BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of infection and malignancy compared with the general population. Infection risk is increased further with the use of disease-modifying antirheumatic drugs (DMARDs), whereas evidence on whether the use of biologic DMARDs increases cancer risk remains equivocal. This single-arm, post-marketing study estimated the incidence of prespecified infection and malignancy outcomes in patients with RA treated with intravenous or subcutaneous abatacept. METHODS: Data were included from seven European RA quality registries: ATTRA (Anti-TNF Therapy in Rheumatoid Arthritis [Czech Republic]), DANBIO (Danish Rheumatologic Database), ROB-FIN (National Registry of Antirheumatic and Biological Treatment in Finland), ORA (Orencia and Rheumatoid Arthritis [France]), GISEA (Italian Group for the Study of Early Arthritis), BIOBADASER (Spanish Register of Adverse Events of Biological Therapies in Rheumatic Diseases), and the SCQM (Swiss Clinical Quality Management) system. Each registry is unique with respect to design, data collection, definition of the study cohort, reporting, and validation of outcomes. In general, registries defined the index date as the first day of abatacept treatment and reported data for infections requiring hospitalization and overall malignancies; data for other infection and malignancy outcomes were not available for every cohort. Abatacept exposure was measured in patient-years (p-y). Incidence rates (IRs) were calculated as the number of events per 1000 p-y of follow-up with 95% confidence intervals. RESULTS: Over 5000 patients with RA treated with abatacept were included. Most patients (78-85%) were female, and the mean age range was 52-58 years. Baseline characteristics were largely consistent across registries. Among patients treated with abatacept, IRs for infections requiring hospitalization across the registries ranged from 4 to 100 events per 1000 p-y, while IRs for overall malignancy ranged from 3 to 19 per 1000 p-y. CONCLUSIONS: Despite heterogeneity between registries in terms of design, data collection, and ascertainment of safety outcomes, as well as the possibility of under-reporting of adverse events in observational studies, the safety profile of abatacept reported here was largely consistent with previous findings in patients with RA treated with abatacept, with no new or increased risks of infection or malignancy.

ASST PINI CTO Hospital Milan Italy

BIOBADASER Research Unit Sociedad Española de Reumatología Madrid Spain

Bristol Myers Squibb Princeton NJ 08534 USA

DANBIO and Copenhagen Center for Arthritis Research Center for Rheumatology and Spine Diseases Centre of Head and Orthopedics Rigshospitalet Glostrup Denmark

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Departments of Medicine and Rheumatology Helsinki University Hospital and Helsinki University Helsinki Finland

DETO Rheumatology Unit University of Bari Bari Italy

Division of Rheumatology University Hospitals of Geneva Geneva Switzerland

Institute of Rheumatology Prague Czech Republic

Rheumatology Department Hospital Clinic of Barcelona Barcelona Spain

Strasbourg University Hospitals Strasbourg France

Zobrazit více v PubMed

Winthrop KL. Infections and biologic therapy in rheumatoid arthritis: our changing understanding of risk and prevention. Rheum Dis Clin North Am. 2012;38:727–745. doi: 10.1016/j.rdc.2012.08.019. PubMed DOI

Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis 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. doi: 10.1001/jama.295.19.2275. PubMed DOI

Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2015;17:212. doi: 10.1186/s13075-015-0728-9. PubMed DOI PMC

Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10:R45. doi: 10.1186/ar2404. PubMed DOI PMC

Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP, Gonzales-Crespo MR, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. 2012;308:898–908. doi: 10.1001/2012.jama.10857. PubMed DOI

Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidermiol Drug Saf. 2011;20:119–130. doi: 10.1002/pds.2046. PubMed DOI

Wadstrom H, Frisell T, Askling J, Anti-Rheumatic Therapy in Sweden Study Group Malignant neoplasms in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors, tocilizumab, abatacept, or rituximab in clinical practice: a nationwide cohort study from Sweden. JAMA Intern Med. 2017;177:1605–1612. doi: 10.1001/jamainternmed.2017.4332. PubMed DOI PMC

Mercer LK, Lunt M, Low AL, Dixon WG, Watson KD, Symmons DP, et al. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2015;74:1087–1093. doi: 10.1136/annrheumdis-2013-204851. PubMed DOI PMC

Dreyer L, Mellemkjaer L, Andersen AR, Bennett P, Poulsen UE, Juulsgaard Ellingsen T, et al. Incidences of overall and site specific cancers in TNF alpha inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry. Ann Rheum Dis. 2013;72:79–82. doi: 10.1136/annrheumdis-2012-201969. PubMed DOI

Ozen G, Pedro S, Schumacher R, Simon TA, Michaud K. Safety of abatacept compared with other biologic and conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: data from an observational study. Arthritis Res Ther. 2019;21:141. doi: 10.1186/s13075-019-1921-z. PubMed DOI PMC

Montastruc F, Renoux C, Dell’Aniello S, Simon TA, Azoulay L, Hudson M, et al. Abatacept initiation in rheumatoid arthritis and the risk of cancer: a population-based comparative cohort study. Rheumatology (Oxford) 2019;58:683–691. doi: 10.1093/rheumatology/key352. PubMed DOI PMC

Huss V, Bower H, Wadström H, Frisell T, Askling J. Short- and longer-term cancer risks with biologic and targeted synthetic disease-modifying antirheumatic drugs as used against rheumatoid arthritis in clinical practice. Rheumatology (Oxford) 2022;61:1810–1818. doi: 10.1093/rheumatology/keab570. PubMed DOI PMC

Grøn KLGB, Nørgaard M, Mehnert F, Østergaard M, Dreyer L, Krogh NS, Hetland ML. Overall infection risk in rheumatoid arthritis during treatment with abatacept, rituximab and tocilizumab; an observational cohort study. Rheumatology (Oxford) 2020;59:1949–1956. doi: 10.1093/rheumatology/kez530. PubMed DOI

Mercer LK, Askling J, Raaschou P, Dixon WG, Dreyer L, Hetland ML, et al. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers. Ann Rheum Dis. 2017;76:386–391. doi: 10.1136/annrheumdis-2016-209285. PubMed DOI PMC

Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis. 2007;66:228–234. doi: 10.1136/ard.2006.055111. PubMed DOI PMC

Toupin-April K, Barton J, Fraenkel L, Li LC, Brooks P, De Wit M, et al. Toward the development of a core set of outcome domains to assess shared decision-making interventions in rheumatology: results from an OMERACT Delphi Survey and Consensus Meeting. J Rheumatol. 2017;44:1544–1550. doi: 10.3899/jrheum.161241. PubMed DOI PMC

Orencia (250 mg powder for concentrate for solution for infusion) Summary of Product Characteristics. 2013. http://www.medicines.org.uk/emc/medicine/19714/SPC/. Accessed 2/2/2018.

Emery P, Durez P, Dougados M, Legerton CW, Becker JC, Vratsanos G, et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial) Ann Rheum Dis. 2010;69:510–516. doi: 10.1136/ard.2009.119016. PubMed DOI PMC

Emery P, Burmester GR, Bykerk VP, Combe BG, Furst DE, Barre E, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis. 2015;74:19–26. doi: 10.1136/annrheumdis-2014-206106. PubMed DOI PMC

Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–1123. doi: 10.1056/NEJMoa050524. PubMed DOI

Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349:1907–1915. doi: 10.1056/NEJMoa035075. PubMed DOI

Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005;52:2263–2271. doi: 10.1002/art.21201. PubMed DOI

Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006;144:865–876. doi: 10.7326/0003-4819-144-12-200606200-00003. PubMed DOI

Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67:1096–1103. doi: 10.1136/ard.2007.080002. PubMed DOI PMC

Schiff M, Pritchard C, Huffstutter JE, Rodriguez-Valverde V, Durez P, Zhou X, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009;68:1708–1714. doi: 10.1136/ard.2008.099218. PubMed DOI PMC

Westhovens R, Kremer JM, Moreland LW, Emery P, Russell AS, Li T, et al. Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study. J Rheumatol. 2009;36:736–742. doi: 10.3899/jrheum.080813. PubMed DOI

Genovese MC, Schiff M, Luggen M, Le Bars M, Aranda R, Elegbe A, et al. Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy. J Rheumatol. 2012;39:1546–1554. doi: 10.3899/jrheum.111531. PubMed DOI

Kremer JM, Russell AS, Emery P, Abud-Mendoza C, Szechinski J, Westhovens R, et al. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis. 2011;70:1826–1830. doi: 10.1136/ard.2010.139345. PubMed DOI PMC

Simon T, Soule B, Hochberg M, Fleming D, Torbeyns A, Banerjee S, et al. Safety of abatacept versus placebo in rheumatoid arthritis: integrated data analysis of nine clinical trials. ACR Open Rheumatol. 2019;1:251–257. doi: 10.1002/acr2.1034. PubMed DOI PMC

Simon TA, Boers M, Hochberg M, Baker N, Skovron ML, Ray N, et al. Comparative risk of malignancies and infections in patients with rheumatoid arthritis initiating abatacept versus other biologics: a multi-database real-world study. Arthritis Res Ther. 2019;21:228. doi: 10.1186/s13075-019-1992-x. PubMed DOI PMC

Simon TA, Suissa S, Skovron ML, Frisell T, Askling J, Michaud K, et al. FRI0118 Infection outcomes in patients with RA treated with abatacept and other DMARDs: results from a 10-year international post-approval study [abstract]. Ann Rheum Dis. 2019;78(Suppl 2):726–7.

de Germay S, Bagheri H, Despas F, Rousseau V, Montastruc F. Abatacept in rheumatoid arthritis and the risk of cancer: a world observational post-marketing study. Rheumatology (Oxford) 2020;59:2360–2367. doi: 10.1093/rheumatology/kez604. PubMed DOI

Lim CH, Chen HH, Chen YH, Chen DY, Huang WN, Tsai JJ, et al. The risk of tuberculosis disease in rheumatoid arthritis patients on biologics and targeted therapy: a 15-year real world experience in Taiwan. PLoS ONE. 2017;12:e0178035. doi: 10.1371/journal.pone.0178035. PubMed DOI PMC

Chiu YM, Lang HC, Lin HY, Yang MT, Fang CH, Yang YW, et al. Risk of tuberculosis, serious infection and lymphoma with disease-modifying biologic drugs in rheumatoid arthritis patients in Taiwan. Int J Rheum Dis. 2014;17(Suppl 3):9–19. doi: 10.1111/1756-185X.12539. PubMed DOI

Simon TA, Suissa S, Skovron ML, Frisell T, Askling J, Michaud K, et al. OP0226 Solid tumour outcomes in patients with RA treated with abatacept and other DMARDs: results from a 10-year international post-approval study [abstract]. Ann Rheum Dis. 2019;78(Suppl 2):190.

Gron KL, Arkema EV, Glintborg B, Mehnert F, Ostergaard M, Dreyer L, et al. Risk of serious infections in patients with rheumatoid arthritis treated in routine care with abatacept, rituximab and tocilizumab in Denmark and Sweden. Ann Rheum Dis. 2019;78:320–327. doi: 10.1136/annrheumdis-2018-214326. PubMed DOI

European Centre for Disease Prevention and Control and World Health Organization ROfE. Tuberculosis surveillance and monitoring in Europe, 2017 data. 2019. https://www.ecdc.europa.eu/sites/default/files/documents/tuberculosis-surveillance-monitoring-Europe-2019-20_Mar_2019.pdf. Accessed 4/2/2021.

Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, et al. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR) Ann Rheum Dis. 2010;69:522–528. doi: 10.1136/ard.2009.118935. PubMed DOI PMC

Silva-Fernandez L, Lunt M, Kearsley-Fleet L, Watson KD, Dixon WG, Symmons DP, et al. The incidence of cancer in patients with rheumatoid arthritis and a prior malignancy who receive TNF inhibitors or rituximab: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. Rheumatology (Oxford) 2016;55:2033–2039. doi: 10.1093/rheumatology/kew314. PubMed DOI PMC

Wu CY, Chen DY, Shen JL, Ho HJ, Chen CC, Kuo KN, et al. The risk of cancer in patients with rheumatoid arthritis taking tumor necrosis factor antagonists: a nationwide cohort study. Arthritis Res Ther. 2014;16:449. doi: 10.1186/s13075-014-0449-5. PubMed DOI PMC