Giacomo De Luca

Advances in potential targeted therapies for Erdheim-Chester disease

ABSTRACT Introduction: Erdheim-Chester disease (ECD) is a rare histiocytosis, characterized by infiltration of aberrant macrophages into multiple tissues and organs causing rampant inflammation and fibrosis. The clinical severity and the nuances of disease pathogenesis must be considered when pondering different treatment strategies for the individual patient. Areas covered: Interferon-α has long represented the first-line treatment for ECD, but its preeminence may be reappraised in the future as new effective medications become available. For example, alternative treatment options include cytokine-blocking agents, which dampen local and systemic inflammation. Of crucial importance, recent evidence indicates that deregulated activation of the mitogen-activated protein kinase (MAPK) pathway due to oncogenic mutations in the BRAF, NRAS, PIK3CA, and MAP2K1 genes is central to the pathogenesis of ECD. These advances in the molecular understanding of ECD as an inflammatory myeloid neoplasm translated into the therapeutic use of small-molecule RAF and MEK inhibitors, with unprecedented results in terms of clinical efficacy. Expert opinion: In the future, the development of ERK inhibitors holds tremendous promise for the treatment of ECD. Combination therapy with small-molecule plus anti-inflammatory agents may prove more beneficial than either treatment alone. New drugs against fibrosis, not amenable to treatment with currently available strategies, remain an unmet clinical need.

QTc interval prolongation in Systemic Sclerosis: Correlations with clinical variables and arrhythmic risk

Article history: Received 13 March 2017 Accepted 16 March 2017 rhythmias, irrespective of QTc interval duration, as well as the potential life-saving role of an ICD-based approach in SSc patientswith cardiac involvement and a high number of VEBs on 24h ECG-Holter [3–5]. On that basis, the authors pathogenetic speculations should be taken with caution before extrapolating them to clinical practice considering the un-

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.

Adult leukoencephalopathies with prominent infratentorial involvement can be caused by Erdheim–Chester disease

BackgroundLeukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL.MethodsWe reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD.ResultsThere were seven males and three females; mean age at clinical onset was 49.6xa0years (range 38–59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up.ConclusionsSymptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease.

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 100u2009mg/day. After 2u2009days, 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.

Myocarditis: An Interleukin-1-Mediated Disease?

Myocarditis is defined by WHO as an inflammatory disease affecting the myocardium, diagnosed by endomyocardial biopsy (EMB) using established histological, immunological, and immunohistochemical criteria; it may be idiopathic, infectious, or autoimmune (1–4). A wide variety of histological myocarditis patterns have been described according to the diverse etiologies and to the stage of the disease at the time of EMB ascertainment. Viral infections represent the most common cause in Europe and North America (5). Different viral genomes can be detected in the myocardium of patients with myocarditis and dilated cardiomyopathy (DCM) using molecular techniques (6–14). When no infectious agents are identified on EMB and other known causes are excluded, autoimmune myocarditis (AMy) is the presumed etiology (15). These so-called “autoimmune myocarditis” or “virus-negative myocarditis” may occur as a distinct disease with exclusive cardiac involvement, or in the context of systemic autoimmune or inflammatory disorders with extracardiac involvement (5, 16–23). n nIt is likely that several etiologic types of myocarditis confluence in a common immune-mediated pathogenic process leading to chronic inflammation and tissue damage. Irrespective of triggering agents, acute inflammation may progress to subacute and chronic stages and eventually result in tissue remodeling, fibrosis, contractile dysfunction, and finally DCM (4, 6, 8, 24–29). Besides contractile dysfunction, both early myocardial inflammation and late fibrotic changes play a critical role in the development of the arrhythmic burden, which makes myocarditis one of the leading causes of sudden death (19, 27–31). Clearly, treatment interventions effectively curbing the acute inflammatory process at an early stage can prevent late cardiac remodeling and improve patient’s outcome. Emerging evidence on the pathogenic mechanisms underlying cardiac inflammation is paving the way to novel, promising treatment strategies for myocarditis.

Letter by Campochiaro et al Regarding Article, “Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor–Related Cardiotoxicity”

In their article on immune checkpoint inhibitor (ICI)–related cardiotoxicity, Escudier et al1 elegantly summarized the clinical features, management, and outcomes of cancer patients from 2 different cardio-oncology centers who developed immune-related cardiac-side effects after treatment with ICIs. There is presently no clear consensus for diagnosing ICI-related cardiotoxicity, which results in remarkable diagnostic heterogeneity. As recently reported,2 immune-mediated myocarditis is the most plausible pathological mechanism by which ICIs can cause cardiotoxicity. At present, the diagnostic gold standard for myocarditis is …