Sustainability in Internal Medicine: A Year-Long Ward-Wide Observational Study.

Population aging and multimorbidity challenge health system sustainability, but the role of assistance-related variables rather than individual pathophysiological factors in determining patient outcomes is unclear. To identify assistance-related determinants of sustainable hospital healthcare, all patients hospitalised in an Internal Medicine Unit (n = 1073) were enrolled in a prospective year-long observational study and split 2:1 into a training (n = 726) and a validation subset (n = 347). Demographics, comorbidities, provenance setting, estimates of complexity (cumulative illness rating scale, CIRS: total, comorbidity, CIRS-CI, and severity, CIRS-SI subscores) and intensity of care (nine equivalents of manpower score, NEMS) were analysed at individual and Unit levels along with variations in healthcare personnel as determinants of in-hospital mortality, length of stay and nosocomial infections. Advanced age, higher CIRS-SI, end-stage cancer, and the absence of immune-mediated diseases were correlated with higher mortality. Admission from nursing homes or intensive care units, dependency on activity of daily living, community- or hospital-acquired infections, oxygen support and the number of exits from the Unit along with patient/physician ratios were associated with prolonged hospitalisations. Upper gastrointestinal tract disorders, advanced age and higher CIRS-SI were associated with nosocomial infections. In addition to demographic variables and multimorbidity, physician number and assistance context affect hospitalisation outcomes and healthcare sustainability.

Long-term clinical outcomes of patients with rheumatoid arthritis and concomitant coronary artery disease.

BACKGROUND: Rheumatoid arthritis (RA) is associated with high morbidity and mortality predominately due to increased cardiovascular risk. Few reports are available regarding the management of coronary artery disease (CAD) in RA patients and the long-term clinical outcomes after coronary revascularization. METHODS AND RESULTS: All consecutive patients with RA were identified by retrospective review at a rheumatology tertiary center in Milan, Italy between 2001 and 2013. RA patients affected by significant CAD (RA-CAD+) were prospectively followed for major adverse cardiovascular and cerebrovascular events (MACCE) after percutaneous coronary revascularization (RA-PCI), coronary artery bypass grafting (RA-CABG) or medical therapy (RA-MT). Among 936 patients with RA, the presence of clinically significant CAD was found in 5.6% (53 patients, RA-CAD+). Of these, 32 patients (60%) underwent PCI (RA-PCI), 10 patients (19%) underwent CABG (RA-CABG) and 11 patients (21%) treated with MT (RA-MT). After a mean follow-up of 9±7 years, the rate of MACCE was 56% in RA-PCI patients, 50% in RA-CABG and 27% in RA-MT patients (P=0.184). The high MACCE rate was mainly driven by repeat coronary revascularization (47%) in the RA-PCI group and high rate of strokes (30%) in RA-CABG patients. CONCLUSION: In patients with rheumatoid arthritis and concomitant coronary artery disease (RA-CAD+), we observed at long-term follow-up a high MACCE rate, predominantly in those who underwent coronary revascularization.

18F-FDG PET reveals unique features of large vessel inflammation in patients with Takayasu's arteritis.

PURPOSE: The object of this study was to assess whether 18F-fluorodeoxyglucose PET/CT (FDG PET/CT) provides novel information in patients with Takayasu's arteritis (TA) in addition to that provided by current activity assessment, to analyse the effects of possible confounders, such as arterial grafts, and to verify whether PET/CT could be informative in lesions <4 mm thick. METHODS: We studied 30 patients with TA, evaluated from October 2010 to April 2014 by both PET/CT and magnetic resonance imaging (MRI). All arterial lesions were evaluated by PET both qualitatively (positive/negative) and semiquantitatively (maximum standardized uptake value, SUVmax), and the thickness of lesions in the MRI field of view was evaluated. In a per-patient analysis, the relationships between the PET data and acute-phase reactants and NIH criteria for active TA were evaluated. In a per-lesion analysis, the relationships between the PET features of each lesion and MRI morphological data were evaluated. The effects of the presence of arterial grafts were also evaluated. RESULTS: Increased FDG uptake was seen in 16 of 30 patients (53%) and in 46 of 177 vascular lesions (26%). Significant periprosthetic FDG uptake was seen in 6 of 7 patients (86%) with previous vascular surgery and in 10 of 11 of grafts (91%). Graft-associated uptake influenced the PET results in three patients (10%) and the SUVmax values in five patients (17%). Of 39 lesions with significant FDG uptake, 15 (38%) were <4 mm thick. Lesion thickness was correlated with lesion SUVmax in FDG-avid lesions only. FDG arterial uptake was not associated with systemic inflammation or NIH criteria. CONCLUSIONS: PET/CT reveals unique and fundamental features of arterial involvement in TA. PET/CT may be useful in the assessment of local inflammatory and vascular remodelling events independent of systemic inflammation during follow-up, even in lesions in which the arterial wall is <4 mm. The presence of arterial grafts is a potential confounder. Prospective studies are required to correlate PET findings with relevant clinical outcomes.

FDG Uptake by Prosthetic Arterial Grafts in Large Vessel Vasculitis Is Not Specific for Active Disease.

OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of 18F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) in the management of LVV remains to be defined. Although [18F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [18F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [18F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [18F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [18F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [18F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [18F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [18F]FDG uptake that is confined to arterial graft sites in patients with LVV does not reflect clinically relevant disease activity or progression. To minimize exposure to immunosuppression and in the face of negative blood culture, clinically quiescent arteritis, normal or stably raised C-reactive protein levels, we elected not to escalate treatment and monitor progression with MRA.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

OBJECTIVE: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity. METHODS: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio. RESULTS: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD. CONCLUSIONS: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Juxta-vertebral lesions in granulomatosis with polyangiitis.

OBJECTIVES: To describe the clinical, pathological, serological, and radiological characteristics of juxta-vertebral masses occurring in patients with granulomatosis with polyangiitis (GPA). METHODS: We analyzed the clinical records of patients with juxta-vertebral lesions from our GPA study cohort and reviewed the English literature for other cases of GPA with juxta-vertebral localization. RESULTS: Out of 74 patients in our GPA study cohort, six (8%) had juxta-vertebral lesions. We found 10 cases of juxta-vertebral GPA described in the English literature. Overall, juxta-vertebral lesions were detected at GPA onset in 11/16 (69%) patients, and preferentially occurred on the right side of the spine (12/15 patients, 80%). Fifteen patients (94%) with juxta-vertebral lesions had systemic GPA. Juxta-vertebral lesions were associated with back pain at GPA onset in 8/16 (50%) patients. In all of them juxta-vertebral lesions resolved or improved after treatment. CONCLUSIONS: Preference for the right-anterior side of the spine, increased 18FDG uptake on PET scan, low or absent invasiveness of the surrounding tissues, and occurrence in the context of systemic disease were the main features of juxta-vertebral GPA. Symptomatic lesions showed a better response to immunosuppressive therapies.

Drug induced exfoliative dermatitis: state of the art.

Drug induced exfoliative dermatitis (ED) are a group of rare and severe drug hypersensitivity reactions (DHR) involving skin and usually occurring from days to several weeks after drug exposure. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the main clinical presentations of drug induced ED. Overall, T cells are the central player of these immune-mediated drug reactions. Here we provide a systematic review on frequency, risk factors, pathogenesis, clinical features and management of patients with drug induced ED.

Chromogranin-A production and fragmentation in patients with Takayasu arteritis.

BACKGROUND: Chromogranin-A (CgA) is a secretory protein processed into peptides that regulate angiogenesis and vascular cells activation, migration and proliferation. These processes may influence arterial inflammation and remodelling in Takayasu arteritis (TA). METHODS: Plasma levels of full-length CgA (CgA439), CgA fragments lacking the C-terminal region (CgA-FRs) and the N-terminal fragment, CgA1-76 (vasostatin-1, VS-1) were analysed in 42 patients with TA and 20 healthy age-matched controls. Vascular remodelling was longitudinally assessed by imaging. CgA peptides were related to markers of systemic and local inflammation, disease activity and vascular remodelling. RESULTS: Levels of CgA-FRs and VS-1 were increased in TA. Treatment with proton-pump inhibitors (PPIs) and arterial hypertension partially accounted for CgA levels and high inter-patient variability. CgA439, CgA-FRs and VS-1 levels did not reflect disease activity or extent. Markers of systemic or local inflammation correlated with higher CgA-FRs and VS-1 in normotensive patients and with higher CgA439 in hypertensive patients. Treatment with non-biologic anti-rheumatic agents was associated with increased CgA-FRs and a distinctive regulation of CgA processing. Reduced blood levels of anti-angiogenic CgA peptides were associated with vascular remodelling in the groups of patients on PPIs and with arterial hypertension. CONCLUSIONS: The plasma levels of CgA fragments are markedly increased in TA as a consequence of disease- and therapy-related variables. Anti-angiogenic forms of CgA may limit vascular remodelling. Given the effect of the various CgA peptides, it is advisable to limit the therapeutic prescriptions that might influence CgA-derived peptide levels to clearly agreed medical indications until further data become available.

Anti-TNFα agents curb platelet activation in patients with rheumatoid arthritis.

BACKGROUND: Cardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Anti-tumour necrosis factor-α (TNFα) agents seem to decrease RA-associated cardiovascular events. We investigated whether (1) TNFα activates human platelets and (2) TNFα pharmacological blockade modulates the platelet-leucocyte reciprocal activation in RA. DESIGN: The expression of platelet TNFα receptors has been assessed by flow cytometry and immunogold electron microscopy. Platelet and leucocyte activation has been assessed also in the presence of antibodies against the TNFα receptors 1 and 2 and of infliximab. TF expression, binding to fibrinogen and phosphatidylserine exposure, has been assessed by flow cytometry, TF activity by coagulation time and by endogenous thrombin generation. Markers of platelet and leucocyte activation have been assessed in 161 subjects: 42 patients with RA, 12 with osteoarthritis, 37 age-matched and sex-matched patients with chronic stable angina and 70 age-matched and sex-matched healthy subjects. RESULTS: TNFα elicited the platelet activation and the expression of TF, which in turn prompted thrombin generation and clot formation. Inhibition of the TNFα-induced activation restricted platelet ability to activate leucocytes and to induce leucocyte TF. TNFα inhibition did not influence platelet activation induced by collagen, ADP or thrombin receptor activating peptide-6. Platelets of patients with RA were more activated than those of controls. Activation was reduced in patients treated with TNFα inhibitors. CONCLUSIONS: TNFα-dependent pathways control platelet activation and TF expression in RA. Further studies will verify whether the protective effect of TNFα inhibitors on cardiovascular events involves their ability to modulate platelet function.

Methotrexate in refractory bilateral juvenile temporal arteritis: Report of a case.

Juvenile temporal arteritis is a rare inflammatory disease of the temporal arteries that affects young adults. The clinical course is benign and the surgical excision of the affected artery is usually curative. Here we report a case of bilateral juvenile temporal arteritis with significant peripheral eosinophilia and elevated IgE, refractory to surgical excision and even to a short course of corticosteroids. Methotrexate, added as a steroid-sparing agent, resulted in a good disease control.

TRPC6 gene variants and neuropsychiatric lupus.

Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) influence patients' quality of life and their survival. Little is known about the pathophysiological bases of NPSLE and accordingly there are no specific therapeutic agents to be employed in this setting. Genetic research in systemic lupus erythematosus (SLE) is rapidly evolving as a tool to find clues about the pathogenic determinants of the disease and of its manifestations. Here, we describe the association of a single nucleotide polymorphic variant of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene with protection from the development of NPSLE in a cohort of 106 patients with SLE. TRPC6 is involved in the regulation of N-methyl-d-aspartate (NMDA) receptor signalling, a major player in post-ischemic neuronal injury and in the pathogenesis of NPSLE. TRPC6 genetic variants are promising candidate predictors of nervous system involvement in SLE, whereas the TRPC6 pathway might constitute a potential novel therapeutic target.

Serum CXCL12 levels on hospital admission predict mortality in patients with severe sepsis/septic shock.

OBJECTIVES: We evaluated serum levels of CXCL12 in patients with severe sepsis/septic shock and controls. METHODS: We enrolled 27 patients admitted to our emergency department with severe sepsis/septic shock and 20 healthy controls. Complete blood count, serum levels of CXCL12, C-reactive protein, lactate, Charlson comorbidity index, sequential organ failure score on hospital admission, and inhospital mortality were evaluated at baseline (T0) and after 24 hours (T24). RESULTS: Mean serum levels of CXCL12 were higher in patients with severe sepsis/septic shock than in healthy subjects (3121 vs 1991 pg/mL; P < .001). We also found that patient who survived had lower serum levels of CXCL12 than those who died (2630 vs 3957 pg/mL; P < .001) but still higher than controls (2630 vs 1991 pg/mL; P = .001) on admission. CXCL12 serum levels were higher in patients with serum lactate greater than 4 mmol/L. CONCLUSIONS: Our data suggest a possible role for CXCL12 as a prognostic marker in severe sepsis/septic shock and give background evidence for larger trials to evaluate the pathophysiologic and clinical role of CXCL12 in sepsis, with respect to other markers of inflammation and hypoxia.

Are atopy and eosinophilic bronchial inflammation associated with relapsing forms of chronic rhinosinusitis with nasal polyps?

BACKGROUND: The aetiopathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) is still unknown. The role of atopy and the concept of united airways in such patients are still a matter of debate. In this pilot study we aimed at evaluating the degree of eosinophilic inflammation and the frequency of atopy in a cohort of CRSwNP patients candidate for Functional Endoscopic Sinus Surgery (FESS) and assessing the association between these factors and relapsing forms of CRSwNP. METHODS: 30 patients (18 men, 12 women) with CRSwNP eligible for FESS were evaluated before and after surgery. Preoperative investigation included: history of previous relapse after FESS, clinical and laboratory allergologic assessment, spirometry, methacholine challenge, blood eosinophilia and determination of the fraction of nitric oxide in exhaled air (FeNO). Nasal fibroendoscopy, spirometry and FeNO determination were also assessed prospectively at 3 and 27 months post-FESS. RESULTS: 18/30 subjects were atopic, 6/18 (33 %) were monosensitized, 16/30 (53 %) were asthmatics and 10/30 (33 %) had non steroidalantinflammatory drugs (NSAIDs) hypersensitivity. Twenty-one patients (70 %) were classified as relapsers, 15/18 (83 %) among atopics, 6/12 (50 %) among non atopics (p = 0.05). Among patients with NSAIDs hypersensitivity, 9/10 (90 %) were relapsers. The median IgE concentration was 161.5 UI/mL in relapsers and 79 UI/mL in non-relapsers (ns). The mean FeNO decreased after FESS (43.1-26.6 ppb) in 84 % of patients, but this effect disappeared over time (FeNO = 37.7 ppb at 27 months). Higher levels of FeNO pre-FESS were detected in atopics, and in particular in relapsing ones (median 51.1 ppb vs 22.1, ns). Higher levels of FeNO pre-FESS were detected in asthmatic patients, especially in those who relapsed (median: 67 vs 64.85 ppb in non-relapsed patients, ns). The Tiffeneau Index (FEV1/FVC) was significantly lower in asthmatic relapsers than in non relapsers asthmatics (94.7 ± 11.1 versus 105 ± 5.9-p = 0.04). Patients with asthma and atopy had a major risk of relapse (p = 0.05). CONCLUSION: In our pilot study, atopy, severe asthma, bronchial inflammation, NSAIDs hypersensitivity and high level of total IgE are possible useful prognostic factors for the proneness to relapse after FESS. The role of allergy in CRSwNP pathogenesis should consequently be given deeper consideration. Allergen specific immunotherapy, combined with anti-IgE therapy, may have an immunomodulatory effect preventing polyps relapse and need to be investigated.

Prospectively-followed pregnancies in patients with inflammatory arthritis taking biological drugs: an Italian multicentre study.

OBJECTIVES: Information on new drugs does not include their possible effects on pregnancy because pregnant women are excluded from clinical trials. Although not classified as teratogenic in animals, limited data is available on biological anti-rheumatic agents and their safety in human pregnancy. The aim of the study is to evaluate the safety of biological drugs in pregnant patients with chronic arthritis. METHODS: Pregnancy outcome and maternal disease variations were prospectively followed in six Italian Rheumatology Centres. Patients exposed to biological agents during the periconceptional period or during pregnancy were included in the study. The occurrence of congenital malformations as well as the obstetric and neonatal outcomes were assessed. RESULTS: Between 1999 and 2013 we identified 79 exposed pregnancies in 67 women affected by different rheumatic diseases with peripheral chronic arthritis. At the time of the start of pregnancy, 56 patients were taking etanercept, 13 adalimumab, 3 infliximab, 2 each certolizumab-pegol and rituximab, 1 each golimumab, anakinra and abatacept. Biological treatment was stopped after a mean of 41 days since documented pregnancy. Live births were reported in 66% of pregnancies. The rate of spontaneous pregnancy loss was 20%. Only one congenital malformation was reported. CONCLUSIONS: TNF-alpha inhibitors can be considered safe in the periconception period, representing a possible therapeutic choice also in young women affected by an aggressive form of chronic arthritis and hoping for a pregnancy. Reports of exposure during 2nd/3rd trimester are still limited and suggest caution. Experience with abatacept, tocilizumab, anakinra and rituximab in pregnancy is insufficient.

Orthopedic Injuries and Their Treatment in Children During Earthquakes: A Systematic Review.

Orthopedic injuries commonly affect children during earthquakes, but reports about them are rare. This setting may lead to different standards of care, but guidelines are still missing in this field. A systematic review was performed to: (1) assess type and body distribution of pediatric earthquake-related injuries, treatment performed, length of stay, and complications; and (2) identify starting points to define standards of care. PubMed database was researched for papers (1999-2014 period) in agreement with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. Inclusion criteria were: English, French, Spanish, or Italian language and data reported about orthopedic lesions in children (≤18 years old). Reviews, letters, commentaries, editorials, and single case reports were excluded. Two independent reviewers selected articles after abstract and full-text reading. Traumatic injuries caused child hospital admissions ranging from 46.9% to 100.0%; 16% to 53% suffered fractures. Lower limbs mostly were involved. Soft-tissue injuries affected 55% of patients. Debridement and external fixation (EF) were the most frequent surgical treatments. Amputation rates varied from 5% to 11%. This study revealed that field hospitals should be prepared to: (1) treat mainly lower extremities fractures in children; and (2) use especially EF techniques. The presence of orthopedic surgeons familiar with pediatric traumatology should be considered.

Beta-adducin and sodium-calcium exchanger 1 gene variants are associated with systemic lupus erythematosus and lupus nephritis.

Genetic research in systemic lupus erythematosus (SLE) is rapidly developing, and numerous sets of genes are being associated with specific clinical subphenotypes in the setting of SLE. On the other hand, basic science studies are revealing strong connections between salt-water balance and inflammation. The aim of this study was to evaluate whether variants of genes known to influence the individual susceptibility to hypertension also influence the renal function in a cohort of SLE patients with and without lupus nephritis (LN). This study is a case-control study with candidate gene approach. A total of 111 patients with SLE (50 with SLE without nephritis, 55 with LN and 6 with simple urinary sediment abnormalities) and 62 healthy controls (HC) were genotyped for NCX1 rs11893826 (NCX1a) and rs434082 (NCX1b) and ADD2 rs4984 SNPs. Patients with ADD2 CT genotype were protected from LN and skin involvement; ADD2 CC | NCX1a AA/AG genotypes were associated with the presence of anti-cardiolipin antibodies; NCX1a AA genotype was slightly more frequent in lupus patients than in HC and associated with relapse risk and higher creatinine in patients with LN. NCX1b GG patients with LN had increased chances to reach complete remission. NCX1b GG | NCX1a GG genotype is associated with joint involvement. ADD2 and NCX1 variants influence the risk and the clinical features of SLE and LN, highlighting their potential role in regulating systemic inflammation and/or the local response to immune-mediated injury.

Parietal and intravascular innate mechanisms of vascular inflammation.

Sustained inflammation of the vessel walls occurs in a large number of systemic diseases (ranging from atherosclerosis to systemic vasculitides, thrombotic microangiopathies and connective tissue diseases), which are ultimately characterized by ischemia and end-organ failure. Cellular and humoral innate immunity contribute to a common pathogenic background and comprise several potential targets for therapeutic intervention. Here we discuss some recent advances in the effector and regulatory action of neutrophils and in the outcome of their interaction with circulating platelets. In parallel, we discuss novel insights into the role of humoral innate immunity in vascular inflammation. All these topics are discussed in light of potential clinical and therapeutic implications in the near future.

Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab.

OBJECTIVE: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are systemic, necrotizing, small-vessel vasculitis associated with circulating anti-neutrophil cytoplasmic autoantibodies (ANCA), and thus called ANCA-associated vasculitides (AAV). The aim of the present study is to evaluate a potential role of interleukin (IL)-6 and its pathway in the pathogenesis of AAV and to review previous evidence of IL-6 in MPA and GPA. METHODS: Blood and histological samples from 10 untreated myeloperoxidase (MPO)-ANCA/proteinase 3 (PR3)-ANCA-positive patients with active AAV were studied. Serum levels of cytokines/chemokines were evaluated by means of a Bio-Plex Multiple Cytokine Assay. IL-6 production at sites of active vasculitis was assessed by means of both immunohistochemistry and in situ hybridization techniques. We also treated a patient with MPA who was resistant or allergic to conventional treatments with a 12-month course of the IL-6 inhibitor tocilizumab and followed him up for 24 additional months. We also reviewed all the published cases in the English literature of histologically confirmed MPA or GPA, in which elevated IL-6 serum levels or intralesional IL-6 expression were reported. RESULTS: IL-6 serum levels were significantly increased in patients with AAV as compared to controls (median = 51.96pg/mL; range: 34.11-84.30; versus 0.68pg/mL; range: 0.01-1.81; P < 0.005). Also, IL-6 was expressed and produced at sites of active vasculitis. Treatment with tocilizumab was able to induce a complete and sustained disease remission in a patient with severe multisystemic MPA, as well as normalization of circulating levels of IL-6-associated pro-inflammatory cytokines and chemokines. Previous evidence of IL-6 pathway activation in AAV is scarce. Increased serum levels of IL-6 were reported in seven clinical studies for a total of approximately 120 patients, mainly affected by GPA. CONCLUSION: The finding of an activated IL-6 pathway in patients with AAV, together with the observed effects of tocilizumab monotherapy, provides evidence for a possible central role of IL-6 in the pathogenesis of AAV and suggests its targeting as a potential treatment.

Coronary microvascular dysfunction in asymptomatic patients affected by systemic sclerosis - limited vs. diffuse form.

BACKGROUND: This observational study was designed to evaluate the prevalence of coronary microvascular dysfunction (CMD) in asymptomatic patients affected by systemic sclerosis (SSc), stratifying the results according to the limited (lcSSc) and the diffuse (dcSSc) forms of the disease. METHODS AND RESULTS: We enrolled 19 consecutive asymptomatic patients with dcSSc (n=7) or lcSSc (n=12). In all subjects, coronary flow reserve (CFR) was assessed by measuring diastolic coronary flow velocities in the left anterior descending artery by pulsed wave Doppler at baseline and after dipyridamole infusion (0.84 mg·kg(-1)·6 min(-1)). Wall motion score index was evaluated at baseline and during stress. We enrolled 20 healthy subjects as controls. Mean CFR was 1.96±0.62 in patients and 2.69±0.47 in controls (P<0.001). Abnormal values of CFR (≤2) were significantly more prevalent in patients than in controls (10/19 vs. 0/20; P<0.001) and in the dcSSc subgroup than in the lcSSc subgroup (6/7 vs. 4/12; P=0.05). An inverse relationship between disease duration (from time of onset of Raynaud's phenomenon) and CFR value was observed in the lcSSc group (correlation coefficient -0.583; P=0.046). Neither patients nor controls had wall motion abnormalities during dipyridamole administration. CONCLUSIONS: A blunted CFR, most likely because of CMD, is more frequent in patients affected by the dcSSc form in the early stages of the disease, whereas it seems to appear later in lcSSc.