ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by systemic and intrarticular inflammation. Fibroblast-like synoviocytes (FLSs) in RA have an activated phenotype with increased expression of pro-inflammatory cytokines and matrix metalloproteiases, which sustain chronic inflammation and damage bone and cartilage. RA-FLSs also display resistance to apoptosis, which accounts for the synovial membrane hyperplasia. SMAC-mimetic compounds antagonise the activity of inhibitors of apoptosis proteins (IAPs), which regulate apoptotic and inflammatory pathways. We investigated whether SMAC127 had pro-apoptotic and anti-inflammatory effects on RA-FLSs. To better recreate an optimal in vitro model of the intrrticular environment, we also studied the effects of the addition of synovial fluid (SF) to cultures. We found that SMAC 127 could down-regulate IAPs levels and could effectively induce apoptosis - as demonstrated by apoptosis assays with Annexin V in different culture conditions and caspase-3 cleavage. Furthermore, SMAC 127 could down-regulate pro-inflammatory cytokines (TNF-alpha, IL-15 and IL-6) and induce an up-regulation of the anti-inflammatory cytokine IL-10. The levels of marix metalloproteinase-1 (MMP-1) where also reduced, whereas we did not observe any significant effects on RANKL/OPG axis. Based on these results, SMAC mimetic compounds could be a very useful treatment in patients with RA since the very early stage of the disease

Fibromyalgia and Shoulder Surgery : a Systematic Review and a Critical Appraisal of the Literature

Fibromyalgia is a common musculoskeletal syndrome characterized by chronic widespread pain and other systemic manifestations, which has demonstrated a contribution to higher postoperative analgesic consumption to other surgeries such as hysterectomies and knee and hip replacements. The aim of this review is to search current literature for studies considering the impact of fibromyalgia on clinical outcomes of patients undergoing shoulder surgery. A systematic literature review was conducted in PubMed/Medline, Embase, and ClinicalTrials.gov in February 2019. Studies were selected based on the following participants, interventions, comparisons, outcomes, and study design criteria: adult patients undergoing surgery for shoulder pain (P); diagnosis of fibromyalgia (I); patients without fibromyalgia (C); outcome of surgery in terms of pain or analgesic or non-steroidal anti-inflammatory drugs consumption (O); case series, retrospective studies, observational studies, open-label studies, randomized clinical trials, systematic reviews and meta-analyses were included (S). Authors found 678 articles, of which four were found eligible. One retrospective study showed that patients with fibromyalgia had worse clinical postoperative outcomes; two retrospective studies reported a higher opioid prescription in patients with fibromyalgia and one prospective observational study found that a higher fibromyalgia survey score correlated with lower quality of recovery scores two days after surgery. The scarce and low-quality evidence available does not allow confirming that fibromyalgia has an impact on postoperative outcomes in shoulder surgery. Future studies specifically focusing on shoulder surgery outcomes may help improvement and personalization of the management of patients with fibromyalgia syndrome (PROSPERO 2019, CRD42019121180)

Total Joint Arthroplasty in Patients with Inflammatory Rheumatic Diseases

Since its introduction, total joint arthroplasty (TJA) has improved the quality of life of patients with degenerative joint disorders. In the last decades, a number of conventional and biological disease-modifying antirheumatic drugs have become available for the treatment of patients with inflammatory rheumatic diseases (IRD), leading to a reduction in the need to undergo TJA. However, TJA is still frequently performed in IRD patients. Both rheumatologists and orthopedics should be aware that patients with IRD have a peculiar perioperative risk profile due to disease-related, patient-related, and surgery-related risk factors. On the basis of current evidence, TJA is a safe procedure for IRD patients as long as an accurate risk stratification and a multidisciplinary approach are applied. We here describe the current strategies for an appropriate surgical management of osteoarthritis in IRD patients and the fascinating opening perspectives that surgeons and clinicians may expect in the future

Tocilizumab Effects on Coagulation Factor XIII in Patients with Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA na\uefve for the drug. Methods: We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements. Results: At baseline, patients with established RA had a median DAS28 of 4.8 (3.2\u20138.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged. Conclusion: The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk

Main Oral Manifestations in Immune-Mediated and Inflammatory Rheumatic Diseases

Oral manifestations are frequent in patients with rheumatic diseases. The aim of this review is to offer readers practical advice concerning the onset, diagnosis and treatment of the main oral manifestations encountered in rheumatological and dental clinics. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, periodontal disease, and dysphagia may be the first expression of a number of rheumatic diseases. Some of these manifestations are aspecific and very frequent, such as oral aphthosis, which can be the first manifestation in patients with systemic lupus erythematosus; some are potentially dangerous, such as jaw claudication during the course of giant cell arteritis; and some are very rare but peculiar, such as strawberry-like gingivitis in patients with granulomatosis with polyangiitis. Other oral manifestations are due to adverse reactions to disease-modifying anti-rheumatic drugs. Oral alterations in rheumatic diseases are frequently overlooked in clinical practice, but their prompt recognition not only allows the local lesions to be appropriately treated, but also makes it possible to identify an underlying systemic disease

Lung Ultrasound Findings and Endothelial Perturbation in a COVID-19 Low-Intensity Care Unit

Hypercoagulability and endothelial dysfunction related to inflammation have been clearly demonstrated in COVID-19. However, their influence on thromboembolism, lung alterations and mortality in low-intensity-care patients with COVID-19 is not completely clarified. Our aims were to evaluate the prevalence of deep vein thrombosis (DVT) with compressive ultrasound (CUS); to describe lung ultrasound (LUS) features; and to study coagulation, inflammatory and endothelial perturbation biomarkers in COVID-19 patients at low-intensity care unit admission. The predictive value of these biomarkers on mortality, need for oxygen support and duration of hospitalization was also evaluated. Of the 65 patients included, 8 were non-survivors. CUS was negative for DVT in all patients. LUS Soldati and Vetrugno scores were strongly correlated (rho = 0.95) with each other, and both significantly differed in patients who needed oxygen therapy vs. those who did not (Soldati p = 0.017; Vetrugno p = 0.023), with coalescent B lines as the most prevalent pattern in patients with a worse prognosis. Mean (SD) levels of thrombomodulin and VCAM-1 were higher in non-survivors than in survivors (7283.9 pg/mL (3961.9 pg/mL) vs. 4800.7 pg/mL (1771.0 pg/mL), p = 0.004 and 2299 ng/mL (730.35 ng/mL) vs. 1451 ng/mL (456.2 ng/mL), p < 0.001, respectively). Finally, in a multivariate analysis model adjusted for age, sex and Charlson score, VCAM-1 level increase was independently associated with death [OR 1.31 (1.06, 1.81; p = 0.036)]. In conclusion, in a cohort of mild COVID-19 patients, we found no DVT events despite the highly abnormal inflammatory, endothelial and coagulation parameters. The presence of lung alterations at admission could not predict outcome. The endothelial perturbation biomarker VCAM-1 emerged as a promising prognostic tool for mortality in COVID-19

Anti-atherogenic modification of serum lipoprotein function in patients with rheumatoid arthritis after tocilizumab treatment, a pilot study

Lipid metabolism derangement contributes to increased cardiovascular risk in Rheumatoid Arthritis (RA). It is still debated whether and how tocilizumab, an interleukin-6 receptor inhibitor used in active RA, impacts cardiovascular risk. We studied the effect of tocilizumab on the regulation of macrophage cholesterol homeostasis, measuring patient serum ability to respectively load (cholesterol loading capacity, CLC) and discharge (cholesterol efflux capacity, CEC) cells with cholesterol. Patients with RA (n = 8) were studied before and after 4 and 12 weeks of tocilizumab treatment. CLC was measured by a fluorimetric assay of intracellular cholesterol content in human macrophages and CEC was measured for the three main pathways, mediated by the transporters Scavenger Receptor class B-type I (SR-BI), ATP binding cassette-G1 (ABCG1) and-A1 (ABCA1) in specific cell models. After 12 weeks of tocilizumab treatment, serum LDL cholesterol levels were increased, while CLC was reduced. HDL cholesterol levels were unchanged, but CEC was significantly ameliorated for the SR-BI and ABCG1 pathways with respect to baseline. Tocilizumab reduces LDL pro-atherogenic potential despite increasing their serum levels and increases HDL protective activity in RA. The data of our pilot study suggest that tocilizumab regulates lipoprotein function in selected patient populations and lay the groundwork for future larger studies

Identification of a Shared Microbiomic and Metabolomic Profile in Systemic Autoimmune Diseases

Dysbiosis has been described in systemic autoimmune diseases (SADs), including systemic lupus erythematosus (SLE), Sjögren’s syndrome (SjS), and primary anti-phosholipid syndrome (PAPS), however the biological implications of these associations are often elusive. Stool and plasma samples from 114 subjects, including in SLE (n = 27), SjS (n = 23), PAPs (n = 11) and undifferentiated connective tissue (UCTD, n = 26) patients, and geographically-matched healthy controls (HCs, n = 27), were collected for microbiome (16s rRNA gene sequencing) and metabolome (high-performance liquid chromatography coupled to mass spectrometry) analysis to identify shared characteristics across diseases. Out of 130 identified microbial genera, a subset of 29 bacteria was able to differentiate study groups (area under receiver operating characteristics (AUROC) = 0.730 ± 0.025). A fair classification was obtained with a subset of 41 metabolic peaks out of 254 (AUROC = 0.748 ± 0.021). In both models, HCs were well separated from SADs, while UCTD largely overlapped with the other diseases. In all of the SADs pro-tolerogenic bacteria were reduced, while pathobiont genera were increased. Metabolic alterations included two clusters comprised of: (a) members of the acylcarnitine family, positively correlating with a Prevotella-enriched cluster and negatively correlating with a butyrate-producing bacteria-enriched cluster; and (b) phospholipids, negatively correlating with butyrate-producing bacteria. These findings demonstrate a strong interaction between intestinal microbiota and metabolic function in patients with SADs.This work was supported by EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant No. 115565