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.
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.
Abstract
Background
Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown aetiology usually affecting young adults. Interestingly, recent evidence from the juvenile ...counterpart of AOSD suggested the emergent high fatality rate of lung disease (LD) in these patients. In this work, we aimed to characterise LD in AOSD, to identify associated clinical features and predictive factors, and to describe long-term outcomes of the disease comparing patients with LD and those without.
Methods
A retrospective assessment of prospectively followed patients, from January 2001 to December 2019, was provided to describe the rate of LD in AOSD, associated clinical features and predictive factors, and long-term outcomes. Patients with AOSD, who were included in
Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale
(GIRRCS) cohort, were assessed.
Results
Out of 147 patients included in GIRRCS cohort, 18 (12.25%) patients were reported to be affected by LD, at the time of diagnosis of AOSD, who were characterised by older age, a higher prevalence of myalgia, of lymph node involvement, of pleuritis, and abdominal pain. Furthermore, patients with LD showed higher values of systemic score and ferritin. Among those clinical variables, older age and systemic score were also independently predictors of LD. Chest CT scans were also obtained, and the most common finding was the peripheral consolidations in 8 (44.4%) patients. Finally, a higher mortality rate, of 38.9%, was registered in patients with LD than others, since it was associated with a significant decreased survival rate.
Conclusions
The presence of LD could suggest an emergent cause of mortality in AOSD, as observed in juvenile counterpart recognising a further marker of severity and poor prognosis to be careful evaluated. Patients with LD were also characterised by some clinical features, higher values of systemic score and ferritin than the others, identifying a subset of patients mostly burdened by systemic signs and symptoms. Although specific designed future studies are needed to fully elucidate the significance of LD in AOSD, a more accurate evaluation and management of this feature could improve the long-term outcomes of these patients.
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.
Abstract
Objectives
To stratify adult-onset Still’s disease (AOSD) patients in distinct clinical subsets to be differently managed, by using a multi-dimensional characterization.
Methods
AOSD ...patients were evaluated by using a hierarchical unsupervised cluster analysis comprising age, laboratory markers systemic score and outcomes. The squared Euclidean distances between each pair of patients were calculated and put into a distance matrix, which served as the input clustering algorithm. Derived clusters were descriptively analysed for any possible difference.
Results
Four AOSD patients clusters were identified. Disease onset in cluster 1 was characterized by fever (100%), skin rash (92%) and arthritis (83%), with the highest ferritin levels mean (S.D.) 14 724 (6837) ng/ml. In cluster 2, the onset was characterized by fever (100%), arthritis (100%) and liver involvement (90%), together with the highest CRP levels 288.10 (46.01) mg/l. The patients in cluster 3 presented with fever (100%), myalgia (96%) and sore throat (92%). The highest systemic score values 8.88 (1.70) and the highest mortality rate (54.2%) defined cluster 3. Fever (100%) and arthritis (90%) were the symptoms at the onset in cluster 4, which was characterized by the lowest ferritin and CRP levels 1457 (1298) ng/ml and 54.98 (48.67) mg/l, respectively.
Conclusion
Four distinct phenotypic subgroups in AOSD could be suggested, possibly associated with different genetic background and pathogenic mechanisms. Our results could provide the basis for a precision medicine approach in AOSD in an attempt to find a clinical and laboratory multidimensional stratification and characterization, which would drive a tailored therapeutic approach in these patients.
Rheumatoid arthritis (RA) is associated with an increased risk of morbidity and mortality, when compared with general population, largely due to enhanced atherosclerotic disease. In this work, we ...aimed at assessing both occurrence and predictive factors of subclinical and clinical atherosclerosis in RA.
From January 1, 2015, to December 31, 2015, consecutive participants with RA, admitted to Italian Rheumatology Units, were assessed in the GIRRCS (Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale) cohort. After that, those participants were followed up in a 3-year, prospective, observational study, assessing the occurrence of subclinical and clinical atherosclerosis and possible predictive factors. McNemar test was employed to assess the changes in subclinical and clinical atherosclerosis, and regression analyses exploited the ORs for the occurrence of those comorbidities.
We analysed 841 participants, mostly female (82.2%) and with median age of 60 years (range 21-90). The remission was achieved and maintained by 41.8% of participants during the follow-up. We observed an increased rate of subclinical atherosclerosis at the end of follow-up (139 vs 203 participants, p < 0.0001), particularly in participants with a disease duration less than 5 years at baseline (70 participants vs 133 participants, p < 0.0001). Type 2 diabetes (T2D) (OR 4.50, 95%CI 1.74-11.62, p = 0.002), high blood pressure (OR 2.03, 95%CI 1.04-4.14, p = 0.042), ACPA (OR 2.36, 95%CI 1.19-4.69, p = 0.014) and mean values of CRP during the follow-up (OR 1.07, 95%CI 1.03-1.14, p = 0.040) were significantly associated with higher risk of subclinical atherosclerosis. We observed an increased rate of clinical atherosclerosis at the end of follow-up (48 vs 76 participants, p < 0.0001). T2D (OR 6.21, 95%CI 2.19-17.71, p = 0.001) was associated with a significant risk of clinical atherosclerosis. The achievement and the maintenance of remission reduced the risk of subclinical (OR 0.25, 95%CI 0.11-0.56, p = 0.001) and clinical atherosclerosis (OR 0.20, 95%CI 0.09-0.95, p = 0.041).
We reported an increased prevalence and incidence of both subclinical and clinical atherosclerosis in 3-year prospectively followed participants, mainly in the subset with a duration of disease less than 5 years. The achievement and the maintenance of remission are associated with a reduction of the risk of subclinical and clinical atherosclerosis. Among "traditional" cardiovascular risk factors, participants with T2D showed a higher risk of clinical and subclinical atherosclerosis.
Highlights • Pulmonary adenocarcinomas of adolescents and young patients (≤30 years of age) have a high prevalence of ALK/ROS1 fusions. • A similar age-dependency is not present in EGFR-mutated ...adenocarcinomas. • ALK+/ROS1+ tumours of young patients are clinically highly aggressive (stage IV). • Crizotinib treatment may be effective in inducing partial regression of the disease
Patients with chronic Inflammatory Arthritis (IA), such as Rheumatoid Arthritis (RA) and Spondyloarthritis (SpA) are more likely to experience psychosocial impairment. Gastrointestinal (GI) symptoms ...are also present, especially in Spondyloarthritis. No data are available on the relationship between gut and brain manifestations and their impact on daily activities in this setting; thus, this study aimed to assess these symptoms in an IA population and identify potential associations. IA patients and a control group were enrolled. The Patient-Reported Outcome Measurement Instrument System (PROMIS
) questionnaire was used to evaluate GI and psychosocial domains. The study included 389 subjects (238 controls and 151 with IA); demographic and clinical data were collected for each participant. IA patients reported both higher psychosocial and GI impairment compared with controls. The logistic regression model revealed a strong association between depression and belly pain (
= 0.035), diarrhea (
= 0.017), bloating (
= 0.018), and reflux (
= 0.01); anxiety was associated with belly pain (
= 0.004), diarrhea (
= 0.019), swallowing alterations (
= 0.004), flatulence (
< 0.001) and reflux (
= 0.008). Moreover, fatigue, sleep disorders, and pain interference were associated with almost all GI symptoms, whereas high physical function scores and satisfaction in social roles decreased the odds of most GI symptoms. IA patients had more significant impairment in both dimensions compared with controls. To address reported symptoms and improve the overall quality of life in rheumatologic patients, a new holistic approach is required.
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