Managing Adult-onset Still's disease: The effectiveness of high-dosage of corticosteroids as first-line treatment in inducing the clinical remission. Results from an observational study

To assess the effectiveness of the treatment with high dosage of corticosteroids (CCSs), as first-line therapy, in inducing remission in naïve Adult-onset Still's disease (AOSD) patients compared with low dosage of CCSs, after 6 months. To further evaluate the rate of patients maintaining the remission and the rate of CCSs discontinuation, after additional 12 months of follow-up.A retrospective evaluation of patients prospectively followed was designed to compare the rate of clinical remission in naïve AOSD patients treated with high dosages of CCSs (0.8-1 mg/kg/day of prednisone-equivalent) or low dosage of CCSs (0.2-0.3 mg/kg/day of prednisone-equivalent), after 6 months. An additional analysis was performed to compare the rate of monocyclic pattern between these groups, after further 12 months of follow-up.The clinical remission was achieved in a higher percentage of patients treated with the first-line treatment with high dosage of CCSs than treated the first-line treatment with low dosage of CCSs. At the end of 18 months of follow-up, a larger percentage of patients treated the first-line treatment with high dosage of CCSs was classified as monocyclic pattern and discontinued CCSs when compared with patients treated the first-line treatment with low dosage of CCSs. Patients defined as CCSs non-responder were treated with methotrexate (MTX)+CCSs or with combination therapy CCSs+MTX+biologic drug. The clinical remission was observed in a percentage of these patients.We showed the effectiveness of the first-line treatment with high dosage of CCSs in inducing clinical remission in naïve AOSD patients when compared with the first-line treatment with low dosage of CCSs. The first-line treatment with high dosage of CCSs was also associated with the achievement of monocyclic pattern and CCSs discontinuation, after 18 months of follow-up

Blocking CD248 molecules in perivascular stromal cells of patients with systemic sclerosis strongly inhibits their differentiation toward myofibroblasts and proliferation: A new potential target for antifibrotic therapy

Background: Fibrosis may be considered the hallmark of systemic sclerosis (SSc), the end stage triggered by different pathological events. Transforming growth factor-β (TGF-β) and platelet-derived growth factor BB (PDGF-BB) are profibrotic molecules modulating myofibroblast differentiation and proliferation, respectively. There is evidence linking CD248 with these two molecules, both highly expressed in patients with SSc, and suggesting that CD248 may be a therapeutic target for several diseases. The aim of this work was to evaluate the expression of CD248 in SSc skin and its ability to modulate SSc fibrotic process. Methods: After ethical approval was obtained, skin biopsies were collected from 20 patients with SSc and 10 healthy control subjects (HC). CD248 expression was investigated in the skin, as well as in bone marrow mesenchymal stem cells (MSCs) treated with TGF-β or PDGF-BB, by immunofluorescence, qRT-PCR, and Western blotting. Finally, in SSc-MSCs, the CD248 gene was silenced by siRNA. Results: Increased expression of CD248 was found in endothelial cells and perivascular stromal cells of SSc skin. In SSc-MSCs, the levels of CD248 and α-smooth muscle actin expression were significantly higher than in HC-MSCs. In both SSc- and HC-MSCs, PDGF-BB induced increased expression of Ki-67 when compared with untreated cells but was unable to modulate CD248 levels. After CD248 silencing, both TGF-β and PDGF-BB signaling were inhibited in SSc-MSCs. Conclusions: CD248 overexpression may play an important role in the fibrotic process by modulating the molecular target, leading to perivascular cells differentiation toward myofibroblasts and interfering with its expression, and thus might open a new therapeutic strategy to inhibit myofibroblast generation during SSc

Poor clinical response in rheumatoid arthritis is the main risk factor for diabetes development in the short-term: A 1-year, single-centre, longitudinal study

Objectives 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). Methods 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. Results 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\u2013up, 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. Conclusions 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

Adult-onset Still's disease: Evaluation of prognostic tools and validation of the systemic score by analysis of 100 cases from three centers

Background: 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. Methods: 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. Results: 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 65 7.0 was reported. Conclusions: 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

Mesenchymal stromal cells and rheumatic diseases: new tools from pathogenesis to regenerative therapies

In recent years, mesenchymal stromal cells (MSCs) have been largely investigated and tested as a new therapeutic tool for several clinical applications, including the treatment of different rheumatic diseases. MSCs are responsible for the normal turnover and maintenance of adult mesenchymal tissues as the result of their multipotent differentiation abilities and their secretion of a variety of cytokines and growth factors. Although initially derived from bone marrow, MSCs are present in many different tissues such as many peri-articular tissues. MSCs may exert immune-modulatory properties, modulating different immune cells in both in vitro and in vivo models, and they are considered immune-privileged cells. At present, these capacities are considered the most intriguing aspect of their biology, introducing the possibility that these cells may be used as effective therapy in autoimmune diseases. Therefore, stem cell therapies may represent an innovative approach for the treatment of rheumatic diseases, especially for the forms that are not responsive to standard treatments or alternatively still lacking a definite therapy. At present, although the data from scientific literature appear to suggest that such treatments might be more effective whether administered as soon as possible, the use of MSCs in clinical practice is likely to be restricted to patients with a long history of a severe refractory disease. Further results from larger clinical trials are needed to corroborate preclinical findings and human non-controlled studies, and advancement in the knowledge of MSCs might provide information about the therapeutic role of these cells in the treatment of many rheumatic diseases

Is minor salivary gland biopsy more than a diagnostic tool in primary Sjorgren's syndrome? Association between clinical, histopathological, and molecular features: A retrospective study

Objectives: Several histological scoring systems, including the focus score, performed in minor salivary glands (MSGs) by hematoxylin-eosin (H&E) staining, have been employed in clinical practice to assess the inflammatory infiltrate and provide the diagnosis of primary Sjorgren's syndrome (pSS). Aims of this study were to integrate different scoring systems and identify potential differences in the molecular profile of lymphoid cytokines related to germinal center (GC) formation and clinical subsets in pSS. Methods: Overall, 104 pSS patients and 40 subjects with sicca non-pSS were retrospectively evaluated. MSG biopsies were evaluated by H&E and immunofluorescence to assess histological pattern, Chisholm and Mason grading system, Tarpley score, a grading for the severity of inflammatory infiltrate, T-/B-cell segregation, and the presence of GC. MSGs from 50 pSS patients and 30 sicca non-pSS patients were processed by real-time PCR to assess LTα, LTβ, BAFF, CXCR4, CXCL12, CXCR5, CXCL13, CCR7, CCL19, and CCL21. Results: GCs presence was associated with anti-Ro/SSA and anti-La/SSB antibodies, hypergammaglobulinemia, salivary gland swelling, higher Tarpley score and focus score, and extraglandular involvement but, at multivariate analysis, only extraglandular involvement was independently associated to GC. pSS patients displayed higher level of all cytokines compared to those with sicca symptoms. GC+ pSS patients displayed higher level of all cytokines compared to those GC-. Conclusions: Our study demonstrates that different histopathological patterns, including GC presence, reflect different cytokine expression and different clinical subsets. We believe that the combined immunofluorescence/molecular approach in MSGs would help to tailor diagnostic and therapeutic approach for different subsets of pSS patients

IL-1β at the crossroad between rheumatoid arthritis and type 2 diabetes: may we kill two birds with one stone?

Although in the past the prevention of joint destruction in rheumatoid arthritis (RA) was strongly emphasized, now a great interest is focused on associated comorbidities in these patients. Multiple data suggest that a large percentage of RA patients are affected by Type 2 Diabetes (T2D), whose incidence has reached epidemic levels in recent years, thus increasing the health care costs. A better knowledge about the pathogenesis of these diseases as well as the mechanisms of action of drugs may allow both policy designers and physicians to choose the most effective treatments, thus lowering the costs. This review will focus on the role of Interleukin (IL)-1β in the pathogenesis of both the diseases, the efficacy of IL-1 blocking molecules in controlling these diseases, and will provide information suggesting that targeting IL-1β, in patients affected by both RA and T2D, may be a promising therapeutic choice

H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome

Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68(+) /H-ferritin(+) and CD68(+) /L-ferritin(+) ; and (iii) interleukin (IL)-1\u3b2, tumour necrosis factor (TNF) and interferon (IFN)-\u3b3. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1\u3b2, TNF and IFN-\u3b3 were increased significantly in MAS. Furthermore, an increased number of CD68(+) /H-ferritin(+) cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68(+) /H-ferritin(+) cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68(+) /L-ferritin(+) cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68(+) /H-ferritin(+) cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68(+) /H-ferritin(+) were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture

Monocytes from patients with rheumatoid arthritis and type 2 diabetes mellitus display an increased production of interleukin (IL)-1\u3b2 via the nucleotide-binding domain and leucine-rich repeat containing family pyrin 3(NLRP3)-inflammasome activation: a possible implication for therapeutic decision in these patients

A better understanding about the mechanisms involved in the pathogenesis of type 2 diabetes mellitus (T2D) showed that inflammatory cytokines such as tumour necrosis factor (TNF) and interleukin (IL)-1\u3b2 play a pivotal role, mirroring data largely reported in rheumatoid arthritis (RA). IL-1\u3b2 is produced mainly by monocytes (MO), and hyperglycaemia may be able to modulate, in the cytoplasm of these cells, the assembly of a nucleotide-binding domain and leucine-rich repeat containing family pyrin (NLRP3)-inflammosome, a cytosolic multi-protein platform where the inactive pro-IL-1\u3b2 is cleaved into active form, via caspase-1 activity. In this paper, we evaluated the production of IL-1 \u3b2 and TNF, in peripheral blood MO of patients affected by RA or T2D or both diseases, in order to understand if an alteration of the glucose metabolism may influence their proinflammatory status. Our data showed, after 24 h of incubation with different glucose concentrations, a significantly increased production of IL-1\u3b2 and TNF in all evaluated groups when compared with healthy controls. However, a significant increase of IL-1\u3b2 secretion by T2D/RA was observed when compared with other groups. The analysis of relative mRNA expression confirmed these data. After 24 h of incubation with different concentrations of glucose, our results showed a significant increase in NLRP3 expression. In this work, an increased production of IL-1\u3b2 by MO obtained from patients affected by both RA and T2D via NLRP3-inflammasome activation may suggest a potential IL-1\u3b2 targeted therapy in these patients

The CD68+/H-ferritin+ cells colonize the lymph nodes of the patients with adult onset Still's disease and are associated with increased extracellular level of H-ferritin in the same tissue: Correlation with disease severity and implication for pathogenesis

In this work, we aimed to evaluate the levels of ferritin enriched in H subunits (H-ferritin) and ferritin enriched in L subunits (L-ferritin) and the cells expressing these two molecules in the lymph node (LN) biopsies obtained from adult-onset Still's disease (AOSD) patients, and the possible correlation among these data and the severity of the disease. Ten patients with AOSD underwent LN biopsy. All the samples were stained by immunofluorescence. A statistical analysis was performed to estimate the possible correlation among both H-ferritin and L-ferritin tissue expression and the clinical picture of the disease. Furthermore, the same analysis was performed to evaluate the possible correlation among the number of CD68+/H-ferritin+ or CD68+/L-ferritin+ cells and the clinical picture. Immunofluorescence analysis demonstrated an increased tissue H-ferritin expression in the LNs of AOSD patients. This increased expression correlated with the severity of the disease. An increased number of CD68 macrophages expressing H-ferritin was observed in the LN samples of our patients. Furthermore, we observed that the number of CD68+/H-ferritin+ cells correlated significantly with the severity of the clinical picture. Our data showed an imbalance between the levels of H- and L-ferritin in LNs of AOSD patients and the evidence of an increased number of CD68+/H-ferritin+ cells in the same organs. Furthermore, a correlation among both the tissue H-ferritin levels and the CD68+/H-ferritin+ cells and the clinical picture was observed