|Year : 2019 | Volume
| Issue : 1 | Page : 1-12
Apremilast in psoriasis and beyond: Big hopes on a small molecule
TP Afra1, T Muhammed Razmi1, Sunil Dogra2
1 Department of Dermatology, IQRAA International Hospital and Research Centre, Calicut, Kerala, India
2 Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||14-Jan-2019|
Department of Dermatology, Venereology and Leprology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Apremilast, an orally administered small molecule inhibitor of phosphodiesterase 4 (PDE4), has been licensed by the US Food and Drug Administration for the management of active psoriatic arthritis (March 21, 2014) and moderate to severe plaque psoriasis (September 23, 2014). It has got approval from Drug Controller General of India for marketing in India in 2017. The drug has drawn much attention from the practising dermatologists for its commendable safety profile and prescription convenience. Introduced initially as an orally administered small molecule in psoriasis patients, the drug has now been used in various other indications as evident by the recent surge in literature for its off-label uses. Being a relatively new drug in the treatment armamentarium of psoriasis and other inflammatory dermatoses; in this review, we will discuss various practical aspects of prescribing oral apremilast, based on the current and emerging literature.
Keywords: Apremilast, efficacy, psoriasis, psoriatic arthritis, safety, small molecules
|How to cite this article:|
Afra T P, Razmi T M, Dogra S. Apremilast in psoriasis and beyond: Big hopes on a small molecule. Indian Dermatol Online J 2019;10:1-12
|How to cite this URL:|
Afra T P, Razmi T M, Dogra S. Apremilast in psoriasis and beyond: Big hopes on a small molecule. Indian Dermatol Online J [serial online] 2019 [cited 2021 Feb 26];10:1-12. Available from: https://www.idoj.in/text.asp?2019/10/1/1/250077
Psoriasis is a chronic inflammatory dermatosis with a waxing and waning course. The management of psoriasis has witnessed a tremendous change over the last 1 decade paving ways to the newer biological agents. While the common systemic agents, such as methotrexate, acitretin, and cyclosporine are associated with end-organ toxicities and treatment-related side effects, the biological agents have the limitations of added costs to the care and inconvenient mode of administration apart from the possibility of iatrogenic immunosuppression. In this background, an agent that is less toxic, cost-effective, convenient to prescribe, and having optimal efficacy is always welcomed by the patients and dermatologists. Apremilast (Otezla; Celgene) was approved by the US Food and Drug Administration (FDA) on March 21, 2014, for the management of active psoriatic arthritis (PsA) in adults. Soon, on September 23, 2014, FDA approved apremilast for treating patients of moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. It has got marketing approval from Drug Controller General of India in 2017. However, there is a paucity of information on apremilast in the Indian literature. Moreover, the existing literature is more focused on its usefulness in PsA. In this review, we would like to comprehensively yet concisely discuss the various clinical aspects of apremilast use in psoriasis and PsA and briefly narrate experience of its use in various inflammatory dermatoses.
| Apremilast, the Versatile Small Molecule|| |
Small molecules are a novel group of agents with a low molecular weight (<1 kD) which act via the modulation of proinflammatory cytokines. They are emerging as therapeutic options in inflammatory dermatosis and other systemic inflammatory conditions owing to their ease of administration through oral or topical route with acceptable efficacy and excellent safety profile. Unlike biologic agents, small molecule drugs are relatively easy to synthesize and less expensive to be produced. Salient differences between small molecules and biological agents have been highlighted in [Table 1].
|Table 1: Salient differences between small molecules and biological agents|
Click here to view
Recently, there is a surge in newer small molecules being licensed for dermatological conditions and also the preexisting small molecules are being explored for newer indications [Table 2]. Of these, apremilast has gained major attention from the practising dermatologists for its versatile use in psoriasis and other inflammatory skin conditions. A thorough knowledge about this drug may benefit the clinicians to tailor their treatment regimen for optimizing the efficacy and tolerability.
| Pharmacology|| |
Phosphodiesterase (PDE) 4 has a role in immune regulation by degrading cyclic adenosine monophosphate (cAMP), a key second messenger. Apremilast suppresses intracellular PDE-4 causing accumulation of cAMP within the cell which modifies the downstream signalling pathways in cells of the innate (e.g., monocytes) and adaptive (e.g., T cells) immune system and nonimmune cells (e.g., keratinocytes, synovial fibroblasts). As a result of PDE-4 inhibition, the levels of proinflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin (IL)-23 decrease and those of anti-inflammatory mediators like IL-10 increase.
The absolute bioavailability of apremilast is around 73%. Its concentration in the plasma peaks (Cmax) in a median of around 2.5 hours; food intake does not affect its clinical activity. Apremilast is metabolized extensively by both CYP-mediated (mainly CYP3A4) oxidative mechanisms (followed by glucuronidation) as well as non-CYP mediated hydrolysis. Hence, serum levels and the efficacy may be decreased by coadministering with the potent CYP enzyme activators like rifampicin, carbamazepine, phenytoin, and barbiturates.
Mild to moderate renal dysfunction or moderate to severe hepatic dysfunction do not change the pharmacokinetics of apremilast to a significant level clinically. However, dose reduction is recommended in those with severe renal dysfunction.
| Dosage and Formulations|| |
The recommended dose of apremilast in adults for psoriasis and psoriatic arthritis is 30 mg twice daily taken orally. The treatment is started with 10 mg morning dose with a daily increment of 10 mg until day 6 when the recommended dose (30 mg bid) for adults is reached which is continued at the same dose thereafter [Table 3]. Such a dose titration minimizes the gastrointestinal side effects. Tablets of 10 and 20 mg in addition to 30 mg are launched in Indian market in 2018. The tablet should be taken as a whole and not to be crushed or cut. A new nail lacquer formulation for nail psoriasis has also been developed, though not yet available commercially.
| Clinical Uses|| |
Licensed uses of apremilast include management of moderate to severe plaque psoriasis and active PsA not responding adequately to disease-modifying antirheumatic drugs (DMARDs). The drug has been extensively studied for these two indications. However, recently, it is tried for many other indications where there is a role for cAMP-mediated anti-inflammatory action [Table 4].
| Psoriasis|| |
The efficacy and safety of apremilast were established through well-conducted clinical trials which showed superior efficacy over placebo. Unlike the clinical trials that followed strict protocols in patient follow-up and treatment plan, the real world data have revealed even better efficacy with the achievement of Psoriasis Area and Severity Index (PASI)-75 in half of the studied population, (c.f one-third in ESTEEM trials). Apremilast was also found to improve psoriasis at difficult sites like palmoplantar, nails, and scalp. It also significantly improved the pruritus and patient quality of life. The outcome of various studies addressing its efficacy as monotherapy in psoriasis is outlined in [Table 5]. Evidence from various clinical studies has established the efficacy of apremilast monotherapy irrespective of previous exposure to the systemic agents.,,, However, in a matching-adjusted indirect comparison of data from pooled trials, efficacy of apremilast was found to be inferior to calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam, (30.4% vs. 52.7%; P < 0.001). However, 4 weeks of Cal/BD foam has also shown superior efficacy over 12 weeks of methotrexate, or acitretin.
Combination therapy [Table 6].: In a long-term study, efficacy and safety of single drug and multidrug treatment (methotrexate, etanercept, and ustekinumab) with apremilast in psoriasis was analyzed and was found that treatment response at 52 weeks was maintained in similar proportions of patients in both the groups (monotherapy, 66.7%; combination therapy, 63.0%; P = 0.787). Proportions of adverse effects were also comparable between the groups (single drug, 14.3%; multidrug, 22.2%; P = 0.484). Safety was not compromised on combining apremilast with other biologic agents in the management of psoriasis and PsA. A retrospective study by Mayba and Gooderham has reported a better drug survival of apremilast in their patients who were also on other systemic agents (16%), compared to poor drug survival reported in apremilast monotherapy (49%, 65%). Hence, combining other systemic agents with apremilast may increase the treatment adherence of patients; however, additional therapeutic benefits in terms of efficacy or tolerability is subject of further research.
| Psoriatic Arthritis|| |
The PALACE 1, 2, and 3 clinical trials assessed apremilast in PsA patients who had previous treatment with conventional synthetic DMARDs (csDMARDs) and/or biologicals along with or without csDMARD.,, PALACE 4 trial was done to analyze apremilast single-drug therapy in csDMARD and biological-naïve populations. ACTIVE trial analyzed the effects of apremilast alone in patients of PsA who had no prior exposure to biologicals but had one csDMARD. Apremilast (30 mg twice daily) use resulted in improvement of clinical features of psoriatic arthritis in both DMARD exposed and nonexposed patients. Around 30% in both the groups have achieved American College of Rheumatology (ACR) response criteria, ACR20 by week 16 compared to around 15% improvement with placebo. Health Assessment Questionnaire Disability Index score has also improved with apremilast compared to placebo. Regarding other indices like ACR50 or ACR70, no significant differences between apremilast vs. placebo group were noted in PALACE trials except in PALACE1 (ACR50 and ACR70) and PALACE4 (ACR50).,,, The ACTIVE trial has demonstrated early onset of action (at week 2) and sustained efficacy of apremilast at 52 weeks in biological-naïve patients with PsA. Enthesitis, dactylitis, physical function, and fatigue were also improved in these trials, and a long-term sustained efficacy was also noted. A recent analysis of the pooled data from PALACE 1-3 trials has demonstrated efficacy of apremilast in improving enthesitis and dactylitis up to 3 years. In a real world study, Ceccarelli et al. have ultrasonographically documented a prompt improvement (within 45 days) in joint inflammatory status with apremilast.
| Adverse Effects and Their Management|| |
Even though apremilast is a well-tolerated drug with a favourable safety profile, its use can cause some adverse events which can be troublesome to the patients leading to noncompliance and withdrawal from the treatment if not addressed timely. The adverse events reported most commonly (≥5% of patients) at its recommended dose in the clinical trials (ESTEEM 1 and 2, PALACE, LIBERATE, ACTIVE, Ohtsuki et al.) as well as real-world postmarketing surveillance were diarrhea, headache, nausea, nasopharyngitis, and upper respiratory tract infections.,,,,, The rates of these adverse events were more during the initial stages of therapy and most of them self-resolved over time. Other less common side effects were depression, suicidal tendency, and weight loss. Adverse events were found to be less common in real-world patients in comparison to clinical trials. Although the product monograph warns against depression, its incidence was not shown to increase in long-term safety analysis. Weight loss was noticed more in patients with higher baseline body mass index and in the first year of treatment and did not result in any clinical sequelae. Serious adverse events reported rarely were major adverse cardiac events, chronic obstructive pulmonary disease, renal calculi, and urinary tract infection. Rare side effects include diverticulitis, hyperpigmentation, postinflammatory lentiginosis, purpura annularis telangiectodes of Majocchi, persistent epiphora, and fanconi syndrome.,,,,, Apremilast is an anti-inflammatory drug and does not cause immunosuppression. Laboratory parameters also did not show any clinically meaningful changes with apremilast treatment. Apremilast did not show any organ-specific or cumulative toxicity. There was no increased risk of infections; opportunistic or reactivation of latent infections, induction of malignancy or other serious adverse events according to the studies on apremilast reported so far. Recurrence of melanoma was noted in a patient with a history of two previous melanomas with nodal metastasis after starting apremilast for psoriasis.
| Diarrhea|| |
- It is the most common adverse event associated with apremilast treatment. Most cases are reported within the first 2 weeks of treatment and are self-resolving within 1 month even with ongoing apremilast. It is of secretory type due to the activation of chloride channels on enterocytes resulting from increased cAMP
- Supportive measures like maintenance of adequate hydration and avoidance of exacerbating factors like over satiety and bloating, dairy products, caffeine, and artificial sweeteners will control most of the episodes. Intractable diarrhea may necessitate pharmacological intervention with bulk-forming agents, bismuth subsalicylate, short-term loperamide, dose reduction, or even treatment discontinuation.
PDE inhibition at the chemoreceptor trigger zone and central neurokinin receptors causes nausea. It is the most common AE, next to diarrhea. It can be managed adequately with supportive measures as for diarrhea. Other treatment options include anticholinergic antihistamines (diphenhydramine, dimenhydrinate, promethazine), ondansetron, prochlorperazine, and amitryptilline.
Recent real world data on apremilast report headache as one of the common adverse events. Ensuring adequate hydration and sleep along with avoidance of stress and other trigger factors are firstline in the management of headache. Nonsteroidal anti- inflammatory drugs (NSAIDs) can be added if needed.
Nasopharyngitis and Upper respiratory tract infections
Supportive measures like hydration, adequate sleep, avoidance of irritants, use of over the counter agents like nasal saline irrigation, antihistamines, and decongestants are useful in controlling upper respiratory tract symptoms. Antibiotics can be used in proven infections.
| Safety, Tolerability, and Drug Survival|| |
Apremilast has been established as a safe and tolerable drug through various clinical trials and real-world studies. In a pooled safety analysis of two-phase 3 randomized controlled trials (RCTs, ESTEEM 1 and 2), adverse events resulted in the withdrawal of therapy only in 11.2% of patients. In a retrospective study, though diarrhea was the adverse event recorded in a higher number of patients, the presence of a headache was the adverse event responsible for most of the apremilast discontinuation. Although the adverse events were lesser in real-world settings (57.2% vs. 66.4%, P < 0.05), the proportion of adverse events leading to reduced tolerance and withdrawal was more (18.8% compared to 5.3%, P < 0.001) in comparison to clinical trials. It may be due to the more frequent clinic visits in clinical trials with possible attendance of patient queries which have resulted in increased tolerance and also the psoriasis being of the more refractory type in real-world patients. However, the studies on real-world patients are based on retrospective data and do not include active elicitation of adverse events.
In a real-world retrospective study with endpoint at 16 weeks of apremilast treatment, 12% of study subjects discontinued the treatment during the initial 4 weeks due to adverse events (mostly gastrointestinal), and another 16% discontinued later owing to decreased efficacy. In a recent systematic review and network meta-analysis of long-term PASI response of newer biologicals and small molecules, etanercept and apremilast were found to have a lowest expected efficacy. In our personal experience, it was found that the patients respond to apremilast quite satisfactorily during the initial period. But, often we need to add other systemic agents or shifting back to the conventional agents after some time due to reduced efficacy. In this context, we would like to discuss some long-term drug survival studies on apremilast. Lee et al. have reported a failure rate of 49% after a median duration of 146 days of treatment. In another study, a failure rate of 65% was noted after a median duration of 200 days. Hence, it appears that around half of the patients discontinue apremilast treatment within 6–8 months due to various reasons including lack of efficacy.
| Cost Analysis|| |
To date, there are no direct comparative studies between apremilast or any other antipsoriatic medication. In an indirect comparative study on cost-effectiveness of apremilast over methotrexate, Armstrong et al. have concluded that incremental cost per PASI-75 with apremilast was very high with no added benefit in terms of efficacy. The additional cost for apremilast over methotrexate for each PASI responder per year was $188,000, which would come around $160,000 if additional costs that would incur for the total monitoring and toxicity costs associated with methotrexate was included. National Institute for Health and Care Excellence (NICE) has evaluated the clinical efficacy and cost efficacy of apremilast in two patient groups with moderate to severe plaque psoriasis (PASI >10 and a Dermatology Life Quality Index (DLQI) ≥10 vs. PASI <10 and a DLQI ≤10) as a part of its single technology appraisal process. In the first group with severe psoriasis, the company has claimed apremilast to be an additional line of management before starting biologicals and as a safe drug in the second group to whom the biological agents are not indicated at present. The evidence review group of this committee was highly critical of the company's claim on cost-effectiveness of the drug (e.g.,: a recently published study funded by the company has shown a similar adherence and lower total healthcare costs with apremilast vs. biologic users), and concluded that the most probable incremental cost-effectiveness ratio for PASI >10 and a DLQI ≥10 group was about ≤30,300 per quality-adjusted-life-year (QALY), and this was higher than the threshold level normally regarded as cost-effective. The similar value for the second group (DLQI ≤10) would be double considering the otherwise less expenditure that would incur in this group with less severe disease. In the context of PsA, according to NICE Appraisal Committee, cost savings obtained on addition of apremilast were not sufficient to make up for the lost clinical effectiveness as QALY was also decreased with apremilast.
A recent systematic review on the cost-effectiveness of biologicals and small molecules in psoriasis concluded that adalimumab as the most cost-effective agent (100% of all aggregated pairwise comparisons), followed by ustekinumab (66.7%) and infliximab (60%). However, the same review has pointed to the conclusions of emerging literature favoring secukinumab (75%) and apremilast (60%). Hence, further pharmacoeconomic analysis regarding the cost-effectiveness of apremilast should be done in the context of superior efficacy reported with apremilast in the real world scenario in comparison to clinical trials.
- Geriatrics (≥65 years of age): Geriatric population may have a more chance of developing common gastrointestinal complications with efficacy similar to as in younger adult patients. So, apremilast should be used cautiously in them. Geriatric patients comprised 10% and 9% of the total study population in PALACE and ESTEEM trials respectively and the efficacy and safety in them were similar to that in the younger population
- Pediatric age group (<18 years of age): The safety and efficacy of apremilast in children have not been studied. Product monograph does not recommend its use in children. However, a case of atopic dermatitis in an 8-year-old boy successfully treated with apremilast (30 mg OD) has been reported. Smith has reported successful use of oral apremilast as a monotherapy in a 14-year-old boy with chronic plaque psoriasis not responding well to topical therapy. Despite the use of adult dose (30 mg BD), no gastrointestinal or other side effects were reported. Currently, a phase 2, multicenter, open-label trial is being conducted in children with psoriasis of age group 6–17 years
- Pregnant Women: Apremilast is contraindicated during pregnancy and in women planning to conceive since it has not been studied in them. FDA places it in pregnancy category C drugs. Direction should be given to stop apremilast at least 2 days before conception
- Lactating Women: Animal studies have shown the presence of apremilast in breast milk. Hence, it is contraindicated in lactating females, considering the lack of human studies
- Renal Impairment: Dose modifications needed in those with severe renal impairment, (creatinine clearance of less than 30 mL per minute). During the initial dose titration, the evening dose is skipped and after 1 week, it is continued at 30 mg once daily dose
- Hepatic Impairment: No dosage adjustment is needed
- Immunosuppression: Apremilast does not target any specific cytokine, but restores a balance of proinflammatory and anti-inflammatory milieu. In a pooled safety analysis of apremilast in patients with psoriasis from two phase 3, RCTs (ESTEEM 1 and 2), there was no increased risk of opportunistic or latent infections like tuberculosis; even though the patients with history of tuberculosis were included in the study. Apremilast was used successfully in a psoriatic patient infected with HIV and hepatitis C. It has also improved psoriatic onychopathy in an HIV-infected patient with severe psoriasis
Since there are no adequate and well-controlled studies of apremilast in patients suffering from severe immunosuppression, severe acute infectious diseases and those on immunosuppressive medicines, an extra care is needed while using it in such subjects. The product monograph states that apremilast is not indicated in combination with potent immunosuppressants like biologicals and cyclosporine. However, recent studies on combination treatments with apremilast did not find any serious adverse outcome with such a combination
- Missed Dose: Take the next dose at theregular time without increasing the dose
- Overdosage: Immediate medical help should be sought and the patient should be managed symptomatically with supportive care.
| Evaluation and Laboratory Monitoring|| |
Body weight should be recorded prior to the initiation of treatment and monitored regularly. Extensive laboratory evaluation and monitoring prior to initiation or while on apremilast treatment is not needed as laboratory variables did not show any meaningful changes in the trials of apremilast. However, pretreatment assessment of renal function is recommended and the dose of apremilast has to be modified in severe renal impairment. Apart from this, the S3 guidelines recommend evaluation of liver enzymes at baseline since there is no long-term experience on the use of apremilast in people with hepatic impairment. Even though the apremilast product monograph does not recommend laboratory monitoring, the S3 guidelines recommend baseline and 3 monthly monitoring of complete hemogram, liver enzymes, and serum creatinine.
| Impact on Metabolic Profile|| |
Apremilast has shown a good metabolic profile in the clinical trials with no significant alterations in laboratory parameters. Apremilast has a neutral impact on atherogenic dyslipidemia, arterial hypertension, obesity, and glucose intolerance unlike cyclosporine or acitretin which may worsen any of these components of metabolic syndrome. Weight loss in the range of 5–10% has been reported in 14.3% of cases and >10% in 5.7% of cases. However, the mean decrease in weight was around 2 kg at 52 weeks follow-up.
| Position in the Treatment Landscape of Psoriasis: Recommendations and Practical Aspects|| |
Recent S3 guidelines on the management of psoriasis recommends apremilast as a second line option if the first-line systemic agents (methotrexate, acitretin, cyclosporine, fumaric acid esters, and phototherapy) fail, are contraindicated or are found to be intolerant. It is indicated for severe disease as defined by a PASI or DLQI score ≥10. NICE recommends stopping apremilast if an adequate response is not attained by 16 weeks. An adequate response is defined as attainment of PASI 75 or PASI 50 with a 5-point reduction in DLQI. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) while strongly recommend csDMARDs and biological DMARDs (bDMARDs) in DMARD naïve patients with peripheral arthritis, recommend apremilast in this setting conditionally. GRAPPA guidelines also strongly recommend bDMARDs and apremilast in patients with peripheral arthritis with an inadequate response to csDMARDs. In patients with psoriatic arthritis and associated plaque psoriasis, GRAPPA strongly recommend csDMARDs, bDMARDs, and apremilast.
Authors have observed a good safety profile with apremilast except for transient gastrointestinal discomfort and headache during the initial few weeks. Appropriate pretreatment counseling regarding the transient nature of these side effects and general measures to decrease gastrointestinal intolerance as discussed above (see adverse effects section) possibly assures compliance. A proactive approach of starting antacid and antiemetic during dose escalation itself may minimize nausea and vomiting symptoms in patients and increase the drug compliance and tolerability. In patients experiencing disturbing gastrointestinal side effects, dose escalation can be completed in 13 days instead of 6 days with single dose at night (off-label). However, in spite of all the measures, a small proportion of patients are unable to tolerate and continue apremilast in dose escalation phase itself. Authors have observed reasonable maintenance of efficacy with apremilast 30 mg once a day or 60 and 30 mg alternate days after their initial disease control in those adult patients who find difficult to tolerate 60 mg/day. It is a plausible treatment option for moderate to severe stable psoriasis (PASI 3-10) with relatively smaller thin plaques along with topical therapy. A recent study documented improvement in ultrasonic evidence of joint inflammation in PsA at half the recommended dose of apremilast. Apremilast has a moderate efficacy in chronic plaque psoriasis, with improvement of lesions at special sites like scalp, palms, and soles. It may also have a pertinent therapeutic role in patients where palmoplantar eczemas and psoriasis are diagnostic dilemma. Though literature supports beneficial role of apremilast in nail psoriasis,, it needs to be substantiated in larger studies. Apremilast is a safe option for patients with immunosuppression as in those affected with HIV. It can be used in scenarios where other systemic agents are contraindicated or not desired as in hepatic impairment, cardiac diseases, metabolic diseases like diabetes mellitus, hypertension, or hyperlipidemia, doubtful posttreatment laboratory monitoring, etc. While biologic agents like etanercept or secukinumab may exacerbate or induce inflammatory bowel disease, apremilast is envisaged to decrease bowel inflammation. Preliminary findings from an ongoing clinical trial report an improvement in ulcerative colitis symptoms and signs with apremilast. Apremilast can be a better option than acitretin to use in women with childbearing potential since the contraceptive advice for a long duration is not necessary. It can also be used as a bridging or maintenance therapy after induction with a systemic agent like cyclosporine or methotrexate in individuals with frequent flares. In resource-poor settings, this low cost, moderately effective molecule with limited need of laboratory monitoring can be strategically used as an adjunctive or rotational therapy along with biologics and conventional systemic treatments for psoriasis minimizing the cost of treatment, side effects, and optimizing the outcome. In 2015, Otezla (apremilast, Celgene Corporation, USA) managed to earn revenues of about $471.7 million, the highest earned by any immunology and inflammation drug in the first full year of launch. Full-year sales in 2017 were $1,279 million, an increase of 26% year-over-year. The sales were primarily driven by volume gains in the U.S. and strong uptake in key international markets like Europe and Japan. Due to its novel mechanism of action, availability of oral dosage form and acceptable safety profile, apremilast has become fast growing molecule in psoriasis therapeutics in Indian drug market in a short span of 1 year.
| Conclusion|| |
In summary, apremilast is reasonably efficacious in psoriasis and PsA with potential clinical use in other inflammatory conditions. Good safety profile, ease of oral administration without a need for screening or ongoing laboratory monitoring makes it a well-sought drug among dermatologists. However, a low drug survival beyond 6–8 months as reported in recent real-world studies and a critical observation on cost-effectiveness by NICE experts necessitate a considered thought on its long-term use as a maintenance therapy. Availability of newer formulations as 10 and 20 mg widens the scope of its use in dose titrations in various settings. Apremilast is a molecule with limited experience among dermatologists and near future will witness its more comprehensive application in psoriasis, PsA, and various inflammatory dermatoses. PDE4 inhibitors with better patient tolerability and more specific mechanism of action in psoriasis and inflammatory dermatoses should be a focus of immediate research. Its safety and efficacy in pediatric age group is also an important area for further exploration.
T.P.A. and M.R.T.: Acquisition of data, design of paper, writing the manuscript, final approval of article. S.D.: Concept and design of paper, critical revision, and intellectual input and final approval of article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Fala L. Otezla (Apremilast), an oral PDE-4 inhibitor, receives FDA approval for the treatment of patients with active psoriatic arthritis and plaque psoriasis. Am Health Drug Benefits 2015;8:105-10.
Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012;83:1583-90.
Kushwaha AS, Repka MA, Narasimha Murthy S. A novel apremilast nail lacquer formulation for the treatment of nail psoriasis. AAPS PharmSciTech 2017;18:2949-56.
Papadavid E, Rompoti N, Theodoropoulos K, Kokkalis G, Rigopoulos D. Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol 2018;32:1173-9.
Wong TH, Sinclair S, Smith B, Fraser C, Morton CA. Real-world, single-centre experience of apremilast for the treatment of moderate to severe psoriasis. Clin Exp Dermatol 2017;42:675-6.
Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz U, Ferrandiz C, et al.
Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: A phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol 2015;173:1387-99.
Reich K, Gooderham M, Green L, Bewley A, Zhang Z, Khanskaya I, et al.
The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol 2017;31:507-17.
Armstrong A, Levi E. Real-world clinical experience with apremilast in a large US retrospective cohort study of patients with moderate to severe plaque psoriasis. J Drugs Dermatol 2017;16:1240-5.
Bewley A, Shear NH, Calzavara-Pinton PG, Hansen JB, Nyeland ME, Signorovitch J. Calcipotriol plus betamethasone dipropionate aerosol foam versus apremilast, methotrexate, acitretin, or fumaric acid esters for the treatment of plaque psoriasis: A matching-adjusted indirect comparison. J Eur Acad Dermatol Venereol 2018. doi: 10.1111/jdv. 15369.
Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J. Maintenance of therapeutic response after 1 year of apremilast combination therapy compared with monotherapy for the treatment of plaque psoriasis: A multicenter, retrospective study. J Am Acad Dermatol 2018;79:953-6.
Metyas S, Tomassian C, Messiah R, Gettas T, Chen C, Quismorio A. Combination therapy of apremilast and biologic agent as a safe option of psoriatic arthritis and psoriasis. Curr Rheumatol Rev 2018. doi: 10.2174/1573397115666181130094455.
Mayba JN, Gooderham MJ. Real-world experience with apremilast in treating psoriasis. J Cutan Med Surg 2017;21:145-51.
Lee EB, Amin M, Wu JJ. Drug survival of apremilast in patients treated for psoriasis in a real-world setting. J Am Acad Dermatol 2018;79:760-1.
Santos-Juanes J, Velasco L, Munguia-Calzada P, Lozano A, Gomez-Diez S. Comment on “Drug survival of apremilast for psoriasis in a real-world setting”. J Am Acad Dermatol 2018;79:e83-4.
Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, et al.
Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol 2015;42:479-88.
Cutolo M, Myerson GE, Fleischmann RM, Liote F, Diaz-Gonzalez F, Van den Bosch F, et al.
APhase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: Results of the PALACE 2 trial. J Rheumatol 2016;43:1724-34.
Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion J, et al.
Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: A phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis 2016;75:1065-73.
Wells AF, Edwards CJ, Kivitz AJ, Bird P, Nguyen D, Paris M, et al.
Apremilast monotherapy in DMARD-naive psoriatic arthritis patients: Results of the randomized, placebo-controlled PALACE 4 trial. Rheumatology (Oxford) 2018. doi: 10.1093/rheumatology/key032.
Nash P, Ohson K, Walsh J, Delev N, Nguyen D, Teng L, et al.
Early and sustained efficacy with apremilast monotherapy in biological-naive patients with psoriatic arthritis: A phase IIIB, randomised controlled trial (ACTIVE). Ann Rheum Dis 2018;77:690-8.
Gladman DD, Kavanaugh A, Gomez-Reino JJ, Wollenhaupt J, Cutolo M, Schett G, et al.
Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: A pooled analysis of the PALACE 1-3 studies. RMD Open 2018;4:e000669.
Ceccarelli F, Lucchetti R, Spinelli FR, Perricone C, Truglia S, Miranda F, et al.
Early response to apremilast treatment in psoriatic arthritis: A real-life ultrasonographic follow-up study. Rheumatology (Oxford) 2018;57:1490-1.
Crowley J, Thaci D, Joly P, Peris K, Papp KA, Goncalves J, et al.
Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol 2017;77:310-7.e1.
Ohtsuki M, Okubo Y, Komine M, Imafuku S, Day RM, Chen P, et al.
Apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of Japanese patients with moderate to severe plaque psoriasis: Efficacy, safety and tolerability results from a phase 2b randomized controlled trial. J Dermatol 2017;44:873-84.
Ighani A, Georgakopoulos JR, Shear NH, Walsh S, Yeung J. Short-term reasons for withdrawal and adverse events associated with apremilast therapy for psoriasis in real-world practice compared with in clinical trials: A multicenter retrospective study. J Am Acad Dermatol 2018;78:801-3.
Lee EB, Amin M, Egeberg A. Adverse events associated with apremilast use and withdrawal for psoriasis in a real-world setting. J Eur Acad Dermatol Venereol 2018;32:e393-4.
Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol 2012;148:890-7.
Abrouk M, Farahnik B, Zhu TH, Nakamura M, Singh R, Lee K, et al.
Apremilast treatment of atopic dermatitis and other chronic eczematous dermatoses. J Am Acad Dermatol 2017;77:177-80.
Saporito RC, Cohen DJ. Apremilast use for moderate-to-severe atopic dermatitis in pediatric patients. Case Rep Dermatol 2016;8:179-84.
Mikhaylov D, Pavel A, Yao C, Kimmel G, Nia J, Hashim P, et al.
Arandomized placebo-controlled single-center pilot study of the safety and efficacy of apremilast in subjects with moderate-to-severe alopecia areata. Arch Dermatol Res 2018. doi: 10.1007/s00403-018-1876-y.
Liu LY, King BA. Lack of efficacy of apremilast in 9 patients with severe alopecia areata. J Am Acad Dermatol 2017;77:773-4.
Magdaleno-Tapial J, Valenzuela-Onate C, Sanchez-Carazo JL, Alegre-de Miquel V. Improvement of alopecia areata with apremilast. Australas J Dermatol 2018. doi: 10.1111/ajd. 12934.
Keren A, Shemer A, Ullmann Y, Paus R, Gilhar A. The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo
. J Dermatol Sci 2015;77:74-6.
Schibler F, Heidemeyer K, Klotgen HW, Keshavamurthy V, Yawalkar N. Apremilast for treatment of recalcitrant aphthous stomatitis. JAAD Case Rep 2017;3:410-1.
Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Turgut Ozturk B, Mat C, et al.
Apremilast for Behcet's syndrome--a phase 2, placebo-controlled study. N Engl J Med 2015;372:1510-8.
Abboud JJ, Whittington A, Ahmed M, Himebaugh JT, Wiley LA, Haffar A, et al.
Apremilast use in a case of cicatricial ectropion secondary to severe lamellar ichthyosis. Ophthalmic Plast Reconstr Surg 2018;34:e76-e7.
Castela E, Tulic MK, Rozieres A, Bourrat E, Nicolas JF, Kanitakis J, et al.
Epidermolysis bullosa simplex generalized severe induces a Th17 response and is improved by Apremilast treatment. Br J Dermatol 2018. doi: 10.1111/bjd. 16897.
Chen T, Levitt J, Geller L. Apremilast for treatment of recurrent erythema multiforme. Dermatol Online J 2017;23. pii: 13030/qt15s432gx.
Vossen A, van Doorn MBA, van der Zee HH, Prens EP. Apremilast for moderate hidradenitis suppurativa: Results of a randomized controlled trial. J Am Acad Dermatol 2018. doi: 10.1016/j.jaad. 2018.06.046.
Weber P, Seyed Jafari SM, Yawalkar N, Hunger RE. Apremilast in the treatment of moderate to severe hidradenitis suppurativa: A case series of 9 patients. J Am Acad Dermatol 2017;76:1189-91.
Paul J, Foss CE, Hirano SA, Cunningham TD, Pariser DM. An open-label pilot study of apremilast for the treatment of moderate to severe lichen planus: A case series. J Am Acad Dermatol 2013;68:255-61.
Eto A, Nakao M, Furue M. Three cases of palmoplantar pustulosis successfully treated with apremilast. J Dermatol 2018. doi: 10.1111/1346-8138.14516.
Haebich G, Kalavala M. Successful treatment of refractory palmoplantar pustulosis with apremilast. Clin Exp Dermatol 2017. doi: 10.1111/ced. 13065.
Laird ME, Tong LX, Lo Sicco KI, Kim RH, Meehan SA, Franks AG, Jr. Novel use of apremilast for adjunctive treatment of recalcitrant pyoderma gangrenosum. JAAD Case Rep 2017;3:228-9.
Pellonnet L, Beltzung F, Franck F, Rouanet J, D'Incan M. A case of severe pityriasis rubra pilaris with a dramatic response to apremilast. Eur J Dermatol 2018;28:128-9.
Krase IZ, Cavanaugh K, Curiel-Lewandrowski C. Treatment of refractory pityriasis rubra pilaris with novel Phosphodiesterase 4 (PDE4) inhibitor apremilast. JAMA Dermatol 2016;152:348-50.
Jeon C, Nakamura M, Sekhon S, Yan D, Wu JJ, Liao W, et al.
Generalized pustular psoriasis treated with apremilast in a patient with multiple medical comorbidities. JAAD Case Rep 2017;3:495-7.
Thompson BJ, Furniss M, Zhao W, Chakraborty B, Mackay-Wiggan J. An oral phosphodiesterase inhibitor (apremilast) for inflammatory rosacea in adults: A pilot study. JAMA Dermatol 2014;150:1013-4.
Adamo S, Nilsson J, Krebs A, Steiner U, Cozzio A, French LE, et al.
Successful treatment of SAPHO syndrome with apremilast 2018;179:959-62.
Kieffer J, Le Duff F, Montaudie H, Chiaverini C, Lacour JP, Passeron T. Treatment of severe hailey-hailey disease with apremilast. JAMA Dermatol 2018. doi: 10.1001/jamadermatol. 2018.2191.
Baughman RP, Judson MA, Ingledue R, Craft NL, Lower EE. Efficacy and safety of apremilast in chronic cutaneous sarcoidosis. Arch Dermatol 2012;148:262-4.
Huff SB, Gottwald LD. Repigmentation of tenacious vitiligo on apremilast. Case Rep Dermatol Med 2017;2017:2386234.
Waki Y, Kamiya K, Komine M, Maekawa T, Murata S, Ishii N, et al.
Acase of anti-laminin gamma1 (p200) pemphigoid with psoriasis vulgaris successfully treated with apremilast. Eur J Dermatol 2018;28:413-4.
Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, et al.
Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol 2015;73:37-49.
Stein Gold L, Bagel J, Lebwohl M, Jackson JM, Chen R, Goncalves J, et al.
Efficacy and safety of apremilast in systemic- and biologic-naive patients with moderate plaque psoriasis: 52-week results of UNVEIL. J Drugs Dermatol 2018;17:221-8.
Di Cesare A, Pescitelli L, Ricceri F, Lazzeri L, Prignano F. Cutaneous hyperpigmentation induced by apremilast. Int J Dermatol 2018;57:473-4.
Sfecci A, Khemis A, Lacour JP, Montaudie H, Passeron T. Appearance of lentigines in psoriasis patients treated with apremilast. J Am Acad Dermatol 2016;75:1251-2.
Kalik JA, Friedman H, Bechtel MA, Gru AA, Kaffenberger BH. Purpura annularis telangiectodes of majocchi associated with the initiation and rechallenge of apremilast for psoriasis vulgaris. JAMA Dermatol 2017;153:1197-8.
Norris MR, Bielory L. Chronic tearing induced by apremilast. Ann Allergy Asthma Immunol 2018. doi: 10.1016/j.anai. 2018.06.027.
Perrone D, Afridi F, King-Morris K, Komarla A, Kar P. Proximal renal tubular acidosis (Fanconi Syndrome) induced by apremilast: A case report. Am J Kidney Dis 2017;70:729-31.
Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, et al.
Efficacy of apremilast in the treatment of moderate to severe psoriasis: A randomised controlled trial. Lancet 2012;380:738-46.
Vujic I, Herman R, Sanlorenzo M, Posch C, Monshi B, Rappersberger K, et al.
Apremilast in psoriasis-a prospective real-world study. J Eur Acad Dermatol Venereol 2018;32:254-9.
Knuckles MLF, Levi E, Soung J. Treating moderate plaque psoriasis: Prospective 6-month chart review of patients treated with apremilast. J Dermatolog Treat 2018:1-5. doi: 10.1080/09546634.2018.1528326.
Ohata C, Ohyama B, Kuwahara F, Katayama E, Nakama T. Real-world data on the efficacy and safety of apremilast in Japanese patients with plaque psoriasis. J Dermatolog Treat 2018:1-4. doi: 10.1080/09546634.2018.1525480.
Kishimoto M, Komine M, Hioki T, Kamiya K, Sugai J, Ohtsuki M. Real-world use of apremilast for patients with psoriasis in Japan. J Dermatol 2018;45:1345-8.
AbuHilal M, Walsh S, Shear N. Use of Apremilast in combination with other therapies for treatment of chronic plaque psoriasis: A retrospective study. J Cutan Med Surg 2016;20:313-6.
Bagel J, Nelson E, Keegan BR. Apremilast and narrowband ultraviolet-B combination therapy for treating moderate-to-severe plaque psoriasis. J Drugs Dermatol 2017;16:957-62.
Danesh MJ, Beroukhim K, Nguyen C, Levin E, Koo J. Apremilast and adalimumab: A novel combination therapy for recalcitrant psoriasis. Dermatol Online J 2015;21.
Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, et al.
Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis 2014;73:1020-6.
Rothstein BE, McQuade B, Greb JE, Goldminz AM, Gottlieb AB. Apremilast and secukinumab combined therapy in a patient with recalcitrant plaque psoriasis. J Drugs Dermatol 2016;15:648-9.
Georgakopoulos JR, Ighani A, Yeung J. Short- and long-term management of an acute pustular psoriasis flare: A case report. J Cutan Med Surg 2017;21:452-6.
Salopek TG. Recurrence of melanoma after starting apremilast for psoriasis. Case Rep Dermatol 2017;9:108-11.
Lambert JA, Raju SV, Tang LP, McNicholas CM, Li Y, Courville CA, et al.
Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. Am J Respir Cell Mol Biol 2014;50:549-58.
Langley A, Beecker J. Management of common side effects of apremilast. J Cutan Med Surg 2018;22:415-21.
Robichaud A, Tattersall FD, Choudhury I, Rodger IW. Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret. Neuropharmacology 1999;38:289-97.
Sawyer LM, Cornic L, Levin LA, Gibbons C, Moller AH, Jemec GB. Long-term efficacy of novel therapies in moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis of PASI response. J Eur Acad Dermatol Venereol 2018. doi: 10.1111/jdv. 15277.
Armstrong AW, Betts KA, Sundaram M, Thomason D, Signorovitch JE. Comparative efficacy and incremental cost per responder of methotrexate versus apremilast for methotrexate-naive patients with psoriasis. J Am Acad Dermatol 2016;75:740-6.
Feldman SR, Pelletier CL, Wilson KL, Mehta RK, Brouillette MA, Smith D, et al.
Real-world US healthcare costs of psoriasis for biologic-naive patients initiating apremilast or biologics. J Comp Eff Res 2018. doi: 10.2217/cer-2018-0097.
Hinde S, Wade R, Palmer S, Woolacott N, Spackman E. Apremilast for the treatment of moderate to severe plaque psoriasis: A critique of the evidence. Pharmacoeconomics 2016;34:587-96.
Sideris E, Corbett M, Palmer S, Woolacott N, Bojke L. The clinical and cost effectiveness of apremilast for treating active psoriatic arthritis: A critique of the evidence. Pharmacoeconomics 2016;34:1101-10.
Kromer C, Celis D, Sonntag D, Peitsch WK. Biologicals and small molecules in psoriasis: A systematic review of economic evaluations. PLoS One 2018;13:e0189765.
Betancourt BY, Biehl A, Katz JD, Subedi A. Pharmacotherapy pearls in rheumatology for the care of older adult patients: Focus on oral disease-modifying antirheumatic drugs and the newest small molecule inhibitors. Rheum Dis Clin North Am 2018;44:371-91.
Smith RL. Pediatric psoriasis treated with apremilast. JAAD Case Rep 2016;2:89-91.
Hochfeld M. Clinical Trial: A Study of Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects With Moderate to Severe Plaque Psoriasis. Available from: https://clinicaltrials.gov/ct2/show/NCT02576678
. [Last accessed on 2018 Oct 30].
Gerosa M, Argolini LM, Artusi C, Chighizola CB. The use of biologics and small molecules in pregnant patients with rheumatic diseases. Expert Rev Clin Pharmacol 2018;11:987-98.
Hoffman MB, Farhangian M, Feldman SR. Psoriasis during pregnancy: Characteristics and important management recommendations. Expert Rev Clin Immunol 2015;11:709-20.
Reddy SP, Shah VV, Wu JJ. Apremilast for a psoriasis patient with HIV and hepatitis C. J Eur Acad Dermatol Venereol 2017;31:e481-2.
Sacchelli L, Patrizi A, Ferrara F, Bardazzi F. Apremilast as therapeutic option in a HIV positive patient with severe psoriasis. Dermatol Ther 2018;31:e12719.
Nast A, Amelunxen L, Augustin M, Boehncke WH, Dressler C, Gaskins M, et al.
S3 Guideline for the treatment of psoriasis vulgaris, update-Short version part 1-Systemic treatment. J Dtsch Dermatol Ges 2018;16:645-69.
Gisondi P, Fostini AC, Fossa I, Girolomoni G, Targher G. Psoriasis and the metabolic syndrome. Clin Dermatol 2018;36:21-8.
Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta-Felquer M, Armstrong AW, et al.
Group for research and assessment of psoriasis and psoriatic arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol 2016;68:1060-71.
Rich P, Gooderham M, Bachelez H, Goncalves J, Day RM, Chen R, et al.
Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with difficult-to-treat nail and scalp psoriasis: Results of 2 phase III randomized, controlled trials (ESTEEM 1 and ESTEEM 2). J Am Acad Dermatol 2016;74:134-42.
Munoz-Santos C, Sola-Ortigosa J, Guilabert A. Rapid improvement of nail matrix psoriasis with apremilast: Clinical and ultrasonographic assessment. Clin Exp Dermatol 2018;43:606-7.
Spadaccini M, D'Alessio S, Peyrin-Biroulet L, Danese S. PDE4 inhibition and inflammatory bowel disease: A novel therapeutic avenue. Int J Mol Sci 2017;18. doi: 10.3390/ijms18061276.
Danese S, Neurath M, Kopon A, Zakko S, Simmons T, Fogel R, et al.
OP006 Apremilast for active ulcerative colitis: A phase 2, randomised, double-blind, placebo-controlled induction study. J Crohn's Colitis 2018;12:S004-S5.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]