Erdheim-Chester disease (ECD) is a rare non-Langerhans systemic histiocytosis of unknown origin. ECD typically involves bilateral symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and infiltration of other organs (1). The diagnosis is based on typical histologic findings, with xanthogranulomatous infiltration of tissue by foamy CD68-positive and CD1a-negative histiocytes. Published data on therapeutic approaches, including surgery, corticosteroids, cytotoxic drugs, stem cell transplantation, and others, are limited to case reports and small series and show generally incomplete and/or transient remission and frequent toxicity (2–4). More recently, interferon-α (IFNα) has been suggested as a treatment option; it has demonstrated variable efficacy and sometimes limited tolerance (5–7). Herein we report on a child with ECD who was treated with anakinra, a recombinant, nonglycosylated homolog of the human interleukin-1 (IL-1) receptor antagonist, and we describe a rationale for this treatment.
The patient, a 10-year-old girl, presented with recurrent fever, elevated erythrocyte sedimentation rate (ESR) and increased C-reactive protein (CRP) levels, bone pain, and failure to thrive, and was diagnosed as having ECD. Bone radiography revealed multiple osteolytic and osteosclerotic lesions in the femurs, tibia, and pelvis. Whole-body magnetic resonance imaging (MRI) showed high-intensity signal of the skeletal bone marrow on fat-suppressed T2-weighted images, retroperitoneal infiltration, and diffuse low-intensity signal in the metadiaphyses (Figure 1C). Histologic findings on bone biopsy confirmed the diagnosis of ECD (Figure 2).
Treatment with subcutaneous IFN alfa-2a (3 × 106 units 3 times per week) resulted in normalization of clinical symptoms, ESR and CRP values, and liver and spleen volumes, significant regression of retroperitoneal infiltration, and improvement of bone marrow signal intensity within 4 months. However, after 10 months of treatment the patient experienced relapse, manifested by fever, bone pain, and increased ESR and CRP levels. Treatment with vinblastine (6 mg/m2/week) and prednisone (2 mg/kg/day) for 6 weeks showed no efficacy. The patient was then treated with PEGylated IFN alfa-2a (1.5 μg/kg/week) (8), with good efficacy. However, after 12 months of treatment, another relapse occurred.
To obtain a rationale for a potential alternative treatment option targeting specific cytokines, IL-1β, IL-6, and tumor necrosis factor α (TNFα) levels in unstimulated and lipopolysaccharide (LPS; 1 μg/ml)–stimulated peripheral blood mononuclear cells (PBMCs), which had been isolated from whole blood samples with Ficoll-Paque and cultured in RPMI, were measured by enzyme-linked immunosorbent assay. Data on the patient were compared with data from 15 healthy controls. As shown in Figure 1A, the unstimulated PBMCs from the patient displayed increased levels of IL-1β (40.3-fold), IL-6 (23.9-fold), and TNFα (5.6-fold). Following LPS stimulation, levels of IL-1β, IL-6, and TNFα were comparable to those in controls. These findings suggested that high basal levels of IL-1 and IL-6 may participate in the pathophysiology of ECD. Serum levels of IL-1β were within the normal range.
We therefore hypothesized that targeting of IL-1 might have a beneficial effect on the disease course, and consequently, treatment with anakinra (2 mg/kg/day) was instituted. Within 1 week, fever and bone pain resolved, and 1 month later, the ESR and CRP normalized (Figure 1B). During the subsequent 10 months the patient gained weight (8 kg) and height (6 cm). However, no significant changes in the bone lesions or retroperitoneal infiltration were seen on MRI 7 months after initiation of this treatment (Figure 1C). During followup, local injection site reactions have been the only side effect observed.
The findings in our patient suggest that overstimulation of IL-1 and IL-6 signaling in PBMCs may contribute to the pathogenesis of ECD. Aouba et al have recently reported successful treatment of 2 adult ECD patients with anakinra (9). They observed high expression of membranous IL-1α on monocytes, which decreased after anakinra treatment. Similar to our results, they did not observe any significant increase of IL-1β levels in patient serum. Our demonstration of increased IL-1β production by PBMCs provides additional rationale for the use of IL-1 signaling–targeting drugs in ECD.
In conclusion, our pediatric case and the 2 adult cases reported by Aouba and colleagues suggest that ECD patients may benefit from treatment with IL-1–targeting drugs, even though this treatment may not be sufficient to completely cure the disease. Prospective multicenter trials are needed to further evaluate the safety, efficacy, and treatment modalities of IL-1–targeting drugs in ECD.