1. Psoriasis

Etiology and Pathophysiology

• Not rlly known; involved interplay between keratinocytes and innate cells, subsequent T cell activation, and inflammation and keratinocyte hyperplasia through various cytokines 

• A prevailing theory is that keratinocytes release antimicrobial peptides in response to injury. On peptide is LL37

• LL37 bound to DNA from other damaged cells can be recognized by TLRs on dendritic cells

• Dendritic cells activate other cells including helper T cells, which seem to play a larger role, specifically the Th17 cells, which produce IL17

• Leads back to increased inflammation, angiogenesis, and keratinocyte hyperplasia

Clinical Presentation

• Plaques: skin lesions red in color, usually covered in flaky, silvery scales; often are itching 

• Can develop in specific areas such as knees or elbows, or can be widespread

• Various comorbidities associated with psoriasis: psoriatic arthritis, hypertension, obesity, diabetes, crohn’s disease, multiple sclerosis, psychological disorders (depression/anxiety)

Agents

Topical agents

• Corticosteroids (hydrocortisone, triamcinolone, betamethasone, clobetasol, etc)

  • Mechanism: antipyretic and vasoconstrictor 

• Calineurin inhibitors (tacrolimus and pimecrolimus)

• Vitamin D3 analogs (calcipotriol, calcitriol)

• Acts on vit D receptor (VDR) on keratinocytes to inhibit keratinocyte proliferation and enhance keratinocyte differentiation 

• Also has direct immune effects by inhibiting interleukin production and some T cell function

Calcineurin Inhibitors

• Cyclosporine (Gengraf), Tacrolimus (Progaf), and Voclosporin (Lupkynis)

  • Tacrolimus topical for psoriasis

• Blocks T-cell proliferation by inhibiting calcineurin leading to a decrease in the production of IL-2 and other cytokines

Interleukin Receptor Antagonist 

• IL-17

  • Secukinumab, ixekizumab, brodalumab, bimekizumab

  • IL-17 is a key cytokine in psoriasis, with keratinocyte expressing IL-17 receptors

  • Affect the IL-17 pathway, leading to reduced cytokine production and reduced inflammation 

• IL-23 (mostly inhibitors)

  • Ustekinumab, risankizumab, guselkumab, tildrakizumab, mirikizumab

  • Guselkumab, tildrakizumab, and risakizumab bind to IL-23 (or subunit of it)

  • Ustekinumab binds to IL-23 and IL-12

Biologics: antidrug antibodies

• Cause some level of immune response against them (AKA immunogenicity)

• As a result of that immunogenicity, our body sometimes produces antibodies against biologics

  • Antidrug antibodies 

• Leads to reduction of failure of response to biologics over time - key reason why patient may need to switch treatments

• Most common anti-cytokine biologics (TND, IL)