Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial
Autoři:
Piero Ruscitti aff001; Francesco Masedu aff002; Saverio Alvaro aff001; Paolo Airò aff003; Norma Battafarano aff004; Luca Cantarini aff005; Francesco Paolo Cantatore aff006; Giorgio Carlino aff007; Virginia D'Abrosca aff008; Micol Frassi aff003; Bruno Frediani aff005; Daniela Iacono aff008; Vasiliki Liakouli aff001; Roberta Maggio aff007; Rita Mulè aff009; Ilenia Pantano aff008; Immacolata Prevete aff010; Luigi Sinigaglia aff004; Marco Valenti aff002; Ombretta Viapiana aff011; Paola Cipriani aff001; Roberto Giacomelli aff001
Působiště autorů:
Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
aff001; Division of Medical Statistics, Department of Biotechnological and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy
aff002; Rheumatology and Clinical Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
aff003; Department of Rheumatology, Gaetano Pini Institute, Milan, Italy
aff004; Research Center of Systemic Autoinflammatory Diseases and Behçet's Disease and Rheumatology-Ophthalmology Collaborative Uveitis Center, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
aff005; Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia Medical School, Foggia, Italy
aff006; Rheumatology Service, ASL Lecce—DSS Casarano and Gallipoli (LE), Casarano (LE), Italy
aff007; Division of Rheumatology, Department of Precision Medicine, University of Campania ‘Luigi Vanvitelli’, Naples, Italy
aff008; Rheumatology Unit, S.Orsola-Malpighi Teaching Hospital, Bologna, Italy
aff009; Rheumatology Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
aff010; Rheumatology Unit, Department of Medicine, University of Verona, Verona, Italy
aff011
Vyšlo v časopise:
Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial. PLoS Med 16(9): e32767. doi:10.1371/journal.pmed.1002901
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pmed.1002901
Souhrn
Background
The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).
Methods and findings
This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481).
In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: −0.85, p < 0.001, 95% CI −1.28 to −0.42) and 6 months (β: −1.05, p < 0.001, 95% CI −1.50 to −0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: −1.04, p < 0.001, 95% CI −1.52 to −0.55) and 6 months (β: −1.24, p < 0.001, 95% CI −1.75 to −0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.
Conclusions
In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.
Trial registration
The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.
Klíčová slova:
Biology and life sciences – Biochemistry – Proteins – Developmental biology – Medicine and health sciences – Pathology and laboratory medicine – Physiology – Diagnostic medicine – Signs and symptoms – Endocrinology – Endocrine disorders – Metabolic disorders – Pharmacology – Rheumatology – Arthritis – Rheumatoid arthritis – Clinical medicine – Clinical immunology – Autoimmune diseases – Immunology – Immune system – Innate immune system – Cytokines – Immune response – Inflammation – Diabetes diagnosis and management – HbA1c – Diabetic endocrinology – Insulin – Immune physiology – Pharmaceutics – Drug therapy – Pharmacokinetics – Drug metabolism – Hemoglobin – Hormones – Molecular development
Zdroje
1. Singh JA, Christensen R, Wells GA, Suarez-Almazor ME, Buchbinder R, Lopez-Olivo MA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009;(4): CD007848. doi: 10.1002/14651858.CD007848.pub2 19821440
2. Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular comorbidity in rheumatic diseases. Nat Rev Rheumatol. 2015;11: 693–704. doi: 10.1038/nrrheum.2015.112 26282082
3. Ruscitti P, Ursini F, Cipriani P, Ciccia F, Liakouli V, Carubbi F, et al. Prevalence of type 2 diabetes and impaired fasting glucose in patients affected by rheumatoid arthritis: Results from a cross-sectional study. Medicine (Baltimore). 2017;96: e7896.
4. Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014;13: 465–476. doi: 10.1038/nrd4275 24854413
5. Berchtold LA, Prause M, Størling J, Mandrup-Poulsen T. Cytokines and Pancreatic β-Cell Apoptosis. Adv Clin Chem. 2016;75: 99–158. doi: 10.1016/bs.acc.2016.02.001 27346618
6. Giacomelli R, Ruscitti P, Alvaro S, Ciccia F, Liakouli V, Di Benedetto P, et al. IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone? Expert Rev Clin Immunol. 2016;12: 849–855. doi: 10.1586/1744666X.2016.1168293 26999417
7. Viswanathan M, Kahwati LC, Golin CE, Blalock SJ, Coker-Schwimmer E, Posey R, et al. Medication therapy management interventions in outpatient settings: a systematic review and meta-analysis. JAMA Intern Med. 2015;175: 76–87. doi: 10.1001/jamainternmed.2014.5841 25401788
8. Pincus T, Sokka T. Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa? Ann Rheum Dis. 2004;63 Suppl 2: ii32–ii9.
9. Duru N, van der Goes MC, Jacobs JW, Andrews T, Boers M, Buttgereit F, et al. EULAR evidence-based and consensus-based recommendations on the management of medium to high-dose glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. 2013;72: 1905–1913. doi: 10.1136/annrheumdis-2013-203249 23873876
10. Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356: 1517–1526. doi: 10.1056/NEJMoa065213 17429083
11. Mehta CR, Tsiatis AA. Flexible sample size considerations using information-based interim monitoring. Drug Information Journal. 2001;35: 1095–1112.
12. Lièvre M, Ménard J, Bruckert E, Cogneau J, Delahaye F, Giral P, et al. Premature discontinuation of clinical trial for reasons not related to efficacy, safety, or feasibility. BMJ. 2001;322: 603–605. doi: 10.1136/bmj.322.7286.603 11238162
13. Pocock SJ. When to stop a clinical trial. BMJ. 1992;305: 235–240. doi: 10.1136/bmj.305.6847.235 1392832
14. Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294: 2203–2209. doi: 10.1001/jama.294.17.2203 16264162
15. Nikfar S, Saiyarsarai P, Tigabu BM, Abdollahi M. Efficacy and safety of interleukin-1 antagonists in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatol Int. 2018;38: 1363–1383. doi: 10.1007/s00296-018-4041-1 29737371
16. Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009;32: 1663–1668. doi: 10.2337/dc09-0533 19542207
17. Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013;381: 1905–1915. doi: 10.1016/S0140-6736(13)60023-9 23562090
18. Schumann DM, Maedler K, Franklin I, Konrad D, Størling J, Böni-Schnetzler M, et al. The Fas pathway is involved in pancreatic beta cell secretory function. Proc Natl Acad Sci U S A. 2007;104: 2861–2866. doi: 10.1073/pnas.0611487104 17299038
19. Ruscitti P, Cipriani P, Di Benedetto P, Liakouli V, Berardicurti O, Carubbi F, et al. Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1beta via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients. Clin Exp Immunol. 2015;182: 35–44. doi: 10.1111/cei.12667 26095630
20. Paquot N, Castillo MJ, Lefèbvre PJ, Scheen AJ. No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab. 2000;85: 1316–1319. doi: 10.1210/jcem.85.3.6417 10720082
21. Di Rocco P, Manco M, Rosa G, Greco AV, Mingrone G. Lowered tumor necrosis factor receptors, but not increased insulin sensitivity, with infliximab. Obes Res. 2004;12: 734–739. doi: 10.1038/oby.2004.86 15090644
22. Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, Llorca J. Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy. Ann N Y Acad Sci. 2010;1193: 153–159. doi: 10.1111/j.1749-6632.2009.05287.x 20398022
23. Bassler D, Briel M, Montori VM, Lane M, Lane M, Glasziou P, Zhou Q, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA. 2010;303: 1180–1187. doi: 10.1001/jama.2010.310 20332404
24. Declaration of Helsinki IV, 41st World Medical Assembly, Hong Kong, September 1989. In: The Nazi doctors and the Nuremberg code: human rights in human experimentation. Annas GJ, Grodin MA, eds. New York: Oxford University Press; 1992. p. 339–42.
25. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design. Br J Cancer. 1976; 34: 585–612. doi: 10.1038/bjc.1976.220 795448
26. Ruscitti P, Ursini F, Cipriani P, Liakouli V, Carubbi F, Berardicurti O, et al. Poor clinical response in rheumatoid arthritis is the main risk factor for diabetes development in the short-term: A 1-year, single-centre, longitudinal study. PLoS ONE. 2017;12: e0181203. doi: 10.1371/journal.pone.0181203 28704564
27. Baghdadi LR, Woodman RJ, Shanahan EM, Mangoni AA. The impact of traditional cardiovascular risk factors on cardiovascular outcomes in patients with rheumatoid arthritis: a systematic review and meta- analysis. PLoS ONE. 2015;10: e0117952. doi: 10.1371/journal.pone.0117952 25689371
28. Peters MJ, van Halm VP, Voskuyl AE, Smulders YM, Boers M, Lems WF, et al. Does rheumatoid arthritis equal diabetes mellitus as an independent risk factor for cardiovascular disease? A prospective study. Arthritis Rheum. 2009;61: 1571–1579. doi: 10.1002/art.24836 19877093
29. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373: 1765–1772. doi: 10.1016/S0140-6736(09)60697-8 19465231
30. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377: 1119–1131. doi: 10.1056/NEJMoa1707914 28845751
31. Tank ND, Karelia BN, Vegada BN. Biological Response Modifiers in Rheumatoid Arthritis: Systematic Review and Meta-analysis of Safety. J Pharmacol Pharmacother. 2017; 8: 92–105. doi: 10.4103/jpp.JPP_155_16 29081616
32. Michaud TL, Rho YH, Shamliyan T, Kuntz KM, Choi HK. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med. 2014;127: 1208–1232. doi: 10.1016/j.amjmed.2014.06.012 24950486
33. Liebner R, Meyer M, Hey T, Winter G, Besheer A. Head to head comparison of the formulation and stability of concentrated solutions of HESylated versus PEGylated anakinra. J Pharm Sci. 2015;104: 515–526. doi: 10.1002/jps.24253 25445200
34. Ikonomidis I, Lekakis JP, Nikolaou M, Paraskevaidis I, Andreadou I, Kaplanoglou T, et al. Inhibition of interleukin-1 by anakinra improves vascular and left ventricular function in patients with rheumatoid arthritis. Circulation. 2008;117: 2662–2669. doi: 10.1161/CIRCULATIONAHA.107.731877 18474811
35. van Poppel PC, van Asseldonk EJ, Holst JJ, Vilsboll T, Netea MG, Tack CJ. The interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion and insulinogenic index in subjects with impaired glucose tolerance. Diabetes Obes Metab. 2014; 16: 1269–1273. doi: 10.1111/dom.12357 25039318
36. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11: 98–107. doi: 10.1038/nri2925 21233852
37. de Rotte MC, de Jong PH, den Boer E, Pluijm SM, Özcan B, Weel AE, et al. Effect of methotrexate use and erythrocyte methotrexate polyglutamate on glycosylated hemoglobin in rheumatoid arthritis. Arthritis Rheumatol. 2014;66: 2026–2036. doi: 10.1002/art.38652 24692301
38. den Uyl D, van Raalte DH, Nurmohamed MT, Lems WF, Bijlsma JW, Hoes JN, et al. Metabolic effects of high-dose prednisolone treatment in early rheumatoid arthritis: balance between diabetogenic effects and inflammation reduction. Arthritis Rheum. 2012;64: 639–646. doi: 10.1002/art.33378 21953589
39. Hoes JN, van der Goes MC, van Raalte DH, van der Zijl NJ, den Uyl D, Lems WF, et al. Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids. Ann Rheum Dis. 2011;70: 1887–1894. doi: 10.1136/ard.2011.151464 21908880
40. van Sijl AM, Boers M, Voskuyl AE, Nurmohamed MT. Confounding by indication probably distorts the relationship between steroid use and cardiovascular disease in rheumatoid arthritis: results from a prospective cohort study. PLoS ONE. 2014;9: e87965. doi: 10.1371/journal.pone.0087965 24498229
41. Lillegraven S, Greenberg JD, Reed GW, Saunders K, Curtis JR, Harrold L, et al. Immunosuppressive treatment and the risk of diabetes in rheumatoid arthritis. PLoS ONE. 2019;14: e0210459. doi: 10.1371/journal.pone.0210459 30673733
42. Schork NJ. Personalized medicine: Time for one-person trials. Nature. 2015; 520: 609–611. doi: 10.1038/520609a 25925459
43. Bluett J, Barton A. Precision Medicine in Rheumatoid Arthritis. Rheum Dis Clin North Am. 2017;43: 377–387. doi: 10.1016/j.rdc.2017.04.008 28711140
44. Cuppen BV, Welsing PM, Sprengers JJ, Bijlsma JW, Marijnissen AC, van Laar JM, et al. Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability. Rheumatology (Oxford). 2016;55: 826–839. doi: 10.1093/rheumatology/kev421 26715775
45. Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389: 2338–2348. doi: 10.1016/S0140-6736(17)31491-5 28612748
46. Donath MY. Multiple benefits of targeting inflammation in the treatment of type 2 diabetes. Diabetologia. 2016;59: 679–682. doi: 10.1007/s00125-016-3873-z 26868493
47. Selvin E, Parrinello CM, Daya N, Bergenstal RM. Trends in Insulin Use and Diabetes Control in the U.S.: 1988–1994 and 1999–2012. Diabetes Care. 2016;39: e33–35. doi: 10.2337/dc15-2229 26721815
48. Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskeletal Disorders. 2011;12: 153. doi: 10.1186/1471-2474-12-153 21736751
49. Cavelti-Weder C, Babians-Brunner A, Keller C, Stahel MA, Kurz-Levin M, Zayed H, et al. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care. 2012;35: 1654–1662. doi: 10.2337/dc11-2219 22699287
50. Rissanen A, Howard CP, Botha J, Thuren T, Global Investigators. Effect of anti-IL-1β anti-body (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial. Diabetes Obes Metab. 2012;14: 1088–1096. doi: 10.1111/j.1463-1326.2012.01637.x 22726220
Štítky
Interné lekárstvoČlánok vyšiel v časopise
PLOS Medicine
2019 Číslo 9
- Statiny indukovaná myopatie: Jak na diferenciální diagnostiku?
- MUDr. Dana Vondráčková: Hepatopatie sú pri liečbe metamizolom väčším strašiakom ako agranulocytóza
- Vztah mezi statiny a rizikem vzniku nádorových onemocnění − metaanalýza
- Nech brouka žít… Ať žije astma!
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
Najčítanejšie v tomto čísle
- Evaluation of approaches to strengthen civil registration and vital statistics systems: A systematic review and synthesis of policies in 25 countries
- Planned mode of delivery after previous cesarean section and short-term maternal and perinatal outcomes: A population-based record linkage cohort study in Scotland
- Effect of a scaled-up neonatal resuscitation quality improvement package on intrapartum-related mortality in Nepal: A stepped-wedge cluster randomized controlled trial
- The Fear Reduction Exercised Early (FREE) approach to management of low back pain in general practice: A pragmatic cluster-randomised controlled trial