4507 N° EUDRACT: 2009-013482-26

Sponsor:

Hôpitaux Universitaires de Strasbourg 1, place de l’Hôpital, F-67 091 STRASBOURG cedex Phone: +33 (0)3 88 11 52 66 Fax: +33 (0)3 88 11 52 40 Email: [email protected]

Coordinating investigator:

Prof. Jacques-Eric GOTTENBERG On behalf of the General Director, Service de Rhumatologie Director of Clinical Research and Innovations Hôpital de Hautepierre Avenue Molière F-67098 STRASBOURG Cedex Phone: +33 (0)3 88 12 79 53 C. GEILLER Fax: +33 (0)3 88 12 81 50 Email: [email protected]

Head methodologist:

Prof. Philippe RAVAUD Département d’épidémiologie, biostatistiques et recherche clinique Hôpital CIC-EC Bichat INSERM U 738 (Modeles et méthodes de l’évaluation thérapeutique des maladies chroniques) APHP - Hôpital Bichat F-75018 Paris Email: [email protected]

1 Downloaded From: https://jamanetwork.com/ on 09/28/2021 LIST OF INVESTIGATORS

CENTER DEPARTMENT AND TELEPHONE EMAIL ADDRESS POSITION LAST and FIRST NAMES ADELI No. FAX ADDRESS Hôpitaux Universitaires de Strasbourg Coordinating Pr GOTTENBERG Jacques- Hôpital de Hautepierre jacques-eric.gottenberg@chru- 671097210 03 88 12 79 53 03 88 12 82 90 investigator Eric Service de Rhumatologie strasbourg.fr Avenue Molière 67098 STRASBOURG Cedex Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre Associate investigator Pr SIBILA Jean 671062743 03 88 12 79 54 03 88 12 8150 [email protected] Service de Rhumatologie Avenue Molière 67098 STRASBOURG Cedex Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre emmanuel.chatelus@chru- Associate investigator Dr CHATELUS Emmanuel 671085553 03 8812 81 15 03 88 12 81 50 Service de Rhumatologie strasbourg.fr Avenue Molière 67098 STRASBOURG Cedex Hôpitaux Universitaires de Strasbourg Hôpital de Hautepierre Associate investigator Dr SORDET Christelle 671093086 03 88 12 81 16 03 88 12 81 50 [email protected] Service de Rhumatologie Avenue Molière 67098 STRASBOURG Cedex

Hôpitaux Universitaires de 9715 Strasbourg ADELI/RPPS Hôpital de Hautepierre Associate investigator CHIFFLOT Hélène 03 88 12 79 61 03 88 12 81 50 [email protected] No. being Service de Rhumatologie requested Avenue Molière 67098 STRASBOURG Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Centre Hospitalier de Mulhouse Hôpital Emile Muller Supervising associate 10003988358 Service de Rhumatologie Dr ARDIZZONE Marc 03 89 64 73 23 03 89 65 83 22 [email protected] investigator (rpps) 20 av du Dr René Laennec BP 1370 68070 MULHOUSE Cedex Centre Hospitalier de Mulhouse Hôpital Emile Muller Service de Rhumatologie Associate investigator Dr AFIF Naji 681042180 03 89 64 73 23 03 89 65 83 22 [email protected] 20 av du Dr René Laennec BP 1370 68070 MULHOUSE Cedex Hôpital Saint-Antoine Supervising associate Service de Rhumatologie Pr BERENBAUM Francis 751577990 01 49 28 25 20 01 49 28 25 13 [email protected] investigator 184 rue du Faubourg Saint Antoine 75012 PARIS Hôpital Saint-Antoine Service de Rhumatologie Associate investigator Dr SELLAM Jérémie 941147928 01 49 28 25 20 01 49 28 25 13 [email protected] 184 rue du Faubourg Saint Antoine 75012 PARIS CHU Nantes- Hôtel-Dieu 02 40 08 48 22 02 40 08 48 30 Supervising associate Service de Rhumatologie Dr BERTHELOT Jean-Marie 441054533 02 40 08 48 01 02 40 08 48 33 [email protected] investigator Rue Saint Herblain 02 40 08 48 25 02 40 08 48 34 44100 NANTES CHU de Limoges Supervising associate Service de Rhumatologie Pr BERTIN Philippe 87022919 05 55 05 64 68 05 55 05 68 89 [email protected] investigator 2, av Martin Luther King 87042 LIMOGES Cedex CHU de Limoges Dr DUFAURET-LOMBARD Service de Rhumatologie carine.dufauret-lombard@chu- Associate investigator 871033 106 05 55 05 68 55 05 55 05 68 89 Carine 2, av Martin Luther King limoges.fr 87042 LIMOGES Cedex CHU de Limoges Service de Rhumatologie 2, av Martin Luther King Associate investigator Dr BONNET Christine 871021630 05 55 05 64 68 05 55 05 68 89 [email protected] 87042 LIMOGES Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU de Limoges Dr VERGNE-SALLE Service de Rhumatologie pascale.vergne-salle@chu- Associate investigator 871026290 05 55 05 64 69 05 55 05 68 89 Pascale 2, av Martin Luther King limoges.fr 87042 LIMOGES Cedex CHU de Limoges Service de Rhumatologie Associate investigator Dr SIMON Anne 871035085 05 55 05 68 55 05 55 05 68 89 [email protected] 2, av Martin Luther King 87042 LIMOGES Cedex Hôpital de la Pitié Salpetrière,APHP Supervising associate Service de Rhumatologie 01 42 17 76 21 Pr FAUTREL Bruno 751605767 0142 17 77 55 [email protected] investigator 83 bd de l’Hôpital 01 42 17 76 20 75013 PARIS

Hôpital de la Pitié Salpetrière,APHP Service de Rhumatologie Associate investigator Dr BANNEVILLE Béatrice 921181814 01 42 17 76 24 01 42 17 77 55 [email protected] 83 bd de l’Hôpital 75013 PARIS

Hôpital de la Pitié Salpetrière,APHP Service de Rhumatologie Associate investigator Pr BOURGEOIS Pierre 751363557 01 42 17 78 01 01 42 17 78 02 [email protected] 83 bd de l’Hôpital 75013 PARIS Centre Hospitalier du Mans Supervising associate Service de Rhumatologie Dr DERNIS Emmanuelle 721028272 02 43 43 25 01 02 43 43 28 10 [email protected] investigator 194 avenue Rubillard 72037 LE MANS Cedex 9 Centre Hospitalier du Mans 02 43 43 26 54 Service de Rhumatologie Associate investigator Dr PUECHAL Xavier 721023638 (direct) 02 43 43 28 10 [email protected] 194 avenue Rubillard 02 43 43 26 56 72037 LE MANS Cedex 9 Centre Hospitalier du Mans Order No. 3078 ; Service de Rhumatologie Associate investigator Dr LASSALE Claire ADELI being 02 43 43 26 56 02 43 43 28 10 [email protected] 194 avenue Rubillard registered 72037 LE MANS Cedex 9 Centre Hospitalier du Mans Service de Rhumatologie Associate investigator ARTRU Laure 7210895000334114 02 43 39 94 39 [email protected] 194 avenue Rubillard 72037 LE MANS Cedex 9

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital Bichat Service de Rhumatologie Supervising associate 10000215227 Pr MEYER Olivier 46 rue Henri Huchard 01 40 25 74 00 01 42 29 06 88 [email protected] investigator (rpps) 75018 PARIS

Hôpital Bichat Service de Rhumatologie Associate investigator HAYEM Gilles 75 1 57232 2 46 rue Henri Huchard 75018 PARIS

Hôpital Bichat Service de Rhumatologie Associate investigator ROUX Fabienne 7566770 46 rue Henri Huchard 75018 PARIS

Hôpital Bichat Service de Rhumatologie Associate investigator BALLARD Magali 951118660 01 40 25 70 27 01 40 25 86 38 [email protected] 46 rue Henri Huchard 75018 PARIS C.H.U. de Grenoble HOPITAL SUD Supervising associate Service de Rhumatologie 04 76 76 72 23 Dr GILSON Mélanie 381090745 ème 04 76 49 61 75 [email protected] investigator 2 étage 04 76 76 54 58 Avenue de Kimberley – B.P. 338 38 434 Echirolles Cedex

C.H.U. de Grenoble HOPITAL SUD Service de Rhumatologie Associate investigator Pr GAUDIN Philippe 381053883 ème 04 76 76 51 36 04 76 76 56 02 [email protected] 2 étage Avenue de Kimberley – B.P. 338 38 434 Echirolles Cedex

C.H.U. de Grenoble HOPITAL SUD Service de Rhumatologie Associate investigator Dr GRANGE Laurent 381074087 ème 04 76 76 73 72 04 76 76 56 02 [email protected] 2 étage Avenue de Kimberley – B.P. 338 38 434 Echirolles Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital de la Conception, APHM Hôpital de Jour Pluridisciplinaire / Supervising associate 04 91 38 35 87 Pr GUIS Sandrine 131175796 Service de Rhumatologie 04 91 38 22 75 [email protected] investigator 04 42 96 36 18 147 Bd Baille 13005 MARSEILLE Centre d'Investigation Clinique Hôpital de la Conception Associate investigator Dr MORANGE Sophie 131148553 04 91 38 41 21 04 91 38 41 21 [email protected] 147 Bd Baille 13005 MARSEILLE Hôpital Ambroise Paré, AP-HP Supervising associate Service de Rhumatologie Pr BREBAN Maxime 921178778 01 49 09 56 72 01 49 09 58 65 [email protected] investigator 9 av. Charles de Gaulle 92100 BOULOGNE BILLANCOURT Hôpital Ambroise Paré, AP-HP 01 49 09 56 72 Service de Rhumatologie Associate investigator Pr LE PARC Jean-Marie 921054987 01 49 09 56 75 01 49 09 58 65 [email protected] 9 av. Charles de Gaulle 01 49 09 56 74 92100 BOULOGNE BILLANCOURT

Hôpital Lariboisière, AP-HP Supervising associate 10000376292 Service de Rhumatologie Pr LIOTE Frédéric 01 49 95 62 91 01 49 95 86 31 [email protected] investigator (rpps) 2, rue Ambroise Paré 75010 PARIS

Hôpital Lariboisière, AP-HP Service de Rhumatologie Associate investigator Dr OTTAVIANI Sebastien 751753716 2, rue Ambroise Paré 01 49 95 63 23 01 49 95 88 30 [email protected] 75010 PARIS

Hôpital Lariboisière, AP-HP Service de Rhumatologie 01 49 95 62 90 Associate investigator Dr RICHETTE Pascal 10001497592 01 49 95 88 30 [email protected] 2, rue Ambroise Paré 01 49 95 63 14 75010 PARIS

Hôpital Lariboisière, AP-HP Service de Rhumatologie 01 49 95 62 90 Associate investigator Dr ALLARD Anne 10004398334 01 49 95 86 31 [email protected] 2, rue Ambroise Paré 01 49 95 63 27 75010 PARIS

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital Lariboisière, AP-HP Service de Rhumatologie 01 49 95 88 25 Associate investigator Dr ORA Jeremy 10100025906 01 49 95 86 31 [email protected] 2, rue Ambroise Paré 01 49 95 63 24 75010 PARIS CHU de Nancy – Hopital Brabois Service de Rhumatologie Supervising associate Pr VALCKENAERE Isabelle 541056750 Rue du Morvan 03 83 15 32 03 03 83 15 31 90 [email protected] investigator 54511 VANDOEUVRE-LES-NANCY Cedex CHU de Nancy - Hôpital Brabois Service de Rhumatologie Associate investigator Pr LOEUILLE Damien 541059507 Rue du Morvan 03 83 15 31 90 03 83 15 31 90 [email protected] 54511 VANDOEUVRE-LES-NANCY Cedex CHU de Nancy - Hôpital Brabois Service de Rhumatologie Associate investigator GILL Ghislaine 541076436 Rue du Morvan 06 64 45 54 24 [email protected] 54511 VANDOEUVRE-LES-NANCY Cedex CHU de Nancy - Hôpital Brabois Service de Rhumatologie Associate investigator SAULIERE Norbert 541075818 Rue du Morvan 03 29 97 04 07 [email protected] 54511 VANDOEUVRE-LES-NANCY Cedex CHU de Nancy - Hôpital Brabois Service de Rhumatologie Associate investigator RAT Anne-Christine 541074050 Rue du Morvan 03 83 15 32 03 03 83 15 31 96 [email protected] 54511 VANDOEUVRE-LES-NANCY Cedex CHU de Caen Service de Rhumatologie Supervising associate Pr MARCELLI Christian 141035154 Avenue de la Côte Nacre 02 31 06 47 49 02 31 06 49 63 [email protected] investigator BP 95182 14033 CAEN Cedex 9

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU de Caen Service de Rhumatologie Associate investigator Dr DENIS Amélie 141049486 Avenue de la Côte Nacre 02 31 06 52 85 02 31 06 49 63 [email protected] BP 95182 14033 CAEN Cedex 9 CHU de Caen Service de Rhumatologie 10004408034 Associate investigator Dr LEON Nathalie Avenue de la Côte Nacre 02 31 06 47 46 02 31 06 49 63 [email protected] (rpps) BP 95182 14033 CAEN Cedex 9 CHU de Caen Service de Rhumatologie Associate investigator Dr SOUQUIERES Geneviève 14101613 9 Avenue de la Côte Nacre 02 31 06 47 46 02 31 06 49 63 [email protected] BP 95182 14033 CAEN Cedex 9 CHU de Caen Service de Rhumatologie Dr JEAN-JACQUES Pierre- Associate investigator 141031948 Avenue de la Côte Nacre 02 31 06 31 06 02 31 06 49 63 [email protected] Yves BP 95182 14033 CAEN Cedex 9 CHU de Caen Service de Rhumatologie Dr COURTHEOUX- 141022269 Associate investigator Avenue de la Côte Nacre 02 31 06 47 46 02 31 06 49 63 [email protected] LESTREHAN Françoise / 03341 BP 95182 14033 CAEN Cedex 9 CHU de Poitiers Hôpital de la Milétrie Supervising associate Dr SOLAU-GERVAIS Elisabeth 861033751 Service de Rhumatologie 05 49 44 44 65 05 49 44 38 59 [email protected] investigator 2 rue de la Milétrie BP 577 86021 POITIERS Cedex CHU de Poitiers Hôpital de la Milétrie Associate investigator Pr DEBIAIS Françoise 861018075 Service de Rhumatologie 05 49 44 44 65 05 49 44 38 59 [email protected] 2 rue de la Milétrie BP 577 86021 POITIERS Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU de Besançon Hôpital Jean Minjoz Supervising associate Pr WENDLING Daniel 251018503 Service de Rhumatologie 03 81 66 82 41 03 81 66 86 86 [email protected] investigator 3 Bd Alexandre Fleming 25000 BESANCON CHU de Besançon Hôpital Jean Minjoz Associate investigator Dr TOUSSIROT Eric 251029500 Service de Rhumatologie 03 81 66 82 41 03 81 66 86 86 [email protected] 3 Bd Alexandre Fleming 25000 BESANCON Groupe Hospitalier Diaconesses - Croix Saint-Simon Supervising associate Service de Médecine Interne et de Dr ZIZA Jean-Marc 75/000 672 8 01 44 64 16 00 01 44 64 33 37 [email protected] investigator Rhumatologie 125 rue d'Avron 75020 PARIS Groupe Hospitalier Diaconesses - Croix Saint-Simon 10001630267 Service de Médecine Interne et de Associate investigator Dr LAHALLE Sophie (rpps) 01 44 64 16 00 01 44 64 33 37 [email protected] Rhumatologie 125 rue d'Avron 75020 PARIS Groupe Hospitalier du Havre Hôpital J. Monod Supervising associate 10001904597 Service de Rhumatologie Dr ALCAIX Didier 02 32 73 33 78 02 32 73 33 79 [email protected] investigator (rpps) 5ème étage - aile 1 Avenue Pierre Mendes France 76290 MONTIVILLIERS Groupe Hospitalier du Havre Hôpital J. Monod 10003770624 Service de Rhumatologie Associate investigator Dr ZARNITSKY Charles 02 32 73 33 78 02 32 73 33 79 [email protected] (rpps) 5ème étage - aile 1 Avenue Pierre Mendes France 76290 MONTIVILLIERS Centre Hospitalier Jean Rougié Service de Rhumatologie et de Supervising associate Dr LASSOUED Slim 461007684 Rééducation Fonctionnelle 05 65 20 50 52 05 65 20 54 19 slim.lassoued@ch-cahors.fr investigator 335 rue du Président Wilson 46005 CAHORS Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Centre Hospitalier Jean Rougié Service de Rhumatologie et de Associate investigator Dr BILLEY Thierry 461008633 Rééducation Fonctionnelle 05 65 20 50 52 05 65 20 54 19 [email protected] 335 rue du Président Wilson 46005 CAHORS Cedex Centre Hospitalier Jean Rougié Service de Rhumatologie et de Associate investigator MOYANO Chantal 46 1 01269 2 Rééducation Fonctionnelle 05 65 20 50 50 05 65 20 50 51 [email protected] 335 rue du Président Wilson 46005 CAHORS Cedex Centre Hospitalier Départemental Les Oudairies Supervising associate 10002588027 Service de Rhumatologie Dr CORMIER Grégoire 02 51 44 61 97 02 51 44 63 79 [email protected] investigator (rpps) Bvd Stéphane Moreau 85925 LA ROCHE SUR YON Cedex

Centre Hospitalier Départemental Les Oudairies Service de Rhumatologie Associate investigator Dr VARIN Stéphane 851028878 02 51 44 61 97 02 51 44 63 79 [email protected] Bvd Stéphane Moreau 85925 LA ROCHE SUR YON Cedex

Centre Hospitalier Départemental Les Oudairies Service de Rhumatologie Associate investigator Dr TANGUY Gilles 85 1 01497 7 02 51 44 61 97 02 51 44 63 79 [email protected] Bvd Stéphane Moreau 85925 LA ROCHE SUR YON Cedex

Centre Hospitalier Départemental Les Oudairies Associate investigator Dr CAULIER Michel 85 10 21 61 8 Service de Rhumatologie 02 51 44 61 97 02 51 44 63 79 [email protected] Bvd Stéphane Moreau 85925 LA ROCHE SUR YON Cedex CHU de Nice Hôpital de l’Archet 1 Service de Rhumatologie Supervising associate Pr EULLER-ZIEGLER Liana 10003274635 151 Route Saint Antoine de 04 92 03 55 12 04 93 86 68 39 [email protected] investigator (rpps) Ginestière 06202 NICE Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU de Nice Hôpital de l’Archet 1 10003433678 Service de Rhumatologie Associate investigator Dr ROUX Christian 04 92 03 54 92 04 93 86 68 39 [email protected] (rpps) 151 Route Saint Antoine de Ginestière 06202 NICE Cedex CHU de Nice Hôpital de l’Archet 1 10003279980 Service de Rhumatologie Associate investigator Dr GRISOT Christian 04 92 03 54 99 04 92 03 90 18 [email protected] (rpps) 151 Route Saint Antoine de Ginestière 06202 NICE Cedex CHU de Nice Hôpital de l’Archet 1 Dr ALBERT-SABONNADIERE 10003435418 Service de Rhumatologie Associate investigator 04 92 03 54 77 04 92 03 90 18 [email protected] Christine (rpps) 151 Route Saint Antoine de Ginestière 06202 NICE Cedex CHU de Nice Hôpital de l’Archet 1 Service de Rhumatologie Associate investigator DASILVA Virginie 151 Route Saint Antoine de Ginestière 06202 NICE Cedex

Centre Hospitalier René Dubos Supervising associate Service de Rhumatologie 01 30 75 43 90 01 30 75 53 56 Dr PERTUISET Edouard 10003976239 [email protected] investigator 6 Avenue de l’Ile de France 01 30 75 42 38 01 30 75 53 51 95300 PONTOISE

Centre Hospitalier René Dubos CERF-PAYRASTRE Service de Rhumatologie Isabelle.cerf-payrastre@ch- Associate investigator 951101005 01 30 75 42 75 01 30 75 53 56 Isabelle 6 Avenue de l’Ile de France pontoise.fr 95300 PONTOISE Hôpital Jean Verdier, AP-HP Service de Médecine Interne Supervising associate Pr FAIN Olivier 931060677 Av 14 juillet 01 48 02 63 96 01 48 02 63 61 [email protected] investigator 93143 BONDY

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur – Centre Corresponding 10002859576 de Rhumatologie 05 67 77 17 56 [email protected] ; Pr CANTAGREL Alain 05.61.32.29.34 associate investigator (rpps) Place du Docteur Baylac 05 61 77 69 72 [email protected] TSA 40031 31059 TOULOUSE Cedex 9 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur – Centre 10002875630 de Rhumatologie Associate investigator Dr CONSTANTIN Arnaud (rpps) 05 61 77 69 76 05 61 77 73 75 [email protected] Place du Docteur Baylac TSA 40031 31059 TOULOUSE Cedex 9 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur – Centre RUYSSEN-WITRAND de Rhumatologie Associate investigator 311118491 05 61 77 76 77 05 61 77 73 75 [email protected] Adeline Place du Docteur Baylac TSA 40031 31059 TOULOUSE Cedex 9 CHU ROUEN – Hôpital Bois Guillaume RDC et 1er étage Supervising associate Pr VITTECOQ olivier 761101898 Pavillon de la Colombière 02 32 88 90 19 02 32 88 91 10 [email protected] investigator Service de Rhumatologie 147, avenue du Maréchal Juin 76230 BOIS GUILLAUME CHU ROUEN – Hôpital Bois Guillaume RDC et 1er étage Associate investigator Dr LE QUERRE Thierry 761114230 Pavillon de la Colombière 02 32 88 90 19 02 32 88 91 10 [email protected] Service de Rhumatologie 147, avenue du Maréchal Juin 76230 BOIS GUILLAUME Centre Hospitalier de Cannes Supervising associate Service de Rhumatologie 04 93 69 72 40 [email protected] Dr BOLLA Gilles 061083911 04 93 69 76 19 investigator 15, rue des Broussailles ou 41 06401 Cannes Centre Hospitalier de Cannes Service de Rhumatologie Associate investigator Dr ASQUIER Caroline 061089694 04 93 69 72 40 04 93 69 76 19 [email protected] 15, rue des Broussailles 06401 Cannes

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Centre Hospitalier de Cannes Service de Rhumatologie Associate investigator AZULAY Johanna 061083911 [email protected] 15, rue des Broussailles 06401 Cannes Hôpital Sud – Service de Rhumatologie Principal investigator Pr PERDRIGER Aleth 35 1 03806 2 02 99 26 71 40 02 99 26 71 90 aleth.perdriger@chu-rennes.fr 16 Bld de Bulgarie 35056 RENNES Hôpital Sud – Service de Rhumatologie Associate investigator Pr CHALES Gérard 35 1 01881 7 02 99 26 71 40 02 99 26 71 90 [email protected] 16 Bld de Bulgarie 35056 RENNES

Hôpital Sud – Service de Rhumatologie Associate investigator Pr GUGGENBUHL Pascal 35 1 04585 1 02 99 26 71 40 02 99 26 71 90 [email protected] 16 Bld de Bulgarie 35056 RENNES Hôpital Sud – Service de Rhumatologie Associate investigator Dr ALBERT Jean-David 35 1 05955 5 02 99 26 71 40 02 99 26 71 90 [email protected] 16 Bld de Bulgarie 35056 RENNES CHU Saint-Etienne Service de Rhumatologie Principal investigator Pr THOMAS Thierry 42 1034 075 0477127649 0477127577 [email protected] Hôpital Nord 42055 SAINT-ETIENNE cedex 2

CHU Saint-Etienne Service de Rhumatologie beatrice.pallotprades@chu-st- Associate investigator Dr PALLOT PRADES Béatrice 10003007324 04 77 12 76 64 0477127577 Hôpital Nord etienne.fr 42055 SAINT-ETIENNE cedex 2

CHU Henri Mondor Service de Rhumatologie 10001258895 Principal investigator Pr CLAUDEPIERRE Pascal 51, avenue du Maréchal de Lattre 01 49 81 47 04 01 49 81 47 03 [email protected] de Tassigny 94010 CRETEIL

CHU Henri Mondor Centre d’Investigation Clinique 01 49 81 37 90 Associate investigator Dr FERKAL Salah 94 11 38646 51, avenue du Maréchal de Lattre 01 49 81 37 97 [email protected] 01 49 81 37 81 de Tassigny 94010 CRETEIL

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU Chenevier-Mondor, APHP Service de Rhumatologie Associate investigator Dr FARRENQ Valérie 94 1 138 96 8 51 av du Maréchal de Lattre de 01 49 81 47 04 01 49 81 47 03 [email protected] Tassigny 94010 CRETEIL Polyclinique de Picardie 03 22 33 31 00 Centre de Rhumatologie Principal investigator Dr BOUMIER Patrick 10001823110 03 22 33 33 33 03 22 33 31 02 [email protected] 49 rue Alexandre Dumas (standard) 800094 AMIENS Cedex Polyclinique de Picardie Centre de Rhumatologie Associate investigator Dr DUCHE Agnès 801037920 03 22 33 31 00 03022 33 31 02 agnes,[email protected] 49 rue Alexandre Dumas 800094 AMIENS Cedex Centre Hospitalier de Belfort- Montbéliard 03 84 98 50 71 Principal investigator Dr BALBLANC Jean-Charles 90 100 603 1 Service de Rhumatologie 03 84 98 56 28 [email protected] 03 84 98 50 70 14 rue de Mulhouse 90000 BELFORT Cedex Centre Hospitalier de Belfort- Montbéliard Associate investigator Dr LOHSE Anne 901008268 Service de Rhumatologie 03 84 98 54 98 03 84 98 56 28 [email protected] 14 rue de Mulhouse 90000 BELFORT Cedex CHU de la Cavale Blanche Service de Rhumatologie Principal investigator Pr SARAUX Alain 291033025 02 98 34 72 67 02 98 49 36 27 [email protected] Boulevard Tanguy Pigent 29609 BREST Cedex CHU de la Cavale Blanche Pr JOUSSE-JOULIN Boulevard Tanguy Pigent Associate investigator 2904572 02 98 34 72 67 02 98 49 36 27 [email protected] Sandrine 29609 BREST Cedex

CHU de la Cavale Blanche valerie.devauchelle-pense@chu- Associate investigator Dr DEVAUCHELLE Valérie 291041986 Boulevard Tanguy Pigent 02 98 34 72 64 02 98 49 36 27 brest.fr 29609 BREST Cedex CHU Gabriel Montpied Service de Rhumatologie Principal investigator Pr SOUBRIER Martin 631036035 58 rue Montalembert BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] 63003 CLERMONT-FERRAND cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU Gabriel Montpied Service de Rhumatologie Associate investigator Dr DUBOST Jean-Jacques 631026952 58 rue Montalembert BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] 63003 CLERMONT-FERRAND cedex CHU de REIMS Hôpital Maison Blanche Service de Rhumatologie Principal investigator Pr ESCHARD Jean-Paul 511020695 03 26 78 43 90 03 26 78 79 39 [email protected] Pôle Locomoteur 45 rue Cognacq jay 51092 REIMS Cedex CHU de REIMS Hôpital Maison Blanche Dr GAGNEUX-LEMOUSSU Service de Rhumatologie Associate investigator 1000 17 38 037 03 26 78 43 73 03 26 78 45 50 [email protected] Laurence Pôle Locomoteur 45 rue Cognacq jay 51092 REIMS Cedex

CHU de REIMS Hôpital Maison Blanche Service de Rhumatologie Associate investigator Dr BROCHOT Pascal 1000 17 13 253 03 26 78 44 70 03 26 78 45 50 [email protected] Pôle Locomoteur 45 rue Cognacq jay 51092 REIMS Cedex

CHU de REIMS Hôpital Maison Blanche Service de Rhumatologie [email protected] Associate investigator Dr VAROQUIER Coralie 51 1 04756 5 03 26 78 43 73 03 26 78 45 50 Pôle Locomoteur [email protected] 45 rue Cognacq jay 51092 REIMS Cedex CHU Montpellier Immuno-Rhumatologie Thérapeutiques des maladies Principal investigator Pr JORGENSEN Christian 10003223319 osseuses et articulaires 04 67 33 77 96 04 67 52 38 42 [email protected] Hopital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU Montpellier Immuno-Rhumatologie Thérapeutiques des Rhumatismes Principal investigator Pr. MOREL Jacques Inflammatoires 04 67 33 87 10 04 67 33 73 11 [email protected] Hôpital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex CH St Philibert Service de Rhumatologie Principal investigator Dr LURASCHI Hélène 59 1 18 962 6 03 20 22 50 59 03 20 22 38 76 [email protected] Rue du grand but 59160 LOMME CH St Philibert Service de Rhumatologie Associate investigator Pr HOUVENAGEL Eric 59 1 11 816 1 03 20 22 50 59 03 20 22 38 76 [email protected] Rue du grand but 59160 LOMME APHM, CHU la Conception Service de Rhumatologie [email protected] Principal investigator Pr LAFFORGUE Pierre 1000 335 60 69 04 91 38 34 61 04 91 38 38 87 147 Bd Baille 13005 MARSEILLE Hôpital Bicêtre, Groupement Hospitalier Universitaire Sud, Principal APHP Pr MARIETTE Xavier 751493586 01 45 21 37 58 01 45 21 37 57 [email protected] investigator Service de Rhumatologie 78 rue du Général Leclerc 94275 LE KREMLIN BICETRE Polyclinique de Riaumont Principal Service de Rhumatologie Dr LEGRAND Jean-Louis 621075266 03 21 44 96 54 03 21 44 82 52 [email protected] investigator Avenue Entre deux Monts 62800 LIEVIN Centre Hospitalier Régional d'Orléans, Hôpital de la Source Principal Dr RIST Stéphanie 451037295 Service de Rhumatologie 02 38 74 40 14 02 38 74 40 12 [email protected] investigator 14, Avenue de l'Hôpital 45 067 Orléans cedex 2 Hôpitaux Civils de Colmar Service de Médecine Interne et Principal de Rhumatologie Dr MOREAU Paul 10002459666 03 89 12 41 34 03 89 12 46 91 [email protected] investigator 39 avenue de la Liberté 68024 COL MAR Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpitaux Civils de Colmar Service de Médecine Interne et Associate investigator MESSER Laurent 681042735 de Rhumatologie 03 89 12 41 34 03 89 12 46 91 [email protected] 39 avenue de la Liberté 68024 COLMAR Cedex Groupe Hospitalier Pellegrin- Tripode Thierry.schaverbek@chu- Principal investigator SCHAEVERBEKE Thierry 331085167 Service de Rhumatologie 05 56 79 55 56 05 56 79 60 84 bordeaux.fr Place Amélie Raba-Léon 33000 BORDEAUX Groupe Hospitalier Pellegrin- Tripode Associate investigator MEHSEN Nadia 10100046175 Service de Rhumatologie 05 56 79 49 54 05 56 79 60 84 [email protected] Place Amélie Raba-Léon 33000 BORDEAUX C.H.U. de Grenoble HOPITAL SUD Service de Rhumatologie 2ème Associate investigator Dr SUDRE Anne 631051661 04 76 76 72 23 04 76 49 61 75 [email protected] étage Avenue de Kimberley – B.P. 338 38 434 ECHIROLLES Cedex CHU Gabriel MONTPIED Servive de Rhumatologie Associate investigator Dr TOURNADRE Anne 441044955 58 rue Montalembert – BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] 63003 CLERMONT-FERRAND cedex

CHU Nantes- Hôtel-Dieu Service de Rhumatologie 1 Associate investigator Pr MAUGARS Yves 441054533 02 40 08 48 24 02 40 08 48 30 [email protected] place Alexis Ricordeau 44093 NANTES

CHU Nantes- Hôtel-Dieu Service de Rhumatologie 1 Associate investigator Dr GLEMAREC Joelle 59/1011866 6 02 40 08 48 24 02 40 08 48 30 [email protected] place Alexis Ricordeau 44093 NANTES

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital Roger Salengro Supervising Service de Rhumatologie Pr FLIPPO René-Marc 59/20458 1 03 20 44 61 20 03 20 44 61 10 rene-marc.flipo@chru-lille.fr investigator Boulevard Prof Emile Laine 59037 LILLE CEDEX

Hôpital Roger Salengro 5920371 Service de Rhumatologie Associate investigator Dr PHILIPPE Peggy ADELI No. 03 20 44 61 20 03 20 44 61 10 [email protected] Boulevard Prof Emile Laine being requested 59037 LILLE CEDEX

Hôpital Roger Salengro Service de Rhumatologie Associate investigator Dr WIBAUX Cécile 10100046175 03 20 44 61 20 03 20 44 61 10 [email protected] Boulevard Prof Emile Laine 59037 LILLE CEDEX

Hôpital Roger Salengro Service de Rhumatologie Associate investigator 591094172 03 20 44 61 20 03 20 44 61 10 [email protected] Dr POUYOL François Boulevard Prof Emile Laine 59037 LILLE CEDEX CHU de REIMS Hôpital Maison Blanche 514843 Service de Rhumatologie Associate investigator Dr Isabelle CHARLOT- ADELI No. 03 26 78 43 90 03 26 78 79 39 [email protected] Pôle Locomoteur LAMBRECHT being requested 45 rue Cognacq jay 51092 REIMS Cedex APHM, CHU la Conception Service de Rhumatologie Associate investigator 131176927 04 91 38 34 61 04 91 38 38 87 [email protected] Dr PHAM Thao 147 Bd Baille 13005 MARSEILLE

APHM, CHU la Conception Service de Rhumatologie Associate investigator 130783236 04 91 38 34 61 04 91 38 38 87 [email protected] Dr MERIC Jean-Camille 147 Bd Baille 13005 MARSEILLE

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital Jean Verdier, AP-HP 11470 Service de Médecine Interne Associate investigator ADELI No. 01 48 02 63 96 01 48 02 63 61 [email protected] Dr MEKINIAN Arsène Av 14 juillet being requested 93143 BONDY CHU Montpellier Service d’immuno-rhumatologie therapeutique Associate investigator 10003754917 04 67 33 77 96 04 67 52 38 42 [email protected] Dr COHEN Jean-David Hopital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex CHU Montpellier Service d’immuno-rhumatologie therapeutique Associate investigator 10003256459 04 67 33 77 96 04 67 52 38 42 [email protected] Dr FABRE Sylvie Hopital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex CHU Montpellier Service d’immuno-rhumatologie therapeutique Associate investigator 10100074045 04 67 33 77 96 04 67 52 38 42 [email protected] Dr PERS Jean-Marie Hopital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex CHU de Saint-Etienne Hôpital Nord Associate investigator 421052101 0477127649 0477127577 [email protected] Dr CHOPIN Florence Service de Rhumatologie 42055 Saint-Etienne cedex 2

CHU de Saint-Etienne Hôpital Nord amouzougan.adamah@chu-st- Associate investigator 421050816 0477127649 0477127577 Dr AMOUZOUGAN Adamah Service de Rhumatologie etienne.fr 42055 Saint-Etienne cedex 2

CHU de Poitiers Hôpital de la Milétrie Associate investigator Dr LOPPIN Elodie 86 10 3663 0 Service de Rhumatologie 05 49 44 44 65 05 49 44 38 59 [email protected] 2 rue de la Milétrie BP 577 86021 POITIERS Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU de Poitiers Hôpital de la Milétrie Associate investigator Dr BRAULT Rachel 867030245 Service de Rhumatologie 05 49 44 44 65 05 49 44 38 59 [email protected] 2 rue de la Milétrie BP 577 86021 POITIERS Cedex CHU de Poitiers Hôpital de la Milétrie Associate investigator Dr AZAÏS Isabelle 10002716644 Service de Rhumatologie 05 49 44 44 65 05 49 44 38 59 [email protected] 2 rue de la Milétrie BP 577 86021 POITIERS Cedex CHU Gabriel MONTPIED Servive de Rhumatologie Associate investigator Pr RISTORI Jean-Michel 631021 58 rue Montalembert – BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] 63003 CLERMONT-FERRAND cedex CHU Gabriel MONTPIED Servive de Rhumatologie Associate investigator Dr MATHIEU Sylvain 635824 58 rue Montalembert – BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] 63003 CLERMONT-FERRAND cedex CHU Gabriel MONTPIED Servive de Rhumatologie Dr MALOCHET – Associate investigator 58 rue Montalembert – BP 69 04 73 75 14 88 04 73 75 14 89 [email protected] GUINAMAND Sandrine 631049335 63003 CLERMONT-FERRAND cedex

Hôpital Roger Salengro Service de Rhumatologie Associate investigator Dr PACCOU Julien 20351 03 20 44 61 20 03 20 44 61 10 [email protected] Boulevard Prof Emile Laine 59037 LILLE CEDEX Hôpital Bicêtre, Groupement Hospitalier Universitaire Sud, APHP Associate investigator Dr DESMOULINS Frederic 10001063725 01 45 21 37 58 01 45 21 37 57 [email protected] Service de Rhumatologie 78 rue du Général Leclerc 94275 LE KREMLIN BICETRE

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Hôpital Bicêtre, Groupement Hospitalier Universitaire Sud, Associate investigator Dr PAVY Stephan 751688342 Service de Rhumatologie 01 45 21 37 58 01 45 21 37 57 [email protected] 78 rue du Général Leclerc 94275 LE KREMLIN BICETRE CHU Montpellier Service d’immuno-rhumatologie therapeutique Associate investigator Dr MOUTERDE Gaël 341125185 04 67 60 59 13 04 67 33 73 11 [email protected] Hopital Lapeyronie 371 Av du Doyen Gaston Giraud 34295 MONTPELLIER Cedex Hôpital de la Pitié Salpetrière, APHP Associate investigator Dr ROZENBERG Sylvie 75 16 82 584 Service de Rhumatologie 01 42 17 76 21 01 42 17 77 55 [email protected] 83 bd de l’Hôpital 75013 PARIS Hôpital de la Pitié Salpetrière, APHP Associate investigator Dr NICOLAS Nathalie 75 16 82 584 Service de Rhumatologie 01 42 17 76 21 01 42 17 77 55 [email protected] 83 bd de l’Hôpital 75013 PARIS Centre Hospitalier de Mulhouse Hôpital Emile Muller Service de Rhumatologie Associate investigator Dr DAHAN Etienne 681047361 03 89 64 73 20 03 89 65 83 22 [email protected] 20 av du Dr René Laennec BP 1370 68070 MULHOUSE Cedex Hôpital Bicêtre, Groupement Hospitalier Universitaire Sud, [email protected] Associate investigator Pr MICELI Corinne 941141608 Service de Rhumatologie 01 45 21 37 58 01 45 21 37 57 paris.fr 78 rue du Général Leclerc 94275 LE KREMLIN BICETRE Hôpital Bicêtre, Groupement Hospitalier Universitaire Sud, Associate investigator Dr SEROR Raphaele 10004417522 Service de Rhumatologie 01 45 21 37 58 01 45 21 37 57 [email protected] 78 rue du Général Leclerc 94275 LE KREMLIN BICETRE

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Institut Mutualiste Montsouris Supervising associate Service de Médecine Interne Dr GAYRAUD Martine 10000470475 01.56.61.67.24 01.56.61.67,29 [email protected] investigator 42 boulevard Jourdan 75674 PARIS cedex 14 Centre d'Investigation Clinique Hôpital de la Conception Dr IARMARCOVAI 147 Bd Baille Associate investigator 131211435 04 91 38 41 21 04 91 38 41 21 [email protected] Gwenaëlle Batiment Néphrologie - 3ème étage 13005 MARSEILLE CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur - Centre de Rhumatologie Associate investigator Dr JAMARD Benedicte 311101190 [email protected] Place du Docteur Baylac - TSA 05 61 77 69 72 05 61 32 29 34 40031 - 31059 TOULOUSE Cedex 9 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur - Centre de Rhumatologie Associate investigator Pr MAZIERES Bernard 311035240 [email protected] Place du Docteur Baylac - TSA 05 61 77 69 72 05 61 32 29 34 40031 - 31059 TOULOUSE Cedex 9 Centre Hospitalier Régional d'Orléans, Hôpital de la Source Associate investigator Dr LESPESSAILLES Eric 10002066982 Service de Rhumatologie 02 38 74 40 14 02 38 74 40 12 [email protected] 14, Avenue de l'Hôpital 45 067 ORLEANS cedex 2 Centre Hospitalier Régional d'Orléans, Hôpital de la Source Associate investigator Dr CORONDAN Anca 451038392 Service de Rhumatologie 02 38 74 40 14 02 38 74 40 12 [email protected] 14, Avenue de l'Hôpital 45 067 ORLEANS cedex 2 Groupe Hospitalier Pellegrin- Tripode Associate investigator Dr RICHEZ Christophe 3313454 Service de Rhumatologie 05 56 79 55 56 05 56 79 60 84 [email protected] Place Amélie Raba-Léon 33000 BORDEAUX

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Centre Hospitalier de Valence Rhumatologie - Département de Supervising associate 04 75 75 75 27 04 75 75 72 75 [email protected] investigator Dr COURET Marie 10002966538 médecine 179 Bd du Maréchal Juin 26953 VALENCE Cedex 9 Centre Hospitalier de Valence Rhumatologie - Département de Associate investigator Dr GIBERT Christelle 10003252607 médecine 04 75 75 75 27 04 75 75 72 75 [email protected] 179 Bd du Maréchal Juin 26953 VALENCE Cedex 9 Centre Hospitalier de Valence Rhumatologie - Département de Associate investigator Dr LEVEQUE-MICHAUD 10003109443 médecine 04 75 75 75 27 04 75 75 72 75 [email protected] Céline 179 Bd du Maréchal Juin 26953 VALENCE Cedex 9 Groupe Hospitalier Diaconesses Hôpital de la Croix Saint-Simon Service de Médecine Interne et Associate investigator 10005188924 01 44 64 33 68 01 44 64 33 37 [email protected] Dr BRAY Marie-Gaëlle de Rhumatologie 125 rue d'Avron 75020 PARIS CHU de REIMS - Hôpital Maison Blanche Service de Rhumatologie - Pôle Associate investigator 511049876 03 26 78 44 70 03 26 78 40 31 [email protected] Dr DIREZ Guillaume Locomoteur 45 rue Cognacq jay 51092 REIMS Cedex CHU de Saint-Etienne Hôpital Nord Associate investigator 1000404043898 04 77 12 76 43 04 77 12 75 77 [email protected] Dr MAROTTE HUBERT Service de Rhumatologie 42055 Saint-Etienne cedex 2

CHU de la Cavale Blanche Service de Rhumatologie Associate investigator Dr MARHADOUR Thierry 10005177976 02 98 34 72 67 02 98 49 36 27 [email protected] Boulevard Tanguy Prigent 29609 BREST Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur - Centre de Rhumatologie Associate investigator Dr ZABRANIECKI Laurent 3108807 05.61.77.69.77 05 61 32 29 34 [email protected] Place du Docteur Baylac - TSA 40031 - 31059 TOULOUSE Cedex 9 CHU Toulouse, Hôpital Purpan Pôle Institut Locomoteur - Centre de Rhumatologie Associate investigator Dr LAROCHE Michel 25/6546 05.61.77.69.77 05 61 32 29 34 [email protected] Place du Docteur Baylac - TSA 40031 - 31059 TOULOUSE Cedex 9 Service de Rhumatologie Hôpital de Hautepierre Associate investigator Dr THEULIN Arnaud 10374 03 88 12 81 16 03 88 12 81 50 [email protected] Avenue Molière 67098 STRASBOURG Cedex

Hôpital de Valence Dr LEVEQUE-MICHAUD Département de médecine Associate investigator 10003109443 04.75.75.75.27 04.75.75.72.75 [email protected] Céline 179 Boulevard Maréchal Juin 26953 VALENCE Cedex 9

Hôpital Jean Verdier, AP-HP 12077 (pending Service de Médecine Interne Associate investigator Dr LAOUBI Khaled 01 48 02 63 96 01 48 02 63 61 [email protected] ADELI No.) Av 14 juillet 93143 BOND

CHU de la Cavale Blanche Service de Rhumatologie Principal investigator Dr CORNEC Divi 6479 02 98 34 72 67 02 98 49 36 27 [email protected] Boulevard Tanguy Pigent 29609 BREST Cedex CHU Saint-Etienne Service de Rhumatologie Principal investigator Dr COLLET Philippe 3327 0477127649 0477127577 [email protected] Hôpital Nord 42055 SAINT-ETIENNE cedex 2

Downloaded From: https://jamanetwork.com/ on 09/28/2021 ASSOCIATED SCIENTIFIC TEAM

POSITION LAST NAME – FIRST CENTER DEPARTMENT AND PHONE FAX EMAIL ADDRESS (Statisticians, associate NAME ADDRESS researchers, etc…)

Département d’épidémiologie, biostatistiques et recherche clinique Hôpital CIC-EC Bichat Pr RAVAUD Philippe 01 40 25 79 31 - [email protected] Statistician INSERM U 738 APHP - Hôpital Bichat 75018 Paris

OTHER TECHNICAL PLATFORMS INVOLVED IN THIS STUDY

Name of the place Contact name Address of the place Phone / Fax Email address (ex: IGBMC, UCBEC, génopole, etc…) Nouvel Hôpital Civil Plateaux technique de biologie Dr Michèle BILLING-GRIMA 0369550785 / UCBEC UCBEC [email protected] 0369551891 1, place de l’hôpital 67091 STRASBOURG Cedex Centre de Ressources Biologiques/Tumorothèque Département de Pathologie 03.88.12.51.27 CRB Dr Agnès NEUVILLE [email protected] Hôpital de Hautepierre 03.88.12.70.52 CHU de Strasbourg 1 avenue Molière, 67098 STRASBOURG Cedex Faculté de Pharmacie UDS EA unit “Physiopathologie EA « Physiopathologie des Arthrites » 03 90 24 41 52 [email protected] / Pr Jacques-Eric GOTTENBERG / des Arthrites” 74 route du Rhin [email protected] Pr Dominique WACHSMANN B.P. 60024 67401 ILLKIRCH Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Laboratoire de Biochimie et de Biologie Moléculaire Laboratoire de Biochimie et Hôpital de Hautepierre 03.88.12.51.27 / Pr Pierre OUDET [email protected] de Biologie Moléculaire CHU de Strasbourg 03.88.12.70.52 1 avenue Molière, 67098 STRASBOURG Cedex

Downloaded From: https://jamanetwork.com/ on 09/28/2021 ABSTRACT

The anti-TNFs have revolutionized the treatment of rheumatoid arthritis (RA) treatment, with more than 28,000 patients currently treated in France. However, 10% of patients do not initially respond to anti-TNF therapy, and a loss in efficacy is observed in 10% of patients in each year of treatment. At the present time, a marketing authorization (AMM) has been granted to four molecules (infliximab, adalimumab, etanercept, and certolizumab), which makes switching to another anti- TNF molecule easy, in the event of treatment failure. The rotation of anti-TNF biotherapy appears effective in about 40 to 60% of patients, although no randomized studies have confirmed this claim. Moreover, no study has demonstrated the structural efficacy of a second anti-TNF agent following treatment failure or loss of response of initial anti-TNF therapy. In controlled trials, three other biotherapies, which do not target TNF, have proven effective in anti-TNF treatment failure cases: rituximab, abatacept, and tocilizumab. These biotherapies have already received the AMM in France for the indication of anti-TNF treatment failure. However, no randomized study has compared these biotherapies with an anti-TNF agent. Only observational data from Swiss and Swedish registers suggests that rituximab might have superior or similar efficacy when compared with anti-TNF rotation. In anti-TNF failure cases, the treatment strategy comprises two therapeutic alternatives: switching to another anti-TNF agent (rotation or “switch”) or initiating another biotherapy. Yet, no treatment strategy trial has compared these two options. This institutional study aims to compare these two strategies in a “pragmatic” trial in order to improve the “real life” management of the RA patients who do not sufficiently respond to an anti-TNF treatment.

Primary objective To compare the symptomatic efficacy of two treatment strategies (rotation of an anti- TNF treatment versus another non-anti-TNF biotherapy) in initial anti-TNF treatment failure cases.

Secondary objectives 1) To compare the structural efficacy of these two treatment strategies 2) To compare the safety of these two treatment strategies 3) To identify predictive factors for the treatment responses

Inclusion criteria

¾ Inclusion criteria for patients

• Adult patient suffering from RA according to the ACR 1987 criteria (4 of the 7 criteria must be met) (Appendix 2) • Presence of at least one erosion detected using conventional X-ray examination and/or ultrasonography and/or MRI • Patient responding insufficiently to 1 anti-TNF treatment (DAS28 3.2), regardless of whether this was linked to primary failure or loss of efficacy (loss of response) • Stable corticosteroid dosage 15mg/day of prednisone equivalent for at least 4 weeks prior to inclusion

Downloaded From: https://jamanetwork.com/ on 09/28/2021 • Stable dosage of background treatment (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, ciclosporin, or gold salts) for at least 4 weeks before inclusion • Written informed consent, dated and signed before initiating any trial-related procedure • Subject insured under the French social security system • Subject having been informed of the prior medical consultation findings

¾ Inclusion criteria for control subjects

• Healthy adult subject • Male or female • Subject insured under the French social security system • Subject having signed an informed consent form

Exclusion criteria

¾ Exclusion criteria for patients

• Major intolerance to the 1st anti-TNF • Prior treatment with 2 anti-TNFs • Prior treatment with abatacept, rituximab, or tocilizumab • Absolute contraindication to all the non-administered anti-TNFs and biological agents of other biotherapy families • No anti-tuberculosis prophylaxis (if necessary) • Patient who cannot be followed up during 12 months • Minors, adults under supervision or guardianship, or deprived of their liberty • Declared pregnancy • Breast-feeding

¾ Exclusion criteria for control subjects

-Pregnancy - Breast-feeding - Adults under law protection

Study design A multicenter, pragmatic, randomized, controlled, open-label study assessing the efficacy at 24 weeks of 2 treatment strategies: rotation of an anti-TNF treatment versus another non-anti-TNF biotherapy (rituximab, abatacept, or tocilizumab) in rheumatoid arthritis patients insufficiently improved by a first anti-TNF. Both strategies, using drugs that have been granted an AMM for anti-TNF treatment failure, are part of a standard treatment approach.

Number of subjects required The main analysis will focus on the comparison of the EULAR responses at 6 months between both groups. With a Type 1 risk set at 5%, enrolling 150 patients into each group will enable us to demonstrate an absolute decrease of 0.6 (i.e., odd ratio [OR] of 0.515), with an 80% power. Given that the rheumatology community

Downloaded From: https://jamanetwork.com/ on 09/28/2021 strongly believes in the relevance of this study to improve the treatment of RA, which is the most common inflammatory rheumatism in France, it is prepared to become fully involved and enroll the 300 patients required.

Study progression The enrollment period is of 36 months. Follow-up duration is 12 months with a total of 4 visits: inclusion visit and three follow-up visits at 3, 6, and 12 months.

Examinations required for the study This study includes a standard biological monitoring, as recommended for each biotherapy, as well as a standard radiographic follow-up (X-ray of hands and feet) at the time of inclusion and at 12 months.

DNA samples will be taken at inclusion, and serum and RNA samples at inclusion and at 6 months, for study purposes. In total, 10 healthy volunteers must be included. Only one blood sample of 2.5mL will be taken for these cases. In comparison with the patient samples, these control samples will allow us to analyze the predictive factors of treatment responses, based on certain messenger RNA expressions. In addition, control samples will also enable us to further develop quantitative real-time PCR analyses.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 CONTENT

LIST OF INVESTIGATORS ...... 2 ASSOCIATED SCIENTIFIC TEAM ...... 25 OTHER TECHNICAL PLATFORMS INVOLVED IN THIS STUDY ...... 25 1. Current knowledge and rationale ...... 32 1.1. A COMPLEX PATHOPHYSIOLOGY: A BETTER UNDERSTANDING OF THE DISEASE FOR A BETTER TREATMENT 3 2 1.1.1. RA, a condition resulting from the interaction between genetic and environmental factors ...... 32 1.1.2. The key role of pro-inflammatory cytokines: TNF-alpha, IL-1, IL-6, and IL-17 . 33 1.1.3. Role of T cells ...... 33 1.1.4. Role of B cells ...... 34 1.1.5. The role of other actors ...... 34 1.2. THE THERAPEUTIC MANAGEMENT PRINCIPLES IN 2009 ...... 34 1.2.1. Tight disease control is essential for articular prognosis: relevance of the activity measurement using the disease activity score (DAS) ...... 34 1.2.2. Tight control of disease activity limits extra-articular complications and improves patients’ prognosis ...... 35 1.2.3. The objectives of RA management in 2009 ...... 35 1.3. A THERAPEUTIC MANAGEMENT THAT IS ONLY PARTIALLY CODIFIED ...... 35 1.3.1. First-line treatment ...... 36 1.3.2. Treatment in the event of methotrexate failure: the anti-TNF-alpha revolution ... 36 1.4. AFTER ANTI-TNF-ALPHA FAILURE: WHAT SHOULD WE DO IN THE ABSENCE OF ANY CONTROLLED TRIAL? 37 1.4.1. The anti-TNF-alpha rotation ...... 37 1.4.2. Abatacept ...... 38 1.4.3. Rituximab (RTX) ...... 40 1.4.4. Tocilizumab ...... 41 1.5. WHY CONDUCT A CLINICAL TRIAL EVALUATING THE BEST STRATEGY IN ANTI-TNF TREATMENT FAILURE CASES? ...... 42 1.6. LACK OF A CONTROLLED TRIAL COMPARING THE USE OF BIOTHERAPIES IN THE EVENT OF ANTI-TNF TREATMENT FAILURE: A DELIBERATE CHOICE OF THE PHARMACEUTICAL INDUSTRY ...... 44 1.7. RESEARCH HYPOTHESES...... 44 1.7.1. Relevance of the question ...... 44 1.7.2. ROC, a representative study for French rheumatology clinical research ...... 45 1.7.3. Expected results ...... 45 1.7.4. Risk-benefit ratio ...... 46 2. Study objectives ...... 46 2.1. PRIMARY OBJECTIVE ...... 46 2.2. SECONDARY OBJECTIVES ...... 46 3. Methodological design of the study ...... 46 3.1. PRIMARY ENDPOINT ...... 46 3.2. SECONDARY ENDPOINTS ...... 47 3.3. EXPERIMENTAL DESIGN ...... 47 3.4. STUDY POPULATION ...... 47 3.4.1. Inclusion criteria ...... 47 3.4.2. Exclusion criteria ...... 48 3.4.3. Study drop-out and premature treatment or follow-up discontinuation ...... 48 3.5. PRACTICAL CONDUCT OF THE TRIAL...... 49 3.5.1. Study duration ...... 49 3.5.2. Subject recruitment method ...... 49 3.5.3. Informing patients and procedure for collecting consent ...... 50

Downloaded From: https://jamanetwork.com/ on 09/28/2021 3.5.4. Visits and examination schedule ...... 51 3.5.5. Biological sample collection ...... 53 3.5.6. Ancillary study “Qualisex” conducted by Prof. Aleth Perdriger ...... 55 3.5.7. Randomization ...... 55 3.6. INVESTIGATIONAL THERAPEUTIC STRATEGIES ...... 55 3.6.1. Therapeutic strategy: anti-TNF rotation ...... 55 3.6.2. Therapeutic strategy: other biotherapy ...... 55 3.6.3. Other treatments and medications that are authorized and non-authorized during the course of the study...... 56 3.6.4. Treatment failure and end of trial ...... 57 4. Safety evaluation – management of adverse events ...... 57 4.1. DEFINITIONS ...... 57 4.1.1. Adverse event ...... 57 4.1.2. Adverse effect ...... 57 4.1.3. Serious adverse event: ...... 57 4.1.4. New event ...... 58 4.1.5. Unexpected serious adverse effect ...... 58 4.1.6. Expected serious adverse effet ...... 58 4.2. PROCEDURES ...... 59 4.3. ESTABLISHMENT OF AN INDEPENDENT OVERSIGHT COMMITTEE ...... 59 5. Statistics ...... 59 5.1. CALCULATION OF THE REQUIRED NUMBER OF SUBJECTS ...... 59 5.2. STATISTICAL ANALYSES ...... 60 6. Right to access data and source documents ...... 61 7. Quality assurance and control ...... 61 7.1. DATA COLLECTION ...... 61 7.2. RESEARCH MONITORING ...... 62 7.3. ARCHIVING ...... 62 8. Ethical and regulatory considerations ...... 63 8.1. INDEPENDENT ETHICS COMMITTEE AND COMPETENT AUTHORITY ...... 63 8.2. SUBJECT INFORMATION AND CONSENT ...... 63 8.3. PROTECTION OF PERSONAL DATA ...... 63 8.4. INSURANCE ...... 64 9. Confidentiality and publication policy ...... 64 10. References ...... 65 11. Appendices ...... 69

Downloaded From: https://jamanetwork.com/ on 09/28/2021 1. Current knowledge and rationale

Rheumatoid arthritis (RA) is the most common inflammatory rheumatism, with a prevalence of about 0.3% of the general population in France [1]. A recent study conducted in the region of the Mayo Clinic showed that the RA incidence has increased over the last 10 years, as compared with preceding years [2]. RA mainly affects women aged 40 to 50, but may start at all ages and also occurs in men. This disease is therefore a serious public health problem due to its frequency, direct costs especially linked to the new immunomodulator treatments (8- 15,000 euros/patient/year), and indirect costs (sick leaves, invalidity declaration, etc.) [3].

1.1. A complex pathophysiology: a better understanding of the disease for a better treatment

1.1.1. RA, a condition resulting from the interaction between genetic and environmental factors

Over the last few years, much progress has been made in understanding the mechanisms of RA. RA can be considered as one of the most relevant interaction models between genetic and environmental factors. Regarding the genetic factors, the association of RA with certain HLA-DR1 and DR4 genotypes, which are encoding the “shared epitope” made up of common aminoacids, has been known for several years. More recently, this association has been shown to be actually limited to the subgroup of patients with anti-citrullinated protein antibodies (ACPA), an autoantibody family to which the anti-cyclic citrullinated protein antibodies (anti-CCP) belong. At the same time, it has been demonstrated that ACPAs precede by several years the onset of the first RA symptoms. The rheumatoid factor and/or ACPAs can therefore be detected more than 5 years prior to the first signs of the disease in 20% of patients. This HLA-ACPA combination suggests that the human leukocyte antigen (HLA) molecules make it possible to recognize not a specific auto-antigen, as it was thought for a long time, but a citrullinated antigen, whatever this antigen might be. In 2006, a Swedish team showed that tobacco acts in synergy with the genetic predisposition factors to facilitate autoantibody secretion [4]. Smoking and carrying predisposing HLA genes are indeed associated with a risk 21 times higher than that of the general population to secrete anti-CCP antibodies. Tobacco actually plays a role by promoting citrullination, as shown in the bronchial cells that were sampled during broncho-alveolar lavages in smoking patients. This association between tobacco and ACPAs is even dose-dependent, since the risk of exhibiting anti-CCP antibodies increases with the daily tobacco intake [5].

Thus, there are currently at least two nosological RA subgroups: - On the one hand, RAs with ACPAs in which genetic predisposition factors are related to HLA-DR1 and DR4, and PTPN22 gene polymorphism, and are promoted through tobacco consumption.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 - On the other hand, RAs with no autoantibodies in which genetic predisposition is linked to HLA- DR3 and to a gene involved in the interferon pathway, namely IRF-5.

1.1.2. The key role of pro-inflammatory cytokines: TNF-alpha, IL-1, IL-6, and IL-17

The complex network of pro-inflammatory cytokines involved in the RA pathophysiology comprises four main cytokines, namely TNF-alpha, IL-1, IL-6, and IL-17, which have been particularly well studied [6]. The overexpression of one or several of these cytokines (transgenic mouse overexpressing TNF-alpha, for instance) or their intra-articular injection may lead to arthritis in animals. These cytokines activate the main cells involved in the RA pathophysiology: osteoclasts, chondrocytes, endothelial cells, as well as innate and adaptive immune cells. Inhibition of these cytokines by monoclonal antibodies or a soluble receptor is effective in mice arthritis models. In RA patients, the synovial fluid levels and (sometimes) serum levels of these cytokines were shown to be increased. In controlled trials, the efficacy of the anti-TNFĮ treatments, of antibodies inhibiting the IL-6 receptor and, to a lesser extent, of the IL-1 receptor antagonist, has underlined the major pathogenic role of these cytokines. The inhibition of IL-17, along with that of T cells responsible for the secretion of this cytokine (Th17), is still being assessed in RA.

Regarding the TNF-alpha, the role of its membrane or soluble fraction probably varies with each condition. Both fractions are not targeted in the same way by each of the three anti-TNF molecules. Furthermore, two of these three treatments exhibit no inhibitory action on lymphotoxin, a cytokine also involved in the pathogenesis of RA. These various anti-TNF action mechanisms help explain the possible efficacy of another anti-TNF when administered following a first anti-TNF treatment failure. Even though TNF-alpha and IL-6 often display a synergistic action and induce their mutual expression in some experimental models, there are also arthritis models predominantly depending on one of these two cytokines. This may account for the efficay of the IL-6 receptor blockers in certain patients who do not sufficiently respond to anti-TNF treatments. This supports the rationale for initiating another biotherapy in these patients.

1.1.3. Role of T cells

Numerous arguments are in favor of a major role played by T cells in the RA pathophysiology. In the initial disease stage, the inflammatory infiltrate of the synovium is mainly made up of CD4+ T cells. Expression by T cells of co-stimulatory molecules, such as CD 28 and CTLA-4, is higher in patients with RA than healthy subjects and is correlated to disease activity. These T cells activate numerous other cells, like B cells, synoviocytes and osteoclasts, resulting in the secretion of inflammatory cytokines and metalloproteinases involved in osteoarticular destruction. The action of anti-TNF agents, which inhibit certain T cells expressing TNF-alpha on their surface, is therefore very different from that of abatacept, which inhibits the 2nd T cell co-stimulatory signal. This may account for the efficacy of abatacept in certain patients who insufficiently respond to anti-TNF treatments, thereby supporting the rationale for initiating another biotherapy in these patients.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 1.1.4. Role of B cells

B cells also play an essential role in the pathophysiology of RA that goes beyond simply synthesising autoantibodies (rheumatoid factors [RF]; ACPA). In addition, B cells are very good antigen-presenting cells. These cells also produce numerous pro-inflammatory cytokines, modulate the T cell repertoire, and co-stimulate them. B cells are found in the target tissue in the course of RA because they infiltrate the synovium and subchondral bone. Their activation appears to take place at an early disease stage, as suggested by the presence of autoantibodies (RF, ACPA) several years prior to the first symptoms onset. Similarly, the articular fluid level of Th2 cytokines (IL4, IL5, and IL13) that activate B cells was shown to be high within the first months of the disease [7]. Serum markers of B cell activation (immunoglobulin, immunoglobulin free light chain, and beta2-microglobulin levels) were reported to be high in recent-onset RA [8]. Very little is known regarding the action of anti-TNF agents on B cells. There may be patients in whom TNF-alpha or B cell activation plays a prevailing pathogenic role. This may account for rituximab efficacy in certain patients who insufficiently respond to anti-TNF treatments, thereby supporting the rationale for initiating another biotherapy in these patients.

1.1.5. The role of other actors

Numerous other cytokines (RANK-RANKL, IL21, IL32, etc.) and cells (synoviocytes, mast cells, neutrophil granulocytes, and other innate immune cells) appear to play a crucial role in the pathophysiology of RA. Each biotherapy (anti-TNF, abatacept, rituximab, or tocilizumab) likely targets these actors in a different way. To better understand the complex pathogenesis of RA, the initiating mechanisms and hierarchy of events leading to rheumatoid synovitis must still be elucidated. However, current knowledge concerning the main actors responsible for this synovitis enabled us to identify key treatment targets (cytokines and/or cells), which have resulted in very effective treatments. With the increasing number of treatment targets, there is now hope that treatment can be individualized for each patient by assigning the “right” molecule to the “right” patient (depending on the prevailing pathogenic mechanisms in this patient) and at the “right” time.

1.2. The therapeutic management principles in 2009

1.2.1. Tight disease control is essential for articular prognosis: relevance of the activity measurement using the disease activity score (DAS)

The patient’s prognosis, which is largely linked to the extent of bone and articular destruction, depends on both the rapidity of diagnosis and effectiveness of therapeutic management. This response capacity is therefore based on early diagnosis and standardized measurement of the disease activity. In current practice, this clinical activity is assessed using the DAS28 score, a clinical-biological composite index taking into account both subjective and objective criteria: number of tender and swollen joints, visual analog scale (VAS) of the disease activity according to the patient, sedimentation rate at 1st hour, or C-reactive protein levels. Numerous clinical trials exploring treatment strategies, such as the TICORA[9], CAMERA[10] or BEST studies [11], have shown that the regular clinical assessment using this score

Downloaded From: https://jamanetwork.com/ on 09/28/2021 and treatment adjustment in the event of persistent activity (DAS28 3.2) do slow down the radiographic progression (also called structural progression) in beginning arthritis. The extent of these destructions is closely linked to the patient’s functional impairment, which is assessed using the health assessment questionnaire (HAQ) score, and disability. By contrast, inadequate management, even when administered for just a few months, puts the patient at risk of long-term negative radiographic progression, as proven in the COBRA study [12]. Control of disease activity significantly improves patients’ quality of life, as well as their social and professional life, especially in all forms of beginning RA, but probably also in active forms, irrespective of the time of onset.

1.2.2. Tight control of disease activity limits extra-articular complications and improves patients’ prognosis

Systemic RA complications are related to the disease activity, and their frequency therefore increases with time since onset of RA. As a result, these complications are more common in RA patients resistant to anti-TNF treatment, often evolving over 5 to 10 years, in comparison with new-onset RA patients. Overall, 20 to 30% of patients therefore develop systemic complications, such as cardiovascular and pulmonary damage, vasculitis, amylose and lymphoma. It has recently been demonstrated that RA is a cardiovascular risk factor equivalent to Type II diabetes [12]. A decrease in cardiovascular mortality has been observed with methotrexate [13] and anti-TNF therapy [14]. Control of the disease activity therefore decreases the occurrence of extra-articular complications, which could improve the follow-up of the most severe RA forms.

1.2.3. The objectives of RA management in 2009

In 2009, the three objectives of RA management are: - To reduce the disease activity by achieving as far as possible a low disease activity level, or even remission - To block radiographic progression - To use corticosteroid therapy with the lowest possible dose levels.

Therefore, the ideal goal targeted by therapeutic management is to induce, as far as possible, remission (DAS28 <2.6), which is probably easier to achieve in recent- onset than older-onset RA. This can also be assessed by measuring the EULAR response (Appendix 1). An effective background treatment must not only significantly reduce the number of tender and swollen joints, as well as the biological inflammatory syndrome, but also include a decrease in or discontinuation of oral corticosteroid therapy and NSAIDs, as the morbidity (especially cardiovascular) associated with these treatments is significant.

1.3. A therapeutic management that is only partially codified

The recommendations made by the scientific societies and health authorities from different countries, such as the recent report of the French Haute Autorité de la Santé (HAS), have modified and standardized the individual practices.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 1.3.1. First-line treatment

Methotrexate at 0.3mg/Kg/week (15 to 25mg/week) is considered the first-line disease-modifying treatment, with leflunomide as a treatment alternative. Methotrexate efficacy must be assessed 3 months after therapy initiation. In some patients displaying, already at disease onset, very severe and devastating damage, a treatment with anti-TNF-alpha can be immediately prescribed, in combination with methotrexate.

1.3.2. Treatment in the event of methotrexate failure: the anti-TNF-alpha revolution

In the event of methotrexate failure, leflunomide therapy or triple combination therapy with methotrexate, sulfasalazine, and plaquenil may be considered. However, a recent controlled trial has demonstrated that a combination of these three disease- modifying therapies was significantly less effective than anti-TNF initiation [15]. In severe RA forms or in poor prognosis cases, a treatment with anti-TNF-alpha is generally initiated, provided that there are no contraindications.

Four anti-TNF-alphas are commonly used, including three monoclonal antibodies (infliximab, adalimumab, and certolizumab) and one soluble receptor (etanercept), with another molecule of this latter family undergoing clinical evaluation (golimumab). Depending on whether the anti-TNF used is a monoclonal antibody or soluble receptor, the mechanisms of action and safety profile (infusion-related reactions to the chimeric antibodies; lesser tuberculosis risk with soluble receptor) were shown to differ. To date, no efficacy study has directly compared the efficacy of these different anti-TNFs.

The development of anti-TNF therapy has represented a true therapeutic revolution for both patients and physicians, as a means to induce remission, to inhibit osteoarticular destruction, to restore a normal quality of life, and to resume professional activity. Their increasingly frequent use has been associated with practice standardization and improved structuring of patient care, along with the widespread use of the DAS28 score, implementation of patient registers in most countries, and distribution of recommendation sheets concerning the anti-TNF use (practical sheets of the Club Rhumatismes et Inflammation [CRI], for instance), particularly in certain everyday life situations (pregnancy, surgery, vaccination, etc.).

Nevertheless, initial anti-TNF efficacy has been reported in only 2/3 of patients, with efficacy loss observed in 10% of patients each year. Overall, about 30% of patients have been reported to discontinue their first anti-TNF therapy in the year it was initiated. As these drugs have been shown to be efficacious in recent-onset RA, HAS recommendations have allowed anti-TNFs to be used as first-line treatment in certain patients with poor prognosis factors. The use of anti-TNFs will therefore inevitably become widespread and could soon concern around 40 to 50% of RA patients in France. Due to the increasing frequency of patients with anti-TNF failure, this will

Downloaded From: https://jamanetwork.com/ on 09/28/2021 lead to a serious problem of therapeutic decision-making, as the management of patients with anti-TNF failure (primary failure or loss of response) is still uncodified.

1.4. After anti-TNF-alpha failure: what should we do in the absence of any controlled trial?

Despite anti-TNF-alpha agents being used for over 10 years, no controlled study has so far codified the management strategy for patients with anti-TNF treatment failure. In practice, two strategies are being used: anti-TNF-alpha rotation or initiation of a new biotherapy directed at another target. Regarding the anti-TNF-alpha rotation, data is exclusively derived from open studies or registers. Concerning the new biotherapies (abatacept, rituximab and tocilizumab), the use of each molecule in the anti-TNF failure setting has only been studied in one randomized trial, using a placebo-controlled design! For anakinra, only very few, small-sized, open-label studies are available, with no proven efficacy. The absence of any “face-to-face” comparison greatly impedes the identification of a relevant treatment strategy.

1.4.1. The anti-TNF-alpha rotation

- What is the rationale behind an anti-TNF rotation? The four anti-TNFs are administered by different routes (intravenously or subcutaneously), display differing pharmacokinetic properties, immunogenicities, and action mechanisms (monoclonal antibody, soluble receptor), and target different molecules (etanercept targets both TNF and lymphotoxin, another cytokine). These four anti-TNFs exhibit different affinity for membrane and soluble TNF receptors. For several years, on account of these differences, clinicians have tended to use a 2nd anti-TNF treatment following a first anti-TNF failure. The efficacy of this strategy, however, has only been assessed by means of registers and cohort studies, rather than controlled trials. Likewise, there is no study available assessing the structural progression in RA patients who have received a 2nd anti-TNF treatment. In the absence of data from randomized trials, and owing to a medical-economic analysis, the National Institute for Health and Clinical Excellence (NICE), the English health authority, has recently recommanded not to switch to another anti-TNF agent following a 1st anti-TNF treatment failure.

- Data derived from literature Several non-randomized studies have suggested the effectiveness of an anti-TNF rotation, with three French studies published to date. A trial conducted in Montpellier, involving 38 patients, revealed the benefits of switching to a 2nd anti-TNF agent (infliximab or etanercept) [16]. A study carried out in Nice reported the effectiveness of the anti-TNF rotation strategy in 32 patients, especially after failure of a single anti- TNF agent [17,18]. A further study conducted in Lille showed the effectiveness of switching from a monoclonal antibody to a soluble receptor, and conversely, in 45% of patients, along with non-effectiveness of administering a 3rd anti-TNF when

Downloaded From: https://jamanetwork.com/ on 09/28/2021 there was no response to a monoclonal antibody and to the soluble receptor [19]. Other similar open-label studies have been conducted in other countries, with comparable results.

The most comprehensive data is currently derived from registers, although it is well known that these registers are not primarily focused on efficacy analysis.

• The English register of the British Society for Rheumatology (BSR) evaluated the symptomatic efficacy of an anti-TNF rotation in 503 patients. After a 15- month follow-up, 74% of patients who had discontinued the first anti-TNF treatment on account of inefficacy responded to the 2nd anti-TNF treatment [20].

• Data from the Stockolm register (STURE) has revealed the benefits of an anti- TNF-alpha rotation [21;22]. The data from the Southern Sweden register revealed an EULAR response to the 2nd anti-TNF at 3 months in 71% of patients [23].

• In the Spanish BIOBADASER register, the therapeutic maintenance level of the 2nd anti-TNF agent was 79% at 1 year (versus 83% for the 1st anti-TNF agent) [24].

• Given its large sample size, the REACT study was one of the major studies designed to assess the rotation of anti-TNF treatments. This was an open-label study evaluating the safety of adalimumab in 6,610 patients. Overall, 899 of these patients had failed to respond or were intolerant to one (599 to infliximab; 188 to etanercept) or two anti-TNF treatments (120 patients) [25]. The reason for discontinuing the 1st anti-TNF treatment was known in 734 patients (544 for inefficiency; 199 for intolerance). An EULAR response at 12 weeks was observed in 78% and 79% of patients previously treated with infliximab or etanercept, respectively (26% and 21% of good EULAR responses, respectively), with an average decrease in DAS28 score of 2.0 points in each group (remission observed in 14% and 13% of patients, respectively). In patients who had primarily failed to respond to the 1st anti- TNF treatment, an EULAR response was observed in only 73% and 75% of patients, respectively. The rate of severe infections was 10.0/100 patients/year in patients previously treated with anti-TNF agents versus 4.0/100 patients/year in those without prior anti-TNF treatment.

• A study that has not yet been published suggests that golimumab, a new molecule of the anti-TNF family, is effective in patients who initially failed to respond to an anti-TNF treatment. This research therefore confirms the previous positive results obtained with the new anti-TNF agents.

1.4.2. Abatacept

• Mechanism of action Abatacept (Bristol Myers Squibb-BMS) is a fusion protein made of the extracellular domain of the human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to

Downloaded From: https://jamanetwork.com/ on 09/28/2021 a modified fragment of the Fc-portion of human immunoglobulin G1 (IgG1), which is therefore unable to bind to the complement. Abatacept selectively modulates a key co-stimulatory signal required for the full activation of the T cells that express CD28. The full activation of T cells requires two signals supplied by antigen-presenting cells: recognition of a specific antigen by the T cell receptor, the TCR (1st signal), and a second co-stimulatory signal. One of the main co-stimulatory pathways involves the binding of the CD80 and CD86 molecules on the surface of antigen-presenting cells to the CD28 receptor expressed on T cells (2nd signal). Abatacept selectively inhibits this co-stimulatory pathway by specifically binding to CD80 and CD86 of the CPAs, with higher affinity than CD28. As a consequence, abatacept mimics the physiological action of CTLA-4, which, by binding to CD80/86, delivers negative co- stimulatory signals.

• AMM of abatacept (2007) In France, abatacept was granted AMM approval for the indication of RA in May 2007. It is indicated, in combination with methotrexate, for the treatment of moderate to severe active RA in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one anti-TNF agent.

• ATTEST study data in patients who failed to respond to methotrexate This was the only study aimed to directly compare 2 biotherapies [26]. The trial involved patients who had insufficiently responded to methotrexate, using a three- arm study design, with patients receiving methotrexate + placebo, methotrexate + infliximab (3mg/Kg), or methotrexate + abatacept. The study’s conclusions were that both biotherapies were superior to placebo, and that abatacept’s efficacy and safety was potentially better to that of infliximab. However, in this study sponsored by the pharmaceutical industry (BMS), the sample size calculations made did not allow for a direct comparison between infliximab and abatacept.

• ATTAIN and ARRIVE study data in patients who failed to respond to the anti- TNF agents ¾ The ATTAIN study [27] was a randomized, double-blind, placebo-controlled Phase III study conducted in 389 patients who had not respnded to at least one anti- TNF agent. Patients received abatacept at a dose of 10mg/Kg or placebo, in combination with methotrexate (MTX). At 6 months, the ACR20 response was 50% in the abatacept + MTX group vs 10% in the placebo + MTX group; the ACR50 response was 20% vs 4%, respectively; and the ACR70 response was 10% vs 2%, respectively. The proportion of patients with induced remission (DAS28 <2.6) was 10% with abatacept vs 0.8% with placebo. ¾ The ARRIVE study [28] was an open-label study conducted in 488 patients previously treated with one anti-TNF agent. At 6 months, the average decrease in DAS28 score was 2.1 points; the proportion of patients with low activity was 24.8%,

Downloaded From: https://jamanetwork.com/ on 09/28/2021 and that of patients with remission 15.8%.

• Safety data Data from open-label extensions of controlled trials were reassuring, particularly concerning the risk of cancer among the 4,134 patients included in 7 clinical trials (8,388 patient/year) [29, 30]. Currently, there is little data from registers available. The ORA (“Orencia and Rheumatoid Arthritis”) register, sponsored by the Société Française de Rhumatologie (French Society for Rheumatology), has included over 300 patients since its implementation in May 2008. The first results originating from this register show that a significant proportion of patients (23%) is being treated with abatacept as monotherapy.

1.4.3. Rituximab (RTX)

• Mechanism of action Rituximab (Roche) is an anti-CD20 chimeric antibody inducing B cell depletion. CD20 is present on the surface of all B cells, except for certain precursors (pro-B cells) and plasma cells. The binding of anti-CD20 to CD20 results in lymphocyte depletion via apoptosis, antibody-depended cell-mediated cytotoxicity (ADCC), and complement- dependent cytotoxicity (CDC) [31]. The action of rituximab on B cells, which are antigen-presenting that also secrete pro-inflammatory cytokines, also affects T cells, leading to a decrease in CD40-ligand expression on the T cells’ surfaces [32].

• AMM for rituximab (2006) In France, rituximab was granted AMM approval for the RA indication in July 2006. The drug is indicated, in combination with methotrexate, for the treatment of severe active RA in adult patients who have had insufficient response or intolerance to the other disease-modifying agents including at least one anti-TNF agent.

• REFLEX, MIRROR and SUNRISE study data in patients who failed to respond to anti-TNF treatments Rituximab, like abatacept, has only been compared to placebo and not to another biotherapy agent! ¾ In the randomized, double-blind, placebo-controlled REFLEX study [33], which included patients who had displayed intolerance or insufficient response to anti-TNF treatments, 308 patients received a combination of methotrexate + rituximab and 209 patients received methotrexate + placebo. Overall, 311 patients had previously been administered a single anti-TNF agent. At 6 months, a EULAR response was observed in 65% of patients, 50% of whom exhibited a good response. This study has also demonstrated a decrease in the structural radiographic progression. ¾ Two new studies assessing diverse treatment dosages (2X500mg vs. 2X1g) and the need of retreatment at 6 months were presented at the last American College of Rheumatology (ACR) meeting in November 2008, but have not yet been

Downloaded From: https://jamanetwork.com/ on 09/28/2021 published. In the MIRROR study, among the 65 patients given one prior biotherapy, 70% of patients treated with 2 cycles of 2X500mg (n=40), and 88% (n=25) of those treated with 2 cycles of 2X1g of rituximab achieved a EULAR response. In the SUNRISE study, the patients who had had insufficient response to an anti-TNF treatment were randomized at 6 months in order to be retreated with either 2X1g of rituximab (if DAS28 >2.6) or placebo. The proportion of patients responding to treatment at 12 months was significantly higher in the patient group having received 2 cycles of rituximab.

• Efficacy data from registers ¾ In the AIR register of the Société Française de Rhumatologie, which has already included 1,500 RA patients, 79% of patients were previously treated with anti-TNF agents and 33% with RTX monotherapy. Among these patients, 54% achieved a EULAR response at 6±3 months following RTX treatment initiation (abstract 1190, ACR meeting 2008). ¾ The Swiss register study [34] conducted in 116 patients treated either with RTX (n=50) after failure of 1 or 2 anti-TNF treatments, or with a 2nd or 3rd anti-TNF agent (n=66) revealed a better efficacy in the RTX group (mean decrease by 1.61 point in DAS28 in patients treated with RTX vs. 0.98 point in those treated with anti-TNF agents). ¾ A study conducted using the STURE register from Stockholm showed the efficacy of RTX in 42 patients to be similar to that of another anti-TNF agent in 445 patients after single anti-TNF agent failure. In addition, RTX also tended to be superior in patients with prior insufficient responses to two anti-TNF agents (abstract 1995, ACR meeting 2008).

• Safety data Safety data from the clinical trials’ extension phases appears reassuring, with a follow-up concerning about 5,000 patient/year (abstract 361, ACR meeting 2008). Depending on the number of treatment cycles, the number of severe infections observed varied between 3.79 and 4.5. Data regarding the patients treated with more than 4 RTX cycles is still limited, yet hypogammaglobulinemia, especially hypo-IgM or more rarely hypo-IgG, may be observed following numerous retreatments. In unselected patients, safety data from the AIR register revealed the number of severe infections to be superior to that observed in the clinical trials (6.5/100 patients/year). So far, there have been no increased rates of cancer or unexpected complications observed.

1.4.4. Tocilizumab

• Mechanism of action Tocilizumab (Roche) is a humanized anti-interleukin-6 receptor (IL-6) antibody that specifically binds to soluble and membrane-bound IL-6 receptors (sIL-6R and mIL- 6R). Tocilizumab has been shown to inhibit signal transduction mediated by both sIL-

Downloaded From: https://jamanetwork.com/ on 09/28/2021 6R and mIL-6R receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by numerous cell types, particularly T and B cells, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes, including T cell activation, induction of immunoglobulin secretion, initiation of hepatic protein synthesis in the acute inflammatory phase, and stimulation of hematopoiesis. IL-6 has also been proven to play a significant role in the pathogenesis of numerous diseases, particularly inflammatory affections, osteoporosis, and neoplasia. In the clinical trial evaluation of tocilizumab, a rapid decrease in CRP, sedimentation rate, and serum amyloid A protein levels was observed. Concerning its effects on acute inflammatory phase markers, tocilizumab treatment was associated with a reduction in platelet counts, yet still within the normal range. The increases in hemoglobin concentrations observed were accounted for by the fact that tocilizumab inhibited the IL-6-induced effects on hepcidin production, thereby increasing iron availability. In the tocilizumab–treated patients, normalization of CRP levels was noticed, starting from the 2nd week onward and being maintained throughout the treatment period.

• AMM for tocilizumab (2009) In France, tocilizumab was granted AMM approval for the RA indication in December 2009. Tocilizumab is indicated, in combination with methotrexate (MTX), for the treatment of moderate to severe active RA patients who have had insufficient response or intolerance to a previous treatment with one or several disease- modifying anti-rheumatic drugs (DMARDs) or anti-TNF agents. In these patients, tocilizumab can be used as monotherapy in the event of MTX intolerance or when MTX therapy continuation appears inadequate.

Controlled clinical trials have shown tocilizumab to be significantly more effective than methotrexate treatment, even in patients with insufficient response to one or several anti-TNF agents (RADIATE study). Tocilizumab was also shown to reduce the progression of osteo-articular destructions in patients who failed to respond to MTX. Safety data derived from clinical trials does not reveal any significant increase in the rates of infection, cancer, or short-term cardiovascular complications. In most cases, the adverse events observed (leukopenia, increased transaminase levels, or lipid profile abnormalities) were moderate, transient, and reversible - either spontaneously or via reduction or discontinuation of tocilizumab and/or methotrexate. Lipid abnormalities were responsive to lipid-lowering treatment, as necessary.

1.5. Why conduct a clinical trial evaluating the best strategy in anti-TNF treatment failure cases?

• There has been no randomized clinical trial conducted in this setting, which is yet very common. Register data is not meant to be used for efficacy analysis purposes. The data derived from registers does not provide us with an answer to the

Downloaded From: https://jamanetwork.com/ on 09/28/2021 above-mentioned question, and the numerous biases inherent to this type of research make the interpretation of findings questionable. The same applies for indirect comparisons.

• In the absence of any well-founded recommendation, the current choice of therapeutic strategy is empirical and dependent on each clinician. The efficacy of the selected treatment after one anti-TNF treatment failure has not been codified, as illustrated by the following three real-life situations: - 2nd anti-TNF agent 4 months (ineffective), abatacept 6 months (ineffective), rituximab 6 months (ineffective), and tocilizumab (authorization for temporary use - ATU) (effective)! - Rituximab 6 months (ineffective), abatacept 6 months (ineffective), tocilizumab 3 months (ineffective), and 2nd anti-TNF agent (effective)! - Abatacept 6 months (ineffective), tocilizumab 3 months (ineffective), 2nd anti- TNF agent 3 months (ineffective), and rituximab (effective)!

In these three examples, the excessively long period (12 to 16 months) during which the disease was not under control entailed the risk of a structural progression, along with a prolonged use of corticosteroids. Clinical trial data, if available, would be instrumental in better guiding the clinicians in their therapeutic choices and help them target more rapidly the effective strategy. The use of biomarkers, which can only be optimally analyzed in a direct comparison trial, could help identify this optimal therapeutic strategy.

• There is no data available concerning the safety of successive biotherapies with different targets. These biotherapies can decrease B cell numbers (at times gammaglobulin levels), T cell activation, and certain cytokine levels as well. To be able to immediately select an effective biotherapy in the event of 1st anti-TNF treatment failure may prevent certain complications, yet still unknown, which may result from administering successive biotherapies, in addition to reducing both direct and indirect RA costs.

• The lack of sound scientific data leaves the way open for imperfect medical- economic models. The lack of clinical data bears the risk of administrative decisions that could restrict the clinician's choice and negatively affect patients. The National Institute for Health and Clinical Excellence (NICE), in Great-Britain, has refrained from recommandig anti-TNF rotation in the event of 1st anti-TNF treatment failure and does not cover the costs of abatacept, this decision being based on arguable medical-economic considerations.

• The question as to the optimal therapeutic strategy is a key issue, as anti- TNFs have been successfully used for over 10 years, and will become more widely used in the near future. Rituximab has been prescribed for 2.5 years, abatacept for 1.5 years, and tocilizumab will soon been granted AMM approval.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Notwithstanding this, certain ongoing strategy studies still evaluate the role of MTX and other conventional background treatments in RA management! The relevance of the question should therefore go widely beyond the 36-month incompressible period required to perform this academic trial.

1.6. Lack of a controlled trial comparing the use of biotherapies in the event of anti-TNF treatment failure: a deliberate choice of the pharmaceutical industry

• It is of note that 10 years after demonstrating the superiority of anti-TNFs compared to MTX, the new biotherapies are still being compared to a controlled group treated with MTX (to which patients insufficiently responded) combined with a placebo instead of an anti-TNF agent. According to the American registry clinicaltrials.gov, of the 75 randomized trials that are currently conducted while using a biological agent in RA patients, only one trial does compare two biological agents. The 74 other trials compare a biological agent to a placebo or a conventional disease-modifying agent treatment (Estellat, Ravaud personal communication). As the methodologist Ioannidis suggested, the fact of not considering appropriate comparator groups when new molecules have been discovered is based on a deliberate choice. The months, and at times the year, during which patients are not effectively treated in the MTX/placebo group also raise ethical issues. • The industrial trials that are currently promoted primarily aim to extend the biotherapy indications to recent-onset RA in patients who are considered MTX- naive or insufficient responders to MTX. No pharmaceutical industry has any advantage in financing a clinical trial that evaluates its own compound in comparison with an effective rival molecule, while aiming to identify biomarkers that are response predictors to any molecule. This would only help segment the market… Only the hospital clinical research program (PHRC) is therefore in the position to promote such a strategy trial.

1.7. Research hypotheses

1.7.1. Relevance of the question

So far, there is no ongoing international clinical trial evaluating the therapeutic strategy in the event of anti-TNF treatment failure (check of the main trial registration websites). During the project’s preparatory phase, we have also consulted several international experts who would have whished to initiate such a trial, but were not able to do so due to lack of finances, such as Paul Emery, a RA specialist in Great- Britain. Our trial’s competition in relation to potential industrial trials is limited, as this study concerns patients who have not responded to the anti-TNF agents, whereas the industrial trials focus on patients who are MTX-naive and anti-TNF-naive.

The relevance of this issue, as well as the independent and unprecedented direct

Downloaded From: https://jamanetwork.com/ on 09/28/2021 “face-to-face” comparison between different biotherapies, appear to motivate all our rheumatologist and internist colleagues who are eager to “play along” and get involved in this trial.

1.7.2. ROC, a representative study for French rheumatology clinical research

Over the last few years, several French multicenter collaborative projects have bloomed, with unification and success.

• Cohort follow-up: ESPOIR (RA), DESIR (spondyloarthritis - SPA), ASSESS (primary Sjögren’s syndrome, national PHRC), and TEARS (primary Sjögren’s syndrome) • Register and observational studies: CORPUS (active patients), AIR (rituximab), ORA (abatacept), and RATIO (anti-TNF) • Clinical strategy trials: GUEPARD (adalimumab + methotrexate vs. methotrexate in recent-onset RA), infliximab in routine use versus on-demand use in SPAs, and STRASS (discontinuation of anti-TNF agents in RA, national PHRC) • Controlled trials: TRIPPS (primary Sjögren’s syndrome) and JOQUER (primary Sjögren’s syndrome)

This dynamic endeavour best underlines the motivation of the study investigators, who also participate in the current project, while highlighting the efficacy of the communication tools available (newsletters; websites), with the support of unifying structures (Société Française de Rhumatologie [SFR], Société Française de Médecine Interne [SFMI], and Club Rhumatismes et Inflammation [CRI]). As the trial will be conducted under the lead of the CRI, these previous successes allow us to reasonably hope that the current project will also be a success. This study must be a representative study demonstrating our community’s motivation and its ability to successfully complete a large-sized strategy trial.

1.7.3. Expected results

The trial’s expected results are as follows:

• Identify which biotherapy is the most appropriate in the event of anti-TNF agent failure by evaluating the risk-benefit ratio of the different drugs that are currently available • Analyze the structural radiographic progression in patients who did not respond to an anti-TNF agent, and this for the first time in a clinical trial setting • Identify factors that are predictive of response to different biotherapies in the event of first anti-TNF treatment failure

Downloaded From: https://jamanetwork.com/ on 09/28/2021 In addition, this treatment strategy trial will likely exhibit a “structural” effect for the entire rheumatology community by improving the quality of patient management.

1.7.4. Risk-benefit ratio

There are no direct benefits derived from participation in this study, as the expected effects are similar to those derived from usual RA management (outside of clinical trials). However, the participation of the patients included will help identify the best treatment strategy following a 1st anti-TNF treatment failure.

2. Study objectives

2.1. Primary objective

The primary objective is to compare the efficacy, at 24 weeks, of an anti-TNF rotation to that of a change to another biotherapy in RA patients with prior insufficient response to an anti-TNF agent.

2.2. Secondary objectives

1) To compare the structural efficacy of both treatment strategies 2) To compare the safety of both treatment strategies 3) To identify predictive factors for the treatment response

3. Methodological design of the study

3.1. Primary endpoint

The primary endpoint selected for this study is the EULAR response at 6 months. Patients who received during the follow up another biologic agent different from the treatment initially assigned will be considered non-responders.

• Justification supporting the choice of the EULAR response DAS28 is an activity score used in everyday practice, in contrast with the ACR response criteria. The EULAR response was assessed in several randomized studies that have been published, evaluating the efficacy of biotherapy in RA patients with insufficient response to anti-TNF agents. In patients with longstanding and treatment-resistant RA, this objective seems more realistic than remission induction. • Justification supporting the 6-month period The required time period to obtain a clinical response differs depending on the molecule used (4 months for anti-TNFs; 6 months for abatacept, rituximab, and

Downloaded From: https://jamanetwork.com/ on 09/28/2021 tocilizumab). Therefore, a 6-month period allows us to assess the clinical response, regardless of the biotherapy used.

3.2. Secondary endpoints

Several secondary endpoints have been selected: - Treatment safety (follow-up of serious adverse events) - EULAR response at 3, 6, and 12 months - Mean DAS28 evolution at 3, 6, and 12 months - Remission rate (DAS28<2.6) or low activity rate (DAS28<3.2) at 3, 6, and 12 months - Therapeutic maintenance at 6 and 12 months - Mean oral corticosteroid use at 6 and 12 months - Structural radiographic progression between inclusion and visit at 12 months

3.3. Experimental design

This is a randomized, controlled, pragmatic, open-label trial evaluating the efficacy of two treatment strategies at 24 weeks: rotation of anti-TNFs versus change to another biotherapy in RA patients with insufficient response to an anti-TNF agent.

• Justification supporting the open-label design of the study: it is a pragmatic study, which must mimic, as much as possible, “real life” conditions. Efficacy will be openly assessed by a clinician. Within the 2 weeks following the V0 visit (inclusion) and the 2 weeks preceding the V2 visit (6 months), patients will also be contacted by a clinical research technician of the Hôpitaux Universitaires de Strasbourg in order to assess treatment efficacy according to DAS28 (blind evaluation) and HAQ auto- questionnaires. • Justification supporting the lack of biotherapy randomization in the “other strategy” arm: to keep the trial pragmatic, the choice of the biotherapy in the “other biotherapy” arm (abatacept, rituximab or, tocilizumab) will be left at the discretion of the clinician who will select the treatment that appears the most appropriate for a given patient.

3.4. Study population

3.4.1. Inclusion criteria

¾ Inclusion criteria for patients

Downloaded From: https://jamanetwork.com/ on 09/28/2021 of whether this was linked to primary failure or loss of efficacy (loss of response) • Stable corticosteroid dosage 15mg/day of prednisone equivalent for at least 4 weeks prior to inclusion • Stable dosage of background treatment (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, ciclosporin, or gold salts) for at least 4 weeks before inclusion • Written informed consent, dated and signed before initiating any trial-related procedure • Subject insured under the French social security system • Subject having been informed of the prior medical consultation findings

¾ Inclusion criteria for control subjects

• Healthy adult subject • Male or female • Subject insured under the French social security system • Subject having signed an informed consent form

3.4.2. Exclusion criteria

¾ Exclusion criteria for patients

• Major intolerance to the 1st anti-TNF • Prior treatment with 2 anti-TNFs • Prior treatment with abatacept, rituximab, or tocilizumab • Absolute contraindication to all the non-administered anti-TNFs and other biological agents of other biotherapy families • No anti-tuberculosis prophylaxis (if necessary) • Patient who cannot be followed up during 12 months • Minors, adults under supervision or guardianship, or deprived of their liberty • Declared pregnancy • Breast-feeding

¾ Exclusion criteria for control subjects

-Pregnancy - Breast-feeding - Adults under law protection

3.4.3. Study drop-out and premature treatment or follow-up discontinuation

Patients are considered as drop-outs if: - They withdraw their consent - The investigator deems it necessary, notably for safety reasons. Patients exhibiting treatment failure or a serious adverse event will be followed up until the end of the study (with or without treatment change/discontinuation).

Downloaded From: https://jamanetwork.com/ on 09/28/2021 If patients withdraw their consent, they will be asked whether they desire to definitively withdraw from the study (treatment discontinuation and end of data) or if they accept that the investigator continues to collect data. This information will be mentioned in the patient’s medical record.

3.5. Practical conduct of the trial

3.5.1. Study duration

Enrollment duration will be 36 months. This is a realistic estimate given the significant number of patients to be enrolled.

Total duration of each patient’s participation in the study will be 12 months. This duration is justified in this pragmatic trial by two main elements: - The necessity for a sufficient time period to assess the therapeutic maintenance level - The necessity for a sufficient time period to assess radiographic RA progression, as certain patients enrolled in this study will likely suffer from old- onset and advanced RA. Moreover, this duration will allow us to assess, in the clinical trial setting, the tolerance of several consecutive biotherapies in patients who have not responded to the initial treatment and will have received another biotherapy after 6 months.

A patient enrolled in the study cannot participate in another biomedical research at the same time, the exclusion period being at least 1 month (4 weeks) after the end of his/her participation.

Total study duration will be 48 months.

3.5.2. Subject recruitment method

This study will be carried out in all the hospital centers that are willing to participate. This willingness to give every center the possibility to participate in the study is linked to the significant number of patients to be recruited, the simple and pragmatic nature of the study, the lack of need to finance study drugs, the absence of excess hospitalization costs, and the fact that most rheumatology units are familiar with participating in clinical studies (registers or other clinical trials). We have scheduled to involve approximately 40 French centers, with an average of 10 patients to be enrolled per center.

The quick recruitment of patients in this trial can be ensured for the following reasons:

• Cases with insufficient response to anti-TNF are quite common. For

Downloaded From: https://jamanetwork.com/ on 09/28/2021 example, 1,000 patients in this situation (including over 500 insufficient responders to 1 anti-TNF) have been enrolled, in a 2-year time frame, in the AIR register by French centers, a majority of which will participate in the current study. Moreover, the AIR register involves only patients treated with rituximab. There are numerous other patients meeting the trial’s inclusion criteria, who are treated with abatacept, as shown by the significant number of patients enrolled into the ORA register (over 300 patients included in 6 months). • It is an easy and pragmatic trial, in accordance with “large simple trials” philosophy of Salim Yusuf • The clinical relevance of this matter has been acknowledged by rheumatologists. The French rheumatologic community agrees with the project, with the support of the Société Française de Rhumatologie (SFR), the Club Rhumatismes et Inflammations (CRI), and the main rheumatology units. • The competition of the trials in the industry is scarce • The methodologist, the principal investigator and the coordinator are experienced in multicenter randomized clinical trials and have the potential to lead the project, to unite the investigators around the trial and to quickly communicate their results.

Control group

The healthy voluntary subjects will be from the medical and paramedical staff of the Strasbourg CHU rheumatology department, who will have been informed about the study.

3.5.3. Informing patients and procedure for collecting consent

Patients During a routine consultation, the investigator (rheumatologist) will offer RA patients with insufficient response to 1 anti-TNF the opportunity to participate in the study, providing full details about the study procedures. The rheumatologist will give the patient: • The information leaflet entitled “Information leaflet for adult patients – Main study” • The informed consent form • The consent form “Biological collection and examinations of genetic characteristics”.

The patient is free to accept or reject this offer. He/she will be given sufficient time to think over his/her decision.

If the patient agrees to participate in the study, the investigator will collect both consent forms, signed and dated, at the inclusion visit. The patient will be given a copy of these documents. The date as to when the patient accepted to participate in the study will be specified in the patient medical record, as will the date of consent withdrawal, if applicable.

Control group

Downloaded From: https://jamanetwork.com/ on 09/28/2021 • The volunteers will be seen by one of the investigators of the Strasbourg CHU, who will provide them with details about the protocol and its implications. At the end of this interview, the volunteers will be handed over an information leaflet and a consent form. • If the volunteer agrees to participate in the study, the investigator will collect the signed and dated consent form. A copy of this document will be given to the voluntary subjet.

3.5.4. Visits and examination schedule

Patient visits and examination schedule

In total, 4 visits are scheduled: inclusion visit (V0), follow-up visit at 12 weeks (V1), follow-up visit at 24 weeks (V2), and follow-up visit at 52 weeks (V3). This schedule has been established in line with the daily practice recommandations for the follow-up of active RA treated with an anti-TNF or another biotherapy. Clinical examinations, hand and feet X-rays, and biological check-ups will be carried out as usual. The only study-specific requirements are answering 6 or 7 questionnaires, depending on the visit (assessment of symptoms and quality of life), and blood sample taking (extra volume).

Each patient’s participation will be structured as follows:

Inclusion visit (V0):

• Checking of inclusion/exclusion criteria: Confirmation of the ineffectiveness of the first anti-TNF treatment (which will be discontinued) Given the usual practices, it has been decided not to include any wash-up period following the first anti-TNF Treatment with NSAIDs, corticosteroids, and standard disease-modifying agent may be continued at stable doses. • Collection of signed and dated consent forms • Blood sampling: 3 blood sample tubes (20mL, 7.5mL, and 2.5mL) for the trial • Blood sampling: 4 blood sample tubes of 5mL each for standard RA follow-up (complete blood count, liver function tests, cholesterol, triglycerides, and plasma protein electrophoresis) • Clinical examination to assess disease progression • Hand and feet X-rays • SF-36, RAPID, HAQ, RAID, WPAI, and Qualisex questionnaires on symptoms and quality of life to be filled in

Follow-up visit at 12 weeks (V1):

• Blood sampling: 4 blood sample tubes of 5mL each for standard RA follow-up • Clinical examination • SF-36, RAPID, HAQ, RAID, WPAI, and PASS questionnaires

Follow-up visit at 24 weeks (V2):

Downloaded From: https://jamanetwork.com/ on 09/28/2021 • Blood sampling: 2 blood sample tubes (20mL and 2.5mL) for the trial • Blood sampling: 4 blood sample tubes of 5mL each for standard RA follow-up • Clinical examination • SF-36, RAPID, HAQ, RAID, WPAI, PASS, and Qualisex questionnaires

Follow-up visit at 52 weeks (V3):

• Blood sampling: 4 blood sample tubes of 5mL each for standard RA follow-up • Clinical examination • Hand and feet X-rays • SF-36, RAPID, HAQ, RAID, WPAI, and PASS questionnaires

Within the 2 weeks following inclusion visit V0 as well as 2 weeks prior to V2 (6 months), patients will receive a telephone call from a clinical research technician of the Hôpitaux Universitaires de Strasbourg. These calls will seek to blindly assess treatment efficacy (self-assessment DAS28 and HAQ). They will be aimed to identify tender and swollen joints, estimate RA activity level, and answer the questionnaire (HAQ) so as to collect information regarding the disease’s impact on daily activities. An information leaflet and an illustration pattern (cf. Appendices 3 and 4) will help patients in completing the auto-DAS 28.

Clinical evaluations:

• The frequency of clinical follow-up visits scheduled for this study has been established according to the daily practice recommandations for the follow-up of active, biotherapy-treated RA. • Follow-up procedures (visits and day hospitalization) will depend, as in common practice, on the biotherapy type chosen by the investigator. For instance, a patient with insufficient response to etanercept and randomly assigned to the “anti- TNF rotation” group may receive either adalimumab or infliximab depending on the investigator’s choice, with follow-up visits (subcutaneous injections at home for adalimumab) or day hospitalizations (intravenous infusion for infliximab), in accordance with the usual practices for these treatments. • In each center, the clinical evaluation will be performed in an open manner by a clinician. The SF-36, RAPID, HAQ, RAID, WPAI, PASS, and Qualisex questionnaires will be filled in by the patient in order to assess patient symptoms and quality of life.

Standard biological analyses:

The samples that are recommended in common practice for the follow-up of RA patients treated with biotherapy, often along with a disease-modifying treatment, will be taken.

Radiographic evaluation:

Downloaded From: https://jamanetwork.com/ on 09/28/2021 • As in daily practice, this evaluation comprises front and ¾ hand and feet X-rays. Each center’s standard technique will be used. An assessment report will be required at inclusion and at 12 months, as recommended in daily practice. • Centralized reading will be carried out by two independent readers, according to the Sharp/Van Der Heijde modified scoring method. • No dispatching of duplicated documents has been planned, but digitized pictures of hand and feet X-rays should be made available. This digital collection methodology has already been validated in other clinical studies.

Summary table:

Inclusion W12 W24 W52 (V0) (V1) (V2) (V3) Allocation of randomization number X Informed consents X Inclusion and exclusion criteria X Clinical examination X X X X Patient questionnaires X X X X Biological examinations X X X X X-rays (hand/foot) X X Serious adverse event reporting X X X

Control group visits and examination schedule

Only 1 visit has been scheduled for blood sampling of a 2.5mL tube for the trial.

3.5.5. Biological sample collection

Research-specific samples will be taken at V0 and V2. Certain ancillary projects, which may be proposed by the investigators, will require specific approval by the principal investigator and the study coordinator, yet will not be funded by the PHRC.

Sample description:

• SERUM: 2 samples of 20mL blood taken at V0 and V2. Serum will be centrifuged and aliquoted (500μL aliquots) in each investigator center. These aliquots will be stored at -80°C in the inves tigator center until being sent on dry ice, before the end of the trial, to the Centre de Ressources Biologiques (CRB) of the Hôpitaux Universitaires de Strasbourg (HUS). They will be stored on site for the duration of the research, then sent to the EA unit “Physiopathologie des Arthrites”, of the Faculté de Pharmacie de l’Université de Strasbourg (UDS) for analysis.

The serum will be used for investigating RA activity markers: - Immune markers (ȕ-2-microglobulin, TNF-Į, immunoglobulin free light chains, BAFF, IL-6, soluble CTLA-4, and IL-17); - Osteoarticular lesion markers.

• DNA: 1 sample of 8mL blood taken at V0.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 The tube will be stored at -80°C in the investigato r center until being sent on dry ice, within 6 months, to the Centre de Ressources Biologiques (CRB) of the Hôpitaux Universitaires de Strasbourg (HUS). After DNA extraction, the samples will be stored at the HUS for the duration of the research, then sent to the EA unit “Physiopathologie des Arthrites” of the Faculté de Pharmacie de l’Université de Strasbourg (UDS) for analysis.

The DNA will be analyzed for: - Distinct genetic features (polymorphisms) associated with an inceased risk of developing RA (polymorphisms of HLA, PTPN22, and IRF5 genes and of other genes whose role(s) may be identified during the study); - Genetic polymorphisms that may alter the response to the treatments assessed in the study (anti-TNF, abatacept, rituximab, and tocilizumab): polymorphisms of TNF-Į, FcȖ receptors, CTLA-4, IL-6, and of other genes whose role(s) may be identified during the study.

• RNA: 2 samples of 2.5mL blood taken at V0 and V2. The PAXgene tubes (for RNA extraction) will be stored at -80°C in the investigator center until being sent on dry ice, within 6 months, to the Centre de Ressources Biologiques (CRB) of the Hôpitaux Universitaires de Strasbourg (HUS). They will be stored on site for the duration of the research, then sent to the EA unit “Physiopathologie des Arthrites” of the Faculté de Pharmacie de l’Université de Strasbourg (UDS) for analysis. RNA analysis will seek to determine the specific expression (increase/decrease) of certain RNA features that are associated with response to the treatments assessed in the study (anti-TNF, abatacept, rituximab, and tocilizumab). The evaluation of a predictive factor associated with response to biotherapies will be carried out by means of quantitative real-time PCR techniques and transcriptome investigation. DNA and RNA analyses will be based on molecular biology techniques, which may take several years, given the development of this technology and of our understanding of RA.

Control group In total, 10 healthy volunteers must be enrolled, for which one blood sample of 2.5mL will be drawned. These control samples will be compared to the patient samples so as to analyze the predictive factors of treatment responses, based on certain messenger RNA expression. These control samples will also enable us to refine the quantitative real-time PCR analyses.

These 2.5mL samples will first be stored at the Hôpitaux Universitaires de Strasbourg, for a maximum of 3 years. They will then be transferred to the EA unit “Physiopathologie des Arthrites”, Faculté de Pharmacie de l’Université de Strasbourg (UDS) for analysis.

These samples will be stored for 30 years and used solely for RA research.

In accordance with applicable laws regarding biomedical research, the samples will be rendered anonymous within the medical units of the participating centers, using a code as well as the first three letters of the first and last name of the patients. Only the coordinating investigator, Professor Jacques-Eric Gottenberg, will have the list associating the patient identity and the code used for anonymization. This list will allow for the destruction of the samples.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 3.5.6. Ancillary study “Qualisex” conducted by Prof. Aleth Perdriger

This study consists of a self-assessment quality of life questionnaire distributed at the inclusion (VO) and 6-month (V2) visits, which will allow us to assess the effects of RA and associated treatments on the patients’ sex life. The Qualisex questionnaire has been amended following the pre-validation phase conducted on 50 RA patients. The ancillary study involving 150 patients treated with biotherapy aims to assess the sensitivity of this amended questionnaire.

The Qualisex questionnaire will be completed by the patient at the V0 and V2 visits. The questionnaires will be rendered anonymous and treated as strictly confidential. Completion of the questionnaire will not be compulsory; patients may choose not to participate in this ancillary study.

Appendices 5 and 6 detail the project of Prof. Perdriger, as well as the questionnaire.

3.5.7. Randomization

The Unité de Recherche Clinique Paris Nord (clinical research unit), under direction of Professor Ravaud, will establish a unique randomization list, with stratification by center and variable block sizes. Randomization will be centralized. For each participating patient, the investigator will be provided the randomization result (anti-TNF rotation or other biotherapy) via a web- based randomization system.

3.6. Investigational therapeutic strategies

3.6.1. Therapeutic strategy: anti-TNF rotation

Depending on the prior anti-TNF, the investigator will select another anti-TNF among the anti-TNF agents that have been granted AMM approval. The drugs will be administered at the recommended doses as follows:

* Adalimumab (HUMIRA, 40mg subcutaneous injection every other week); * Etanercept (ENBREL, 50mg subcutaneous injection once a week); * Infliximab (REMICADE, 2-hour intravenous injection with a 3mg/Kg dosage at W0, W2, W6, and every 2 months thereafter); The infliximab dosage may be increased to 5mg/Kg. The other anti-TNF and biotherapy doses are unchangeable; * Certolizumab (CIMZIA®): 400mg at W0, W2, and W4, then 200mg subcutaneously every other week).

• Conditions of administration will be in accordance with the summary of product characteristics.

3.6.2. Therapeutic strategy: other biotherapy

Downloaded From: https://jamanetwork.com/ on 09/28/2021 The investigator will select another biological agent among those that have been granted AMM approval. The drugs will be administered at the recommended doses as follows: * Abatacept (ORENCIA, 30-minute intravenous injection of 500mg for patients weighing 60Kg, 750mg for those weighing between 60 and 100Kg, and 1,000mg for those weighing >100Kg. Infusions will be administered at W0, W2, W4, and then every month thereafter); * Rituximab (MABTHERA, 4-hour intravenous injection for the first infusion, at 500mg or 1g at W0 and W2; in case of relapse, injections will be repeated at 6 months or later); * Tocilizumab (RoActemra, 1-hour intravenous injection of 500mg every 4 weeks).

• Conditions of administration will be in accordance with the summary of product characteristics. • Biotherapy doses will be administered at fixed dosages.

3.6.3. Other treatments and medications that are authorized and non-authorized during the course of the study.

• The investigational biotherapies can be administered as monotherapy, as in common practice, but can also be combined with a conventional background treatment (the dosage of which must have been stable for at least 4 weeks prior to study inclusion): (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, ciclosporin, or gold salts). Given the pragmatic trial design, all concomitant treatments are permitted (conventional background treatment or monotherapy, which was the case for 20% of the AIR and ORA register patients, along with oral corticosteroids without threshold dosage). It is preferable that the background treatment dosage remain stable during the study, especially in the first 6 months; the investigator may however adjust the dose if necessary. Any dose modification should be recorded in the case report form. • Concomitant medications will not be codified (whether combined with DMARDS or not), except for corticosteroid therapy that must be kept stable for the first 6 months. • An oral corticosteroid therapy that has been given at stable dosage for at least 4 weeks before inclusion can be continued during the study. As in daily practice, if the patient’s clinical condition permits, the corticosteroid therapy dosage should be decreased during follow-up and eventually discontinued. In accordance with real-life circumstances, no decreasing schedule will be provided. A secondary objective of this study is to assess the total cumulative dose of corticosteroids used during the study. Patients with an oral corticosteroid therapy dose >10mg/day at 6 months will be considered non-responsive. • Parenteral or injectable (intra-articular) corticosteroid therapy is permitted but must be recorded in the case report form. • Any other routine care treatment is permitted but must be recorded in the case report form. • Anakinra (Kinéret) has been granted AMM approval for the RA indication, but this medication has not been specifically assessed in anti-TNF failure cases. Given the modest benefit-risk ratio compared to anti-TNFs, this drug is rarely prescribed for

Downloaded From: https://jamanetwork.com/ on 09/28/2021 patients not responding to anti-TNF agents. This treatment has not been accepted as alternative biotherapy within this study.

3.6.4. Treatment failure and end of trial

Given the pragmatic design of this study, no recommendation has been made regarding the selection of a new biotherapy if the biotherapy administered during the study is not well tolerated or ineffective. The choice will be left to the discretion of the clinician. The physician will choose the treatment that appears the most appropriate for a given patient.

At the end of the primary endpoint evaluation period, at W24, or earlier, if required by the patient’s clinical condition, the investigator is free to change biotherapy or any other medication as needed. At the end of the study period, at W52, the patients will be seen again by their physicians for their usual follow-up.

4. Safety evaluation – management of adverse events

Biotherapies are commonly used in rheumatologic practice for the management of RA. Based on current knowledge, rare occurrences of severe adverse events have been reported.

4.1. Definitions

4.1.1. Adverse event

Any untoward and harmful event occurring in a person participating in a biomedical study, regardless of the cause of this event.

4.1.2. Adverse effect

Any untoward and harmful reaction to a study drug, regardless of the dose administered.

4.1.3. Serious adverse event:

Is considered to be serious: - Any event resulting in death - Any event that is life-threatening - Any event requiring hospitalization or prolongation of hospitalization - Any event resulting in persistent or significant incapacity/disability - Any event resulting in a congenital abnormality/birth defect

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Other events that do not correspond to the above-mentioned criteria may also be considered “potentially serious”, notably certain biological abnormalities. It will be left to the investigator’s discretion to decide whether or not to report these events.

4.1.4. New event

A new event is an event that may jeopardize the study participants’ safety. The following scenarios may be considered new events: - Intermediate analysis results when relevant to the participants’ safety (notably insufficient efficacy); - Increased serious adverse event rates in a treated patient group; - Animal study results that provide new safety data about the product; - Generally speaking, any new information that may lead to an unfavourable re- evaluation of the benefit-risk ratio of the study.

4.1.5. Unexpected serious adverse effect

Any adverse effect of which the nature, severity, or progression is not in accordance with the information contained in the summary of product characteristics.

4.1.6. Expected serious adverse effet

The serious adverse effects expected within the protocol are only linked to the administered treatment and are described in the relevant SPCs.

• The risks related to anti-TNFs (adalimumab, etanercept, or infliximab), which have been commercialized in France since 2000, primarily consist of an increased risk of infections, which may be severe at times (i.e., tuberculosis). The other known risks related to anti-TNFs include: intolerance reactions at the injection site, heart failure, or rarely observed immune reactions. There is no known risk of cancer with the exception of a possible increased risk of skin cancer. • Rituximab, which has been commercialized in France since 1997, has also been associated with a risk of (at times severe) infection but not including tuberculosis. The other rituximab-related risks are intolerance reactions at the injection site, and, more rarely, a decrease in white blood cells or cardiovascular defects. There is no known risk of cancer or immune reactions. • Abatacept, which has been commercialized in France 2007, is also associated with a risk of (at times severe) infection but not including tuberculosis. The other risks include intolerance reactions at the injection site and, very rarely, cutaneous psoriasis plaque. There is no known risk of cancer or immune reactions. • Tocilizumab, which has been commercialized in 2009, is also associated with a risk of (at times severe) infection. Although there is no documented risk of tuberculosis, the same detection and prevention measures against latent TB as for the other anti-TNFs apply and will be handled by the investigator. The other risks include intolerance reactions at the injection site, a decrease in white blood cells, cholesterol level abnormalities (no known risk of heart attack) and, more rarely, abnormal liver function test results (no known risk of severe hepatitis).

Downloaded From: https://jamanetwork.com/ on 09/28/2021 4.2. Procedures

The occurrence of a serious adverse event must be assessed by the investigator at each follow-up visit.

When a serious adverse event is detected, it must be followed up to complete resolution or until deemed permanent.

All adverse events (regardless of relation to study drug) must be documented in the patient’s medical file. Expected serious adverse events must be described in the patient’s medical file and recorded in the patient’s case report form. The following information is required:

9 Severity (mild, moderate, or severe) 9 Relationship to investigational product (suspected or not suspected) 9 Duration of the event (start and end dates or ongoing) 9 Seriousness

Any change in severity, relationship to the investigational product, interventions required to treat the event or progression must also be followed up and documented.

Notification of unexpected serious adverse events to the AFSSAPS and to the independent Ethics Committee will be carried out in accordance with current regulations. The investigator must notify the sponsor of any serious adverse events and new events (irrespective of the relationship to the study drug) within 24 working hours. A specific form must be completed by the investigator and sent to the Direction de la Recherche Clinique et de l’Innovation by fax at +33 (0)3.88.11.52.40.

4.3. Establishment of an independent oversight committee

Given that the medications are used within AMM indications, an independent serious adverse events management committee has not been established for this study.

5. Statistics

5.1. Calculation of the required number of subjects • The main analysis will focus on comparing the EULAR response at 6 months between the two groups. With a Type 1 risk of 5%, enrolling 150 patients in each group will enable us to demonstrate an absolute decrease of 0.16 (i.e., OR of 0.515), with an 80% power. • It is always extremely difficult to carry out sample size calculations if only a few studies are available, possibly rendering the initial hypotheses for sample size calculations incorrect (Problems in sample size calculation reporting in 1 2 randomized controlled trials. Pierre Charles M.D. , Bruno Giraudeau PH.D. , 1 1 1 Agnes Dechartres, M.D. , Gabriel Baron, PH.D , Philippe Ravaud, M.D/PH.D. BMJ 2009 in press). If our calculation hypotheses prove incorrect, an

Downloaded From: https://jamanetwork.com/ on 09/28/2021 approach with benefit-risk curves will be applied, as suggested by Shakespeare TP [36].

5.2. Statistical analyses

• The qualitative variables will be expressed by number, percentage, and missing data per response type, and the quantitative variables by number and mean±standard deviation. Asymmetrical variables will be expressed by median and interquartile range (25th percentile – 75th percentile). These analyses will be carried out based on the ITT sample. For each group (anti-TNF rotation and other biotherapy) and each assessment date, the qualitative variables will be expressed by number, percentage, and missing data per response type, and the quantitative variables by number and mean±standard deviation. • The primary endpoint is the comparison of the 6-month EULAR response. The statistical analysis of the primary endpoint will be carried out based on the ITT sample (i.e., all randomized patients will be analyzed according to their initial group). The ITT analysis allows us to minimize bias and preserve the initial comparability after randomization. Therefore, a primary endpoint value at 24 weeks is required for every randomized patient. In the event that this 24-week value is missing and in order to carry out an ITT analysis, the missing value will be replaced using the LOCF approach, which uses the last available data. The sensitivity analysis will be carried out using the maximum bias approach, i.e., “positive treatment responder = yes” in a first analysis, and “negative treatment responder = no” in a second analysis. The consistency of analysis outcomes will be assessed.

• Secondary analyses:

1) Comparison of both groups using a Chi-squared analysis of patient proportions:

- EULAR responders at 3, 6, and 12 months; - ACR20, ACR50, ACR70 and ACRn responders at 3, 6 and 12 months; - Patients in remission (DAS28 <2.6) or low activity (DAS28 <3.2) at 3, 6, and 12 months. 2) Comparison between each biotherapy of the « other biotherapy » group of ACR20, ACR50, ACR70 and ACRn responders3) Analysis of therapeutic maintenance levels with each biotherapy at 6 and 12 months (survival curves). 4) Variance analysis for repeated measures in order to analyze corticosteroid treatment, radiological score, and DAS28 at 3 and 12 months in each group.

• A sensitivity analysis will be performed taking into account several initial parameters that may impact clinical progression, notably the patient and investigator preferences of biotherapy. • For all statistical analyses, the superiority tests will be bilateral, with Type 1 risk set at 5%.

The statistical analyses will be conducted by Gabriel Baron at the Epidemiology, Biostatistics and Clinical Research unit of the Hôpital Bichat (Paris, 18th arrondissement) under the responsibility of Professor Philippe Ravaud. The software used for the analysis will be SAS Version 9.2.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 6. Right to access data and source documents

In accordance with the applicable laws and regulations, the investigator grants direct access to data and source documents to personnel in charge of quality control of the study duly as authorized by the sponsor and to all staff involved in the trial. These personnel will need to take all necessary precautions to ensure the confidentiality of data concerning investigational products, trials, participants, particularly regarding their identity and outcomes. The data collected by these individuals during quality controls or audits will be rendered anonymous.

The investigators agree to comply with the requirements of the sponsor and regulatory authorities with respect to audit or study inspection. The audit may be applicable to any stage of the study, from drafting of the protocol to the publication of the results, as well as to classification of data used or generated during the study. .

7. Quality assurance and control

7.1. Data collection

A case report form will be used for data input. The CRF pages will be duplicated. In this case report form, the investigator will record, for each patient and each visit, the efficacy and safety data (DAS28), dose of concomitant medications (oral corticosteroid therapy, and conventional background treatment), and data related to the patient questionnaires.

Study-related data will be transferred by the investigator (or someone designated by the investigator) from the source document (medical record, laboratory results, etc.) to the case report form, for every subject enrolled in the study.

All data required by the study protocol must be recorded in the case report form, and the investigator must justify all missing data. The data must be transferred into the case report forms as they are collected for both clinical and para-clinical data. The data will be copied clearly and legibly in black ink in order to facilitate duplication and computerization. False data detected in the CRF will be clearly crossed out, and the correct data will be recorded in the CRF, provided with the date and initials of the team member who affected the change. Subject anonymity will be ensured on all study documents using a code and the first three letters of the first and last name of the participating individual, or eradication of nominative data on the duplicated source documents intended for research documentation.

Computerized data on file will be reported to the CNIL in accordance with the applicable procedures.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 7.2. Research monitoring

A clinical research associate (CRA), delegated by the sponsor, will visit each study center during study implementation and one or several times during the trial, depending on the enrollment rate, as well as at the end of the trial.

The CRAs will visit the investigator centers according to the patient follow-up schedule specified in the protocol, the enrollment rate in the centers, and the corresponding risk level assigned to the study.

Site initiation visit in each center: This visit must take place prior to enrollment of the first patient and is aimed at establishing the protocol and meeting the biomedical study personnel.

During the first monitoring visit in each center, the CRA will verify the first case report (at least) 100% (per investigator, if there are several investigators per center).

During the next visits, the CRA will verify case report forms as the study progresses. The principal investigator of each centre and the other participating investigators agree to monitoring visits at regular intervals.

These visits aim at: 9 Confirming that the study is being conducted in compliance with the protocol; 9 Verifying informed consent form signatures; 9 Verifying reporting of serious adverse events and adverse event-related data; 9 Monitoring traceability of the investigational drugs; 9 Ensuring quality control: comparison of CRF data with source documents, verification of data accuracy, missing data, and data consistency in accordance with protocol procedures.

Final visit: collection of CRFs, biomedical study documents, and archiving.

7.3. Archiving

The following essential trial-related documents will be retained by the investigator for at least 15 years after the last follow-up visit of the last subject: 9 Investigator site file; 9 CRFs, completed and signed by the investigator; 9 Study-specific source documents required for the research.

This indexed archiving includes: - Copies of the written approval of the Institutional Ethics Committee; - Successive protocol versions (identified by a version number and version date); - Correspondence with the sponsor; - Subject signed consent forms, in sealed envelopes, with the corresponding inclusion list or register; - Study-specific appendices; - Final trial report based on statistical and quality control analyses (duplicate sent to the sponsor);

Downloaded From: https://jamanetwork.com/ on 09/28/2021 - Audit certificates that may have been issued during the study.

The database used for the statistical analyses will be archived by the individual in charge of the analyses (paper-based or digital).

8. Ethical and regulatory considerations

The research will be performed in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. To this end, a copy of the scientific committments dated and signed by the investigator of each participating center will be delivered to the sponsor’s representative.

8.1. Independent Ethics Committee and Competent Authority

In accordance with current regulations, the sponsor will submit the protocol to the Independent Ethics Committee (IEC) EST IV for review and approval, and a Clinical Trial Authorization to the AFSSAPS, Competent Authority (CA). Any major amendment made to the protocol must also be submitted to the Independent Ethics Committee ICE EST IV and the AFSSAPS, Competent Authority (CA) for approval. No enrollment or pre-enrollment can occur before CA and ICE approvals, and sponsor initiation of the study.

8.2. Subject information and consent Before enrollment in the trial, each eligible subject (or his/her legal representative) will be fully informed of the study. The information provided to the subjects is summarized in a written document provided to the subject, whose consent is required. Once this information has been delivered and the investigator has confirmed the subject (or his/her legal representative) understands the implications of his/her participation in the trial, the subject (or his/her legal representative) will be required to give his/her written consent. The subject remains free to choose not to participate in the study and can withdraw consent at any time, regardless of reason, without prejudice or other negative consequences.

A duplicate of the consent form signed by both the participating subject and investigator will be delivered to the subject (or his/her legal representative).

8.3. Protection of personal data

Personal data processing will be carried out in accordance with the terms specified by French law n° 78-17 of January 6, 1978, on infor mation technology, files, and civil liberties, as amended by the French law n°2004-801 of August 6, 2004 and the implementing regulations.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 An automatic data processing authorization request as part of the medical research will be submitted to the CNIL (Commission Nationale de l'Informatique et des Libertés).

8.4. Insurance

The Hôpitaux Universitaires de Strasbourg, sponsor of this study, have provided insurance covering their own civil liability and those of any stakeholder involved in the conduct of the clinical trial for the whole duration of the study, regardless of the relation between the stakeholders and the sponsor.

9. Confidentiality and publication policy

In accordance with Article R.5121-31 of the French Public Health Code, the investigators and every person involved in the trial are bound by the obligation of professional confidentiality, especially regarding the nature of the products used, the trial, the participants, and the outcomes. The PI or the coordinator, for a multicenter study, must ensure patient anonymity and retain a confidential patient identification list.

Any report, oral or written communication as part of this study must be transmitted to the sponsor and published in accordance with the publication policy of the Hôpitaux Universitaires de Strasbourg.

The Hôpitaux Universitaires de Strasbourg are owners of the data, and no use or disclosure to third parties can take place without their prior consent. The Hôpitaux Universitaires de Strasbourg must be stated as the sponsor of the biomedical research and source of financial support, when appropriate. The terms “Hôpitaux Universitaires de Strasbourg” must appear in the author’s address.

The final study report will be written by the PI, coordinator, and study methodologist. This report will be submitted to each investigator for review. After obtaining consensus, the final version must be validated by investigator signature and sent to the sponsor soon after the termination of the study. A report written according to the reference report of the Competent Authority will be sent to the Competent Authority and to the IEC within 1 year after termination of the study, defined as the last follow- up visit of the last enrolled subject. This deadline is set at 90 days in the event of early study termination.

The PI and coordinator will be the first and last signatories, respectively, of the study publication. The investigators of the centers with high patient enrollments will be cited as co-authors.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 10. References

1. Guillemin, F. Saraux A, Guggenbuhl P, Roux CH, Fardellone P, Le Bihan E, Cantagrel A, Chary-Valckenaere I, Euller-Ziegler L, Flipo RM, Juvin R, Behier JM, Fautrel B, Masson C, Coste J. Prevalence of rheumatoid arthritis in France: 2001. Ann Rheum Dis, 2005. 64; 1427-30. 2. Gabriel S, C.C., Maradit Kremers H, Therneau TM, The rising incidence of rheumatoid arthritis. Arthritis Rheum, 2008. 58(suppl); S453; 773. 3. Fautrel, B, Clarke AE, Guillemin F, Adam V, St-Pierre Y, Panaritis T, Fortin PR, Menard HA, Donaldson C, Penrod JR. Costs of rheumatoid arthritis: new estimates from the human capital method and comparison to the willingness- to-pay method. Med Decis Making, 2007. 27; 138-50. 4. Klareskog, L., Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, Rönnelid J, Harris HE, Ulfgren AK, Rantapää-Dahlqvist S, Eklund A, Padyukov L, Alfredsson L. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum, 2006. 54; 38-46. 5. Salliot C, B.C., Saraux A, Combe B, Dougados M Smoking is a risk factor for trhe production of anti-CCP and the diagnosis of RA only in patients who carry HLA-DRB1, with a dose-effect: results from the ESPOIR cohort. Arthritis Rheum, 2008. 58(suppl1); S878;1940. 6. Dayer, J.M., The saga of the discovery of IL-1 and TNF and their specific inhibitors in the pathogenesis and treatment of rheumatoid arthritis. Joint Bone Spine, 2002. 69; 123-32. 7. Raza K, Falciani F, Curnow SJ, Ross EJ, Lee CY, Akbar AN, Lord JM, Gordon C, Buckley CD, Salmon M. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther, 2005. 7; R784-95. 8. Gottenberg, J.E, Aucouturier F, Goetz J, Sordet C, Jahn I, Busson M, Cayuela JM, Sibilia J, Mariette X. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren's syndrome. Ann Rheum Dis, 2007. 66(1); 23-7. 9. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet, 2004. 364(9430): p. 263-9. 10. Verstappen, S.M., Jacobs JW, van der Veen MJ, Heurkens AH, Schenk Y, ter Borg EJ, Blaauw AA, Bijlsma JW. Utrecht Rheumatoid Arthritis Cohort study group. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis, 2007. 66;1443-9. 11. Goekoop-Ruiterman, Y.P., de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum, 2005. 52; 3381-90. 12. Boers, M., Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet, 1997. 350;309-18. 13. Choi, H.K., Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet, 2002. 359; 1173-7. 14. Jacobsson, L.T., Turesson C, Nilsson JA, Petersson IF, Lindqvist E, Saxne T, Geborek P. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis, 2007. 66; 670-5. 15. Van Vollenhoven R, E.S., Geborek P, Petersson IF, Coster L, Waltbrand E, et al In patients with early RA who fail initial methotrexate, the addition of anti- TNF yields better ACR and EULAR responses than the addition of conventional DMARDs/ 1-year results of the SWEFOT clinical trial. Arthritis Rheum, 2008. 58(suppl1); S539;1003. 16. Cohen G, Courvoisier N, Cohen JD, Zaltni S, Sany J, Combe B. The efficiency of switching from infliximab to etanercept and vice-versa in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2005 Nov-Dec;23; 795-800 17. Brocq O, Plubel Y, Breuil V, Grisot C, Flory P, Mousnier A, Euller-Ziegler L. Etanercept--infliximab switch in rheumatoid arthritis 14 out of 131 patients treated with anti TNFalpha]. Presse Med. 2002;31; 1836-9. 18. Brocq O, Albert C, Roux C, Gerard D, Breuil V, Ziegler LE. Adalimumab in rheumatoid arthritis after failed infliximab and/or etanercept therapy: experience with 18 patients. Joint Bone Spine. 2004 Nov;71; 601-3. 19. Solau-Gervais E, Laxenaire N, Cortet B, Dubucquoi S, Duquesnoy B, Flipo RM. Lack of efficacy of a third tumour necrosis factor alpha antagonist after failure of a soluble receptor and a monoclonal antibody. Rheumatology (Oxford). 2006; 45; 1121-4. 20. Hyrich, K.L., Lunt M, Watson KD, Symmons DP, Silman AJ. British Society for Rheumatology Biologics Register. Outcomes after switching from one anti- tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum, 2007. 56; 13-20. 21. van Vollenhoven R, Harju A, Brannemark S, Klareskog L. Treatment with infliximab (Remicade) when etanercept (Enbrel) has failed or vice versa: data from the STURE registry showing that switching tumour necrosis factor alpha blockers can make sense. Ann Rheum Dis. 2003; 62 ; 1195-8 22. Wick MC, Ernestam S, Lindblad S, Bratt J, Klareskog L, van Vollenhoven RF. Adalimumab (Humira) restores clinical response in patients with secondary loss of efficacy from infliximab (Remicade) or etanercept (Enbrel): results from the STURE registry at Karolinska University Hospital. Scand J Rheumatol. 2005; 34:353-8 23. Karlsson JA, Kristensen LE, Kapetanovic MC, Gülfe A, Saxne T, Geborek P. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford). 2008;47;507-13. 24. Gomez-Reino JJ, Carmona L; BIOBADASER Group. Switching TNF antagonists in patients with chronic arthritis: an observational study of 488 patients over a four-year period. Arthritis Res Ther. 2006;8:R29.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 25. Bombardieri S, Ruiz AA, Fardellone P, Geusens P, McKenna F, Unnebrink K, Oezer U, Kary S, Kupper H, Burmester GR; Research in Active Rheumatoid Arthritis (ReAct) Study Group. Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology (Oxford). 2007 ;46.1191-9. 26. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, Saldate C, Li T, Aranda R, Becker JC, Lin C, Cornet PL, Dougados M. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67:1096-103. 27. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, Birbara C, Box J, Natarajan K, Nuamah I, Li T, Aranda R, Hagerty DT, Dougados M. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005 ;353:1114-23 28. Schiff MH, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, Li T, Bahrt K, Kelly S, Le Bars M, Genovese MC. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-TNF therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2008 [Epub ahead of print 29. Simon TA, Smitten AL, Franklin J, Askling J, Lacaille D, Wolfe F, Hochberg MC, Qi K, Suissa S. Malignancies in the rheumatoid arthritis abatacept clinical development program: An epidemiological assessment. Ann Rheum Dis. 2008. [Epub ahead of print] 30. Sibilia J, Westhovens R. Safety of T-cell co-stimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007 ;25(5 Suppl 46):S46-56 31. Sibilia J, Gottenberg JE, Mariette X. Rituximab: a new therapeutic alternative in rheumatoid arthritis. Joint Bone Spine. 2008 ;75:526-32. 32. Sfikakis PP, Boletis JN, Lionaki S, Vigklis V, Fragiadaki KG, Iniotaki A, Moutsopoulos HM. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum. 2005;52:501-13. 33. Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC; REFLEX Trial Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006 ;54:2793-806 34. Finckh A, Ciurea A, Brulhart L, Kyburz D, Möller B, Dehler S, Revaz S, Dudler J, Gabay C; Physicians of the Swiss Clinical Quality Management Program for Rheumatoid Arthritis. B cell depletion may be more effective than switching to an alternative anti-tumor necrosis factor agent in rheumatoid arthritis patients with inadequate response to anti-tumor necrosis factor agents. Arthritis Rheum. 2007;56:1417-23. 35. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti- tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008 ;67:1516-23.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 36. Shakespeare TP, Gebski VJ, Veness MJ, Simes J.Improving interpretation of clinical studies by use of confidence levels, clinical significance curves, and risk-benefit contours. Lancet. 2001 ;357 : 1349-53.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 11. Appendices

Annexe 1: Définition de la réponse EULAR et des critères ACR

Critères EULAR

DAS28 Amélioration du DAS28 par rapport à la (valeur à valeur de base : l’évaluation finale) > 1,2 > 0,6 et < < 0,6 1,2 ≤ 3,2 Bon répondeur > 3,2 et ≤ Répondeur 5,1 modéré > 5,1 Non- réponde ur

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Annexe 2: Critères ACR 1987 de PR

1. Raideur matinale (articulaire ou périarticulaire) d’au moins une heure. 2. Arthrite d’au moins trois articulations (atteinte simultanée constatée par un médecin et due à une tuméfaction des tissus mous ou à un épanchement articulaire. Les 14 régions concernées sont les IPP, MCP, poignets, coudes, genoux et chevilles). 3. Arthrite des articulations de la main (au moins une région tuméfiée au niveau des IPP, MCP ou poignets). 4. Arthrite symétrique (atteinte simultanée et bilatérale des articulations ou groupes d’articulations définis en 2. L’atteinte simultanée des IPP, MCP, et MTP est acceptable même en l’absence de symétrie parfaite). 5. Nodules rhumatoïdes (nodosités sous-cutanées constatées par un médecin sur des crêtes osseuses ou des surfaces d’extension ou en situation périarticulaire). 6. présence du facteur rhumatoïde 7. Lésions radiologiques typiques sur les clichés des mains et des poignets (déminéralisation en bande évidente ou érosions

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Annexe 3: Note d’information concernant les appels téléphoniques

Madame, Monsieur,

Vous avez accepté de participer à l’étude « ROC » évaluant différents traitements de la polyarthrite rhumatoïde. Conformément à la notice d’information qui vous a été remise, vous trouverez dans ce document plus de détails concernant le déroulement de 2 appels téléphoniques qui seront effectués par Monsieur Hecketsweiler, technicien de recherche clinique de l’Hôpital de Strasbourg. Le but de ces appels sera de connaître votre évaluation concernant votre gêne et l’activité de la polyarthrite. Un premier appel téléphonique sera effectué dans les deux semaines suivant le début de l’étude, et un second appel 6 mois après. Ces entretiens nécessiteront environ 20 à 30 minutes de votre temps. Nous vous demandons de ne pas indiquer au technicien votre traitement, qu’il ne doit pas connaître.

Chaque appel ce déroulera en trois étapes :

1) On vous demandera d’évaluer sur une échelle de 0 à 100 l’activité globale de votre polyarthrite (douleur-gonflement-gêne) durant les deux derniers jours. La note 0 signifiant que la polyarthrite « va le mieux possible » et 100 qu’elle «va le plus mal que vous puissiez imaginer », par rapport à l’activité que vous avez connu.

2) Dans un deuxième temps, quelques questions sur votre gêne dans la vie de tous les jours vous seront posées (facilité à vous habiller, manger, bouger par exemple).

3) Enfin, il vous sera demandé de compter : - Le nombre de vos articulations douloureuses - Le nombre de vos articulations qui sont gonflées Pour cela nous vous demanderons de vous aider de la feuille de schémas qui vous a été remise. Grâce à ces schémas, vous pourrez repérer les articulations à évaluer, comme le fait votre médecin lorsqu’il vous examine.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 Pour les poignets, épaules, coudes et genoux, faire le test en mobilisant, c’est à dire en bougeant ces articulations.

Pour les mains : - faire le test une première fois en usant de votre autre main (main droite pour examiner votre main gauche et vice-versa) ,en appuyant avec le pouce sur le dos de l’articulation et l’index sur la paume de la même articulation, avec la même force pour chaque articulation pour compter le nombre d’articulations douloureuses à la pression. - faire le test une deuxième fois, en utilisant la même position de l’index et du pouce pour chercher une sensation de mouvement liquidien et appréciez votre impression visuelle (y a-t-il un gonflement apparent de part et d’autre de l’articulation) pour compter le nombre d’articulations gonflées.

Ne tester que les articulations représentées sur les dessins.

Lorsque le technicien vous téléphonera, il vous demandera de faire ces tests. Si vous le voulez, il pourra vous rappeler quelques minutes plus tard pour vous laisser le temps de l’évaluation. Afin de vous aider, vous pourrez cocher dans chaque tableau situé sous les schémas, vos articulations douloureuses, puis gonflées. Vous pourrez ensuite transmettre plus facilement vos réponses au technicien.

Nous vous remercions par avance du temps que vous nous consacrerez qui nous sera très utile pour interpréter les résultats de cette étude évaluant différents traitements de la PR.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

Annexe 4: Schéma des articulations

Merci de compter : - Dans un premier temps, le nombre d’articulations douloureuses - Dans un second temps, pour le nombre d’articulations gonflées

Faire le test en bougeant les articulations pour les épaules coudes, poignets et genoux

Pour vous aider vous pouvez cocher dans les cases les articulations douloureuses puis les gonflées :

Lettres : Articulations : Douleurs (cochez) Gonflements (cochez) A Poignet gauche B Coude gauche C Epaule Gauche D Epaule droite E Coude droit F Poignet droit G Genoux droit H Genoux gauche

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

Faire le test en palpant les articulations de chaque main : une première fois pour les douleurs et une seconde fois pour les gonflements

Pour vous aider vous pouvez cocher dans les cases les articulations douloureuses puis les gonflées de chaque main:

Chiffres : Couleurs : Douleurs Gonflements Lettres : Couleurs : Douleurs Gonflements (cochez) (cochez) (cochez) (cochez) 1 Orange I Gris 2 Jaune J Noir 3 Bleu ciel K Bleu ciel 4 Noir L Jaune 5 Gris M Orange 6 Vert clair N Rouge 7 Violet O Vert foncé 8 Bleu foncé P Bleu foncé 9 Vert foncé Q Violet 10 Rouge R Vert clair

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

Annexe 5: Elaboration et validation d’un questionnaire portant sur la sexualité des personnes atteintes de polyarthrite rhumatoïde

Coordinatrice principale : Pr Aleth Perdriger, CHU Rennes Méthodologiste : Dr Laure Gossec, CHU Cochin, Paris Médecin sexologue : Mme le Docteur Catherine Solano, Paris

Version octobre 2009

Plan

1. Contexte 2. Objectif 3. Type d’étude 4. Elaboration du questionnaire 4.1 FOCUS GROUP Participants Organisation 4.2 FORMULATION DU QUESTIONNAIRE 4.3. TEST DE FAISABILITE ET DE COMPREHENSION DU QUESTIONNAIRE 4.4.FINALISATION DU QUESTIONNAIRE. 5. Validation préliminaire du questionnaire 5..1 VALIDITE DE CONTENU, DE CONSTRUIT ET DE CORRELATION 5.2 REPRODUCTIBILITE 5.3 FAISABILITE 6. Sensibilité au changement 7.Bénéfices attendus 8.Aspects pratiques. 8.1 ETHIQUE. 8.2 ANONYMAT ET QUALITE DU RESPECT DE L’ETHIQUE 8.3FINANCEMENT 8.4COORDINATION 8.5DIFFUSION DES RESULTATS 8.6 PLANNING DE DATES

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

1. Contexte

Il est établi que les patients qui souffrent d’une PR peuvent également se plaindre de troubles de la sexualité. Ces troubles de la sexualité sont évalués comme important pour les personnes atteintes de PR puisqu’ils le sélectionnent comme domaine reflétant l’impact de la maladie (ref Gossec ARD dec 08 online first). Un certain nombre de patients évoquent une responsabilité de la PR dans la survenue de ces difficultés sexuelles.

Cependant, à ce jour il est difficile de mesurer les troubles de la sexualité dans la PR et les relations de la PR avec ces troubles de la sexualité, du fait de l’absence d’un questionnaire ayant de bonnes propriétés métrologiques (ref Boers Omeract filter 1992 J Rheum).

Les biothérapies améliorent divers aspects des symptômes de la polyarthrite rhumatoïde, y compris la qualité de vie (refs à ajouter). Cependant, l’effet éventuel des biothérapies sur la sexualité dans la PR n’est pas évalué, du fait de l’absence de questionnaire.

2. Objectif

L’objectif de ce travail est l’élaboration et la validation d’un questionnaire permettant d’évaluer le retentissement de la maladie et de ses traitements sur la sexualité des patients souffrant de PR. L’intérêt de ce travail est l’utilisation de ce questionnaire pour quantifier la responsabilité de la maladie sur d’éventuels troubles sexuels des malades et , donc comme instrument de mesure d’efficacité thérapeutique.

3. Type d’étude

Il s’agit d’une étude descriptive, observationnelle, (ave un suivi ?), qui se déroulera en trois étapes : - Elaboration du questionnaire : étude bicentrique (Paris, Rennes) prenant en compte les données de la littérature, l’avis d’un groupe d’experts comprenant un médecin sexologues, et l’opinion de patients, par une technique focus group et DELPHI modifiée. L’élaboration du questionnaire se fera selon un processus défini ci- dessous. - Validation du questionnaire : validation « pilote ». La validation du questionnaire respectera les règles établies par le groupe de méthodologistes de l’OMERACT (Outcoem Measures in Rheumatology). Il s’agira d’une validation préliminaire du questionnaire obtenu : validité de construit, faisabilité, reproductibilité et sensibilité au changement.

La cible est : tous les patients souffrant de polyarthrite rhumatoïde.

4. Elaboration du questionnaire

4.0 Réunion préparatoire :

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

Organisation cet été d’une réunion pour définir les objectifs de ce travail et l’organisation du focus group. Avis du sexologue sur la façon de parler de la sexualité avec les malades, choix des thèmes permettant de construire le questionnaire (fatigue, douleur, libido, sécheresse, regard, plaisir etc.) L’objectif est d’aborder la sexualité sous un aspect qualitatif, et de rechercher les paramètres pouvant être considérés comme pertinents pour l’analyse des relations entr PR et sexualité.

4.1 Focus group

Participants Sexologue (Paris), 6-7 personnes atteintes de PR dont au moins un patient expérimenté dans les groupes de parole, 2 rhumatologues dont un modérateur de séance. Organisation Une réunion d’une journée à Paris est organisée en septembre 2009, de type focus group pour faire ressortir par une discussion, les aspects essentiels des troubles de la sexualité dans la PR. Est ce qu’on mesure la même chose que par la qualité de vie ? Est-ce un aspect à part ?

4.2 Formulation du questionnaire

Participants : sexologue et les 2 rhumatologues Objectif : une liste de 2 à 10 questions permettant d’évaluer la sexualité. Etablir une cotation des réponses. Méthodes : le nombre de questions reflètent l’importance du domaine pour les patients du focus group. Prévoir une gestion des données manquantes.

4.3. Test de faisabilité et de compréhension du questionnaire

Test auprès de 10 patients du questionnaire sexualité seul pour vérifier la compréhension, l’acceptabilité, la compréhension des questions, les difficultés. (rester à coté pendant le remplissage et discuter du phrasing, des difficultés ou incompréhensions etc...en fait ce n'est pas le résultat qui compte mais le remplissage).

Pour les études qualitatives (entretiens pour générer des idées, analyse de compréhension…), l’important est d’être le plus exhaustif possible et donc de n’oublier personne (même ceux qui ne représentent que peu de personnes). Des hommes, des femmes, âges différents, qui travaillent ou non, zones géographiques différentes (au moins Paris/province ; ou rural/urbain)

Bien noter les commentaires qui peuvent mener (si répétés) à modifier le questionnaire légèrement.

Diffusion du test auprès de quelques soignants : je propose de le montrer à B Fautrel et C Beauvais, ainsi que 2 soignants : une infirmière de Cochin, et une de Rennes, pour vérifier l’acceptabilité.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

Montrer aussi le questionnaire à des associations de patients .

4.4.Finalisation du questionnaire.

Confrontation des résultats de l’étape précédente et éventuelle adaptation du questionnaire. Date prévue : avant le 4 novembre.

5. Validation préliminaire du questionnaire

5..1 Validité de contenu, de construit et de corrélation

Il s’agit de mesurer ce que l’on souhaite mesurer, c'est-à-dire la sexualité. Il n’existe pas de gold standard à ce sujet.

Design : transversal Patients : PR certaine, patients sélectionnés pour être représentatifs de la variabilité des patients, on visera 20-30% d’hommes et une répartition en termes d’âge et d’ancienneté de maladie, ainsi que d’ancienneté de biothérapie. Nombre de sujets : 50 patients (25 à Cochin, 25 à Rennes). Évaluation : remplissage d’un questionnaire patient comprenant le questionnaire sexualité et des questions générales ainsi que des questionnaires qualité de vie, fatigue, activité du rhumatisme, dépression. Analyse : en l’absence de gold standard, on regardera la corrélation avec - Autres questionnaires de sexualité - corrélation avec les mesures de self efficacy, de qualité de vie et de fatigue et dépression.

Il faut donc préparer un CRF avec -note d'information -des données sur la PR : ancienneté, symptômes actuels (douleur fatigue RAID), HAQ (afin de comparer les données sexualité à ces données), SF36, un questionnaire de dépression (HADS ?) et coping (RAI ?) - et intégrer dedans le nouveau questionnaire sexualité quand il sera finalisé - plus d’éventuels autres questionnaires de sexualité. - Partie médecin : le DAS28, le traitement par biothérapie oui/non.

5.2 Reproductibilité

Design : étude longitudinale sur 48h-7 jours. Patients : ceux de la phase précédente qui acceptent de remplir 2 fois le questionnaire Nombre de sujets : 30. Évaluation : remplissage du questionnaire sexualité à 2 reprises à 48h-7j d’intervalle. Analyse : accord par kappa et ICC.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

5.3 Faisabilité

Evaluation de la satisfaction/acceptabilité, pourcentage de données manquantes.

6. Sensibilité au changement

Il s’agit d’évaluer l’effet de biothérapies sur la sexualité. Objectifs : valider la sensibilité du questionnaire aux variations de l’activité de la PR Design : étude longitudinale sur 6 mois. Patients : patients ayant une PR, traités par biothérapie (PHRC ROC ?) Nombre de sujets : à préciser, a définir en fonction de l’objectif principal et des critères de quantification du questionnaire qui auront été élaborés. Voir avec le CRI pour l’inclusion. Évaluation : remplissage du questionnaire avant et après la biothérapie. Utilisation du questionnaire pour évaluer l’influence d’un traitement sur l’évolution de la sexualité des patients. Intérêt : analyser si un questionnaire sur la sexualité peut réellement être un instrument de mesure du caractère actif ou sévère de la PR Analyse : effet de la biothérapie sur la sexualité par standardised response means. Analyser les corrélations entre les variations obtenues avec le questionnaire sur la sexualité et les variations de l’activité patients (DAS, HAQ, EMIR…) sous traitement.

7. Bénéfices attendus

Le travail de type focus group permettra d’obtenir une meilleure compréhension sur la sexualité dans la PR. Le questionnaire sur la sexualité pourra servir d’outil d’évaluation d’efficacité thérapeutique ainsi que pour des enquêtes. (cf objectifs).

8. Aspects pratiques.

8.1 Ethique.

Le projet sera mené en accord avec les règles de la bonne pratique médicale, les accord d’Helsinki, après accord d’un comité d’éthique pour la validation de la sensibilité au changement et après consentement oral de chaque patient participant à l’élaboration.

8.2 Anonymat et qualité du respect de l’éthique

Les données seront remplies anonymement et transmises au centre coordinateur. La saisie sera réalisée anonymement (simple saisie). Les questionnaires et la base de données ne seront pas transmis à d’autres études.

8.3 Financement

Aucun pour l’élaboration. PHRC et éventuelle place d’une aide pharmaceutique pour la validation : à préciser. 8.4 Coordination

Downloaded From: https://jamanetwork.com/ on 09/28/2021 PHRC national 2009 HUS n°4507

La coordinatrice principale est le Pr A Perdriger. La méthodologiste est le Dr Laure Gossec.

8.5 Diffusion des résultats

Les résultats de l’étude seront diffusés via des congrès tel le congrès de la SFR 2010 et via une publication. Les co auteurs seront les personnes ayant participé activement au projet.

8.6 Planning de dates

Il est prévu les dates suivantes - Elaboration du questionnaire : focus group septembre 09 - Questionnaire finalisé avant mi novembre 2009 - Validation préliminaire en 2009 - Sensibilité au changement : 2010 (appel d’offre PHRC novembre 09) - Présentation au Congrès de la SFR décembre 2010 de l’élaboration - Rédaction d’un article avant le 31/12/2010

Downloaded From: https://jamanetwork.com/ on 09/28/2021 ,QLWLDOHVGXVXMHW 1GHFHQWUH 1SDWLHQW 3+5&1 +861 |___|___|___| |___|___|___| |___|___| °BB°BB°BB°

Elaboration d’un questionnaire sur la sexualité dans la polyarthrite rhumatoïde

Madame, Mademoiselle, Monsieur,

Nous vous proposons de participer à un projet de Recherche concernant l’influence de votre maladie sur la sexualité. Le but de cette lettre d’information est de vous expliquer ce projet. N’hésitez pas à solliciter votre rhumatologue si quelque chose ne vous semble pas clair ou si vous avez d’autres questions.

Objectif Votre médecin vous propose de participer à un projet intitulé « élaboration d’un questionnaire sur la sexualité dans la polyarthrite rhumatoïde ». Cette étude est réalisée en même temps que l’étude ROC que vous avez accepté, mais il s’agit d’une étude distincte, sans aucune obligation de votre part. Le but est d’élaborer et de valider un questionnaire pour évaluer la sexualité dans la polyarthrite.

Description Il est prévu qu’au moins 150 patients remplissent, comme vous, ce questionnaire dans toute la France, avant le changement de traitement qui vous est proposé, puis 6 mois plus tard. Cette étude ne durera pour chaque patient inclus que la durée nécessaire pour remplir ce questionnaire. Le questionnaire comprend des questions portant sur l’influence de votre polyarthrite sur votre vie sexuelle, Le questionnaire fait 3 pages et est rempli en 5 minutes environ. Il n’y aura pas d’évaluation spécifique par le médecin, et pas d’autres examens à réaliser.

Renseignements confidentiels Tous les renseignements fournis pour cette étude sont absolument confidentiels et soumis au secret médical. Les questionnaires seront traités dans la plus stricte confidentialité. Les données enregistrées à l’occasion de cette étude pourront faire l’objet d’un traitement informatisé par les médecins coordonnateurs de l’étude mais uniquement de façon anonyme, en utilisant un numéro et non pas vos noms et prénoms.

Downloaded From: https://jamanetwork.com/ on 09/28/2021 ,QLWLDOHVGXVXMHW 1GHFHQWUH 1SDWLHQW 3+5&1 +861 |___|___|___| |___|___|___| |___|___| °BB°BB°BB°

Questionnaire sexualité et polyarthrite : validation du questionnaire

Ce questionnaire contient des informations importantes sur votre qualité de vie actuellement. Veuillez répondre aux questions suivantes, même si vous pensez qu’elles ne vous concernent pas en ce moment, il n’y a pas de bonne ni de mauvaise réponse. Pour chaque question, veuillez cocher la réponse qui correspond le mieux à ce que vous ressentez ou pensez. Ce questionnaire sera analysé de façon tout à fait anonyme. Merci.

Date de ce jour : jour /__/__/ mois /__/__/ 2010

1) Questionnaire sexualité

Ces questions concernent les conséquences de votre polyarthrite rhumatoïde sur votre vie sexuelle. Merci d’entourer le chiffre qui correspond le mieux à votre état, au cours des 3 derniers mois.

1. Au cours des 3 derniers mois : votre état de santé a-t-il été responsable d’une perturbation de votre vie sexuelle ?