Background Alemtuzumab, an anti-CD52 monoclonal antibody, was administered (cumulative dose range 1–420mg) to a cohort of patients with severe RA between 1991–941. We previously reported significant delays in immune reconstitution detectable 12 years after administration2.
Objectives To perform the 20 year follow-up of our unique cohort with regards to morbidity, mortality, lymphocyte reconstitution, circulating cytokines and response to vaccination.
Methods Mortality and morbidity data (Mar 2006–Jan 2015) were collected from death certificates, case notes or interview. Alemtuzumab patients were age, sex and disease duration matched with RA controls. For both groups circulating lymphocyte subsets (CD4+ and CD8+ naïve, central memory and effector memory T cells; naïve, memory and CD5+ B cells and CD19+CD24hiCD38hi Bregs; NK Cells and NK T Cells) were quantified by multicolour flow cytometry. Serum IL-15 and IFN-γ were measured by ELISA (MSD) and antigenic responses by generation of protective titres (as conventionally defined) following vaccination with influenza, Pneumovax II and combined diphtheria/tetanus/poliovirus vaccines
Results 16 patients were alive at the time of this study, 9 agreed to interview, vaccines and peripheral blood analysis, a further 4 had case note review only and 3 were uncontactable. 8 matched RA controls were also recruited. Since our last review 10 patients had died with causes of death consistent with a population with long-standing RA. There was no suggestion of compromised immune function with no increase in new autoimmune conditions or severe infections in living patients. Alemtuzumab patients continued to demonstrate abnormalities in their lymphocyte compartment with persistent significant reductions in CD4+ and CD8+ central memory cells, CD5+ B Cells and a new finding of significantly reduced naïve B cells when compared with previous analysis2. For the first time we examined CD19+CD24hiCD38hi Bregs which were also significantly reduced. Nonetheless vaccine responses were comparable between alemtuzumab recipients and controls. In addition, there were significantly higher IL-15 and IFN-γ levels in the serum of the alemtuzumab cohort. IL-15 levels inversely associated with CD4+ total memory and central memory T cells.
Conclusions In this unique patient cohort, after 20 years the effects of alemtuzumab treatment persist. Despite lymphocyte abnormalities, satisfactory vaccine responses are mounted and opportunistic infections remain absent. We hypothesise the reduced T-cell compartments trigger IL-15 via homeostatic mechanisms which, as a bystander effect, may activate NK cells causing IFN-γ release. An activated NK compartment could explain the lack of opportunistic infections in patients with lymphocyte abnormalities for 20+ years.
As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long term drug safety and stages of immune recovery.
Isaacs JD et al. Arthritis Rheum 2001;44(9):1998–2008
Anderson AE et al. Rheumatology (Oxford) 2012;51(8):1397–406
Disclosure of Interest None declared
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