|Year : 2016 | Volume
| Issue : 2 | Page : 75-82
Apremilast: A dermatologic perspective
Aditya Kumar Bubna
Department of Dermatology, Sri Ramachandra University, Chennai, Tamil Nadu, India
|Date of Web Publication||20-Dec-2016|
Aditya Kumar Bubna
Department of Dermatology, Sri Ramachandra University, Porur, Chennai - 600 116, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Apremilast is an oral phosphodiesterase 4 inhibitor, now approved by the Food and Drug Administration in the management of psoriatic arthropathy (PsA). As biologic therapy is associated with significant amounts of adverse effects, newer treatment options with an efficacious outcome, sans the toxicity, is something all clinicians would implement readily in their therapeutic regimens. Apremilast is one such drug which has shown promise in the management of psoriasis, PsA, and a few other dermatologic disorders. This review will throw light on the dermatologic perspective regarding apremilast.
Keywords: Apremilast, phosphodiesterase 4 inhibitor, psoriasis, psoriatic arthropathy
|How to cite this article:|
Bubna AK. Apremilast: A dermatologic perspective. Indian J Drugs Dermatol 2016;2:75-82
| Introduction|| |
The pioneering work in understanding phosphodiesterase (PDE) inhibitors began in the 1950s by Sutherland and Rall. , However, it was only in the 1970s that the anti-inflammatory properties of PDE inhibitors were demonstrated.  Since then, this class of drugs have been utilized in a number of diseases in medicine such as airway hyperactivity, erectile dysfunction, rheumatoid arthritis, ankylosing spondylitis, Alzheimer's disease, and multiple sclerosis.  Till date, 11 families of the PDE enzyme have been identified, based on specific sequencing and biochemical properties.  Out of these enzymes, the PDE-4 enzyme has been found to play a role in the mechanics of a number of inflammatory diseases, because of its liberal expression in the vascular endothelium, smooth muscles, immunologic cells, and keratinocytes. Drugs targeting this enzyme have shown immense promise in reducing the inflammation produced following activity of this enzyme. Some of the drugs belonging to this category include rolipram, roflumilast, apremilast, and AN-2728. Out of these, apremilast and AN-2728 have found to have applications in dermatology. AN-2728 is a boron containing topical compound that has been developed in the treatment of psoriasis.  Apremilast is a systemically administered PDE-4 antagonist, an orally administered small molecule, which has shown great promise in treating patients with psoriasis and a few other dermatologic disorders. This article will focus on the pharmacology of apremilast.
| Mechanism of action|| |
In the human body, normal homeostasis is maintained by the immune system which turns off immune responses when not desired. One of the important modulators in this process is cAMP, the levels of which in turn are determined by the enzyme PDE. Out of the 11 types of PDE in the human body, Type 4 is specific to cAMP and therefore drugs interacting with this enzyme play an important role in alleviating symptoms associated with chronic inflammatory disorders.  PDE-4 levels are predominantly concentrated within inflammatory cells, natural killer cells, and keratinocytes. ,, Apremilast, a specific PDE-4 antagonist, acts by specifically targeting a central pathogenic mechanism, binding directly to the PDE-4 enzyme and bypassing complex antigen-receptor interactive immunoregulatory mechanisms. Once drug-enzyme binding occurs, a series of events follow, the foremost being increased levels of cAMP, which in turn plummets the levels of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-23, IL-12,  and leukotriene B4, and also increases the levels of anti-inflammatory cytokines such as IL-10.  In addition, apremilast also binds to toll-like receptor 4 in peripheral blood mononuclear cells, further reducing the production of pro-inflammatory cytokines.  Apremilast also reduces the activity of nitric oxide synthase, , an enzyme responsible for the synthesis of nitric oxide which is an important pro-inflammatory mediator, thereby preventing trafficking of macrophages and myeloid dendritic cells to the dermis and epidermis in psoriatic skins. In this way, apremilast plays a noteworthy anti-inflammatory role. A gist regarding the anti-inflammatory role of apremilast has been represented in [Figure 1].
| Pharmacokinetics|| |
Apremilast is an orally administered drug. Postintake, it is rapidly absorbed by the body reaching its peak plasma concentration after 2-3 h. The bioavailability of apremilast is around 73% and its mean apparent volume of distribution is 87 L. Apremilast has a t 1/2 of 6-9 h.  Metabolism of apremilast occurs through a cytochrome (CYP) 3A4-mediated oxidative metabolism, followed by glucuronidation, nonenzymatic hydrolysis, and a non-CYP 3A4-mediated metabolism.  Apremilast is eliminated mainly by the renal route, though some of the drug is also excreted through the feces. 
| Indications|| |
Although originally a drug marketed for psoriasis, there are a number of other dermatologic indications for which apremilast has been utilized and has been summarized in [Table 1].
Psoriasis is a chronic inflammatory cutaneous disorder, affecting up to 2%-5% of the world population. Owing to the chronic course displayed in this condition, long-term treatment is necessitated. Traditionally, drugs employed in this setting, such as methotrexate (Mtx), cyclosporine A (CsA), and azathioprine (Azt), are associated with serious adverse effects and warrant proper monitoring throughout treatment.  Biologic therapies, on the other hand, though effective have their own disadvantages related to treatment resistance, hospital admission, parenteral administration, adverse effect profile, expenses and management requiring a specialist setting.  Therefore, there is an ongoing research for the discovery of an ideal drug for managing psoriasis. Apremilast is a small orally available molecule that has demonstrated its worth for the same. Apremilast directly targets the central initiator mechanism in the pathogenesis of psoriasis, and in this way modulates the expression of various inflammatory mediators involved in this process. An open-label, single-arm, pilot study done by Gottlieb et al. demonstrated the clinical efficacy of apremilast in managing patients with severe plaque-type psoriasis. The 19 patients who were enrolled in this study were treated with 20 mg of apremilast once daily for 29 days. Out of the 19 patients, 17 completed the entire study. Only those patients were included in the study who had severe plaque type of psoriasis for at least 6 months, which involved at least 15% of the total body surface area, and who were candidates eligible for systemic therapy or phototherapy and had not received any systemic treatment since the past six months. The end result of the study clearly indicated the therapeutic justification for the use of apremilast in plaque-type psoriasis. After 29 days of treatment with apremilast, it was noted that T-cells and CD11c cells were reduced from the dermis and epidermis by 28.8% and 42.6%, respectively, for T-cells and 18.5% and 40.2%, respectively, for CD11a cells. In addition, the mRNA expression of nitric oxide synthase was reduced by 66.5% from baseline in responders, which was again statistically significant (P < 0.0001). Along with this, apremilast showed reduction in the epidermal thickness by a mean of 20.5% from the baseline on day 29. Apart from these parameters, the clinical parameters also substantiated the beneficial role of apremilast. In 73.7% of the patients in this study, an improvement in psoriasis was witnessed as per the Psoriasis Area Severity Index (PASI) score, with 17.6% of the patients having a reduction of >50% of their PASI score from the baseline. Adverse effects were also very mild and not suspected of having a causal relationship with apremilast. Thus, we see the effectiveness of apremilast in treating patients with psoriasis. Other studies, , throwing light on the excellent therapeutic outcome of plaque-type psoriasis, have been summarized in [Table 2].
|Table 2: Some of the studies demonstrating the beneficial role of apremilast in plaque-type psoriasis |
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Psoriatic arthropathy (PsA) is a chronic inflammatory disorder, encountered in 30% of psoriatic patients and around 1% of the general population. Owing to the risk of irreversible joint damage which begins very early in the course of the disease, it is essential to intervene early enough to avert these changes and obtain a better life quality in these patients. Approved treatments for PsA include both biologic and non biologic therapies. Biologic therapies include etanercept, adalimumab, golimumab, and infliximab. However, owing to the high costs involved with these drugs, nonbiologic treatments such as Mtx, sulfasalazine, leflunomide, and CsA are used as first-line treatment modalities here. However, the drawback with these drugs is that the efficacy of these disease-modifying anti-rheumatic drugs has not been well established as per clinical studies.  Therefore, a drug which is therapeutically effective and also affordable to patients becomes a necessity in this scenario. Apremilast has shown to fulfill these requirements. In the three programs conducted under the title of Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE), for 52 weeks, apremilast did show promise in managing these patients. The primary end point was assessed at 16 weeks following treatment with apremilast, with two dosing protocols and comparing it with a placebo group, with an improvement of >20 in the American College of Rheumatology score (ACR20). In the PALACE 1 study,  the ACR20 response rates were 31.3% (P = 0.0140) and 39.8% (P = 0.0001) for the groups receiving apremilast 20 mg twice daily and 30 mg twice daily, respectively, compared to only 19.4% for the placebo group. In the PALACE 2 study,  the group receiving 20 mg of apremilast twice daily demonstrated an ACR20 response rate of 38.4% (P = 0.0002) and the group getting apremilast 30 mg twice daily showed an ACR20 response rate of 34.4% (P = 0.0024), compared to only 19.5% for the placebo group. In the PALACE 3 study,  the ACR20 response rates were 29.4% (P = 0.02) for the apremilast 20 mg twice daily group and 42.8% (P < 0.0001) for the group receiving 30 mg of apremilast twice daily versus 18.9% for the placebo group. In all the three studies, ACR20 responses were maintained in patients who had taken apremilast in the two dosing schedules as highlighted till week 52. Other parameters assessed similarly were reductions in the swollen joint counts and tender joint counts which showed pertinent levels of reduction post apremilast intake and have been summarized in [Table 3].
|Table 3: Psoriatic Arthritis Long-term Assessment of Clinical Efficacy studies demonstrating reductions in swollen joint counts and tender joint counts following apremilast intake |
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Also in the above-mentioned studies, the drug was very well tolerated by patients with only mild-to-moderate levels of side effects. Thus, we can clearly see the beneficial contribution made by this new drug in the management for PsA, and therefore it has been approved by the Food and Drug Administration in the management of this spectrum of psoriasis.
Lichen planus (LP) is a chronic inflammatory disease, primarily affecting the skin, mucous membranes, and nails. It has been seen that 15%-20% of patients with LP demonstrate a relapsing and remitting course, often resistant to most conventional modalities of treatment.  In such cases, there would always be the need of newer and better alternatives for therapy. It is plausible that apremilast with its anti-inflammatory properties could help regression of skin lesions in LP. An open-label pilot study done by Paul et al. in ten biopsy-proven patients with LP demonstrated the beneficial effects of apremilast for the same. Apremilast was administered to these patients at a dose of 20 mg twice daily for 12 weeks. At the end of 12 weeks, three of the patients showed complete clearance of lesions. In the remaining seven patients though good clinical improvement was noticeable, complete clearance was not seen. Therefore, it was concluded that apremilast could be considered a safe and effective alternative to the current treatment options in the armamentarium of LP. However, more double-blind randomized controlled trials would be mandatory to evaluate the effectiveness and safety of apremilast for this indication.
Atopic dermatitis (AD) is a chronic relapsing eczematous disorder which in moderate-to-severe proportions cannot be solely managed by topical agents alone, thus necessitating the usage of systemic immunosuppressive agents, which in turn is associated with unwanted adverse reactions.  Increased levels of PDE activity, in patients with AD, have been clearly elucidated. The heightened activity of this enzyme in turn leads to leukocyte hyperactivity and inflammatory changes. Topical cipamfylline cream, a PDE-4 blocker (not commercially available), has demonstrated clinical efficacy in atopic skins.  Orally, PDE-4 blockers have been employed in the management of a number of inflammatory diseases.  In AD, the beneficial mechanics of apremilast is not fully known. Yet, the following properties of apremilast may help in reducing the inflammation seen in atopic skins:
a. Apremilast may reverse the increased PDE-4 activity of immune cells in AD, reverting the immune cells to a less active state, thus bringing about a considerable decrease in the cytokines released from T-cells
b. Apremilast's property of PDE-4 blocking increases the levels of cAMP, bringing about phosphorylation of protein kinase A. This in turn activates cAMP response element binding (CREB), a transcription factor, which may have an anti-inflammatory role in cells of the immune system. However, the entire role of the CREB pathway in AD is not fully known at present, but ongoing research in this regard would help throw more light in this scenario 
c. BAD, a well-known pro-apoptotic factor, is actively targeted by protein kinase A, which in turn inactivates BAD.  BAD, if not inactivated, binds to bcl-2, an antiapoptotic factor, and nullifies its effect.  Skins of AD patients treated with ultraviolet light showed an increased expression of bcl-2, thus concluding that this antiapoptotic factor may be protective in AD.  Thus, by inactivating BAD, PDE-4 inhibitors may indirectly demonstrate therapeutic activity
d. IL-12 and CCR3 are two chemokines found elevated in the lesional skin and blood of patients with AD. ,, Apremilast may modify these immune pathways and thus prove beneficial in AD. However, more detailed analysis of these pathways is warranted for the same.
A pilot study done with apremilast in 16 adult patients with AD by Samrao et al. demonstrated the beneficial effects of apremilast in both groups receiving the drug. The group that received 20 mg of apremilast twice daily for 3 months demonstrated a significant decrease in pruritus from the baseline (P = 0.02) and also in the Dermatology Life Quality Index (DLQI) (P = 0.003). The group that received apremilast 30 mg twice daily for 6 months showed a significant reduction of the Eczema Area and Severity Index (EASI) scores and DLQI at 3 months and 6 months and is tabulated in [Table 4].
|Table 4: Eczema Area and Severity Index scores and Dermatology Life Quality Index at 3 and 6 months following apremilast use for atopic dermatitis in the study by Samrao et al|
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Second, the safety profile of apremilast was much better when compared with other cytotoxic drugs used in AD. The EASI scores obtained in this study after 6 months clearly demonstrated the efficacy of apremilast in AD, at par with other traditional therapeutic agents used in AD, with the advantage of being devoid of end-organ toxicity as seen with drugs such as Mtx, Azt, and CsA. However, more randomized controlled studies would definitely be required to determine more accurate estimates with regard to the efficacy and safety of apremilast in patients with AD.
Sarcoidosis is a chronic granulomatous multisystem disorder. Pro-inflammatory cytokines such as TNF-α, interferon gamma, IL-2, IL-12, and IL-23 play a major role in the pathogenesis of the disease. Pentoxifylline, a PDE-4 antagonist, has shown to produce a good therapeutic outcome in sarcoidosis.  However, owing to its toxicity profile, its use has been limited. Apremilast is a newer PDE-4 blocker with a better toxicity profile compared to pentoxifylline and therefore may find a role in the management of these patients. A study done by Baughman et al. evaluating the efficacy of apremilast in chronic cutaneous sarcoidosis in 15 patients receiving 20 mg of the drug on a twice daily basis for a period of 12 weeks did confirm the beneficial properties of apremilast for the same. At the end of 12 weeks, the Sarcoidosis Activity and Severity Index score decreased significantly with apremilast therapy, and on analysis of paired before and after treatment photographs also significant clinical improvement was demonstrable. Thus, apremilast was found to be effective and safe in treating persistent lesions of sarcoidosis, as highlighted in this study. However, further studies are mandated to examine the safety and efficacy of apremilast for sarcoidosis.
Discoid lupus erythematosus
Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder characterized by erythematous plaques with adherent scales and mediated by Th (helper)-1 cells.  There have been numerous treatment options in the armamentarium for DLE such as antimalarials, systemic glucocorticoids, gold, retinoids, sulfasalazine, CsA, thalidomide, and clofazimine, to name a few. De Souza et al. have demonstrated the favorable response following apremilast intake in DLE patients in a single-arm open-label pilot study. All eight patients in this study were given 20 mg of apremilast twice daily, and after an 85-day period, they were evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). The CLASI showed a significant decrease with P < 0.05 after 85 days of apremilast treatment. However, none of the patients achieved complete clinical clearing of lesions. As far as the toxicity profile was concerned, it was very well tolerated by all patients. Though useful for DLE, more studies are mandated to warrant the usage of apremilast for this dermatosis.
Apremilast has demonstrated efficacy in oral and genital aphthae associated with Behcet's disease (BD), at a dosage of 30 mg twice daily, without major organ involvement. After a 12-week treatment program, there was a complete response of ulcers in 71% of the treated patients compared to only 29% of the patients given placebo with P < 0.0001 which was statistically significant. Along with lesion improvement, there was a considerable reduction in pain associated with the ulcers, following apremilast administration. Other parameters that showed improvement here were quality of life and progression of disease activity. However, when treatment was withdrawn, there was a relapse of both oral and genital aphthae.  More studies regarding the usage of apremilast for BD is definitely warranted to qualify for its usefulness in this indication.
Strong CYP450 inducers such as rifampicin, phenobarbitone, carbamazepine, and phenytoin should not be simultaneously administered with apremilast as they could significantly reduce the levels of apremilast in the body. Both Mtx and apremilast can be administered together if desired as both drugs lack pharmacokinetic interactions. 
Apart from hypersensitivity to the drug, there are no current contraindications for apremilast.
The most common adverse effects encountered with apremilast are diarrhea, nausea, and headache. Other side effects include upper respiratory tract infection, vomiting, nasopharyngitis, upper abdominal pain, hypersensitivity, dyspnea, cough, and skin rash. However, most of these side effects have a mild-to-moderate intensity, with a self-limiting nature. As far as the laboratory parameters are concerned, no significant abnormalities have been encountered. , Overall, apremilast is a safe drug with a favorable toxicity profile.
| Conclusion|| |
To conclude, it can be clearly appreciated that apremilast could revolutionize the treatment of many of the chronic inflammatory dermatosis encountered. As it does not interfere with immune suppression, rather by targeting the central inflammatory signaling pathways, it proves to have an added advantage over the conventional drugs used for the above indications. Second, with its better toxicity profile, it has an added advantage over the other drugs because of the long-term treatment regimens employed for most of these disorders.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Sutherland EW, Rall T. The properties of an adenosine ribonucleotide produced with cellular particles, ATP, mg, and epinephrine or glucagon. J Am Chem Soc 1957;79:3608.
Sutherland EW, Rall TW. Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles. J Biol Chem 1958;232:1077-91.
Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y, Shearer GM. Modulation of inflammation and immunity by cyclic AMP. Science 1974;184:19-28.
Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4 inhibitors in clinical dermatology. Dermatol Online J 2014;20:22608.
Lipworth BJ. Phosphodiesterase inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005;365:167-75.
Akama T, Baker SJ, Zhang YK, Hernandez V, Zhou H, Sanders V, et al.
Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis. Bioorg Med Chem Lett 2009;19:2129-32.
Pagès L, Gavaldà A, Lehner MD. PDE4 inhibitors: A review of current developments (2005-2009). Expert Opin Ther Pat 2009;19:1501-19.
Palfreeman AC, McNamee KE, McCann FE. New developments in the management of psoriasis and psoriatic arthritis: A focus on apremilast. Drug Des Devel Ther 2013;7:201-10.
Aslam A, Griffiths CE. Drug therapies in dermatology. Clin Med (Lond) 2014;14:47-53.
Salari P, Abdollahi M. Phosphodiesterase inhibitors in inflammatory bowel disease. Expert Opin Investig Drugs 2012;21:261-4.
Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol 2012;83:1583-90.
Serezani CH, Ballinger MN, Aronoff DM, Peters-Golden M. Cyclic AMP: Master regulator of innate immune cell function. Am J Respir Cell Mol Biol 2008;39:127-32.
Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, et al.
Apremilast, a cAMP phosphodiesterase 4 inhibitor, demonstrates anti-inflammatory activity in vitro
and in a model of psoriasis. Br J Pharmacol 2010;159:842-55.
Schett G, Wollenhaupt J, Papp K, Joos R, Rodrigues JF, Vessey AR, et al.
Oral apremilast in the treatment of active psoriatic arthritis: Results of a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2012;64:3156-67.
Gottlieb AB, Strober B, Krueger JG, Rohane P, Zeldis JB, Hu CC, et al.
An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast. Curr Med Res Opin 2008;24:1529-38.
Wu A, Rohane P, Ng J, DeGroot B, Colgan B, Laskin OL, et al.
Safety/tolerability and pharmacokinetics of multiple oral doses of apremilast in healthy male subjects. Clin Pharmacol Ther 2012;91:S26.
Hoffmann M, Kumar G, Schafer P, Cedzik D, Capone L, Fong KL, et al.
Disposition, metabolism and mass balance of [(14) C] apremilast following oral administration. Xenobiotica 2011;41:1063-75.
Wu A, Scheffler M. First-time-in-man, safety/tolerability and pharmacokinetics of ascending oral doses of apremilast (APR) in healthy subjects (HS). J Invest Dermatol 2011;131:S86.
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol 2009;61:451-85.
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.
Papp KA, Kaufmann R, Thaci D, Hu C, Day RM, Sutherland D. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: Results from a phase II, multi-center, randomized, double blind, placebo controlled, parallel group, dose comparison study. J Eur Acad Dermatol Venereol 2013;27:e376-83.
Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al.
Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol 2009;60:643-59.
Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD et al
. Treatment of psoriatic arthritis in a phase 3 randomized placebo controlled trial with apremilast, an oral phosphodoesterase 4 inhibitor. Clin Rheum Dis 2014;73:1020-6.
Cutolo M, Myerson GE, Fleischmann RM, Liote F, Diaz-Gonzalez F, Van den Bosch F, et al.
Long-term (52 week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis (PALACE 2). Arthritis Rheum 2013;65:S346-7.
Edwards CJ, Blanco FJ, Crowley J, Hu C, Stevens RM, Birbara CA, et al.
Long-term (52-week) results of a phase 3, randomized, controlled trial of apremilast, an oral phosphodiesterase 4 inhibitor in patients with psoriatic arthritis and current skin involvement (PALACE 3). Arthritis Rheum 2013;65:S132.
Asch S, Goldenberg G. Systemic treatment of cutaneous lichen planus: An update. Cutis 2011;87:129-34.
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.
Schmitt J, Schäkel K, Schmitt N, Meurer M. Systemic treatment of severe atopic eczema: A systematic review. Acta Derm Venereol 2007;87:100-11.
Griffiths CE, Van Leent EJ, Gilbert M, Traulsen J; Cipamyflline Study Group. Randomized comparison of the type 4 phosphodiesterase inhibitor cipamfylline cream, cream vehicle and hydrocortisone 17-butyrate cream for the treatment of atopic dermatitis. Br J Dermatol 2002;147:299-307.
Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs 2007;8:364-72.
Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. J Immunol 2010;185:6413-9.
Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, et al.
Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 1999;3:413-22.
Yang X, Liu L, Sternberg D, Tang L, Galinsky I, DeAngelo D, et al.
The FLT3 internal tandem duplication mutation prevents apoptosis in interleukin-3-deprived BaF3 cells due to protein kinase A and ribosomal S6 kinase 1-mediated BAD phosphorylation at serine 112. Cancer Res 2005;65:7338-47.
Breuckmann F, von Kobyletzki G, Avermaete A, Kreuter A, Altmeyer P. Efficacy of ultraviolet A1 phototherapy on the expression of bcl-2 in atopic dermatitis and cutaneous T-cell lymphoma in vivo
: A comparison study. Photodermatol Photoimmunol Photomed 2002;18:217-22.
Yawalkar N, Uguccioni M, Schärer J, Braunwalder J, Karlen S, Dewald B, et al.
Enhanced expression of eotaxin and CCR3 in atopic dermatitis. J Invest Dermatol 1999;113:43-8.
Hamid Q, Naseer T, Minshall EM, Song YL, Boguniewicz M, Leung DY. In vivo
expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 1996;98:225-31.
Shida K, Koizumi H, Shiratori I, Matsumoto M, Kikkawa S, Tsuji S, et al.
High serum levels of additional IL-18 forms may be reciprocally correlated with IgE levels in patients with atopic dermatitis. Immunol Lett 2001;79:169-75.
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.
Park MK, Fontana JR, Babaali H, Gilbert-McClain LI, Stylianou M, Joo J, et al.
Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2009;26:121-31.
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.
Chang AY, Werth VP. Treatment of cutaneous lupus. Curr Rheumatol Rep 2011;13:300-7.
De Souza A, Strober BE, Merola JF, Oliver S, Franks AG Jr. Apremilast for discoid lupus erythematosus: Results of a phase 2, open-label, single-arm, pilot study. J Drugs Dermatol 2012;11:1224-6.
Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Ozturk BT, Mat C, et al
. Apremilast for the treatment of Behcet's syndrome: A phase II randomized, placebo controlled, double blind study. Arthritis Rheum 2013;65 10 Suppl: S322.
Poole RM, Ballantyne AD. Apremilast: First global approval. Drugs 2014;74:825-37.
Reich K, Griffiths C, Leonardi C, Papp K, Kircik L, Day R, et al.
Long term safety and tolerability of apremilast, an oral phosphodiesterase4 inhibitor, in patients with moderate to severe psoriasis: Results from a phase III, randomized, controlled trial (ESTEEM 1). J Am Acad Dermatol 2014;70:AB174.
Mease PJ, Kavanaugh A, Adebajo AO, Gomez-Reino JJ, Wollenhaupt J, Gladman DD, et al.
Laboratory abnormalities in patients with psoriatic arthritis receiving apremilast, an oral phosphodiesterase 4 inhibitor: Pooled safety analysis three phase 3, randomized controlled trials. Arthritis Rheum 2013;65:S151.
[Table 1], [Table 2], [Table 3], [Table 4]