Adult-onset Still’s disease (AOSD) is a chronic inflammatory disease of unknown etiology which commonly affects young adults. Treatment of AOSD patients includes nonsteroidal anti-inflammatory drugs, ...corticosteroids, and DMARDs. Interleukin (IL)-6 blockade is an attractive therapeutic option for AOSD because this cytokine contributes to the pathogenesis of major AOSD symptoms. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that blocks the effects of IL-6. Preliminary results of TCZ in AOSD have been promising. Here, we reported our experience evaluating both the safety and the efficacy of 12 months therapy with TCZ in 11 patients with AOSD refractory to corticosteroids and MTX therapy, followed for 18 months, including the first 12 months of active treatment and the last 6 months to evaluate the activity of the disease when the treatment was discontinued. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and improvement of systemic symptoms at the 3, 6, 12, and 18-months follow-up periods. Our patients rapidly responded and experienced a sustained clinical remission over time during active treatment. Disease Activity Score 28 decreased from 5.62 (3.75–8.28) median (range) at baseline to 1.61(0.49–3.5) at month 12. EULAR remission was achieved in 81.82 % at 12 months. Tender joint and swollen joint counts displayed a progressive reduction during active therapy study period. During treatment, we observed a resolution of fever in our AOSD patient. In conclusion, TCZ might represent a suitable option for the therapy of refractory AOSD patients.
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. ...Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFβ signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFβ signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFβ-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases.
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.
Historically, primary Sjögren’s syndrome (pSS) was thought to be a T helper (h) 1 driven disease due to the predominance of CD4+T lymphocytes and their products in target organs and peripheral blood ...of patients. In the last decades, the identification of a number of T cell subsets, including Th17, T regulatory (Treg), and follicular helper T cells, challenged this long-standing paradigm and prompted to identify their role in pSS pathogenesis. In addition the impact of abnormal proinflammatory cytokine production, such as IL-6, IL-17, IL-22, and IL-23, has also attracted considerable attention. However, although several studies have been carried out in experimental models and patients with pSS, many aspects concerning the role of Treg cells and IL-17/Th17 cell system in pSS pathogenesis are not fully elucidated. In particular, the role played by different IL-17-producing T cell subsets as well as the effects of pharmacological therapies on Treg/Th17 cell balance represents an intriguing issue. The aim of this review article is to provide an overview of current knowledge on Treg cells and IL-17-producing T cells in pSS pathogenesis. We believe that these insights into pSS pathogenesis may provide the basis for successful therapeutic intervention in this disease.
Microvascular damage is pivotal in the pathogenesis of systemic sclerosis (SSc), preceding fibrosis, and whose trigger is not still fully understood. Perivascular progenitor cells, with profibrotic ...activity and function, are identified by the expression of the isoform 12 of ADAM (ADAM12) and this molecule may be upregulated by transforming growth factor-β (TGF-β). The goal of this work was to evaluate whether pericytes in the skin of patients with diffuse cutaneous SSc (dcSSc) expressed ADAM12, suggesting their potential contribution to the fibrotic process, and whether TGF-β might modulate this molecule.
After ethical approval, mesenchymal stem cells (MSC) and fibroblasts (FB) were isolated from bone marrow and skin samples collected from 20 patients with dcSSc. ADAM12 expression was investigated in the skin and in isolated MSC and FB treated with TGF-β by immunofluorescence, quantitative real-time PCR, and western blot. Further, we silenced ADAM12 expression in both dcSSc-MSC and -FB to confirm the TGF-β modulation.
Pericytes and FB of dcSSc skin showed an increased expression of ADAM12 when compared with healthy control skin. TGF-β in vitro treatment induced a significant increase of ADAM12 in both SSc-MSC and -FB, with the higher levels observed in dcSSc cells. After ADAM12 silencing, the TGF-β ability to upregulate α-smooth muscle actin in both SSc-MSC and SSc-FB was inhibited.
Our results suggest that in SSc, pericytes that transdifferentiate toward activated FB are present in the vascular tree, and TGF-β, while increasing ADAM12 expression, may modulate this transdifferentiation.
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.
Objective
Patients with primary Sjögren’s syndrome (pSS) may develop a potentially severe disease with extra-glandular involvement and lymphoma insurgence. Minor salivary gland biopsy is routinely ...used in the disease diagnosis, but its potential role as a biomarker for clinical disease presentation and prognosis is still poorly understood.
Methods
We performed a systematic review and meta-analysis on clinical presentation and prognosis in pSS patients who underwent minor salivary gland biopsy at diagnosis according to the PRISMA guidelines.
Results
We included five retrospective studies and 589 pSS patients. Ectopic GCs presence was not associated with a significant increase in the odds ratio for the clinical variables explored such as salivary gland swelling, arthritis, and Raynaud’s phenomenon. As far as serological features are concerned, ectopic GCs presence accounted for an increased ratio of antibodies anti-SSA (OR = 3.13, 95% CI: 1.25–7.85, p = 0.02, I
2
= 79%), anti-SSB (OR = 3.94, 95% CI: 1.50–10.37, p = 0.0005, I
2
= 80%), and RFs presence (OR = 3.12, 95% CI: 1.94–5.00, p < 0.00001, I
2
= 0%).
Conclusions
This study showed that the association between ectopic GC in salivary glands identifies a clinical subset characterized by autoantibodies presence, and probably pSS patients affected from a more severe disease.
Abstract
Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. ...The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.
Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown aetiology affecting young adults, which is burdened by life-threatening complications, mostly macrophage activation ...syndrome (MAS). Interferons (IFNs) are signalling molecules that mediate a variety of biological functions from defence against viral infections, to antitumor and immunomodulatory effects. These molecules have been classified into three major types: IFN I, IFN II, IFN III, presenting specific characteristics and functions. In this work, we reviewed the role of IFNs on AOSD and MAS, focusing on their pathogenic role in promoting the hyperinflammatory response and as new possible therapeutic targets. In fact, both preclinical and clinical observations suggested that these molecules could promote the hyperinflammatory response in MAS during AOSD. Furthermore, the positive results of inhibiting IFN-γ in primary hemophagocytic lymphohistiocytosis may provide a solid rationale to arrange further clinical studies, paving the way for reducing the high mortality rate in MAS during AOSD.
Abstract
Atlantoaxial joint is a possible affected site during rheumatoid arthritis (RA) and, in this work, we evaluated its occurrence and associated characteristics in a “real-life” cohort. By a ...medical records review study of RA patients longitudinally followed-up, the occurrence of severe atlantoaxial joint involvement was estimated (incidence proportion and incidence rate per 1000 person-years at risk). Regression analyses were also exploited to evaluate possible associated factors. Based on these findings, a prospective recruitment was performed to build a descriptive cross-sectional study in evaluating a subclinical atlantoaxial joint involvement in patients with the same clinical characteristics. Retrospectively, 717 patients (female 56.6%, age 64.7 ± 12.3 years) were studied. The incidence proportion of severe atlantoaxial joint involvement was 2.1% 1.5–2.5, occurring in 15 out of 717 patients, and identified by both MRI and CT scan. Considering over 3091 person-years, an incidence rate of 5.2 × 1000 2.9–8.3 person-years was estimated. Regression analyses suggested that male gender, a longer disease duration, ACPA positivity and extra-articular manifestations resulted to be significantly associated with a severe atlantoaxial joint involvement. Given these findings, 30 asymptomatic patients were selected according to these clinical characteristics and underwent MRI of cervical spine. To date, almost 50% of these asymptomatic patients showed a subclinical atlantoaxial joint involvement. The occurrence of the severe atlantoaxial joint involvement in RA patients was estimated in a “real-life” setting. Male gender, ACPA positivity, long disease duration, and extra-articular manifestations could be associated with the severe atlantoaxial joint involvement in RA. MRI could provide a useful clinical tool to early evaluate the atlantoaxial joint involvement in RA, also in asymptomatic patients.
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