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Lancet. 2009 Nov 7;374(9701):1617-25. doi: 10.1016/S0140-6736(09)61302-7.

Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.

Collaborators (694)

Dupas JL, Godeberge P, Hugot JP, Nahon S, Sabaté JM, Tucat G, Colombel JF, Cosnes J, Gendre JP, Lémann M, Hébuterne X, Cortot A, Bouhnik Y, Laharie D, Flourié B, Lerebours E, Beaugerie L, Peyrin-Biroulet L, Allez M, Messing B, Cadiot G, Marteau P, Soulé JC, Gornet JM, Veyrac M, Duclos B, Beau P, Bourreille A, Baumer P, Carbonnel F, Heresbach D, Metman EH, Florent C, Blain A, Faucheron JL, Potier P, Boehm C, Kurtz T, Lamouliatte H, Nion-Larmurier I, Delchier JC, Chaussade S, Weiss AM, Cézard JP, Siproudhis L, Sondag D, Jian R, Souquet JC, Bord P, Coffin B, D'almagne H, Delasalle P, Fournier R, Cavicchi M, Souffran MH, Vandromme L, Guedon C, Seksik P, Michiels C, Renard P, Rogier P, Gouilloud S, Rotenberg A, Savoye G, Thevenin A, Mallet L, Brazier F, Jean F, Justum AM, Latrive JP, Gerbal JL, Pierrugues R, Chardonnal G, Picon L, Reix N, Drouët D'aubigny N, Uettwiller H, Courillon Mallet A, Palacci A, Bensaude RJ, Bonniaud P, Empinet O, Nisard A, Rudelli A, Tubiana B, Capelle P, Dabadie A, Evard D, Julien PE, Picon-Coste M, Schneider S, Goldfain D, Bellanger J, Blondelot JP, Lamy P, Lemière S, Mockly JF, Pellat B, Gatineau-Sailliant G, Nalet B, Nancey S, Kusielewicz D, Loison P, Popot JM, Merite F, Roux JP, Afchain P, Blanquart A, Heyries L, Reville M, Viron D, Zerbib F, Claviere C, Léostic D, Pouderoux P, Moitry A, Hagège H, Humeau B, Lederman E, Lescut D, Luneau F, Mesnard B, Smadja L, Steinberg M, Brun M, Macaigne G, Marchal JL, Ollivier S, Ouvry D, Perche JP, Rambaud S, Benamouzig R, Cazenave JL, Coffin JC, Blazquez M, Lagneau M, Person B, Wittersheim C, Napoleon B, Cemachovic I, Iglicki F, Howaizi M, Leprince E, Leurent B, Morin T, Darsouni R, Attar A, Baron P, Breton A, Gillion JM, Guemene JM, Jouffre C, Moreau X, Claude P, Quinton A, Abitbol V, Brichard JM, Desaint B, Bouygues M, Chatrenet P, Salmeron M, Silvie J, Waldner B, Emery Y, Moraillon A, Kunkel D, Dubois P, Faure P, L'Hirondel C, Labérenne JE, Moreau P, Pereira A, Plihon G, Wolff T, Ngo Y, Boruchowicz A, Jost B, Gotlib JP, Danne O, Raoux P, Ramond-Bouhali MJ, Baetz A, Veyres B, Chapoutot C, Le Dréau G, Filippi J, Mudry J, Kalt P, Minault S, Bounin PA, Andréani T, Charneau J, Reijasse D, Bolze JL, Thaunat JL, Le Couteulx C, Maurage C, Bader R, Codjovi P, Migairou JL, Morali A, Rey P, Molard BR, Petit R, Koch S, Cassan P, Deschamps JP, Meicler Caby C, Meurisse JJ, Prades P, Boulant J, Diacono M, Monsch JM, Dupuy JF, Bellaiche G, Guegan M, Comte JM, Cayla JM, Le Tallec F, Meurisse F, Desurmont P, Roget L, Bouyssou P, Le Gall B, Bloch F, Larvol L, Jullien M, Moreau J, Rebouissoux L, Decroix B, Dib N, Dieterling P, Lenormand F, Lagier E, Fallourd P, Charpin S, Bertrand H, Bommelaer G, Battistelli D, Delon B, Dentant L, Dorval E, Dumortier J, Gaye-Bareyt E, Gerosa Y, Guez C, Mornet M, Benfredj P, Piperaud R, Stremsdoerfer N, Verdier E, Grinholtz A, Barjonet G, See A, Arotçarena R, Baudet A, Broyer J, Charachon A, Blondon H, Mouton P, Claudez H, Labat-Labourdette J, Haëm J, Estable P, Levy P, Rosenbaum A, Balavoine Y, Blanchi A, Coutarel P, Delaperriere N, Dervichian M, Marois F, Seroka J, Michaud L, Leroy O, Meyran E, Poilroux B, Tensaouti A, Paupard T, Agard D, Beaulieu S, Benfiguig K, Capony P, Cottereau J, Desreumaux P, Dramard JM, Duché M, Mamou P, Etienney I, D'Abrigeon G, Godeberge B, Puech J, Roger J, Lapalus MG, Bauret P, Houcke P, Pornin B, Champigneulle B, Cuissard L, David XR, Lombard F, Granveau A, Hamon JF, Ink O, Blondel F, Namias A, Pillon D, Reignier A, Tordjman G, Christidis C, Zirabe S, Audebert M, Bion E, Bourgeaux C, Poupardin C, Deplaix P, Fratini G, Garnier T, Desseaux G, Magois H, Lochum S, Vergier JF, Texereau P, Rat C, Uzzan F, Vidal A, Vinante N, Watrin B, Wurtz-Huckert C, Barre B, Chaslin Ferbus D, Contou JF, Coupier D, David B, Gargot D, Huc D, Barraya R, Faroux R, Fourgeaud JL, Grimprel H, Auroux J, Rey JF, Arnoux JP, Lentini F, Tardy L, Mouterde O, Spyckerelle C, Vacherot B, Weissman A, Alpérine M, Le Sidaner A, Bonnet-Eymard PO, Colson JL, Pellet D, Deltombe B, Edouard A, Maechel H, Jaillet JC, Genes J, Leveque AM, Lucidarme D, Maignan P, Mallier Gehrke N, Sanchez J, Tusseau F, Casteur A, Bottlaender J, Constantini D, Coton T, Even P, Druart F, Riot F, Gauchet JM, Hecquet G, Henry G, Hochain P, Arpurt JP, Medini A, Dartois-Hoguin M, Moindrot H, Emery P, Periac P, Prunier A, Renkes P, Tawil-Longreen C, Vincent E, Vitte RL, Loeb C, Carwana A, Barbereau D, Bohon P, Corrieri-Baizeau C, Sahy D, Derreveaux P, David D, Desbazeille F, Fontenelle P, Slama JL, Le Mercier Y, Certin M, Reig JJ, Rosa I, Helbert T, Tounian P, Turner L, Perot V, Aillet L, Pauwels A, Barré P, Nury B, Cazalbou C, Devulder F, Durget A, Dubroca J, Gaudy D, Greff M, Jacques C, Lafarge J, Kezachian G, Le Gall R, Pariente A, Pinault T, Bismuth M, Boyer-Darrigrand N, Bretagnolle P, Carpentier S, Cholet F, Theodore C, Combes R, Combet F, Delanoe C, De Montigny S, Soudan D, Fourdan O, Minier G, Languepin J, Roche J, Ginies JL, Nouel O, Petitgars P, Robin E, Hamm R, Roques JF, Roussin-Bretagne S, Sénéjoux A, Muron S, Bardoux N, Berthelemy P, Madonia P, Carles B, Reynier C, Cuillerier E, Dadamessi I, Danis J, Debenes B, Dubuc-Rey N, Lesur G, Jouet P, Lenaerts C, Garret M, Mineur A, Chabry B, Pigot F, Rossi V, Tennenbaum R, Salloum J, Slaoui MH, Mathieu S, Papapietro V, Viola S, Bezet A, Altman C, Audan A, Calabet J, Masliah C, Fayemendy L, Duruy M, Gauffeny B, Helie L, Imani K, Janin-Manificat R, Galmiche JP, Kerlirzin A, Bedenne L, Locher C, Michaudel G, Missonnier G, Rinaldi-Dovio M, Rouillon JM, Ecuer S, Patenotte A, Bronstein JA, Baty V, Bougnol M, Bourbon P, Cerbelaud P, Chavaillon A, Boiffin F, Dubern B, Duval De Laguierce I, Greco F, Bouhot F, Grandmaison B, Gros P, Targues G, Corallo J, Boutin J, Guillan J, Barbieux JP, Loury Lariviere I, Le Genissel H, Leroi H, Bellaiche M, Elie-Legrand MC, Dapoigny M, Denoyel P, Pienkowski P, Pouche P, Saurfelt MM, Thorel JM, Piche T, Travers B, Tuvignon P, Zalcberg M, Boulay G, Zamora C, Samama J, Ricotie E, De Fleury P, Maille F, Mougenel JL, Gonot O, Menat JP, Kaassis M, Lang F, Abramowitz L, Ganne N, Pecriaux O, Seyrig JA, Sobhani I, Parmentier T, Van Nieuwenhuyse A, Weber FX, Glibert A, Bineau C, Canet B, Collin C, Cordet F, Parlier DD, Carre D, Peytier A, Fein F, Barouk J, Dewannieux J, Hartwig J, Jouve JL, Laplane B, Lascar G, Legrand C, Le Marchand P, Liebaert MP, Terdiman-Pire M, Abdelli N, Neveu D, De La Lande P, De Saint Louvent P, Pelatan C, Petit A, Richecoeur M, Texier F, Cazals JB, Tissot B, Mourrut C, Doubremelle M, Foltz M, Gautier-Jubé F, Martin J, Khouri E, Lons T, Carlier-Bandu M, Monnin JL, Roche H, Willemin B, Houard X, Fatisse A, Algard M, Arab K, Borel I, Lagarrigue C, Chryssostalis A, Boutroux D, Dupuychaffray JP, Khaddari S, Mion F, Puy-Montbrun T, Girardet JP, Gury B, Landau A, Le Bihan M, Nieuviarts S, Ollivry J, Le Bourgeois P, Piquet MA, Escartin MP, Systchenko R, Venezia F, Wantiez M, Lesage X, Zrihen E, Aygalenq P, Dieumegard B, Savarieau B, Bulois P, Cattan S, Diez JL, Fauchot O, Durous E, Gazut V, Guilleminet C, Bories JM, Joly Le Floch I, Vove JP, Lelouch S, Lévy P, Lhopital F, Marcato N, Mozer-Bernardeau M, Nousbaum JB, Cattan P, Plane A, Raymond JM, Roseau G, Rozental G, Boustière C, Bonny C, Cordier-Collet M, Courat L, Croguennec B, Delaunay-Tardy K, Labarriere D, Geagea E, Gottrand F, Gelsi E, Thiefin G, Wohlschies E, Miguet M, Ponsot P, Suzanne J, Teste Y, Dupont Gossart AC, Baroni JL, Benchaa B, Blanc G, Maroy B, Bonjean P, Brézault C, Bridoux-Henno L, Chayette C, Auby D, Fiorucci R, Galindo G, Hubert G, Bonneau G, Marinier E, Pouteau M, Alamdari A, Delbende B, Chamouard P, D'Abravanel P, Dall'Osto H, Hervé S, Lefebvre J, Levoir D, Lillo P, Rouch M, Mathonnet M, De Lustrac M, Ramond FJ, Roupret B, Soupison A, Ait-Ouadda D, Barbaza Y, Bayart B, Bottini T, Cochet F, Goderel I, Maury O, Mbonyingo L, Pourtau V, Romain-Huttin L, Sallé AV, Trang J, Admane H, Drouet E.

Abstract

BACKGROUND:

Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a prospective observational cohort study.

METHODS:

19,486 patients with inflammatory bowel disease, of whom 11,759 (60.3%) had Crohn's disease and 7727 (39.7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29-40).

FINDINGS:

At baseline, 5867 (30.1%) of patients were receiving, 2809 (14.4%) had discontinued, and 10,810 (55.5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0.90 per 1000 (95% CI 0.50-1.49) patient-years in those receiving, 0.20/1000 (0.02-0.72) patient-years in those who had discontinued, and 0.26/1000 (0.10-0.57) patient-years in those who had never received thiopurines (p=0.0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5.28 (2.01-13.9, p=0.0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease.

INTERPRETATION:

Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders.

FUNDING:

Programme Hospitalier de Recherche Clinique National (AOM05157), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.

PMID:
19837455
DOI:
10.1016/S0140-6736(09)61302-7
[Indexed for MEDLINE]

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