Vitamin D3 and Interferon Beta-1b in Patients With MS
Vitamin D3 and Interferon Beta-1b in Patients With MS
Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS).
Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests.
Results Median change in BOD was 287 mm in the placebo group and 83 mm in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19–82) nmol/l to 110 (range 67–163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate.
Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS.
Trial registration number EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.
Finland is located between latitudes 60°N and 70°N and belongs to a high risk region for multiple sclerosis (MS), with a prevalence of 100–200 per 100 000 inhabitants in different areas. Diminished capacity of vitamin D to regulate immune responses as a consequence of low serum concentrations of 25-hydroxyvitamin D (25(OH)D) could be one environmental factor to explain the latitude association with MS prevalence. There is a growing body of evidence to support this vitamin D hypothesis in MS. The risk of MS is higher in individuals born in the spring and among women born to mothers with low milk or vitamin D intake during pregnancy. Intake of vitamin D from multivitamin supplements, high sun exposure in childhood or adolescence, and serum levels of vitamin D >100 nmol/l are all associated with a lower incidence of MS.
Vitamin D also seems to regulate clinical disease activity in patients with established MS. MS patients have lower 25(OH)D levels during MS relapses than in remission. Prospective and retrospective studies have demonstrated a lower relapse risk with higher serum levels of 25(OH)D. Serum 25(OH)D levels correlate with disability in progressive forms of MS. Seasonal fluctuations in the numbers of gadolinium (Gd) enhancing MRI lesions in MS as well as an inverse correlation between brain MRI activity in MS patients and serum 25(OH)D at the population level have been described.
In Finland, almost half of newly diagnosed MS patients have moderate to severe vitamin D deficiency during the winter. Most newly diagnosed Finnish MS patients start interferon β (IFNB) or glatiramer acetate therapy as soon as the McDonald diagnostic criteria for relapsing–remitting MS (RRMS) are fulfilled. The therapeutic efficacy of IFNB in MS is known to be only partial. Therefore, several trials investigating the efficacy of combination therapies have been initiated. Recently, a large multinational trial including 307 MS patients failed to show any benefit of 80 mg of simvastatin as an add on therapy to IFNB-1a. Nevertheless, vitamin D is considered to have tolerogenic immunological effects but is not known to influence lymphocyte trafficking, in contrast with IFNB. Therefore, the mechanism of action of vitamin D could be complementary to IFNB and lead to an additive clinical effect.
The specific objectives of this randomised, double blind, placebo controlled trial were to study: (a) whether a once weekly dose of 20 000 IU (500 μg) of vitamin D3 as an add on to IFNB-1b 250 μg subcutaneously every other day is safe and well tolerated and (b) to what extent it increases serum levels of 25(OH)D, and whether it has an effect on MRI and clinical variables (including T2 lesion load and new T2 or T1 Gd enhancing lesions, relapse rate and disability) in comparison with a group that received IFNB-1b and placebo capsules.
Abstract and Introduction
Abstract
Objectives To study the safety and efficacy of vitamin D3 as an add on therapy to interferon β-1b (IFNB) in patients with multiple sclerosis (MS).
Methods 1 year, double blind, placebo controlled, randomised study in 66 MS patients. The primary outcomes were T2 burden of disease (BOD) on MRI scans, proportion of patients with serum levels of 25-hydroxyvitamin D (25(OH)D) ≥85 nmol/l or intact parathyroid hormone (PTH) ≤20 ng/l, and number of adverse events. Secondary outcomes were number of MRI enhancing T1 lesions and new T2 lesions, annual relapse rate, changes in the Expanded Disability Status Scale score, timed 25 foot walk test and timed 10 foot tandem walk tests.
Results Median change in BOD was 287 mm in the placebo group and 83 mm in the vitamin D group (p=0.105). Serum levels of 25(OH)D increased from a mean of 54 (range 19–82) nmol/l to 110 (range 67–163) nmol/l in the vitamin D group. 84% of patients reached a serum 25(OH)D level >85 nmol/l in the vitamin D group and 3% in the placebo group (p<0.0001). Patients in the vitamin D group showed fewer new T2 lesions (p=0.286) and a significantly lower number of T1 enhancing lesions (p=0.004), as well as a tendency to reduced disability accumulation (p=0.071) and to improved timed tandem walk (p=0.076). There were no significant differences in adverse events or in the annual relapse rate.
Conclusion Vitamin D3 add on treatment to IFNB reduces MRI disease activity in MS.
Trial registration number EudraCT number 2007-001958-99 and ClinicalTrialsGov number NCT01339676.
Introduction
Finland is located between latitudes 60°N and 70°N and belongs to a high risk region for multiple sclerosis (MS), with a prevalence of 100–200 per 100 000 inhabitants in different areas. Diminished capacity of vitamin D to regulate immune responses as a consequence of low serum concentrations of 25-hydroxyvitamin D (25(OH)D) could be one environmental factor to explain the latitude association with MS prevalence. There is a growing body of evidence to support this vitamin D hypothesis in MS. The risk of MS is higher in individuals born in the spring and among women born to mothers with low milk or vitamin D intake during pregnancy. Intake of vitamin D from multivitamin supplements, high sun exposure in childhood or adolescence, and serum levels of vitamin D >100 nmol/l are all associated with a lower incidence of MS.
Vitamin D also seems to regulate clinical disease activity in patients with established MS. MS patients have lower 25(OH)D levels during MS relapses than in remission. Prospective and retrospective studies have demonstrated a lower relapse risk with higher serum levels of 25(OH)D. Serum 25(OH)D levels correlate with disability in progressive forms of MS. Seasonal fluctuations in the numbers of gadolinium (Gd) enhancing MRI lesions in MS as well as an inverse correlation between brain MRI activity in MS patients and serum 25(OH)D at the population level have been described.
In Finland, almost half of newly diagnosed MS patients have moderate to severe vitamin D deficiency during the winter. Most newly diagnosed Finnish MS patients start interferon β (IFNB) or glatiramer acetate therapy as soon as the McDonald diagnostic criteria for relapsing–remitting MS (RRMS) are fulfilled. The therapeutic efficacy of IFNB in MS is known to be only partial. Therefore, several trials investigating the efficacy of combination therapies have been initiated. Recently, a large multinational trial including 307 MS patients failed to show any benefit of 80 mg of simvastatin as an add on therapy to IFNB-1a. Nevertheless, vitamin D is considered to have tolerogenic immunological effects but is not known to influence lymphocyte trafficking, in contrast with IFNB. Therefore, the mechanism of action of vitamin D could be complementary to IFNB and lead to an additive clinical effect.
The specific objectives of this randomised, double blind, placebo controlled trial were to study: (a) whether a once weekly dose of 20 000 IU (500 μg) of vitamin D3 as an add on to IFNB-1b 250 μg subcutaneously every other day is safe and well tolerated and (b) to what extent it increases serum levels of 25(OH)D, and whether it has an effect on MRI and clinical variables (including T2 lesion load and new T2 or T1 Gd enhancing lesions, relapse rate and disability) in comparison with a group that received IFNB-1b and placebo capsules.
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