Impact of belimumab therapy on the quality of life in patients with systemic lupus erythematosus: A cohort study.

Systemic lupus erythematosus (SLE) is a chronic and extremely disabling connective-tissue autoimmune disease with a tremendous impact on the quality of life (QoL). Belimumab, a B-lymphocyte-stimulator-specific inhibitor, is the first biologic drug approved as add-on therapy in patients with active, refractory auto-antibody-positive SLE.The impact of belimumab on the QoL of SLE patients was evaluated using a generic questionnaire short-form health survey 36 (SF-36) and the disease-specific questionnaire SLE-specific quality of life (SLEQoL).The Italian version of the SLEQoL and the SF-36 were administered to 46 SLE patients before and after 6 months of belimumab therapy. The control population consisted of 40 age-matched healthy individuals. The questionnaires were completed before and after belimumab treatment and the results were compared using the Wilcoxon signed-rank test. In addition, data from healthy controls and SLE patients were compared using the Mann-Whitney test. Dichotomous variables were compared using Fisher's exact test.For SLE patients, the addition of belimumab to their therapeutic regimen significantly improved their health-related QoL (HRQoL), according to the results of the SF-36 and SLEQoL. The comparison of the data obtained before and after belimumab treatment showed a decrease in all six SLEQoL domains and an increase in all eight SF-36 domains. Moreover, treatment led to a reduction in the median prednisone dose, to 0 mg/day (IQR 0-4.5 mg/day). Before belimumab therapy, SLE patients had a worse HRQoL than the control group, based on both questionnaires, but after belimumab treatment the outcome scores between SLE patients and controls were similar, suggesting that belimumab therapy resulted in a strong improvement in HRQoL. These findings were supported by a decrease in the SELENA-SLEDAI score, a measure of disease activity.In addition to clinical remission and low disease activity, the goals of an innovative therapeutic strategy for SLE should include the attainment of a good HRQoL. Our study demonstrates that the combined use of the SF-36 and SLEQoL questionnaires can provide clinicians with a better understanding of the HRQoL of SLE patients.

Disparities in the prevalence of clinical features between systemic juvenile idiopathic arthritis and adult-onset Still's disease.

OBJECTIVE: To compare clinical features and treatments of patients with systemic JIA (sIJA) and adult-onset Still's disease (AOSD). METHODS: The clinical charts of consecutive patients with sJIA by International League of Association of Rheumatology criteria or AOSD by Yamaguchi criteria were reviewed. Patients were seen at a large paediatric rheumatology referral centre or at 10 adult rheumatology academic centres. Data collected included clinical manifestations, inflammation biomarkers, systemic score, macrophage activation syndrome (MAS), parenchymal lung disease, disease course, disability, death and medications administered. RESULTS: A total of 166 patients (median age at diagnosis 5 years) with sJIA and 194 patients with AOSD (median age at diagnosis 41 years) were included. The frequency of fever, rash, arthralgia, abdominal pain, MAS, parenchymal lung disease and increased acute phase reactants and ferritin were comparable between the two cohorts. Patients with sJIA had a higher prevalence of arthritis, whereas patients with AOSD had experienced leucocytosis and extra-articular organ involvement more frequently. Patients with AOSD were given more commonly low-dose corticosteroids, whereas biologic DMARDs were administered first-line more frequently in patients with sJIA. CONCLUSION: We found remarkable disparities in the prevalence of clinical manifestations between the two illnesses, which may partly depend on their classification by different criteria.

Adult-onset Still's disease with elderly onset: results from a multicentre study.

OBJECTIVES: In this study, we aimed at describing the clinical characteristics, life-threatening complications occurrence, and mortality of adult-onset Still's disease (AOSD) patients with elderly onset. METHODS: A multicentre retrospective study of prospectively followed-up AOSD patients included in Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort was performed. RESULTS: Out of 221 assessed patients, 37 (16.7%) had an onset of the disease aged over 60 years. When compared with younger patients, these were characterised by a higher prevalence of pericarditis (p=0.008), comorbidities (p<0.0001), and mortality (p=0.023). Age predicted the presence of serositis in both univariate (HR: 1.02, 95%CI: 1.01-1.03, p=0.007) and multivariate analyses (HR: 1.02, 95%CI: 1.01-1.04, p=0.007). Age was also a significant predictor of parenchymal lung disease in both univariate (HR: 1.03, 95%CI: 1.01-1.05, p=0.017) and multivariate analyses (HR: 1.03, 95%CI: 1.00-1.05, p=0.048). Furthermore, age resulted to be a negative predictor of polycyclic pattern only in univariate analysis (HR: 0.99, 95%CI: 0.97-1.00, p=0.048). Finally, age significantly predicted the mortality in both univariate (HR: 1.03, 95%CI: 1.00-1.06, p=0.034) and multivariate analyses (HR: 1.05, 95%CI: 1.01-1.08, p=0.012). CONCLUSIONS: Clinical features of AOSD patients in the elderly were described in our cohort. Although the main clinical characteristics were similar comparing older and younger patients, patients aged over 60 years at disease onset were characterised by an increased prevalence of serositis, comorbidities, mostly cardiometabolic, and a higher mortality rate. Age predicted the presence of parenchymal lung disease and mortality, and it could be considered a negative prognostic factor in AOSD.

SARS-CoV-2 Inflammatory Syndrome. Clinical Features and Rationale for Immunological Treatment.

The current pandemic coronavirus, SARS-CoV-2, is a global health emergency because of its highly contagious nature, the great number of patients requiring intensive care therapy, and the high fatality rate. In the absence of specific antiviral drugs, passive prophylaxis, or a vaccine, the treatment aim in these patients is to prevent the potent virus-induced inflammatory stimuli from leading to the acute respiratory distress syndrome (ARDS), which has a severe prognosis. Here, the mechanism of action and the rationale for employing immunological strategies, which range from traditional chemically synthesized drugs, anti-cytokine antibodies, human immunoglobulin for intravenous use, to vaccines, are reviewed.

CD20-Mimotope Peptides: A Model to Define the Molecular Basis of Epitope Spreading.

Antigen-mimicking peptide (mimotope)-based vaccines are one of the most promising forms of active-immunotherapy. The main drawback of this approach is that it induces antibodies that react poorly with the nominal antigen. The aim of this study was to investigate the molecular basis underlying the weak antibody response induced against the naïve protein after peptide vaccination. For this purpose, we analyzed the fine specificity of monoclonal antibodies (mAb) elicited with a 13-mer linear peptide, complementary to theantigen-combining site of the anti-CD20 mAb, Rituximab, in BALB/c mice. Anti-peptide mAb competed with Rituximab for peptide binding. Even so, they recognized a different antigenic motif from the one recognized by Rituximab. This explains their lack of reactivity with membrane (naïve) CD20. These data indicate that even on a short peptide the immunogenic and antigenic motifs may be different. These findings highlight an additional mechanism for epitope spreading and should be taken into account when designing peptides for vaccine purposes.

Classic pyoderma gangrenosum.

Pyoderma gangrenosum is a rare inflammatory ulcerative skin disease of unknown etiology. We report an image of a patient with pyoderma gangrenosum who presented right leg ulcers with violaceous margins, histologically characterized by mono- and polynuclear cell infiltrates. The patient was successfully treated with cyclosporin A.

Adipose failure through adipocyte overload and autoimmunity.

Metabolic syndrome poses a great worldwide threat to the health of the patients. Increased visceral adiposity is recognized as the main determinant of the detrimental clinical effects of insulin resistance. Inflammation and immune system activation in the adipose tissue (AT) have a central role in the pathophysiology of metabolic syndrome, but the mechanisms linking increased adiposity to immunity in the AT remain in part elusive. In this review, we support the central role of adipocyte overload and relative adipose failure as key determinants in triggering immune aggression to AT. This provides a mechanistic explanation of the relative metabolic wellness of metabolically normal obese people and the disruption in insulin signaling in metabolically obese lean people.

Endothelial cells in tumor microenvironment: insights and perspectives.

The tumor microenvironment is a highly complex and dynamic mixture of cell types, including tumor, immune and endothelial cells (ECs), soluble factors (cytokines, chemokines, and growth factors), blood vessels and extracellular matrix. Within this complex network, ECs are not only relevant for controlling blood fluidity and permeability, and orchestrating tumor angiogenesis but also for regulating the antitumor immune response. Lining the luminal side of vessels, ECs check the passage of molecules into the tumor compartment, regulate cellular transmigration, and interact with both circulating pathogens and innate and adaptive immune cells. Thus, they represent a first-line defense system that participates in immune responses. Tumor-associated ECs are involved in T cell priming, activation, and proliferation by acting as semi-professional antigen presenting cells. Thus, targeting ECs may assist in improving antitumor immune cell functions. Moreover, tumor-associated ECs contribute to the development at the tumor site of tertiary lymphoid structures, which have recently been associated with enhanced response to immune checkpoint inhibitors (ICI). When compared to normal ECs, tumor-associated ECs are abnormal in terms of phenotype, genetic expression profile, and functions. They are characterized by high proliferative potential and the ability to activate immunosuppressive mechanisms that support tumor progression and metastatic dissemination. A complete phenotypic and functional characterization of tumor-associated ECs could be helpful to clarify their complex role within the tumor microenvironment and to identify EC specific drug targets to improve cancer therapy. The emerging therapeutic strategies based on the combination of anti-angiogenic treatments with immunotherapy strategies, including ICI, CAR T cells and bispecific antibodies aim to impact both ECs and immune cells to block angiogenesis and at the same time to increase recruitment and activation of effector cells within the tumor.

Idiopathic and connective tissue disease-associated pulmonary arterial hypertension (PAH): Similarities, differences and the role of autoimmunity.

Pre-capillary pulmonary arterial hypertension (PAH) is hemodynamically characterized by a mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg, pulmonary capillary wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) > 2. PAH is classified in six clinical subgroups, including idiopathic PAH (IPAH) and PAH associated to connective tissue diseases (CTD-PAH), that will be the main object of this review. The aim is to compare these two PAH subgroups in terms of epidemiology, histological and pathogenic findings in an attempt to define disease-specific features, including autoimmunity, that may explain the heterogeneity of response to therapy between IPAH and CTD-PAH.

Predicting Factors of Worse Prognosis in COVID-19: Results from a Cross-sectional Study on 52 Inpatients Admitted to the Internal Medicine Department.

BACKGROUND: The initial phases of the COVID-19 pandemic posed a real need for clinicians to identify patients at risk of poor prognosis as soon as possible after hospital admission. AIM: The study aimed to assess the role of baseline anamnestic information, clinical parameters, instrumental examination, and serum biomarkers in predicting adverse outcomes of COVID-19 in a hospital setting of Internal Medicine. METHODS: Fifty-two inpatients consecutively admitted to the Unit of Internal Medicine "Baccelli," Azienda Ospedaliero - Universitaria Policlinico of Bari (February 1 - May 31, 2021) due to confirmed COVID-19 were grouped into two categories based on the specific outcome: good prognosis (n=44), patients discharged at home after the acute phase of the infection; poor prognosis, a composite outcome of deaths and intensive care requirements (n=8). Data were extracted from medical records of patients who provided written informed consent to participate. RESULTS: The two study groups had similar demographic, anthropometric, clinical, and radiological characteristics. Higher interleukin 6 (IL-6) levels and leucocyte count, and lower free triiodothyronine (fT3) levels were found in patients with poor than those with good prognosis. Higher IL-6 levels and leucocyte count, lower fT3 concentration, and pre-existing hypercholesterolemia were independent risk factors of poor outcomes in our study population. A predicting risk score, built by assigning one point if fT3 < 2 pg/mL, IL-6 >25 pg/mL, and leucocyte count >7,000 n/mm3, revealed that patients totalizing at least 2 points by applying the predicting score had a considerably higher risk of poor prognosis than those with scoring <2 points [OR 24.35 (1.32; 448), p = 0.03]. The weight of pre-existing hypercholesterolemia did not change the risk estimation. CONCLUSION: Four specific baseline variables, one anamnestic (pre-existing hypercholesterolemia) and three laboratory parameters (leucocyte count, IL-6, and fT3), were significantly associated with poor prognosis as independent risk factors. To prevent adverse outcomes, the updated 4-point score could be useful in identifying at-risk patients, highlighting the need for specific trials to estimate the safety and efficacy of targeted treatments.

Immune escape of multiple myeloma cells results from low miR29b and the ensuing epigenetic silencing of proteasome genes.

BACKGROUND: Activation of CD28 on multiple myeloma (MM) plasma cells, by binding to CD80 and CD86 on dendritic cells, decreases proteasome subunit expression in the tumor cells and thereby helps them evade being killed by CD8+ T cells. Understanding how CD28 activation leads to proteasome subunit downregulation is needed to design new MM therapies. METHODS: This study investigates the molecular pathway downstream of CD28 activation, using an in vitro model consisting of myeloma cell lines stimulated with anti-CD28-coated beads. RESULTS: We show that CD28 engagement on U266 and RPMI 8226 cells activates the PI3K/AKT pathway, reduces miR29b expression, increases the expression of DNA methyltransferase 3B (DNMT3B, a target of miR29b), and decreases immunoproteasome subunit expression. In vitro transfection of U266 and RPMI 8226 cells with a miR29b mimic downregulates the PI3K/AKT pathway and DNMT3B expression, restores proteasome subunit levels, and promotes myeloma cell killing by bone marrow CD8+ T cells from MM patients. Freshly purified bone marrow plasma cells (CD138+) from MM patients have lower miR29b and higher DNMT3B (mRNA and protein) than do cells from patients with monoclonal gammopathy of undetermined significance. Finally, in MM patients, high DNMT3B levels associate with shorter overall survival. CONCLUSIONS: Altogether, this study describes a novel molecular pathway in MM. This pathway starts from CD28 expressed on tumor plasma cells and, through the PI3K-miR29b-DNMT3B axis, leads to epigenetic silencing of immunoproteasome subunits, allowing MM plasma cells to elude immunosurveillance. This discovery has implications for the design of innovative miR29b-based therapies for MM.

Non-Classical HLA Class 1b and Hepatocellular Carcinoma.

A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.

Unraveling the Role of Peroxisome Proliferator-Activated Receptor ß/Δ (PPAR ß/Δ) in Angiogenesis Associated with Multiple Myeloma.

Growing evidence suggests a role for peroxisome proliferator-activated receptor ß/δ (PPAR ß/δ) in the angiogenesis, growth, and metastasis of solid tumors, but little is known about its role in multiple myeloma (MM). Angiogenesis in the bone marrow (BM) is characteristic of disease transition from monoclonal gammopathy of undetermined significance (MGUS) to MM. We examined the expression and function of PPAR ß/δ in endothelial cells (EC) from the BM of MGUS (MGEC) and MM (MMEC) patients and showed that PPAR ß/δ was expressed at higher levels in MMEC than in MGEC and that the overexpression depended on myeloma plasma cells. The interaction between myeloma plasma cells and MMEC promoted the release of the PPAR ß/δ ligand prostaglandin I2 (PGI2) by MMEC, leading to the activation of PPAR ß/δ. We also demonstrated that PPAR ß/δ was a strong stimulator of angiogenesis in vitro and that PPAR ß/δ inhibition by a specific antagonist greatly impaired the angiogenic functions of MMEC. These findings define PGI2-PPAR ß/δ signaling in EC as a potential target of anti-angiogenic therapy. They also sustain the use of PPAR ß/δ inhibitors in association with conventional drugs as a new therapeutic approach in MM.

Cutaneous polyarteritis nodosa and pulmonary arterial hypertension: An unexpected liaison. A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a form of medium-sized vessel necrotizing vasculitis. It is a rare, skin-limited variant of polyarteritis nodosa, characterized by dermal and subcutaneous tissue involvement. The most common findings in cPAN include digital gangrene, livedo reticularis, and tender subcutaneous nodules. However, while limited to the skin, cPAN results in significant morbidity and mortality due to the accompanying skin ischemia and necrosis, such that patients are vulnerable to superinfection. Here, we describe a unique presentation of cPAN associated with pulmonary arterial hypertension (PAH). METHODS: A 78-year-old female presented with digital ischemia and leg ulcers associated with PAH. Skin biopsy showed necrotizing fibrinoid necrosis of the small- and middle-sized vessels of the dermis. A diagnosis of cPAN and PAH was made. The patient was treated with glucocorticoids, vasodilators, and cyclophosphamide. RESULTS: She died due to severe sepsis complications. CONCLUSION: To date, this is the first case report describing the association between cPAN and PAH. In this case, PAH is a complication of the cutaneous vasculitides suggesting that vasculopathy could play a role in the pathophysiology of PAH. However, the underlying pathophysiological mechanisms still have to be firmly established.

Clinical characteristics of obese patients with adult-onset Still's disease. Data from a large multicentre cohort.

OBJECTIVES: To evaluate the impact of obesity in patients with adult-onset Still's disease (AOSD) and to assess their clinical characteristics and disease outcomes. METHODS: The clinical features of AOSD patients with a body mass index (BMI)≥30 were assessed among those included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. RESULTS: Out of 139 AOSD patients, who had BMI registered in our database, 26 (18.7%) had a BMI≥30. A lower rate of sore throat (P<0.05), pericarditis (P<0.05), and pleuritis (P<0.05) was shown in obese patients. Additionally, obese patients showed higher values of C-reactive protein (CRP) (P<0.05) and ferritin (P<0.05) than others. Furthermore, obese patients were characterised by biologic disease-modifying antirheumatic drug (bDMARD) failure in subsequent follow-up (P<0.05). They also presented higher rate of comorbidity than non-obese patients (P<0.05). Finally, obesity predicted the presence of a chronic disease course in both univariate (HR: 1.72, 95%CI: 1.03-2.51, P<0.05) and multivariate analyses (HR: 1.85, 95%CI: 1.45-2.89, P<0.05). Obesity was also a significant predictor of bDMARD failure in AOSD patients in both univariate (HR: 3.03, 95%CI: 1.42-6.45, P<0.01) and multivariate analyses (HR: 3.59, 95%CI: 1.55-8.27, P<0.01). CONCLUSION: Obese patients at the time of diagnosis of the disease were characterised by a lower prevalence of sore throat, serositis, as well as by higher values of CRP and ferritin. Obesity was also a predictive factor for a chronic disease course and bDMARD failure, thus highlighting a subset of patients with AOSD to be carefully managed.

Early and Late Response and Glucocorticoid-Sparing Effect of Belimumab in Patients with Systemic Lupus Erythematosus with Joint and Skin Manifestations: Results from the Belimumab in Real Life Setting Study-Joint and Skin (BeRLiSS-JS).

AIM: To assess the efficacy of belimumab in joint and skin manifestations in a nationwide cohort of patients with SLE. METHODS: All patients with skin and joint involvement enrolled in the BeRLiSS cohort were considered. Belimumab (intravenous, 10 mg/kg) effectiveness in joint and skin manifestations was assessed by DAS28 and CLASI, respectively. Attainment and predictors of DAS28 remission (<2.6) and LDA (≥2.6, ≤3.2), CLASI = 0, 1, and improvement in DAS28 and CLASI indices ≥20%, ≥50%, and ≥70% were evaluated at 6, 12, 24, and 36 months. RESULTS: DAS28 < 2.6 was achieved by 46%, 57%, and 71% of patients at 6, 12, and 24 months, respectively. CLASI = 0 was achieved by 36%, 48%, and 62% of patients at 6, 12, and 24 months, respectively. Belimumab showed a glucocorticoid-sparing effect, being glucocorticoid-free at 8.5%, 15.4%, 25.6%, and 31.6% of patients at 6, 12, 24, and 36 months, respectively. Patients achieving DAS-LDA and CLASI-50 at 6 months had a higher probability of remission at 12 months compared with those who did not (p = 0.034 and p = 0.028, respectively). CONCLUSIONS: Belimumab led to clinical improvement in a significant proportion of patients with joint or skin involvement in a real-life setting and was associated with a glucocorticoid-sparing effect. A significant proportion of patients with a partial response at 6 months achieved remission later on during follow-up.

Derivation and validation of four patient clusters in Still's disease, results from GIRRCS AOSD-study group and AIDA Network Still Disease Registry.

BACKGROUND: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients. METHODS: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters. RESULTS: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients. CONCLUSIONS: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.

Drug resistance in multiple myeloma: Soldiers and weapons in the bone marrow niche.

Multiple myeloma (MM) is still an incurable disease, despite considerable improvements in treatment strategies, as resistance to most currently available agents is not uncommon. In this study, data on drug resistance in MM were analyzed and led to the following conclusions: resistance occurs via intrinsic and extrinsic mechanisms, including intraclonal heterogeneity, drug efflux pumps, alterations of drug targets, the inhibition of apoptosis, increased DNA repair and interactions with the bone marrow (BM) microenvironment, cell adhesion, and the release of soluble factors. Since MM involves the BM, interactions in the MM-BM microenvironment were examined as well, with a focus on the cross-talk between BM stromal cells (BMSCs), adipocytes, osteoclasts, osteoblasts, endothelial cells, and immune cells. Given the complex mechanisms that drive MM, next-generation treatment strategies that avoid drug resistance must target both the neoplastic clone and its non-malignant environment. Possible approaches based on recent evidence include: (i) proteasome and histone deacetylases inhibitors that not only target MM but also act on BMSCs and osteoclasts; (ii) novel peptide drug conjugates that target both the MM malignant clone and angiogenesis to unleash an effective anti-MM immune response. Finally, the role of cancer stem cells in MM is unknown but given their roles in the development of solid and hematological malignancies, cancer relapse, and drug resistance, their identification and description are of paramount importance for MM management.

Tumor necrosis factor­α in systemic lupus erythematosus: Structure, function and therapeutic implications (Review).

Tumor necrosis factor­α (TNF­α) is a pleiotropic pro­inflammatory cytokine that contributes to the pathophysiology of several autoimmune diseases, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis and systemic lupus erythematosus (SLE). The specific role of TNF­α in autoimmunity is not yet fully understood however, partially, in a complex disease such as SLE. Through the engagement of the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), both the two variants, soluble and transmembrane TNF­α, can exert multiple biological effects according to different settings. They can either function as immune regulators, impacting B­, T­ and dendritic cell activity, modulating the autoimmune response, or as pro­inflammatory mediators, regulating the induction and maintenance of inflammatory processes in SLE. The present study reviews the dual role of TNF­α, focusing on the different effects that TNF­α may have on the pathogenesis of SLE. In addition, the efficacy and safety of anti­TNF­α therapies in preclinical and clinical trials SLE are discussed.

Cardiovascular Risk in Patients With Takayasu Arteritis Directly Correlates With Diastolic Dysfunction and Inflammatory Cell Infiltration in the Vessel Wall: A Clinical, ex vivo and in vitro Analysis.

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Atherosclerosis leads to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched atherosclerotic patients (Controls). In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical changes of the vessel wall were evaluated as well. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. The degree of dysfunction appears associated with uric acid levels. A significant increase in aortic stiffness was also observed and associated with levels of peripheral T lymphocytes. CD3+ CD4+ cell infiltrates were detected in the vessel wall samples of TAK patients, whose mean percentage of Tregs was lower than Controls at T0, but increased significantly at T18. Opposite behavior was observed for Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms underlie vessel damage, including atherosclerosis, in TAK patients compared with Controls. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.