BackgroundPatients with autoimmune systemic diseases (ASDs) can be counted among frail populations as regards the predisposition to COVID-19 due to the frequent visceral organ involvement and comorbidities, as well as the ongoing immunomodulating treatments.ObjectivesOur long-term multicenter telephone survey prospectively investigated the prevalence, prognostic factors, and outcomes of COVID-19 in Italian ASD patients during the first 3 pandemic waves.MethodsA large series of 3,918 ASD patients (815 M, 3103 F; mean age 59±12SD years) was consecutively recruited at the 36 referral centers of COVID-19 & ASD Italian Study Group. In particular, ASD series encompassed the following conditions: rheumatoid arthritis (n: 981), psoriatic arthritis (n: 471), ankylosing spondylitis (n: 159), systemic sclerosis (n: 1,738), systemic lupus (172), systemic vasculitis (n: 219), and a miscellany of other ASDs (n: 178). The development of COVID-19 was recorded by means of telephone survey using standardized symptom-assessment questionnaire (1).ResultsA significantly increased prevalence of COVID-19 (8.37% vs 6.49%; p<0.0001) was observed in our ASD patients, while the cumulative death rate revealed statistically comparable to the Italian general population (3.65% vs 2.95%; p: ns). In particular, among the 328 ASD patients complicated by COVID-19, 57 (17%) needed hospitalization, while mild-moderate manifestations were observed in the large majority of individuals (83%). In addition, 12/57 hospitalized patients died due to severe interstitial pneumonia and/or cardiovascular manifestations.Interestingly, a significantly higher COVID-19-related death rate was observed in systemic sclerosis patients compared to the Italian general population (6.29% vs 2.95%; p=0.018). Other adverse prognostic factors to develop COVID-19 were the patients’ older age, male gender, pre-existing ASD-related interstitial lung involvement, and chronic steroid treatment. Conversely, patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) showed a significantly lower prevalence of COVID-19 compared to those without (3.58% vs 46.99%; p=0.000), as well as the chronic administration of low dose aspirin in a subgroup of SSc patients (with 5.57% vs without 27.84%; p=0.000).ConclusionThe cumulative impact of COVID-19 on ASD patients after the first 3 pandemic waves revealed less severe than that observed during the first phase of pandemic (1), especially with regards to the death rate that was comparable to the Italian general population in spite of the increased prevalence of complicating COVID-19 in the same ASD series.Ongoing long-term treatments, mainly csDMARDs, might usefully contribute to generally positive outcomes of in this frail patients’ population.Of note, a significantly increased COVID-19-related mortality was recorded in only SSc patients’ subgroup, possibly favored by pre-existing lung fibrosis. Among different ASD, SSc deserves special attention, since it shares the main pathological alterations with COVID-19, namely the interstitial lung involvement and the endothelial injury responsible for diffuse microangiopathy.Besides SSc, the patients’ subgroups characterized by older age, chronic steroid treatment, pre-existing interstitial lung disease, and/or impaired COVID-19 vaccine response (1-3), may deserve well-designed prevention and management strategies.References[1]Ferri C, et al. Ann Rheum Dis. 2020 Oct 14 doi: 10.1136/annrheumdis-2020-219113.[2]Ferri C et al. J Autoimmun. 2021 Dec;125:102744. doi: 10.1016/j.jaut.2021.102744.[3]Visentini M et al. Ann Rheum Dis. 2021 Nov 24. doi: 10.1136/annrheumdis-2021-221248Disclosure of InterestsNone declared
Background Bone marrow (BM)-derived mesenchymal stem cells (MSC) are currently under investigation for their potential role in the management of some autoimmune diseases. Besides their regenerative effects and ability to induce tissue repair, MSC seem to possess potent immunomodulatory and anti-inflammatory effects, either by direct cell-cell interaction or by secreting different molecules able to exert a paracrine effects on local environment. Objectives Aim of the study was to evaluate the paracrine effects of BM-MSCs mesenchymal stem cells (MSC) isolated from normal individuals and patients with systemic sclerosis (SSc), on proliferation and cytokine production of cutaneous fibroblasts. Methods Fibroblasts obtained from skin punch biopsies (10 dcSSc patients and 5 healthy donors -HD) were cultured in vitro. MSC were isolated by plastic adherence from SSc and HD bone marrow (BM). Co-cultures were assessed with HD or SSc fibroblasts with HD or SSc MSC. Fibroblast proliferation was assessed by WST-1 assay and data were expressed as median percentage of 3 replicates. Levels of TGF-β, Stem Cell Factor (SCF), and metalloproteinase MMP-9 were detected in the co-culture supernatants by commercial ELISA Kits. Results Co-culture assays confirmed our previous results: an inhibition of SSc fibroblast proliferation, higher when fibroblasts were cultured with nBM MSCs (% of fibroblast proliferation vs fibroblasts without MSCs (100%): 75.8±9.9% with SSc MSCs vs 64.7±8.3% with nBM MSCs; P=0.038). In the presence of fibroblasts from healthy subjects, MSCs from normal and SSc BM equally inhibited proliferation. In comparison with basal values, the levels of the cytokines showed only in the presence of SSc fibroblasts and HD MSC a significant reduction in the content of SCF (mean±SD: 14.68±3.4 pg/ml vs 11.48±4.4; P=0.01) and TGF-β (3169.8±810 pg/ml vs 2450±900; P=0.0098), while no significant changes were observed in the presence of SSc MSC. As regards MMP-9, the basal value (mean±SD: 0.008±0.01 ng/ml) significantly increased in the presence of both HD (0.035±0.02; P=0.003) and SSc (0.094±0.072 ng/ml; P=0.01) MSC. Conclusions Our findings demonstrate that normal MSC (more than SSc-MSC) may provide an important signal for skin fibroblasts, and particularly for SSc fibroblasts, by both exerting anti-proliferative effects and down-regulating their activation state. The present results may reinforce the perspective for a future use of BM-MSC as a therapeutic option in SSc, namely for their anti-fibrotic potential. Disclosure of Interest None Declared
BackgroundIloprost (ILO) is a synthetic analogue of prostacyclin PGI2 with a potent vasodilator action, an anti-proliferative effect on smooth muscle cells and inhibition of platelet aggregation. ILO is employed intravenously for the control of Raynaud Phenomenon and digital ulcers. Up to now, no agreement has been reached on the regimen (dosage and frequency) to be used in SSc patients.ObjectivesTo identify the most common side effects that are developed during ILO infusion in SSc.Methods81 SSc patients, classified according to ACR EULAR criteria, derived from two Italian centers, were submitted to ILO infusion: patients were subclassified according to the edematous or fibrotic/atrophic phase of the disease. ILO was infused (6–8 hour infusion, dose ranging from 0.5 to 1.0 ng/kg/ min) (1) with a progressive increase of the dosage up to the achievement of patient's tolerance: the infusion on pump was started at 5 ml/hour and increased every half an hour up to 20 ml/hour (a dose of 4 mcg/h which corresponds to 1ng/kg)according to patients tolerance and appearance of side effects.ResultsOut of 81 patients, 16 were in the edematous phase with puffy fingers (digital edema). In this cohort, 5 individuals (31.2%) developed diarrhea and 9 (56.2%) developed hypotension during the infusion. When the drug was withdrawn patients had an immediate amelioration but when ILO was restarted, they again developed diarrhea or hypotension that led to definitive interruption of the treatment. Moreover, 10/16 patients (62.5%) experienced significant and painful digital swelling which led to the tapering of the infusion dosage below 10 ml/hr (which corresponds to 0.5 ng/kg per min); out of 10 patients, only one could continue the treatment while the other 9 had to be withdrawn due to the maintenance of the intense digital pain due to vasodilation. Finally, 11 patients (68.7%) reported flushing and 7 (43.7%) headache, but they were always controlled with the reduction of the infusion below 10 ml/hr. Out of 81 patients, 65 were in the atrophic/ fibrotic phase: 10 patients (15.3%) developed diarrhea and 24 pts (37%) hypotension that led to temporary withdrawal: when ILO was restarted and kept below 10 ml /hr, no side effects were experienced. In 23 cases (35.3%) flushing and in 8 cases (12.3%) headache were experienced, but were well controlled with infusion reduction below 10 ml/hr.ConclusionsILO was well tolerated in SSc patients characterized by fibrotic phase, where side effects could be managed by reducing/modulating the infusion rate. In edematous patients, ILO infusion should be decided in case where the severity of Raynaud's phenomenon or the presence of digital ulcers strongly suggests its use.ReferencesWigley FM, et a Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study Ann Intern Med. 1994;120:199–206Disclosure of InterestNone declared
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