What causes psoriasis?
A trigger causes recruitment of a number of inflammatory mediators including interferon-alpha, ILs, TNFa, and TGF-b. The net effect of this inflammatory process is recruitment of T cells, neutrophils, dendritic cells, and fibroblasts to the area and ultimately a proliferation of keratinocytes at the affected area
What are some drugs available for psoriasis?
-Calcipotriene and Calcitriol
How does Adalimumab work?
SC drug that acts as a TNFa monoclonal that binds TNFa and blocks its interactions with the p55 and p75 cell surface receptors
How does Alefacept work?
IM recombinant human LFA-3/IgG1 fusion protein that binds to CD2 on memory effector T-cells, which prevents T-cell activation and promotes apoptosis
How does Apremilast work?
PO drug that is a phosphodiesterase 4 inhibitor which increases cellular cAMP (consequences poorly understood)
How does Etancercept (Enbrel) work?
SC drug that consists of the extracellular ligand-binding portion of human p75 TNF receptor linked to IgG FC that binds to TNF to inactivate it (but does not affect TNF production or serum levels)
How does Infliximab work?
IV drug that is a chimeric (mouse-human) IgG1k monoclonal against TNFa to bind and neutralize both soluble and transmembrane TNFa
How does Uztekinamab work?
Human IgG1-kappa monoclonal Ab that binds to the p40 subunits IL-12 and Il-23 for treatment of psoriasis
How should patients be adviced when taking biologicals like etancercept or infliximab?
These drugs cause immunosuppression (dont initiate in a patient with active infection) and could potentiate infection (partiuclarly URI). Advise patients to report any signs/symptoms of infection and avoid live vaccines during use.
These can also increase the likelihood of malignancy
AEs reported in biologicals like etancercept, infliximab, and adalimumab?
-CHF or hypotension/angina and LFT elevation (especially in Infliximab)
-lupus-like syndrome (myalgias, skin rashes, fatigue)
-injection site rxns in those injected SC or IM (adal, alefacept, etancercept)
Another class of agents used to treat psoriasis (and some for acne) are the retinoids. How do they work?
Retinoids produce anti-inflammatory, anti-tumoral, and immunomodulatory effects and on the skin can stimulation keratinization and decrease sebum secretion and sebaceous gland size (isotretinoin)
What malignancy are retinoids used for?
acute promyelocytic leukemia (act on the nuclear retinoid receptors (RXR/RARa)
How do retinoids cause increased basal keratinocyte proliferation?
Topical application of a retinoid activates RXR/RAR heterodimers in suprabasal heratinocytes, causing activation of yet unidentified transcription factors. These, in turn, activate the synthesis of heparin-binding epidermal growth factor (HB-EGF) and amphiregulin (AR). Throguh activation of EGF-r, HB-EGR and AR cause keratinocte proliferation.
Note about RAR/RXR receptors
Targeting RARs predominantly affects cellular differentiation and proliferation (i.e. tretinoin, adapalene, and tazarotene are primarily used in acne, psoriasis, and photoaging) while targeting RXRs predominantly induces apoptosis are better suited for tumor related use (Bexarotene and alitretinoin used in mycosis fungoides and Kaposi sarcoma)
What are some of the toxicities of retinoids?
Acute toxicity resembles vitamin A toxicity including dry skin, nosebleeds, reduced night vision, and hair loss
ALL oral retinoids are potent teratogens
What should be monitored if giving retinoids?
Baseline serum lipids, serum transaminases, CBC and a pregnancy test should be obtained prior to therapy
What symptoms are more selective to RAR-selective retinoids?
mucocutaneous and musculoskeletal symptoms
What symptoms are more selective to RXR-selective retinoids?
What are the uses of topical retinoids?
These are 1st line agents for non-inflammatry (comedonal) acne (and can be used in combo for inflammatory acne) that work by correcting abnormal follicular keratinization, reducing P. acnes counts, and reducing inflammation
Also effective in reducing fine wrinkles and dyspigmentation associated with photoaging by inhibiting MMP activation via UV radiation and reducing keratinocyte atypia
AEs of topical retinoids?
Erythema, desquamation, buring and stinging as well as icnreases suceptibility to sunburn
How does Calcipotriene work for psoriasis treatment?
This is a topical agent that binds to vitamin D receptors and complexing with RXRa and binding DNA vitamin D response elements to modulate epidermal differentiations and inflammation, leading to improvement in psoriatic plaques
AEs of Calcipotriene (Dovonex)?
1) Irritation when applied topically
2) Hypercalcemia and/or hypecalciuria at high doses that can present as GI disturbances, HTN, weight loss, muscle weakness, and polydipsia
2) Increased susceptibility to UV-induced skin cancer
Alternative to Calcipotriene?
Calcitriol for sensitive areas of skin
Corticosteroids are another treatment option for acne. How do they help?
They are commonly employed in inflammatory acne syndromes and are anti-pruritic and vasoconstrictive
the potency of these drugs are based on their ability to blanch skin
How do corticosteroids work?
Cortisol binds to the cytoplasmic glucocorticoid receptor resulting in migration to the nucleus and anti-inflammatory properties then follow via several mechanisms including inactivation of NFkB
Note that the effectiveness of corticosteroids varies based on conditions of skin involvement. What are some situations that are highly responsive to steroids?
What are some situations that are not very responsive to steroids?
-psorasis of nails and palmo/plantar surfaces
Which areas of skin are assoicated with more systemic absorption than others?
scrotal skin > forehead > scalp > palm > forearm > plantar foot
What are fluorinated steroids?
preparations that are designed for increased potency but should NOT be applied to the face for risk of rosacea-like skin rash that can be precipitated by various triggers including stress, menopause, and food allergies
AEs of Topical Corticosteroid use?
-Iatrogenic Cushing's syndrome with protracted use
-Dermal atrophy (cigarette paper appearing skin with tendency for purpura and ecchymosis) (below)
What is Benzoyl Peroxide?
Topical pro-drug for acne that is converted to benzoic acid and liberates free radicals that are lethal to propiobacterium acnes (the predominant organism in sebaceous follicles and comedones) that typically results in resolution of acen within 4-6 weeks.
What is another noteworthy effect of Benzoyl Peroxide?
T or F. Benzoyl Peroxide commonly bleaches hair or colored fabrics
T. Avoid contact with eyes and mucous membranes
How does Salicyclic Acid work?
Topical keratolytic agent that causes desquamation of skin for hyperkeratonic skin disorders such as psoriasis, calluses, and acne
AEs of Salicylic Acid?
May cause contact irritation and prolonged exposure over large areas, especially in childrens and patients with renal and heptic impairment may increase risk of salicyclism
Neonatal toxicity via breast milk and contact toxicity possible
What are the symptoms of salicyclism?