Key Points• Treatment with vemurafenib induced a dramatic response in 3 patients with histiocytosis harboring BRAF V600E mutations.• Tumor response was observed in both Erdheim-Chester disease and Langerhans cell histiocytosis. IntroductionErdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterized by the infiltration of tissues by foamy CD68 ϩ CD1a Ϫ histiocytes. 1 It is a systemic disease with diverse manifestations: the clinical course mainly depends on the extent and distribution of the disease, and ranges from asymptomatic bone lesions to life-threatening manifestations. 2 Rare cases of ECD associated with Langerhans cell histiocytosis (LCH) have been reported. 3 Unlike ECD, LCH histiocytes are CD1a ϩ and frequently infiltrate the epidermis in skin lesions. 4 Interferon ␣ (IFN) is generally the first choice for ECD therapy and improves survival. It should be prescribed at high dose if there is central nervous system and/or cardiovascular involvement. 2 However, long-term IFN treatment can lead to severe side effects and some patients are refractory to treatment. Moreover some patients with CNS and/or cardiovascular infiltrations develop secondary resistance to high-dose of IFN. Alternative treatments include recombinant human interleukin-1 receptor antagonist, cladribine, thyrosine kinase inhibitors, autologous hematopoietic stem cell transplantation. 2 However, the optimal second line therapeutic strategy remains to be defined, mostly because these treatments have been evaluated in only small numbers of patients. Despite recent therapeutic progress the overall mortality remains high (18% of the 84 ECD patients seen at our institution). BRAF V600E mutations have been observed in 38% to 69% of cases of LCH. [5][6][7] We recently reported BRAF V600E mutations in 54% of 24 patients with ECD. 8 Vemurafenib, an inhibitor of mutant BRAF, has shown some efficacy against 2 diseases (melanoma and hairy-cell leukemia) associated with the BRAF V600E mutation. 9,10

Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = −0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = −0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

Vemurafenib has an objective and sustained efficacy in BRAF(V600E)-mutated ECD as second-line therapy. In contrast to melanoma, no resistance has emerged to date after 6 to 16 months.

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