Comprehensive Guide to Dermocorticoids: Mechanism, Classification, and Clinical Practice

Introduction to Dermocorticoids

Dermocorticoids, also referred to as local or topical corticosteroid therapy, denote the application of corticosteroids via the topical route. These were introduced into the field of dermatology in the 1950s by Sulzberger and Witten, following the demonstration of the anti-inflammatory properties of hydrocortisone. Their discovery profoundly transformed the management of inflammatory skin diseases (dermatoses).

In modern dermatology, dermocorticoids represent a major therapeutic class and are the primary medication of choice for approximately $85\%$ of dermatologists in the USA. They possess three primary activities:

• Anti-inflammatory activity.
• Antiproliferative activity.
• Antipruriginous (anti-itch) activity.

Numerous dermatological conditions—whether inflammatory, dysimmune, or tumoral—are sensitive to these agents. However, at the time of their introduction, the lack of a precise therapeutic schema led to "anarchic" use. Consequently, prescriptions must now follow strict rules to maximize clinical benefit while minimizing the risk of side effects.

Chemical Structure of Dermocorticoids

Corticosteroids, or anti-inflammatory steroids, share the same basic skeleton as steroid hormones. They are characterized by two carbon chains attached to carbon 17 ($C17$) and are specifically known as $C21$ steroids.

Cortisone, the first corticosteroid invented, lacks topical effectiveness. The reduction of the carboxyl group at position 11 of the molecule results in the formation of hydrocortisone. The basic structure involves a polycyclic arrangement with carbons numbered 1 through 21, including specific groups at position 11 (hydroxyl or carboxyl) and the characteristic $D$ ring at $C17$.

Mechanism of Action

The molecular mechanisms of glucocorticoids are highly complex and not yet fully understood. Upon application to the skin, the corticosteroid crosses the cell membrane via simple diffusion. Once inside the cytoplasm, it binds to a specific intracytosolic receptor.

This receptor belongs to the steroid receptor superfamily, which includes receptors for progesterone, estrogens, thyroid hormones, retinoic acid, and Vitamin D. In its inactive state, the receptor is bound to a protein complex consisting of $HSP90$ and $P59$. Bonding with its ligand (the corticosteroid) causes the dissociation of the receptor from this protein complex, allowing the ligand-receptor pair to migrate into the cell nucleus.

The Glucocorticoid Receptor (GR)

The receptor is ubiquitous but its density remains variable across different tissues. It consists of three primary domains:

• A/B Domain: An activation/immunogenic domain at the $N$-terminal.
• C Domain: The DNA-binding domain ($DBD$).
• E/F Domain: The ligand-binding domain ($LBD$) at the $COOH$-terminal, which also mediates dimerization through the $AF2$ region.

Genomic Regulation of Transcription

Inside the nucleus, the activated receptor forms dimers and interacts with specific DNA sites:

• GRE (Glucocorticoid Response Elements): Interaction here exerts an activation of transcription, increasing the production of anti-inflammatory proteins such as lipocortin-1 (annexin-1), Interleukin 10 ($IL\text{-}10$), and the $I\kappa B$ protein.
• nGRE (Negative Glucocorticoid Response Elements): These are negative binding sites where the receptor inhibits the transcription of certain genes, leading to a decrease in proteins like specific keratins and proopiomelanocortin (POMC).

Indirect Action via Transcription Factors

The primary anti-inflammatory and immunosuppressive effects are often linked to interactions with transcriptional regulatory proteins rather than direct DNA binding. The receptor inhibits the following factors:

• Activator Protein-1 (AP-1): This factor normally activates genses for cytokines and collagenases. The steroid-receptor complex prevents $AP\text{-}1$ from binding to its sites.
• Nuclear Factor-kappaB (NF-kB): A key regulator of genes for infection, inflammation, and stress. It is usually held inactive in the cytoplasm by $I\kappa B$. Glucocorticoids inhibit $NF\text{-}\kappa B$ by activating the transcription of the gene for $I\kappa B$ and through direct interaction with a subunit of $NF\text{-}\kappa B$.

Non-Genomic Effects

Glucocorticoids also exert non-genomic effects that occur outside of transcriptional regulation, mediated either by the cytosolic receptor or membrane-bound receptors.

Pharmacodynamic Properties

Molecular Targets

Dermocorticoids act on various molecular mediators:

• Pro-inflammatory Cytokines: Inhibition of $IL\text{-}1, 2, 3, 4, 5, 6, 8, 11, 12, 15, 16$, $TNF\text{-}\alpha$, $IFN\text{-}\gamma$, and colony-stimulating factors ($CSF$, $M\text{-}CSF$, $GM\text{-}CSF$).
• Immunosuppressive Cytokines: Stimulation of $TGF\text{-}\beta$, which inhibits pro-inflammatory cytokine production.
• Inflammatory Mediators: Inhibition of Phospholipase $A2$ and Cyclo-oxygenase 2 ($COX\text{-}2$). They promote Lipocortin-1, which has anti-phospholipase $A2$ activity, decreasing arachidonic acid synthesis.
• Adhesion Molecules: Inhibition of $ICAM\text{-}1$ and $ELAM\text{-}1$.

Cellular Targets

• Macrophages: Inhibition of differentiation, myelopoiesis, $HLA$ class II antigen expression, cytokine/prostaglandin/leukotriene production, chemotaxis, phagocytosis, and tumoricidal/fungicidal/bactericidal activities.
• Neutrophils: Inhibition of adhesion to endothelial cells, slowing their influx to inflammatory sites.
• Eosinophils, Basophils, and Mast Cells: Inhibition of IgE-dependent release of histamine and leukotriene $C4$, and inhibition of mast cell degranulation.
• Lymphocytes: Inhibition of production and function of T-helper, suppressor, and cytotoxic cells. They favor the production of Th2 pathway cells over Th1. B-lymphocytes are less sensitive, but their proliferation can be inhibited.

Therapeutic Actions

• Anti-inflammatory Activity: Includes vasoconstriction of the dermis, which is the basis for the McKenzie test. The McKenzie test measures the intensity of skin blanching under occlusion to establish a potency scale.
• Immunosuppressive Activity: Reduces the number and function of Langerhans cells and impacts the antigen presentation function of macrophages.
• Anti-mitotic Activity: Induces epidermal atrophy (reversible) by affecting keratinocytes. It causes long-term depigmentation by affecting melanocytes. It inhibits fibroblasts, reducing collagen and proteoglycan synthesis, which can lead to irreversible dermal atrophy (stretch marks or vergetures). This effect is sought after for treating keloid scars and psoriasis.

Classification of Dermocorticoids

Classification is based on the McKenzie vasoconstriction test and clinical trial data. There are four levels of anti-inflammatory potency:

• Class IV (Very Strong): Example: Clobetasol propionate (Brand names: Dermoval, Clotasol).
• Class III (Strong): Examples: Betamethasone dipropionate (Brand names: Diprolène, Diprosone, Betasone), Mometasone furoate (Brand: Cortisaf), Hydrocortisone butyrate (Brand: Locoïd), Hydrocortisone aceponate (Brand: Efficort).
• Class II (Moderate): Example: Desonide (Brand: Locapred).
• Class I (Weak): Example: Hydrocortisone (Brand names: Hydracort, Cortiderm).

Pharmacokinetics

Bioavailability

Absorption depends on multiple factors:

• Surface area of application.
• Duration of contact.
• Occlusion: This can increase absorption by a factor of $10\times$ by increasing the degree of hydration, local temperature, and contact time.

Reservoir Effect and Tachyphylaxis

• Reservoir Effect: Dermocorticoids accumulate in the stratum corneum and are released gradually into deeper layers. This effect is lost if the stratum corneum is pathologically damaged.
• Tachyphylaxis (Acute Tolerance): This is a resistance developed by the dermatosis to the treatment after prolonged, uninterrupted applications. It occurs faster with more powerful corticosteroids and higher concentrations. Notably, side effects do not plateau with tachyphylaxis; they continue to worsen.

Modalities of Utilization

Choice of Potency and Excipient

The choice depends on the benefit/risk ratio, the type of affection, the surface area, the location (site) of lesions, and the patient's age. For children, very strong (Class IV) corticosteroids should be reserved for specialized use under strict supervision.

• Ointments (Pommades): Suited for dry, non-oozing, keratotic lesions. Avoid in folds or on oozing skin.
• Creams: Suited for skin folds and oozing (suintantes) lesions.
• Lotions: Suited for hairy (pileuses) zones. Avoid if lesions are oozing.
• Tablets/Aerosols/Fluid bases: Used for buccal (mouth) lesions.

Quantification and Application

• Dosage: Adults typically use approximately $30\,g/week$ for maintenance with Class II or III.
• Finger Tip Unit (FTU): One FTU is the amount of cream squeezed from a $5\,mm$ diameter tube onto the last phalanx of an adult index finger. $1\,FTU = 0.5\,g$, which covers a surface area equivalent to two adult hands ($\approx 312\,cm^2$).
• Frequency: In acute cases, treatment can stop abruptly or rapidly. In chronic cases, a slow tapering (spacing of applications) is required to avoid "rebound." Proactive maintenance therapy may be useful in atopic dermatitis and psoriasis.

Clinical Indications

• Very Strong Potency: Palmo-plantar psoriasis, lichenification (neurodermatitis), lichen planus, hypertrophic scars/keloids, bullous pemphigoid, plaque scleroderma, pretibial myxedema, alopecia areata (pelade), mastocytosis, and discoid cutaneous lupus.
• Strong and Moderate Potency: Contact eczema, atopic dermatitis, localized psoriasis (scalp, face, inverse psoriasis), stasis dermatitis, lichen planus, non-parasitic prurigo, dyshidrosis, nummular eczema, insect bites, sunburn (erythème solaire), granuloma annulare, and sarcoidosis.
• Weak Potency: Seborrheic dermatitis and eyelid eczema.

Contraindications

• Any infectious dermatosis: Viral (especially Herpes and Varicella), bacterial, or fungal.
• Acne.
• Rosacea.
• Diaper rash (Érythème fessier).

Side Effects

Local Side Effects

• Cutaneous Atrophy: Epidermal atrophy appears within $1\text{-}3$ weeks and is reversible within $4$ weeks of stopping (manifests as "cigarette paper" skin or bruising). Dermal atrophy is definitive/irreversible (manifests as telangiectasias, purpura, and purple stretch marks).
• Infection: Masking of infections (e.g., Tinea incognita, where a fungal infection's appearance is altered by steroids), aggravation of Herpes, and secondary infections.
• Ocular Effects: Glaucoma and cataracts if used near eyelids.
• Others: Hypopigmentation (more visible in pigmented skins), hypertrichosis, and granuloma glutéal (seen in infants treated with fluorinated derivatives for diaper rash).
• Tachyphylaxis and Rebound: Rebound phenomenon occurs upon abrupt withdrawal from prolonged treatment.

Systemic Side Effects

These occur with powerful steroids or large surface areas:

• Cushing's Syndrome.
• Growth retardation in children.
• Diabetes and Hypertension ($HTA$).
• Osteoporosis.
• Gastric ulcers.
• Hydro-sodium retention.
• Suppression of the Hypothalamic-Pituitary-Adrenal ($HPA$) axis.

Pregnancy and Allergy

• Pregnancy: Low-level evidence suggests a possible risk of cleft palate in the first trimester and low birth weight with very strong dermocorticoids. Caution is required.
• Contact Allergy: Affects $1\text{-}5\%$ of chronic patients. Suspect allergy if a typically sensitive dermatosis fails to respond or if an eczematous reaction occurs at the site. This can be due to the excipient or the steroid molecule itself. Epicutanous tests (patch tests) are required for confirmation.

Monitoring and Conclusion

Surveillance

Patients must be reviewed regularly. Monitoring involves:

• Clinical search for side effects.
• Counting the number of tubes used.
• Monitoring growth curves in children.
• Monitoring systemic effects if powerful steroids are used.
• If treatment fails, clinicians must reconsider the diagnosis, check for patient compliance (observance), or discuss corticosteroid resistance.

Conclusion

Dermocorticoids are an effective and often irreplaceable therapeutic tool. However, their potency is directly proportional to their potential side effects. Strict adherence to prescription rules ensures optimal profit with minimal inconvenience.