Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21than the non-autoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
Azzopardi L, Thompson SA, Harding KE, Cossburn M, Robertson N, Compston A, Coles AJ, Jones JL. Predicting autoimmunity after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry:: 10.1136/jnnp-2013-307042. [Epub ahead of print]
OBJECTIVE:We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now ‘redundant’ enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value.
DESIGN:Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now ‘redundant’ IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity.
RESULTS:The ‘redundant kit’, and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the ‘redundant’ kit had predictive utility.
CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.
The risk of Lemtrada is that is going to cause (a) neutralizing antibodies that can stop it working and (b) unwanted and sometimes life-threatening (if not detected quick enough) autoimmunities. This occurs in 20-40% of MSers within a few years of treatment. The docs at Cambridge have been investigating this and have ways to stop the neutralising antibodies and have found a marker they think shows your risk of developing autoimmunity. This type of study has not been reported of the phase III trials….With a large sample one could have seen if this had mileage as a pre screen to mitigate risk…
One would think that people early in disease have most to gain, but may not take the risk. But those with disability may be be more willing to take the risk……but will it work. The manufacturer could I guess work this out in relation to say ability to induce NEDA and prior disease duration.