Erdheim-Chester disease: from palliative care to targeted treatment

Abstract

Erdheim-Chester disease (ECD) is a life-threatening multi-systemic non-Langerhans histiocytosis with cardiovascular complications as the leading cause of death. ECD affects the kidneys in up to 30% of cases, with fibrotic tissue deposition in the perirenal fat and renal hilum. Diagnosis is usually based on histological analysis of the pathologic tissue, which typically shows xanthogranulomatous infiltrates of foamy CD68+/CD1a- histiocytes surrounded by fibrosis. A consistent percentage of patients affected by ECD develop renal failure and hypertension as a consequence of renal artery stenosis and hydronephrosis. These conditions have been generally treated with the placement of stents and nephrostomies that frequently led to disappointing outcomes. Before the introduction of interferon-alpha (IFNα) treatment, the mortality rate was as high as 57% in the long term. Recent studies have granted new insights into the pathogenesis of ECD, which seems to bear a dual component of clonal and inflammatory disease. These advances led to use specific therapies targeting either the oncogenes (BRAF(V600E)) or the effectors of the immune response implicated in ECD (IL-1, TNFα). Drugs such as anakinra (recombinant human IL-1 receptor antagonist), infliximab (monoclonal antibody against TNFα) and vemurafenib (inhibitor of mutant BRAF) showed promising results in small single-centre series. Although larger trials will be needed to address the impact of these drugs on ECD prognosis and to select the most effective treatment, targeted therapies hold the premises to drastically change the outcome of this condition.

Keywords: Erdheim–Chester disease; anakinra; infliximab; renal failure; vemurafenib.

Fig. 1.

Histological analysis of the perirenal fat in a patient with ECD, showing fibromuscular and adipose tissue with infiltrates of foamy histiocytes surrounded by fibrosis.

Fig. 2.

Hypothesis on the pathogenesis of ECD (see text for explanation). H^BRAF: BRAF^V600E mutated histiocytes; SASP: senescence-associated secretory phenotype; H: wild-type histiocytes; Th: T-helper lymphocytes.