Valutazione di un pattern di biomarcatori sierici in pazienti con Osteoartrosi Nodale ed Erosiva della mano

L'osteoartrosi (OA) è una malattia degenerativa che colpisce principalmente la cartilagine articolare e causa dolore e disabilità nelle attività di tutti i giorni nei soggetti affetti. Nei paesi sviluppati, l'OA è la più comune patologia articolare, con un impatto significativo sulla spese mediche, sia in termini di costi diretti e indiretti. La mano è una sede comune di interessamento periferico dell’osteoartrosi primaria; le articolazioni interfalangee prossimali (IFP) e distali (IFD) insieme all’articolazione trapezio-metacarpale (rizoartrosi) , costituiscono le sedi più tipiche di localizzazione della malattia. L'obesità è un fattore di rischio noto per l'OA. Il legame tra sovrappeso e OA può essere spiegato con l'aumento dello stress articolare che accompagna un eccesso ponderale. Tuttavia, lo stress meccanico non spiega l'osservazione che l'essere obesi sia anche associato con OA di articolazioni non-portanti come quelle della mano. Questa osservazione suggerisce che i fattori sistemici associati con l’obesità abbiano un ruolo nella patofisiologia della malattia. Negli ultimi anni, un grosso sforzo scientifico è stato indirizzato all’analisi di alcune molecole, secrete dal tessuto adiposo, chiamate adipocitochine, che potrebbero spiegare, almeno in parte il legame tra obesità e OA della mano. Le adipocitochine (tra cui le più note sono leptina, adiponectina, visfatina e resistina) sono coinvolte in un'ampia gamma di processi fisiologici nel corpo umano, compresi l'immunità, la formazione di massa ossea e l'omeostasi del glucosio. Tuttavia, i dati presenti in letteratura per lo più provengono da studi in vitro o cross-sezionali che utilizzano l’OA del ginocchio come modello. Tuttavia l’OA del ginocchio è la meno adatta per studi sui fattori metabolici associati con l'obesità nell’artrosi perché il ginocchio è anche influenzato dllo stress meccanico. Scopo del nostro studio è stato quello di valutare i livelli di leptina, adiponectina e visfatina (oltre a PCR ultrasensibile, mieloperossidasi e CTX-II) in soggetti con OA nodale (48) ed OA erosiva (50) delle mani comparati ad un gruppo di 21 controlli

Muscle pathology patterns in possibly adjuvant related autoimmune/inflammatory syndrome (ASIA)

Growing evidence shows a link for biologically inert molecules, such as vaccine adjuvants and silicone implants, with the occurrence of autoimmunity-related disorders, defined as autoimmune/inflammatory syndrome induced by adjuvant-ASIA (1). Clinical conditions encompass siliconosis, the Gulf war syndrome, the macrophagic myofasciitis syndrome (MMF), post-vaccination phenomena and the spectrum of related syndromes is expanding (2). Involvement of skeletal muscle in ASIA is acknowledged in MMF, defined by long-term persistence of vaccine alum adjuvants within macrophages at sites of previous immunization. A few reports describe vaccine and silicone implants related autoimmune inflammatory myopathies (3). We carried out an immunopathological analysis of skeletal muscle biopsy in a case of MMF and two cases of possible ASIA myositis, chronologically subsequent to breast silicone implant. MMF showed the typical fascial/ perimysial macrophagic invasion, with no endomysial mononuclear infiltrates and fibral neolocalization of MHC-I complex restricted to the adjacency of macrophage deposits. The first myositis case presented with a subacute onset twenty years after an uneventful additive breast silicone implant. Endomysial inflammation, microangiopathy and multifocal fibral localization of MHC-II complex were observed. In the second patient, the onset of proximal weakness, myalgiae and a tenfold increase of creatinkinase levels occurred seven years after an unsuccessful additive mastoplasty, with rupture of prostheses and re-implantation three years later. Muscle biopsy, besides inflammation changes, showed peculiar myofibrillar disruption, with MHC-I reactive sarcoplasmic inclusions expressing several structural muscle proteins. Molecular pathogenesis of ASIA is yet undefined: genetical susceptibility is currently investigated (1,2). Due to the role of vaccines in medicine and the wide use of silicon medical devices, identification of their cause/effect link with autoimmunity is of great interest

Dose-Dependent Impairment of the Immune Response to the Moderna-1273 mRNA Vaccine by Mycophenolate Mofetil in Patients with Rheumatic and Autoimmune Liver Diseases

The purpose of this study was to evaluate the efficacy and safety of the Moderna-1273 mRNA vaccine for SARS-CoV-2 in patients with immune-mediated diseases under different treatments. Anti-trimeric spike protein antibodies were tested in 287 patients with rheumatic or autoimmune diseases (10% receiving mycophenolate mofetil, 15% low-dose glucocorticoids, 21% methotrexate, and 58% biologic/targeted synthetic drugs) at baseline and in 219 (76%) 4 weeks after the second Moderna-1273 mRNA vaccine dose. Family members or caretakers were enrolled as the controls. The neutralizing serum activity against SARS-CoV-2-G614, alpha, and beta variants in vitro and the cytotoxic T cell response to SARS-CoV-2 peptides were determined in a subgroup of patients and controls. Anti-SARS-CoV-2 antibody development, i.e., seroconversion, was observed in 69% of the mycophenolate-treated patients compared to 100% of both the patients taking other treatments and the controls (p < 0.0001). A dose-dependent impairment of the humoral response was observed in the mycophenolate-treated patients. A daily dose of >1 g at vaccination was a significant risk factor for non-seroconversion (ROC AUC 0.89, 95% CI 0.80-98, p < 0.0001). Moreover, in the seroconverted patients, a daily dose of >1 g of mycophenolate was associated with significantly lower anti-SARS-CoV-2 antibody titers, showing slightly reduced neutralizing serum activity but a comparable cytotoxic response compared to other immunosuppressants. In non-seroconverted patients treated with mycophenolate at a daily dose of >1 g, the cytotoxic activity elicited by viral peptides was also impaired. Mycophenolate treatment affects the Moderna-1273 mRNA vaccine immunogenicity in a dose-dependent manner, independent of rheumatological disease

COVID-19 in rheumatic diseases in Italy: first results from the Italian registry of the Italian Society for Rheumatology (CONTROL-19)

OBJECTIVES: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance. METHODS: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry. RESULTS: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death. CONCLUSIONS: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Fibromyalgia Syndrome and Spa Therapy: Myth or Reality?

Abstract: Fibromyalgia syndrome (FS) is a common musculoskeletal disorder characterized by otherwise unexplained chronic widespread pain, a lowered pain threshold, high tender point counts, sleep disturbances, fatigue, headache, irritable bowel syndrome, morning stiffness, paraesthesias in the extremities, often psychological distress and depressed mood. Consequently, FS has a negative impact on working capacity, family life, social functioning and quality of life. Because of unknown etiology and not clearly understood pathogenesis, there is no standard therapy regime for FS. A variety of medical treatments, including antidepressants, opioids, analgesic or non-steroidal anti-inflammatory drugs, sedatives, muscle relaxants and antiepileptics, have been used to treat FS. Currently, no pharmacological treatment for FS is consistently successful. According to recent guidelines, the optimal treatment of FS requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological treatment modalities. Spa therapy is a popular treatment for FS in many European countries, as well as in Japan and Israel. However, despite their long history and popularity spa treatments are still the subject of debate and their role in modern medicine is still not clear. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of spa therapy in FS. We also provide some suggestions for further development in this area

Intravenous immunoglobulins and antiphospholipid syndrome: How, when and why? A review of the literature

The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (β2GPI) antibodies. The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation, while in obstetric APS, the accepted first-line treatment consists in low-dose aspirin (LDA) plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). Recently, new emerging treatment modalities, including intravenous immunoglobulins (IVIG), have been implemented to manage APS refractory to conventional therapy. The objective of this review is to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG in the obstetric form, CAPS and on primary or secondary thromboprophylaxis. We analyzed 35 studies, reporting the effects of IVIG in APS patients, and we discussed their results. IVIG in obstetric APS seem to be very useful in selected situations (patients not responsive to the conventional treatment, concomitant autoimmune manifestations or infections or patients in whom anticoagulation is contraindicated). IVIG treatment represents an important component of the combination therapy of CAPS and they could be useful, in addition to the standard therapy, to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment. Anyway, in some cases we also found controversial results that claim the need of further well-designed studies to definitely state the efficacy and tolerability of IVIG in CAPS, obstetric and non-APS

Punch biopsy for fat tissue collection in amyloidosis: is it time to stop needle aspiration?

5nonenoneGuidelli, Giacomo M.aria; Bardelli, Marco; Selvi, Enrico; Galeazzi, Mauro; De Stefano, RenatoGuidelli, GIACOMO MARIA; Bardelli, Marco; Selvi, Enrico; Galeazzi, Mauro; De Stefano, Renat

Granulomatosis with polyangiitis and intravenous immunoglobulins: A case series and review of the literature

Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy.We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500. mg/kg/daily for 3 consecutive days for 9. months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3. months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data