B. Guglielmi

The multifaceted clinical presentations and manifestations of Erdheim–Chester disease: comprehensive review of the literature and of 10 new cases

Objectives Erdheim–Chester disease (ECD) is a rare inflammatory disorder characterised by organ infiltration by non-Langerhans’ histiocytes. Although rare, ECD is clearly an overlooked diagnosis. No data specifically addressing the most frequent presentations of ECD at the time of onset in a large cohort of patients are currently available. Methods We reviewed all the published cases in the English literature of histologically-confirmed ECD. We excluded reports in which data regarding onset and diagnosis were not univocal, as well as repeated reports of the same case(s). We also included in the analysis 10 new unpublished patients from our cohort. We analysed the disease presentation with particular regard to the manifestations that induced patients to seek medical attention and their subsequent evolution. Results In the cumulative cohort of 259 cases, ECD predominantly presented with skeletal symptoms, diabetes insipidus, neurological and constitutional symptoms. Diabetes insipidus and constitutional symptoms, if not present at onset, seemed to only seldom develop. There were differences in ECD presentation and course among different age groups of patients. Conclusions Physicians should be aware of the extraordinarily heterogeneous clinical presentations and manifestations of ECD in order to include ECD in the differential diagnosis of several conditions.

BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease

Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAFV600E mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients’ peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAFV600E has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways. Methods We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes. Results BRAFV600E mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS. Conclusions The oncogenic BRAFV600E mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.

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.

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.

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.

OP0113 Switching Biologic Agents in Refractory Adult-Onset Still's Disease: Efficacy and Safety in A Cohort of 20 Patients at A Single Referral Center

Background No data is available on the long-term clinical outcome of Adult-Onset Stills Disease (AOSD) patients treated with biological drugs, nor on the efficacy and safety of switching biologics in the management of refractory cases.1 Objectives To evaluate the efficacy and safety of switching biological agents in a large, monocentric cohort of 20 patients with refractory AOSD. Methods Twenty Italian AOSD patients treated with biological agents were followed-up at our Institution for at least 24 months. For each case we retrospectively evaluated the disease course, the efficacy of treatment, and the potential adverse effects. Efficacy was evaluated as “Complete response” (CR: absence of articular and systemic manifestations, normalization of inflammatory indexes, >50% reduction in the corticosteroid dosage); “Partial response” (PR: clinical improvement without normalization of inflammatory markers, nor >50% reduction in the dose of steroids); or “Treatment failure” (TF: persistence/worsening of disease manifestations, persistent elevation of inflammatory markers, or need for an increased dose of corticosteroids despite 2 months of treatment). Results The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. Five patients were switched to a different biologic because of lack of efficacy. In 3 patients, a third biologic was necessary to achieve disease control. Biologics eventually determined a clinical response in all patients. Anakinra was used in all 20 patients; etanercept, tocilizumab and adalimumab was used in 6, 4, and 1 patient, respectively. Sixteen patients responded to anakinra (80%; CR 70%; PR 10%). Four patients (20%) did not respond to anakinra, and of these three responded to tocilizumab, and one responded to adalimumab. Etanercept was used unsuccessfully in six patients. Patients with systemic manifestations showed better responses than patients with chronic articular disease (p<0.05). Overall, biologic agents determined a significant reduction in the dose of the associated therapy with corticosteroids (p<0.0001) and DMARDs (p<0.05). Three patients experienced herpes zoster reactivation. Conclusions Biological agents represent a pivotal therapeutic resource for AOSD patients refractory to conventional treatment. Although the biologic drug of choice may prove ineffective, switching between biologics ultimately resulted in a clinical response in all patients without significant adverse effects, hence the importance of pursuing a tailored treatment approach. Although IL-1 blockade with anakinra represents the mainstay of treatment, IL-6 blockade may be more effective in patients with chronic articular involvement. Both anakinra and tocilizumab were more effective than TNF-α blockers. Patients with SD are more likely to respond favorably to biologics than patients with CAD. Different pathogenic mechanisms underlying SD and CAD, or the development of irreversible articular damage in CAD, may account for the differences in response to treatment. References Al-Homood IA. Biologic treatments for adult-onset Stills disease. Rheumatology 2013. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2153

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

AB0708 Efficacy of oral tacrolimus in two patients with scleritis and relapsing polychondritis

Background Relapsing polychondritis (RP) is a rare autoimmune disorder characterized by recurrent inflammation of cartilage and connective tissue.1 The pathogenesis revolves around an immune reaction to type II collagen, which is abundant in cartilage and sclera.1 Ocular involvement occurs in up to 65% of patients2 and often manifests as scleritis, a potentially eye-threatening condition characterized by the infiltration of sclera by inflammatory cells. Prompt immunosuppressive therapy is needed to avoid debilitating sequelae. Topical tacrolimus showed promising results in the treatment of several ocular inflammatory conditions,3 but the efficacy of oral tacrolimus in the treatment of scleritis is undetermined. Objectives To describe the efficacy of oral tacrolimus in 2 patients with RP and active resistant scleritis. Methods Two patients with RP and active scleritis in spite of previous treatments with steroids, methotrexate, and systemic cyclosporineA (discontinued due to side effects), were administered tacrolimus (0.08-0.1 mg/kg daily, 2.5mg twice daily) for one year. The efficacy of the treatment was assessed by periodic immuno-ophtalmic examinations. Results A complete, sustained resolution of the ocular inflammation was observed in both cases shortly after tacrolimus initiation. Corticosteroids were tapered and discontinued without the appearance of disease flares. In the following year, patients remained on tacrolimus, and experienced no recurrence of symptoms. Conclusions Scleritis is a chronic, progressive inflammation associated with several autoimmune and vasculitic diseases. Immunosuppressive therapy is needed to avoid ocular complications potentially leading to visual impairment or visual loss. Tacrolimus is an immunosuppressive drug which has an analogous mechanism of action to cyclosporinA (CyA): both inhibit calcineurin and dampen signal transduction downstream of the T-cell receptor, thus inhibiting the transcription of IL-2.4 CyA shows moderate efficacy in the management of ocular inflammation.5 In our 2 patients with refractory scleritis, we opted for a treatment with oral tacrolimus, also based on the encouraging results of tacrolimus ointment in ocular inflammation.3 In both patients, we observed a complete, sustained, relapse-free resolution of the ocular inflammation. Although this observation needs to be confirmed in larger studies, oral tacrolimus seems to be effective for refractory ocular inflammation and scleritis associated with active RP. References Letko E, et al. Relapsing polychondritis: a clinical review. Semin Arthritis Rheum 2002;31:384-395. Yoo JH, et al. Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Semin Ophthalmol 2011;26:261-269. Miyazaki D, et al. Therapeutic effects of tacrolimus ointment for refractory ocular surface inflammatory diseases. Ophthalmology 2008;115:988-992. Liu J, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 1991;66:807–15. Kaçmaz RO, et al. Cyclosporine for ocular inflammatory diseases. Ophthalmology 2010;117:576-584. Disclosure of Interest None Declared

FRI0486 Cardiac cine mri in erdheim-chester disease: data from a large italian cohort

Background Erdheim-Chester disease (ECD) is a rare, inflammatory disease of unknown etiology, characterized by xanthogranulomatous infiltration of tissues by foamy, CD 68+, CD1a-, S-100- macrophages [1]. ECD almost invariably involves long bones but may also feature extra-skeletal involvements. Cardiovascular and neurological involvements in particular are associated with the worst prognosis [2]. Objectives To investigate the role of cardiac cine Magnetic Resonance Imaging (MRI) in detecting heart involvement and functional impairment in ECD. Methods Six patients with histologically-proven ECD and cardiac involvement previously demonstrated by echocardiography and/or contrast enhanced CT scanning, underwent morphological and ECG-gated MRI with mitral/tricuspid transvalvular flow evaluation and study of myocardium viability after infusion of paramagnetic contrast agent. Results In all cases, cardiac cine MRI detected the presence of infiltrative pathological tissue which typically showed a non homogeneous signal in STIR sequences, in accordance with the presence of adipose tissue, and late focal enhancement, indicating the presence of a fibro-granulomatous component. In our cohort of patients the infiltrated heart structures were: right atrium in all cases (100%), left atrium in two patients (33%), interatrial septum in one case (16%), right coronary artery with preserved flow, in four patients (66%), right atrio-ventricular sulcus in four patients (66%), left atrio-ventricular sulcus in one case (16%). In five patients (83%) the MRI disclosed the presence of pericardial effusion (three patients had circumferential pericardial effusion, two patients had only posterior pericardial effusion) with thickened pericardium, medium size 2.6 mm (range 1.5 – 4 mm). The right ventricle (RV) end-diastolic volume (EDV) and the left ventricle (LF) EDV were reduced in five patients (83%), medium volume 80 mL (range 60 – 90 mL) and 98.8 mL (range 92 – 107 mL) respectively. The RV and LF ejection fractions were always normal. The RV and LV diastolic functions were abnormal in all cases: in four patients the E wave was not recognizable, in two cases the E/A wave ratio was inverted. Conclusions Cardiac cine MRI is a reproducible, non-invasive, operator-independent [3] technique that is extremely useful to identify the pathological infiltrate of ECD, to precisely define the anatomical location and extension of the disease, and to quantify the cardiac functional impairment. Cardiac cine MRI is thus a fundamental tool to assess the severity of the disease and to objectively follow-up its progression. References Haroche, J., L. Arnaud, and Z. Amoura, Erdheim-Chester disease. Curr Opin Rheumatol. 24(1): p. 53-9. Haroche, J., et al., Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review. Medicine (Baltimore), 2004. 83(6): p. 371-92. Gupta, A., et al., Cardiac MRI in restrictive cardiomyopathy. Clin Radiol. 67(2): p. 95-105 Disclosure of Interest None Declared

THU0373 Clinical presentation of erdheim-chester disease: Data from a cohort of 10 patients and review of the literature

Background Erdheim-Chester disease (ECD) is a rare, inflammatory disease of unknown etiology, characterized by the infiltration of non-Langerhans histiocytes. ECD typically involves long bones, with almost pathognomonic nuclear medicine finding. The overall prognosis is poor. Although the overall prevalence of ECD is low, it is still a largely overlooked diagnosis. Its broad clinical spectrum at presentation is often elusive, since infiltration of different organs may lead to disparate and confounding manifestations. Moreover, as subsequent manifestations can develop over years, a timely assessment of the diagnosis can be difficult. Objectives To characterize the presentation of ECD at the time of onset and the evolution of the clinical picture, with particular reference to the symptoms which induced patients to seek medical attention. Methods We analyzed the presentation at the time of onset, at diagnosis, and the subsequent clinical manifestations in a cohort of 10 ECD patients followed up at our Institution. Moreover we searched the English-language medical literature indexed in PubMed using the keyword “Erdheim-Chester” or “Erdheim-Chester disease”, including in our analysis the histologically-proven cases. Moreover, we divided the cumulative cohort of patients in three groups according to the patient age at presentation (<40, 40-69, >70 years), and performed on the different subgroups the same analyses. Results We found 249 patients in the literature fulfilling the proposed criteria. In the cumulative group of 259 patients, the overall frequency of symptoms at onset and during the whole course of the disease were, respectively: skeletal (bone pain and/or bone masses), in 26 and 47% of patients; diabetes insipidus, in 22 and 26%; neurological, in 22 and 49%; constitutional, in 19 and 25%); related to retroperitoneal involvement, in 14 and 34%; pulmonary in 12 and 20%; cutaneous, in 11 and 23%; cardiovascular, in 7 and 22%. Under 40 years of age, the presenting symptoms were: neurological (35%), skeletal (29%), diabetes insipidus (29%), constitutional (15%), pulmonary (4%). Between 40-69 years the presenting symptoms were: skeletal (24%), diabetes insipidus, neurologic and constitutional (21%), related to retroperitoneal (21%), pulmonary (14%), cardiac (8%). Over 70 years of age the presentations were: skeletal (32%), pulmonary (20%), diabetes insipidus (20%), neurologic (12%), cardiac (12%), related to retroperitoneal involvement (4%). Conclusions ECD manifests in the general population more frequently with skeletal symptoms (bone pain and/or masses), diabetes insipidus, neurologic, and constitutional symptoms. Interestingly, diabetes insipidus and constitutional symptoms due to ECD, if not present early in the course, only rarely develop. There seem to be differences in ECD presentation and course in specific age-groups. Physicians should be aware of this clinical entity to consider it in the differential diagnosis of many different clinical manifestations. References Veyssier-Belot C et al. Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine 1996; 75:157-69. Haroche J et al. Erdheim-Chester disease. Curr Opin Rheumatol 2012; 24: 53-9 Disclosure of Interest None Declared