Robust long-term immunity to SARS-CoV-2 in patients recovered from severe COVID-19 after interleukin-6 blockade.

BACKGROUND: Whether interleukin-6 (IL-6) blockade in patients with COVID-19 will affect the protective immunity against SARS-CoV-2 has become an important concern for anti-IL-6 therapy. We aimed to investigate the effects of IL-6 blockade on long-term immunity to SARS-CoV-2. METHODS: Prospective, longitudinal cohort study conducted in patients hospitalized for severe or critical COVID-19 with laboratory confirmed SARS-CoV-2 infection. We assessed humoral (anti-S1 domain of the spike [S], anti-nucleocapsid [N], anti-trimeric spike [TrimericS] IgG, and neutralizing antibodies [Nab]) and T-cell (interferon-γ release assay [IGRA]) responses and evaluated the incidence of reinfections over one year after infection in patients undergoing IL-6 blockade with tocilizumab and compared them with untreated subjects. FINDINGS: From 150 adults admitted with confirmed SARS-CoV-2 infection, 78 were 1:1 propensity score-matched. Patients receiving anti-IL6 therapy showed a shorter time to S-IgG seropositivity and stronger S-IgG and N-IgG antibody responses. Among unvaccinated subjects one year after infection, median (Q1-Q3) levels of TrimericS-IgG (295 vs 121 BAU/mL; p = 0.011) and Nab (74.7 vs 41.0 %IH; p = 0.012) were higher in those undergoing anti-IL6 therapy, and a greater proportion of them had Nab (80.6% vs 57.7%; p = 0.028). T-cell immunity was also better in those treated with anti-IL6, with higher median (Q1-Q3) interferon-γ responses (1760 [702-3992] vs 542 [35-1716] mIU/mL; p = 0.013) and more patients showing positive T-cell responses in the IGRA one year after infection. Patients treated with anti-IL6 had fewer reinfections during follow-up and responded to vaccination with robust increase in both antibody and T-cell immunity. INTERPRETATION: IL-6 blockade in patients with severe COVID-19 does not have deleterious effects on long-term immunity to SARS-CoV-2. The magnitude of both antibody and T-cell responses was stronger than the observed in non-anti-cytokine-treated patients with no increase in the risk of reinfections. FUNDING: Instituto de Salud Carlos-III (Spain).

Tocilizumab Induces IL-10-Mediated Immune Tolerance in Invasive Candidiasis.

The existence of a hyperinflammatory state has been observed in patients with invasive fungal infections (IFI). It is being postulated whether morbidity from IFI may, in part, be a consequence of an unnecessarily prolonged or exaggerated proinflammatory immune response including interleukin 6 (IL-6) post-infection, in a host with dysregulated or compromised immunity. This, in turn, induces collateral host injury at the tissue and organ level, leading to adverse outcomes. Tocilizumab has become widely used as an immunomodulator in the treatment of inflammatory conditions. Here, we evaluated the use of tocilizumab to curb post-infective inflammatory flare in the setting of an in-vivo mouse model for invasive candidiasis. Following Candida infection, the tocilizumab-treated mice showed improved short-term survival compared with the saline-treated control mice. There was a reduced inflammatory response mounted by the host, coupled with reduced IL-6 but increased IL-10 levels. TNF-α and IFN-γ responses were not affected. Tocilizumab facilitated immune tolerance by selectively inducing IL-10, producing CD8α+ conventional dendritic cells (DCs) and peripheral T-regulatory cells, over CD11b+ conventional DCs and plasmacytoid DCs. We demonstrate here the sequelae from immunomodulatory manipulation and the basis whereby the use of monoclonal antibodies may be further explored in IFI.

Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. TRIAL DESIGN: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. PARTICIPANTS: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. INTERVENTION AND COMPARATOR: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. MAIN OUTCOMES: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. RANDOMISATION: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. TRIAL STATUS: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany.

BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.

Juvenile idiopathic arthritis: management and therapeutic options.

THE GOALS OF TREATMENT FOR JUVENILE IDIOPATHIC ARTHRITIS (JIA) INCLUDE: suppression of inflammation, achievement of remission, relief of pain, maintenance of function and doing so with minimal toxicity. Important discoveries over the past 10-15 years have led to more targeted treatments for children with JIA. The International League of Associations for Rheumatology (ILAR) classification system for childhood arthritides, better assessment tools for clinical response, improved definitions of remission, new imaging techniques and evidence in gene expression profiling have all contributed to the development of more targeted treatments. Nonsteroidal anti-inflammatory agents still have a role in mild disease and intra-articular steroid injections continue to be used most commonly in patients with oligoarticular JIA. Disease-modifying agents such as methotrexate have demonstrated efficacy and safety; however, in many patients, the disease remains active despite this treatment. These children now receive more targeted treatment including the tumor necrosis factor alpha (TNFα) inhibitors, interleukin-1 blockade, interleukin-6 blockade, selective costimulation modulators and selective B-cell blockade. The biologic targeted therapies have changed the strategy in which we treat our children with JIA; however, there remains much to be learned about the long-term effects and safety of these medicines.