Polynesian Variant Of Idiopathic Multicentric Castleman Disease

Multicentric Castleman Disease (MCD) is an uncommon non-clonal lymphoproliferative disease that traditionally has high morbidity and carries a poor prognosis, with median survival of 26-30 months. There has been growing interest in using interleukin-6 (IL-6) as a therapeutic target due to its role in the pathogenesis of MCD. In our practice, we noted a high number of Polynesian patients with idiopathic MCD (iMCD) and their prognosis appeared good. We therefore carried out a retrospective review. Via email survey, laboratory audit and our local database we identified 13 patients with MCD. Twelve patients were HIV and HHV8 negative hence classified as having iMCD; one patient was positive for HIV and HHV8.

Of the twelve patients with iMCD (five females, seven males), the median age at diagnosis was 53 (41 - 70). Eleven patients had plasma cell variant; one patient’s MCD subtype was not available. 83.3% (10 of 12 patients) were of Polynesian decent: New Zealand Maori (4), Samoan (3), and Niuean (3). Polynesian subjects had fewer general symptoms compared to literature: weight loss 40%, fever 20%;  Skin lesions were observed in 60%, 60% had splenomegaly and 40% had polyarthrialgia related to MCD. There is a recognized association between autoimmune disease and MCD. In our series, 6 of the 12 patients had some form of autoantibodies, including antinuclear antibodies, extractable nuclear antibodies and anti-cardiolipin antibodies; however only 2 patients had confirmed autoimmune diseases, with Grave’s disease in one and concurrent autoimmune haemolytic anaemia and coeliac disease in another patient. The median baseline gammaglobulin (IgG) was 61g/L (12- 96), C-reactive protein (CRP) was 105mg/L (39 - 219) and hemoglobin (Hb) was 89g/L (50 - 118), excluding one Polynesian patient who was an outlier with a CRP of 1 and Hb of 140. We traced pre-diagnosis electronic records of biochemical markers, such as total protein and total globulin levels, an indirect marker for hypergammaglobulinaemia. We could not find a normal value amongst the Polynesian patient group prior to the diagnosis, abnormalities were noted up to 6 years pre-diagnosis. Despite the biochemical derangement of most patients, performance status was high and 80% of the Polynesian patients remained at work. The mean duration of disease after tissue diagnosis was 5.3 years whereas the mean duration of biochemical evidence of disease presence was 9.2 years.

Various therapies including corticosteroid (dexamethasone or prednisone), Rituximab and chemotherapeutic agents were used with mixed but mostly non-durable response until 2009 when those needing treatment were given targeted treatment to block IL-6 with Tocilizumab (6) or Siltuximab (2 in a randomized double-blind placebo controlled study; results will be presented separately). Tocilizumab was administered as an intravenous infusion (at 8mg/kg) in a 3-4 weekly cycle. We used CRP as a measure of the response to treatment. By aiming for a low CRP (i.e. less than 20mg/L) rather than a normal CRP value, at the end of each cycle, we were able to increase the time interval between treatment cycles and therefore rationalize treatment frequency. The median duration of therapy was 19 months during which we saw normalization of Hb in 6/6 of patients, their median hemoglobins increasing from 87g/L (69 - 140) to 133g/L (118 - 157). There were significant improvement of IgG from 65g/L (42 - 96) to 32g/L (17 - 59); CRP from 86mg/L (39 - 160) to 4mg/L (1 - 23). Treatment was stopped in 2/6 patients with subsequent relapse, and response to tocilizumab retreatment. There were three deaths in the entire patient group, only 1/10 Polynesian, and all three patients died before IL-6 specific therapy became available.

Because most patients had high levels of IgG, we reviewed all patients tested at North Shore Hospital in the past 3 years with a polyclonal increase of IgG>35g/l and identified 3 further patients, all Polynesian, with blood test consistent with iMCD. Clinical follow-up on these patients was not available.

Our review demonstrates a disproportionately large group of Polynesians with iMCD, with distinctively favourable disease outcome. iMCD shows promising response to IL-6 targeted therapy. Based on the chronicity of the IgG elevation and the genetic association, we speculate that the up-regulation of IL-6 could be related to a defect in IL-6 regulation. Similar clinical cases have also been described in Japan.