Overview: Psoriasis Treatment with Apremilast

Despite the large number of therapeutic agents currently available for psoriasis, patients’ desire for a safe, oral medication — one with fewer side effects than methotrexate — has been elusive. A step in that direction was made with the approval of apremilast (Otezla, Celgene Corporation) for psoriasis and psoriatic arthritis.

Mechanism of Action
Apremilast is a specific inhibitor of phosphodiesterase-4 (PDE4) enzyme. PDE inhibitors should not be unfamiliar. The most widely used drug in humans, caffeine, is a non- specific PDE inhibitor. PDE inhibitors prevent the breakdown of cyclic adenosine monophosphate (AMP), raising intracellular cyclic AMP levels and reducing production of multiple cytokines. Unlike widely used biologics, being a small molecule, apremilast can be taken orally. PDE4 is the critical PDE enzyme in inflammatory cells, and therefore PDE4 inhibitors can be effective as anti-inflammatory drugs with few side effects.
 
Dosing
The standard dosing of apremilast is 30 mg twice a day. In order to improve tolerability and prevent diarrhea with the initiation of treatment, dermatologists can consider introducing the drug gradually (Table 1). Celgene, apremilast’s manufacturer, provides convenient bubble pack aged sample kits that make a gradually increasing starting dose more convenient. In patients with severe renal impairment (creatinine clearance <30 mL/minute), dose adjustment should be considered; starting with 10 mg in the morning on days 1 to 3 and then titrating to 20 mg on days 4 and 5. Maintenance dose with severe renal impairment is 30 mg once daily in the morning starting on day 6. There is no need to reduce the dose in patients with hepatic failure. Using apremilast with CYP450 enzyme inducers (such as rifampin, phenobarbital, carbamazepine and phenytoin) is not recommended, but there are no significant drug–drug interactions with oral contraceptives, ketoconazole or methotrexate.
 
Efficacy
In a Phase III study of apremilast for moderate-to-severe psoriasis, 33.1% of patients achieved 75% reduction in Psoriasis Area and Severity Index (PASI 75) after 16 weeks of treatment. Apremilast’s efficacy is less than that of biologics, less than that of perhaps half the usual dose of etanercept (Enbrel, Amgen Inc.; PASI 75 of ~40%)1
and less than the effectiveness of the usual doses of adalimumab (Humira, AbbVie Inc.) or ustekinumab (Stelara, Janssen Biotech Inc.), which offer PASI 75 rates of about 67% to 70%. Apremilast can be a good therapeutic choice for moderate-to-severe psoriasis for those patients who are willing to consider a medication that seems very safe but which does not result in the great majority of patients having a significantly good response to treatment. It may be a good choice for patients unable to take methotrexate or for patients who did not see satisfying results from methotrexate and who do not wish to begin an injectable biologic treatment. Apremilast’s wholesale price is less than biologics but more than $20,000/year, and that may be a hurdle for some patients.
 
Side Effects
The most common observed distinctive side effect is diarrhea, seen in roughly 8% to 15% of patients. Other side effects include nausea, vomiting, weight loss, headache and upper respiratory tract infection. More rare side effects include gastroesophageal reflux disease, hypersensitivity, migraine and suicidal ideation. In order to decrease the risk of diarrhea and other common side effects, gradual dose increase is recommended. No cases of tuberculosis or lymphoma were reported through week 16. There was no apparent increased risk of serious opportunistic infection. In case of severe side effects, discontinuation of therapy should be considered. Although the side effects are not as severe as the potential side effects of methotrexate, they could have the potential to reduce patients’ adherence. Common side effects of apremilast tend to fade over time and mostly resolve after 15 days of treatment, so efforts should be made to encourage patients to develop a habit of taking this medication through this period and beyond. Due to lack of studies in pregnant women, apremilast is considered Pregnancy Category C. Apremilast should only be used in pregnant or breastfeeding women if the potentialbenefit justifies the potential risk.
 
Monitoring
Weight monitoring is recommended as modest weight loss is seen in some patients (something many patients might consider a benefit of the drug). Discontinuation of therapy should be considered in case of significant weight loss. Renal function should also be assessed. Patients should be monitored for mood changes, depression and suicidal thoughts during therapy (Table 2).
 
Tips and Tricks
1. Use the start-up packs to help minimize the risk of diarrhea. Developing diarrhea late in therapy is unusual.
2. Adherence is usually worse in clinical practice than in clinical studies. That could limit the effectiveness of apremilast, which is not the most effective drug to begin with. Help patients develop a plan to assure good adherence.
3. If patients are worried about the drug, let them know that caffeine is also a PDE inhibitor.
4. Apremilast should only be used in pregnant or breastfeeding women if the potential benefit justifies the potential risk.
5. Some patients may find the possible weight loss side effect to be a positive attribute about the drug.
6. Consider dosage reduction in patients with severe renal impairment (creatinine clearance <30 mL/minute).
7. No laboratory monitoring is required for patients on apremilast.
 
This article is an excerpt from the book, Practical Psoriasis Management. Dr. Moradi Tuchayi is a postdoc fellow at Massachusetts General Hospital in Boston, MA.
 
Disclosure: The author reports no relevant financial relationships.
 
Reference
1. Signorovitch JE, Betts KA, Yan YS, et al. Comparative efficacy of biological treatments for moderate-to-severe psoriasis: a network meta-analysis ad- justing for cross-trial differences in reference arm response. Br J Dermatol. 2015;172(2):504-512