Elena Baldissera

Pentraxin-3 as a Marker of Disease Activity in Takayasu Arteritis

BACKGROUND Because pentraxin-3 (PTX3) is produced by immune and vascular cells in response to proinflammatory signals, it may be a useful biomarker for defining disease activity in patients with Takayasu arteritis. OBJECTIVE To compare PTX3 levels in patients who have Takayasu arteritis with those in healthy and infected controls, and to compare accuracy of PTX3 levels with that of C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) for distinguishing active and inactive disease. DESIGN Cross-sectional, noninterventional study conducted between September 2005 and October 2008. SETTING Immunology and rheumatology clinic at a university hospital in Italy. PATIENTS 57 consecutive patients with Takayasu arteritis and known disease activity, 57 healthy blood donor controls, and 15 patients with acute infection. MEASUREMENTS Disease activity by clinical criteria; plasma PTX3 and CRP levels and ESR. RESULTS 27 patients had active Takayasu arteritis; 30 had inactive disease. Levels of PTX3 were higher in patients with active disease (median, >2.14 ng/mL [range, 0.57 to 48.18 ng/mL]) than in those with inactive disease (median, 0.63 ng/mL [range, 0.00 to 1.64 ng/mL]) and were higher than in healthy patients (median, 0.11 ng/mL [range, 0 to 1.20 ng/mL]) or those with acute infection (median, 0.26 ng/mL [range, 0 to 0.75 ng/mL]). A plasma PTX3 level greater than 1 ng/mL was more accurate than normal thresholds of CRP or ESR for distinguishing active from inactive disease. LIMITATION The study excluded patients with unknown or equivocal disease status. CONCLUSION Plasma levels of PTX3 could help distinguish active from inactive Takayasu arteritis but should not be adopted for clinical use until the findings are confirmed in a broader spectrum of patients whose disease activity is unknown or equivocal before testing.

Treatment of Refractory Takayasu Arteritis with Tocilizumab: 7 Italian Patients from a Single Referral Center

Objective. The aim of our study was to evaluate the safety and the efficacy of tocilizumab (TCZ) for refractory Takayasu arteritis (TA). Methods. We retrospectively assessed the outcome of blocking interleukin (IL)-6 with TCZ in 7 consecutive patients with refractory TA using a combination of clinical and imaging assessment. Results. During a median followup visit at 14 months, 4 patients taking TCZ [including 2 nonresponders to tumor necrosis factor (TNF) inhibitors] achieved clinical response, suggesting a nonredundant role for IL-6 in TA. Inflammatory markers normalized in all patients treated with TCZ. However, vascular progression occurred in 4 patients, suggesting the involvement of other inflammatory pathways and confirming the limitations of erythrocyte sedimentation rate and C-reactive protein for disease activity assessment while taking TCZ. Three patients experienced adverse events and 2 suspended TCZ. Conclusion. TCZ may be effective in a subset of patients with refractory TA, even in cases of unresponsiveness to TNF inhibitors. Inflammatory markers are not valid markers of TA activity on TCZ. Further studies are needed to confirm these preliminary observations.

Efficacy of traditional and biologic agents in different clinical phenotypes of adult-onset Still's disease

OBJECTIVE To evaluate the efficacy of antiinflammatory agents, steroids, immunosuppressants, and biologic agents in patients with adult-onset Stills disease (AOSD) who have either chronic articular disease or nonchronic disease. METHODS Forty-five patients with AOSD were seen and followed up for at least 2 years at our institution, from 1991 to 2008. The majority of patients were treated with several therapeutic regimens; a total of 152 efficacy trials were administered. Data regarding the type of medication, the dosage used, and the outcome of these trials were collected and analyzed. RESULTS Our data showed that the efficacy of monotherapy with a nonsteroidal antiinflammatory drug was very low (16%) and confirmed good efficacy of steroid therapy (63%), particularly in patients without chronic articular disease (78%). Patients whose disease did not respond to steroid therapy at the time of disease onset were at risk of the subsequent development of chronic arthritis. Disease-modifying antirheumatic drug (DMARD) monotherapy was successful in controlling steroid-resistant or steroid-dependent disease in 60% of patients. Methotrexate and cyclosporine showed the best response rates. The combination of high-dose steroids and cyclosporine was administered to successfully control some acute life-threatening complications. Only 6 patients had disease that was both steroid resistant and DMARD resistant. Treatment with biologic agents eventually led to satisfactory control of disease manifestations in 5 (83%) of these 6 patients. CONCLUSION Steroids were less effective in patients with chronic articular disease than in those with nonchronic disease. The administration of DMARDs early after disease onset could be beneficial in patients with steroid-resistant disease who are at risk of the development of chronic articular disease. Biologic agents proved to be highly effective in both steroid-resistant and DMARD-resistant AOSD.

Oxidative Stress Elicits Platelet/Leukocyte Inflammatory Interactions via HMGB1: A Candidate for Microvessel Injury in Sytemic Sclerosis

AIMS An abnormal generation of reactive oxygen species (ROS) is thought to contribute to systemic sclerosis (SSc), fostering autoimmunity, fibrosis, and vascular inflammation. The function of the prototypic damage-associated molecular pattern, high mobility group box 1 (HMGB1), depends on its redox status. Here we investigate whether oxidative stress regulates the cross-talk between leukocytes and platelets via HMGB1, thus contributing to vessel inflammation in SSc. RESULTS The oxidation of HMGB1 amplified its ability to activate neutrophils, as detected assessing the redistribution of primary granule molecules and the transactivation of the β2 integrin chain CD18. Activated platelets are a source of bioactive HMGB1 and via P-selectin stimulated neutrophils to generate ROS. Oxidized extracellular HMGB1, soluble or associated to platelet membrane or to platelet-derived microparticles (PDμPs), further increased leukocyte activation. Leukocyte activation abated in the presence of inhibitors of HMGB1 or of catalase, which catalyzes the dismutation of hydrogen peroxide into water and molecular oxygen. The redistribution of the content of primary granules and the transactivation of β2 integrins characterized blood leukocytes of SSc patients and membrane HMGB1 was significantly higher in patients with pulmonary hypertension or with diffuse SSc. HMGB1(+) microparticles (μPs) purified from SSc patients, but not HMGB1(-) μPs purified from control subjects, activated in vitro healthy neutrophils, and HMGB1 inhibitors reversed the effects of μPs. INNOVATION AND CONCLUSION ROS dramatically increase the ability of extracellular HMGB1 to activate blood leukocytes. This event might contribute to maintain the microvascular injury of patients with SSc.

Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-α-elicited endothelial activation

TNF‐α plays an important role in the natural history of rheumatoid arthritis (RA), a systemic disease characterized by endothelial activation and synovial involvement with bone erosions. Neuroendocrine signals contribute as well to RA, but their role is poorly understood. We measured in 104 RA patients and in an equal number of sex‐ and age‐matched, healthy controls the blood levels of chromogranin A (CgA), a candidate marker linking the neuroendocrine system to TNF‐α‐mediated vascular inflammation. CgA levels were significantly higher in patients with RA and remained stable over time. High levels of CgA were significantly associated with severe extra‐articular manifestations, namely pulmonary fibrosis, rheumatoid vasculitis, serositis, and peripheral neuropathy. RA sera curbed the response of human microvascular endothelial cells to TNF‐α, as assessed by the expression of ICAM‐1, the release of MCP‐1/CCL2, and the export of nuclear high‐mobility group box 1; the effect abated in the presence of anti‐CgA antibodies. The efficacy of the blockade was significantly correlated with the CgA concentration in the serum. The recombinant aminoterminal portion of CgA, corresponding to residues 1–78, had similar inhibitory effects on endothelial cells challenged with TNF‐α. Our results suggest that enhanced levels of CgA identify patients with extra‐articular involvement and reveal a negative feedback loop that limits the activation of endothelial cells in RA.

Takayasu Arteritis: Intravascular Contrast Medium for MR Angiography in the Evaluation of Disease Activity

OBJECTIVE Takayasu arteritis is difficult to diagnose, and the evaluation of disease activity is even more challenging. Laboratory, clinical, and radiologic criteria are limited indicators of disease activity. Gadofosveset trisodium is a recently introduced intravascular contrast agent. In this study we sought to investigate a correlation between clinical activity and enhancement of vascular wall thickening in patients with Takayasu arteritis who underwent MR angiography with gadofosveset. SUBJECTS AND METHODS Twenty-three consecutively registered patients (21 women, two men) with Takayasu arteritis underwent MR angiography of the supraaortic trunks, aorta, and visceral vessels. Intravascular contrast medium was used to correlate thickened vessel wall enhancement with clinical criteria of disease activity. ECG-triggered black-blood first-pass high-resolution steady-state imaging was performed for all patients. RESULTS Before MR angiography, 14 patients were considered to have active disease. Heterogeneous structural involvement of the vascular tree was found. Twenty of 23 patients (87.0%) had supraaortic trunk involvement, including 12 of the 14 patients (85.7%) with active disease. Seventeen of the 23 patients (73.9%) had aortic and visceral vessel involvement, including 12 of the 14 patients (85.7%) with active disease. On steady state images in the active disease group, the mean signal-to-noise-ratio increased from 17.4 to 35.3 after gadofosveset injection (p > 0.0001), while in the nonactive disease group it increased from 52.8 to 69.6 (p = 0.08). A cutoff of 40% was best for differentiating active from inactive disease (sensitivity, 100%; specificity, 89%; positive predictive value, 92%; negative predictive value, 100%). CONCLUSION Use of intravascular contrast medium significantly increases the effectiveness of MR angiography in differentiating active and inactive disease.

An Intense and Short-Lasting Burst of Neutrophil Activation Differentiates Early Acute Myocardial Infarction from Systemic Inflammatory Syndromes

Background Neutrophils are involved in thrombus formation. We investigated whether specific features of neutrophil activation characterize patients with acute coronary syndromes (ACS) compared to stable angina and to systemic inflammatory diseases. Methods and Findings The myeloperoxidase (MPO) content of circulating neutrophils was determined by flow cytometry in 330 subjects: 69 consecutive patients with acute coronary syndromes (ACS), 69 with chronic stable angina (CSA), 50 with inflammation due to either non-infectious (acute bone fracture), infectious (sepsis) or autoimmune diseases (small and large vessel systemic vasculitis, rheumatoid arthritis). Four patients have also been studied before and after sterile acute injury of the myocardium (septal alcoholization). One hundred thirty-eight healthy donors were studied in parallel. Neutrophils with normal MPO content were 96% in controls, >92% in patients undergoing septal alcoholization, 91% in CSA patients, but only 35 and 30% in unstable angina and AMI (STEMI and NSTEMI) patients, compared to 80%, 75% and 2% of patients with giant cell arteritis, acute bone fracture and severe sepsis. In addition, in 32/33 STEMI and 9/21 NSTEMI patients respectively, 20% and 12% of neutrophils had complete MPO depletion during the first 4 hours after the onset of symptoms, a feature not observed in any other group of patients. MPO depletion was associated with platelet activation, indicated by P-selectin expression, activation and transactivation of leukocyte β2-integrins and formation of platelet neutrophil and -monocyte aggregates. The injection of activated platelets in mice produced transient, P-selectin dependent, complete MPO depletion in about 50% of neutrophils. Conclusions ACS are characterized by intense neutrophil activation, like other systemic inflammatory syndromes. In the very early phase of acute myocardial infarction only a subpopulation of neutrophils is massively activated, possibly via platelet-P selectin interactions. This paroxysmal activation could contribute to occlusive thrombosis.

IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients

Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre. Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as ‘definite’ or ‘possible’ according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI). Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with ‘definite’ IgG4-RD and 15 with ‘possible’ IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24–51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking. Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Systemic pentraxin-3 levels reflect vascular enhancement and progression in Takayasu arteritis

IntroductionProgression of arterial involvement is often observed in patients with Takayasu arteritis (TA) thought to be in remission. This reflects the failure of currently used biomarkers and activity criteria to detect smouldering inflammation occurring within arterial wall. Pentraxin-3 (PTX3) is a soluble pattern recognition receptor produced at sites of inflammation and could reveal systemic as well as localized inflammatory processes. We verified whether the blood concentrations of PTX3 and of C-reactive protein (CRP) in patients with Takayasu arteritis (TA) might reflect vascular wall involvement, as assessed by signal enhancement after contrast media administration, and the progression of arterial involvement.MethodsA cross-sectional single-centre study was carried out on 42 patients with TA that comprised assessment of PTX3, of CRP and erythrocyte sedimentation velocity (ESR). In total, 20 healthy controls and 20 patients with Systemic Lupus Erythematous (SLE) served as controls. Vascular imaging was carried out by magnetic resonance angiography, doppler ultrasonography and computed tomography angiography.ResultsPatients with TA and SLE had higher plasmatic PTX3 and CRP concentrations than healthy controls (P = 0.009 and 0.017, respectively). PTX3 levels did not correlate with those of CRP. Patients with active systemic TA had significantly higher concentrations of CRP but similar levels of PTX3 than patients with quiescent disease. In contrast, patients with vascular inflammation detectable at imaging had higher PTX3 concentrations (P = 0.016) than those in which vessel inflammation was not evident, while CRP levels were similar. The concentration of PTX3 but not that of CRP was significantly higher in TA patients with worsening arterial lesions that were not receiving antagonists of tumor necrosis factor-? or interleukin-6.ConclusionsArterial inflammation and progression of vascular involvement influence plasma PTX3 levels in TA, while levels of CRP accurately reflect the burden of systemic inflammation. These results support the contention that PTX3 reflects different aspects of inflammation than CRP and might represent a biomarker of actual arteritis in TA.

Neuroendocrine Modulation Induced by Selective Blockade of TNF‐α in Rheumatoid Arthritis

Abstract:  Tumor necrosis factor‐α (TNFα) is a main actor in the pathogenesis of rheumatoid arthritis (RA), interacting with other molecules in complex mechanisms. The neuroendocrine system is known to be involved and Chromogranin A (CHGA) serum levels are elevated in patients with RA. We evaluated the effect of the selective blockade of TNF‐α, induced by treatment with anti‐TNF‐α monoclonal antibodies (mAbs), on the serum levels of CHGA and on its correlation with TNF‐α and TNF‐α receptors (TNFRs) serum levels. Seven patients with RA have been treated with the anti‐TNF‐α mAb, infliximab. We measured the serum levels of TNF‐α, its receptors (tumor necrosis factor receptor‐I [TNFR‐I] and tumor necrosis factor receptor‐II [TNFR‐II]), and CHGA before and during the treatment. We also measured, as a control, the serum levels of CHGA, TNF‐α, and soluble TNFRs in 14 patients who were being treated with infliximab, adalimumab, or etanercept and in 20 matching negative controls. The serum levels of TNFR‐I and TNFR‐II, which are a sensitive marker for the TNF‐α pathway, correlated with those of CHGA before treatment (Pearsons coefficient, respectively, 0.59 and 0.53). Treatment with anti‐TNF‐α mAb provided a significant clinical response in all patients and the correlation between CHGA and TNFR‐I and TNFR‐II was no more evident during treatment (respectively, −0.09 and −0.07). TNF‐α blockade allows a clinical effect in patients with RA and modifies the correlation between CHGA and TNFRs, suggesting that TNF‐α and CHGA reciprocally interfere in the pathogenesis of RA, through intermediate adaptors, whose identification warrants further studies.