90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients.

Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and Ulcerative Colitis (UC), are multifactorial disorders characterized by a chronic inflammatory status with the secretion of cytokines and immune mediators. Biologic drugs targeting pro-inflammatory cytokines, such as infliximab, are broadly used in the treatment of IBD patients, but some patients lose responsiveness after an initial success. The research into new biomarkers is crucial for advancing personalized therapies and monitoring the response to biologics. The aim of this single center, observational study is to analyze the relationship between serum levels of 90K/Mac-2 BP and the response to infliximab, in a cohort of 48 IBD patients (30 CD and 18 UC), enrolled from February 2017 to December 2018. In our IBD cohort, high 90K serum levels were found at baseline in patients who then developed anti-infliximab antibodies at the fifth infusion (22 weeks after the first), becoming non-responders (9.76 ± 4.65 µg/mL compared to 6.53 ± 3.29 µg/mL in responder patients, p = 0.005). This difference was significant in the total cohort and in CD, but not significant in UC. We then analyzed the relationship between serum levels of 90K, C-reactive protein (CRP), and Fecal calprotectin. A significant positive correlation was found at baseline between 90K and CRP, the most common serum inflammation marker (R = 0.42, p = 0.0032). We concluded that circulating 90K could be considered a new non-invasive biomarker for monitoring the response to infliximab. Furthermore, 90K serum level determination, before the first infliximab infusion, in association with other inflammatory markers such as CRP, could assist in the choice of biologics for the treatment of IBD patients, thereby obviating the need for a drug switch due to loss of response, and so improving clinical practice and patient care.

Case Report: New-Onset Rheumatoid Arthritis Following COVID-19 Vaccination.

Efficient protection against coronavirus disease 2019 (COVID-19) has been achieved by immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, efficient immune responses against this novel virus by vaccination are accompanied by a wide variety of side effects. Indeed, flares or new-onset of autoimmune disorders have been reported soon after the COVID-19 vaccination. Although pro-inflammatory cytokine responses play pathogenic roles in the development of autoimmunity, cytokines charactering COVID-19 vaccination-related autoimmune responses have been poorly understood. Given that mRNA derived from COVID-19 vaccine is a potent inducer for pro-inflammatory cytokine responses, these cytokines might mediate autoimmune responses after COVID-19 vaccination. Here we report a case with new-onset rheumatoid arthritis (RA) following COVID-19 vaccination. Serum concentrations not only of arthrogenic cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but also of type I interferon (IFN) were elevated at the active phase in this case. Induction of remission by methotrexate and tocilizumab was accompanied by a marked reduction in serum concentrations of type I IFN, IL-6, and TNF-α. These results suggest that production of type I IFN, IL-6, and TNF-α induced by COVID-19 vaccination might be involved in this case with new-onset RA.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).

Role of Tocilizumab in the Treatment of COVID-19 Patients with Cytokine Storm: A Case Series.

The in-hospital mortality in patients with COVID-19 could be correlated with severe acute respiratory syndrome coronavirus-2 induced hyper-inflammation, which is attributed to an unconstrained inflammatory cytokine storm. The pro-inflammatory cytokine, specifically, interleukin-6 plays a prominent role in the cytokine storm and may result in alveolar-capillary blood-gas exchange dysfunction. Therefore, the method to block the signal transduction pathway of interleukin-6 could be a potential treatment for severe COVID-19 patients. In this case series of three patients with severe COVID-19, we focus on the rationale for utilization of tocilizumab, an anti-interleukin-6 receptor antibody, which could block the signal transduction pathway of interleukin-6. The observations from this study allowed us to hypothesize that the infusions of tocilizumab may not reduce the elevated level of interleukin-6, and hence may not be a significant therapeutic for reducing in-hospital mortality associated with COVID-19. Additionally, it could also be speculated that interleukin-6 may not be a potentially actionable target cytokine to treat COVID-19-associated cytokine storms. Keywords: COVID-19; cytokines; interleukin-6.

Biochemical and immunological aspects of COVID-19 infection and therapeutical intervention of oral low dose cytokine therapy: a systematic review.

The novel coronavirus (SARS-CoV-2) pandemic has now spread to all corners of the world. It causes severe respiratory syndromes which is one of the leading causes of death. Evidence shows that the novel SARS-CoV-2 has close similarities with other coronaviruses, SARS and MERS. So, SARS-CoV-2 might use the similar mechanisms of these viruses to attack the host cells. The severity of COVID-19 is associated with various factors, one of the major reasons is immune dysregulation or immune suppression. Immunity plays a significant role in maintaining the body in a healthy condition. In order to induce a timely immune response against the invaded pathogens, both innate and adaptive immunity must be in an active state. During the viral infection, there will be an excessive generation of pro-inflammatory cytokines known as cytokine storm and also, the antiviral agents in the body gets inhibited or inactivated through viral mechanisms. Thus, this might be the reason for the transition from mild symptoms to more severe medical conditions which leads to an immediate need for the invention of a new medicine.This review aims to show the host-viral interaction along with immune response, antiviral mechanism and effectiveness of oral low dose cytokines against the virus as a therapeutic approach.

Antiviral properties of placental growth factors: A novel therapeutic approach for COVID-19 treatment.

The current challenge of the COVID-19 pandemic is complicated by the limited therapeutic options against the virus, with many being anecdotal or still undergoing confirmatory trials, underlining the urgent need for novel strategies targeting the virus. The pulmotropic virus causes loss of oxygenation in severe cases with acute respiratory distress syndrome (ARDS) and need for mechanical ventilation. This work seeks to introduce placental extract-derived biologically active components as a therapeutic option and highlights their mechanism of action relevant to COVID-19 virus. Human placenta has been used in clinical practice for over a century and there is substantial experience in clinical applications of placental extract for different indications. Aqueous extract of human placentacontains growth factors, cytokines/chemokines, natural metabolic and other compounds, anti-oxidants, amino acids, vitamins, trace elements and biomolecules, which individually or in combination show accelerated cellular metabolism, immunomodulatory and anti-inflammatory effects, cellular proliferation and stimulation of tissue regeneration processes. Placental extract treatment is proposed as a suitable therapeutic approach consideringthe above properties which could protect against initial viral entry and acute inflammation of alveolar epithelial cells, reconstitute pulmonary microenvironment and regenerate the lung. We reviewed useful therapeutic information of placental biomolecules in relation to COVID-19 treatment. We propose the new approach of using placental growth factors, chemokines and cytokine which will execute antiviral activity in coordination with innate and humoral immunity and improve patient's immunological responses to COVID-19. Executing a clinical trial using placental extract as preventive, protective and/or therapeutic approach for COVID-19treatment could advance the development of a most promising therapeutic candidate that can join the armamentaria against the COVID-19 virus.

Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions.

The coronavirus disease-19 pandemic (COVID-19), which appeared in China in December 2019 and rapidly spread throughout the world, has forced clinicians and scientists to take up extraordinary challenges. This unprecedented situation led to the inception of numerous fundamental research protocols and many clinical trials. It quickly became apparent that although COVID-19, in the vast majority of cases, was a benign disease, it could also develop a severe form with sometimes fatal outcomes. Cytokines are central to the pathophysiology of COVID-19; while some of them are beneficial (type-I interferon, interleukin-7), others appear detrimental (interleukin-1ß, -6, and TNF-α) particularly in the context of the so-called cytokine storm. Yet another characteristic of the disease has emerged: concomitant immunodeficiency, notably involving impaired type-I interferon response, and lymphopenia. This review provides an overview of current knowledge on COVID-19 immunopathology. We discuss the defective type-I IFN response, the theoretical role of IL-7 to restore lymphocyte repertoire, as well as we mention the two patterns observed in severe COVID-19 (i.e. interleukin-1ß-driven macrophage activation syndrome vs. interleukin-6-driven immune dysregulation). Next, reviewing current evidence drawn from clinical trials, we examine a number of cytokine and anti-cytokine therapies, including interleukin-1, -6, and TNF inhibitors, as well as less targeted therapies, such as corticosteroids, chloroquine, or JAK inhibitors.