Effects of l-Arginine Plus Vitamin C Supplementation on l-Arginine Metabolism in Adults with Long COVID: Secondary Analysis of a Randomized Clinical Trial.

Altered l-arginine metabolism has been described in patients with COVID-19 and has been associated with immune and vascular dysfunction. In the present investigation, we determined the serum concentrations of l-arginine, citrulline, ornithine, monomethyl-l-arginine (MMA), and symmetric and asymmetric dimethylarginine (SDMA, ADMA) in adults with long COVID at baseline and after 28-days of l-arginine plus vitamin C or placebo supplementation enrolled in a randomized clinical trial, compared with a group of adults without previous history of SARS-CoV-2-infection. l-arginine-derived markers of nitric oxide (NO) bioavailability (i.e., l-arginine/ADMA, l-arginine/citrulline+ornithine, and l-arginine/ornithine) were also assayed. Partial least squares discriminant analysis (PLS-DA) models were built to characterize systemic l-arginine metabolism and assess the effects of the supplementation. PLS-DA allowed discrimination of participants with long COVID from healthy controls with 80.2 ± 3.0% accuracy. Lower markers of NO bioavailability were found in participants with long COVID. After 28 days of l-arginine plus vitamin C supplementation, serum l-arginine concentrations and l-arginine/ADMA increased significantly compared with placebo. This supplement may therefore be proposed as a remedy to increase NO bioavailability in people with long COVID.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

Body mass index as a driver of selection of biologic therapy in rheumatoid arthritis. Results from the US-CLARA study.

PURPOSE: Body mass index (BMI) demonstrated to influence the clinical response to different drugs in rheumatoid arthritis (RA). The aim of this study was to investigate the role of BMI in the achievement of remission in active RA patients starting the treatment with abatacept. METHODS: Data regarding 130 RA patients enrolled in the UltraSound-CLinical ARthritis Activity (US-CLARA) study were retrospectively analyzed. Patients were assessed at baseline (when starting abatacept treatment) and at 3- and 6-months. An extensive clinimetric evaluation, including a new ultrasound (US)/clinical composite disease activity index, termed US-CLARA, was performed at every timepoints. Outcome of interest of the study was the impact of BMI on the achievement of the Disease Activity Score 28-joints erythrocyte sedimentation rate (DAS28-ESR) or the ACR/EULAR Boolean remission criteria at 6 month. RESULTS: At 6-month 26 out of 130 patients were defined as responders to abatacept. Comparing the baseline characteristics of responders to non-responders, US-CLARA showed a statistically significant difference between the two groups. The logistic regression analysis showed that the two indipendent variables, predictive of treatment response (keeping the DAS28-ESR and/or Boolean remission criteria as dependent variable), were the self-tender joint count assessment (p = 0.0412) and the ultrasound score (p = 0.0211). No other baseline variable, notably BMI, was associated to 6-month abatacept response. CONCLUSIONS: BMI does not influence the abatacept response in RA patients with active disease. During abatacept treatment, the clinical response can be achieved despite a condition of overweight or obesity.

Recommendations for the use of biologic therapy in rheumatoid arthritis: update from the Italian Society for Rheumatology I. Efficacy.

Given the availability of novel biologic agents for the treatment of rheumatoid arthritis (RA), various national scientific societies have developed specific recommendations in order to assist rheumatologists in prescribing these drugs. The Italian Society for Rheumatology (Società Italiana di Reumatologia, SIR) decided to update its recommendations and, to this end, a systematic literature review was carried out and the evidence derived from it was discussed and summarised as expert opinions. Levels of evidence, strength of recommendations and levels of agreement were reported. The recommendations reported are intended to help prescribing rheumatologists to optimise the use of biologic agents in patients with RA seen in everyday practice; they are not to be considered as a regulatory rule.

Synovial fluid-derived T helper 17 cells correlate with inflammatory activity in arthritis, irrespectively of diagnosis.

We analyzed peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 16 rheumatoid arthritis (RA), 9 spondyloarthritis (SpA), 3 microcrystal arthritis patients, to define the presence of Th17 and Th1 and their relationship with inflammatory activity, and TCR-zeta chain and ZAP-70 levels. Th17 were significantly higher in SF than in PB and more abundant in microcrystal arthritis patients compared to the other groups. Irrespectively of the diagnosis, SF Th17 percentages correlated with joint (SF total leukocyte count, neutrophil percentage) and systemic (C reactive protein [CRP], fibrinogen, erythrocyte sedimentation rate) inflammation markers. SF Th1 percentages directly correlated with inflammation and disease activity (CRP, swollen joint count [SJC]) indices in SpA, but not in RA patients. These observations support the role of Th17 in the pathogenesis of inflammatory arthritides. The TCR-zeta(dim) lymphocytes in SF were found to produce the highest amounts of cytokines including IL-17, whereas no ZAP-70 impairment was associated to Th17.