The fibroid phenotype of biological naïve patients with rheumatoid arthritis are less likely to respond to anti-IL-6R treatment.

Type III collagen gene expression is upregulated in the synovium of patients with rheumatoid arthritis (RA) presenting the fibroid phenotype. The soluble type III collagen formation biomarker, PRO-C3, is known to measure fibrogenesis in fibrotic diseases. In this exploratory study, we aimed to investigate the association between fibrogenesis (PRO-C3) and the disease- and treatment response in patients with RA. We measured PRO-C3 in subsets of two clinical trials assessing the effect of the anti-interleukin-6 (IL-6) receptor treatment tocilizumab (TCZ) as monotherapy or polytherapy with methotrexate. PRO-C3 levels had weak or very weak correlations with the clinical parameters (Spearman's). However, when the patients were divided into Disease Activity Score-28 groups characterized by the erythrocyte sedimentation rate (DAS28-ESR), there was a statistical difference between the PRO-C3 levels of the different groups (p < 0.05). To determine the response in relation to PRO-C3, a cut-off based on PRO-C3 levels and patients in remission (DAS28-ESR ≤ 2.6) was identified. This showed that a reduction in PRO-C3 after treatment initiation was associated with decreased DAS28-ESR and a higher response rate in patients with low PRO-C3 levels than in those with high PRO-C3 levels. This indicates that a fibrotic component affects the responsiveness of patients.

The role of IL-6 and IL-6 blockade in COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

The Role of Tocilizumab in Cytokine Storm and Improving Outcomes in COVID-19.

To date, severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has infected millions of individuals worldwide. This virus causes coronavirus disease 2019 (COVID-19) and has led to numerous deaths worldwide. A large percentage of infected patients present asymptomatically, augmenting the spread of the virus. Symptomatic COVID-19 commonly causes mild to severe respiratory disease and fever, but some individuals experience serious complications resulting in death. Immune compromised, high risk, and elderly individuals are at an increased risk of more severe consequences of the illness such as respiratory failure, organ dysfunction, and shock. Cytokine storm (also known as cytokine release syndrome (CRS)), a systemic inflammatory response that can be triggered by an infection, has been associated with the symptom progression of COVID-19. This review evaluates several published studies that have implemented tocilizumab (TCZ), an IL-6 receptor antibody (US20120253016A1), in COVID-19 treatment. Outcomes and biomarkers of patients treated with TCZ are compared to patients treated with standard of care regimens. Interleukin-6 (IL-6), a prominent inflammatory cytokine involved in CRS in various inflammatory conditions, may have a vital role in the underlying mechanism involved in debilitating SARS-CoV-2 infections and could serve as a viable treatment target. Studies suggest that TCZ may aid in the recovery of patients with COVID-19 and reduce mortality.

Short-term efficacy of the IL6 receptor antibody tocilizumab in patients with HIV-associated multicentric Castleman disease: report of two cases.

Multicentric Castleman disease (MCD) is a lymphoproliferative disorder caused by human herpesvirus 8 (HHV8) infection HIV associated MCD (HIV-MCD) presents with various clinical symptoms. Many HIV-negative MCD patients are often treated with anti-human interleukin-6 (IL6) receptor monoclonal antibodies (tocilizumab), and successful results have been reported. IL-6 plays an important role in the development of both HIV-positive and HIV-negative MCD; however, the efficacy of tocilizumab in HIV-MCD patients is unknown. We herein report the clinical and biologic courses of two HIV-MCD patients treated with tocilizumab. In both cases, a significant and rapid clinical improvement was observed after the first infusion. However, the treatment efficacy was not maintained for a long period, and relapse occurred at 15 and 22 weeks, respectively. Both patients received rituximab and subsequently achieved complete clinical remission. Our report, in addition to data presented in the literature, suggests that tocilizumab could be an initial treatment option in patients with HIV-MCD.

Immunotherapeutic implication of IL-6 blockade.

IL-6 is a cytokine featuring redundancy and pleiotropic activity. While IL-6 contributes to host defense against acute environmental stress, continuous IL-6 production plays a significant pathological role in various autoimmune and chronic inflammatory diseases. To counter this drawback, tocilizumab, a humanized anti-IL-6 receptor antibody, was developed. Clinical trials have verified the efficacy of tocilizumab for patients with rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis, resulting in approval of this innovative biologic for their treatment. Moreover, a considerable number of case reports and pilot studies have indicated the beneficial effects of tocilizumab on other autoimmune and chronic inflammatory diseases. Further clinical studies to evaluate the efficacy and safety of tocilizumab for these diseases are essential.

Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis.

Tocilizumab is a humanized anti-IL-6 receptor (IL-6R) monoclonal antibody for the treatment of rheumatoid arthritis (RA). A dose of 8 mg/kg produces adequate blockade of IL-6 receptors throughout a dosing interval, as confirmed by sustained high levels of tocilizumab-bound soluble IL6-R complex and normalization of C-reactive protein levels. Studies have confirmed 8 mg/kg every 4 weeks as the optimal dose and 4 mg/kg as the starting dose for the treatment of RA, with favorable efficacy and acceptable safety profiles. After 8 mg/kg, steady-state peak and trough concentrations were 183 ± 86 and 9.7 ± 11 µg/ml, respectively. Tocilizumab serum exposures increased more than proportionally to the dose increase from 2-10 mg/kg. Total clearance is concentration dependent, with non-linear receptor-mediated clearance dominant at low concentrations (<25 µg/ml). Tocilizumab exposures are not affected by common concomitant medications in RA patients, but decreased IL-6 activity resulted in increased CYP3A4 activity and hence decreased exposures of CYP3A4 substrates.