Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study.

BACKGROUND: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. METHODS: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. FINDINGS: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. INTERPRETATION: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects. FUNDING: None.

Structural damage in rheumatoid arthritis: comparison between tendon damage evaluated by ultrasound and radiographic damage.

OBJECTIVE: To compare structural damage assessed by conventional radiography and tendon damage assessed by musculoskeletal US (MSUS) at wrist and ankle in RA patients. METHODS: We evaluated 72 consecutive patients [56 (77.8%) females] with RA. The MSUS evaluation consisted in a B-mode examination of bilateral extensor carpi ulnaris and tibialis posterior tendons. Tendon damage was defined and scored according to OMERACT. A total score for the tendon damage score (TDS) was calculated by summing the grades for each tendon. For the radiographic evaluations we used the van der Heijde score; a total radiographic score (RTS) was calculated by summing a bone erosion score (ERS) and a joint space narrowing score (JSNS). RESULTS: We evaluated 288 tendons. The mean (s.d.) of TDS was 2.3 (1.8). Fifty-four (75%) patients presented tendon damage of at least one tendon. From all evaluated tendons, 134 (46.5%) had no tendon damage, 146 (50.7%) had grade 1 and 8 (2.8%) had grade 2 tendon damage. The mean (s.d.) for RTS was 91.4 (97), for ERS was 47.3 (61.9) and for JSNS was 44.1 (37.2). We found a significant correlation between disease duration and both TDS and RTS (r = 0.413 and r = 0.560, respectively; P < 0.0001). We found a good significant correlation between TDS and all variables of radiographic structural damage (RTS, r = 0.65; ERS, r = 0.637; JSNS, r = 0.618; P < 0.001). CONCLUSION: The MSUS assessment of only four tendons can be an additional feasible method to assess structural damage in RA patients.

Does ultrasound-scored synovitis depend on the pharmacokinetics of subcutaneous anti-TNF agents in patients with rheumatoid arthritis?

OBJECTIVE: The aim of this study was to investigate the influence of the pharmacokinetics of s.c. anti-TNF agents on the grade of US-detected synovitis in RA patients. METHODS: Fifty RA patients were prospectively recruited from the Biologic Therapy Unit of our hospital. Inclusion criteria were being in treatment with s.c. anti-TNF agents and having had neither changes in therapy nor local corticosteroid injections in the previous 3 months. Patients underwent clinical, laboratory [28-joint DAS (DAS28) and Simplified Disease Activity Index (SDAI)] and US assessment at two time points, i.e. at peak plasma drug concentration and at trough plasma drug concentration. US assessments were performed blindly to the anti-TNF agent, the administration time and the clinical and laboratory data. Twenty-eight joints were investigated for the presence and grade (0-3) of B-mode synovitis and synovial power Doppler signal. Global indices for B-mode synovitis (BSI) and Doppler synovitis (DSI) were calculated for 12 joints and for wrist-hand-ankle-foot joints. B-mode US remission was defined as a BSI <1 and Doppler US remission as a DSI <1. RESULTS: There were no significant differences between the clinical, laboratory and B-mode and Doppler US parameters at peak time and trough time (P = 0.132-0.986). There were no significant differences between the proportion of patients with active disease and those in remission according to DAS28, SDAI, B-mode US and Doppler US at peak time and trough time assessments (P = 0.070-1). CONCLUSION: Our results suggested that s.c. anti-TNF pharmacokinetics do not significantly influence US-scored synovitis in RA patients.

Idiopathic recurrent pericarditis treated successfully with tumour necrosis factor alpha blocking agents (anti-TNF-α).

Idiopathic recurrent pericarditis (IRP) is defined by 2 or more episodes of acute pericarditis of unknown etiology. Either auto-immune or auto-inflammatory diseases are suspected. Usually, non-steroidal anti-inflammatory drugs, colchicine or low dose steroid treatments are effective, however, side effects and/or non-response patients are frequent. We report on three paediatric patients with IRP from our paediatric rheumatology unit. The patients were non-responders to standard therapy and were treated with tumour necrosis factor alpha blocking agents (anti-TNF-α) and showed significant improvement. In two patients, the treatment was tapered and then stopped following several years of therapy. Symptoms flared in the last patient when therapy was tapered more quickly. We conclude that anti-TNF-α can be useful in selected cases of IRP.