The Calcitriol Study A Randomised Placebo Controlled Clinical Trial to Test the Effects of Calcitriol in Steroid Resistant Asthma.
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Background Over five million people in the UK are receiving treatment for asthma. Corticosteroids (steroids) are the mainstay of asthma therapy but some patients do not respond fully to steroid treatment, they are characterised as being steroid resistant (SR) and are at high risk of morbidity and mortality. Earlier data from our laboratory has shown evidence that in vitro treatment with the active form of vitamin D, - 1!,25-dihydroxyvitamin D3 or calcitriol - enhanced responsiveness to steroids for induction of the anti inflammatory cytokine IL-10. This thesis discusses the results of a proof of concept clinic trial - ‘The Calcitriol Study’ - which hypothesized that concomitant in vivo treatment with oral calcitriol improves the clinical responsiveness to systemic steroid (prednisolone) therapy. The study further allowed investigation of the in vitro cytokine profile of patients with SR and steroid sensitive (SS) asthma. Th17 cells and their hallmark cytokine IL-17A are proposed to play a role in the pathology of severe asthma, including SR asthma, and this work tested the susceptibility of IL-17A and other pro inflammatory cytokines important in asthma to inhibition by steroids and calcitriol in vivo and in culture. Methods Adult patients with moderate/severe asthma (FEV1 <80% predicted) with demonstrable reversibility of airways obstruction underwent a two-week, pharmacodynamically standardised course of oral prednisolone (screening phase) to delineate steroid resistance a <10% improvement in FEV1. Patients were then randomly assigned to receive calcitriol (n=12) or indistinguishable placebo (n=11) for four weeks, with a repeat course of prednisolone during the final two weeks (treatment phase). Changes in lung function (!FEV1) in response to prednisolone were compared between the placebo and calcitriol groups in the treatment phase, and within groups between the screening and treatment phases. Asthma Control Questionnaires and fractional exhaled nitric oxide (FeNo) were scored and analysed as secondary endpoints. All participants had serum 25(OH)D levels measured at baseline. CD8-depleted PBMCs were isolated from SS and SR asthmatics and healthy controls and cultured with or without dexamethasone and / or calcitriol. Cytometric bead array, ELISA, qPCR and intracellular cytokine staining were used to assess cytokine production. Results 5 Treatment with calcitriol improved the clinical response to steroids in patients classified as clinically steroid resistant (SR) in a within group comparison of changes in FEV1. However, there was no significant difference seen between the two groups from screening to the end of the trial. A striking dichotomy was observed between SR and SS asthma patients in terms of their cytokine profiles; SS patients, who showed the biggest improvement in lung function after a course of prednisolone had the highest levels of IL-10 in culture in response to dexamethasone, whereas SR patients, whose lung function failed to improve, had significantly greater levels of IL-17A. Treatment with steroids appeared to aggravate production of this pro-inflammatory cytokine but in vitro and in vivo calcitriol not only resulted in a significant reduction of IL-17A levels but also restored the impaired, steroid-induced anti-inflammatory IL-10 response in SR patients. Serum 25(OH)D levels at baseline correlated positively with IL-13 in culture, a Th2 cytokine known to be associated with steroid responsive asthma. Conclusion Calcitriol may have the potential to improve the clinical responsiveness of asthma patients to systemic steroid therapy in SR asthma. These data identify immunological pathways that likely underpin the beneficial clinical effects of calcitriol in SR asthma, by directing the SR cytokine profile towards a more SS type, suggesting strategies to characterise vitamin D responder immune phenotypes.
AuthorsNanzer, Alexandra M
- Theses