Date Published: September 12, 2019
Publisher: Public Library of Science
Author(s): Piero Ruscitti, Francesco Masedu, Saverio Alvaro, Paolo Airò, Norma Battafarano, Luca Cantarini, Francesco Paolo Cantatore, Giorgio Carlino, Virginia D’Abrosca, Micol Frassi, Bruno Frediani, Daniela Iacono, Vasiliki Liakouli, Roberta Maggio, Rita Mulè, Ilenia Pantano, Immacolata Prevete, Luigi Sinigaglia, Marco Valenti, Ombretta Viapiana, Paola Cipriani, Roberto Giacomelli, Sanjay Basu
Abstract: BackgroundThe 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 findingsThis 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.ConclusionsIn 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 registrationThe trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.
Partial Text: The management of rheumatoid arthritis (RA) has been significantly improved over the last 2 decades by the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) associated with the treat-to-target approach . However, despite the significant reduction of the joint structural damages, several studies have shown that cardiovascular (CV) events are emerging as the leading cause of death in these patients, thus pointing out the close association between RA and CV disease (CVD) . In fact, the ‘traditional’ CV risk factors and the systemic proinflammatory process during RA may synergise the enhancement of CVD burden in these patients [2,3]. As far as the role of traditional CV risk factors in RA is concerned, an increased association has been highlighted between RA and aberrant glucose metabolism, explaining the elevated prevalence of type 2 diabetes (T2D) and insulin resistance (IR) in these patients . Remarkably, interleukin-1β (IL-1β), IL-6, and tumour necrosis factor (TNF), which are involved in the pathogenesis of RA, may also play a pivotal role in the development of IR . Interestingly, the increased glucose levels stress the pancreatic islets and insulin-sensitive tissues, leading to hyperproduction of IL-β via nucleotide-binding oligomerization domain-like receptors-, leucine-rich repeat-, and pyrin domain–containing 3 (NLRP3) inflammasome [4,5]. This overexpressed IL-1β contributes to pathogenesis of T2D, leading to both dysfunction and apoptosis of β-cells, with consequent decreased insulin production . Furthermore, IL-1β could directly inhibit glucose-stimulated insulin secretion and trigger the intrinsic mitochondrial apoptotic pathway in β-cells . The recent knowledge of the contribution of inflammatory processes to the pathogenesis of T2D has suggested new antidiabetic therapeutic strategies in which bDMARDs, which are commonly used in the treatment of RA, may be effective in improving glucose abnormalities . However, despite the growing body of evidence from preclinical and clinical studies confirming the role of targeting inflammatory cytokines in improving clinical and laboratory outcomes in T2D patients , no clinical trial specifically designed to evaluate the glycaemic outcome in patients with RA and T2D has been planned, so far.
We did an open-label, randomised, parallel-group trial in patients with RA and T2D recruited from 12 Italian rheumatologic clinics to investigate whether IL-1 inhibition could improve both glycaemic and inflammatory parameters when compared with participants treated with TNFi. When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to stoppage of the study for early benefit. The study hypothesis was unexpectedly proven earlier than the predesignated timetable schedule, and with a larger percentage of anakinra-treated participants meeting the primary end point than TNFi-treated participants. Our results suggest that inhibition of IL-1 by anakinra may enable therapeutic targeting of both disorders, and use of a single agent may help in the management of both inflammatory and metabolic disease.