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Monday, June 2, 2014

The effects of calcitriol treatment in glucocorticoid resistant asthma

The current and most effective treatment for asthma therapy is the use of glucocorticoids by improving the clinical features and airway inflammation associated with asthma. However, a cohort of well-defined asthma patients exists in whom high-dose glucocorticoid treatment is not only clinically ineffective, but potentially detrimental.  Several mechanisms have been proposed to contribute to glucocorticoid resistance, including vitamin D insufficiency. Nanzer et al recently published data that glucocorticoid resistant patients fail to synthesize the anti-inflammatory cytokine interleukin-10 (IL-10) in response to glucocorticoid in vitro compared to glucocorticoid sensitive patients (J Allergy Clin Immunol 2014; 133(6): 1755-1757). When resistant patients ingested a form of vitamin D called calcitriol (1,25-dihydroxyvitamin D3) in combination with glucocorticoid, levels of IL-10 were restored in vivo and ex-vivo. Taken together, these data along with epidemiological evidence linking vitamin D insufficiency/deficiency with poor clinical response to asthma treatment provided the rationale for the authors to perform a proof-of-concept clinical trial.

A small group of glucocorticoid resistant severe asthmatics were chosen and placed on a 2-week course of oral prednisolone and then randomly assigned placebo or 0.25ug calcitriol twice daily for 4 weeks. During the last 2 weeks patients repeated a course of oral prednisolone. The authors hypothesized that the concomitant calcitriol therapy would improve clinical glucocorticoid responsiveness in these patients. They did not expect the short course of calcitriol to restore Vitamin D sufficiency, but to address the short-term effects of calcitriol itself.


A within group comparison showing the change in lung function during the initial screening in response to 2-weeks oral prednisolone versus the response to an identical course of prednisolone plus either placebo or calcitriol, revealed a modest but significant improvement in absolute and predicted FEV₁ within the calcitriol but not the placebo arm. Furthermore, a trend for a positive correlation between baseline serum Vitamin D concentrations and change in predicted lung function following prednisolone was observed in placebo patients. This data suggests that treatment with a short course of calcitriol may improve the clinical glucocorticoid responsiveness in asthma, including patients classified as clinically glucocorticoid resistant. While larger studies with clinically well-defined cohorts are warranted, these results are very encouraging for the treatment of glucocorticoid resistant asthma. 

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