Systemic Therapy for Nail Psoriasis

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Despite the range of systemic therapeutic options for psoriasis, psoriatic nail dystrophies are often unaddressed and untreated.1 The dearth of psoriatic nail disease in evidence-based medicine is discordant with the pertinence of nail psoriasis to disease prognosis. Up to between 80% to 90% of all patients with plaque psoriasis will have at least one incidence of nail psoriasis in their lifetime.2 Although the incidence of nail psoriasis is higher in patients with moderate to severe plaque psoriasis,3 up to 50% of all patients with plaque psoriasis have chronic nail involvement.4 Of note, nail psoriasis is not just associated with plaque psoriasis, but also with psoriatic arthritis. Up to 80% of patients with psoriatic arthritis have nail involvement,3 thus the correct diagnosis of nail psoriasis can guide a physician to screen for arthritis.

The clinical presentation of nail psoriasis depends on the location of the inflammatory process: nail matrix or nail bed (Figure 1).5-7 If disease originates in the nail matrix, there is pitting, leukonychia, and crumbling. If disease originates in the nail bed, there may be subungal hyperkeratosis, onycholysis, and splinter hemorrhages. The main differential diagnosis of nail psoriasis is onychomycosis. With shared features such as hyperkeratosis or crumbling of the nail, the two can be difficult to distinguish8; however, signs such as nail pitting, oil drop discoloration, and onycholysis are more commonly seen in nail psoriasis than in onychomycosis (Figure 2).6 

figure 1

Figure 1. Clinical presentation of moderate to severe fingernail psoriasis.5-7

Options for treating moderate to severe fingernail psoriasis include topical therapies (eg, steroids), procedures (eg , nail removal or phototherapy), oral systemics, and biologics.9 When treating psoriasis, it is important to remember that because fingernail growth takes 5 to 7 months, improvements in nail psoriasis often lag behind improvements appreciated on the skin.9 

figure 2

Figure 2. Clinical presentation of nail psoriasis vs onychomycosis.6

Assessing Psoriatic Nail Disease

There are several standardized approaches in which psoriatic nail disease may be evaluated, classified, and described. The Nail Psoriasis Severity Index (NAPSI) provides a way to assess disease severity and monitor response to medication. This scoring system divides each nail into 4 quadrants and looks at disease severity therein (Figure 3). A quadrant is assigned 1 point if it contains signs of nail bed disease: onycholysis, splinter hemorrhages, subungal hyperkeratosis, and/or oil drop dyschromia. A quadrant is also assigned1 point if it has nail matrix disease: pitting, crumbling, leukonychia, and/or red lunular spots. Each of the 4 quadrants can equal up to 2 points (1 point for the matrix and 1 for nail bed disease), with a maximum severity score per individual nail equaling 8.10 Rather than assess all nails, an acceptable alternative is to focus on the most diseased “target” nail and assign a separate point for each of the 8 signs of nail psoriasis to each quadrant. In this targeted method, the chosen nail has a maximum severity score of 32, with up to 8 points possible per quadrant. 

Figure 3. The Nail Psoriasis Severity Index method of scoring and assessing nail psoriasis.1

figure 3

A modified NAPSI score (mNAPSI) was developed in 2005.11 The original NAPSI is based on whether there is any presence of nail bed and/or nail matrix disease in each quadrant, with a maximum of 8 points assigned per nail. The mNAPSI looks at the nail as a whole (no quadrants) and assigns a score based on severity of specific signs, such as pitting, crumbling, onycholysis or oil drop dyschromia, and subungal hyperkeratosis. Each appearance of these signs of nail disease is assigned a score based on severity: 0 for clear, 1 for mild, 2 for moderate, 3 for severe.12 By examining the whole nail, the mNAPSI better accounts for irregular distribution of psoriasis manifestations. The more quantitative mNAPSI was found to increase scoring sensitivity, decrease inter-rater variability11, and better reflect the response of the nail psoriasis to treatment than the original NAPSI.11,12 

Evidence-Based Systemic Treatments for Nail Psoriasis

Relative to the plethora of psoriasis-related data currently published, there are only a few studies in which improvement in nail psoriasis is reliably assessed as a primary or secondary endpoint, particularly with respect to systemic therapies. That said, over the last decade, several randomized, large-scale clinical trials have provided efficacy data for the use of systemic therapies to treat nail psoriasis. Additionally, several of these studies provide compelling data directly comparing efficacies (see UNCOVER and VOYAGE trials, below). In all of the following studies, safety data was consistent with prior trials of these medications for the treatment of plaque psoriasis. 

Anti-TNF Medications and Nail Psoriasis

Anti-tumor necrosis factor-α (Anti-TNF-α/anti-TNF) medications have long been used for the treatment of a variety of inflammatory diseases. TNF-α is an inflammatory cytokine that is produced by almost every dysregulated cell in psoriasis pathogenesis, including dendritic cells, T cells, macrophages, and keratinocytes. TNF-α production leads to increased immune cell activation, differentiation, and proliferation. Currently, there are several FDA-approved anti-TNF agents for the treatment of plaque psoriasis: certolizumab pegol (Cimzia), etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Etanercept acts as a soluble TNF-α receptor that binds and competitively inhibits excess plasma TNF-α. Infliximab, certolizumab pegol, and adalimumab are antibodies that bind and inactivate soluble and membrane-bound TNF-α molecules. Anti-TNFs are often referred to as “first-generation” biologics because TNF-α is produced by many inflammatory conditions, making it a wider target than other biologics.13

Adalimumab

In 2017, the FDA expanded its indication to include moderate to severe fingernail psoriasis.14 To date, adalimumab is the first and only biologic that provides FDA-approved use and efficacy data for the treatment of fingernail psoriasis in its prescribing information.15 Data included on the label was obtained through a phase 3, randomized, double-blind study that evaluated improvement in nail psoriasis as a primary endpoint.14,15 Participants received adalimumab 40 mg or placebo every other week for 26 weeks (Period A), followed by all participants receiving adalimumab for an additional 26 weeks (Period B). Nails were assessed using the mNAPSI at baseline and week 26, as well as the Physician Global Assessment of Finger Nail Psoriasis (PGA-F). 

Results from the study include16

  • At the end of period A, 47% of participants on adalimumab and 3% of participants on placebo met the preliminary mNAPSI 75 endpoint (P<.001). 
  • PGA-F scores of 0 or 1 were reached by 49% of participants on adalimumab vs 7% of participants on placebo (P<.001). 
  • Nail pain improved in participants on adalimumab. 
  • Similar responses to treatment were seen in most participants at the end of period B, whether or not they took adalimumab or placebo for period A. 
  • No new safety risks were identified with the 40 mg every other week treatment with adalimumab for 52 weeks. 

Anti IL-17 Medications and Nail Psoriasis

IL-17 (particularly IL-17A) is the main cytokine implicated in the dysregulation of keratinocyte proliferation and differentiation seen in psoriasis. IL-17 is pro-inflammatory, produced by many immune cells (natural killer cells, cytotoxic T cells, neutrophils) and is upregulated in psoriatic lesions. IL-17 biologics FDA-approved for the treatment of plaque psoriasis include: secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). These medications belong to a group of second-generation biologics that more specifically target the IL-23/TH17 pathway implicated in psoriasis pathogenesis. Secukinumab and ixekizumab are antibodies that bind and neutralize IL-17A. Brodalumab binds and inactivates IL-17 receptor A, which may block the effects of more subsets of IL-17 (not just 17A). The anti-IL17 antibodies are highly effective, rapid treatments for psoriasis. They are generally safe, with the most common side effect being an increased risk of developing mild infections, primarily of the upper respiratory tract, or uncomplicated mucocutaneous candida.13

Secukinumab

Seckinumab is another FDA-approved treatment with data demonstrating efficacy for nail psoriasis. Secukinumab is an anti-IL17A antibody indicated for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis, as well as active ankylosing spondylitis.17 Noteworthy data on its efficacy was found in the TRANSFIGURE trial, which included 198 participants randomized to secukinumab 150 mg, secukinumab 300 mg, or placebo.18 Participants received secukinumab or placebo once a week for 5 weeks, then monthly for 16 weeks. After 16 weeks, participants receiving placebo were re-randomized to secukinumab 150 mg or 300 mg for the remainder of the 132-week study period. 

Results from the TRANSFIGURE trial include18:

  • At week 16:
    • Both doses of secukinumab were superior to placebo (primary endpoint met).
    • Mean NAPSI percent changes from baseline: -45% for 300-mg secukinumab, -38 to 39% for 150-mg secukinumab, -11% for placebo.
    • Visible improvement in nail psoriasis.
    • Safety results were consistent with previous studies.
  • At week 132:
    • Mean NAPSI percent changes from baseline: -68.7% for 300-mg secukinumab, -52.7% for 150-mg secukinumab.
    • All immunogenicity developed to secukinumab over the course of the trial was transient.19

Ixekizumab

Ixekizumab, an anti-IL-17A antibody, received FDA approval for the treatment of plaque psoriasis in 2016 and psoriatic arthritis in 2017. Approval was based on data from the UNCOVER 1, 2, and 3 trials, which included a total of 806 participants with nail psoriasis at baseline. In addition, to examining the efficacy of ixekizumab on plaque psoriasis, the trial measured mean changes in NAPSI scores and improvements in nail psoriasis.20

Select results on improvements in nail psoriasis from the UNCOVER trials include21:

  • At week 12:
    • Greater mean percent NAPSI improvements found in those treated with ixekizumab (every 4 weeks 37%, every 2 weeks 35%) vs etanercept (20%) or placebo (-34%). 
    • Complete resolution (NAPSI = 0) was achieved in approximately 38% of patients treated with ixekizumab, 10% of those treated with etanercept (P<0.05), and in 4% of patients treated with placebo (P<.001). 
  • At week 60:
  • Those treated with etanercept or placebo were switched at week 12 to ixekizumab for the remainder of the trial, to week 60. 
  • Regardless of initial treatment prior to week 12, the mean percent of NAPSI improvement was >80%, with >50% achieving complete resolution (NAPSI = 0).

Anti-IL23 Medications and Nail Psoriasis

IL-23 is a proinflammatory cytokine upstream of IL17 in the pathogenesis of psoriasis. In the presence of IL-23, naïve T cells differentiate into TH17 cells. IL-23 activates TH17 cells to release pro-psoriasis cytokines such as IL-17A. Anti-IL23 medications that are FDA-approved for the treatment of plaque psoriasis include guselkumab (Tremfya), ustekinumab (Stelara) and, recently, tildrakizumab (Ilumya). Ustekinumab is an antibody that binds to the shared subunit of, and thus inhibits, cytokines IL-12 and IL-23. Guselkumab and tildrakizumab are antibodies that target the p19 subunit of cytokine IL-23, without interfering with the shared subunit with cytokine IL-12 (unlike ustekinumab); the role of IL-12 in psoriasis pathogenesis is more controversial and there is evidence of anti-psoriatic effects of IL-12; additionally, fewer adverse events are expected with the inhibition of just one cytokine.13

Guselkumab

The VOYAGE trials assessed the efficacy of guselkumab, an anti-IL-23 antibody, on nail psoriasis symptoms, among other areas of the body compared with adalimumab and placebo. Both trials are still in process, but preliminary results show potential for this biologic.22 

In VOYAGE-1, participants with moderate to severe plaque psoriasis were randomized into 3 treatment arms22: placebo administered every 4 weeks followed by guselkumab 100 mg at weeks 16 and 20, then every 8 weeks through week 44; guselkumab 100 mg administered every 4 weeks followed by every 8 weeks through week 44; and adalimumab 80 mg at baseline, 40 mg at week 1, then 40 mg every 2 weeks through week 27. Overall, 58.7% of participants had nail psoriasis. 

Among participants with a baseline fingernail Physician’s Global Assessment (f-PGA) score of ≥2, the proportions of participants achieving PGA-F scores of clear (0) or minimal (1) was compared at week 16. Slightly more than half (50.9%) of participants with nail psoriasis treated with guselkumab achieved an improved PGA-F of 0 or 1 at Week 16, which is clinically and statistically significant (P<.001) when compared with adalimumab- and placebo-treated patients (39.1% and 15.9%). Additionally, 56.3% of participants in the guselkumab treatment arm and 62.4% of those in the adalimumab treatment arm achieved PGA-F of 0 or 1 at week 24, though the difference between the 2 groups was not statistically significant. By week 48, 74.7% of participants in the guselkumab arm and 61.8% of those in the adalimumab arm achieved PGA-F scores of 0 or 1.22

Other notable results from VOYAGE-1 include:22

  • At week 16, participants given placebo experienced a negative percent improvement from baseline in NAPSI (worsened nail disease). 
  • Participants given guselkumab and adalimumab experienced a 34.4% and 38% mean improvement in NAPSI at week 16 (P<.001). 
  • NAPSI score continued to improve in both the guselkumab and adalimumab treatment groups at weeks 24 and 48, with no statistically significant difference between their percentages. 

In VOYAGE-2, participants were also randomized into 1 of 3 treatment arms: placebo every 4 weeks for 12 weeks followed by guselkumab 100 mg for weeks 16 and 20; guselkumab 100 mg every 4 weeks for 20 weeks; adalimumab 80 mg at baseline, 40 mg at week 1 followed by 40 mg every 2 weeks through 23 weeks. 

Select results from VOYAGE-2 include:22

  • At week 16, >50% of participants treated with guselkumab or adalimumab achieved a PGA-F score of 0 or 1 compared with 15% of those in the placebo arm.
  • Similar to VOYAGE-1, participants treated with adalimumab achieved greater improvements in nail psoriasis, as reflected by f-PGA and NAPSI, at weeks 16 (P<.001) and 24 (P>0.3). 

Oral PDE4 Inhibitor and Nail Psoriasis

Phosphodiesterases (PDE) are enzymes present within many cells that degrade cyclic adenosine monophosphate (cAMP). PDE4 is particularly prevalent in immune cells and is believed to modulate inflammation. PDE4 inhibition appears to decrease production of cytokines such as TNF-α. The only PDE4 inhibitor FDA-approved for the treatment of plaque psoriasis is apremilast (Otezla). The exact mechanism of action is unclear, but apremilast is a small molecule PDE4 inhibitor taken orally. Though it acts systemically, it is not considered a “biologic.”13

Apremilast

Apremilast is an oral PDE4 inhibitor approved for the treatment of active psoriatic arthritis and moderate to severe plaque psoriasis. Rather than target one inflammatory cytokine involved in psoriatic pathogenesis, as many of the biologics do (eg, IL-23 or IL-17), through PDE4 inhibition, apremilast affects many downstream mediators of inflammation. While the exact pathogenesis is not clear, the result is a more balanced system of pro- vs anti-inflammatory signals and decreased systemic inflammation. 

Data from the UNVEIL trial showed efficacy of apremilast among 221 participants with nail and scalp psoriasis.23 Participants were randomized to apremilast 30 mg twice a day for 16 weeks or placebo. After 16 weeks, participants in the placebo arm were switched to apremilast. All participants received treatment for 52 weeks. NAPSI was used to assess the efficacy of treatment on nail psoriasis symptoms, with the target nail defined as the nail with worst psoriasis involvement at baseline.

Select results from UNVEIL include23:

  • At week 16, the mean percentage change from baseline in NAPSI score was -10.5% in the placebo group and -28.9% in the apremilast group (P=0.12). 
  • Continued improvement in NAPSI score was seen in participants who remained on apremilast through week 52 (with a mean percentage change from baseline of -51.9%).
  • Participants who switched from placebo to apremilast at week 16 demonstrated improvement in NAPSI scores (with a mean percentage change from baseline of -52.7%). 
  • At week 16, NAPSI-50 was achieved by 18.5% of participants in the placebo group and by 26.8% of participants in the apremilast group (P=0.50). 
  • The proportion of participants who achieved NAPSI-50 increased from week 16 to week 52 among those who were on apremilast for 52 weeks and those who switched to apremilast from placebo at week 16. 

Although differences in NAPSI 50 response with apremilast compared with placebo were numerically greater at week 16, the number of participants with nail psoriasis at baseline was low (n=83) and thus statistical significance was not demonstrated (P=.50). However, continued improvement was seen with apremilast treatment up to 52 weeks. The efficacy,24 safety and tolerability of apremilast in the UNVEIL study was consistent with previous studies.25,26

In addition, data from the LIBERATE study showed improved nail psoriasis symptoms. The LIBERATE study included 250 participants who were randomized to placebo, apremilast 30 mg twice day, or etanercept 50 mg weekly for 16 weeks followed by all participants continuing or switching to apremilast through 104 weeks.27 Consistent with previous studies, including UNVEIL, the proportions of participants with nail psoriasis at baseline who achieved NAPSI 50 at week 16 were higher with apremilast (25%) and etanercept (48%) compared with placebo (10.9%, P=.07 vs apremilast and P<.0001 vs etanercept). At week 104, NAPSI 50 response was 60.4% in the apremilast group, 65.2% in the etanercept/apermilast group, and 48.6% in the placebo/apremilast group. The mean percentage change from baseline in NAPSI score continued to improve among participants in the apremilast group and was sustained among participants in the etanercept/apermilast group through week 104. 

Table

Therapies in Action

Despite the many therapies available, nail psoriasis has long been considered difficult to treat. It should be evident that we now have solid data showing us that nail psoriasis can be properly assessed and effectively treated with several medications.

Comparing efficacy among these medications is difficult, as the above study designs vary in important ways: medication strength and frequency, participant population, time-points assessed (eg, week 16 vs week 26), and measures of treatment success (eg, percentage of participants in each treatment group reaching NAPSI 75 vs percent improvement in NAPSI), etc. 

There are only a few studies that directly compare biologics to assess for relative treatment efficacy for the treatment of nail psoriasis. The aforementioned studies that directly compare treatments, and from which we can draw more concrete comparisons, include UNCOVER (ixekizumab vs etanercept), VOYAGE (guselkumab vs adalimumab), and LIBERATE (apremilast vs etanercept). 

Although there is much more work to be done, we can draw several comparisons from the preliminary data. The UNCOVER results show that at week 12, the ixekizumab treatment group had greater mean percent NAPSI improvement than the etanercept treatment group. The VOYAGE trials show that at week 16 guselkumab shows a greater improvement in nail psoriasis than adalimumab, but by week 24 both treatment groups achieved comparable improvement. The LIBERATE trial found that by week 16, a greater percentage of the etanercept treatment group achieved NAPSI 50 when compared to those receiving apremilast. 

As investigation of treatment efficacy on nail psoriasis is a newly blossoming field, more direct comparative studies are required to conclusively say one treatment is definitely superior to another. Until more conclusive comparisons can be made, which treatment is right for your patient should be personalized based on factors such as disease severity, drug contraindications, and side effect profiles (Table).28 For now, it is comforting to know that there are many evidence-based medicines that can effectively treat nail psoriasis. 

 

Ms Wind is a medical student at Albert Einstein College of Medicine (AECOM) in New York, NY. 

Dr Weinberg is an associate clinical professor of dermatology at the Icahn School of Medicine at Mount Sinai in New York, NY.

Disclosures: Ms Wind reports no relevant financial relationships.

 Dr Weinberg received speaker honoraria from Novartis, Eli Lilly and Company, Amgen, AbbVie Inc, Sun Pharmaceutrical Industries Ltd, and research grants from Novartis, Eli Lilly and Company, Amgen, and AbbVie Inc.

References

1. Reich K. Approach to managing patients with nail psoriasis. J Eur Acad Dermatol Venereol. 2009;23(suppl 1):15-21. 

2. Langenbruch A, Radtke MA, Krensel M, Jacobi A, Reich K, Augustin M. Nail involvement as a predictor of concomitant psoriatic arthritis in patients with psoriasis. Br J Dermatol. 2014;171(5):1123-1128.

3. Langley RG, Saurat JH, Reich K; Nail Psoriasis Delphi Expert Panel. Recommendations for the treatment of nail psoriasis in patients with moderate to severe psoriasis: A dermatology expert group consensus. J Eur Acad Dermatol Venereol. 2012;26(3):373-381. 

4. Augustin M, Krüger K, Radtke MA, Schwippl I, Reich K. Disease severity, quality of life and health care in plaque-type psoriasis: A multicenter cross-sectional study in Germany. Dermatology. 2008;216(4):366-372. 

5. Jiaravuthisan MM, Sasseville D, Vender RB, Murphy F, Muhn CY. Psoriasis of the nail: Anatomy, pathology, clinical presentation, and a review of the literature on therapy. J Am Acad Dermatol. 2007;57(1):1-27. 

6. Pasch MC. Nail psoriasis: A review of treatment options. Drugs. 2016;76(6):675-705. 

7. Manhart R, Rich P. Nail psoriasis. Clin Exp Rheumatol. 2015;33(5 suppl 93):S7-S13.

8. Armstrong AW. Nail psoriasis. UpToDate. https://www.uptodate.com/contents/nail-psoriasis.Updated March 12, 2018. Accessed January 8, 2019.

9. Crowley JJ, Weinberg JM, Wu JJ, Robertson AD, Van Voorhees AS; National Psoriasis Foundation. Treatment of nail psoriasis: Best practice recommendations from the Medical Board of the National Psoriasis Foundation. JAMA Dermatol. 2015;151(1):87-94. 

10. Rich P, Scher RK. Nail Psoriasis Severity Index: A useful tool for evaluation of nail psoriasis. J Am Acad Dermatol. 2003;49(2):206-212.

11. Parrish CA, Sobera JO, Elewski BE. Modification of the Nail Psoriasis Severity Index. J Am Acad Dermatol. 2005;53(4):745-746.

12. Klaassen KM, Van de kerkhof PC, Bastiaens MT, Plusjé LG, Baran RL, Pasch MC. Scoring nail psoriasis. J Am Acad Dermatol. 2014;70(6):1061-1066.

13. Rønholt K, Iversen L. Old and new biological therapies for psoriasis. Int J Mol Sci. 2017;18(11):2297. doi:10.3390/ijms18112297

14. FDA. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125057. Accessed May 24, 2017.

15. Humira [package insert]. Chicago, IL: AbbVie Inc; 2002. 

16. Elewski BE, Okun MM, Papp K, et al. Adalimumab for nail psoriasis: Efficacy and safety from the first 26 weeks of a phase 3, randomized, placebo-controlled trial. J Am Acad Dermatol. 2018;78(1):90-99e1. doi:10.1016/j.jaad.2017.08.029

17. Cosentyx [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2017.

18. Reich K, Sullivan J, Arenberger P. Secukinumab is effective in subjects with nail psoriasis: 16 week results from the Transfigure Study. Presented at: 23rd World Congress of Dermatology; June 8-13, 2015; Vancouver, Canada. Abstract 3086561. 

19. Study of safety, tolerability, and efficacy of secukinumab in subjects with moderate to severe nail psoriasis (TRANSFIGURE) [NCT01807520]. US National Library of Medicine. Published March 8, 2013. Updated March 13, 2018. https://clinicaltrials.gov/ct2/show/NCT01807520. Accessed January 8, 2019.

20. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356.

21. Van de kerkhof P, Guenther L, Gottlieb AB, et al. Ixekizumab treatment improves fingernail psoriasis in patients with moderate-to-severe psoriasis: Results from the randomized, controlled and open-label phases of UNCOVER-3. J Eur Acad Dermatol Venereol. 2017;31(3):477-482.

22. Blauvelt A, Papp K, Griffiths CEM, et al. Efficacy of guselkumab within specific body regions in patients with moderate-to-severe plaque psoriasis: Results from the Phase 3 VOYAGE 1 study. Presented at: the American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, FL. Abstract 4768.

23. Jackson M, Alikhan A, Lebwohl M, et al. Improvement in scalp and nails with apremilast in patients with moderate plaque psoriasis naive to systemic and biologic therapy: 52-Week results of the UNVEIL Study. Presented at: 26th Congress of the European Academy of Dermatology and Venereology; September 13-17, 2017; Geneva, Switzerland. Abstract 1946.

24. Rich P, Gooderham M, Bachelez H, 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(1):134-142.  

25. Papp K, Reich K, Leonardi CL, 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(1):37-49.  

26. Paul C, Cather J, Gooderham M, 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(6):1387-1399.

27. Reich K, Gooderham M, Bewley A, et al. Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment: Findings from the LIBERATE study. J Eur Acad Dermatol Venereol. 2018;32(3):397-402.

28. Treatment comparison. National Psoriasis Foundation. https://www.psoriasis.org/sites/default/files/treatment_comparison_chart_2018.pdf. Accessed January 8, 2019.