LAUSR

Dear Editor, Idiopathic multicentric Castleman’s disease (iMCD) is a poorly understood lymphoproliferative disorder driven by the overrepresentation of interleukin (IL)-6 [1–5]. Since IL-6 plays a central role in the pathogenesis of iMCD, the normalization of serum IL-6 level is indispensable for the complete cure of the disease. To date, it remains unclear whether long-term treatment with tocilizumab can normalize levels of serum IL-6 in patients with iMCD. We herein report 6 cases with iMCD which showed negative HIV serology and no replicating HHV-8 virus by polymerase chain reaction in the peripheral blood. Median age at diagnosis was 48 years (range 45–55 years) and 4 of 6 (66.7%) were female. All patients were treated with long-term intravenous tocilizumab (8 mg/kg, every 2 weeks) with the median duration of 74 months (range 8–175 months). Ageand sex-matched patients with untreated active IgG4-related disease and six healthy donors were included as controls. The levels of serum IL-6 were strikingly higher in untreated active patients with iMCD (median level, 19.5 pg/ mL: range 8.6–41.8 pg/mL) compared to IgG4-related disease (median level, 1.5 pg/mL: range 0.8–3.5 pg/mL, P = 0.0022) and healthy donors (median level, 1.7 pg/ mL: range 0.9–2.4 pg/mL, P = 0.0022) (Fig. 1a). Significant improvement of hyperimmunoglobulinemia (median level, 5375 mg/dL: range 2896–10,800 mg/dL vs. median level, 2063 mg/dL: range 830–2434 mg/dL, P = 0.0313; Fig. 1b), levels of serum CRP (median level, 8.13 mg/dL: range 5.11–11.88 mg/dL vs. median level, 0.14 mg/dL: range 0.02–0.79 mg/dL, P = 0.0313; Fig. 1c), and anemia (median level, 8.6 g/dL: range 7.6– 12.1 g/dL vs. median level, 13.0 g/dL: range 11.2–14.1 g/ dL, P = 0.0313; Fig. 1d) was demonstrated after long-term treatment with tocilizumab, but elevation of serum IL-6 were not normalized in all patients (median level, 19.45 pg/mL: range 8.6–41.8 pg/mL vs. median level, 307.0 pg/mL: range 105–752 pg/mL, P = 0.0313; Fig. 1e). Furthermore, the case which was followed by the accidental cessation of tocilizumab due to the orthopedic surgery resulted in immediate relapse of the disease and the status was re-stabilized by re-introduction of tocilizumab after the surgery (Fig. 1f). To our knowledge, our study is the first report clearly showing the effect of long-term treatment with tocilizumab on levels of serum IL-6 in patients with iMCD. Our results emphasize that underlying disease process inducing hyper IL-6 is not corrected despite long-term treatment with tocilizumab as shown by the continued high levels of serum IL-6. In line with this observation, lifelong administration of tocilizumab is required to control disease activity because we observed the recurrent case after the accidental cessation of long-term tocilizumab. Interestingly, in contrast, recent reports demonstrated the normalization of serum IL-6 levels in parallel with disease improvement after treatment with tocilizumab in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, a unique clinicopathologic variant of MCD [6–8]. Thus, iMCD is a distinct disease entity from TAFRO syndrome even though some of the characteristics including hyper IL-6 and histopathology of lymph node are similar between the two diseases. Further research around * Tsutomu Takeuchi [email protected]