Rheumatoid arthritis (RA) is an inflammatory disease typically affecting the joints, but the systemic inflammatory process may involve other tissues and organs. Many extra-articular manifestations ...are recognized, which are related to worse long outcomes. Rheumatoid nodules are the most common extra-articular feature, found in about 30% of patients. Secondary Sjögren's syndrome and pulmonary manifestations are observed in almost 10% of patients, also in the early disease. Active RA with high disease activity has been associated with an increased risk of such features. Male gender, smoking habit, severe joint disease, worse function, high pro-inflammatory markers levels, high titer of rheumatoid factor, and HLA-related shared epitope have been reported as clinical predictors of occurrence of these rheumatoid complications. In addition, there is a little evidence deriving from randomized controlled trials in this field, thus the therapeutic strategy is mainly empiric and based on small case series and retrospective studies. However, considering that these extra-articular manifestations are usually related to the more active and severe RA, an aggressive therapeutic strategy is usually employed in view of the poor outcomes of these patients.
The extra-articular features of RA remain, despite the improvement of joint damage, a major diagnostic and therapeutic challenge, since these are associated with a poor prognosis and need to be early recognized and promptly managed.
The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. ...Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.
Adult-onset Still's disease (AOSD) is rare inflammatory disease of unknown etiology that usually affects young adults. The more common clinical manifestations are spiking fevers, arthritis, ...evanescent rash, elevated liver enzymes, lymphadenopathy, hepatosplenomegaly, and serositis. The multi-visceral involvement of the disease and the different complications, such as macrophage activation syndrome, may strongly decrease the life expectancy of AOSD patients.
This study aimed to identify the positive and negative features correlated with the outcome of patients. A retrospective analysis of AOSD patients prospectively admitted to three rheumatologic centers was performed to identify the clinical features present at the time of diagnosis and to predict the possible outcome. Furthermore, we investigated the as yet to be validated prognostic value of the systemic score previously proposed.
One hundred consecutive AOSD patients were enrolled. The mean systemic score showed that the majority of patients had a multi-organ involvement. Sixteen patients showed different complications, mainly the macrophage activation syndrome. A strong increase of inflammatory markers was observed. All patients received steroids at different dosages, 55 patients in association with immunosuppressive drugs and 32 in association with biologic agents. Sixteen patients died during the follow-up. Regression analysis showed that the higher values of the systemic score and the presence of AOSD-related complications, assessed at the time of diagnosis, were significantly correlated with patient mortality. A prognostic impact of the systemic score of ≥ 7.0 was reported.
Our study showed that a higher systemic score and the presence of AOSD-related complications at the time of diagnosis were significantly associated with mortality. Of note, a cut-off at 7.0 of the systemic score showed a strong prognostic impact in identifying patients at risk of AOSD-related death.
In the present study, we aimed to evaluate whole-body insulin sensitivity in systemic sclerosis (SSc) patients and to compare the results with controls with no autoimmune rheumatic disease (non-ARD) ...and with patients affected by rheumatoid arthritis (RA).
In all patients and controls, oral glucose tolerance test (OGTT) was performed according to the World Health Organization (WHO) recommendations. Plasma glucose and insulin concentrations were measured at time 0 and then after 30, 60, 90, and 120 minutes. Whole-body insulin sensitivity (ISI), insulinogenic index (IGI), oral disposition index (ODI), and insulin resistance (HOMA-IR) were estimated accordingly.
A total of 41 SSc patients were evaluated and, for comparison, 41 individuals with RA and 82 non-ARD control patients were recruited. OGTT yielded a proportion of normotolerant individuals among SSc patients higher than in RA controls (p = 0.040) but lower than in the non-ARD group (p = 0.028). The ISI was significantly higher in SSc patients compared with RA controls (p <0.001) and with non-ARD patients (p <0.001). Significant differences emerged also when analysing the HOMA-IR, which was lower in SSc patients than in RA (p <0.001) and non-ARD (p <0.001) groups. Additionally, IGI was lower in SSc patients compared with RA (p = 0.011) and with non-ARD controls (p <0.001), whereas ODI was not significantly different between groups.
Interestingly, we found that SSc patients are more insulin sensitive than those with RA and even than individuals without inflammatory diseases. In contrast, no significant difference was found in terms of β-cell function.
The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating ...whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).
This study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481). In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody ACPA 70.2%) with active disease (Disease Activity Score-28 DAS28: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: -0.85, p < 0.001, 95% CI -1.28 to -0.42) and 6 months (β: -1.05, p < 0.001, 95% CI -1.50 to -0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index BMI) after 3 months (β: -1.04, p < 0.001, 95% CI -1.52 to -0.55) and 6 months (β: -1.24, p < 0.001, 95% CI -1.75 to -0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs.
In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D.
The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.
Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of ...disease prognosis. Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX. The aim of this study was to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients.
Forty-one patients with early pSS and active disease (EULAR Sjogren's syndrome disease activity index, ESSDAI ≥ 6) were enrolled in the study. Patients were treated with either RTX or DMARDs in two different Rheumatology centers and followed up for 120 weeks. Clinical assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-reported global disease activity pain, sicca symptoms and fatigue on visual analogic scales, unstimulated saliva flow and Schirmer's I test at week 12, 24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to week 120. Two labial minor salivary gland (MSG) biopsies were obtained from all patients at the time of inclusion in the study and at week 120.
Our study demonstrated that RTX treatment results in a faster and more pronounced decrease of ESSDAI and other clinical parameters compared to DMARDs treatment. No adverse events were reported in the two groups. We also observed that RTX is able to reduce glandular infiltrate, interfere with B/T compartmentalization and consequently with the formation of ectopic lymphoid structures and germinal center-like structures in pSS-MSGs.
To our knowledge, this is the first study performed in a large cohort of early active pSS patients for a period of 120 weeks. We showed that RTX is a safe and effective agent to be employed in pSS patients with systemic, extra-glandular involvement. Furthermore, our data on pSS-MSGs provide additional biological basis to employ RTX in this disease.
Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast ...activity. The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts. In this context, interleukin- (IL-) 1β, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis. The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis. In this paper, we review the available literature on the role of IL-1β in the pathogenesis of bone loss. Furthermore, we analysed the role of IL-1β in bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1β therapy in this field.
Objective To assess the predictive role of ferritin and C-reactive protein (CRP) on occurrence of macrophage activation syndrome (MAS) and mortality in patients with adult onset Still's disease ...(AOSD), a rare and severe disease, included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. Methods The predictive role, at the time of diagnosis, of serum levels of ferritin and CRP on occurrence of MAS and mortality, was evaluated by logistic regression analyses and receiver-operating characteristic (ROC) curves were built to identify patients at high risk of MAS and mortality, respectively. Results In assessed 147 patients with AOSD, levels of ferritin were predictive of MAS (OR: 1.971; P: 0.002; CI 95%: 1.280-3.035). The ROC curve showed that the best cut-off for ferritin was 1225 ng/ml in predicting MAS (sensitivity 88%; specificity 57%). Levels of CRP were predictive of mortality in these patients (OR: 2.155; P: 0.007; CI 95%: 1.228-3.783). The ROC curve showed that the best cut-off for CRP was 68.7 mg/L in predicting mortality (sensitivity 80%; specificity of 65%). Conclusions We reported the predictive role of ferritin and CRP on MAS and mortality, respectively, in a large cohort of patients with AOSD, identifying subsets at higher risk of poor prognosis. Considering that the analysis of CRP and ferritin is widely available, these results could be readily transferable into clinical practice, thus improving the management of patients with AOSD.
Despite of the European League Against Rheumatism (EULAR) provided different sets of recommendations for the management of cardiovascular risk in inflammatory arthritis patients, it must be pointed ...out that cardiometabolic comorbidity, such as type 2 diabetes (T2D), remains still underdiagnosed and undertreated in patients affected by rheumatoid arthritis (RA).
In this work, we designed a single centre, prospective study in order to better investigate the occurrence of T2D during the course of 1 year of follow-up. Furthermore, we evaluated the role of both traditional cardiovascular and RA-specific related risk factors to predict the occurrence of new T2D.
In this study, we evaluated 439 consecutive RA patients and we observed that 7.1% of our patients (31/439) developed T2D, after 12 month of prospective follow-up. The regression analysis showed that the presence of high blood pressure, the impaired fasting glucose (IFG) at the first observation and the poor EULAR-DAS28 response, after 12 months of follow-up, were significantly associated with an increased likelihood of being classified as T2D. Similarly, we observed that 7.7% of our patients (34/439) showed IFG after 12 months of prospective follow-up. The regression analysis showed that the presence of high blood pressure and the poor EULAR-DAS28 response after 12 months of follow-up, were significantly associated with an increased likelihood of showing IFG.
Our study supports the hypothesis of a significant short-term risk of T2D in RA patients and of a close associations between uncontrolled disease activity and glucose metabolism derangement. Further multicentre, randomised-controlled studies are surely needed in order to elucidate these findings and to better ascertain the possible contribution of different therapeutic regimens to reduce this risk.
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