A Long-Term (5-Year) Sustained Efficacy of Tocilizumab for Multicentric Castleman’s Disease and the Effect on Pulmonary Complications.

Multicentric Castleman’s disease (MCD) is an atypical lymphoproliferative disease, which is closely associated with dysregulated overproduction of interleukin-6 (IL-6). These patients have numerous complications including secondary amyloidosis, paraneoplastic mucocutaneous disease, renal failure, and pulmonary manifestations such as diffuse lymphoid hyperplasia. We previously reported on a 60 weeks study of the humanized anti-human IL-6 receptor monoclonal antibody tocilizumab (TCZ) in patients with MCD and showed that TCZ provides rapid clinical improvement in constitutional symptoms as well as biochemical markers such as c-reactive protein, erythrocyte sedimentation rate, serum amyloid A, hemoglobin, and albumin levels. In this long-term follow-up over 5 years, we investigated the efficacy and safety of TCZ. Patients received TCZ monotherapy at 8 mg/kg intravenously every 2 weeks for 5 years. The dose and dosing interval were allowed to be adjusted according to disease activity. Pulmonary diffuse lymphoid hyperplasia was examined by high resolution computed tomography (HRCT) and evaluated and scored by 2 independent radiologists who were blinded to the time sequence of the images and clinical response of each patient. This study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice guidelines. Thirty-five patients were enrolled in this clinical trial and 30 patients (86%) continued TCZ treatment over the period of 5 years. The reduction in size of enlarged lymph nodes as reported previously was sustained. Clinical improvement in constitutional symptoms as well as the improvement of laboratory markers was maintained. Twenty-two patients had received corticosteroids at baseline (mean corticosteroid dose was 16.5 mg/day prednisolone equivalent), and 11 patients (50%) were able to discontinue corticosteroid therapy without flare. Pulmonary diffuse lymphoid hyperplasia was identified in 31 patients at baseline. Significant improvement was observed in the scores of centrilobular nodules, interlobular septal thickening, bronchovascular bundle thickening and ground glass attenuation with 50 to 60% reductions evaluated by HRCT over the 5 year period. No statistically significant change was observed in scores of cyst and airspace consolidation. TCZ was generally well tolerated during this 5 years treatment. The majority of adverse events (AEs) were mild to moderate in severity. Most frequently reported AEs were mild to moderate infections such as common cold and urinary tract infections (2.3 AEs / patient year). In conclusion, in this 5 years extension study tocilizumab demonstrated an excellent long term efficacy on inflammatory manifestations and pulmonary diffuse lymphoid hyperplasia. Tocilizumab treatment also showed a very good safety profile.