Alessandro Tomelleri

Tocilizumab in patients with multisystem Erdheim–Chester disease

ABSTRACT Treatment of Erdheim–Chester disease (ECD), a rare non-Langerhans histiocytosis, relies on interferon-α, chemotherapeutic agents such as purine analogs, cytokine-blocking agents and BRAF inhibitors. Since interleukin (IL)-6 levels are elevated in serum and lesions of ECD patients, we evaluated the therapeutic efficacy and safety of IL-6 blockade with tocilizumab. We conducted an open-label, single-arm, phase II, prospective study of tocilizumab in three patients with multisystem ECD and poor tolerance/contraindications to IFN-α. Modifications of symptoms attributed to ECD represented the criteria for evaluation of clinical response. Changes at positron emission tomography scan, computed tomography scan, and magnetic resonance imaging at month 6 represented the main criteria for the evaluation of radiological response. Sustained complete clinical response and partial radiological improvement were observed in two patients, paralleled by modulation of systemic pro-inflammatory mediators. In spite of disease stabilization or improvement at extra-neurological sites, a third patient experienced a radiologic and clinical progression of central nervous system involvement, mirrored by a dramatic increase of circulating IL-6 and related cytokines. These findings indicate that IL-6 inhibition can be effective in ECD, but caution is advisable in patients with neurologic involvement. IL-6 emerges as a central mediator in ECD pathogenesis.

The fibrogenic chemokine CCL18 is associated with disease severity in Erdheim-Chester disease

ABSTRACT Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by xanthogranulomatous tissue infiltration by foamy histiocytes. Fibrosis, a histologic hallmark of ECD, is responsible for lesion growth and clinical manifestations. Unraveling molecular fibrotic pathway in ECD would allow the identification of new pharmacologic targets. In this study, we evaluated serum and tissue samples from a large cohort of ECD patients focusing on two major pro-fibrotic mediators, TGF-β1 and chemokine ligand 18 (CCL18). We found a marked increase in CCL18 but not TGF-β1 levels in serum and lesions of ECD patients (p < 0.001), independently of treatment status and consistently over time. Using a linear mathematical model, we also found that elevated CCL18 serum levels correlate with both number and severity of disease localizations. These findings suggest the involvement of CCL18-induced fibrosis in ECD pathogenesis, providing a rationale for exploring CCL18 inhibition as a treatment for progressive fibrosis in ECD.

Treating heart inflammation with interleukin-1 blockade in a case of Erdheim-Chester Disease.

Pericarditis is an inflammatory heart disease, which may be idiopathic or secondary to autoimmune or auto-inflammatory diseases and often leads to severe or life-threatening complications. Colchicine and non-steroidal anti-inflammatory drugs represent the mainstay of treatment, whereas use of corticosteroids is associated with recurrence of disease flares. While effective and safe anti-inflammatory therapies remain an unmet clinical need, emerging clinical and experimental evidence points at a promising role of inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1). We thus evaluated treatment with the IL-1 receptor antagonist anakinra in a case of extremely severe pericarditis with cardiac tamponade and heart failure secondary to Erdheim–Chester disease (ECD), a rare clonal disorder of macrophages characterized by rampant inflammation and multiorgan involvement. A 62-year-old man was admitted to the Emergency Department with severe pericardial effusion requiring the creation of a pleuro-pericardial window. A whole-body contrast-enhanced computed tomography pointed at a diagnosis of ECD with involvement of the heart and pericardium and of the retroperitoneal space. Over the following days, an echocardiography revealed a closure of the pleuro-pericardial window and a relapse of the pericardial effusion. Treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist, was started at a standard subcutaneous dose of 100 mg/day. After 2 days, we observed a dramatic clinical improvement, an abrupt reduction of the inflammatory markers, and a reabsorption of the pericardial effusion. Anakinra was maintained as monotherapy, and the patient remained asymptomatic in the absence of disease flares for the following year. Recent studies point at inhibition of IL-1 activity as an attractive treatment option for patients with refractory idiopathic recurrent pericarditis. Anakinra treatment may also have a role in patients with pericarditis in the setting of systemic inflammatory disorders, such as ECD.

AB0647 Takayasu’s arteritis in italy: clinical presentation, diagnostic delay and vascular pattern

Background Takayasu arteritis(TA) is a large vessel vasculitis1. At disease presentation TA patients may present with inflammatory symptoms, sometimes associated with vascular pain. As arterial lesions ensue, more characteristic features may be found, such as limb claudication, decreased or absent pulses, vascular bruits, discrepancies in blood pressure2. Since initial symptoms are often non-specific, early detection of TA is challenging and patients at diagnosis frequently have established damage3 Objectives To describe symptoms presentation and vascular involvement in a large cohort of Italian TA patients. To assess the diagnostic delay associated with symptoms and arteries involved at presentation Methods Data from 114 TA patients diagnosed according to ACR classification criteria at our tertiary centre were retrospectively collected. Signs and symptoms subsequently attributed to TA, age at first symptom onset, and age at diagnosis were analysed. The diagnostic delay was calculated. Arteries involved before the diagnosis were identified. Non-parametric statistic tests were used Results The cohort included mostly female patients(104;91.2%). Mean age at first symptom subsequently attributed to TA was 30.5 years(±13.1). Age at presentation of first TA related symptom was 18–40 years in 68 (59.6),<18 years in 20 (17.5%),>40 years in 26 (22.8%)patients. Mean age at diagnosis was 36 years(±12.7). Mean diagnostic delay was 65.6 months(±85.3). Diagnostic delay was >1 year in 75 patients(65.8%). The most frequent finding before diagnosis was raised inflammatory markers(82.4%), the least common pulmonary hypertension(2.8%). The features significantly associated with a diagnostic delay >1 year were arthralgias, hypertension, previous vascular surgery. The mean diagnostic delay(in months) was significantly higher in patients with raised inflammatory markers(8.4±4.9 vs 100.5±121.8,p=0.005), carotidynia(5.8±5.7 vs 34.2±32.9,p=0.034) and in patients who had upper limb claudication(11.0±13.2 vs 65.44±77.01,p=0.002). Data about arteries involved before diagnosis were available for 86 patients(75.4%). They were: subclavian in 43 (50%), carotid in 38 (44.2%), renal in 19 (22.1%), abdominal aorta in 18 (20.9%), ascending aorta in 15 (17.4%), axillary in 12 (14%), vertebral in 11 (12.8%), superior mesenteric in 10 (11.6%), thoracic aorta in 10 (11.6%), aortic arch in 9 (10.5%), celiac tripod in 9 (10.5%), brachiocephalic in 8 (9.3%), iliac in 8 (9.3%), coronary in 6 (7%), femoral in 6 (7%), pulmonary in 5 (5.8%), brachial in 3 (3.5%), popliteal in 2 (2.3%) patients. There was no significant difference in the arteries involved between patients diagnosed <1 year and >1 year from symptoms onset. Mean diagnostic delay was not significantly different according to the arteries involved Conclusions In Italy TA diagnosis is burdened with an important diagnostic delay. In our cohort it seems that the presence of both specific and non-specific symptoms is associated with delayed recognition of TA. Moreover, the need for vascular surgery in young women should rise the concern about TA References [1] Weyand, C. M. & Goronzy, J. J. Medium- and large-vessel vasculitis. N. Engl. J. Med. 349, 160–9 (2003). [2] Kerr, G. S. et al. Takayasu arteritis. Ann. Intern. Med. 120, 919–29 (1994). [3] Numano, F., Okawara, M., Inomata, H. & Kobayashi, Y. Takayasu’s arteritis. Lancet356, 1023–1025 (2000). Disclosure of Interest A. Tomelleri: None declared, C. Campochiaro: None declared, S. Sartorelli: None declared, C. Sembenini: None declared, S. Franchini: None declared, F. Motta: None declared, D. Vanni: None declared, G. Cavalli: None declared, E. Baldissera: None declared, L. Dagna Grant/research support from: The Unit has received unrestricted educational grants from Abbvie, BMS, Celgene, Mundipharma, Novartis, MSD, Pfizer, Roche, and SOBI.

FRI0325 Prevalence of takayasu arteritis in young women with acute ischemic heart disease

Background Takayasu arteritis (TA), a systemic vasculitis typically occurring in female patients aged ≤40, can affect the coronary arteries and cause ischemic heart disease. The prevalence of TA among young females with acute ischemic heart disease is undetermined. Objectives In this study, we investigated the prevalence of TA in young women presenting with ischemic heart disease in the Emergency Department. Methods We conducted a retrospective evaluation of the hospital records of 172,790 consecutive female patients aged <45, who accessed the Emergency Department of our institution over 8 consecutive years (2007–2015). The prevalence of TA and of other etiologies of ischemic heart disease was determined. Diagnosis of TA was established based on the 1990 American College of Rheumatology criteria. Results Overall, 2,090 women aged <45 presented to the Emergency Department with chest pain, dyspnea, palpitations, angina, heart failure, or cardiac arrest; 40 had confirmed acute ischemic heart disease. The etiology was “classic” atherosclerosis in 24 cases (60%), TA in 4 cases (10%), vasospasm and sympathomimetic drug abuse in 3 cases each (7.5%), coronary artery dissection and microvascular angina in 2 cases each (5%), Takotsubo and radiation-induced cardiomyopathy in 1 case each (2.5%). Conclusions Although a diagnosis of TA is likely to be overlooked, TA is not infrequent in younger females presenting with acute ischemic heart disease. Specifically, TA accounted for 10% of cases of acute ischemic heart disease in female patients aged <45, a finding relevant to the diagnosis and management of these young patients. Disclosure of Interest None declared

THU0363 Pilot Study of TOCILIZUMAB in Patients with Erdheim-Chester Disease

Background Erdheim-Chester disease (ECD) is a rare, systemic disorder of unknown etiology, characterized by tissue infiltration with CD68+, CD1a- foamy histiocytes. ECD is still a chronically debilitating disease without a gold-standard treatment. Evidence is accumulating that inflammatory cytokines and chemokines are responsible for histiocytes recruitment and activation. In particular, recent data showed that IL-6 is strongly expressed in ECD lesions and increased serum levels of IL-6 have been implicated in the systemic manifestations observed in ECD. Objectives We intend to assess the efficacy and safety of IL-6 blockade in patients with ECD. Methods We are conducting an open-label, single-arm, phase II, prospective, pilot study of tocilizumab (TCZ) in ECD (ClinicalTrials.gov NCT01727206; Eudra-CT 2012-003151-11). We planned to treat 6 patients (with contraindications or unresponsive to IFN-α) with the IL-6 receptor inhibitor TCZ 8 mg/kg monthly. We are collecting clinical, laboratory and radiological data, by means of total-body computed tomography (CT) scan, Technetium-99m methylene diphosphonate (99mTc-MDP) bone-scan, fluorine-18-2-fluoro-d-glucose positron emission tomography (FDG-PET), brain and cardiac Magnetic Resonance Imaging (MRI). We are also evaluating the levels of pro-inflammatory cytokines and chemokines before, during and after therapy, in order to evaluate the network of soluble factors shown to be involved in ECD pathogenesis and its possible modulation after TCZ treatment. The Mann-Whitney U test for unpaired was chosen to compare data obtained from ECD patients and controls. The significance level was set at 0.05 (two-tailed p distribution). Results We present data from per protocol interim analysis on the first three patients who completed the protocol so far. All patients achieved significant improvement of all the clinical manifestations and laboratory findings (follow up at 12 months). Repeated whole-body CT scans, FDG-PET imaging and 99mTc-MDP bone scans confirmed the clinical and biochemical improvement in all patients. Cardiac MRI of the patient who had cardiovascular involvement showed an improvement of the diastolic function. However, the single patient who had CNS involvement had neurological progression, albeit showing improvement of other disease sites. During follow-up, we demonstrated a progressive reduction of circulating pro-inflammatory cyto-chemokines levels found to be increased before treatment. Plasma levels of IL-6 increased in all patients after the first infusion, as already shown in patients with other diseases treated with TCZ. Conclusions Although these data must be completed with the final analysis and possibly by larger studies, the interim analysis of the trial support the efficacy and safety of IL-6 targeting with TCZ in ECD patients, in particular when CNS is not involved. Of interest, TCZ showed beneficial effects on ECD cardiovascular involvement, which has been shown to be poorly responsive to most currently available treatments. References Stoppacciaro A et al. Arthritis Rheum. 2006 Dec;54(12):4018-22. Dagna L et al. Rheumatology (Oxford). 2010 Jun;49(6):1203-6. Mossetti G et al. Clin Exp Rheumatol. 2003 Mar-Apr;21(2):232-6. Arnaud L et al. Blood. 2011 Mar 10;117(10):2778-82. doi: 10.1182/blood-2010-06-294108. Acknowledgements This work was supported by a research grant from the Italian Ministry of Health to Lorenzo Dagna (GR-2009-1594586). Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5705

THU0372 The Role of Echocardiography and Cardiac MRI in Erdheim-Chester Disease

Background Erdheim-Chester disease (ECD) is a rare, inflammatory disease of unknown etiology. It is characterized by the xanthogranulomatous infiltration of tissues by foamy, CD 68+, CD1a-, S-100- macrophages [1]. ECD almost invariably involves long bones but frequently features extra-skeletal involvements. Cardiovascular and neurological ECD are associated with the worst prognosis [2]. Objectives To compare the role of echocardiography and cardiac cine Magnetic Resonance Imaging (MRI) in detecting the heart involvement and functional impairment in ECD. Methods Eight sequential patients with histologically-proven ECD, underwent echocardiography and morphological and ECG-gated MRI with mitral/tricuspid transvalvular flow evaluation and study of myocardium viability after infusion of paramagnetic contrast agent Results Echocardiography disclosed a cardiac mass in 4 out of 8 studied patients (50%). Detected mass had no specific ultrasound feature, except for right atrioventricular sulcus localization. The mean major diameter of the cardiac mass was 31.00 mm (range 25.00 – 37.00 mm). Pericardial effusion was detected in 6 out of 8 patients (75%), always circumpherential. Mean pericardial effusion at its greatest width was 17.60 mm (range 5.00 – 30.00 mm). Left ventricle (LV) and right ventricle (RV) morphology and function were within the normal range. Cardiac magnetic resonance, disclosed the presence of cardiac ECD involvement in 8 out of 8 studied patients (100%). In all cases a cardiac mass was present, involving the right atrioventricular sulcus, right atrial free wall and right coronary artery origin. Mean major mass diameter was 26.25 mm (range 15.00 – 40.00 mm). Cardiac mass had distinctive radiological features in all cases: dishomogeneous signal intensity in STIR sequences, with focal areas of hyperintensity consistent with active inflammation, due to focal infiltration by pathological, xantogranulomatous tissue and hypointense areas consistent with fibrosis; rapid enhancement during perfusion sequences and peculiar high signal intensity in late enhancement sequences. At cine MRI pericardial effusion was circumpherential in all cases, and its mean greatest width was 20.00 mm (range 10.00 – 50.00 mm). All patients had pericardial thickening, mean thickness was 4.38 mm (range 3.00 – 9.00 mm). RV EDV was reduced in 6 out 8 patients (75%), mean value was 110.14 mL. RV diastolic function was impaired in all patients. LV EF was within normal range in all patients, mean EF was 63% (range 53 – 78%). LV EDV was reduced in 4 out of 8 patients (50%) and increased in 1 patient. Conclusions Echocardiography is less sensitive than cardiac MRI (50% vs 100%) in detecting pathological tissue. This is probably due to the right chambers localization, usually worse studied with a trans-thoracic approach, besides the intrinsic limits of trans-thoracic ultrasound primarily operator dependence and risk of suboptimal acoustic window. Cardiac MRI is a fundamental tool for monitoring patients affected by ECD and eventually for modifying patients therapy. References Haroche J et al. Erdheim-Chester disease. Rheum Dis Clin North Am 2013 Haroche J et al. Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review. Medicine 2004 Acknowledgements This work was supported in part by a grant from the Italian Ministry of Health to LD (GR-2009-1594586). Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4490