‘Upgrading’ psoriasis responsibly

Psoriasis is a ‘pacemaker’ in dermatology. Substantial progress has been made regarding our understanding of its pathophysiology and genetic background, fuelling developments in cutaneous biology in general. Besides, the clinical perspective on psoriasis is currently changing, taking into consideration comorbidity and the systemic dimensions of this seemingly organ‐specific inflammation. The availability of drugs exhibiting fewer contraindications and improved long‐term safety opened a discussion around replacing a relatively limited (regarding both objectives and duration) ‘therapeutic’ by a much broader ‘management’ approach when it comes to treating psoriasis as a systemic disease. The question arises whether this ‘upgrade’ is warranted.     

Nikolsky's sign: is it‘dry’ or is it ‘wet’?

Nikolsky's sign refers to the ability to induce peripheral extension of a blister as a consequence of applying lateral pressure to the border of an intact blister. Although initially used in reference to the pemphigus group of blistering dermatoses, a positive Nikolsky's sign can be seen in other bullous diseases such as toxic epidermal necrolysis and staphylococcal scalded skin syndrome. Appreciating whether the blister is‘wet’or‘dry’at the site of a positive Nikolsky's sign may have both diagnostic and prognostic significance which I illustrate with several clinical cases. Lastly, I review the significance of a positive Nikolsky's sign.     

Pharmacokinetics and ‘bioactivation’ of MPA

In order to display its pharmacological and therapeutic effects, a local corticosteroid has to be bioavailable at its target site in the skin. The intensity and duration of its activity depend on the time course of its concentration in the target tissue, the number of receptors within this, tissue and on the intrinsic pharmacological activity of the molecule respectively of its active metabolite(s). It is commonly accepted that the desired and the adverse corticosteroid effects are mediated by receptor mechanisms. Since all nucleated cells contain corticosteroid receptors with the same specifity yet in different numbers, a dissociation between wanted anti-inflammatory and unwanted local and systemic effects is not achievable at the receptor level. A certain dissociation seems to be possible pharmacokinetically: structural modification of the corticosteroid molecule, especially introduction of suitable side chains, can lead to high concentrations of the active principal at the site of the desired effect and to low levels at the site of undesired effects. In the following, the most important pharmacokinetic properties of methylprednisolonaceponate (MPA), the active ingredient of Advantan® are presented: MPA is a di-ester of the non-halogenated methylprednisolone with a propionate group at C-atom 17 and an acetate group at C-atom 21. The introduction of both ester groups increase markedly the lipophilicity of the molecule and thus penetration into the skin. In addition the acetate side chain at C21 prevents a so-called acyl-migration of the propionic acid from C17 to C21 and thus stabilizes the molecule. After penetration out of the formulation into the living skin, MPA is hydrolized by the esterases in the epidermis and dermis at position 21, leading to the formation of methylprednisolone-17-propionate (MP-17-Prop). MP-17-Prop binds more strongly to the corticosteroid receptor than the parent substance MPA and represents the active principle in the skin. This so-called ‘bioactivation’ proceeds distinctly faster in damaged and inflamed skin compared to healthy skin. After percutaneous absorption MP-17-Prop is inactivated by conjugation with glucuronic acid and is excreted mainly in the urine.     

Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun‐tan jabs’?

While ultraviolet radiation (UVR) is a major cause of skin ageing and carcinogenesis, public pursuit of a novel tanning strategy circumventing the need for UVR is increasingly reported in the media and scientific press. This involves the subcutaneous self‐administration of unregulated products labelled as melanotan I and/or II, synthetic analogues of α‐melanocyte stimulating hormone (α‐MSH), as obtained via the internet, tanning salons and gyms. The Medicines and Healthcare products Regulatory Authority has recently raised awareness of the public health risk of transmission of blood‐borne viruses from the needle sharing that may occur, and of the potential impurity of these products. Dermatologists should also be aware that these agents can complicate the clinical presentation of patients with pigmented lesions; their use may be suspected in unexpectedly tanned individuals with rapidly pigmenting naevi. Meanwhile, the regulated α‐MSH analogue afamelanotide (Clinuvel Pharmaceuticals Ltd, Melbourne, Australia) is showing promise for its photoprotective potential, and is undergoing phase II and III clinical trials in people with photosensitivity disorders and those prone to nonmelanoma skin cancer. The photoprotective and other biological effects of α‐MSH analogues await full determination.