JAK/STAT pathway and molecular mechanism in bone remodeling.

JAK/STAT signaling pathway is involved in many diseases, including autoimmune diseases, which are characterized by a close interconnection between immune and bone system. JAK/STAT pathway is involved in bone homeostasis and plays an important role in proliferation and differentiation of some cell types, including osteoblasts and osteoclasts. Different molecules, such as cytokines, hormones, and growth factors are responsible for the activation of the JAK/STAT pathway, which leads, at the nuclear level, to start DNA transcription of target genes. Bone cells and remodeling process are often influenced by many cytokines, which act as strong stimulators of bone formation and resorption. Our aim, through careful research in literature, has been to provide an overview of the role of the JAK/STAT pathway in bone remodeling and on bone cells, with a focus on cytokines involved in bone turnover through this signal cascade. The JAK/STAT pathway, through the signal cascade activation mediated by the interaction with many cytokines, acts on bone cells and appears to be involved in bone remodeling process. However, many other studies are needed to completely understand the molecular mechanism underlying these bone process.

Gender differences in early systemic sclerosis patients: a report from the EULAR scleroderma trials and research group (EUSTAR) database.

OBJECTIVES: To describe differences in clinical presentation between men and women in a large group of patients with early (<3 years' duration) systemic sclerosis (SSc) according to disease subsets. METHODS: A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research database (EUSTAR) was performed. Patients fulfilling preliminary ACR 1980 classification criteria for SSc, with less than 3 years from the first non-Raynaud's symptom at first entry, were selected. A group of patients with less than 3 years from the first SSc symptom, including Raynaud's phenomenon, was also analysed. SSc related variables, including antibodies, SSc subsets, disease activity and organ involvement were included. Descriptive and bivariate analyses were performed. RESULTS: A total of 1,027 patients were included, 90% Caucasian, 80% women, and 40% with diffuse cutaneous disease. In early stages of SSc, men showed more frequently than women active disease, diffuse cutaneous subset, anti-Scl-70 antibodies, elevated acute phase reactants, muscular and pulmonary involvement. Differences between men and women were confirmed in the limited, but not in the diffuse SSc subset. The results were similar when 650 patients with less than three years from the first SSc symptom, including Raynaud's phenomenon, were analysed. CONCLUSIONS: In early stages of SSc, men present signs and symptoms of more severe disease. In the limited disease subset, men might appear with clinical features and organ involvement similar to those of the diffuse subgroup. In clinical practice, the identification of such differences might help to select the appropriate management for each particular patient.

Clinical determinants of elevated systolic pulmonary artery pressure measured by transthoracic Doppler echocardiography in early systemic sclerosis.

OBJECTIVES: To explore the prevalence and clinical associations of elevated systolic pulmonary artery pressure (sPAP), measured by Transthoracic Doppler-echocardiography (TTE) in patients with early systemic sclerosis (SSc). METHODS: A cross-sectional analysis of the prospective EULAR Scleroderma Trial and Research (EUSTAR) database was performed. SSc patients with <3 years from the first non-Raynaud's phenomenon (RP) symptom at baseline EUSTAR visit, were selected. Elevated sPAP was defined as sPAP>40 mmHg on baseline TTE. First visit SSc related variables, including disease subsets, antibodies and visceral involvement, were examined. RESULTS: From 1,188 patients, 81% were women. Mean (SD) age at first non-RP symptom was 50 (14) years, 55% had limited cutaneous SSc (lcSSc) and 42% active disease. Elevated sPAP was found in 17% of patients, both lcSSc and diffuse cutaneous SSc (dcSSc). In lcSSc, older age at first non-RP symptom, ACA positivity, joint contractures, restrictive defect and lower DLCO, were independently associated with elevated sPAP. In dcSSc, older age at first non-RP symptom, longer time between RP onset and first non-RP symptom, digital ulcers, cardiac blocks, and proteinuria were associated with elevated sPAP. CONCLUSIONS: The prevalence of elevated sPAP on TTE in early SSc patients is considerable. Association with cardiac, lung and renal involvement suggests that, although some patients might have pulmonary arterial hypertension, others may present pulmonary hypertension secondary to lung or heart involvement. Our findings emphasize the need to consider right heart catheterisation in selected early SSc patients with PH suspicion, to clearly determine the cause of PH.

Rare forms of inflammatory myopathies - part I, generalized forms.

INTRODUCTION: The idiopathic inflammatory myopathies traditionally comprise dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, anti-synthetase syndrome, and inclusion body myositis. In this review, we aimed to cover the less common forms of generalized myositis. AREAS COVERED: We identified rare forms of widespread myositis on the basis of list provided by the homepage of the Neuromuscular disease center of Washington University, USA and on the basis of the authors' knowledge. We searched PubMed® and EMBASE® for relevant articles on these forms with the aim of providing as much as possible information on their clinical manifestations as well as guidance on their work-up and treatment. EXPERT OPINION: There is substantial heterogeneity among the various rare forms of generalized myositis in terms of their frequency and characterization. Some forms are reasonably well defined, while others may not represent truly well-defined diseases, but rather variants of other myopathies. The landscape of rare forms appears to have evolved over time, with some forms now being better characterized, while others, such as SARS-Cov-2- and immune checkpoint inhibitor-related myositis have come to the fore only in recent years. Knowledge about rare forms of myositis can aid in their recognition and treatment.

Rare forms of inflammatory myopathies - part II, localized forms.

INTRODUCTION: The idiopathic inflammatory myopathies traditionally comprise dermatomyositis, polymyositis, the anti-synthetase syndromes, immune-mediated necrotizing myopathy and inclusion body myositis. However, there are uncommon localized forms that are less known. In this review, we aimed to cover these uncommon forms. AREAS COVERED: We identified rare forms of localized myositis on the basis of list provided by the homepage of the Neuromuscular disease center of Washington University, USA and on the basis of the authors' knowledge. We searched PubMed® for relevant articles on these forms with the aim of providing as much as possible information on their clinical manifestations as well as guidance on their work-up and treatment. EXPERT OPINION: herein, we provide un updated description of rare forms of localized myositis. These forms are often difficult to diagnose because of their localized nature and are sometimes misdiagnosed as tumors. Knowledge about these rare forms of localized myositis can aid in their recognition and treatment.

Rheumatological Diseases in HIV Infection.

A review of the available literature was performed in order to summarize the pathogenic and clinical connections between HIV infection and rheumatological syndromes. The increasing life expectancy during human immunodeficiency virus (HIV) infection has led to the observation of many rheumatological manifestations over the years in these types of patients. Although the pathological mechanisms are still not fully understood, several rheumatological diseases have been more commonly observed in the general population, especially after the advent of highly active antiretroviral therapy (HAART), and sometimes clinical and serological findings are influenced by the underlying condition which defines a characteristic onset or development of the disease. Autoimmune diseases occur during specific stages of the HIV infection, depending on the underlying pathogenic mechanism being mainly influenced by the CD4+ cells count. Several rheumatological diseases show peculiar clinical manifestations influenced by the underlying HIV infection leading to specific features less commonly observed in the healthy population. Conversely to pathological findings, broadly, HIV-1-neutralizing antibodies (BnAb) observed in several autoimmune diseases, such as SLE, could play a protective role in HIV infection. It is important to evaluate the onset of autoimmune diseases in HIV patients in order to start the appropriate treatment to avoid harmful events. More studies are needed to enlighten the trend of autoimmune diseases during HIV infection. Pathogenic mechanisms and clinical manifestations of rheumatological diseases during HIV infection are discussed in this review.

Abnormalities of insulin-like growth factor-I signaling and impaired cell proliferation in osteoblasts from subjects with osteoporosis.

IGF-I regulates bone acquisition and maintenance, even though the cellular targets and signaling pathways responsible for its action in human bone cells are poorly understood. Whether abnormalities in IGF-I action and signaling occur in human osteoblasts under conditions of net bone loss has not been determined. Herein we carried out a comparative analysis of IGF-I signaling in primary cultures of human osteoblasts from osteoporotic and control donors. In comparison with control cells, osteoporotic osteoblasts showed increased tyrosine phosphorylation of the IGF-I receptor in the basal state and blunted stimulation of receptor phosphorylation by IGF-I. Augmentation of basal IGF-I receptor phosphorylation was associated with coordinate increases in basal tyrosine phosphorylation of insulin receptor substrate (IRS)-2 and activation of Erk, which were also minimally responsive to IGF-I stimulation. By contrast, phosphorylation levels of IRS-1, Akt, and glycogen synthase kinase-3 were similar in the basal state in control and osteoporotic osteoblasts and showed marked increases after IGF-I stimulation in both cell populations, even though these responses were significantly lower in the osteoporotic osteoblasts. The IGF-I signaling abnormalities in osteoporotic osteoblasts were associated with reduced DNA synthesis both under basal conditions and after stimulation with IGF-I. Interestingly, treatment of the osteoporotic osteoblasts with the MAPK kinase inhibitor PD098059 reduced the elevated levels of Erk phosphorylation and increased basal DNA synthesis. Collectively, our data show that altered osteoblast proliferation in human osteoporosis may result from dysregulation of IGF-I receptor signaling, including constitutive activation of the IRS-2/Erk signaling pathway, which becomes unresponsive to IGF-I, and defective induction of the IRS-1/Akt signaling pathway.

The incidence of cardiovascular events in Italian patients with systemic lupus erythematosus is lower than in North European and American cohorts: implication of disease-associated and traditional risk factors as emerged by a 16-year retrospective GIRRCS study: GIRRCS=Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale.

Previous study from our group has pointed out a lower number of cardiovascular (CV) events in Italian patients with systemic lupus erythematosus (SLE) than in North European and American ones. This study aims to assess the incidence of the first CV event in a large, multicenter, Italian cohort of patients with SLE and search for differences in disease and traditional risk factors among distinct cohorts.Clinical charts of SLE patients consecutively admitted to 5 Italian rheumatologic centers from November 1st 2000 to December 31st 2015 and free of CV events at baseline were retrospectively studied. CV cumulative incidence (ie, the proportion of patients who experienced a new CV event over the follow-up period) and CV incidence rate (ie, the number of events in the cohort divided by the total number of years at risk) were evaluated. The detected incidences were compared with those reported in SLE cohorts from other countries.The median duration of follow-up was 6 years (IQR = 3-11). During the observational period, 37 (cumulative incidence = 7.2%) patients had a first episode of CV event with an incidence rate of 10.1/1000 person-years. The CV cumulative incidence and incidence rate detected in our Italian cohort were lower than those from most North European and American cohorts, characterized by a high impact of traditional risk factors. Nevertheless, the cumulative incidence was similar to that reported in a Spanish cohort with a high frequency of traditional risk factors (geographic impact), while the incidence rate was only slightly higher than that in the Baltimore cohort, which is characterized by a strict follow-up of patients (medical impact).Our results confirmed that Italian lupus patients have a low incidence of CV events. Moreover, the geographic origin, traditional risk factors, and medical approach appear to have an impact on CV disease in SLE.