Silvia Sartorelli

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.

Anti-cytokine treatment for Takayasu arteritis: State of the art.

Takayasu arteritis (TA) is a rare and idiopathic large-vessel arteritis typically affecting young women which has important morbidity and mortality. There are no animal models of TA and pathogenesis is still mysterious. Clinical assessment lacks accurate activity indexes and is based on the integration of clinical, laboratory and radiological data. TA rarity has hampered randomized clinical trials and the achievement of high-quality evidence to guide clinical activity. Prevention of vascular progression, with progressive vessel wall remodelling and hyperplasia, is the main therapeutic goal. Medical therapy remains the mainstay of management and comprises traditional immunosuppressive agents and anti-inflammatory drugs, such as steroids and blockers of pivotal cytokines, TNF-α and IL-6. These strategies however only partially limit vascular progression, indicating that local molecular events are involved. Here we discuss recent data suggesting that selected cellular components of TA lesions should be evaluated as novel therapeutic targets.

Chromogranin-A production and fragmentation in patients with Takayasu arteritis

BackgroundChromogranin-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).MethodsPlasma 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.ResultsLevels 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.ConclusionsThe 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.

Procalcitonin in Takayasu Arteritis

To the Editor: Procalcitonin (PCT) is an acute-phase protein, a precursor of the hormone calcitonin1. Microbial constituents and proinflammatory mediators such as tumor necrosis factor-α (TNF), interleukin 6 (IL-6), and interferon-γ induce ubiquitous PCT expression during bacterial, parasitic, or fungal infections1,2. PCT enhances inflammatory response during sepsis, when excessive PCT production can be toxic, increasing mortality in animal models1. In humans, PCT has been demonstrated to be a more accurate marker of systemic bacterial infections than C-reactive protein (CRP)3, and it correlates with the severity of sepsis and mortality risk1. For these reasons, PCT is increasingly used for diagnosis, prognostic stratification, and treatment of patients with systemic bacterial or fungal infections. However, PCT elevation has been reported in noninfectious conditions, including inflammatory states associated with antineutrophil cytoplasmic antibodies-associated vasculitis, Kawasaki disease, and Goodpasture syndrome2. The clinical usefulness of PCT as a biomarker in patients with systemic autoimmune diseases has not been fully defined2. One metaanalysis showed that PCT had higher specificity but lower sensitivity than … Address correspondence to Dr. E. Tombetti, San Raffaele University Hospital, Unit of Internal Medicine and Clinical Immunology, Via Olgettina 60, 20132 Milan, Italy. E-mail: tombetti.enrico{at}hsr.it

SAT0335 Differential Modulation of The Chromogranin-A System in Takayasu Arteritis and Systemic Lupus Erythematosus

Background Chromogranin-A (CgA) is a multi-source protein proteolitically processed into a family of peptides with various paracrine and endocrine functions. CgA-derived peptides influence vascular biology and neoangiogenesis: CgA1–439 (CgA439) and vasostatin-1 (VS1, CgA1–76) have anti-angiogenic properties, while fragments lacking the C-terminal domain (CgA-FRs) are pro-angiogenic. The mechanisms regulating vascular events and systemic inflammation in Takayasu Arteritis (TA) and Systemic Lupus Erythematosus (SLE) are poorly characterized. Objectives To evaluate how the CgA system is modulated in TA and SLE Methods 42 consecutive patients (pts) with TA were enrolled and matched with 20 age- and sex- matched SLE pts and 20 healthy subjects (HCs). Exclusion criteria were moderate/severe heart failure or contraindication to MR angiography (MRA). TA pts were longitudinally studied with 2 MRAs (12 months apart). Disease activity was assessed with NIH criteria and SLEDAI in the TA and SLE group, respectively. Arterial progression was defined as the appearance of new lesions or worsening of pre-existing lesions at MRA. CgA peptides and total CgA (CgAtot) were quantified with validated ELISAs. CgA processing was studied by ratios of CgA peptides to CgAtot. The antiangiogenic CgA potential was quantified in TA by summing the ranks of CgA439 and VS1. Results Median age of TA patients (39W, 3M) was 46 (IQR 34–54) years. Median disease duration was 10 (IQR 7–14) years for TA, and 13 (7–21) years for SLE. Twelve TA and 8 SLE pts had active disease. Thirty TA and 10 SLE pts received proton pump inhibitors (PPI), which are known to increase CgA levels. Nine TA pts (8 treated with PPIs) underwent arterial progression. Serum CgA-FR were significantly higher in TA pts than in SLE pts (p<0.001) and HCs (p<0.001); VS1 was higher in SLE and TA than HCs (p<0.001 and p=0.020, Fig 1A). CgA processing was similar in TA and HCs; a distinctive processing was evident in SLE, with higher VS1/CgAtot (p<0.001 Vs Ta and HCs) and lower CgA-FR/CgAtot (p=0.001 Vs TA and 0.009 Vs HCs, Fig 1B). PPI increased serum CgA-FR, with a greater effect in TA, and quenched of the distinctive SLE-associated processing (Fig 1C). CgA peptides did not correlate with disease activity in TA nor in SLE. However, in the homogeneous group of TA pts on PPI, arterial progression was associated with reduced a reduced antiangiogenic CgA potential (p=0.010). Conclusions A selective processing of CgA is evident in SLE, whose molecular bases are unknown. TA associates with a greater increase in CgA-FR levels than SLE during PPI therapy. CgA peptides do not correlate with disease activity. Antiangiogenic CgA potential is reduced in TA pts on PPI undergoing progression, underlining the importance of angiogenesis in arterial remodelling and suggesting an involvement of CgA peptides in TA pathogenesis. Disclosure of Interest None declared

SAT0292 Clinical, Imaging and Laboratory Variables Fail to PREDICT Morphological Vascular Progression in Takayasu Arteritis

Background Takayasu arteritis (TA) is an orphan idiopathic inflammatory disease. A major pitfall in TA is the absence of a reliable modality to describe disease evolution and activity. Morphological vascular progression represents a significant clinical outcome, given the prognostic impact of cardiovascular complications. Objectives We verified if variables currently used in clinical practice as well as functional imaging data could predict the concurrent morphological progression. Methods We used Magnetic Resonance Angiography (MRA) as the reference for the assessment of disease evolution and morphological progression and we performed an exhaustive follow-up of patients with multiple MRA assessments. We selected and retrospectively evaluated 16 TA patients, for which 38 couples of MRA examinations performed within 24 months were available. Morphological progression within each couple was defined as the occurrence of new lesion(s) or worsening of at least one of the pre-existing lesions. Wall contrast enhancement (CE) was expressed as the difference of CNR (Contrast to Noise Ratio) pre- and post- infusion of contrast medium. Results Morphological progression occurred in 18 out of 38 couples of MRA examinations, despite effective treatment selected based on the most recent information available in the literature. All variables commonly used in the clinical practice failed to predict TA progression, except for maximum neutrophils values and radiological progression in the year preceding the first MRA of each couple. Wall CE at the first MRA examination within each couple was not associated with progression at the following MRA examination. Conclusions Most clinical, laboratory and functional imaging variables, currently associated with TA activity, fail to predict the vascular progression. Since they well reflect the activation of cardinal systemic inflammatory pathways, our data suggest that other inflammatory pathways contribute to the clinical outcomes of TA patients. Their identification and as such the identification of more effective targeted molecular therapies represent a major unmet medical need. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5598