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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.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterised by tissue infiltration by foamy CD68+ CD1a− histiocytes.1 The disease has pleomorphic clinical manifestations, including long bones and extraskeletal involvement, and may be life-threatening, particularly when heart and central nervous system are affected.1 ECD histiocytes secrete proinflammatory cytokines2 and carry activating mutations along the RAS-RAF-MEK-ERK protein kinase signalling pathway, most commonly the BRAFV600E oncogenic mutation.3 4 Accordingly, patients with ECD have been treated with cytokine inhibitors, including infliximab,1 ,5 and, more recently, with the BRAFV600E inhibitor vemurafenib.6 The latter, however, induces sustained but partial clinical responses and recurrences on discontinuation,6 underlining the need for more effective therapeutic strategies. To identify the outcomes downstream constitutive ERK phosphorylation in ECD histiocytes and their response to small molecule-based inhibition, we performed three-dimensional (3D) culture of tissues from three BRAFV600E-mutated ECD patients in the RCCS bioreactor7 (and online supplementary methods) in the presence/absence of vemurafenib or infliximab, used as control.### Supplementary data [annrheumdis-2018-214432supp001.pdf] All patient samples maintained production of prototypical cytokines and chemokines2 in bioreactor, thus validating this technology also for ECD; moreover, infliximab, and, to a lesser degree, vemurafenib, significantly decreased cyto-chemokines …

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.