JC-2015-DH7 (September)

-Contains a monthly selection of articles from the top medical and dermatology journals. (Prof. JH Saurat M.D.)
-To view the abstracts, please click on the link at the top of the 1st post. This redirects you to the journal of the matching issue.

Shingles (Herpes Zoster): a more Effective Vaccine

Postby CFH » Tue Aug 18, 2015 1:01 am

Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults.
Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang SJ, Levin MJ, McElhaney JE, Poder A, Puig-Barberà J, Vesikari T, Watanabe D, Weckx L, Zahaf T, Heineman TC; ZOE-50 Study Group.
N Engl J Med. 2015 May 28;372(22):2087-96. doi: 10.1056/NEJMoa1501184. Epub 2015 Apr 28.

Shingles (Herpes Zoster) is a common disorder caused by the reactivation of the Varicella Zoster Virus (VZV) in individuals who had chicken pox (90% of individuals were infected, usually in childhood)

The disorder presents as vesicules clustered in crops (Herpetiform) which are usually limited to a dermatome. Involvement of multiple dermatomes should raise the suspicion of immunodeficience (such as in HIV infection)
Lesions are usually preceded by a tingling/burning sensation.

Shingles usually self-limiting and recovery can be speed up by the use of antivirals (such as acyclovir)

In individuals over 55-60, pain can remain after the ocurence of the active episode and this justifies the use of a vaccine in this population group. Indeed post-herpetic neuralgia is an often difficult to manage condition in hospital outpatient pain-units.

A vaccine is already present but it is not universally efficient:
-Indeed, the Zostavax vaccine (Merck) showed an around 50% efficacy against herpes zoster and a 66.5% efficacy against postherpetic neuralgia in individuals over 60
-Also the vaccine becomes less effective after 70 (=37.6%)
-Also this is a live attenuated vaccine and is contraindicated in individuals with immunosuppression

In this US study, published in the New England Journal of Medicine authors demonstrate the safety and efficacy of a subunit of VZV consiting of glycoprotein E and the AD01 adjuvant system (HZ/su, Glaxo Smith Kline (GSK)). It is a recombinant (non-living) subunit vaccine.

Methods
-phase 3 study (safety and efficacy already suggested in Phase 1 and 2 studies)
-15411 individuals over 50 (divided into 3 groups* 50-59, 60-69, over 70)
–2 intramuscular doses of vaccine* compared with placebo

Results
–6 individuals vaccinated developed Shingles (7698 received the vaccine) in in 3.2 mean follow up period (210 individuals developed shingles in the placebo group (n=7713)
-This amounts to an overall efficacy of 97.2% efficacy of the vaccine. The efficacy of the vaccine in individuals over 70 remained similar to the 2 other age groups.
Mild self-limiting local reactions were present in 17% of cases (vs 3% placebo): injection site reaction (in around 80% of cases, systemic reaction (66%, myalgia, fatigue, headache, shivering, fever, gastrointestinal symptoms)
-Severe reactions and the death rate was similar in treated and untreated groups

Conclusion
This non-live vaccine appears to offer (at the time of publication) the best preventive options against Herpes Zoster (Shingles) and its accompanying persisting pain.

Comment
-Phase 2 (Phase 1 studies need mainly to show safety, Phase 3 studies concern larger groups). Phase 3 studies are needed before the drug is approved, marketable, and eventually reimbursed (country-to-country basis)
-Phase 3 studies needs to demonstrate superior efficacy when compared to the cost to be remibursed US vc UK (Nice National Institute for Clinical Excellence)
-It is not surprising therefore that this study is performed by GSK Pharmaceuticals, the company who develops the vaccine.


*[The HZ/su vaccine contains 50 μg of recombinant VZV glycoprotein E and the liposome-based AS01B adjuvant system containing 50 μg of 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and 50 μg of Quillaja saponaria Molina, fraction 21 (QS21)]


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Minimal Scarring…possible: some Fibroblasts are Guilty

Postby CFH » Wed Aug 19, 2015 3:18 pm

Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential.
Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, Januszyk M, Krampitz GW, Gurtner GC, Lorenz HP, Weissman IL, Longaker MT.
Science. 2015 Apr 17;348(6232):aaa2151. doi: 10.1126/science.aaa2151.

"Will I get a scar from the procedure ?" - a question that often comes up

Fibroblasts...

...are the cells building up the dermis. They are embryologically derived from the mesoderm*.
...secrete structural components of the dermis (extracellular matrix), which consists of collagen, hyaluronic acid….components which are responsible for the tensile strength and aspect of the skin. A reduction of their activity results for example in loss of volume such as that which is seen in aging.
...play an indispensable role, yet are poorly understood. However, this study done in mice shows that there are at least 2 lineages of fibroblasts (in mice), and that one of them (so called fibrogenic fibroblasts) is responsible for the bulk of connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation.

Original article



In this US study published in Science, the Key findings are as follows:
The Engrailed-1 (En1) gene is expressed in fibrogenic lines of fibroblasts.
By using transgenic mice expressing the diphteria toxin receptor and adding diphtheria toxin the En1 lineage is removed and henceforward leads to diminished connective tissue deposition in wounds and significantly reduces melanoma growth in the dorsal skin of mice.
Although scarring formation is decreased, the tensile strength of the wound is maintained, suggesting that the wound remains functional.
Identified surface marker of this lineage of fibroblasts: CD26/dipeptidyl peptidase-4 (DPP4).
Small molecule–based inhibition of CD26/DPP4 enzymatic activity in the wound bed of wild-type mice during wound healing results in diminished cutaneous scarring after surgical excisional-induced wounding.
Conclusion
Although done in mice, understanding of the presence of specific populations of fibroblasts responsible for scar formation (fibrogenesis) brings a new perspective in the treatment of wounds healing (scar prevention).
The results of this research in mice can perhaps be extrapolated to understanding and treating fibrotic disease, cancer progression in humans.



*Other cells derived from the mesoderm: Langerhans' cells, macrophages, mast cells, fibroblasts, blood vessels, lymph vessels, muscles, and adipocytes.
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JC-2015-DH7 (September)

Postby CFH » Wed Sep 16, 2015 9:11 am

Page 4: http://dermatologicahelvetica.com/en/ar ... clesID=117

1-Specific anti–interleukin-23 therapy may win the race : a head to head study

2-Darier disease: the brain too !

3-A single fibroblast lineage responsible for the fibrotic response

4-Spironolactone limits topical steroid atrophy

5-A new and better vaccine against herpes zoster

6-Zoster immunity in the skin of older individuals
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