Multicentric Castleman’s disease (MCD) is a rare lymphoproliferative disorder and systemic symptoms, most of which have been linked to the hyper-function of interleukin 6 (IL-6). In 1989, we suggested that MCD was caused by continuous production of IL-6 in affected lymph nodes. Current therapy tocilizumab, an anti-IL-6 receptor antibody, improves most MCD symptoms and abnormal laboratory findings, proving that IL-6 is indeed a key molecule in MCD pathogenesis.
Despite this key discovery, are still critical variables that remain unknown and need to be researched if treatment for MCD is to progress. Such questions include: what is the cause of MCD, what induces IL-6 production, what are the diagnostic markers, and which subpopulation of MCD patients are sensitive or resistant to tocilizumab therapy.
In an effort to solve these variables, we attempted to find diagnostic markers by identifying which biomarkers are responsive to anti-IL-6 therapy. Beads based multiplex assay was used to identify disease-specific biomarkers using patients’ serum. Characteristics of serum cytokine / chemokine / soluble receptor level in MCD patients were compared with those of rheumatoid arthritis (RA) patients (a chronic inflammatory disease), influenza (acute viral infection) and healthy subjects.
We observed that among 31 markers IL-6, IL-8, IL-13, GM-CSF, RANTES, and VEGF were elevated in more than two-third of MCD patients. On the other hand, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-9, IL-10, IL-13, GM-CSF, IFN-α, MIP-1α, MCP-1, RANTES were elevated in RA patients, and IL-6, IL-10, MCP-1, PDGF, MIP-1b and RANTES were elevated in influenza patients.
After tocilizumab therapy, production of most of biomarkers remained elevated in MCD, however all elevated biomarkers decreased in RA.
These data suggest that the activation mechanism might differ in each inflammatory disease and further research is needed to further extricate those specific to MCD.