Abstract
Introduction
The molecular and pharmacological complexity of biologic disease-modifying antirheumatic drugs used for the management of rheumatoid arthritis (RA) favors the occurrence of adverse drug reactions (ADRs), which should be constantly monitored in post-marketing safety studies.
Objective
The aim of this study was to identify signals of disproportionate reporting (SDR) of clinical relevance related to the use of biologic drugs approved for RA and other autoimmune diseases.
Methods
All suspected ADRs registered in the FDA Adverse Event Reporting System between January 2003 and June 2016 were collected. The reporting odds ratio was used as a measure of disproportionality to identify possible SDRs related to biologics. Those involving important medical events and designated medical events (DME) were prioritized.
Results
In total, 2602 SDRs were prioritized. The most commonly reported were ‘Infections and infestations’ (32.2%) and ‘Neoplasms benign, malignant, and unspecified’ (20.4%), and were mainly related to use of infliximab (25.3%, p < 0.001, and 28.8%, p = 0.002, respectively). Sixty-three signals involving DMEs were identified, most of which were related to rituximab (n = 27), and were mainly due to ‘blood disorders’. Amongst the DMEs detected for more than one biologic, ‘intestinal perforation’ and ‘pulmonary fibrosis’ were related to most of them.
Conclusions
The results of this study highlight possible safety issues associated with biologics, whose relationship should be more thoroughly investigated. Our results contribute to future research on the identification of clinically relevant risks associated with these drugs, and may help contribute to their rational and safe use.
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References
Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960–77.
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38.
Patel H, Lissoos T, Rubin DT. Indicators of suboptimal biologic therapy over time in patients with ulcerative colitis and Crohn’s disease in the United States. PLoS One. 2017;12(4):e0175099.
Jabbar-Lopez ZK, et al. Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol. 2017;137(8):1646–54.
Palmer JB, et al. Treatment patterns and costs for anti-TNFalpha biologic therapy in patients with psoriatic arthritis. BMC Musculoskelet Disord. 2016;17:261.
Singh JA, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;2:Cd008794.
Verhoef LM, et al. bDMARD dose reduction in rheumatoid arthritis: a narrative review with systematic literature search. Rheumatol Ther. 2017;4(1):1–24.
Woodrick RS, Ruderman EM. Safety of biologic therapy in rheumatoid arthritis. Nat Rev Rheumatol. 2011;7(11):639–52.
Giezen TJ, et al. Mapping the safety profile of biologicals: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase. Drug Saf. 2010;33(10):865–78.
Coloma PM, et al. Postmarketing safety surveillance : where does signal detection using electronic healthcare records fit into the big picture? Drug Saf. 2013;36(3):183–97.
Hauben M, Aronson JK. Defining ‘signal’ and its subtypes in pharmacovigilance based on a systematic review of previous definitions. Drug Saf. 2009;32(2):99–110.
Hauben M, et al. The role of data mining in pharmacovigilance. Expert Opin Drug Saf. 2005;4(5):929–48.
International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. European Medicines Agency. Electronic transmission of individual case safety reports message specification (ICH ICSR DTD Version 2.1) 2001. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM149932.pdf. 06 Jun 2015.
U.S. Food and Drug Administration. FDA adverse event reporting system (FAERS): Latest quarterly data files. 2015. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082193.htm. 10 Oct 2015.
ClinicalTrials.gov. A service of the U.S. National Institutes of Health. 2016. https://clinicaltrials.gov/. 20 Jan 2016.
DrugBank. Drug & drug target database. 2016. http://www.drugbank.ca/. 20 Jan 2016.
Drugs.com. Drug index a to z. 2016. http://www.drugs.com/. 15 Jan 2016.
European Medicines Agency. European public assessment reports. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. 30 Sept 2016.
U.S Food and Drug Administration. Drugs@FDA. 2016. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. 20 Jan 2016.
GenericDrugs. Therapeutic equivalent brand and generic drugs. 2016. http://www.ndrugs.com/. 20 Jan 2016.
Singh JA, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1–26.
Smolen JS, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3–15.
Wong CK, et al. Standardisation of the FAERS database: a systematic approach to manually recoding drug name variants. Pharmacoepidemiol Drug Saf. 2015;24(7):731–7.
International Organization for Standardization-Country Codes-ISO 3166. 2015. http://www.iso.org/iso/home/standards/country_codes.htm. 15 Nov 2015.
International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. Medical dictionary for regulatory activities (MedDRA). 2016. http://www.ich.org/products/meddra.html. 15 Sept 2016.
Hubbard RE, O’Mahony MS, Woodhouse KW. Medication prescribing in frail older people. Eur J Clin Pharmacol. 2013;69(3):319–26.
Cunningham G. Adverse drug reactions in the elderly and their prevention. Scott Med J. 1997;42(5):136–7.
Cutroneo PM, et al. Safety profile of biological medicines as compared with non-biologicals: an analysis of the italian spontaneous reporting system database. Drug Saf. 2014;37(11):961–70.
Hernández MV, Meineri M, Sanmartí R. Lesiones cutáneas y terapia biológica con antagonistas del factor de necrosis tumoral. Reumatología Clínica. 2013;9(1):53–61.
Wisniewski AF, et al. Good signal detection practices: evidence from IMI PROTECT. Drug Saf. 2016;39(6):469–90.
Seabroke S, et al. Performance of stratified and subgrouped disproportionality analyses in spontaneous databases. Drug Saf. 2016;39(4):355–64.
van Puijenbroek EP, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10.
European Medicines Agency. Designated Medical Event (DME) list. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000587.jsp&mid=WC0b01ac0580727d1b. 15 Oct 2016.
European Medicines Agency. 19.1 IME list. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_000166.jsp&mid=WC0b01ac0580a68f78. Accessed 2 June 2018.
Mendes D, Alves C, Batel-Marques F. Safety profiles of adalimumab, etanercept and infliximab: a pharmacovigilance study using a measure of disproportionality in a database of spontaneously reported adverse events. J Clin Pharm Ther. 2014;39(3):307–13.
Giezen TJ, et al. Evaluation of post-authorization safety studies in the first cohort of EU Risk Management Plans at time of regulatory approval. Drug Saf. 2009;32(12):1175–87.
Poluzzi E, et al. Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA adverse event reporting system (AERS). In: Karahoca, editor. Data mining applications in engineering and medicine. Croatia: InTech; 2012. p. 265–302.
Codreanu C, Damjanov N. Safety of biologics in rheumatoid arthritis: data from randomized controlled trials and registries. Biol Targets Ther. 2015;9:1–6.
Dixit R, et al. Challenges of general safety evaluations of biologics compared to small molecule pharmaceuticals in animal models. Expert Opin Drug Discov. 2010;5(1):79–94.
Giezen TJ, Mantel-Teeuwisse AK, Leufkens HG. Pharmacovigilance of biopharmaceuticals: challenges remain. Drug Saf. 2009;32(10):811–7.
Giezen TJ, et al. Safety-related regulatory actions for biologicals approved in the United States and the European Union. Jama. 2008;300(16):1887–96.
Mota LMHD, et al. Segurança do uso de terapias biológicas para o tratamento de artrite reumatoide e espondiloartrites. Revista Brasileira de Reumatologia. 2015;55:281–309.
Gottlieb AB. Tumor necrosis factor blockade: mechanism of action. J Investig Dermatol Symp Proc. 2007;12(1):1–4.
Silva LC, Ortigosa LC, Benard G. Anti-TNF-alpha agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy. 2010;2(6):817–33.
Mitoma H, et al. Molecular mechanisms of action of anti-TNF-alpha agents—comparison among therapeutic TNF-alpha antagonists. Cytokine. 2016;101:56–63.
Wallis RS, et al. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38(9):1261–5.
Raaschou P, et al. Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden. BMJ. 2016;352:i262.
Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56(9):2886–95.
Lapeyre-Mestre M, et al. Pharmacoepidemiology studies: what levels of evidence and how can they be reached? Therapie. 2013;68(4):241–52.
van Vollenhoven RF, et al. Longterm safety of rituximab: final report of the rheumatoid arthritis global clinical trial program over 11 years. J Rheumatol. 2015;42(10):1761–6.
Kasi PM, et al. Clinical review: serious adverse events associated with the use of rituximab—a critical care perspective. Critical Care. 2012;16(4):231.
Alomar MJ. Factors affecting the development of adverse drug reactions (Review article). Saudi Pharm J. 2014;22(2):83–94.
Bohra C, Sokol L, Dalia S. Progressive multifocal leukoencephalopathy and monoclonal antibodies: a review. Cancer Control. 2017;24(4):1073274817729901.
Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009;18(6):427–36.
Michel C, et al. Can disproportionality analysis of post-marketing case reports be used for comparison of drug safety profiles? Clin Drug Investig. 2017;37(5):415–22.
Downey C. Serious infection during etanercept, infliximab and adalimumab therapy for rheumatoid arthritis: a literature review. Int J Rheum Dis. 2016;19(6):536–50.
Berghen N, et al. Malignancies and anti-TNF therapy in rheumatoid arthritis: a single-center observational cohort study. Clin Rheumatol. 2015;34(10):1687–95.
Raval G, Mehta P. TNF-alpha inhibitors: are they carcinogenic? Drug Healthc Patient Saf. 2010;2:241–7.
Solomon DH, Mercer E, Kavanaugh A. Observational studies on the risk of cancer associated with tumor necrosis factor inhibitors in rheumatoid arthritis: a review of their methodologies and results. Arthritis Rheum. 2012;64(1):21–32.
Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Dev Ther. 2013;8:87–100.
Nakayama S. Autoimmune hepatitis triggered by anti-TNF-alpha therapy. Case Rep Med. 2013;2013:561748.
Rodrigues S, et al. Autoimmune hepatitis and anti-tumor necrosis factor alpha therapy: a single center report of 8 cases. World J Gastroenterol. 2015;21(24):7584–8.
Mourad AA, et al. Adverse reactions to infliximab and the outcome of desensitization. Ann Allergy Asthma Immunol. 2015;115(2):143–6.
Flaig T, et al. Tocilizumab-induced pancreatitis: case report and review of data from the FDA adverse event reporting system. J Clin Pharm Ther. 2016;41(6):718–21.
Strangfeld A, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2017;76(3):504–10.
Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2014;43(5):613–26.
Hammond IW, et al. Database size and power to detect safety signals in pharmacovigilance. Expert Opin Drug Saf. 2007;6(6):713–21.
van der Heijden PG, et al. On the assessment of adverse drug reactions from spontaneous reporting systems: the influence of under-reporting on odds ratios. Stat Med. 2002;21(14):2027–44.
Blenkinsopp A, et al. Patient reporting of suspected adverse drug reactions: a review of published literature and international experience. Br J Clin Pharmacol. 2007;63(2):148–56.
van Grootheest K, et al. Pharmacists’ role in reporting adverse drug reactions in an international perspective. Pharmacoepidemiol Drug Saf. 2004;13(7):457–64.
Hadi MA, et al. Pharmacovigilance: pharmacists’ perspective on spontaneous adverse drug reaction reporting. Integr Pharm Res Pract. 2017;6:91–8.
Fletcher AP. Spontaneous adverse drug reaction reporting vs event monitoring: a comparison. J R Soc Med. 1991;84(6):341–4.
Hazell L, Shakir SA. Under-reporting of adverse drug reactions : a systematic review. Drug Saf. 2006;29(5):385–96.
Pierfitte C, et al. Is reporting rate a good predictor of risks associated with drugs? Br J Clin Pharmacol. 1999;47(3):329–31.
Hartnell NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy. 2004;24(6):743–9.
Hoffman KB, et al. The Weber effect and the United States Food and Drug Administration’s adverse event reporting system (FAERS): analysis of sixty-two drugs approved from 2006 to 2010. Drug Saf. 2014;37(4):283–94.
Pariente A, et al. Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf. 2007;30(10):891–8.
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Ariane G. S. Araujo, Helena H. L. Borba, Fernanda S. Tonin, Luana Lenzi, Rafael Venson, Roberto Pontarolo, and Astrid Wiens have no conflicts of interest directly relevant to the content of this article.
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Araujo, A.G.S., Borba, H.H.L., Tonin, F.S. et al. Safety of Biologics Approved for the Treatment of Rheumatoid Arthritis and Other Autoimmune Diseases: A Disproportionality Analysis from the FDA Adverse Event Reporting System (FAERS). BioDrugs 32, 377–390 (2018). https://doi.org/10.1007/s40259-018-0285-2
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DOI: https://doi.org/10.1007/s40259-018-0285-2