How do systemic treatments work for psoriasis?

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How do systemic treatments work for psoriasis?

Systemic treatments for psoriasis are medications that work throughout the entire body, rather than being applied locally to the skin. These treatments are typically used for moderate to severe cases of psoriasis or for patients who have not responded adequately to topical therapies or phototherapy. Systemic treatments can be categorized into traditional systemic treatments and biologic therapies. Here’s a detailed explanation of how systemic treatments work for psoriasis:

1. Traditional Systemic Treatments

a. Methotrexate

Mechanism of Action: Methotrexate is an antimetabolite that inhibits dihydrofolate reductase, an enzyme involved in DNA synthesis and cell replication. This inhibition slows down the rapid turnover of skin cells in psoriasis and has immunosuppressive effects.
Efficacy: Methotrexate reduces inflammation and scaling by decreasing the proliferation of keratinocytes and the activity of T-cells. It is effective in controlling both skin lesions and psoriatic arthritis.
Side Effects: Potential side effects include liver toxicity, bone marrow suppression, and gastrointestinal issues. Regular monitoring of liver function and blood counts is necessary.

b. Cyclosporine

Mechanism of Action: Cyclosporine is an immunosuppressant that inhibits calcineurin, a protein involved in the activation of T-cells. By reducing T-cell activation, cyclosporine decreases inflammation and the immune response that drives psoriasis.
Efficacy: Cyclosporine is highly effective for rapid control of severe psoriasis and can significantly reduce symptoms.
Side Effects: Long-term use is associated with nephrotoxicity (kidney damage), hypertension, and increased risk of infections. Monitoring kidney function and blood pressure is essential.

c. Acitretin

Mechanism of Action: Acitretin is a retinoid, which is a derivative of vitamin A. It normalizes the growth cycle of skin cells and reduces keratinocyte proliferation.
Efficacy: Acitretin is effective in reducing scaling and thickness of psoriatic plaques and is often used in combination with phototherapy.
Side Effects: Potential side effects include dry skin, hair loss, elevated liver enzymes, and teratogenicity (birth defects). It is contraindicated in women of childbearing potential unless strict contraception is used.

2. Biologic Therapies

Biologic therapies are advanced systemic treatments that target specific components of the immune system involved in psoriasis. They are typically administered via injection or intravenous infusion.

a. Tumor Necrosis Factor-alpha (TNF-α) Inhibitors

Examples: Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira)
Mechanism of Action: TNF-α inhibitors block the action of TNF-α, a pro-inflammatory cytokine that plays a central role in the inflammatory process of psoriasis. By inhibiting TNF-α, these biologics reduce inflammation and keratinocyte proliferation.
Efficacy: TNF-α inhibitors are effective in reducing the severity of psoriasis and controlling symptoms of psoriatic arthritis.
Side Effects: Potential side effects include increased risk of infections, injection site reactions, and rare cases of demyelinating diseases and heart failure. Regular monitoring for infections and other adverse effects is required.

b. Interleukin (IL) Inhibitors

IL-17 Inhibitors: Secukinumab (Cosentyx), Ixekizumab (Taltz)
- Mechanism of Action: IL-17 inhibitors block the activity of IL-17, a cytokine that promotes inflammation and keratinocyte proliferation in psoriasis.
- Efficacy: IL-17 inhibitors are highly effective in reducing psoriasis symptoms and achieving clear or nearly clear skin.
- Side Effects: Increased risk of infections, potential exacerbation of inflammatory bowel disease (IBD).
IL-12/23 Inhibitors: Ustekinumab (Stelara)
- Mechanism of Action: Ustekinumab targets both IL-12 and IL-23, cytokines involved in the differentiation and activity of T-cells that drive the inflammatory response in psoriasis.
- Efficacy: Effective in reducing psoriasis severity and symptoms of psoriatic arthritis.
- Side Effects: Risk of infections, possible increase in malignancy risk.
IL-23 Inhibitors: Guselkumab (Tremfya), Risankizumab (Skyrizi)
- Mechanism of Action: IL-23 inhibitors specifically target IL-23, reducing the activation of Th17 cells and subsequent inflammation.
- Efficacy: Highly effective in achieving and maintaining clear skin.
- Side Effects: Similar to other biologics, with increased infection risk being the most common.

3. Janus Kinase (JAK) Inhibitors

Example: Tofacitinib (Xeljanz)
Mechanism of Action: JAK inhibitors block the activity of Janus kinase enzymes involved in the signaling pathways of various cytokines that drive the inflammatory process in psoriasis.
Efficacy: Effective in reducing psoriasis symptoms and controlling psoriatic arthritis.
Side Effects: Increased risk of infections, elevated cholesterol levels, potential blood clots. Regular monitoring is necessary.

4. Phosphodiesterase 4 (PDE4) Inhibitors

Example: Apremilast (Otezla)
Mechanism of Action: PDE4 inhibitors reduce the production of pro-inflammatory cytokines by inhibiting the enzyme phosphodiesterase 4, which plays a role in the inflammatory signaling pathways.
Efficacy: Effective in reducing psoriasis symptoms and controlling psoriatic arthritis.
Side Effects: Gastrointestinal issues (nausea, diarrhea), headache, weight loss. Generally well-tolerated with fewer serious side effects compared to other systemic treatments.

5. Benefits and Considerations

a. Benefits

High Efficacy: Systemic treatments, particularly biologics, are highly effective in managing moderate to severe psoriasis and achieving significant symptom relief.
Improved Quality of Life: By controlling psoriasis symptoms, systemic treatments can significantly improve the quality of life for patients.

b. Considerations

Side Effects: Systemic treatments can have serious side effects, and regular monitoring is essential to manage these risks.
Cost: Biologic therapies can be expensive, and access may be limited by insurance coverage and cost considerations.
Long-Term Use: Long-term safety data for newer biologics are still being gathered, and patients need ongoing evaluation to ensure continued efficacy and safety.

Conclusion

Systemic treatments for psoriasis, including traditional systemic treatments and biologic therapies, offer effective options for managing moderate to severe cases. These treatments work by targeting different components of the immune system and the inflammatory pathways involved in psoriasis. While highly effective, systemic treatments come with potential side effects and risks that require careful monitoring and management. Understanding the mechanisms, benefits, and considerations of systemic treatments helps in optimizing psoriasis management and improving patient outcomes.