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
doi: 10.1371/journal.pmed.1002901



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 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.


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, number NCT02236481.

Klíčová slova:

Medicine and health sciences – Rheumatology – Arthritis – Rheumatoid arthritis – Clinical medicine – Clinical immunology – Autoimmune diseases – Immunology – Immune system – Innate immune system – Cytokines – Immune response – Inflammation – Diagnostic medicine – Diabetes diagnosis and management – HbA1c – Signs and symptoms – Endocrinology – Endocrine disorders – Diabetic endocrinology – Insulin – Metabolic disorders – Immune physiology – Pharmaceutics – Drug therapy – Pathology and laboratory medicine – Pharmacology – Pharmacokinetics – Drug metabolism – Biology and life sciences – Biochemistry – Proteins – Hemoglobin – Hormones – Physiology – Developmental biology – Molecular development


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