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We conducted a screening analysis to assess the presence of a characteristic extracellular circulating microRNAs (ci-miRNAs) profile in Behcet's syndrome (BS). Total RNA was extracted from platelets-free plasma (PFP) samples obtained from 16 BS patients and 18 healthy controls. Ci-miRNAs profiling was conducted by using dedicated Agilent microarray hybridization and data extraction technology. Statistical analysis of data extracted from microarray scanning revealed the deregulation of 36 ci-miRNAs, which turned out be differentially expressed between BS patients and healthy controls. Detailed experimental methods and data analysis were described here. The raw and normalized microarray data were deposited into Gene Expression Omnibus (GEO) under accession number {"type":"entrez-geo","attrs":{"text":"GSE145191","term_id":"145191"}}GSE145191.

The relationship between immune system and cancer has met a Copernican revolution. Indeed, the inflammation is recognized as a hallmark feature of tumor development. In particular, it has been observed the opposing effects of cancer-associated inflammation, ranging from positive local effects, such as T-cell mediated cytotoxicity leading to tumor inhibition, through to cancer development and progression. In the last few years, we have learned that within the tumor microenvironment a complicate network of cells communicates to form the local immune response. It is well known that the presence of tumor necrosis and inflammatory infiltrate, constituted by T regulatory cells, fewer Th1 cells, a lot of myeloid-derived suppressor cell and expansion of M2 macrophages, promotes tumor growth and progression. The field of cancer immunotherapy has experienced alternating periods of success and failure in the development of cancer therapies. The current breakthrough in cancer immunotherapy results from the identification and subsequent targeting of checkpoint mechanisms in T cells with antibodies against CTLA-4, PD-1 and PD-L1. CTLA-4 and PD-1 are co-inhibitory receptors found on the cell surface of T cells.

Systemic lupus erythematosus is frequently associated with antiphospholipid syndrome. Patients with lupus-antiphospholipid syndrome are characterized by recurrent arterial/venous thrombosis, miscarriages, and persistent presence of autoantibodies against phospholipid-binding proteins, such as β2-Glycoprotein I. We investigated the cytokine production induced by β2-Glycoprotein I in activated T cells that infiltrate in vivo atherosclerotic lesions of lupus-antiphospholipid syndrome patients. We examined the helper function of β2-Glycoprotein I-specific T cells for tissue factor production, as well as their cytolytic potential and their helper function for antibody production. Lupus-antiphospholipid syndrome patients harbor in vivo activated CD4+ T cells that recognize β2-Glycoprotein I in atherosclerotic lesions. β2-Glycoprotein I induces T-cell proliferation and expression of both Interleukin-17/Interleukin-21 and Interferon-γ in plaque-derived T-cell clones. β2-Glycoprotein I-specific T cells display strong help for monocyte tissue factor production, and promote antibody production in autologous B cells. Moreover, plaque-derived β2-Glycoprotein I-specific CD4+ T lymphocytes express both perforin-mediated and Fas/FasLigand-mediated-cytotoxicity. Altogether, our results indicate that β2-Glycoprotein I is able to elicit a local Interleukin-17/Interleukin-21 and Interferon-γ inflammation in lupus-antiphospholipid syndrome patients that might lead, if unabated, to plaque instability and subsequent arterial thrombosis, suggesting that the T helper 17/T helper 1 pathway may represent a novel target for the prevention and treatment of the disease.

ObjectivesBehçet’s syndrome (BS) is a rare systemic vasculitis often complicated by thrombotic events. Given the lack of validated biomarkers, BS diagnosis relies on clinical criteria.In search of novel biomarkers for BS diagnosis, we determined the profile of plasmatic circulating microRNAs (ci-miRNAs) in patients with BS compared with healthy controls (HCs).Methodsci-miRNA profile was evaluated by microarray in a screening cohort (16 patients with BS and 18 HCs) and then validated by poly(T) adaptor PCR (PTA-PCR) in a validation cohort (30 patients with BS and 30 HCs). Two disease control groups (30 patients with systemic lupus erythematosus (SLE) and 30 patients with giant cell arteritis (GCA) were also analysed.ResultsFrom the microarray screening, 29 deregulated (differentially expressed (DE)) human ci-miRNAs emerged. A hierarchical cluster analysis indicated that DE ci-miRNAs clearly segregated patients from controls, independently of clinical features. PTA-PCR analysis on the validation cohort confirmed the deregulation of miR-224-5p, miR-206 and miR-653-5p. The combined receiver operating characteristic (ROC) curve analyses showed that such ci-miRNAs discriminate BS from HCs (and BS with active vs inactive disease), as well as BS from patients with SLE and GCA.The functional annotation analyses (FAAs) showed that the most enriched pathways affected by DE ci-miRNAs (ie, cell–matrix interaction, oxidative stress and blood coagulation) are related to thrombo-inflammatory mechanisms. Accordingly, the expression of the three ci-miRNAs from the validation cohort significantly correlated with leucocyte reactive oxygen species production and plasma lipid peroxidation.ConclusionsThe ci-miRNA profile identified in this study may represent a novel, poorly invasive BS biomarker, while suggesting an epigenetic control of BS-related thrombo-inflammation.

OBJECTIVE Since Behcet's syndrome (BS) is the prototype of inflammation-induced thrombosis, immunosuppressants are recommended in place of anticoagulants. We undertook this study to assess the clinical efficacy and the corticosteroid-sparing effect of adalimumab (ADA)-based treatment versus disease-modifying antirheumatic drug (DMARD) therapy in a large retrospective cohort of patients with BS-related venous thrombosis. METHODS We retrospectively collected data on 70 BS patients treated with DMARDs or ADA-based regimens (ADA with or without DMARDs) because of venous complications. Clinical and imaging evaluations were performed to define vascular response. We explored differences in outcomes between ADA-based regimens and DMARDs with respect to efficacy, corticosteroid-sparing role, and time on treatment. We also evaluated the role of anticoagulants as concomitant treatment. RESULTS After a mean ± SD follow-up period of 25.7 ± 23.2 months, ADA-based regimens induced clinical and imaging improvement of venous thrombosis more frequently (P = 0.001) and rapidly (P < 0.0001) than did DMARDs. The mean dose of corticosteroids administered at the last follow-up visit was significantly lower with ADA-based regimens than with DMARDs (P < 0.0001). The time on treatment was significantly longer with ADA plus DMARDs than with DMARDs alone (P = 0.002). No differences were found in terms of efficacy and time on treatment between DMARDs or ADA-based regimens among patients who received anticoagulants and those who did not. CONCLUSION In this large retrospective study, we have shown that ADA-based regimens are more effective and rapid than DMARDs in inducing resolution of venous thrombosis in BS patients, allowing reduction of steroid exposure. Moreover, our findings suggest that anticoagulation does not modify the efficacy of either ADA-based regimens or DMARDs for venous complications.

Objective.Macrophage activation syndrome (MAS) is a reactive form of hemophagocytic lymphohistiocytosis, which can complicate adult-onset Still disease (AOSD). We investigated AOSD clinical features at the time of diagnosis, to assess predictors of MAS occurrence. Further, we analyzed the outcomes of patients with AOSD who experience MAS.Methods.Patients with AOSD admitted to any Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale center were retrospectively analyzed for features typical of AOSD, MAS occurrence, and their survival rate.Results.Of 119 patients with AOSD, 17 experienced MAS (12 at admission and 5 during followup). Twelve patients with MAS at first admission differed from the remaining 107 in prevalence of lymphadenopathy and liver involvement at the time of diagnosis. In addition, serum ferritin levels and systemic score values were significantly higher in the patients presenting with MAS. At the time of diagnosis, the 5 patients who developed MAS differed from the remaining 102 in the prevalence of abdominal pain, and they showed increased systemic score values. In the multivariate analysis, lymphadenopathy (OR 7.22, 95% CI 1.49–34.97, p = 0.014) and abdominal pain (OR 4.36, 95% CI 1.24–15.39, p = 0.022) were predictive of MAS occurrence. Finally, MAS occurrence significantly reduced the survival rate of patients with AOSD (p < 0.0001).Conclusion.MAS occurrence significantly reduced the survival rate in patients with AOSD. Patients with MAS at baseline presented an increased prevalence of lymphadenopathy and liver involvement, as well as high serum ferritin levels and systemic score values. The presence of lymphadenopathy and abdominal pain was associated with MAS occurrence.

In neuro Behçet disease with multiple sclerosis‐like features, diagnosis could be challenging. Here, we studied the cerebrospinal fluid and serum inflammatory profile of 11 neuro Behçet and 21 relapsing‐remitting multiple sclerosis patients. Between the soluble factors analyzed (MMP9, TNF α, IL6, CXCL13, CXCL10, CXCL8, IFN γ, IL10, IL17, IL23, and others) we found MMP9 increased in neuro Behçet serum compared to multiple sclerosis and decreased in cerebrospinal fluid. Furthermore, neuro Behçet analysis of circulating natural killer CD56DIM subset suggests their potential involvement in increased MMP9 production. We believe that these findings may have a translational utility in clinical practice.

Objectives In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behcet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjogren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.

Raynaud's phenomenon (RP) is a clinical disorder characterized by recurrent, reversible episodes of digital vasospasm. RP can be classified as primary (pRP) or secondary, depending on whether it occurs as a benign condition (not disease-associated) or is associated with other diseases, mainly of the connective tissues. In both cases, it can be triggered by environmental factors, as indicated by the increased incidence of pRP episodes following exposure to cold, vibration injury or chemicals. The purpose of this prospective case-control study was to assess, in an Italian cohort of 132 pRP patients, the association of the phenomenon with demographic, lifestyle habits, environmental and work-related factors. Compared to healthy controls, pRP was found to be inversely associated with the use of contact lenses (OR = 0.4; p = 0.004) and of chlorous-based disinfectants (OR = 0.3; p

Background— Behçet disease (BD) is a systemic vasculitis with a broad range of organ involvement, characterized by a multisystemic, immune-inflammatory disorder involving vessels of all sizes and often complicated by thrombosis. Systemic redox imbalance and circulating neutrophil hyperactivation have been observed in BD patients and are thought to be responsible for impaired coagulation. We here focused on the pathogenetic mechanisms potentially linking immune cell activation and thrombosis, and specifically examined whether neutrophil activation can affect fibrinogen modifications and consequently elicit thrombosis. Methods and Results— Blood samples were collected from 98 consecutive BD patients attending our dedicated Center and from 70 age- and sex-matched healthy controls; in all patients fibrinogen function and structure, fibrin susceptibility to plasmin-lysis, plasma redox status, leukocyte oxidative stress markers, and possible reactive oxygen species sources were examined. Thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis were significantly impaired in BD patients ( P P P P r 2 =0.33, P r 2 =0.07, P r 2 =0.073, P Conclusions— In BD patients, altered fibrinogen structure and impaired fibrinogen function are associated with neutrophil activation and enhanced reactive oxygen species production whose primary source is represented by neutrophil NADPH oxidase.

Objective To investigate efficacy, safety and survival of belimumab and to identify predictors of drug response and drug discontinuation in patients with active SLE in clinical practice. Patients and methods Data of SLE patients, treated with belimumab, from 11 Italian prospective cohorts were analyzed. SLEDAI-2K, anti-dsDNA, C3, C4, prednisone daily dose, DAS-28, 24-h proteinuria, CLASIa (Cutaneous LE Disease Area and Severity Index Activity) were recorded at baseline and every 6 months. SLE Responder Index-4 (SRI-4) was calculated at 12 and 24 months. Demographic and clinical features and comorbidities were included in the univariate and multivariate analysis. Adverse events were recorded at each visit. Statistics was performed using the SPSS software. Results We studied 188 SLE patients, mean follow-up 17.5 ± 10.6 months. The most frequent manifestations, which required the use of belimumab, were polyarthritis (45.2%) and skin rashes (25.5%). SRI-4 was achieved by 77.0% and 68.7% of patients at 12 and 24-months. Independent predictors of 12-month response were SLEDAI-2K ≥ 10 (OR 40.46, p = 0.001) and polyarthritis (OR 12.64, p = 0.001) and of 24-month response were SLEDAI-2K ≥ 10 (OR 15.97, p = 0.008), polyarthritis (OR 32.36, p = 0.006), and prednisone ≥7.5 mg/day (OR 9.94, p = 0.026). We observed a low rate of severe adverse events. Fifty-eight patients (30.8%) discontinued belimumab after a mean follow-up of 10.4 ± 7.5 months. The drug survival was 86.9%, 76.9%, 69.4%, 67.1%, and 61.9% at 6, 12, 18, 24, and 30 months, respectively. No factors associated with drug discontinuation were found. Conclusion Belimumab is effective and safe when used in clinical practice setting.

Objectives: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the “central vein sign”) improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS). Methods: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing–remitting MS, 3-dimensional T2*-weighted and T2–fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed. Results: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%. Interpretation: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283–294., SCOPUS: ar.j, info:eu-repo/semantics/published

Systemic lupus erythematosus (SLE) commonly affects women of childbearing age. Hypertension, antiphospholipid syndrome, and lupus nephritis are risk factors for adverse maternal/fetal outcome. The aim of this retrospective cohort study is to compare pregnancy outcomes in patients with and without SLE nephritis, using a multidisciplinary approach and a broad prophylaxis protocol.Data were collected from 86 pregnancies complicated by SLE. Twenty-seven women with nephropathy before pregnancy stated as the study group and 59 formed the control group. Each group received a prophylactic treatment based on their clinical characteristics. Results were expressed as mean ± SD, percentage and χThe prophylactic treatment (60.4% of the patients) significantly controlled the complications related to some risk factors, such as antiphospholipid antibodies (aPL) and nephritis. Preeclampsia occurred in 14.8% of patients. Patients with pregestational hypertension showed a 2.75 odds ratio of adverse events when compared to the group without chronic hypertension. The presence of proteinuria was associated with a risk of preeclampsia 2.45 times greater, as well as serum creatinine1.2 mg/dL, which was related to a risk 1.25 times higher than the risk observed in patients with serum creatinine1.2 mg/dL. A 6-month inactive disease was associated with a better outcome. A value of Estimated Glomerular Filtration Rate (eGFR) 90 mL/min/1.73 mA multidisciplinary approach in a tertiary care center and a broad prophylactic treatment protocol to patients affected by SLE and complicated by nephritis may definitively foster a successful pregnancy.

Microparticles (MPs) are irregularly shaped small vesicles of heterogeneous size released from the plasma membrane in a tightly controlled process, after different stimuli. MPs have been associated with proinflammatory effects and also with autoimmune processes, being a source of autoantigenic nuclear material, which can form immune complexes. In addition, recent reports have linked a large number of autoimmune disorders to an increased risk of thrombosis, and MPs seem to promote the potential for thrombotic events. A growing mass of evidence supports the idea that MPs could contribute to the generation of an inflammation-induced hypercoagulability state, having a relevant role in the pathogenesis of the thrombotic phenomena associated to autoimmune disease, such as systemic lupus erythematosus, antiphospholipid antibody syndrome, and systemic vasculitis. In this review, we focus on the procoagulant properties of circulating MPs and analyze their contribution to the pathogenesis of autoimmune diseases.

Background Belimumab is used to treat several systemic lupus erythematosus (SLE) manifestations and predictors of response are advisable in clinical practice. Objectives To explore the effects of belimumab treatment on skin involvement in SLE patients in a real-life setting. Methods SLE patients treated with belimumab (10 mg/kg day 0, 14, 28 and then every 28 days), as add-on therapy in 11 Italian cohorts were prospectively followed-up for 24 months. Skin involvement was measured by the CLASIa score (Cutaneous Cutaneous LE Disease Area and Severity Index Activity) at baseline and every six months until month 24. Damage was measured by CLASI-Damage (CLASId). Response was defined as CLASIa The following variables were tested to determine baseline predictors of response at 12, 18 and 24 months: gender, age, disease duration, SLE activity index 2000 (SLEDAI-2K) ≥10, prednisone dose >7.5 mg/day, baseline CLASIa and CLASId, concomitant immunesuppressants (yes/no) and number of previous immunesuppressants. Statistical analysis was performed with SPSS 22.0 software. Results 188 patients were studied, among whom 48 (25.5%) had skin involvement as the leading feature for belimumab therapy. Mean follow-up period was 17.5±10.96 months. Thirty-eight patients completed a 6-month follow-up; 27 completed a 12-month follow-up; 19 completed a 18-month follow-up and 15 completed a 24-month follow-up. Fourteen patients discontinued due to adverse events (7/14, 50%), lack of efficacy (4/14, 28.5%) or other causes (3/14, 21.4%). CLASIa, daily prednisone dosage and SLEDAI-2K significantly decreased during the follow-up (p Conclusions Belimumab use in cutaneous involvement is associated with reduced activity in skin lesions and hindrance of skin damage. Early use of belimumab before damage is established is likely to be associated with a better response. Acknowledgements dr. Margherita Zen, dr. Maddalena Larosa, dr. Francesca Ometto, dr. Mara Felicetti for helping in data collection and statistical analysis Disclosure of Interest None declared

Background and aims To investigate effectiveness, damage accrual and predictors of response to belimumab in active SLE patients in clinical practice setting. Methods 188 active SLE patients with anti-dsDNA antibodies and low C3 and/or C4, from 11 Italian centres, were treated with belimumab as add-on-therapy. Gender, age, disease duration, polyarthritis, skin rashes, glomerulonephritis, haematological involvement, SLEDAI-2K≥10, prednisone ≥7,5 mg/day and concomitant immunosuppressants were used to determine baseline predictors of 12- and 24 month response according to SRI-4. Data were analysed by SPSS (version 22.0). Results Prominent clinical manifestations are summarised in Table 1. Clinical and serological variables at baseline, 12 and 24 months are reported in Table 2. SRI-4 was achieved by 71.3% and 68.7% of patients at 12 and 24 months, respectively. 92% of 12 month responders maintained SRI-4 response at 24 months; conversely, 87.5% of non-responders at 12 months were non-responders even at 24 months. Drug discontinuation for any cause was observed in 36.2% of patients; median treatment duration was 12 months. Damage accrual variation was significant between 5 years before drug initiation and baseline (p Conclusions Belimumab seems to be effective and to reduce damage accrual in SLE patients in clinical practice setting. Patients with arthritis and high disease activity were the best responders to belimumab.

Background Several studies showed a close relationship between Rheumatoid Arthritis (RA) and accelerated atherosclerosis [1,2]. At the best of our knowledge, no such study has been carried out in a large Italian series. Objectives To investigate the prevalence of presence of subclinical atherosclerosis and history of cardio-cerebrovascular events (CVEs), in 1266 patients consecutively admitted to Rheumatology Units throughout the whole Italy. Methods From 01/01/2015 to 31/12/2015, 1266 consecutive patients admitted to GIRRCS centres, satisfying ACR/EULAR criteria for RA were investigated for: i. traditional cardiovascular risk factors: gender, age, smoking habit, cholesterol, triglycerides, glycemia, systemic arterial hypertension (SAH), metabolic syndrome (MS), type 2 diabetes (T2D); ii. RA aspects: disease duration as assessed from the first symptom, disease activity as evaluated by DAS28, radiographic damage by joint X-ray, and joint surgery; iii. subclinical atherosclerosis, as assessed by ultrasound technique and/or atherosclerotic peripheral lesions; iv. history of CVEs. Results We evaluated 1176 patients out of 1266, that were investigated for both CVEs and subclinical atherosclerosis. They were mostly females (80.52%), with a median age of 60 years (range 18–91 years), a median disease duration of 12 years (range 0.8–25 years), seropositive in 69.21%. Nineteen percent were in remission; 17.51% presented low disease activity; 39.45% moderate disease activity, 22.61% high disease activity. Out of 1176 patients, 217 (18%) showed evidence of subclinical atherosclerosis: a figure lower than that reported worldwide (32.7%) [2]. Eighty-two patients (6.9%) had a history for CVEs (58 myocardial infarction, 38 heart failure, 10 ischemic transitory attack, 7 Stroke), too this figure is lower than that reported worldwide (8.5%) [3,4]. In multivariate analysis, older age (p=0.0001, OR:1.069, CI95%:1.05–1.09), MS (p=0.0001, OR:3.417, CI95%:2.16–5.40) and SAH (p=0.0001, OR:3.714, CI95%:2.23–6.17) and high disease activity (p=0.001, OR:2.117, CI95%:1.35–3.32) were significantly associated with the presence of subclinical atherosclerosis. Male gender (p=0.0001, OR:3.465, CI95%:1.94–6.185), MS (p=0.005, OR:2.542, CI95%:1.29–4.52), T2D (p=0.007, OR:2.324, CI95%:1.29–4.29) and SAH (p=0.001, OR:4.921, CI95%:2.14–11.45) and higher disease activity (p=0.003, OR:1.316, CI95%:1.15–1.68) were significantly associated with a history of CVEs. Conclusions This is the first Italian multicenter study on subclinical and clinical atherosclerosis in patients with RA. We pointed out a low prevalence of both subclinical atherosclerosis and history of CV events. Nonetheless, a high disease activity and presence of cardiovascular risk factors were found to play a role, similarly to other countries. References Ruscitti P, et al. PLoS One. 2017;12:e0170108. Ambrosino P, et al. Thromb Haemost. 2015;113:916–30. Solomon D et al. Ann Rheum Dis. 2010;69:1920–5. Avina-Zubieta JA, et al. Ann Rheum Dis. 2012;71:1524–9. Disclosure of Interest None declared

Systemic lupus erythematosus (SLE) is considered an autoimmune disease with multiorgan involvement. Many advances have been made during the last decade regarding inflammatory pathways, genetic and epigenetic alterations, adaptive and innate immune system mechanisms specifically involved in SLE pathogenesis. Apoptosis has been proposed as an important player in SLE pathogenesis more than a decade ago. However, only recently new key apoptotic pathways have been investigated and the link between apoptotic debris containing autoantigens, innate immunity and ongoing inflammation has been further elucidated. Better understanding of cellular mechanisms and involved cytokines contributed to the development of new biological drugs specifically addressed for SLE therapy.

The antiphospholipid antibody syndrome is a systemic, acquired, immune-mediated disorder characterized by episodes of venous, arterial, or microcirculation thrombosis and/or pregnancy abnormalities, associated with the persistent presence of autoantibodies, confirmed at least in two occasions 12 weeks apart, directed to molecular complexes consisting of phospholipids and proteins. Antiphospholipid antibody syndrome should always be considered as a potential diagnosis especially for young patients presenting with a history of thrombotic events, in particular when they occur without any obvious external trigger or any inherited thrombophilic mutation (even if 2006 criteria do not exclude antiphospholipid antibody syndrome in patients with other inherited or acquired prothrombotic conditions), or for women with recurrent pregnancy losses or later fetal deaths. Many other disorders are able to mimic antiphospholipid antibody syndrome, so a broad range of alternative diagnoses should be investigated and ruled out during clinical workup.

Antiphospholipid syndrome (APS) is characterized by recurrent arterial/venous thrombosis and miscarriages in the persistent presence of autoantibodies against phospholipid-binding proteins (aPLs), such as β2 glycoprotein I (β2GPI). In addition to the aPL thrombophilic effect, arterial thrombosis was related to accelerated atherosclerosis in animal models; however, contrasting findings were reported in primary APS patients with regard to the increased number of plaques or abnormal arterial wall thickness. We investigated the cytokine production induced by β2GPI in activated T cells that infiltrate in vivo atherosclerotic lesions of primary APS patients with atherothrombosis. We also examined the helper function of β2GPI-specific T cells for monocyte matrix metalloproteinase-9 and tissue factor production, as well as their cytolytic potential and their helper function for Ab production. APS patients with atherothrombosis harbor in vivo–activated CD4+ T cells that recognize β2GPI in atherothrombotic lesions. β2GPI induces T cell proliferation and IFN-γ expression in plaque-derived T cell clones. β2GPI-specific T cells display helper function for monocyte matrix metalloproteinase-9 and tissue factor production and promote Ig production in autologous B cells. Moreover, plaque-derived β2GPI-specific CD4+ T lymphocytes express perforin-mediated and Fas/Fas ligand–mediated cytotoxicity. β2GPI, and especially the DI domain, drive a local Th1 inflammatory response, with subsequent plaque instability that eventually favors atherothrombosis. This finding may explain the association between aPLs and arterial thrombosis, despite the lack of evidence of surrogate markers for atherosclerosis in primary APS.

Systemic lupus erythematosus (SLE) is considered a typical protean systemic autoimmune disease. It is characterized by multiorgan and multisystem involvement. Virtually, SLE may affect almost any organ during the disease course. Several pathogenic pathways have been reported to sustain inflammation in affected tissues in patients with SLE. Recently, the apoptotic process was thoroughly investigated. The link between apoptotic debris containing autoantigens and innate immunity activation has been also further elucidated. Indeed, as far as the role of lymphocytes in SLE pathogenesis is concerned, the “T-lymphocyte centric” SLE hypothesis has recently been counterbalanced with a newer “B-lymphocyte centric” theory, which was mainly supported by the emerging data arising from B-cell target therapy studies. In this chapter we provide an overview of both the traditional and the more recently discovered immunological pathways that drive inflammation and contribute to organ damage in SLE.

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

A 20-year-old man with mental impairment, was referred to us for evaluation of recurring idiopathic urticaria episodes, characterized by a diffuse spreading of wheals and severe itching lacking response to traditional antihistamines. Upon physical examination, he showed a persistent, generalized, reticular, red-bluish vascular skin pattern in association with diffuse arborizing telangiectasias. Such lesions were present from an early age. Laboratory and instrumental tests, performed in order to exclude any condition associated with livedo did not evidence pathological results. He was found to be positive for antinuclear autoantibodies (ANA; 1:640). Histopathologically, numerous dilated capillary vessels associated with sparse extravasated erythrocytes were observed in the upper dermis. We performed an autologous serum skin test (ASST), which resulted in a positive, suggesting an autoimmune basis of the condition. On the basis of clinical and histopathological findings, and in the absence of other clinical and laboratory data suggesting other neoplastic, immunological or systemic diseases, the diagnosis of cutis marmorata telangiectatica congenita (CMTC) associated with chronic autoimmune urticaria (CAIU) was made. CMTC is a rare congenital vascular disorder, consisting in an anomalous, persistent, red-bluish marbling of the skin, that can be associated with a wide spectrum of cutaneous and extracutaneous anomalies. In our case, neither physical examination nor instrumental investigation demonstrated any of these anomalies, with the exception of cognitive impairment. We report this case because of the rarity of a diagnosis of CMTC in an adult patient, because this condition has almost always previously been diagnosed in infancy, or it comes to observation because of the presence of associated disorders, as in our case for chronic urticaria.

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behcet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behcet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behcet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients.

A large number of diseases can mimic a vasculitis. The diagnosis can be challenging due to the similarity with several diseases that have a different pathogenesis. As reported in the literature, incontinentia pigmenti (IP), a rare genetic disorder, can present vascular alterations on eye, brain and lung. We report a case of peripheral arterial disease in a patient with IP, suggesting further vascular localizations of the disease.

Cerebral MR imaging (MR) and proton-MR spectroscopy (H-MRS) data are lacking in neurologically asymptomatic patients with Behçet's disease (BD). Aim of the following work was to assess MR and H-MRS characteristics of brain involvement over time in patients with BD without clinical neurological involvement. Forty cerebral MR and 12 H-MRS examinations obtained over a one to nine year follow-up in 17 patients with (group A n=9) or without (group B n=8) neurological involvement were retrospectively reviewed. Four group-B patients had a normal first MR examination whereas all group-A and four group-B patients showed single (n?3) or multiple (n=10) subcortical white matter foci of signal change. Large midbrain, basal ganglia or subcortical white matter lesions were depicted in six group-A patients. Comparison between initial and last MR examinations revealed 28 new small-to-medium size lesions. Over the course of the study, lesion enhancement was seen in five patients all belonging to group A. NAA/Cr and Cho/Cr ratios of supraventricular white matter did not show significant differences between patients and healthy controls or between group-A and group-B patients. Clinically silent cerebral involvement in the form of small-to-medium size subcortical lesions may be present at MR examination in BD patients. Large brainstem and basal ganglia lesions associated with overt neurological symptoms are characteristic of the disease. H-MRS of cerebral normal-appearing white matter does not show any significant metabolic change in BD.

Behcet syndrome is a systemic inflammatory disorder characterized by multiorgan involvement such as oral and genital ulcers, uveitis, skin lesions as well as by less frequent, but often more severe, central nervous system and vascular manifestations. The pathogenetic mechanisms are still incompletely known; however the interaction between a specific genetic background and environmental or infectious factors certainly contributes to the immune dysregulation that characterizes this disease. The discovery of new immunological pathways in Behcet syndrome pathogenesis may help us to set up new treatments. In this review, we will focus our attention on the possible mechanisms underlying Behcet syndrome pathogenesis and their potential role as novel therapeutic targets.

Background: Gastrointestinal involvement is one of the most serious in Behçet disease, potentially leading to severe complications. Aim of this study was to investigate at mucosal level the T-cell responses in Behçet patients with early intestinal involvement. Methods: We isolated T cells from intestinal mucosa of 8 patients with intestinal symptoms started within 6 months. T lymphocytes were cloned and analyzed for surface phenotype and cytokines production. Results: We obtained 382 T-cell clones: 324 were CD4+ and 58 were CD8+. Within the 324 CD4+ clones, 195 were able to secrete IFN-γ and TNF-α, but not IL-4, nor IL-17 thus showing a polarized Th1 profile, whereas CD4 clones producing both IFN-γ and IL-17 (Th1/Th17 profile) were 79. Likewise, the number of CD8 clones producing type 1 cytokines was higher than those of CD8 clones producing both type 1 and 2 cytokines. Almost all intestinal-derived T-cell clones expressed perforin-mediated cytotoxicity and Fas–Fas Ligand-mediated pro-apoptotic activity. Conclusions: Our results indicate that in the early stages of the disease, both Th1 and Th17 cells drive inflammation leading to mucosal damage via abnormal and long-lasting cytokines production as well as via both perforin- and Fas–Fas ligand-mediated cytotoxicity. Finally, all the T cells at mucosal level were able to produce large amount of TNF-α, suggesting that its production is a property of intestinal T cells of patients with early active intestinal disease. These results support the therapy with anti-TNF-α agents and suggest the use of anti-IL-17 monoclonal antibodies in Behçet patients with early intestinal involvement.

Behcet syndrome (BS) is considered a recurrent systemic inflammatory disorder characterized by multiorgan involvement such as bipolar aphtosis, uveitis, skin lesions, and less often central nervous system (CNS) and/or vascular manifestations. Despite the amount of new data accumulated during the recent years, the pathogenetic mechanisms underlying BS still remain partially unknown; however, the interaction between a specific genetic background and environmental factors or infectious agents significantly contribute to the immune system dysregulation and to BS development.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases with multiorgan involvement. SLE presents many genetic and epigenetic associations and the pathogenesis is characterized by a complex network of alterations affecting both adaptative and innate immunity. The disclosure of novel mechanisms of SLE pathogenesis suggested new therapeutic targets, based on interference with the cytokine pathways or on depletion of the immune cells.

Rai prevents lupus nephritis by impairing the development and expansion of both proinflammatory Th17 and Th1 cells. Rai, a Shc adapter family member, acts as a negative regulator of antigen receptor signaling in T and B cells. Rai−/− mice develop lupus-like autoimmunity associated to the spontaneous activation of self-reactive lymphocytes. Here, we have addressed the potential role of Rai in the development of the proinflammatory Th1 and Th17 subsets, which are centrally implicated in the pathogenesis of a number of autoimmune diseases, including lupus. We show that Rai−/− mice display a spontaneous Th1/Th17 bias. In vitro polarization experiments on naive and effector/memory CD4+ T cells demonstrate that Rai−/− favors the development and expansion of Th17 but not Th1 cells, indicating that Rai modulates TCR signaling to antagonize the pathways driving naive CD4+ T cell differentiation to the Th17 lineage, while indirectly limiting Th1 cell development in vivo. Th1 and Th17 cell infiltrates were found in the kidneys of Rai−/− mice, providing evidence that Rai−/− contributes to the development of lupus nephritis, not only by enhancing lymphocyte activation but also by promoting the development and expansion of proinflammatory effector T cells. Interestingly, T cells from SLE patients were found to have a defect in Rai expression, suggesting a role for Rai in disease pathogenesis.

L’asma bronchiale (AB) e una malattia ostruttiva delle vie aeree relativamente frequente, mentre la Granulomatosi eosinofila con poliangioite (Eosinophilic Granulomatosis with Polyangiitis, EGPA), piu nota come Sindrome di Churg-Strauss, rientra tra le malattie rare; infatti, solo una percentuale molto bassa di pazienti con AB sviluppera nel tempo una EGPA; tuttavia, l’asma e presente nel 98–100% dei pazienti con EGPA. Dal punto di vista epidemiologico, si stima un numero di nuovi casi di EGPA pari a 0,11–2,66/1 milione di abitanti per anno con una prevalenza pari a 102➀5/1 milione di abitanti [1, 2]. Colpisce indistintamente uomini e donne, anche se alcuni studi hanno evidenziato una maggiore incidenza nel genere maschile, manifestandosi a qualsiasi eta, con un picco tra i 38 e i 54 anni [3].