Rates of, and risk factors for, severe infections in patients with systemic autoimmune diseases receiving biological agents off-label

Arthritis Research & Therapy

Cándido Díaz-Lagares¹⁴  Roberto Pérez-Alvarez²  Francisco J García-Hernández¹³  María M Ayala-Gutiérrez¹⁰  José Luis Callejas¹¹  Agustín Martínez-Berriotxoa¹²  Javier Rascón⁹  Luis Caminal-Montero⁵  Albert Selva-O'Callaghan⁶  Joaquim Oristrell⁷  Carmen Hidalgo¹  Ricardo Gómez-de-la-Torre⁴  Luis Sáez³  Jesús Canora-Lebrato⁸  María-Teresa Camps¹⁰  Norberto Ortego-Centeno¹¹  María-Jesús Castillo-Palma¹³  Manuel Ramos-Casals¹⁴ 

[1] Servicio de Medicina Interna, Hospital Virgen de las Nieves, Avda. Fuerzas Armadas, Granada, 18014, Spain

[2] Servicio de Medicina Interna, Hospital Meixoeiro, Meixoeiro, Vigo, 36200, Spain

[3] Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario Miguel Servet, Paseo Isabel la Católica, Zaragoza, 50009, Spain

[4] Servicio de Medicina Interna, Hospital de Avilés, C/Camino Heros, Avilés, 33401, Spain

[5] Servicio de Medicina Interna, Hospital Universitario Central de Asturias, C/Celestino Villamil, Oviedo, 33006, Spain

[6] Servicio de Medicina Interna, Hospital Vall d'Hebron, Passeig Vall d'Hebron, Barcelona, 08035, Spain

[7] Servicio de Medicina Interna, Hospital Parc Taulí, C/Parc Taulí, Sabadell, 08208, Spain

[8] Hospital Universitario de Fuenlabrada, Camino del Molino, Fuenlabrada, 28942, Spain

[9] Servicio de Medicina Interna, Hospital Son Dureta, C/Andrea Doria, Palma de Mallorca, 07014, Spain

[10] Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Carlos Haya, Avda. Carlos Haya, Málaga, 29010, Spain

[11] Unidad de Enfermedades Autoinmunes Sistémicas, Hospital San Cecilio, Avda. Dr. Olóriz, Granada, 18012, Spain

[12] Servicio de Medicina Interna, Hospital de Cruces, Plaza Cruces-Gurutzeta, Barakaldo, 48903, Spain

[13] Unidad de Colagenosis, Servicio de Medicina Interna, Hospital Virgen del Rocío, Avda. Manuel Siurot, Sevilla, 41013, Spain

[14] Laboratorio de Enfermedades Autoinmunes Josep Font, IDIBAPS, Hospital Clínic, C/Villarroel, Barcelona, 08036, Spain

关键词: vasculitis;    Sjögren syndrome;    systemic lupus erythematosus;    adalimumab;    etanercept;    infliximab;    rituximab;    Infection rate;   

Others  :  1098651
DOI  :  10.1186/ar3397

 received in 2011-01-13, accepted in 2011-07-11,  发布年份 2011

【 摘 要 】

Introduction

The purpose of this observational study was to analyze the rates, characteristics and associated risk factors of severe infections in patients with systemic autoimmune diseases (SAD) who were treated off-label with biological agents in daily practice.

Methods

The BIOGEAS registry is an ongoing Spanish prospective cohort study investigating the long-term safety and efficacy of the off-label use of biological agents in adult patients with severe, refractory SAD. Severe infections were defined according to previous studies as those that required intravenous treatment or that led to hospitalization or death. Patients contributed person-years of follow-up for the period in which they were treated with biological agents.

Results

A total of 344 patients with SAD treated with biological agents off-label were included in the Registry until July 2010. The first biological therapies included rituximab in 264 (77%) patients, infliximab in 37 (11%), etanercept in 21 (6%), adalimumab in 19 (5%), and 'other' agents in 3 (1%). Forty-five severe infections occurred in 37 patients after a mean follow-up of 26.76 months. These infections resulted in four deaths. The crude rate of severe infections was 90.9 events/1000 person-years (112.5 for rituximab, 76.9 for infliximab, 66.9 for adalimumab and 30.5 for etanercept respectively). In patients treated with more than two courses of rituximab, the crude rate of severe infection was 226.4 events/1000 person-years. A pathogen was identified in 24 (53%) severe infections. The most common sites of severe infection were the lower respiratory tract (39%), bacteremia/sepsis (20%) and the urinary tract (16%). There were no significant differences relating to gender, SAD, agent, other previous therapies, number of previous immunosuppressive agents received or other therapies administered concomitantly. Cox regression analysis showed that age (P = 0.015) was independently associated with an increased risk of severe infection. Survival curves showed a lower survival rate in patients with severe infections (log-rank and Breslow tests < 0.001).

Conclusions

The rates of severe infections in SAD patients with severe, refractory disease treated depended on the biological agent used, with the highest rates being observed for rituximab and the lowest for etanercept. The rate of infection was especially high in patients receiving three or more courses of rituximab. In patients with severe infections, survival was significantly reduced. Older age was the only significant predictive factor of severe infection.

【 授权许可】

   
2011 Díaz-Lagares et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Silverman GJ, Weisman S: Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003, 48:1484-1492.
• [2]Ramos-Casals M, Brito-Zerón P, Muñoz S, Soto MJ, BIOGEAS STUDY Group: A systematic review of the off-label use of biological therapies in systemic autoimmune diseases. Medicine (Baltimore) 2008, 87:345-364.
• [3]Meijer JM, Meiners PM, Vissink A, Spijkervet FK, Abdulahad W, Kamminga N, Brouwer E, Kallenberg CG, Bootsma H: Effectiveness of rituximab treatment in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010, 62:960-968.
• [4]Dass S, Bowman SJ, Vital EM, Ikeda K, Pease CT, Hamburger J, Richards A, Rauz S, Emery P: Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann Rheum Dis 2008, 67:1541-1544.
• [5]Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, Utset TO, Gordon C, Isenberg DA, Hsieh HJ, Zhang D, Brunetta PG: Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010, 62:222-233.
• [6]Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group: Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010, 363:221-232.
• [7]Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group: Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010, 363:211-220.
• [8]Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, Salvarani C, Xu W, Visvanathan S, Rahman MU, Infliximab-GCA Study Group: Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007, 146:621-630.
• [9]Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P, Cimmino M, Gerli R, Catanoso MG, Boiardi L, Cantini F, Klersy C, Hunder GG: Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007, 146:631-639.
• [10]Baughman RP, Lower EE, Bradley DA, Raymond LA, Kaufman A: Etanercept for refractory ocular sarcoidosis: results of a double-blind randomized trial. Chest 2005, 128:1062-1047.
• [11]Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J: Inefficacy of infliximab in primary Sjögren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjögren's Syndrome (TRIPSS). Arthritis Rheum 2004, 50:1270-1276.
• [12]Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, Hamuryudan V, Yazici H: Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J Rheumatol 2005, 32:98-105.
• [13]Rossman MD, Newman LS, Baughman RP, Teirstein A, Weinberger SE, Miller W Jr, Sands BE: A double-blinded, randomized, placebo-controlled trial of infliximab in subjects with active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2006, 23:201-208.
• [14]Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR: Etanercept in Sjögren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 2004, 50:2240-2245.
• [15]Wegener's Granulomatosis Etanercept Trial (WGET) Research Group: Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005, 352:351-361.
• [16]Martínez-Taboada VM, Rodríguez-Valverde V, Carreño L, López-Longo J, Figueroa M, Belzunegui J, Mola EM, Bonilla G: A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008, 67:625-630.
• [17]Ramos-Casals M, García-Hernández FJ, de Ramón E, Callejas JL, Martínez-Berriotxoa A, Pallarés L, Caminal-Montero L, Selva-O'Callaghan A, Oristrell J, Hidalgo C, Pérez-Alvarez R, Micó ML, Medrano F, Gómez de la Torre R, Díaz-Lagares C, Camps M, Ortego N, Sánchez-Román J, BIOGEAS Study Group: Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010, 28:468-476.
• [18]Terrier B, Amoura Z, Ravaud P, Hachulla E, Jouenne R, Combe B, Bonnet C, Cacoub P, Cantagrel A, de Bandt M, Fain O, Fautrel B, Gaudin P, Godeau B, Harlé JR, Hot A, Kahn JE, Lambotte O, Larroche C, Léone J, Meyer O, Pallot-Prades B, Pertuiset E, Quartier P, Schaerverbeke T, Sibilia J, Somogyi A, Soubrier M, Vignon E, Bader-Meunier B, Mariette X, Gottenberg JE, Club Rhumatismes et Inflammation: Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 2010, 62:2458-2466.
• [19]Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP, British Society for Rheumatology Biologics Register: Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid artritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2006, 54:2368-2376.
• [20]Galloway JB, Hyrich KL, Mercer LK, Dixon WG, Fu B, Ustianowski AP, Watson KD, Lunt M, BSRBR Control Centre Consortium, Symmons DP, on behalf of the British Society for Rheumatology Biologics Register: Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid artritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford) 2011, 50(1):124-131.
• [21]Dixon WG, Carmona L, Finckh A, Hetland ML, Kvien TK, Landewe R, Listing J, Nicola PJ, Tarp U, Zink A, Askling J: EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology. Ann Rheum Dis 2010, 69:1596-1602.
• [22]Gürcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR: A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009, 9:10-25.
• [23]Nam JL, Winthrop KL, van Vollenhoven RF, Pavelka K, Valesini G, Hensor EM, Worthy G, Landewé R, Smolen JS, Emery P, Buch MH: Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of RA. Ann Rheum Dis 2010, 69:976-986.
• [24]Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lortholary O, Mariette X, Research Axed on Tolerance of Biotherapies Group: Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French Research Axed on Tolerance of Biotherapies registry. Arthritis Rheum 2009, 60:1884-1894.
• [25]Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, van Vollenhoven RF, Klareskog L: Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists. Ann Rheum Dis 2007, 66:1339-1344.
• [26]Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, British Society for Rheumatology Biologics Register Control Centre Consortium, on behalf of the British Society for Rheumatology Biologics Register: Serious infection following anti-tumor necrosis factor _ therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum 2007, 56:2896-2904.
• [27]Carmona L, Descalzo MA, Perez-Pampin E, Ruiz-Montesinos D, Erra A, Cobo T, Gómez-Reino JJ, BIOBADASER and EMECAR Groups: All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis 2007, 66:880-885.
• [28]Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V: Anti-TNF antibody therapy in rheumatoid artritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006, 295:2275-2285.
• [29]Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, Gromnica-Ihle E, Antoni C, Herzer P, Kekow J, Schneider M, Zink A: Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005, 52:3403-3412.
• [30]Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M, Shatin D, Saag KG: Risk of serious bacterial infections among rheumatoid artritis patients exposed to tumor necrosis factor antagonists. Arthritis Rheum 2007, 56:1125-1133.
• [31]Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE: Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002, 46:2287-2293.
• [32]Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE: Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002, 46:2294-2300.
• [33]Lacaille D, Guh DP, Abrahamowicz M, Anis AH, Esdaile JM: Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients with rheumatoid arthritis. Arthritis Rheum 2008, 59:1074-1081.
• [34]Gottenberg JE, Ravaud P, Bardin T, Cacoub P, Cantagrel A, Combe B, Dougados M, Flipo RM, Godeau B, Guillevin L, Le Loët X, Hachulla E, Schaeverbeke T, Sibilia J, Baron G, Mariette X, AutoImmunity and Rituximab registry and French Society of Rheumatology: Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 2010, 62:2625-2632.
• [35]BIOGEAS [http://www.biogeas.es] webcite