Immunopharmacology/Musculoskeletal System Pharmacology: Overview

The rapid technological advancement over the past few decades has profoundly influenced the scientific approaches that shape the therapeutic landscape. Undoubtedly, immunopharmacology is an important player in the modern era of transition toward precision medicine that is largely defined by the identification of patient-specific therapies. According to the Immunopharmacology Section - ImmuPhar of the International Union of Basic and Clinical Pharmacology (IUPHAR), immunopharmacology is considered to be the youngest area of pharmacology dealing with the selective modulation, mostly up- or down-regulation, of specific immune responses that are often accomplished by immune cell subsets with specialized functions. Although the recent biotechnological progress has made available new classes of drugs with improved selectivity and/or specificity, agents possessing immunomodulating activities have been used in clinical practice for more than 70years. A pertinent example from the late 1940s is the counteraction of the inflammatory response upon administration of cortisone in patients with rheumatoid arthritis. © 2022 Elsevier Inc. All rights reserved

The Anxiety and Depression in Rheumatoid Arthritis Patients Treating with Disease-Modifying Anti-Rheumatic Drugs during the COVID-19 Pandemic.

Objective: Anxiety and depression are associated with the risk of illness, presence of physical symptoms, and poor health in the COVID-19 epidemic. Our aim is to assess the severity of anxiety and depression in rheumatoid arthritis (RA) patients treated with disease-modifying anti-rheumatic drugs during the COVID-19 pandemic. Material and methods: The study is a longitudinal, hospital-based survey study including 102 RA patients receiving disease-modifying anti-rheumatic drugs with a mean of 55,2±11,9 years. Demographic data, educational status, marital status, employment status, economic status, patients with psychiatric disorders (with the use of prescribed medication for treatment), and medications were recorded. The severity of depression and anxiety were evaluated with the Beck Anxiety and Depression Inventory at the first and second visit of the follow-up during the pandemic period. Results: The mean Beck depression inventory score was found to be higher in the conventional synthetic DMARDs group than in biological DMARDs (12,1±8,2 vs 11,6±9,2, p=0,554). 46 (65,7%) had mild to severe anxiety symptoms in RA patients treated with conventional synthetic DMARDs, on the first visit. There was no significant difference in anxiety and depression status between the first and second visits. The difference in anxiety and depression symptoms between RA patients receiving conventional synthetic and biological DMARDs does not attain statistical significance. Also, no significant differences were found in anxiety and depression scores in the comparisons for gender, education, marital, working, and economic status. Conclusions: The severity of depression and anxiety were higher in RA patients receiving conventional synthetic DMARDs and biological DMARDs during the COVID-19 pandemic. Also, RA patients are likely to experience anxiety and depression during the period of the pandemic.

[Immuno-inflammatory rheumatic diseases and COVID-19: analysis of clinical outcomes according to the data of the register of patients of the Novosibirsk region receiving therapy with genetically engineered biological drugs].

BACKGROUND: Currently, observations are accumulating indicating the negative effect of therapy with a number of biologic disease-modifying anti-rheumatic drugs (bDMARDs) drugs on the course of COVID-19. These facts determine the relevance of studying the factors of severe course and unfavorable outcome in immuno-inflammatory rheumatic diseases (IIRD) patients treated with bDMARDs in order to develop tactics for managing this category of patients in a pandemic. AIM: To evaluate the influence of clinical and demographic factors on the risk of development, severity of the course and clinical outcomes of a new coronavirus infection in patients suffering from IIRD and receiving therapy with genetically engineered biological drugs. MATERIALS AND METHODS: A retrospective analysis of the database of the register of patients with IIRD receiving bDMARDs in the Novosibirsk region was performed, which included 318 patients, 94 of whom had indications of having suffered viral infection/pneumonia for the period from 01.04.2020 to 31.12.2020. RESULTS: According to the data obtained, at the time of the analysis, 94 people out of 318 patients with IIRD had a new coronavirus infection. Most (53%) of the patients had a mild infection. At the same time, the nosological form, the use of anti-rheumatic drugs and glucocorticoids did not increase the risks of severe coronavirus infection. When using bDMARDs, only anti-B-cell therapy (rituximab) associated with statistically significant increase in the risk of severe/extremely severe COVID-19. The mortality rate according to the analysis of the register was 6,38%. CONCLUSION: Patients with IIRD have a high risk of severe coronavirus infection, while the severity of the disease is associated with the type of therapy performed.

Prevalence of coronavirus disease 2019 in a multiethnic cohort of patients with autoimmune rheumatic diseases in Qatar.

BACKGROUND: Autoimmune rheumatic diseases (ARDs) are characterized by immune dysfunction and associated with an increased risk of infections, which were of significant concern during the coronavirus disease 2019 (COVID-19) pandemic. Variable rates of COVID-19 incidence have been reported in patients with ARDs; however, the true effect of this infection on this patient population is still unclear. We, therefore, aimed to evaluate the COVID-19 prevalence among a multiethnic cohort of patients with ARDs in Qatar. MATERIAL AND METHODS: We used telephonic surveys to collect demographic and clinical information of patients with ARD in Qatar between April 1 and July 31, 2020, including any close contact with a COVID-19 case at home or work and polymerase chain reaction (PCR)-confirmed COVID-19 diagnosis. An electronic medical records review was conducted to verify pertinent data collected through the surveys. Prevalence with 95% confidence interval (CI), Student's t-tests, and chi-square/Fisher's exact tests were used for univariate analyses, whereas multivariate logistic regression was used to identify factors associated with COVID-19. RESULTS: The study included 700 patients with ARD (mean age, 43.2 ± 12.3 years), and 73% were female. Until July 2020, 75 (11%, 95% CI 9%-13%) patients had COVID-19. Factors associated with COVID-19 included being a man (adjusted odds ratio [aOR] 2.56, 95% CI 1.35-4.88, p = 0.01) and having close contact with a COVID-19 case (aOR 27.89, 95% CI 14.85-52.38, p = 0.01). Disease severity and rheumatic medications had no significant association with the odds of contracting COVID-19. In the 86 patients with ARD having close contact, the frequency of hydroxychloroquine utilization was lower in patients who contracted COVID-19 than in those who did not (35% vs 72.5%, p = 0.01). CONCLUSIONS: In Qatar, patients with ARDs had an overall higher prevalence of COVID-19 than global estimates. Being male and having close contact with a COVID-19 case were strongly associated with COVID-19 as reported globally. The presence of comorbid conditions, disease-specific factors, and rheumatic medications had no significant effect on the risk of COVID-19 in our study suggesting alternative mechanisms to the increased prevalence.

Corrigendum: The Impact of Anti-rheumatic Drugs on the Seroprevalence of Anti-SARS-CoV-2 Antibodies in a Cohort of Patients With Inflammatory Arthritis: The MAINSTREAM Study.

[This corrects the article DOI: 10.3389/fmed.2022.850858.].

SARS-Cov2 acute and post-active infection in the context of autoimmune and chronic inflammatory diseases.

The clinical and immunological spectrum of acute and post-active COVID-19 syndrome overlaps with criteria used to characterize autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Indeed, following SARS-Cov2 infection, the innate immune response is altered with an initial delayed production of interferon type I (IFN-I), while the NF-kappa B and inflammasome pathways are activated. In lung and digestive tissues, an alternative and extrafollicular immune response against SARS-Cov2 takes place with, consequently, an altered humoral and memory T cell response leading to breakdown of tolerance with the emergence of autoantibodies. However, the risk of developing severe COVID-19 among SLE and RA patients did not exceed the general population except in those having pre-existing neutralizing autoantibodies against IFN-I. Treatment discontinuation rather than COVID-19 infection or vaccination increases the risk of developing flares. Last but not least, a limited number of case reports of individuals having developed SLE or RA following COVID-19 infection/vaccination have been reported. Altogether, the SARS-Cov2 pandemic represents an unique opportunity to investigate the dangerous interplay between the immune response against infectious agents and autoimmunity, and to better understand the triggering role of infection as a risk factor in autoimmune and chronic inflammatory disease development.

The Impact of Anti-rheumatic Drugs on the Seroprevalence of Anti-SARS-CoV-2 Antibodies in a Cohort of Patients With Inflammatory Arthritis: The MAINSTREAM Study.

Objectives: Given the high occurrence of asymptomatic subsets, the true prevalence of SARS-CoV-2 infection in rheumatic patients is still underestimated. This study aims to evaluate the seroprevalence of SARS-CoV-2 antibodies in rheumatic musculoskeletal diseases (RMD) patients receiving immunomodulatory drugs. Methods: All consecutive patients with rheumatoid arthritis or spondyloarthritis receiving disease-modifying antirheumatic drugs (DMARDs) evaluated between 4th May and 16th June 2020 were included. All participants were tested for anti-SARS-CoV-2 antibodies (IgG, IgM, IgA) by ELISA and were questioned about previous COVID-19 symptoms and clinical course. Results were compared with healthy population from the same region and with a control group of healthy subjects diagnosed with confirmed COVID-19. Results: The study population includes 358 patients. The overall prevalence of anti-SARS-CoV-2 antibodies (18.4%) was higher than prevalence rate based on swab-positivity (1.12%) or clinically suspected cases (10.6%), but consistent with seroprevalence observed in the healthy population. Among seropositive patients 58% were asymptomatic. Mean anti-SARS-CoV-2 titer was comparable with the control group. No differences in seroprevalence were observed according to age, sex, rheumatic disease and treatment with conventional, biologic or targeted synthetic DMARDs, whereas glucocorticoids and comorbidities resulted in higher seroprevalence rate. Conclusions: The results of this study are reassuring about the low impact of RMDs and immunomodulatory therapies on the risk and clinical course of COVID-19 and on humoral immune response to SARS-CoV-2 infection.

COVID-19: An Archetype Innate Immunity Reaction and Modes of Treatment.

The magnitude of the SARS-CoV-2 pandemic found health systems unprepared, not allowing for prompt evaluation, collaboration among specialities and treatment of severely ill patients admitted to intensive care units, with many of them having an unfortunate outcome. Current data demonstrate an acute immune dysregulation in severe forms of the disease. The above is concluded by clinical evolution and laboratory findings, indicating a severe inflammatory response of the innate immune system, initiating predominately with the involvement of the respiratory tract epithelial cells, occasionally progressing to thrombotic diathesis and related complications. Besides the clinical manifestations, the immune response expresses an extremely high acute phase reactants repertoire including hyperferritinemia, hyper-fibrinogenaemia, and a storm of cytokines that require an alternative view and collaboration with rheumatologists. Thrombotic diathesis in some cases may not attribute only to a possible disseminated intravascular coagulation, but also to an additional activation of adaptive immunity and the development of the antiphospholipid syndrome. Unifying speciality evaluation and treatment may improve patient outcomes by recognizing early the evolving syndromes, treating properly, in a stratifying manner, with medications that alleviate the inflammatory reaction. Corticosteroids, colchicine, hydroxychloroquine/chloroquine, and possibly potent immunosuppressants are in the armamentarium. Additionally, biologics that interrupt the innate immune dysfunction, such as IL-1, IL-6 and selective JAK inhibitors, are also used. Convalescent plasma therapy and human immunoglobulin may be restricted for those whom the proposed treatments are found inadequate. The above combined with antiretroviral medications may improve the outcome until the development of safe and effective vaccination.

Risk of COVID-19 infection in patients with rheumatic disease taking disease-modifying anti-rheumatic drugs.

BACKGROUND AND OBJECTIVE: Patients with rheumatic disease taking long-term disease-modifying anti-rheumatic drugs (DMARDs) are expected to have a higher risk of infection due to the alterations in cellular immunity associated with these medications. However, the potential risks associated with these drugs remain unclear. This study aimed to estimate the risk of COVID-19 infection in patients with rheumatic disease taking disease-modifying anti-rheumatic drugs. METHODS: Patients with autoimmune rheumatic disease taking DMARDs with or without long-term (> 6 months) HCQ treatment prior to the COVID-19 outbreak were selected consecutively. The diagnosis of COVID-19 was made based on the history of symptoms suggestive of the disease and/or serum IgG positivity. During statistical analysis, the risk of COVID-19 infection was calculated in rheumatic patients taking DMARDs versus controls, as well as in patients taking HCQ versus those who are not. The ORs and 95% CIs were also calculated. The participants in the control group were selected from individuals without RD. RESULTS: A total of 800 patients with RD and 449 controls were analyzed. COVID-19 infection was detected in 16.8% of rheumatic patients versus 17.6% of controls (OR 0.95; 95% CI 0.7-1.28). The proportions of COVID-19 infection in HCQ users versus non-users were 15.3% and 18.1%, respectively (OR 0.87; 95% CI 0.61-1.26). These results remained unchanged after adjusting for all covariates using logistic regression analysis. CONCLUSION: These findings indicate that rheumatic patients taking DMARDs are not at a higher risk of COVID-19 infection, and that HCQ therapy has no influence on the risk of COVID-19 infection. Key points • The risk of COVID-19 infection is not higher in patients with RD on DMARD therapy. • The prevalence of COVID-19 infection in HCQ users has not significant difference relative to non-users. • Significant percent of RD patients taking DMARDs had asymptomatic infection. • There was a positive association between leflunamide therapy and the risk of COVID-19 infection.

COVID-19 and Disease-Modifying Anti-rheumatic Drugs.

PURPOSE OF REVIEW: Patients on disease-modifying anti-rheumatic drugs (DMARDs) remain concerned about potential risks of severe COVID-19 outcomes. Meanwhile, several DMARDs have been proposed as COVID-19 therapies. RECENT FINDINGS: In patients with autoimmune diseases, baseline glucocorticoid use is associated with severe COVID-19. While classes of DMARDs (e.g., conventional synthetic, targeted synthetic, and biologic) do not appear to be associated with higher risk, specific medications such as rituximab and sulfasalazine may be associated. Randomized clinical trials (RCTs) show that glucocorticoids reduce mortality in severe COVID-19. RCTs suggest other agents, such as baricitinib, may improve COVID-19 outcomes in certain populations. Baseline glucocorticoid use raises the risk of severe COVID-19 in patients with autoimmune diseases, but glucocorticoids are an effective treatment for those with severe COVID-19. Further research is needed to inform DMARD management in autoimmune disease patients during the pandemic and the role of DMARDs in COVID-19 treatment.

Clinical management of patients with rheumatoid arthritis during the COVID-19 pandemic.

Introduction: Coronavirus disease 2019 (COVID-19) pandemic raises a great challenge in the management of patients with rheumatoid arthritis (RA), which are generally more susceptible to infection events because of the autoimmune condition itself and the treatment with immunomodulatory drugs. The use of disease-modifying anti-rheumatic drugs (DMARDs), including biologics and targeted-synthetic DMARDs, has aroused particular interest because of both their immunosuppressive effects and their hypothetical potential in COVID-19 treatment.Areas covered: For this narrative review, a literature search was conducted between December 2019 and February 2021 on PubMed including epidemiological studies, gathering the main evidence available to date about the impact of COVID-19 on RA patients and the influence of anti-rheumatic drugs on patients' susceptibility to this infection. We also summarize the recommendations from the international guidelines on the management of rheumatic diseases and treatments in this pandemic context, especially focused on RA.Expert opinion: About a year after the outbreak of the pandemic, we are able to answer some of the most relevant questions regarding patients with RA and their management in this pandemic context. Our efforts must now be directed toward consolidating the currently available data with more rigorous studies and facing new issues and challenges including, foremost, vaccination.