Maurizio Papa

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.

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.

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.

A true posterior tibial artery aneurysm: A case report

Aneurysms of infrapopliteal arteries are rare. The etiology is usually traumatic, and most aneurysms are false. The English-language literature reports only 33 cases of infrapopliteal arterial true aneurysms, of which 8 involve the posterior tibial artery. The etiology of these lesions is unclear; a fibromuscular fibrodysplasia similar to ulnar aneurysm may be hypothesized, but traumatic, atherosclerotic, inflammatory, and other pathological processes are also probably involved. The natural history seems to be related to thrombosis and distal embolism more than to rupture. Surgical indications are debated. Aneurysm repair with a complete restoration of the blood flow through the affected artery is particularly challenging owing to the small size of the vessels, and ligation may be required. We report, to the best of our knowledge, the first case of an atherosclerotic posterior tibial artery true aneurysm successfully treated with aneurysmectomy and end-to-end direct reconstruction with a documented good long-term patency. Clinical features, imaging findings, and surgical management are described; indications and treatments (open or endovascular) are discussed.

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.

Antalgic Flexion of the Lower Limb: An Unusual Presentation of Aortoiliac Infection with Psoas Muscle Abscess Four Case Reports

Psoas abscess with aortoiliac infection is rare. Patients are often symptomatic for a long time before the correct diagnosis is made. The authors report 4 cases in which the presenting symptom was an antalgic flexion of the left thigh. In 2 patients the cause was an aortic graft infection with enteric fistula; in the other 2, infection developed after transfemoral endovascular procedures. Open surgical treatment was performed in 3 cases and percutaneous drainage in 1. One surgical patient with a late diagnosis eventually died of sepsis; the other 3 are alive and well at mean follow-up of 14 months.

SAT0350 Functional Characterisation of Takayasu Arteritis Vascular Lesions by MR and FDG-PET/CT Provides Non-Redundant Information over Clinical Assessment

Background Disease activity (DA) assessment in Takayasu arteritis (TA) is an unresolved enigma as systemic inflammation and current activity measures poorly correlate with arterial progression. Morphological imaging, e.g. with morphological magnetic resonance (MR) sequencies, is the goal standard to evaluate arterial progression after its occurrence, and it is not clear whether functional characterisation of the lesions (e.g. contrast enhancement at MR or fluorodesoxyglucose [FDG] uptake at FDG-PET/CT [PET]) can predict arterial progression before its occlusion. We are prospectively following 60 TA patients with functional and morphological imaging to understand the predictors of arterial progression. Here we present the baseline assessment of the first 47 patients. Objectives to verify if activity measures, and functional lesion characterisation with PET or MR provide independent information. Methods Cross-sectional analysis of 47 TA patients according to ACR criteria followed at our Institution and undergoing closely related MR, PET and clinical evaluation. DA was evaluated with NIH criteria, indian Takayasu activity score (ITAS2010) and physician global assessment (PGA). At MR, arterial lesions were characterized by length, thickness and percentage of stenosis. Contrast to noise ratio (CNR) was calculated, when technically possible. Each vascular lesion uptake large enough to be evaluated by PET was evaluated with a quantitative (SUVmax) method. Per patients and per lesion analyses were performed. Results The median interval between MR and PET was 24 days. TA was active in 25, 17 and 35 patients according to NIH criteria, ITAS2010 and PGA (including active and grumbling disease). In total, MR identified 333 arterial lesions (median lesion N per patient 6, IQR 1–15). At the “per patient” analysis, median CNRmax at MR was 12,43 (IQR 0,00–54,29). CNRmax did not correlate with acute-phase markers nor activity measures, except for ITAS-CRP (rho 0.300, p=0,038). PET showed significant uptake in 18 patients. Meadian SUVmax was 1,19 (IQR 0,00–9,00). SUVmax did not correlate with activity measures. At the “per lesions” analysis, 56 lesions had positive uptake in PET. There was no correlation between the degree of enhancement at MR and of FDG uptake at PET (rho 0,094, p=0,529). Conclusions Current activity measures, mainly based on systemic inflammation, and functional characterisation of the arterial lesions by MR and FDG-PET provide independent information in TA. The prospective part of this study will clarify the clinical relevance and the predictive values for progression of these different pieces of information. Disclosure of Interest None declared

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

Magnetic Resonance Imaging of the Aorta

Non-invasive imaging techniques have now completely replaced invasive angiography in the diagnosis of aortic disease. Among the non-invasive cardiovascular diagnostic methods, magnetic resonance imaging (MRI) holds a central role, beside ultrasonography and computed tomography. The main strengths of MRI in the setting of aortic disease lie in the large spectrum of techniques available, which give the possibility of studying any single aspect of the patient’s aortic disease, ranging from characterization of an aortic wall thickening, to precise measurements of the vessel diameter, as well as functional and quantitative evaluation of the vessel flow. Moreover, the recent technological advances have improved magnetic resonance performance and have further expanded the techniques available, making MRI more suitable also for application in the emergency setting.