Psoriasis is a disease that has been estimated to affect approximately 3.15%, or 5 million people, in the United States alone (Kurd & Gelfand, 2009). The inflammatory disease is a chronic condition that is often characterized by overproliferation of epidermal keratinocytes that condense into plaques along the skin. Furthermore, approximately 40% of patients with psoriasis go on to develop psoriatic arthritis, affecting the joints and further impairing the patient (Mease & Armstrong, 2014). In addition to the discomfort the plaques cause patients, psoriasis has also been implicated in increasing the risk for other pathologies such as atherosclerosis, myocardial infarctions, and strokes, causing this condition to be of serious concern to healthcare providers (Kurd & Gelfand, 2009).

USES AND MECHANISM

When looking at the biochemistry of the symptoms, phosphodiesterases play a key role in the conversion of cyclic adenosine monophosphate (AMP) into AMP, which mediates inflammatory signaling. Apremilast aims to alleviate psoriatic symptoms by serving as a phosphodiesterase inhibitor, specifically by inhibiting phosphodiesterase 4 (PDE-4) in monocytes, T cells, and neutrophils (Mease & Armstrong, 2014; Papp et al., 2015). This reduction of PDE-4 activity allows for an increase in intracellular cyclic AMP, which downregulates inflammatory signaling in T helper (Th) cells 1 and 17, causes inhibition of tumor necrosis factor alpha and interleukins 10, 17, and 23, and also decreases activity of nitric oxide synthase (Schafer, Chen, Fang, Wang, & Chopra, 2015). Ultimately, this causes a decrease in the number of myeloid dendritic and T cells that enter psoriatic plaques, diminishing the redness, thickness, and scaling of the plaques (Papp et al., 2015).

In addition to being approved by the Food and Drug Administration for treating psoriasis and psoriatic arthritis (Celgene Corporation, 2015), apremilast proved to be effective at reducing mouth ulcers formed in Behcet's syndrome, by the same mechanism detailed above (Hatemi et al., 2015).

DOSAGE

Apremilast is initiated with a 5-day titration outlined in Table 1. This specific method of dosage is used to offset the gastrointestinal issues that apremilast may induce, most notable of which is diarrhea. Because of the specific dosages required per day, apremilast comes in 10-, 20-, and 30-mg oral pills and can be taken without food. It should be noted that, in patients with severe renal issues (defined as a creatinine clearance lower than 30 ml/min), dosage should be restricted to 30 mg, once per day. However, those with only mild to moderate renal impairment are advised to follow the normal protocol (Celgene Corporation, 2015).

Table. No title available.

ADVERSE EFFECTS

Because of the high incidence of PDE-4 in the central nervous system, inhibition of this enzyme via apremilast commonly causes nausea and vomiting. In addition, diarrhea, headaches, upper respiratory tract infections, nasopharyngitis, upper abdominal pain, increased incidence of depression, and other presentations listed in Table 2 are all reported as potential side effects. It is of note that 10% of patients on apremilast were also observed to have a 5%-10% decrease in weight when compared with those on a placebo treatment, which is not reflected in the table below. However, of all the side effects that were documented in this study, only 2 of the 920 patients had serious enough reactions to warrant stopping treatment (Celgene Corporation, 2015), and in a separate study, 96% of patients on apremilast dealing with negative effects described them as being mild to moderate (Papp et al., 2012). In another study, diarrhea was reported as being the most frequent adverse effect of apremilast use; however, in all of those cases, the symptoms resolved without intervention before the trial ended (Kavanaugh et al., 2014).

Table. No title available.

Apremilast is also classified by the Food and Drug Administration as a pregnancy category C drug, meaning that it is not ideal for pregnant patients, but if the benefits outweigh the potential risks, it can still be administered. The only contraindications listed for the drug are for patients who are known to have sensitivity issues with apremilast or to any of its excipients (Celgene Corporation, 2015).

DRUG INTERACTIONS

Apremilast was noted to have decreased efficacy when paired with cytochrome P450 enzyme inducers such as rifampin, phenobarbital, carbamazepine, and phenytoin. Apremilast is also largely metabolized by CYP3A4, but there were no recorded interactions with any other CYP3A4 substrates (Celgene Corporation, 2015).

ALTERNATIVE OPTIONS

The current standard of treatment of psoriasis ranges in a wide variety of approaches. Topical approaches such as corticosteroid creams are the most often prescribed but come with their own risk-benefit ratios and disadvantages. The potency of corticosteroids has been known to cause a wide variety of side effects, from skin atrophy to systemic issues such as Cushing's disease, and as a result, application is often limited to twice daily for 2 consecutive weeks (Menter & Griffiths, 2007). In comparison, apremilast was safely prescribed and used in clinical trials for up to 24 weeks, and so provided a long-term solution for patients (Mease & Armstrong, 2014).

In conjunction with the topical treatments, phototherapy has also been employed to treat psoriasis. Current treatment often entails UVB light therapy two to three times per week and a relatively low side-effect-to-benefit profile, if proper precautions, such as covering the eyes, face, and genitals during treatment, are taken (Menter & Griffiths, 2007). However, although this does serve as an effective treatment for psoriasis, it does not seem to have the same efficacy in treating psoriatic arthritis, which apremilast was also effective at alleviating (Kumar et al., 2013; Mease & Armstrong, 2014).

Of oral alternatives, pills such as methotrexate, acitretin, and cyclosporine are prescribed as systemic treatments. Because of ease of application, these are most often used in patients with physical disabilities and for those who have had insufficient results with steroids and phototherapy. When comparing efficacy, in two separate studies using 16-week Psoriasis Area and Severity Index-75 scores (defined as a 75% reduction in Psoriasis Area and Severity Index score) as their primary end point, 47.5% (Baranauskaite et al., 2012) and 41.9% (Barker et al., 2011) of patients achieved this goal with methotrexate. Comparatively, three different studies on apremilast showed that only 33.1%, 28.1% (Celgene Corporation, 2015), and 31.7% (Hinde, Wade, Palmer, Woolacott, & Spackman, 2016) of patients reached this same end point. However, these alternatives have their downsides as well. Methotrexate, the most commonly used oral alternative, is associated with serious side effects because of its function as an immunosuppressant. Another issue comes with its teratogenic potential, as it is a Class X medication that should not be taken during, or even 3 months before pregnancy, limiting the range of patients who can use it in comparison with those who can take apremilast (Menter & Griffiths, 2007).

Another class of treatments used as alternatives are "biologics," including drugs such as etanercept, infliximab, adalimumab, and ustekinumab. These drugs serve to only partially dampen the immune response to prevent the extensive side effects of other immunosuppressive drugs. Biologics also prove to be a good alternative as they do not contain the teratogenic nature of other options such as methotrexate and so are far less harmful to pregnant patients (Emer, Frankel, & Zeichner, 2010). However, because of their mechanism of action, constant laboratory testing is required, especially to check for active Tuberculosis, a task that is not required with apremilast usage (Janssen Biotech, 2015).

CONCLUSION

New drugs are constantly being produced that give greater autonomy to the patients, and apremilast serves as that new potential therapy for psoriasis. Functioning as a phosphodiesterase inhibitor, it is able to effectively decrease the inflammatory properties of psoriatic plaques, treat psoriatic arthritis, and alleviate oral ulcers in Behcet's syndrome. Its ability to be taken orally, as well as its lower potency, allows Apremilast to be a safer, longer lasting alternative to current methods and shows great promise in becoming the new standard of care for patients with psoriasis.

REFERENCES