More Contention About Vitamin D and Osteoporosis


Wholesale vitamin D supplementation may not prevent osteoporosis, judges a review of clinical trials. Other news: A novel drug that directly targets IL-6 up for regulatory scrutiny, newfound mutations in Sjögren's syndrome, and why eczema itches.

Last week's articles on rheumatology topics in the major non-rheumatology journals.Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysisLancet, October 11, 2013

“Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate,” write the authors of a new meta-analysis. The various trials included in the analysis assessed the effects of vitamin D supplementation without calcium on bone mineral density (BMD). A small benefit was seen at the femoral neck, but not at any other site.

However, BMD is a surrogate outcome, and only a modest predictor of fracture risk, an accompanying editorial pointed out. Given simultaneously with calcium, vitamin D induced a significant reduction of 11% in hip fractures and a modest increase in hip BMD.

However, the main mechanism of action for vitamin D is to promote calcium absorption in the gut, not incorporation of calcium in bone. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort studyBMJ, October 9, 2013

A cohort study in nearly 300,000 girls (ages 10-17) found no evidence of links between exposure to quadrivalent human papillomavirus (HPV) vaccine and autoimmune, neurological, or venous thromboembolic adverse events.

Although associations with Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes were initially observed, these were weak and not temporally related to vaccine exposure.

First IL-6–blocking drug nears approval for rare blood disorderNature Medicine, October 7, 2013

Janssen has submitted applications for siltuximab for treatment of multicentric Castleman’s disease to regulatory agencies in the US and Europe, on the basis of results in a 79-person clinical trial. If approved, siltuximab will be the first drug on the market that directly targets interleukin-6 (IL-6), although other drugs do target the IL-6 signaling pathway.

Multicentric Castleman’s disease involves the overproduction of B cells in the lymph nodes, which is frequently caused by an excessive release of IL-6, a key mediator of B cell growth.

The results of the placebo-controlled trial will be reported at a scientific meeting by the end of 2013, according to the company. In an open-label, phase 1 trial with 37 patients, almost all experienced at least one clinically beneficial response to siltuximab treatment, and a dozen saw their tumors reduced by half.

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjgren's syndromeNature Genetics, October 2013

The first genome-wide association study for Sjgren's syndrome found new disease-related mutations in six genes:

•  IRF5 and STAT, which are upstream regulators of the immune response;
•  CXCR5 which directs traffic for lymphocytes and may explain why immune cells target moisture-producing glands;
•  TNIP1, which binds to TNFAIP3, and upregulates the immune system;
•  IL12A, a cell messenger that modulates immune responses; and
•  BLK, a B-cell gene which might upregulate antibodies.

An HLA association was already known.

The Epithelial Cell-Derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch Cell, October 3, 2013

The itch in eczema may be caused when neurons trigger immune cells.

Thymic stromal lymphopoietin (TSLP) receptors on immune cells create inflammation on the skin and also in the lungs, gut, and nasal passages. In a mouse study, researchers found TSLP receptors in itch-sensitive neurons, which also release cytokines that cause inflammation. In this model, calcium-sensitive keratinocytes release TSLP, activating both primary afferent neurons and immune cells to promote inflammatory responses on the skin and in the airways.


Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of sclerodermaNature, Oct. 9, 2013

Systemic scleroderma (SSc) was reversed in human tissue culture.

A genetic cause for SSc has yet to be identified and the disease does not recur in families, making it difficult to study. However, stiff skin syndrome (SSS) does run in families and is similar to SSc.

In a mouse model, the SSS mutation induces inflammatory changes in the skin related to the level of integrins. In mouse SSS and human SSc tissue culture, the autoimmune reaction and fibrosis could be reversed by reducing the integrin or cytokine inflammatory mediators.

SSS, and by extension SSc, seems to involve an autoimmune reaction to excess production of integrins, suggesting a possible drug target.


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