Systemic Therapy for Psoriasis

Systemic Tx Indications - Stepping Up Strategy

• Indications for Systemic Therapy:

  • Moderate-to-severe plaque psoriasis: BSA > 10%, PASI > 10, or DLQI > 10. (📌 Rule of 10s often cited)
  • Psoriatic Arthritis (PsA): Requires systemic treatment to prevent joint damage.
  • Severe, unstable forms: Erythrodermic psoriasis, generalized pustular psoriasis (GPP).
  • Failure, contraindication, or intolerance to topical therapy and/or phototherapy.
  • Psoriasis in special sites (e.g., face, palms, soles, genitals) if refractory and causing significant QoL impact.

• Stepping Up Strategy:

⭐ Methotrexate is often the first-line conventional systemic for chronic plaque psoriasis & PsA due to efficacy/cost.

Conventional Agents - Old School Power

• Methotrexate (MTX)

  • MOA: Antifolate, ↓ DNA synthesis.
  • Dose: 7.5-25 mg weekly. Test 5-10 mg. Folic acid 1-5 mg daily (not MTX day).
  • AEs: Hepatotoxicity, myelosuppression, mucositis, pulmonary fibrosis. Teratogenic.
  • Monitor: CBC, LFTs, renal function.
  • 📌 MTX: Marrow, Teratogen, X-Liver/Lungs/Mucosa.

• Cyclosporine (CsA)

  • MOA: Calcineurin inhibitor; ↓ IL-2 & T-cell activation. Rapid.
  • Dose: 2.5-5 mg/kg/day.
  • AEs: Nephrotoxicity, HTN, hypertrichosis, gingival hyperplasia, ↑ malignancy.
  • Monitor: BP, Sr.Cr, K+, Mg++, lipids.
  • Use: Severe, erythrodermic, pustular psoriasis. Short-term.

• Acitretin

  • MOA: Oral retinoid; normalizes keratinocyte differentiation.
  • Dose: 0.3-1 mg/kg/day (e.g., 25-50 mg daily).
  • AEs: Teratogenic (avoid pregnancy 3 years post-Rx!), mucocutaneous dryness, ↑TGs, hepatotoxicity.
  • Monitor: LFTs, lipids, pregnancy tests.
  • Use: Pustular, erythrodermic psoriasis. Good with phototherapy (Re-PUVA).

  • ⭐ Acitretin: Key for pustular psoriasis. ⚠️ Extreme teratogen (contraception 3 years post-Rx).

Biologic Therapies - Targeted Takedown

• General: mAbs targeting key psoriatic cytokines.
• Screening (All):
  • TB (QFT/TST, CXR).
  • Hep B, C; HIV.
  • CBC, LFT, KFT.
  • Vaccines (killed only during therapy).
• TNF-α Inhibitors: (Infliximab, Adalimumab, Etanercept)
  • Target: TNF-α.
  • Risks: Infections (TB), demyelination, lupus, CHF.
  • 📌 Mnemonic: "Eat In Adda" (Etanercept, Infliximab, Adalimumab)
• IL-17 Inhibitors: (Secukinumab, Ixekizumab, Brodalumab)
  • Target: IL-17A/IL-17RA.
  • Risks: Candidiasis, neutropenia, IBD flare. Brodalumab: ⚠️ Suicidal ideation.
• IL-12/23 Inhibitor: (Ustekinumab)
  • Target: p40 subunit (IL-12 & IL-23).
  • Risks: Infections.
• IL-23 Inhibitors (p19 specific): (Guselkumab, Risankizumab, Tildrakizumab)
  • Target: p19 subunit (IL-23).
  • Risks: URI.

⭐ TNF-α inhibitors require mandatory screening for latent tuberculosis (LTBI) due to risk of reactivation.

Newer Drugs & Combos - Fresh Frontiers

• Oral Small Molecules (OSMs): Advancing psoriasis management.
  • Apremilast (Otezla):
    • PDE4 inhibitor; ↑ cAMP, ↓ TNF-α, IL-23, IL-17.
    • Dose: 30 mg BID.
    • Common SE: GI upset, headache (transient). No routine lab monitoring.
  • Deucravacitinib (Sotyktu):
    • Selective TYK2 inhibitor (allosteric); blocks IL-23/IL-12/Type 1 IFN.
    • Dose: 6 mg OD.
    • Superior to Apremilast; fewer JAK-inhibitor class concerns.
  • JAK inhibitors (e.g., Tofacitinib):
    • Primarily for PsA; off-label severe psoriasis.
    • ⚠️ Boxed warning: MACE, VTE, malignancy.

⭐ Deucravacitinib, an oral selective TYK2 inhibitor, uniquely targets the IL-23 pathway with a favorable safety profile compared to pan-JAK inhibitors.

High‑Yield Points - ⚡ Biggest Takeaways

• Methotrexate: First-line systemic agent, requires folic acid, monitor for hepatotoxicity; teratogenic.
• Cyclosporine: Offers rapid control, monitor for nephrotoxicity and hypertension.
• Acitretin: Effective for pustular psoriasis; highly teratogenic (contraception 3 years post-stop).
• Biologics (TNF-α, IL-17/23 inhibitors): Indicated for moderate-to-severe refractory psoriasis.
• Apremilast: Oral PDE4 inhibitor, an alternative for moderate psoriasis, fewer monitoring needs.
• Pre-treatment screening: Essential for latent TB and hepatitis B/C before biologics & methotrexate.
• Avoid systemic corticosteroids: High risk of rebound pustular psoriasis upon withdrawal.