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
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.
One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated ...interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this “unique” cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy.
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•One of the hallmarks of COVID-19 is the cytokine storm that provokes systemic inflammation.•Elevated levels of interleukin-17A (IL-17A) are associated to disease severity and progression.•We propose IL-17A as a silent amplifier of the COVID-19 immune response and (potentially) related therapy.
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.
An accurate prediction of cardiovascular (CV) risk in patients with Axial Spondyloarthritis (axSpA) is a strong unmet need, as CV risk algorithms poorly perform in these subjects. The aim of this ...study was to establish whether the persistence of high C-reactive protein (CRP) and high disease activity may be considered predictive factors of CVD in axSpA. 295 patients without personal history of CVD, were consecutively enrolled in this study. To evaluate the relationship between CV events occurrence (fatal and non-fatal) and the persistence of increased CRP levels, ASDAS (Ankylosing Spondylitis Disease Activity Score) > 2.1, and BASDAI (Bath Ankylosing Spondylitis Disease Activity) > 4 during the follow-up, univariable and multivariable Cox Proportional Hazard Models have been performed. During follow-up (we analyzed 10-years retrospective data), 23 patients had a CV event. Multivariable Cox Proportional Hazard Models showed a strong association between CV event and the persistency of increased CRP levels (namely, percentage of visits in which CRP levels were increased) (HR = 1.03; 95%CI 1.015-1.045; p < 0.001), of ASDAS > 2.1 (HR = 1.014, 95%CI 1.000-1.028, p = 0.047), and of BASDAI > 4 (HR 1.019, 95%CI 1.006-1.033, p = 0.006) during follow-up, after adjustment for age, sex, and diabetes. This study suggests that persistence of increased CRP levels and high disease activity may be considered biomarkers to identify those axSpA patients at higher risk of CVD. Innovative axSpA-specific CV risk score, including these variables, have to be developed.
In patients with psoriatic arthritis (PsA) an increased cardiovascular (CV) risk has been observed. Recently, a EULAR taskforce suggested to use a multiplication by the factor of 1.5 of CV risk ...algorithms in patients with inflammatory arthritis. This study aims to evaluate the performance of five original and adapted according to EULAR recommendations CV risk algorithms in PsA: SCORE, CUORE, Framingham Risk Score (FRS), QRISK2, and Reynold's Risk Score (RRS).
Prospectively collected data from two Italian cohorts were used. Discriminatory ability for CV risk prediction was evaluated by the area under the ROC curves. Calibration between predicted and observed events was assessed by Hosmer-Lemeshow (HL) tests. Sensibility and specificity were calculated for low-to-intermediate and intermediate-to-high risk cut-offs.
One hundred fifty-five patients were enrolled with an observation of 1550 patient/years. Area under the ROC were 0.7679 (95% CI 0.64768 to 0.88812), 0.864 (95% CI 0.79675 to 0.93278), 0.7575 (95% CI 0.65784 to 0.85708), 0.8660 (95% CI 0.79428 to 0.93772), and 0.7183 (95% CI 0.57795 to 0.85862) for SCORE, CUORE, FRS, QRSIK2, and RRS, respectively. HL tests demonstrated poor model fit (p<0.05) for SCORE, CUORE, and RRS. Discriminative ability and calibration were not improved by adaption of the algorithms according to EULAR recommendations. Up to 80% of CV events occurred in patients at "low risk" and up to 93% of CV events in patients at "low-intermediate risk".
Adaption of the CV risk algorithms according to EULAR indications did not provide improvement in discriminative ability and calibration in patients with PsA.
Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis ...(PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.
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