Reply: Hypercalcaemia rather than high dose vitamin D₃ supplements could exacerbate multiple sclerosis

Sir,

Hereby we would like to reply to the comments by Smolders et al. (2019) regarding our recent publication describing a clinical deterioration in a murine model of multiple sclerosis upon high-dose vitamin D supplementation, which is mediated by a T cell-stimulatory effect of secondary hypercalcaemia (Häusler et al., 2019). Smolders et al. highlight that several high-dose vitamin D supplementation studies in multiple sclerosis patients reaching 25(OH)D median levels of up to 380 nmol/l reported no hypercalcaemia (Smolders et al., 2010; Hupperts et al., 2019) and only single cases of hypercalciuria (Rolf et al., 2019) occurring in both the treatment and placebo groups. Moreover, the authors described no development of pro-inflammatory T cells after high-dose vitamin D supplementation, concluding that hypercalcaemia rather than high-dose vitamin D₃ supplements could exacerbate multiple sclerosis. We agree with this suggestion, observing that a moderate dose of vitamin D suppressed experimental autoimmune encephalomyelitis (EAE) and that direct in vitro exposure of murine or human T cells to vitamin D and its metabolites even at supra-physiological doses inhibited proliferation and pro-inflammatory differentiation. By contrast, directly exposing murine, but also human CD4+ and CD8+ T cells to hypercalcaemic concentrations caused an increased susceptibility to activation, an upregulation of pro-inflammatory gene products as well as an enhanced capacity of activated T cells to transmigrate across a blood–brain barrier model. Moreover, raising calcium concentrations directly in vivo resulted in increased expression of activation markers on CD4+ and CD8+ T cells.

We want to emphasize that our investigations hereby support that vitamin D itself exerts a favourable effect in inflammatory CNS demyelinating disease; furthermore, we fully agree that our experimental data by no means can be used to extrapolate how regularly and/or persistently hypercalcaemia occurs upon high-dose vitamin D supplementation in patients with multiple sclerosis; to date it indeed has only been reported in a few cases on high dose vitamin D therapy, especially when combined with calcium intake (Jansen et al., 1997; Avenell et al., 2014; Bjelakovic et al., 2014). Yet we believe that our mechanistic observations caution that an uncritical and continuous supplementation with very high doses of vitamin D as propagated by few individuals in the field may not be advisable, especially when possible effects on the calcium metabolism are not regularly monitored. In this situation, the undesirable effects of hypercalcaemia, including the newly reported activation of potentially pathogenic T cells, may indeed occur more frequently and outweigh any possible benefit of vitamin D itself. We believe that the comments by Smolders et al. thus adequately contextualize our experimental data, and that we can jointly conclude on the note that moderation and monitoring may be advisable in vitamin D supplementation of multiple sclerosis.

Data availability

Data sharing is not applicable to this article as no new data were created or analysed in this study.

Funding

D.H. is supported by the Startprogramm of the Universitätsmedizin Göttingen. M.S.W. receives research support from the National Multiple Sclerosis Society (NMSS; PP 1660), the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. S.S.Z. is supported by grants from the National Institutes of Health (1 RO1NS092835-01; 1 R01 AI131624-01A1; 1 R21 NS108159-01), the NMSS (1 RG1701-26628) and the Maisin Foundation.

Competing interests

The authors report no competing interests.

References

Author notes