Interleukin-6 in Rheumatoid Arthritis

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Abstract

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.

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Most cited references 69

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Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Xiaobo Yang, Yuan Yu, Jiqian Xu … (2020)

Summary Background An ongoing outbreak of pneumonia associated with the severe acute respiratory coronavirus 2 (SARS-CoV-2) started in December, 2019, in Wuhan, China. Information about critically ill patients with SARS-CoV-2 infection is scarce. We aimed to describe the clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia. Methods In this single-centered, retrospective, observational study, we enrolled 52 critically ill adult patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital (Wuhan, China) between late December, 2019, and Jan 26, 2020. Demographic data, symptoms, laboratory values, comorbidities, treatments, and clinical outcomes were all collected. Data were compared between survivors and non-survivors. The primary outcome was 28-day mortality, as of Feb 9, 2020. Secondary outcomes included incidence of SARS-CoV-2-related acute respiratory distress syndrome (ARDS) and the proportion of patients requiring mechanical ventilation. Findings Of 710 patients with SARS-CoV-2 pneumonia, 52 critically ill adult patients were included. The mean age of the 52 patients was 59·7 (SD 13·3) years, 35 (67%) were men, 21 (40%) had chronic illness, 51 (98%) had fever. 32 (61·5%) patients had died at 28 days, and the median duration from admission to the intensive care unit (ICU) to death was 7 (IQR 3–11) days for non-survivors. Compared with survivors, non-survivors were older (64·6 years [11·2] vs 51·9 years [12·9]), more likely to develop ARDS (26 [81%] patients vs 9 [45%] patients), and more likely to receive mechanical ventilation (30 [94%] patients vs 7 [35%] patients), either invasively or non-invasively. Most patients had organ function damage, including 35 (67%) with ARDS, 15 (29%) with acute kidney injury, 12 (23%) with cardiac injury, 15 (29%) with liver dysfunction, and one (2%) with pneumothorax. 37 (71%) patients required mechanical ventilation. Hospital-acquired infection occurred in seven (13·5%) patients. Interpretation The mortality of critically ill patients with SARS-CoV-2 pneumonia is considerable. The survival time of the non-survivors is likely to be within 1–2 weeks after ICU admission. Older patients (>65 years) with comorbidities and ARDS are at increased risk of death. The severity of SARS-CoV-2 pneumonia poses great strain on critical care resources in hospitals, especially if they are not adequately staffed or resourced. Funding None.

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Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.

P Conti, G Ronconi, A Caraffa … (2020)

Coronavirus-19 (COVI-19) involves humans as well as animals and may cause serious damage to the respiratory tract, including the lung: coronavirus disease (COVID-19). This pathogenic virus has been identified in swabs performed on the throat and nose of patients who suffer from or are suspected of the disease. When COVI-19 infect the upper and lower respiratory tract it can cause mild or highly acute respiratory syndrome with consequent release of pro-inflammatory cytokines, including interleukin (IL)-1β and IL-6. The binding of COVI-19 to the Toll Like Receptor (TLR) causes the release of pro-IL-1β which is cleaved by caspase-1, followed by inflammasome activation and production of active mature IL-1β which is a mediator of lung inflammation, fever and fibrosis. Suppression of pro-inflammatory IL-1 family members and IL-6 have been shown to have a therapeutic effect in many inflammatory diseases, including viral infections. Cytokine IL-37 has the ability to suppress innate and acquired immune response and also has the capacity to inhibit inflammation by acting on IL-18Rα receptor. IL-37 performs its immunosuppressive activity by acting on mTOR and increasing the adenosine monophosphate (AMP) kinase. This cytokine inhibits class II histocompatibility complex (MHC) molecules and inflammation in inflammatory diseases by suppressing MyD88 and subsequently IL-1β, IL-6, TNF and CCL2. The suppression of IL-1β by IL-37 in inflammatory state induced by coronavirus-19 can have a new therapeutic effect previously unknown. Another inhibitory cytokine is IL-38, the newest cytokine of the IL-1 family members, produced by several immune cells including B cells and macrophages. IL-38 is also a suppressor cytokine which inhibits IL-1β and other pro-inflammatory IL-family members. IL-38 is a potential therapeutic cytokine which inhibits inflammation in viral infections including that caused by coronavirus-19, providing a new relevant strategy.

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Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.

Josef Smolen, André D Beaulieu, Andrea Rubbert-Roth … (2008)

Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. F Hoffmann-La Roche, Chugai Pharmaceutical.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 23 July 2020

Publication date Collection: August 2020

Volume: 21

Issue: 15

Electronic Location Identifier: 5238

Affiliations

[1 ]Allergy and Clinical Immunology, Fondazione Policlinico Universitario A, Gemelli IRCCS, Catholic University, 00168 Rome, Italy; valentina.carusi@ 123456libero.it (C.V.); simona.altamura@ 123456guest.policlinicogemelli.it (A.S.); gloria.andriollo@ 123456libero.it (A.G.); eleonora.nucera@ 123456unicatt.it (N.E)

[2 ]Emergency Medicine, Fondazione Policlinico Universitario A, Gemelli IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; cliodnaghfranza@ 123456gmail.com

Author notes

[* ]Correspondence: franco.pandolfi@ 123456unicatt.it

[†]

These authors contributed equally to this work.

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Franza Laura https://orcid.org/0000-0001-8638-7565

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Publisher ID: ijms-21-05238

DOI: 10.3390/ijms21155238

PMC ID: 7432115

PubMed ID: 32718086

SO-VID: 9339db80-cfaf-488f-bab5-f524b9efce83

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Interleukin-6 in Rheumatoid Arthritis

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Most cited references 69

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies.

Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial.

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