Boswellic acids immunomodulate T cell populations in relapsing-remitting multiple sclerosis in the SABA phase IIa clinical trial

Background: Boswellic Acids (BAs), the main biologically active compound of frankincense (Boswellia ssp.), are orally available and have exhibited a safe and favourable side effect profile for the treatment of relapsing-remitting Multiple Sclerosis (RR-MS) in an open-label, two-center, baseline-to-treatment phase IIa trial. Effects on the primary MRI outcome and secondary clinical outcome parameters strongly suggest a positive influence on disease activity in RR-MS patients. BAs are known to exhibit anti-inflammatory activities, however, their immunological effect/s in RR-MS patients are not fully understood. Methods: In parallel to the phase IIa study with a standardized frankincense extract (produced by Alpinia Laudanum, Switzerland, and containing BAs as active ingredient) we performed an immunological substudy in n = 28 BA-treated RR-MS patients, who completed the study. Multicolour flow cytometric analysis was performed longitudinally ex vivo in n = 26 patients at three time points before, during early and during late treatment, respectively. Cytokine levels for interleukin(IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, tumor necrosis factor-alpha, interferon-gamma and transforming growth factor-beta in serum were measured at the same time points in n = 28 patients by highly sensitive single or multiplex analysis (MesoScale; Singulex) after all patients had completed the study. Results: We observed distinct alterations in CD3+ T cell subpopulations in our BA-treated patient cohort: While in the CD4+ T cell subset CTLA-4 expression and the percentage of CD4+CD25high Foxp3+ T cells increased significantly during treatment (p < 0.01), we found a significant decrease in the percentage of IL17-producing CD8+T cells coinciding with an increase in IL10-producing CD8+ T cells (p < 0.01). The analysis of other leucocyte and lymphocyte subpopulations, i.e. monocytes, B cells, natural killer cells and dendritic cells showed no alterations before and after BA-treatment. White blood cell counts and lymphocyte counts in general remained unaltered throughout the whole study. In regard to cytokine levels in serum, we observed significant decreases in IL-17A, GM-CSF and IL-2 during BA-treatment (p < 0.05). Conclusions: Treatment with boswellic acids in a phase IIa clinical trial leads to immunomodulatory effects on T cell subsets consistent with the inhibition of inflammatory disease activity as shown by MRI and clinical outcomes

A standardised frankincense extract reduces disease activity in relapsing-remitting multiple sclerosis (the SABA phase IIa trial)

OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results

Successful replication of GWAS hits for multiple sclerosis in 10,000 Germans using the exome array.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values &lt; 5 &times; 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values &lt; 10(-5) . The effect of nine SNPs in the HLA region remained (P &lt; 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations