pinghang～熱血白袍～

最近剛好探討到圓禿（ＡＡ：alopecia areata）的機轉～

以及steroid為何可以治療此疾病，因此以下就查了一下有關topical steroid的一些作用機轉。予以記錄。

Topical steroid:

資料來源

(皮膚科聖經Fitzpatricks Dermatology 7's edition，and KATZUNG and TREVOR's pharmacology)

▪ MECHANISM OF ACTION

Corticosteroids have specific and nonspecific effects that are related to different mechanisms of action, including:

 anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Most of the effects of corticosteroids on cells are mediated by binding of the corticosteroid to its receptor in the cytosol, followed by translocation of the drug-receptor complex to a region of the nuclear DNA known as the corticosteroid responsive element,

where it is then able to stimulate or inhibit transcription of the adjacent genes, thus regulating the inflammatory process.

大部分都是進入核中結合影響轉錄轉譯後才發揮功能!(Systemic steroid也是)

Anti-Inflammatory Effects

Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2, an enzyme responsible for the formation of prostaglandins, leukotrienes, and other derivatives of the arachidonic acid pathway.

Corticosteroids also inhibit transcription factors, such as activator protein 1 and nuclear factor κB, that are involved in the activation of pro-inflammatory genes.

Genes known to be upregulated by corticosteroids and that play a role in the resolution of inflammation include lipocortin andp11/calpactin-binding proteins, both involved in the release of arachidonic acid. Lipocortin I inhibits phospholipase A2, reducing the release of arachidonic acid from phospholipids.

Corticosteroids also decrease the release of interleukin 1α (IL-1α), an important pro-inflammatory cytokine, from keratinocytes.

Other proposed mechanisms for the anti-inflammatory effects of corticosteroids include inhibition of phagocytosis and stabilization of lysosomal membranes of phagocytizing cells.

Immunosuppressive Effects

The effectiveness of corticosteroids is, in part, also due to their immunosuppressive properties. Corticosteroids suppress the production and effects of humoral factors involved in the inflammatory response, inhibit leukocyte migration to sites of inflammation, and interfere with the function of endothelial cells, granulocytes, mast cells, and fibroblasts. Several studies have shown that corticosteroids can cause mast cell depletion in the skin.

 Experiments also show that topical corticosteroids cause local inhibition of chemotaxis of neutrophilsin vitro, and decrease

the number of Ia+ Langerhans cells in vivo.

Corticosteroids reduce eosinophilia in patients with asthma.

 They also reduce T-cell proliferation and induce T-cell apoptosis, in part from inhibition of the T-cell growth factor IL-2.

In addition, several cytokines are directly affected by corticosteroids, including IL-1, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, and IL-8. These effects may also be a result of the steroid action on antigen presenting cells.

似乎看起來對免疫抑制的反映主要是在影響到T cell整個的活性，也可藉由影響IL-2影響Th1 and Th2的分化，而間接影響到B cell and CD8 T cell的功能。還有影響到巨噬細胞的一些活性，所以應該也不是集中在CD8 T cell。所以治療AA效果可能不夠好。

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@藥理課本免疫概念的補充:

Activated TH cells secrete IL-2, a cytokine that initiate proliferation and activation of 2 subsets of helper T cells, TH1 and TH2.

活化的TH cell(CD4是由class II MHC-peptide complex活化)會釋放IL-2而開始增生TH1 and TH2

1.TH1 cells orchestrate cell-mediated immunity and delayed hypersensitivity reactions.

TH1-->IFN-r, IL-2, TNF-beta-->activate macrophages, CD8 cytotoxic T lymphocytes and NK cells(CD8 T cell 藉由 class I MHC 上之小段peptide辨認) 所以TH1可影響使CD8 T cell活化

2.TH2 cells 由B lymphocyte表現之class II MHC-peptide complex活化會開始釋放IL-4, IL-5, IL-6, IL-10, IL-13-->induce B cell proliferation and differatiation into  memory B cells and antibody-secreting plasma cells.

TH2可影響使B cell開始增生分化

3.B cell and T cell之增生和分化又可藉由一些內生因子調控:例如IL-10可下降TH1之反應,INF-r可下降TH2之反應

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Antiproliferative Effects

The antiproliferative effect of topical corticosteroids is mediated by inhibition of DNA synthesis and mitosis, partly explaining the therapeutic action of these drugs in scaling dermatoses. Fibroblast activity and collagen formation are also inhibited by topical corticosteroids

Vasoconstriction

The mechanism by which corticosteroids induce vasoconstriction is not yet completely clear.

It is thought to be related to inhibition of natural vasodilators such as histamine, bradykinins, and prostaglandins.

 Topical steroids cause capillaries in the superficial dermis to constrict, thus reducing erythema. The ability of a given corticosteroid agent to cause vasoconstriction usually correlates with its anti-inflammatory potency, and thus, vasoconstriction assays are often used to predict the clinical activity of an agent. These assays, in combination with double-blind clinical trials, have been used to separate the topical corticosteroids into seven classes based on potency. Class 1 includes the most potent, while class 7 contains the least potent.

附上AA之corticosteroids之治療:

治療前言:看起來這個病很難治，輕微的不治療也是一個適當選擇，因為通常會自己恢復!

CONSERVATIVE MANAGEMENT

All of the currently available treatments for alopecia areata have a high failure rate and none alters the natural history of the disease.

After discussion of the options patients may therefore opt not to be treated, other than to wear a wig if appropriate.

‘No treatment’ is a legitimate option in patients with a short history and limited disease, in view of the high rate of spontaneous remission in this group.

附上AA之corticosteroids之治療:效果似乎都不太好。

1.TOPICAL CORTICOSTEROIDS

Topical corticosteroids are widely used to treat alopecia areata. There is some evidence of efficacy if potent corticosteroids are used under occlusionm, but less aggressive treatment regimens are probably ineffective.

2.INTRALESIONAL CORTICOSTEROIDS

Intralesional corticosteroids are the most effective approach for treating patchy alopecia areata. Hydrocortisone acetate (25 mg/mL) and triamcinolone acetonide (5 to 10 mg/mL) are commonly used, either by subdermal injection or using a needle-less device.

Multiple injections repeated monthly are usually necessary, limited by patient discomfort.

Intralesional corticosteroids are not appropriate in rapidly progressive or extensive disease.

Especially with triamcinolone injections, there is a significant risk of inducing skin atrophy, which may increase exponentially with each repeated injection.

3.SYSTEMIC CORTICOSTEROIDS

Oral corticosteroid therapy can induce short-term hair regrowth in patients with alopecia areata; however, hair regrown is usually lost after treatment is discontinued.Newer regimens that involve pulsed oral corticosteroids (e.g., prednisolone 200 mg once weekly for 3 months or dexamethasone 5 mg daily for 2 consecutive days/week for 3 months) may also induce hair regrowth in some patients. No significant side effects have been reported in published series but cannot be ruled out, and long-term benefits have not been shown.