Intestinal microbiota changes induced by TNF-inhibitors in IBD-related spondyloarthritis

BACKGROUND: The close relationship between joints and gut inflammation has long been known and several data suggest that dysbiosis could link spondyloarthritis (SpA) to inflammatory bowel diseases (IBD). The introduction of biological drugs, in particular tumour necrosis factor inhibitors (TNFi), revolutionised the management of both these diseases. While the impact of conventional drugs on gut microbiota is well known, poor data are available about TNFi. AIM: To investigate the impact of TNFi on gut microbiota. METHODS: We evaluated 20 patients affected by enteropathic arthritis, naïve for biological drugs, treated with TNFi at baseline and after 6 months of therapy. All patients followed a Mediterranean diet. Patients performed self-sampling of a faecal sample at baseline and after 6 months of therapy. NGS-based ITS and 16S rRNA gene sequencing was performed, followed by the taxonomic bioinformatics analysis. RESULTS: After 6 months of therapy, we detected a remarkable increase in Lachnospiraceae family (Δ +10.3, p=0.04) and Coprococcus genus (Δ +2.8, p=0.003). We also noted a decreasing trend in Proteobacteria (Δ −8.0, p=0.095) and Gammaproteobacteria (Δ −9, p=0.093) and an increasing trend in Clostridia (Δ +8.2, p=0.083). We did not find differences between TNFi responders (SpA improvement or IBD remission achieved) and non-responders in terms of alpha and beta diversity. CONCLUSIONS: Our findings are consistent with the hypothesis that TNFi therapy tends to restore the intestinal eubiosis

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

Bacterial cytosolic proteins with a high capacity for Cu(I) that protect against copper toxicity

Abstract Bacteria are thought to avoid using the essential metal ion copper in their cytosol due to its toxicity. Herein we characterize Csp3, the cytosolic member of a new family of bacterial copper storage proteins from Methylosinus trichosporium OB3b and Bacillus subtilis . These tetrameric proteins possess a large number of Cys residues that point into the cores of their four-helix bundle monomers. The Csp3 tetramers can bind a maximum of approximately 80 Cu(I) ions, mainly via thiolate groups, with average affinities in the (1–2) × 10 17 M −1 range. Cu(I) removal from these Csp3s by higher affinity potential physiological partners and small-molecule ligands is very slow, which is unexpected for a metal-storage protein. In vivo data demonstrate that Csp3s prevent toxicity caused by the presence of excess copper. Furthermore, bacteria expressing Csp3 accumulate copper and are able to safely maintain large quantities of this metal ion in their cytosol. This suggests a requirement for storing copper in this compartment of Csp3-producing bacteria

COVID-19 prognosis in systemic lupus erythematosus compared with rheumatoid arthritis and spondyloarthritis: results from the CONTROL-19 Study by the Italian Society for Rheumatology

Introduction Data concerning SARS-CoV-2 in patients affected by SLE are contradicting.The aim of this study was to investigate disease-related differences in COVID-19 prognosis of patients affected by rheumatic diseases before vaccination; we tested the hypothesis that patients with SLE may have a different outcome compared with those with rheumatoid arthritis (RA) or spondyloarthritis (SPA).Methods We analysed data from the national CONTROL-19 Database with a retrospective, observational design, including rheumatic patients affected by COVID-19. The principal outcome measure was hospitalisation with death or mechanical ventilation. Differences between SLE, RA and SPA were analysed by univariable and multivariable logistic regression models.Results We included 103 patients with SLE (88.2% female, mean age 48.9 years, 50.4% active disease), 524 patients with RA (74.4% female, mean age 60.6 years, 59.7% active disease) and 486 patients with SPA (58.1% female, mean age 53.2 years, 58% active disease).Outcome prevalence was not different between patients with SLE and those with RA (SLE 24.5%, RA 25.6%), while patients with SPA showed a more favourable outcome compared with those with SLE (SPA 15.9%); data from the multivariable analysis confirmed this result.In SLE, age >65 years (OR 17.3, CI 5.51 to 63.16, p<0.001), hypertension (OR 6.2, CI 2.37 to 17.04, p<0.001) and prednisone (PDN) use (OR 3.8, CI 1.43 to 11.39, p=0.01) were associated with severe outcomes, whereas hydroxychloroquine use was found to be protective (OR 0.3, CI 0.14 to 0.91, p=0.03).Conclusion Our data suggest that patients with SLE and RA do not show a different COVID-19 outcome, while patients with SPA have a more favourable disease course compared with those with SLE. Risk of hospitalisation with ventilation or death was associated with age >65 years, hypertension and PDN use in patients with SLE

Increased COVID-19 mortality in patients with rheumatic diseases: results from the CONTROL-19 study by the Italian Society for Rheumatology

Objectives: To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy. Methods: We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results. Results: We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29-4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55-2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs. Conclusions: Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases

Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance.

AimTo determine characteristics associated with more severe outcomes in a global registry of people with systemic lupus erythematosus (SLE) and COVID-19.MethodsPeople with SLE and COVID-19 reported in the COVID-19 Global Rheumatology Alliance registry from March 2020 to June 2021 were included. The ordinal outcome was defined as: (1) not hospitalised, (2) hospitalised with no oxygenation, (3) hospitalised with any ventilation or oxygenation and (4) death. A multivariable ordinal logistic regression model was constructed to assess the relationship between COVID-19 severity and demographic characteristics, comorbidities, medications and disease activity.ResultsA total of 1606 people with SLE were included. In the multivariable model, older age (OR 1.03, 95% CI 1.02 to 1.04), male sex (1.50, 1.01 to 2.23), prednisone dose (1-5 mg/day 1.86, 1.20 to 2.66, 6-9 mg/day 2.47, 1.24 to 4.86 and ≥10 mg/day 1.95, 1.27 to 2.99), no current treatment (1.80, 1.17 to 2.75), comorbidities (eg, kidney disease 3.51, 2.42 to 5.09, cardiovascular disease/hypertension 1.69, 1.25 to 2.29) and moderate or high SLE disease activity (vs remission; 1.61, 1.02 to 2.54 and 3.94, 2.11 to 7.34, respectively) were associated with more severe outcomes. In age-adjusted and sex-adjusted models, mycophenolate, rituximab and cyclophosphamide were associated with worse outcomes compared with hydroxychloroquine; outcomes were more favourable with methotrexate and belimumab.ConclusionsMore severe COVID-19 outcomes in individuals with SLE are largely driven by demographic factors, comorbidities and untreated or active SLE. Patients using glucocorticoids also experienced more severe outcomes

Systemic sclerosis sine scleroderma: clinical and serological features and relationship with other cutaneous subsets in a large series of patients from the national registry 'SPRING' of the Italian Society for Rheumatology

Objective: To describe demographic, clinical and laboratory features of systemic sclerosis sine scleroderma (ssSSc) in a large multicentre systemic sclerosis (SSc) cohort. Methods: Data involving 1808 SSc patients from Italian Systemic sclerosis PRogression INvestiGation registry were collected. The ssSSc was defined by the absence of any cutaneous sclerosis and/or puffy fingers. Clinical and serological features of ssSSc were compared with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets. Results: Among patients with SSc, only 61 (3.4%) were classified as having ssSSc (F/M=19/1). Time from Raynaud's phenomenon (RP) onset to diagnosis was longer in ssSSc (3 years, IQR 1-16.5) than lcSSc (2 years, IQR 0-7), and dcSSc (1 year, IQR 0-3) (p<0.001). Clinical ssSSc phenotype was comparable to lcSSc, except for digital pitting scars (DPS) (19.7% vs 42%, p=0.01), but significantly milder than dcSSc, particularly for digital ulcers (DU) (6.6% vs 35.7%, p<0.001), oesophagus (46.2% vs 63.5%, p=0.009), lung (mean diffusion capacity for carbon monoxide 72.2±19.6 vs 62.4±22.8, p=0.009; mean forced vital capacity 105.6±21.7 vs 89.2±20.9, p<0.001) and major videocapillaroscopic alterations (late pattern 8.6% vs 47.6%, p<0.001). Moreover, in ssSSc the percentages of anticentromere and antitopoisomerase were comparable to lcSSc (40% and 18.3% vs 36.7% and 26.6%), but divergent respect to dcSSc (8.6% and 67.4%, p<0.001). Conclusion: The ssSSc is a quite rare disease variant characterised by clinico-serological features comparable to lcSSc, but significantly different from dcSSc. Overall, longer RP duration, low percentages of DPS and peripheral microvascular abnormalities, and increased anti-centromere seropositivity distinguish ssSSc. Further investigations based on national registries might provide useful insights on the actual relevance of the ssSSc within the scleroderma spectrum

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants