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Topical Treatment of Psoriasis: Molecular Beneficial Effects of Combining Vitamin D Analogues with Moderate-strength Corticosteroids

Psoriasis is an autoinflammatory condition which affects on average 2% of the world population (0.1% to 0.2% in Japan). Inflammation is driven by a complex interplay between immune and skin cells involving key cytokines such as Interleukin 17a (Il-17a), Il-23 and TNF alpha.

In most cases psoriasis can be managed topically which includes lesions limited to a few areas (extensors, scalp).

In more severe psoriasis (more extensive, joint pain, nail involvement) systemic treatments may be required such as phototherapy, oral (small molecules) or injected (biologics) therapy..

Topical treatments can be conservative, such as moisturizers that reduce scaling. However when redness is present topical corticosteroids are often prescribed. Corticosteroids reduce inflammation and when combined with vitamin analogues, they become more effective (see below)

Introducing calcipotriol (more after the conclusion of the study)
-Calcipotriol carries the research name MC903, after Martin Calverey who first synthesized it. Contrarily to its precursor (1alpha25 (OH)2 D3), it has 100 times less action on calcium metabolism.
-Calcipotriol is a vitamin D analogue. It slows down the rate of skin cell growth, flattens psoriasis lesions, and removes scales.

Introducing combination treatments
-Combination treatment (topical Vitamin D analogues + steroids) shown in clinical trials to work much better than alternating treatments and ointment (2001) and gel (2008) were made available

The idea of using Calcipotriol in psoriasis
Shigeto Morimoto (Japan), had described how one of his patients suffering from senile osteoporosis when traeated orally with alfacalcidol showed a remarkable improvement in his lifelong psoriasis
-It has been found that Vitamin D receptors are present in keratinocytes (1979). Calcipotriol also inhibits fibroblast rowth (1983), and induces keratinocyte differentiation (1985)

Inflammation is driven by a complex interplay between immune and skin cells involving key cytokines such as Interleukin 17a (Il-17a), Il-23 and TNF alpha.

At the time of its development, calcipotriol was compared with all other topical treatments available at that time and sequential treatment of calcipotriol with a topical steroid turned out to be particularly positive. Therefore dermatologists sought to evaluate the combination of both treatments.

In 2015, this study from Denmark shows the specific molecular anti-inflammatory effects of this combination:

How was the study done ?
-Cell cultures were done from Psoriasis lesions biopsied from 5 patients (ex vivo) as primary human cells (in vitro) that recapitulate key cellular activities of psoriatic inflammation
Comparison of cytokines and inflammatory cell participants was done between vehicle controls, monotreatment, and combination treatment: betamethasone dipropionate + calciportiol

What were the results ?
1. Il-17 and TNF alpha secretion was significantly reduced in combination treatment cultures
2. Additive effect to reduce the secretion of: Il-23 and TNFalpha by Dendritic Cells (DC), Il-17a and TNFalpha by T lymphocytes (CD4+ and CD8+)
3. Diminished inflammatory response of Keratinocytes stimulated by Th17
4. Stimulation of Il-10 secretion in psoriatic skin
5. Increased secretion of type 2 cytokines by T cells (Th2/Treg associated cytokine)
6. Modulate differentiation processes of DC and T cells

-6 specific molecular effects have been found and they highlight the beneficial and complementary effects of calciportriol combined with bethamethasone diproprionate
-It acts in a specific immunomodulatory manner (differentiation and activation processes) in contrast with a broader immunosuppressive effect as seen with corticosteroid monotherapy (inhibits activity of diffrentiated cells). In other words the corticosteroid acts on inhibition of broad inflammation whereas the vitamin D analogue acts on specific differentiation and activation of involved cells.



Did you know ?

Why was combining vitamin D analogues with topical steroids such a challenge ?
Calcipotriol is unstable at low pH whereas topical steroids are unstable at high pH. A stable compromising pH was found by putting the active ingredients in a non-aqueous compound.

A word on the vitamin D pathway
-It is converted from precursors to Cholecalciferol  in the skin through the action of sunlight. This pathway is important for bone strength.
Cholecalciferol is inactive: it is converted to its active form by two hydroxylations: the first in the liver, the second in the kidney, to form calcitriol, whose action is mediated by the vitamin D receptor, a nuclear receptor which regulates the synthesis of hundreds of enzymes and is present in virtually every cell in the body.



Source of information: P01-41[O1-31] – Lovato P. et al. Key immune modulatory effects exerted by combination of calcipotriol and corticosteroids on psoriasis inflammation. JSID Annual Meeting (Japanese Society of Investigative Dermatology, 日本研究皮膚科学会) 2015 – Okayama, Japan
Bibliography: Maiddin WS. To Heal the Skin – The Heroes Behind Discoveries in Dermatology. 1st Edition 2015. Lincare Books