Blocking IL-17: A Promising Strategy in the Treatment of Systemic Rheumatic Diseases

Systemic rheumatic diseases are a heterogeneous group of autoimmune disorders that affect the connective tissue, characterized by the involvement of multiple organs, leading to disability, organ failure and premature mortality. Despite the advances in recent years, the therapeutic options for these diseases are still limited and some patients do not respond to the current treatments. Interleukin-17 (IL-17) is a cytokine essential in the defense against extracellular bacteria and fungi. Disruption of IL-17 homeostasis has been associated with the development and progression of rheumatic diseases, and the approval of different biological therapies targeting IL-17 for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) has highlighted the key role of this cytokine. IL-17 has been also implicated in the pathogenesis of systemic rheumatic diseases, including systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and systemic sclerosis (SSc). The aim of this review is to summarize and discuss the most recent findings about the pathogenic role of IL-17 in systemic rheumatic and its potential use as a therapeutic option

Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocrine Manner

Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4(+) T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naive Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORgammat in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4(+) T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4(+) T cell-mediated diseases

Can we validate a clinical score to predict the risk of severe infection in patients with systemic lupus erythematosus? A longitudinal retrospective study in a British Cohort

OBJECTIVE: Severe infections are a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Our primary objective was to use data from a large Spanish cohort to develop a risk score for severe infection in SLE, the SLE Severe Infection Score (SLESIS) and to validate SLESIS in a separate cohort of 699 British patients. DESIGN AND SETTING: Retrospective longitudinal study in a specialist tertiary care clinic in London, UK. PARTICIPANTS: Patients fulfilling international classification criteria for SLE (n=209). This included 98 patients who had suffered severe infections (defined as infection leading to hospitalisation and/or death) and 111 randomly selected patients who had never suffered severe infections. OUTCOMES: We retrospectively calculated SLESIS at diagnosis for all 209 patients. For the infection cases we also calculated SLESIS just prior to infection and compared it to SLESIS in 98 controls matched for disease duration. We carried out receiver operator characteristic (ROC) analysis to quantify predictive value of SLESIS for severe infection. RESULTS: Median SLESIS (IQR) at diagnosis was higher in the infection group than in the control group (4.27 (3.18) vs 2.55 (3.79), p=0.0008). Median SLESIS prior to infection was higher than at diagnosis (6.64 vs 4.27, p<0.001). In ROC analysis, predictive value of SLESIS just before the infection (area under the curve (AUC)=0.79) was higher than that of SLESIS at diagnosis (AUC=0.63). CONCLUSIONS: We validated the association of SLESIS with severe infection in an independent cohort. Calculation of SLESIS at each clinic visit may help in management of infection risk in patients with SLE. Prospective studies are needed to confirm these findings

Angiopoietin-2 Promotes Inflammatory Activation in Monocytes of Systemic Sclerosis Patients

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-alpha) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: Results from the COVIDSER study

Objectives To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. Methods The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. Results A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients'' hospitalisation. Conclusions The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.

Current and emerging diagnosis tools and therapeutics for giant cell arteritis

Introduction: Giant cell arteritis (GCA) is the most common large-vessel vasculitis in individuals older than 50 years from Western countries. The goal of the treatment is to achieve improvement of symptoms and clinical remission as well as decrease the risk of severe vascular complications. Areas covered: The review summarizes the main epidemiological and clinical features of GCA and discusses in depth both the classic and the new therapies used in the management of GCA. Expert commentary: Prednisone/prednisolone of 40-60 mg/day is the mainstay in GCA therapy. It yields improvement of clinical features and reduces the risk of permanent visual loss in patients with GCA. Other drugs are used in patients who experience relapses (flares of the disease) or side effects related to glucocorticoids. Methotrexate is the most common conventional immunosuppressive drug used as a glucocorticoid sparing agent. Among the new biologic agents, the most frequently used is the recombinant humanized anti-IL-6 receptor antibody, which is effective to improve clinical symptoms, decrease the cumulative prednisone dose and reduce the frequency of relapses in these patients. Anti-tumor necrosis factor-α therapy is not useful in GCA. Experience with other biologic agents, such as abatacept or ustekinumab, looks promising but it is still scarce