Microsoft Word - May 2021 - IDR - 1239 proof.docx SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 203 IN-DEPTH REVIEW Apremilast as an Off-Label Therapeutic Agent: A Comprehensive Review of Safety and Efficacy Data in the Literature for Combination Therapy and Inflammatory Dermatoses Justin W. Marson, MD1, Mark G. Lebwohl, MD2 1SUNY Downstate Health Sciences University, Brooklyn, NY 2Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY Apremilast is an oral, small molecule phosphodiesterase 4 (PDE4) inhibitor that was originally US food and drug administration (FDA) approved for the management of psoriatic arthritis and chronic plaque psoriasis in 2014.1 By inhibiting the degradation of cyclic adenosine monophosphate (cAMP), apremilast modulates the activity of multiple immune cell lines including macrophages, neutrophils and natural killer cells within the Th1 and Th17 pathways as well as myriads of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12) and IL-23 as well as anti-inflammatory cytokines such as IL-10.2,3 Clinically, this has translated into successful, ABSTRACT Objective: To review the literature regarding the efficacy and safety of off-label use of apremilast in combination therapies for psoriasis and psoriatic arthritis and for other currently off-label inflammatory dermatoses. Methods: The Medline database was queried for all relevant articles published between 2014 and 2021 using exploded MeSH terms and keywords pertaining to the following themes: off-label, combination therapy, biologics, biologic therapy, methotrexate, and systemic psoriasis therapy. The Boolean term “AND” was used to find the intersection of these themes with the term “apremilast.” Results: 8 case series and 6 case reports investigated the use of apremilast in combination therapy for psoriasis and psoriatic arthritis. Addition of apremilast improved PASI scores by 31.8-77.4% among case series and 80-100% among case reports with adverse effects primarily consisting of gastrointestinal symptoms. 5 randomized-control trials (RCT), 9 open-label trials, 18 case series, and 30 case reports investigated the use of apremilast for off-label dermatoses. In RCTs, apremilast showed potential efficacy for atopic dermatitis and hidradenitis suppurativa. Open-label trials found apremilast efficacious for atopic dermatitis, allergic contact dermatitis, chronic pruritus, cutaneous sarcoidosis, discoid lupus erythematosus, hidradenitis suppurativa, lichen planus, prurigo nodularis, rosacea, and vitiligo. Limitations: Small sample size and short follow up duration for available randomized-control and open- label trials. Current data from case series/reports potentially limits generalizability of findings. Conclusion: Apremilast's safety profile makes it a potential efficacious, non-biologic systemic agent for monotherapy and combination therapy for a wide range of inflammatory dermatoses. INTRODUCTION SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 204 non-biologic oral therapy for patients with psoriasis and psoriatic arthritis with first signs of meaningful response notable within 2 weeks.4-6 The efficacy of apremilast is complemented by its safety profile.7 Clinical trials have shown that the most common treatment- emergent adverse events (TEAE) are gastrointestinal related (diarrhea, nausea), weight loss, upper respiratory tract infections and that apremilast does not increase risk of malignancy or opportunistic infections.7 Furthermore, post-marketing surveillance as well as clinical and pharmacological data have not supported (if not refuted) correlation between depression and apremilast.8,9 Because apremilast is an oral, non-biologic systemic agent with a favorable safety profile, there has been growing interest in its application for other off-label use in either combination therapy for FDA-approved conditions or for other inflammatory dermatoses. This growing interest in expanding indication earned apremilast FDA-approval in 2019 for use in Behçet’s syndrome in 2019.1,10 Additional studies have also investigated the off-label use of apremilast in conjunction with other therapies, including biologics and methotrexate for more recalcitrant cases of psoriasis or psoriatic arthritis.6,11-13 The purpose of this study is to review the literature for off-label uses of apremilast with respect to other inflammatory conditions as well as combination therapies. A review of the literature pertaining to off- label use of apremilast as well as combination therapies was conducted. The Medline database was queried for all relevant articles published between 2014 and 2021 using exploded MeSH terms and keywords pertaining to the following themes: off-label, biologics, methotrexate, and systemic psoriasis therapy. The Boolean term “AND” was used to find the intersection of these themes with the term “apremilast.” Studies were limited to English-only manuscripts with available full-text. Details regarding study design (case reports, case- series, open-label trial or randomized controlled trials (RCTs)), outcomes, follow- up duration, and treatment-emergent adverse events (TEAE) were abstracted. Combination Therapy for Psoriasis and Psoriatic Arthritis The advances in understanding psoriasis as a systemic inflammatory condition fostered the development of immunomodulating targeted biologic agents, many of which are able to reach 100% improvement as captured by the psoriasis activity and severity index (PASI100).14,15 However, longitudinal studies have demonstrated a decrease in efficacy of certain biologic agents over time.15-18 This secondary failure or biologic fatigue can be observed in up to 20-30% of patients as little as 1-4 years after initially reaching PASI75, potentially due to the creation of neutralizing anti-drug antibodies leading to subtherapeutic serum drug levels.15-17 While switching biologics can recapture efficacy, these effects may not be durable and are also dependent on the selected drug and drug class.18 Alternatively, studies have also investigated combining different drug classes and mechanisms of action with durable and efficacious results.13,19-31 Several case series and reports found patients who experienced secondary failure while on a METHODS RESULTS SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 205 biologic or other non-biologic systemic agents (e.g. methotrexate) obtained PASI50-100 throughout a follow up period of 3-9 months with similar treatment-emergent adverse effects [TEAE] to monotherapy (Table1).13,19-25,26-31 Collectively several case studies have noted that the addition of apremilast to either systemic biologic or nonbiologic therapies had a mean additional improvement in PASI scores between 31.8- 77.4% for patients that were either unsatisfied with their current regimen or experienced secondary failure.13,19,21,22 While additional efficacy varied depending on the pre-apremilast regimen, most patients saw durable results with a range of means between 12 and 31 weeks.13,19-25 Several studies also found additional benefit in combining narrow-band UVB (nbUVB) phototherapy with apremilast, with additional improvements in PASI of 76.4-81.5%.13,25 Furthermore, none of these therapeutic combinations resulted in severe infections in the management of psoriasis or psoriatic arthritis. Only one study noted 3 upper respiratory tract infections over 16 weeks.22 In one study, 14 patients opted to discontinue apremilast prior to the 12-week follow-up due to “intolerable” gastrointestinal symptoms (n = 9), headache (n = 1), a transient urticarial rash (n = 1) and 2 due to patient preference.28 Overall, 20-25% of patients experienced self-limited diarrhea, nausea, and weight loss. Depression or depressive symptoms were not noted in patients on any combination therapy with apremilast.18-25 Several studies compared apremilast monotherapy to combination therapy with apremilast and found no significant difference in the rate of treatment- emergent adverse effects (TEAE).22,23 Several case reports also found utility of apremilast in combination therapies, especially in more recalcitrant cases of psoriasis, which had failed multiple topical and systemic agents.26-31 In 5 out of the 6 cases, patients saw additional significant reduction in the severity of their psoriasis with the addition of apremilast to their systemic agent, with only 1 instance of mild diarrhea.26,28-31 One report further detailed improvement in both psoriasis and psoriatic arthritis with the sequential initiation of apremilast 30 mg BID and secukinumab 300 mg monthly with achieved PASI100 and reduced eight tender and seven swollen joints to 2 tender and no swollen joints in 16 weeks.31 Only 1 case, in which the patient had a rare HLA-C*18:01 mutation causing multiple-regimen resistant, recalcitrant psoriasis, did not see improvement with the addition of apremilast to ustekinumab.27 Together these data demonstrate a pattern of efficacy and safety when apremilast is added or included in combination therapy, especially for patients with a history of recalcitrant psoriasis. Randomized-control and open-label trials investigating off-label apremilast use Apremilast’s unique combination of safety profile and multifaceted mechanism of action have sparked interest into potential uses in other inflammatory dermatoses. As a result, several randomized-control trials (RCT), open-label trials, case reports, and case series have investigated, with varying degrees of success, how apremilast may fit into the therapeutic framework for conditions including (but not limited to) other papulosquamous, vesiculobullous, granulomatous dermatoses, connective tissue, and pigmentary disorders (Table 3- 5).32-96 Alopecia Areata A randomized control trial of patients with long standing moderate to severe alopecia areata (AA) (>50% involvement of the scalp) SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 206 Table 1. Case Series of Combination Therapies including Apremilast for Psoriasis and Psoriatic Arthritis Study Mean Age (SD) Sex M/F Add’l PsO subtype Combination Regimen (n) Follow-up Period Weeks, mean (SD) Mean %PASI* Improvement (SD) TEAE† (n) Diar Naus Wt Infxn AbuHilal et al.13 48.8 47.3 37.7 52.6 52.4 53.2 53.4 7/3 5/10 1/3 4/1 5/8 5/2 6/7 -- +nbUVB (10) +Methotrexate (15) +Cyclosporine (4) +Acitretin (5) +TNF-inhibitor (13) +TNF-inhibitor & Methotrexate (7) +Ustekinumab (13) 12 (0) 81.5 67.8 63.3 76.5 70.4 76.8 77.4 4 4 1 2 3 2 4 1 2 1 1 2 1 2 -- -- -- -- -- -- -- -- -- -- -- -- -- -- Takamura et al.19 51.4 (2.4) 14/0 -- 2 PsA -- -- 1 PsA +Infliximab (1) +Adalimumab (3) +Secukinumab (2) +Ixekizumab (2) +Ustekinumab (6) 24 (0) 77 31.8 (32.1) 35.7 (22.2) 39.6 (10.3) 67.2 (30.0) -- 1 1 1 2 -- -- -- 1 -- -- 2‡ -- -- -- -- -- -- -- -- Metyas et al.20 -- -- 22 PsA +Adalimumab (6) +Infliximab (4) +Golimumab (3) +Certolizumab Pegol (2) +Etantercept (2) +Ustekinumab (5) R: 12-42 R:4-68 R:12-44 R:4-36 R:4-28 R:16-106 -- 2 2 1 -- Saccheli et al.21 48.25 (10.9) 1/3 2 PsA +Secukinumab (4) 31 (5.03) 75.4 (20.7) Yes -- -- -- Ighani et al.22 51.5 (11.9) 51/38 51 PsA +Phototherapy (2) +Cyclosporine (3) +Methotrexate (19) +Sulfasalazine (2) +Etanercept (18) +Adalimumab & Methotrexate (8) +Infliximab (7) +Adalimumab (5) +Secukinumab (3) +Ustekinumab (14) +Ustekinumab & Acitretin (3) +Infliximab & Methotrexate (2) 16 (0) 51.3 15 10 9 URI (4) Abignano et al.23 51.5 (2) 17/15 32 PsA 26 PsO +Methotrexate (16) +Sulfasalazine (1) 22.9 (13.5) -- 5 2 -- -- SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 207 +Hydroxychloroquine (2) +Leflunomide (1) +Certolizumab (1) +Golimumab (2) +Ustekinumab (1) +Adalimumab (1) +Etanercept (1 +Secukinumab (1 +Tocilizumab (1) +Methotrexate & Sulfasalazine (1) +Methotrexate & Hydroxychloroquine (1) +Methotrexate & Certolizumab (1) +Methotrexate & Ustekinumab (1) Wald et al. 24 -- -- -- +Methotrexate (1) 11.4 (0) -- -- Yes -- -- Bagel et al.25 47 (11) 17/12 -- +nbUVB (29) 12 (0) 76.4 -- 2 -- -- -- indicates specific data not provided *%PASI improvement after addition of apremilast to current regimen, †not mutually exclusive unless otherwise noted, ‡>5% original body weight Diar – Diarrhea; F – Female; Infxn – infection; M – Male; Naus – nausea; PASI – psoriasis area and severity index; PsA – psoriatic arthritis; PsO – psoriasis; R – Range; SD – standard deviation; TEAE – treatment-emergent adverse events; Wt – weight loss SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 208 Table 2. Case Reports of Combination Therapy Using Apremilast 30 mg twice daily/60 mg daily for Psoriasis and Psoriatic Arthritis Study Age Sex PsO subtype Prior Regimens Combination Regimen Follow- up (wks) %PASI improvement TEAE d/c Tx? Czarnowic ki et al.26 50 M PPP Topical Steroids, Tacrolimus, excimer laser, Acitretin +Acitretin (25mg/d) 8 90 -- No Armesto et al.27 28 F Erythroderma PsO Methotrexate, Cyclosporine, Infliximab, Adalimumab, Etanercept, Ustekinumab, Secukinumab, Golimumab, Certolizumab, Apremilast monotherapy +Adalimumab (40mg/wk) & Methotrexate (10mg/wk) & Prednisone taper (20mg/day) +Brodalumab (210mg/wk) & Methotrexate (20mg/wk) & prednisone (30 mg/day) 4 36 -- 86 -- -- Worsening prompted change of biologic Galluzzo et al.28 63 M PsO, HLA-C*18:01 Infliximab, Etanercept, Ustekinumab, Adalimumab, Infliximab re-trial, Ustekinumab re-trial, Secukinumab +Ustekinumab (45 mg) 12 --† -- Worsening condition Rothstein et al.29 67 M PsO, PsA Ustekinumab, Infliximab, Adalimumab, Acitretin, Cyclosporine, Secukinumab, +Secukinumab (300mg/month) 12 80% BSA to 5%† Mild diarrhea No Danesh et al.30 31 M PsO Topical Steroids, nbUVB, Acitretin, Etanercept, Adalimumab +Adalimumab (40mg/QOW) 16 Improved† -- No Nisar31 23 M PsO, PsA Cyclosporine, Sulfasalazine, Methotrexate, Adalimumab, Ustekinumab, Infliximab +Secukinumab (300mg/month) 16 100 & PsARC 8 tender/7 swollen joints to 2 tender/0 swollen -- No †PASI scores not available %PASI – percent improvement in psoriasis area and severity index after addition of apremilast to current regimen; d/c Tx– discontinued therapy; F – female; M – male; PPP – palmarplantar psoriasis; PsA – psoriatic arthritis; PsARC – psoriatic arthritis response criteria; PsO – plaque psoriasis; QOW – every other week; TEAE – treatment-emergent adverse effects; wks – weeks SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 209 found that apremilast 20 mg BID over 24 weeks was not superior to placebo in achieving 50% reduction in severity of alopecia tool (SALT50) score.32 The authors note that this may be due to the severity and chronicity of disease in study participants, small sample size, and short duration of the study.32 Several case series and reports have found more positive results with 40- 87% of participants experiencing sustained regrowth of scalp hair and eyelashes.33-37,43 Of note, authors of these studies found patients with more refractory cases were less likely to respond to apremilast monotherapy. TEAE consisted mostly of gastrointestinal distress (nausea, diarrhea) which was transient or tolerable with dose decrease33. In rare instances, persistent arthralgias, nausea and/or diarrhea led to premature discontinuation of apremilast.32 Atopic Dermatitis, Chronic Pruritus, Prurigo Nodularis, Hand Eczema, and Allergic Contact Dermatitis Mixed results have been found regarding apremilast’s use in AD, similar eczematous disorders in the atopic spectrum of disorders (e.g., chronic pruritus, prurigo nodularis, hand eczema) and allergic contact dermatitis (ACD). A phase II RCT found that apremilast 30 mg BID trended towards improvement, though did not significantly improve atopic dermatitis than placebo.38 When the dose was increased to 40 mg BID, there was a significant improvement in eczema area and severity index (EASI) score and dermatology life quality index (DLQI) as well as improvement in biochemical markers of AD.38 However, the increased dose also led to increased incidence of cellulitis (n=6) which ultimately lead to termination of this arm of the study.38 2 of the 6 cases of cellulitis were deemed serious and occurred in patients with diabetes; one of those cases may have also been associated with an observed case of glomerulonephritis.38 Open-label trial results have also yielded conflicting conclusions. An open-label trial with a 20 mg BID (n=6) and 30 mg BID (n = 10) arm found that they were both significantly effective in improving pruritus (20 mg BID; p=.02; 30 mg BID, p=.008) as well as quality of life (20 mg BID, p = .003; 30 mg BID, p = .01) among participants within 12 weeks and that 30 mg BID yielded significantly improved EASI score at 24 weeks.39 1 patient in the 20 mg arm withdrew from the study after experiencing an outbreak of herpes zoster.39 A smaller open-label trial of 5 participants found a 20% worsening of EASI scores over 16 weeks, leading to drug withdrawal of 4 participants (2 due to worsening AD and 2 due to nonadherence).40 Interestingly the authors of this trial noted the patients with atopic dermatitis had a worse EASI score at the outset.40 Case series and reports have shown that, for atopic dermatitis patients that responded to apremilast, improvement was noted beginning at 2 weeks of therapy and was overall well tolerated.41-43 Studies have also investigated management of other eczematous, pruritic conditions (chronic pruritus, prurigo nodularis, hand eczema, allergic contact dermatitis) with apremilast and found trends towards improvement in itch and quality of life.44-46 Participants with prurigo nodularis saw a 15% improvement in visual analog scale (VAS) for itch and a 21% improvement in the DLQI as well as a trend in decreasing interleukin 10 (IL-10) and IL-31 expression over 12 weeks, however the changes were not statistically significant.44 Separately, 66% of participants with chronic pruritus saw resolution of their itch over 16 weeks with material improvement in DLQI.45 However, results were not statistically significant likely SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 210 due to a small sample size, exacerbated by 7 participants withdrawing early (5 due to non-serious TEAE).45 Interestingly a small open-label trial found apremilast 20 mg BID improved EASI scores by 42% for patients with ACD over 12 weeks with limited TEAE.40 Cutaneous Sarcoidosis An open-label trial found that apremilast 20 mg BID significantly improved cutaneous sarcoidosis (as measured by the sarcoidosis activity and severity index (SASI) and investigator-visual evaluation) within 12 weeks although there were no changes in erythema, desquamation, or area of involvement.47 Of the 15 participants, 2 patients withdrew due to nausea and “jitteriness” and 3 patients who completed the study noted relapsing and worsening of their lesions after discontinuation.47 Discoid Lupus Erythematosus Among participants with discoid lupus erythematosus (DLE) who completed an open-label trial of apremilast 20 mg BID monotherapy, there was a significant improvement in cutaneous lupus erythematosus disease area and severity index (CLASI) score by day 85.48 50% of participants also noted resolution of scalp lesions during the study. However, 4 of 8 participants withdrew early: 2 due to disease progression and 2 due to TEAEs (lichenoid reaction and neuropathy) that both resolved with discontinuation of apremilast.48 Hidradenitis Suppurativa Several RCTs, open-label trials and case series/reports have investigated apremilast for the management of hidradenitis suppurativa (HS). A RCT of 20 participants with moderate HS (15 on apremilast 30 mg BID) found 53.3% achieved a 50% reduction in hidradenitis suppurativa clinical response (HiSCR50) as well as significant improvement in nodules and itch within 16 weeks.[49] The authors of this RCT found apremilast modulated levels of S100A12 and IL-17A and IL-17F, suggesting these as potential modulators of HS pathogenesis.50 Furthermore, in a 2 year follow up study, of the 8 participants that achieved HiSCR50, 4 patients maintained HiSCR at the 1 and 2 year mark with minimal and manageable TEAE (primarily gastrointestinal related).51 Of the 4 that discontinued, 1 discontinued due to complete resolution of symptoms, 2 due to “active pregnancy wish”, and only 1 discontinued as a result of intractable nausea after 6 months.51 An open-label trial of 20 patients found similar results with 60% reaching HiSCR50 by week 24.52 In both the initial RCT and open-label trial, TEAE were primarily gastrointestinal (nausea, diarrhea), headache, only 1 patient withdrew due to severe myalgias and arthralgias and there were no severe TEAE or severe infections.49,52 Smaller case series (n = 9) and case reports had similar findings of significant improvement in pain and DLQI with similar safety profile.53-55 Lichen Planus, Oral Lichen Planus, Lichenoid Dermatitis In an open-label trial of apremilast 20 mg BID, 3 out of 10 patients with corticosteroid- refractory lichen planus met the studies primary end point of improvement by ≥2 grades on the physician global assessment (PGA).56 However, further examination of all participants revealed a significant improvement in lesion count, target area lesion severity score (TALSS), itch and DLQI within 12 weeks.56 1 of 10 participants also had oral involvement and had material decrease in buccal lesions (40% to 12% surface area).56 4 weeks after discontinuation of apremilast, no significant difference was noted in study end points.[56] There were no serious TEAE, though 1 participant did develop asymptomatic SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 211 antinuclear antigen (ANA) positivity during the study.56 Several case series and reports have found apremilast was also effective in managing oral lichen planus with improvement within 2-4 weeks of initiation with only minor TEAEs that were adequately managed with dose reduction to 30 mg daily without compromising efficacy.57-59 A final case series of 5 patients found apremilast was effective in halting (3/5) and even resolving (2/5) lichenoid and interface dermatitis without inducing severe TEAE.60 Rosacea An open-label trial investigated the use of apremilast 20 mg BID for the management of erythematotelangiectasia (ETR) and papulopustular (PPR) rosacea among 10 participants with moderate to severe disease.61 By 12 weeks, there was a significant decrease in PGA, ETR rating overall erythema, and nontransient erythema with the latter two persisting for 1 month after discontinuation of therapy. No difference was found in number of papules/pustules at the end of the study versus baseline.61 Overall, apremilast was well tolerated with only 2 urinary (UTI) and upper respiratory tract (URI) infections neither of which necessitated dose decrease or drug withdrawal.61 Vitiligo A RCT investigating apremilast and narrow- band ultraviolet B (nbUVB) phototherapy for the management of vitiligo failed to meet its primary endpoint and found no significant difference at either 24 or 48 weeks between vitiligo area and severity index (VASI) score, vitiligo extent score (VES), vitiligo European task force (VETF) score, or DLQI between apremilast and nbUVB and placebo and nbUVB.62 Interestingly, a split-body trial investigated the combination of apremilast and narrow-band UVB (nbUVB) 2-3 times weekly for the management of vitiligo in darker phototypes (Fitzpatrick IV-VI).63 Over 3 phases, each lasting 16 weeks, patients receiving combination apremilast and nbUVB therapy had a significantly greater improvement in primary endpoint of >50% repigmentation (p=.001) and vitiligo area and severity index (VASI) (p=.0001) than nbUVB monotherapy.63 In the RCT, authors note 2 serious side effects, 1 being a suicide attempt that was attributed to apremilast treatment while the split-body study noted a majority of drug withdrawal were due to non- compliance with nbUVB regimen and reported no serious TEAEs.62,63 A case series of 13 patients found 61.5% achieved at least partial repigmentation (with as needed topical tacrolimus) and a 7.1% reduction in VASI.64 Additional case reports have found improvement in both recalcitrant acral and generalized vitiligo without lasting or serious TEAEs.65,66 Case series and reports detailing efficacy of apremilast for off-label dermatoses Palmoplantar pustulosis Although once considered a subtype of palmoplantar psoriasis, beginning in 2007 palmoplantar pustulosis has been deigned its own entity.67 Although several studies, including RCTs and open-label trials, have shown efficacy for multiple biologic and non- biologic therapies for palmoplantar psoriasis, there is less rigorous information for palmoplantar pustulosis, including with regards to apremilast.67 Several retrospective observational studies, including two case series of 10 and 3 patients found that after 2 weeks of apremilast 30 mg BID, there was significant improvement in both signs and symptoms of palmoplantar pustulosis, including ~62% improvement in palmoplantar psoriasis area and severity index (PPPASI) score, 66% reduction in number of pustules, and 66% in DLQI score.68-72 Furthermore, the median SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 212 Table 3. Randomized-Control Trials and Open-Label Trials for Off-Label Uses of Apremilast. Study Condition Study Type & Size (n on apremilast) Mean age (SD); %Male Dosage Duration (wks) Results TEAE Mikhaylov et al32 Alopecia Areata RCT (20) 37.1 (14.4); 20 30 mg BID 24 1/20 achieved at least SALT50 Improvement not significantly different from placebo (p=0.38) 3 early d/c due to TEAE Nausea (4), Diarrhea (3), URI (1), Tinea Pedis (1), arthralgia (1) Simpson et al38 Atopic Dermatitis RCT (58) 39.2 (--); 53.4 30 mg BID 12+12 31% achieved EASI50 by week 12 vs 32.8% on placebo. Not significantly different than placebo, though trend towards increased clinical improvement. Higher incidence of LE cellulitis (6 total, 2 serious) in 40 mg group leading to d/c of treatment arm in study. TEAE in >5% participants: Diarrhea, nausea, headache, nasopharyngitis, URI, abdominal discomfort, cellulitis, dyspepsia Serious TEAE: 30 mg: SCC (1), PNA (1) 40 mg: SI (1), Cellulitis (2), GN (1) Simpson et al38 Atopic Dermatitis RCT (63) 38.3 (--); 49.2 40 mg BID 12+12 Significant improvement in EASI score (31.6% vs 11.0% p<.04) and DLQI 27.3% vs 2.7%, p<0.05) by week 12 vs placebo, decrease in inflammatory markers (K16, p<.001; Ki67+ cells, p<.001; Th17 and Th17/22 markers, p<.05) Samrao et al39 Atopic Dermatitis Open-label trial (6) 38 (--); 83 20 mg BID 12 Significant improvement in VAS pruritus (p=.02) and DLQI (p=.003) 1 early d/c: Herpes Zoster(1) Nausea(2), Loose Stool(3), URI(2), Headache(2) Samrao et al39 Atopic Dermatitis Open-label trial (10) 45 (--); 50 30 mg BID 24 12 weeks: Significant improvement in EASI (p=.008) and DLQI (p=.01). 24 weeks: Significant improvement in EASI (p=.002), VAS (p=.003), and DLQI (p=.001) Nausea(9), Loose Stools(4), URI(3), other infection(3), Headache (2) Disease flare requiring rescue topical therapy (2) Volf et al40 Atopic Dermatitis Open-label trial (5) 43 (14.5); 40 20 mg BID 16 20% worsening in EASI 4 early d/c: 2 d/t worsening AD, 2 due to non-adherence Volf et al40 Allergic Contact Dermatitis Open-label trial (4+1 ACD & AD) 43.6 (15.7); 60 20 mg BID 12 42% reduction in EASI 40% at least EASI50 1 early d/c: d/t worsening of ACD SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 213 Clark et al45 Chronic Pruritus Open-label trial (10) 75 (--); 40 30 mg BID 16 No significant difference in NRS Itch or DLQI. Of note: 2/3 patients completed study noted material improvement in NRS itch (9.5 and 8 to 0) and DLQI. 7 d/c: TEAE(5), resolution of itch(1), use of prohibited Tx(1) Nausea(3), Diarrhea(3), Headache(1), Presyncope(1) Baughman et al47 Cutaneous Sarcoidosis Open-label trial (15) -- (--); 6.7 20 mg BID 12 Significantly decreased SASI induration at 4 weeks(p<.002) and 12 weeks(p<.005). Improved investigator-visual evaluation (p<.02) 2 patients decreased dose to 20 mg daily due to “jitteriness”(1) and nausea (1) De Souza et al48 DLE Open-label trial (8) 47.1 (12.3); 12.5 20 mg BID ~12 Significant improvement in CLASI score by day 85 (p=.01) and among patients that completed study (p=.03) 2/4 patients with complete regression of scalp lesions 4 early d/c: 2 d/t TEAE, 2 d/t disease progression Nausea (4), Diarrhea (1), Headache (2), Lichenoid Dermatitis (1), Neuropathy (1) Vossen et al49 HS RCT (15) 35.7 (13); 20 30 mg BID 16 53.3% on apremilast achieved HiSCR50 vs 0% of placebo Significant improvement in nodules (p=.011), NRS pain (p=.009), NRS itch (p=.015) No significant difference in DLQI 2 d/c: personal socioeconomic issues(1), severe myalgia/arthralgia(1) Headache (7), Diarrhea (7) Nausea (4), Vomiting (2), Depressed feeling (1), Non-serious infections (5), Sore throat (1), Pyelonephritis (1) Kerdel et al52 HS Open-label (20) 32.5 (10); 30 30 mg BID 24 60% achieved HiSCR50 Diarrhea (4), Nausea (3), URI (2), Depression (2), SI (1), abscess (1), UTI (1) Paul et al56 LP Open-label (10) 48.8 (12.8) 20 mg BID 12 3/10 achieved primary end point. Significant decrease in lesion count (p=.002), PGA (p=.0078), TALSS (p=.0078), SVAS (p=.0059) and DLQI (p=.002) Headache (4), new-onset ANA positivity (1) Todberg et al44 Prurigo Nodularis Open-label trial (10) 61.7 (10); 50 -- 12 No significant improvement over 12 weeks Mean VAS pruritus improvement from 8.7 to 7.4 Mean DLQI improvement 11.2 to 8.8 3 d/c: 2 due to lack of efficacy, 1 due to intermittent fever Diarrhea, nausea, abdominal pain in 5 patients, recurrent fever (1) SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 214 Thompson et al61 Rosacea Open-label trial (10) 39-74 yo; 30 20 mg BID 12 Significant decrease in PGA (p=.02), Overall Erythema (p=.001), ETR rating (p=.005) and nontransient erythema (p=.04) UTI(2), URI(2) Kemis et al62 Vitiligo RCT (38) 49.5 (13.4); 36.8 30 mg BID & nbUVB 52 No significant difference in VASI, VEF, VETF, or DLQI between apremilast and placebo 2 serious TEAE: suicide attempt (1), benign amygdala tumor (1) Diarrhea, abdominal pain, headache Kim et al63 Vitiligo RCT Split-body (23) --; -- 30 mg BID & nbUVB 48 Apremilast and nbUVB increased probability of >50% repigmentation (p=.001), improved VASI (p=.0001) compared to nbUVB monotherapy 14 d/c, majority due to non- compliance with nbUVB, TEAE (4) ANA – Anti-nuclear antibody; AD – Atopic Dermatitis; CLASI – cutaneous lupus erythematosus disease area and severity index; d/c – discontinued; DLE – discoid lupus erythematosus; DLQI – Dermatology Life Quality Index; EASI - Eczema Area and Severity Index; GN – glomerulonephritis; HS – hidradenitis suppurativa; HiSCR - Hidradenitis Suppurativa Clinical Response; HiSCR50 – 50% reduction in Hidradenitis Suppurativa Clinical Response; LE – lower extremity; NRS Itch– numeric rating scale Itch; NRS pain – numeric rating scale pain; PGA – physician global assessment; PNA – pneumonia; RCT – randomized-control trial; SALT50 – 50% reduction in severity of alopecia tool; SASI – sarcoidosis activity and severity index; SCC – squamous cell carcinoma; SI – suicidal ideation; SVAS – subject visual analog scale for itch; TALSS – target area lesion severity score; Tx – treatment; URI – upper respiratory tract infection; UTI – urinary tract infection; VAS – visual analog scale; VASI – vitiligo area and severity index; VEF – vitiligo extent score; VETF – vitiligo European task force score SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 215 Table 4. Case Series: Off-label Dermatoses and Apremilast. 18 case series listed alphabetically by dermatosis. Study Condition Sample size (n) Mean age (SD); %Male Dosage Duration weeks (SD) Results TEAE Taneja et al33 Alopecia Areata 15 25.8 (3.2); 86.7 30 mg BID (n=4) 30 mg daily (n=11) 37.2 (13.6) 15/15 patients noted hair regrowth, 13/15 with >50% response, 4/15 with >75% response Gastrointestinal side- effects (nausea, diarrhea, vomiting)(11) that lead to dose decrease Weber et al34 Alopecia Areata 5 34.8 (13.0); 0 30 mg BID 24 1/5 responded with regrowth lasting 18 months, 2/5 had slight transient regrowth, 2/5 without response Nausea (3), Diarrhea(1) Liu & King35 Alopecia Areata 9 38.8 (21.4); 44.4 30 mg BID 16.8 (4.8) 8/9 patients without improvement 1/9 with increased hair loss at 6 months -- Abrouk et al41 Atopic Dermatitis 5 50.2 (10.8); 80 30 mg BID 18.4 (16.3) Noticeable improvement in 2-4 weeks 4/5 patients with ≥75% improvement Nausea(1), Weight loss(1), pancreatitis(1, unrelated) Qiblawi et al73 Calcinosis Cutis 2 66 F 59 F 30 mg BID* 30 mg BID† 24 12 Improvement noted within 8 weeks Softening of plates of calcifications leading to calcium fragment extrusion Decreased dose and later discontinued due to recurrent infections at calcification areas -- Bitar et al74 Dermatomyositis 3 57 F 64 F 62 F 30 mg BID‡ 104 12 36 CDASI 43 à0 Muscle improvement CDASI 41 à7, able to taper off other Tx CDASI 62 à18 Nausea(1), Diarrhea(1) -- d/c treatment after flare and transitioned to IVIg Narang et al75 Erythema Nodosum Leprosum 2 34 M 31 M 30 mg BID 30 mg BID 20 12 Resolution of constitutional symptoms and significant improvement in skin lesions in 2 weeks Significant improvement in 4 weeks, and no new lesions 3 months after self- discontinuing -- -- SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 216 Bishnoi et al76 Granuloma Annulare 4 ~60 F ~43.3 (5.8); 0 30 mg BID 30 mg BID 12 6-8 Significant response within 6 weeks, almost clear by 12 weeks Significant response within 6-8 weeks Mild diarrhea, myalgia Myalgia, nausea Kieffer et al77 Hailey-Hailey disease 4 52.5 (5);25 30 mg BID 26 (4) 3/4 achieve PGA 1 after 6 months, 1/4 achieve PGA 1-2 after 5 months Diarrhea (2), Myalgia (1) requiring dose reduction to 30 mg daily Weber et al52 Hidradenitis Suppurativa 9 44.3 (13.5); 66.6 30 mg BID Range: 2 days – 36 weeks Significant reduction in sartorius score (p=.028), pain (p=.026) and DLQI (p=.021) 3 d/c due to TEAE: GERD(1), depression(1), insurance coverage(1) Weight loss(2), Nausea (1), Loose stool (1), dry cough (1) Bettencourt57 LP (oral) 3 70 (3.6); 100 30 mg BID 18.7 (6.1) Improvement noted within 2-4 weeks. 1/3 required intermittent prednisone for flares. 3/3 eventually had complete resolution of oral lesions 1/3 nausea and diarrhea requiring dose decrease to 30 mg daily Ravichandran & Kheterpal60 Lichenoid & Interface dermatitis 5 50.8 (18.0); 0 30 mg BID 52.8 (32.3) 3/5 no new lesions on apremilast 2/5 near complete remission on apremilast 1 patient decrease dose to 30 mg daily due to TEAE; 2 patient d/c due to insurance denial of coverage Diarrhea(2), Nausea(2), URI(1), Weight loss(1), Vomiting(1) Hadi & Lebwohl78 LPP/FFA 4 58.8 (21.2); 0 30 mg BID -- 2/4 improvement in scalp inflammation and pruritus in 12 weeks 2/4 with minimal improvement, TEAE lead to dose decrease then d/c gastrointestinal discomfort (3), depressive symptoms (1) Kaushik et al79 Orofacial Granulomatosis 5 33 (14.5); 40 30 mg BID 12 4/5 with response, 3/5 with significant reduction in labial swelling and erythema Diarrhea (2), Headache (2), vomiting Kato et al68 Palmoplantar Pustulosis 10 Median: 63.7; 20 30 mg BID 15.1 (5.9) After 2 weeks, mean improvement PPPASI 61.9% (p=.013), PC decrease 66% (p=.029), DLQI 66% (p = .009), VAS itch 62.5% (p=.026). Median 6.9 weeks to PPPASI50 and 2.9 weeks to 3 d/c due to diarrhea 2 decrease dose to 30 mg daily due to diarrhea 1 transiently decrease dose then resumed 30 SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 217 PC50 mg BID due to itch Frequent bowel movement (8), diarrhea (6), weight loss (3), palpitations (1), headache (1) Eto et al69 Palmoplantar Pustulosis 3 51.7 (10.7); 0 30 mg BID 32 Near complete resolution after 2 weeks Mild epigastric discomfort (1) Cohen et al80 Seborrheic Dermatitis 3 46 (20.5); 66 30 mg BID 12 Results notable within 3 months, complete clearance in 1 patient, 2 with mild localized SD Nausea (1) Majid et al64 Vitiligo 13 33.8 (12.2); 61.5 30 mg BID & as needed tacrolimus 12 61.5% of participants achieving partial repigmentation, including in areas without topical medication usage Mean VASI reduction 7.1% (p<.04) Headache, nausea, vomiting, abdominal pain 2/13 patients -- indicates data not explicitly available. If dosage missing, implied 30 mg BID *in addition to topical and intralesional sodium thiosulfate, pentoxifylline, minocycline, amlodipine, percutaneous ultrasonic lithotripsy †in addition to topical and intralesional sodium thiosulfate, diltiazem, pentoxifylline, minocycline, surgical extraction of calcium fragments ‡in addition to prior regimen: mycophenalate mofetil and prednisone (3), and hydroxychloroquine(1) BID – twice daily; CDASI – cutaneous dermatomyositis activity and severity index; d/c – discontinued; DLQI - dermatology-life quality index; GI – gastrointestinal; GERD – gastroesophageal reflux disorder; HS – hidradenitis suppurativa; IVIg – intravenous immunoglobulin; LP – Lichen Planus; LPP/FFA – lichen planopilaris/frontal fibrosing alopecia; M – male; mg – milligrams; PGA – physician global assessment; PPPASI – palmoplantar psoriasis area and severity index; PPPASI50 – 50% reduction in PPPASI; PC – pustule count; PC50 – 50% reduction in PC; SD – standard deviation; TEAE – treatment-emergent adverse effect; URI – upper respiratory tract infection; VASI – vitiligo area and severity index SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 218 time to 50% reduction in PPPASI and pustule count was 6.9 and 2.9 weeks, respectively.68 Of note, there were 5 participants in the 10-participant trial that withdrew (n = 3) or required dose reduction (n = 2) during the study due to diarrhea.68 Additional Dermatoses The combination of apremilast’s unique mechanism of action, safety profile (especially compared to other non-biologic systemic agents) as well as no need for regular laboratory monitoring have piqued interest in its use for a wide breadth of other dermatoses including (and likely not limited to): Acrodermatitis continua of Hallipeau, calcinosis cutis, chronic actinic dermatitis, dermatomyositis, erythema nodosum leprosum, folliculitis decalvans, granuloma annulare, Hailey-Hailey disease, lichen planopilaris/frontal fibrosing alopecia, orofacial granulomatosis, Anti-lamin γ1 (p200) pemphigoid, pemphigus vulgaris, pityriasis rubra pilaris, pyoderma gangernosum, seborrheic dermatitis, SAPHO, and vitiligo (Table 4 and 5).73-96 In these cases, apremilast has had material effect for patients with refractory disease to first and second line treatment and, surprisingly, is often used successfully as monotherapy. Although only FDA-approved for psoriasis, psoriatic arthritis and Behçet’s disease, apremilast’s mechanism of action has proven to have sustained efficacy for multiple inflammatory dermatoses without increasing rates of serious TEAEs. Many of the studies demonstrated apremilast’s efficacy especially for psoriasis for which FDA-approved first (and second line) therapies may have lost efficacy18-31 or for other moderate to severe dermatoses that were not suitably managed long-term by corticosteroids, or other non-biologic systemic agents32-96. In several cases, apremilast had the same relatively rapid onset of activity (~2-4 weeks) as seen in psoriasis, despite the various diverging types of inflammatory conditions treated.41,42,47,55,57,68,69,70,72,75,81,84,87,91,93 Furthermore, studies that investigated changes in known cytokine cascades suggest that apremilast and PDE-4 inhibition may achieve its efficacy by targeting inflammatory mediators unaffected or not primarily affected by current first-line agents.36-40,42,43,46,49,54,55,58,59,65,66,81-96 In addition to efficacy, consideration should be given to apremilast’s safety profile. While gastrointestinal TEAEs (most commonly nausea, diarrhea, vomiting), weight loss and headache do occur, they are often transient or manageable with dose modification.33,37,42,47,57,58,60,68,72,77 While several infections were documented across the collected studies, they usually occurred as a result of comorbid conditions (e.g., diabetes)38 and were predominately not severe infections. While depressive symptoms have been noted, in all the reviewed studies only 1 case was suicidal ideation/attempt directly associated with apremilast therapy.62 Additional studies have investigated the association of depression with apremilast and continually noted its safety regarding mental health.9 The safety profile is further highlighted by the fact that regular laboratory monitoring is not needed nor required for patients on apremilast.1,67 Taken together, apremilast has several unique characteristics that make it an attractive potential complementary or alternative therapeutic option for patients that are adverse to or are not ideal DISCUSSION SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 219 Table 5. Case Reports: Off-Label Dermatoses and Apremilast. 30 case reports listed in alphabetical order by dermatosis. Study Condition Age, Sex Dosage Duration weeks Results TEAE Magdaleno-Tapial et al36 Alopecia Areata 52 F -- 15 Regrowth of eyelashes and scattered scalp hair -- Chhabra et al37 Alopecia Totalis 11 M 30 mg qAM, 10 mg qPM & Plate-rich Plasma 24 Improved -- Saporito and Cohen42 Atopic Dermatitis 8 M 30 mg daily 8 Improvement noted starting at 2 weeks -- Farahnik et al43 Atopic Dermatitis + Alopecia Areata 55 M 30 mg BID 10 Subjective improvement in pruritus in 4 weeks with substantial decrease in erythema and stabilization of hair loss with some scalp hair regrowth in 10 weeks Transient nausea and “gas” Calleja Algarra et al81 Acrodermatitis continua of Hallopeau 75 M 30 mg BID 24 Improvement noted within 1 month, persistent improvement in onychodystrophy noted at 6 months Georgakopoulos et al82 Acrodermatitis continua of Hallopeau 68 M 30 mg BID & infliximab 5mg/Kg every 8 weeks 24 Used as maintenance, minimal onychodystrophy at 6 month follow up -- Lanna et al83 Acrodermatitis continua of Hallopeau 58 M 30 mg BID 4 DLQI improved from 10 to 0 over 4 weeks -- Kaushik et al84 Chronic actinic dermatitis 36 F 30 mg daily & low-potency topical and oral corticosteroids 12 Significant improvement in 4 weeks with clearance by 6 weeks -- Charlton et al85 Dermatomyositis ~50 F 30 mg BID & prednisone 7.5 mg/d, diltiazem 120 mg daily, yearly zolendronate 28 Resolution of heliotrope rash, facial erythema, scalp pruritus. No change in cutaneous calcinosis -- Sanchez-Martinez et al86 Erythema Nodosum Leprosum 23 F 30 mg BID 24 Asymptomatic by 6 month follow up Self-limited headache, mild diarrhea Fassler et al87 Folliculitis Decalvans 28 M -- & as needed 2% chlorhexidine shampoo 25 Significant nearly complete remission by 3 weeks -- Di Altobrando et Hailey-Hailey 68 F -- 144 Significant remission without further -- SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 220 al88 disease application of topical corticosteroids Navarro-Trivino et al46 Hand eczema Pruritus 65 M 30 mg BID 4 Improved -- Garcovich et al54 HS (+ PsA) 73 M 51 M 30 mg BID 30 mg BID 16 16 Improved HS-PGA: 4 à 2 Improved DLQI: 23 à 6 Improved HS-PGA: 5 à 3 Improved DLQI: 25 à 9 None by 60 weeks None by 72 weeks Lanna et al55 Hidradenitis Suppurativa (+PsO) 55 M 30 mg BID PASI95, Hurley stage decrease 2 to 0-1 and DLQI from 22 to 0 within 20 days -- AbuHilal et al58 LP (Oral) 44 F 30 mg daily 12 Improvement in buccal/gingival lesions Nausea with 30 mg BID Hafner et al59 LP (Oral), esophageal stenosis 74 F -- 4 Complete resolution of dysphagia and erosive stomatitis -- Haebich & Kalavala70 Palmoplantar Pustulosis 75 F 30 mg BID ~52 Resolved within 4 weeks -- Haller et al71 Rituxmimab- associated Palmoplantar Pustulosis 57 F 30 mg BID Significant improvement within 6 weeks -- Carrascosa et al72 Palmoplantar Pustulosis 77 F 30 mg daily ~52 Near complete resolution of pain/pustules within 2 weeks Mild diarrhea resolved with dose reduction from BID to daily Waki et al89 Anti-lamin γ1 (p200) pemphigoid (+ PsO) 57 M 60 mg daily & prednisolone taper (30 mg/d to 15 mg/d) ~36 Able to taper prednisolone 2.5 mg ever 5-7 weeks without flare -- Meier et al90 Pemphigus Vulgaris 62 F 30 mg BID & 2 mg mycophenolate mofetil and 20 mg prednisone 32 ABSIS 38à0 Reduction in anti-Dsg1 and anti- Dsg3 antibodies and increase in Treg and Tfreg cells -- Krase et al91 PRP 70 M 30 mg BID 32 Initial improvement noted within 4 weeks with complete resolution within 6-8 months GI upset Cho et al92 PRP 60 F 30 mg daily 24 Complete resolution at 8 weeks, Mild headache SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 221 sustained at 24 weeks Pellonnet et al93 PRP 47 M 30 mg BID 28 Complete resolution at 4 weeks, sustained to 28 weeks -- Molina-Figuera et al94 PRP 61 F 30 mg BID 28 Near complete clearance at 8 weeks and able to discontinue at 28 weeks due to resolution. Remained symptoms free 12 weeks after d/c -- Vernero et al95 Pyoderma Gangrenosum 35 M -- & prednisone and vedolimumab for Crohn’s disease 19 Consistent improvement in pain and lesion re-epithelialization at 15 weeks -- Adamo et al96 SAPHO 24 F 30 mg BID 28 92.3% reduction in PPPASI Transient headache, diarrhea, nausea, vomiting resolved within 4 weeks Plachouri et al65 Vitiligo (+ PsO) 59 M 30 mg BID 24 Repigmentation of vitiligo on neck and trunk without much affect at extremities. Near complete clearence of PsO plaques -- Huff & Gottwald66 Vitiligo 52 F 30 mg BID & IM triamcinolone 60 mg 52 Slow repigmentation proximal to distal over 6.5 months, 60-70% repigmentation on face, chest arms by 11 months -- -- indicates data not explicitly available. If dosage missing, implied 30 mg BID ABSIS – autoimmune bullous skin disorder intensity score; BID – twice daily; DLQI - dermatology-life quality index; DSG – desmoglein; GI – gastrointestinal; HS-PGA – hidradenitis suppurativa-physician global assessment; LP – Lichen Planus; M – male; mg – milligrams; F – female; PPPASI – palmoplantar psoriasis area and severity index; PRP – pityriasis rubra pilaris; PsA – psoriatic arthritis; PsO – psoriasis; qAM – every morning; qPM – every afternoon/evening; SAPHO – synovitis, acne, pustulosis, hyperostosis and osteitis; TEAE – treatment-emergent adverse effect; Treg – regulatory T-cell; Tfreg – follicular regulatory T-cell SKIN May 2021 Volume 5 Issue 3 Copyright 2021 The National Society for Cutaneous Medicine 222 candidates for current therapies. Additional studies may further elucidate ways apremilast monotherapy and combination therapy, especially in the setting or recalcitrant psoriatic arthritis, may be used to improve patient care and outcomes for psoriasis and other inflammatory dermatoses. Apremilast is an oral, non-biologic systemic agent that inhibits phosphodiesterase 4 activity to modulate inflammation. While transient gastrointestinal side effects are common, especially early-on in therapy, it has a relatively innocuous safety profile that makes it a potential efficacious agent for monotherapy and combination therapy for a wide range of inflammatory dermatoses. Conflict of Interest Disclosures: JWM has no relevant disclosures. MGL is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen Research & Development, LLC, Leo Pharmaceutucals, Ortho Dermatologics, Pfizer, and UCB, Inc.and is a consultant for Aditum Bio, Allergan, Almirall, Arcutis, Inc., Avotres Therapeutics, BirchBioMed Inc., BMD skincare, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy’s Laboratories, Serono, Theravance, and Verrica. Funding: None Corresponding Author: Justin W. Marson, MD Department of Dermatology SUNY Downstate Health Sciences University Brooklyn, NY, 11203 Fax: 732-802-7207 Email: justin.w.marson@gmail.com References: 1. Apremilast. Package Insert. 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