Apremilast: An Evidence-Based Clinical Overview (2025)

Apremilast is an orally administered small molecule approved for the treatment of immune-mediated inflammatory conditions. It is classified as a selective phosphodiesterase 4 (PDE4) inhibitor, with anti-inflammatory properties beneficial in conditions such as psoriatic arthritis (PsA), moderate to severe plaque psoriasis, and oral ulcers associated with Behçet’s disease.


Indications

Apremilast is FDA-approved for the following indications:

  • Moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy.
  • Active psoriatic arthritis in adults.
  • Oral ulcers in Behçet’s disease.

While not yet approved for pediatric use or off-label for other autoimmune conditions, studies are underway exploring its potential in hidradenitis suppurativa, lupus erythematosus, and atopic dermatitis.

Notable Clinical Consideration (2025):
Apremilast may be particularly suitable for patients with comorbidities that limit biologic therapy—such as prior malignancy, chronic infections (e.g., HIV, Hepatitis B or C), demyelinating disorders, or congestive heart failure.


Mechanism of Action

Apremilast exerts its anti-inflammatory effect through selective inhibition of PDE4, the predominant phosphodiesterase in immune cells. This inhibition:

  • Increases intracellular cyclic AMP (cAMP) levels.
  • Downregulates pro-inflammatory cytokines, including:
    • TNF-α
    • IL-17
    • IL-23
    • IFN-γ
  • Upregulates anti-inflammatory cytokines like IL-10.

This shift reduces inflammation in both skin and joints, improving clinical outcomes without broad immunosuppression.


Dosage and Titration

DayMorning DoseEvening Dose
Day 110 mg
Day 210 mg10 mg
Day 310 mg20 mg
Day 420 mg20 mg
Day 520 mg30 mg
Day 6 and onward30 mg30 mg
  • Maintenance Dose: 30 mg PO twice daily.
  • No food restrictions; may be taken with or without meals.
  • Tablets should not be crushed or split.

Clinical Evidence (2025 Update)

  • ESTEEM 1 & 2 Trials: Showed significant improvement in Psoriasis Area and Severity Index (PASI-75) scores at week 16 vs placebo.
  • PALACE Trials: Demonstrated sustained improvement in ACR20 responses and physical function in PsA patients over 5 years.
  • RELIEF Study: Confirmed efficacy in reducing oral ulcers in Behçet’s disease, with symptom relief seen as early as week 2.

Common Adverse Effects

  • Gastrointestinal:
    • Diarrhea (17–19%)
    • Nausea (17%)
  • Neurologic:
    • Headache (12%)
  • Others:
    • Upper respiratory tract infection
    • Weight loss
    • Depression and mood disturbances

GI side effects usually occur within the first 2 weeks and typically resolve without discontinuation.


Serious Risks & Precautions

  • Weight Loss:
    • Monitor weight periodically.
    • Discontinue if unexplained weight loss >10% of baseline occurs.
  • Depression & Suicidal Ideation:
    • Screen patients with history of depression.
    • Discontinue if mood worsens.
  • Use in Pregnancy:
    • Category C. Animal studies show teratogenic effects.
    • Use only if potential benefit justifies potential fetal risk.
    • Avoid in women trying to conceive.

Drug Interactions

Strong CYP3A4 inducers may significantly reduce apremilast efficacy. Avoid co-administration with:

  • Carbamazepine
  • Phenytoin
  • Phenobarbital
  • Rifampin
  • St. John’s Wort

Contraindications

  • Known hypersensitivity to apremilast.
  • Severe hepatic impairment (limited data).
  • Children under 18 years (not FDA-approved).
  • Pregnancy and lactation (weigh risk/benefit carefully).

Storage

  • Store at ≤30°C (86°F).
  • Protect from excessive moisture.
  • Keep in original container until ready to use.

Brand Names

  • Otezla® (originator by Amgen)
  • Available globally with generic options in select regions.

Conclusion

Apremilast represents a non-biologic, orally administered immunomodulatory therapy with a favorable safety profile. It offers a biologic-sparing option particularly advantageous for patients in whom injectable therapies are contraindicated or poorly tolerated.

As more long-term data emerge, especially in the context of comorbid populations, apremilast continues to play an important role in the personalized management of chronic inflammatory dermatologic and rheumatologic diseases.


References:

  • Mease PJ, et al. Lancet Rheumatol. 2024;6(3):e148-e158.
  • Papp KA, et al. J Am Acad Dermatol. 2023;89(4):749-758.
  • FDA Label for Otezla (Apremilast) – Revised 2025.
  • ClinicalTrials.gov (NCT04632640, NCT05234868)

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