Apremilast: Oral Treatment for Psoriasis and Related Conditions
Comprehensive guide to apremilast (Otezla), an oral PDE4 inhibitor for psoriasis and Behçet disease.
Apremilast: An Oral Treatment for Psoriasis and Behçet Disease
Apremilast (Otezla®, Celgene) is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4), an enzyme that plays a critical role in chronic inflammation associated with psoriasis and other inflammatory skin conditions. As an oral medication, apremilast offers patients an alternative to injectable biologic therapies and provides a convenient treatment option for moderate-to-severe plaque psoriasis and other inflammatory dermatological conditions.
Introduction and Regulatory Approval
Apremilast represents a significant advancement in oral immunomodulatory therapy for dermatological conditions. The drug was approved by the United States Food and Drug Administration (FDA) in September 2014 for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy. Following its US approval, the European Medicines Agency (EMA) granted marketing authorisation in January 2015, and New Zealand approved the medication for psoriasis in November 2016.
In July 2019, the therapeutic scope of apremilast expanded when the FDA approved its use for treating mouth ulcers associated with Behçet disease, broadening its clinical applications beyond psoriasis to other inflammatory conditions affecting the oral mucosa.
Mechanism of Action
Apremilast functions as a selective phosphodiesterase 4 (PDE4) inhibitor that modulates intracellular inflammatory signaling pathways. The drug works by inhibiting the enzyme PDE4, which normally converts cyclic adenosine monophosphate (cAMP) into adenosine monophosphate (AMP). By blocking this conversion, apremilast causes an intracellular accumulation of cAMP.
This accumulation of cAMP leads to significant anti-inflammatory effects by selectively reducing the production of multiple inflammatory mediators, including:
- CX-CL9 and CX-CL10 (chemokines)
- Interferon-gamma (IFN-γ)
- Tumor necrosis factor-alpha (TNF-α)
- Interleukins (IL-2, IL-8, IL-12, and IL-23)
By decreasing the production of these pro-inflammatory cytokines and chemokines, apremilast reduces the overall inflammatory response associated with psoriasis and other inflammatory skin diseases.
Uses and Clinical Applications
Apremilast is approved and indicated for several dermatological conditions, with well-established efficacy in specific patient populations:
Approved Uses
- Moderate-to-severe plaque psoriasis: In adult patients who are candidates for phototherapy or systemic therapy
- Psoriatic arthritis: For adult patients with moderately to severely active disease
- Behçet disease: Treatment of oral ulcers associated with Behçet disease in adults
Off-Label Uses
Clinical studies and case reports have demonstrated efficacy in several conditions not yet formally approved:
- Palmoplantar psoriasis (affecting palms and soles)
- Scalp psoriasis
- Atopic dermatitis (eczema)
- Alopecia areata (hair loss)
- Hidradenitis suppurativa (chronic inflammatory skin condition)
- Aphthous stomatitis (mouth ulcers)
- Chronic actinic dermatitis
Mixed efficacy has been reported for lichen planus, sarcoidosis, and discoid lupus erythematosus, suggesting variable therapeutic benefit in these conditions.
Dosing and Administration
Apremilast requires a careful 5-day titration schedule to allow patients to reach the therapeutic dose while minimizing gastrointestinal side effects during the initiation phase. The medication is started at a low dose and gradually increased over the first five days until the recommended maintenance dose is achieved.
The standard dosing regimen for psoriasis, psoriatic arthritis, and Behçet disease follows this titration pattern:
- Day 1: Gradual increase from morning to evening
- Days 2-5: Progressive dose escalation to the therapeutic level
- Maintenance: Standard therapeutic dose reached by day 6
Patients should consult approved product datasheets in their country for specific dose schedules, as these represent the official source of information for approved uses, doses, and safety information.
How to Use Apremilast
Apremilast is administered as an oral medication, taken by mouth with or without food. The convenience of oral administration makes it an attractive option for patients seeking to avoid injection-based therapies. Patients should follow the prescribed dosing schedule carefully, particularly during the initial titration phase, to optimize therapeutic benefit and minimize adverse effects.
Regular monitoring by healthcare providers is recommended during treatment initiation to assess tolerability and efficacy. Patients should maintain consistent dosing schedules and report any concerning side effects to their healthcare provider promptly.
Drug Interactions
Like all medications, apremilast has the potential for drug-drug interactions. Patients taking apremilast should inform their healthcare providers of all other medications, supplements, and herbal products they are using. Certain medications may affect apremilast metabolism or efficacy, and some drug combinations may increase the risk of adverse effects. Healthcare providers will review the patient’s complete medication list to identify potential interactions before prescribing apremilast.
Adverse Effects and Safety Profile
Apremilast’s safety was thoroughly evaluated in three randomized, double-blind, placebo-controlled trials (ESTEEM 1 and ESTEEM 2) involving 1,426 adult subjects with moderate-to-severe plaque psoriasis. These landmark trials provided comprehensive safety data and established the medication’s tolerability profile.
Common Adverse Reactions
The following adverse effects were reported in greater than 1% of apremilast-treated subjects with higher frequency than in placebo groups during the initial 16-week treatment period:
| Adverse Effect | Placebo (%) | Apremilast (%) |
|---|---|---|
| Diarrhea | 8 | 20 |
| Nausea | 7 | 17 |
| Upper respiratory tract infection | 6 | 9 |
| Tension headache | 4 | 8 |
| Headache | 4 | 6 |
| Abdominal pain | 2 | 4 |
| Vomiting | 2 | 4 |
| Frequent bowel movements | 0 | 2 |
| Depression | 0 | 1 |
| Bronchitis | 0 | 1 |
Gastrointestinal effects, particularly diarrhea and nausea, represent the most common adverse reactions associated with apremilast use. These effects are often most pronounced during the initial titration phase and frequently improve with continued treatment as patients develop tolerance.
Less Common Adverse Effects
- Migraine
- Sinus headache
- Folliculitis (hair follicle infection)
- Tooth abscess
Depression and Mood Changes
Mental health monitoring is important during apremilast therapy. Although depression was reported in a small percentage of patients, healthcare providers should maintain vigilance for mood changes, depressive symptoms, or suicidal ideation. Patients with a history of depression or psychiatric conditions should discuss this with their healthcare provider before starting apremilast, and they should report any mental health changes during treatment.
Weight Loss
Weight loss has been observed in some patients taking apremilast. The mechanism behind this effect and its clinical significance require ongoing monitoring. Patients should maintain awareness of their weight during treatment and discuss any significant weight changes with their healthcare provider.
Alcohol Consumption
Patients taking apremilast should consider limiting or avoiding alcohol consumption, as combining alcohol with this medication may increase the risk of gastrointestinal side effects or compromise therapeutic efficacy. Healthcare providers should discuss alcohol use with patients and provide specific recommendations based on individual circumstances.
Use in Special Populations
Pregnancy and Nursing Mothers
The safety of apremilast during pregnancy has not been adequately established. Women of childbearing potential should use effective contraception during apremilast therapy and discuss pregnancy planning with their healthcare provider. The medication’s presence in breast milk and potential effects on nursing infants are not fully characterized, making breastfeeding a consideration that requires discussion with healthcare providers.
Paediatric Use
Apremilast has demonstrated efficacy in some pediatric dermatological conditions, including atopic dermatitis and moderate hidradenitis suppurativa in young patients. However, efficacy and safety data in pediatric populations remain limited compared to adult studies. Use in children requires careful consideration and discussion with pediatric dermatologists.
Geriatric Use
Older adults may tolerate apremilast well, though age-related changes in drug metabolism and the presence of comorbid conditions should be considered during treatment planning. Dose adjustments are not routinely required based on age alone, but careful monitoring is recommended.
Renal and Hepatic Impairment
Patients with severe renal or hepatic impairment may require dose adjustments or careful monitoring during apremilast therapy. Healthcare providers should evaluate kidney and liver function before prescribing this medication and during ongoing treatment, particularly in patients with pre-existing renal or hepatic disease.
Allergic Reactions
Although uncommon, allergic reactions to apremilast may occur. Patients with known hypersensitivity to apremilast or any component of the formulation should not receive this medication. Any signs of allergic reaction, including rash, itching, swelling, or difficulty breathing, require immediate medical attention.
Clinical Efficacy Data
The ESTEEM 1 and ESTEEM 2 clinical trials established apremilast’s efficacy in moderate-to-severe plaque psoriasis:
| Measure | ESTEEM 1 Placebo | ESTEEM 1 Apremilast | ESTEEM 2 Placebo | ESTEEM 2 Apremilast |
|---|---|---|---|---|
| Number randomized | 282 | 562 | 137 | 274 |
| PASI 75 Response (%) | 5.3 | 33.1 | 5.8 | 28.8 |
| sPGA Clear/Almost Clear (%) | 3.9 | 21.7 | 4.4 | 20.4 |
These results demonstrate that apremilast achieved significantly higher response rates compared to placebo, with approximately one-third of ESTEEM 1 patients and one-quarter of ESTEEM 2 patients achieving a 75% improvement in their Psoriasis Area and Severity Index (PASI-75) score—a key measure of clinical efficacy in psoriasis treatment.
Comparison with Other Treatments
Evidence suggests apremilast is less effective than biologic agents in treating moderate-to-severe psoriasis. However, as an oral medication with a distinct mechanism of action, apremilast offers advantages including avoidance of injections, convenient oral dosing, and a different side effect profile compared to biologic therapies. Treatment selection should be individualized based on patient factors, disease severity, comorbidities, and preference for oral versus injectable therapy.
Frequently Asked Questions (FAQs)
Q: How long does it take for apremilast to work?
A: Most patients require 8-12 weeks of consistent treatment to assess apremilast’s full efficacy. Some patients may experience improvement sooner, while others may require longer treatment duration. Response varies significantly among individuals.
Q: Can apremilast be used with other psoriasis treatments?
A: Apremilast may be combined with topical treatments and phototherapy. Combining apremilast with systemic treatments or biologics requires careful medical supervision and discussion with your healthcare provider regarding potential interactions and safety.
Q: What should I do if I experience severe gastrointestinal side effects?
A: Contact your healthcare provider immediately. They may adjust your dosing schedule, recommend over-the-counter remedies, or suggest dietary modifications. Severe gastrointestinal symptoms should never be ignored, as they may indicate the need for alternative treatment approaches.
Q: Is apremilast safe for long-term use?
A: Long-term safety data from extended clinical trials supports ongoing apremilast use in appropriate patient populations. However, regular monitoring by healthcare providers is essential to assess continued benefit and identify any emerging safety concerns.
Q: Can I stop apremilast abruptly if I want to become pregnant?
A: No. You should consult your healthcare provider before stopping apremilast or making any changes to your medication regimen during pregnancy planning. Your provider will discuss the risks and benefits specific to your situation and help develop an appropriate treatment plan.
References
- Apremilast – StatPearls — National Center for Biotechnology Information, U.S. National Library of Medicine. 2024. https://www.ncbi.nlm.nih.gov/books/NBK572078/
- Apremilast. Key clinical-trial evidence — DermNet New Zealand. 2015. https://dermnetnz.org/topics/key-clinical-trial-evidence-for-apremilast
- Apremilast in dermatology: A review of literature — David N, Ali A, Jfri A, et al. Dermatologic Therapy. 2020. https://onlinelibrary.wiley.com/doi/abs/10.1111/dth.14261
- Guidelines for the management of psoriasis — DermNet New Zealand. 2023. https://dermnetnz.org/topics/guidelines-for-the-treatment-of-psoriasis
- Psoriasis: Symptoms, Treatment, Images and More — DermNet New Zealand. 2025. https://dermnetnz.org/topics/psoriasis
- FDA Approval History for Apremilast — U.S. Food and Drug Administration. 2014–2019. https://www.fda.gov/
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