Clinical effectiveness of novel rosacea therapies

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ScienceDirect Clinical effectiveness of novel rosacea therapies Brittany Feaster1, Abigail Cline1, Steven R Feldman1,2,3 and Sarah Taylor1 Rosacea is a common inflammatory skin disease that is difficult to manage because of the unknown etiology and due to its variable manifestations. These facts and the few new available treatment options make it difficult to select a really effective treatment. This review aims to assess the efficacy and safety of novel treatment options for rosacea. The topical alpha adrenergic agonist oxymetazoline reduces rosacea-related erythema. Topical ivermectin improves lesion count, inflammation, and maintenance of remission of rosacea compared to topical metronidazole. Procedural therapies including pulsed dye laser, radiofrequency, and dual frequency ultrasound are promising as both monotherapies or in combination. Although there are several effective treatment modalities for rosacea management, treatments options should be tailored for the specific clinical scenario. Addresses 1 Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, United States 2 Department of Pathology, Wake Forest School of Medicine, WinstonSalem, NC, United States 3 Department of Social Sciences & Health Policy, Wake Forest School of Medicine, Winston-Salem, NC, United States Corresponding author: Cline, Abigail ([email protected])

hypertrophy of the nose. Ocular rosacea (OR) includes tearing, itching, stinging, dryness, and other ocular involvement [2]. However, clinical manifestations do overlap and may progress. There is minor improvement in understanding rosacea’s pathogenesis and, therefore, only a few new available treatments have occurred during the last years. All these facts make it unclear which options are most effective. Recent studies were reviewed with an emphasis on newly FDA approved topical therapies as well as new studies on old procedural therapies. This review aims to assess the efficacy and safety of novel treatment options for rosacea [3,4].

Methods A PubMed search included keywords, ‘effectiveness and rosacea therapy’, ‘effectiveness and rosacea treatment’, ‘rosacea management’, ‘rosacea treatment outcome’, and ‘rosacea therapy efficacy’. Articles included were in English and ranged from January 2016 through June 2018. Clinical trials with a sample size less than ten were excluded. A total of 11 peer reviewed clinical trials were reviewed.

Topical therapies Oxymetazoline

Current Opinion in Pharmacology 2019, 46:14–18 This review comes from a themed issue on Dermatology Edited by Sonja Sta¨nder and Mette Deleuran

https://doi.org/10.1016/j.coph.2018.12.001 1471-4892/ã 2018 Elsevier Ltd. All rights reserved.

Introduction Rosacea is a chronic skin disorder associated with inflammation of the face and a broad diversity of cutaneous manifestations. Rosacea occurs in 10% of the population, most commonly among individuals with Fitzpatrick skin types I and II [1]. Rosacea is divided into four subtypes: erythethematotelangiectatic, papulopustular, phymatous, and ocular. Erythematotelangiectatic rosacea (ETR) includes telangiectasia, erythema, and flushing. Papulopustular rosacea (PPR) includes erythema and flushing with papules and pustules. Phytamous rosacea (PHY) includes thickening of the skin often involving tissue Current Opinion in Pharmacology 2019, 46:14–18

Oxymetazoline cream 1.0% is a vasoconstrictive alphaadrenergic agonist [5]. Previously utilized in nasal and ophthalmic formulations, oxymetazoline is FDAapproved as a topical treatment for persistent facial erythema in rosacea [6,7]. Persistent facial erythema may present both during and/or between rosacea flares due to cutaneous vascular changes. Oxymetazoline results in a symptomatic reduction of the erythema associated with rosacea due to its ability to a time-limited action on the alpha 1a receptor and inhibit chronic vascular changes and vasodilation [8] (Table 1). In a 52-week trial, once daily application of oxymetazoline decreased persistent facial erythema. 36.7% and 43.4% of patients experienced a minimum 2 grade composite improvement in the Clinician Erythema Assessment (CEA) and Subject Self-Assessment for rosacea facial redness (SSA) assessments at hours 3 and 6 after the first dose, respectively. 0.7% of patients reported a rebound effect following treatment based on the CEA and SSA assessments. The topical medication was safe and well tolerated. Mild to moderate treatment-related adverse events (TRAE) were reported by 8.2% of patients. Most commonly reported were dermatitis, paresthesia, pain, and pruritus at the application site [9]. www.sciencedirect.com

Novel rosacea therapies Feaster et al. 15

Table 1 Comparison of studies on topical therapies for rosacea Patients (n)

Medication

Draelos et al. [9 ]

n = 440

OXY

Tanghetti et al. [10]

n = 885

OXY

R, DB, VC, PG

29 days

Taieb et al. [18]

n = 757

IVM versus MTZ

R, IB, PG

36 weeks

Schaller et al. [3,4,17]

n = 161

IVM versus MTZ

R, IB, PG

52 weeks

Gold et al. [21]

n = 190

IVM + BR/12 weeks versus IVM/12 weeks + BR/8 weeks

R, DB, PG, VC

12 weeks

Authors 

Study

Study duration

Results

52 weeks

Treatment related TEAEs = 8.2% Improvement in CEA and SSA  composite 2 grade = 36.7% and 43.4% at 3 and 6 hours Improvement in composite CEA and SSA  1 grade = 40.3% versus 19.1% CEA: 59.8% versus 39.3% at hour 12 SSA: 56.3% versus 34.7% at hour 12 P < 0.001 Median relapse time = 115 days versus 85 days Relapse rates = 62.4% versus 68.4% Median days free of tx = 196 days versus 169.5 days MCID in DLQI = Week 16: 65.4% versus 39.2%; P = 0.001 Week 52: 68.8% versus 40.4%; P = 0.003 Mean EQ-5D = 0.941 versus 0.896 IGA score clear or almost clear = Week 16: 82.5% versus 63.0%; P = 0.005 IGA score clear or almost clear = 55.8% versus 36.8%; P = 0.007 Treatment related AE = 4.2% versus 10%

R = Randomized, C = Controlled, P = Pilot, VC = Vehicle Controlled, IB = Investigator Blind DB = Double Blind, SB = Single Blind, SF = Split Face, PG = Parallel Group, RS = Retrospective, PS = Prospective, OS = Open Stud.

Within the first hour, 22.6% of oxymetazoline-treated patients improved their composite CEA and SSA scores at least 1 grade compared to 8.0% with the vehicle. Twelve hours post dose, 40.3% of oxymetazoline patients improved their composite CEA and SSA scores compared to 19.1% vehicle patients (P < 0.001). Three hours post treatment, 37% of oxymetazoline patients who had improved composite scores were satisfied or very satisfied with their facial appearance compared to 8% of vehicle. Twelve hours post treatment, 46% of oxymetazoline patients were satisfied compared with 14% of vehicle [10]. Ivermectin

Ivermectin (IVM) 1% cream is approved to treat rosacearelated inflammation [11,12]. IVM’s efficacy is due to anti-inflammatory and anti-parasitic action that reduces the density of Demodex mites [13,14]. While Demodex are part of normal skin flora, increased density is associated with rosacea, suggesting a possible role in mediating this condition [15,16].

At Week 52, 68.8% of IVM had MCID versus 40.4% of MTZ patients (P = 0.003). Also at Week 16, 82.5% of IVM patients had an Investigator’s Global Assessment (IGA) score of 0 or 1 compared to 63.0% with MTZ (P = 0.005) [17]. IVM-treated patients had both longer maintained remission compared to MTZ patients (115 versus 85 days) and lower percentages of relapse after treatment discontinuation (62.7% versus 68.4%) (P = 0.0365) [18]. IVM can also be combined with brimonidine (BR); an alpha2 receptor agonist that was the first topical treatment approved for treatment of rosacea-related facial redness and erythema [19,20]. At 12 weeks, 55.8% of IVM + BR patients reported an IGA score of clear/almost clear compared to 36.8% of vehicle patients (P = 0.007). 4.2% of IVM + BR patients reported a TRAE compared to 10% on BR monotherapy, suggesting that adjuvant IVM has the potential for increased efficacy and safety [21].

New studies on old procedural therapies IVM had superior efficacy compared to topical metronidazole (MTZ) 0.75%. The minimal clinically important difference (MCID) in Dermatology Life Quality Index (DLQI) score was evaluated at Week 16 and Week 52 following once daily IVM versus twice daily MTZ. At Week 16, 65.4% of IVM patients had an MCID in DLQI compared to 39.2% of MTZ patients (P  0.001). www.sciencedirect.com

Procedural therapies for the treatment of rosacea include the 595 nm-pulsed dye laser (PDL), dual wavelength long-pulsed 775 nm alexandrite/1,064 nm neodymium: yttrium-aluminum (LPAN), radiofrequency (RF), and dual frequency ultrasound (DFU). The laser wavelengths are absorbed by hemoglobin, resulting in elimination of cutaneous vascular lesions [22,23] (Table 2). Current Opinion in Pharmacology 2019, 46:14–18

16 Dermatology

Table 2 Comparison of studies on procedural therapies for rosacea Authors

Patients (n)

Medication

Study

Study Duration

Results

Soo Ko et al. [31]

n = 107

Minocycline versus PDL + Minocycline

RS

52 weeks

Micali et al. [32]

n = 10

BR versus BR + ND:YAG

P, OS

4 weeks

Kim et al. [26]

n = 50

RF versus PDL

R, C, SB, SF

16 weeks

Seo et al. [25]

n = 49

LPAN versus PDL

R, SB

6 months

Park et al. [29]

n = 21

FMR versus vehicle

R, PS, SB, SF

12 weeks

Park et al. [30]

n = 42

DFU

R

12 weeks

Total recurrence rate = 42.1% Minocycline recurrence rate = 48.3% PDL + Minocycline recurrence rate = 34.7% Recurrence-free survival; P = 0.011 BR = reduction of erythema, minimal telangiectasia persisted BR + ND:YAG = reduction of erythema and telangiectasia Total Improvement in severity score: P < 0.01 RF: 13.9–8.2 PDL:13.8–7.2 Total Reduction Mean Erythema Index: P = 0.05 RF: 27% PDL: 31% Mean reduction of erythema index = 3.6% versus 2.8%; P = 0.812 PGA = 88.9% versus 89.5%; P = 1.0 SSA = 77.8% versus 84.2%; P = 0.842 Mean reduction of erythema index = Week 12: 13.6% Mean IGA score = Week 12: 2.0 versus 0.38; P < 0.001 Mean IGA scores in patients w/ improvement = 2.47 PSA = 81% Mean EI = Week 12: 16.312.7; P < 0.01 Mean TEWL = Week 12: 35.8 g m 1 h 1 to 22.8 g m 1 h 1; P < 0.01

R = Randomized, C = Controlled, P = Pilot, VC = Vehicle Controlled, IB = Investigator Blind DB = Double Blind, SB = Single Blind, SF = Split Face, PG = Parallel Group, RS = Retrospective, PS = Prospective, OS = Open Stud.

PDL successfully eliminates symptoms such as erythema and telangiectasia. ND:YAG and the alexandrite lasers are viable treatment modalities [24]. A comparative study looked at LPAN versus PDL over a period of six months. On a short-term follow-up, more patients PDL-treated patients had 50% or more improvement of PGA evaluation. The PDL group had improvement of 68.4% compared with 50% according to the PGA assessment. Both lasers had similar improvement based on the mean change in erythema index, PGA, and SSA assessments at a long-term follow-up at six months [25]. PDL and RF had similar efficacy in treating ETR and PPR as evaluated by the severity score and erythema index. For PPR patients, RF treatment had greater reduction in severity score and papulopustular lesions than PDL. The severity score decreased from 16 at baseline to 6 at week 12; (P < 0.001) among PPR patients treated with RF. PPR patients who received PDL therapy had their severity scores decrease from 16 at baseline to 10 at week 12; (P < 0.05) [26]. RF devices are used for noninvasive aesthetic skin treatments by using heat to regenerate collagen. Fractional Microneedling Radiofrequency (FMR) is a new RF device undergoing evaluation for its treatment of rosacea [27,28]. In a Current Opinion in Pharmacology 2019, 46:14–18

randomized, split-face clinical trial assessing FMR, 81% of patients improved on the treated side with a mean improvement of 20% compared to the untreated side according to IGA standards. While FMR may be an additional treatment option for rosacea, it results in only moderate improvement [29]. With high frequencies up to 10 MHz, DFU controls matrix metalloproteinases (MMPs) and heat shock proteins (HSPs). While DFU is most commonly associated with anti-aging and skin rejuvenation therapies, recently it has been investigated as a treatment option for rosacea. Forty-two patients underwent DFU treatment once weekly for 12 weeks. By Week 12, the erythema index among patients with ETR decreased from 97.4% at 4 weeks to 79.4%. For patients with PPR, the erythema index improved from 90.6% at 4 weeks to 75.4% at Week 12. The transepithelial water loss (TWEL) decreased in the ETR group from 91.1% at 4 weeks to 71.5% at 12 weeks. With PPR patients, the TEWL reduced from 97.5% to 61.6%. For both assessments, the PPR group had higher rates of improvement. No TRAE were reported [30]. Combination treatment of oral minocycline with PDL reduced rosacea recurrence one-year post treatment. The combination group had a recurrence rate of 34.7% compared to minocycline monotherapy patients who had a recurrence rate of 48.3%. Therefore, combination www.sciencedirect.com

Novel rosacea therapies Feaster et al. 17

systemic and procedural therapy may more effectively treat rosacea and reduce relapse rates [29]. Another combination treatment is topical brimonidine with ND:YAG laser. While BR monotherapy reduced erythema, minimal telangiectasias persisted. Combination BR + ND:YAG laser decreased both erythema and telangiectasias, emphasizing the efficacy of combined therapy [31].

Conclusion Rosacea is a chronic skin disorder with a profound impact on patient quality of life. There is a strong need for continued rosacea research for new emergent treatment options for rosacea management. Novel rosacea therapies and research are limited when compared with other inflammatory skin diseases. Given the somewhat limited novel treatments for rosacea management, it is unlikely that a single modality will result in complete and permanent resolution. However, current treatment options yield good results when tailored to the right clinical scenario. Topicals such as oxymetazoline and ivermectin are efficacious and safe options for rosacea. DFU is a promising alternative new physical treatment modality. Although FMR warrants further evaluation because therapy resulted in only moderate improvement, this treatment may prove beneficial for patients who failed other treatments. Combination therapies including topical medications and lasers are powerful tools that can effectively reduce rosacea-related erythema, inflammatory lesions, and telangiectasias [32,33].

Conflict of interest statement Feldman has received research, speaking and/or consulting support from a variety of companies including Galderma, GSK/Stiefel, Almirall, Leo Pharma, Boehringer Ingelheim, Mylan, Celgene, Pfizer, Valeant, Abbvie, Samsung, Janssen, Lilly, Menlo, Merck, Novartis, Regeneron, Sanofi, Novan, Qurient, National Biological Corporation, Caremark, Advance Medical, Sun Pharma, Suncare Research, Informa, UpToDate and National Psoriasis Foundation. He is founder and majority owner of www.DrScore.com and founder and part owner of Causa Research, a company dedicated to enhancing patients’ adherence to treatment. Brittany Feaster and Abigail Cline have no conflicts to disclose.

Funding None.

References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:  of special interest  of outstanding interest 1.

Rainer B, Kang S, Chien A: Rosacea: epidemiology, pathogenesis, and treatment. DermatoEndocrinology 2017, 9: e1361574.

www.sciencedirect.com

2.

Abokwidir M, Feldman S: Rosacea management. Skin Appendage Disord 2016, 2:26-34.

3.

Schaller M, Scho¨fer H, Homey B, Hofmann M, Gieler U, Lehmann P, Luger TA, Ruzicka T, Steinhoff M: Rosacea management: update on general measures and topical treatments. J German Soc Dermatol 2016, 6:17-27.

4.

Schaller M, Scho¨fer H, Homey B, Gieler U, Lehmann P, Luger TA, Ruzicka T, Steinhoff M: State of the art: systemic rosacea management. J German Soc Dermatol 2016, 6:29-37.

5.

RHOFADE: (oxymetazoline HCl) Cream 1%. Allergan; 2017.

6.

Del Rosso J: Topical a-agonist therapy for persistent facial erythema of rosacea and the addition of oxymetazoline to the treatment aramentarium: where are we now? J Clin Aesthetic Dermatol 2017, 10:28-32.

7.

Kuang A, DuBois J, Attar M, Ahluwalia G: Clinical pharmacokinetics of oxymetazoline cream following topical facial administration for the treatment of erythema associated with rosacea. J Drugs Dermatol 2018, 17:213-220.

8.

Hoover R, Erramouspe J: Role of topical oxymetazoline for management of erythematotelangiectatic rosacea. Ann Pharmacother 2018, 52:263-267.

Draelos Z, Gold M, Weiss R, Baumann L, Grekin S, Robinson D, Kempers S, Alvandi N, Weng E, Berk D, Ahiuwalia G: Efficacy and safety of oxymetazoline. J Am Acad Dermatol 2018, 78: 1156-1163. Examined the long term efficacy and safety of oxymetazoline cream 1.0% in moderate to severe persistent erythema of rosacea.

9. 

10. Tanghetti E, Dover J, Goldberg D, Dhawan S, Luo L, Berk D, Ahluwalia G, Alvandi N: Clinically relevant reduction in persistent facial erythema of rosacea on the first day of treatment with oxymetazoline cream 1.0%. J Drugs Dermatol 2018, 17:621-626. 11. Siddiqui K, Gold L, Gill J: The efficacy, safety, and tolerability of ivermectin compared with current topical treatments for the inflammatory lesions of rosacea: a network meta-analysis. Springerplus 2016, 5:1151. 12. Cardwell L, Alinia H, Tuchayi S, Feldman S: New developments in the treatment of rosacea- role of once-daily ivermectin cream. Clin Cosmet Investig Dermatol 2016, 9:71-77. 13. Schaller M, Gonser L, Belge K, Braunsdorf C, Nordin R, Sceu A, Borelli C: Dual anti inflammatory and anti-parasitic action of topical ivermectin 1% in papulopustular rosacea. Euro Acad Dermatol Venereol 2017, 31:1907-1911. 14. Del Rosso J: Topical ivermectin: data supporting dual modes of action in rosacea. J Clin Aesthetic Dermatol 2017, 10:39-42. 15. Ebbelaar C, Venema A, Van Dijk M: topical ivermectin in the treatment of papulopustular rosacea: a systematic review of evidence and clinical guideline recommendations. Dermatol Ther 2018. 16. Moran E, Foley R, Powell F: Demodex and rosacea revisited. Clin Dermatol 2017, 35:195-200. 17. Schaller M, Dirschka T, Keme´ny L, Briantais P, Jacovella J:  Superior efficacy with ivermectin 1% cream compared to metronidazole 0.75% cream contributes to a better quality of life in patients with severe papulopustular rosacea: a subanalysis of the randomized, investigator-blinded ATTRACT study. Dermatol Ther 2016, 6:427-436. Phase 3 clinical trial demonstrates superior efficacy with ivermectin compared with metronidazole for severe papulopustular rosacea patients. 18. Taieb A, Khemis A, Ruzicka T, Bara´nska-Rybak W, Berth-Jones J, Schauber J, Briantais P, Jacovella J, Passeron T: Maintenance of remission following successful treatment of papulopustular rosacea with ivermectin 1% cream vs. metronidazole 0.75% cream: 36-week extension of the ATTRACT randomized study. Euro Acad Dermatol Venereol 2016, 30:829-836. 19. Tanghetti E, Jackson J, Belasco K, Friedrichs M, Hougier F, Johnson S, Kerdel F, Palceski D, Hong C, Hinek A, Cadena M: Optimizing the use of topical brimonidine in rosacea Current Opinion in Pharmacology 2019, 46:14–18

18 Dermatology

management: panel recommendations. J Drugs Dermatol 2015, 14:33-40. 20. Jackson J, Knuckles M, Minni J, Johnson S, Belsasco K: The role of brimonidine tartrate gel in the treatment of rosacea. Clin Cosmet Investig Dermatol 2015, 8:529-538. 21. Gold L, Papp K, Lynde C, Lain E, Gooderham M, Johnson S, Kerrouche N: Treatment of rosacea with concomitant use of topical ivermectin 1% cream and brimonidine 0.33% gel: a randomized, vehicle-controlled study. J Drugs Dermatol 2017, 16:909-916. 22. Treatment outcomes of long pulsed Nd: YAG laser for two different subtypes of rosacea. J Clin Aesthetic Dermatol 2015, 8:16-20. 23. Bernstein E, Kligman A: Rosacea treatment using the newgeneration, high energy, 595 nm, long pulse-duration pulseddye laser. Lasers Surg Med 2008, 40:233-239. 24. Hofmann M, Lehmann P: Physical modalities for the treatment of rosacea. J German Soc Dermatol 2016, 6:38-43. 25. Seo H, Kim J, Kim H, Choi Y, Kim W: Prospective comparison of dual wavelength long-pulsed 755-nm alexandrite/1064-nm neodymium:yttrium-aluminum-garnet laser versus 585-nm pulsed dye laser treatment for rosacea. Ann Dermatol 2016, 28:607-614. 26. Kim S, Lee Y, Seo Y, Lee J, Im M: Comparative efficacy of radiofrequency and pulsed dye laser in the treatment of rosacea. Dermatol Surg 2017, 43:204-209.

Current Opinion in Pharmacology 2019, 46:14–18

27. Sadick N, Rothaus K: Minimally invasive radiofrequency devices. Clin Plastic Surg 2016, 43:567-575. 28. Hongcharu W, Gold M: Expanding the clinical application of  fractional radiofrequency treatment: findings on rhytides, hyperpigmentation, rosacea, and acne redness. J Drugs Dermatol 2015, 14:1298-1304. Application of Dual-frequency ultrasound demonstrates clinical improvement as a new treatment for rosacea. 29. Park S, Kwon H, Yoon J, Min S, Suh D: Clinical and histologic effects of fractional microneedling radiofrequency treatment on rosacea. Dermatol Surg 2016, 42:1362-1369. 30. Park J, Ahn M, Cho E, Park E, Kim K: Dual-frequency ultrasound as a new treatment modality for refractory rosacea: a retrospective study. Dermatol Surg 2018, 0:1-7. 31. Soo Ko H, Ju Suh Y, Won Byun J, Seong Choi G, Shin J: Pulsed dye laser treatment combined with oral minocycline reduces recurrence rate of rosacea. Ann Dermatol 2017, 29:543-547. 32. Micali G, Dall’Oglio F, Verzi A, Luppino I, Bhatt K, Lacarrubba F: Treatment of erythemato-telangiectatic rosacea with brimonidine alone or combined with vascular laser based on preliminary instrumental evaluation of the vascular component. Lasers Med Sci 2017, 33:1397-1400. 33. Schaller M, Almeida LMC, Bewley A, Cribier B, Dlova NC, Kautz G, Mannis M, Oon HH, Rajagopalan M, Steinhoff M et al.: Rosacea treatment update: recommendations from the global ROSacea Consensus (ROSCO) panel. Br J Dermatol 2017, 176:465-471.

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