Evolving Understanding of Rosacea Calls for Fresh Thinking and New Treatment Approaches

Major Phenotypes

These major phenotypes may occur independently or concurrently (Figures 1-4).

  • Papules and pustules. Red, acne-like but often smaller, sometimes accompanied by white heads, often surface across the cheeks and nose. Nodules may also occur.4,10,12-14
  • Flushing. Prolonged vascular phenomena is common, except in darker skin tones, where this may occur without obvious erythema. In rosacea, flushing can take place almost immediately after neurovascular stimulation by trigger factors.4-6,10,12,14,15  
  • Telangiectasia. Telangiectases are common structural signs of rosacea and are predominantly centrofacial.10
  • Ocular manifestations. Ocular rosacea can be mild, moderate, or severe and may appear when no other phenotypes are apparent. Common symptoms include light sensitivity and foreign object sensation.10

Secondary Phenotypes

Secondary signs and symptoms include:

  • Burning or stinging. These sensations normally occur on erythematous skin without scales, although scaling may also occur.10,16 Pruritus is not a typical rosacea characteristic but may occur.
  • Edema. Facial swelling may accompany or follow prolonged erythema or flushing as a result of postcapillary extravasation during inflammation.17 Edema may last for days and can be aggravated by inflammatory changes. Solid facial edema (persisting hard, nonpitting edema) can occur independently of redness, papules and pustules, or phymatous changes. Typically, rosacea-related edema involves a combination of blood and lymphatic vessels.4.10
  • Dry appearance. Central facial skin may become rough and scaly, resembling dry skin. Its appearance is similar to that of an eczematous dermatitis. Rosacea may appear with seborrheic dermatitis. The dry appearance may be associated with burning or stinging sensations and may be caused by irritation rather than the disease process.10
rosacea

Figures 1-4: The major phenotypes of rosacea include papules and pustules, flushing, telangiectasia, and ocular manifestations. These can appear concomitantly and even episodically along with secondary phenotypes, which include burning or stinging, edema, dry appearance.

Rosacea’s various phenotypes can appear concomitantly and even episodically, but research suggests that all are likely to result from the same underlying inflammatory continuum4-7and that individual cases may progress in severity and worsen to include additional phenotypes.18,19  

Nevertheless, research has shown that more than half of rosacea patients present with a combination of different subtypes.2

What remains clear is that untreated cases of rosacea generally worsen. One big drawback of the current treatments is that most are not curative and generally require patients to try several different medications and drug combinations to find an effective treatment.20 

But what is more concerning are the risks surrounding current treatment paradigms: First, dermatologists often reflexively turn to oral antibiotics, raising concerns about both systemic antibiotic resistance and adverse events. Second, many of the available topical therapies are associated with cutaneous irritation and patient nonadherence. For example, patients often complain of itching, burning, and other discomfort with topical therapies, despite the understanding that this is hypersensitive skin. But the question remains: Are these concerns functions of the disease or the treatment?

Antibiotic Resistance: A Huge and Growing Problem

The topic of antibiotic resistance has been analyzed extensively.21-24 Similarly, the need for broad-based antibiotic stewardship initiatives has been widely
discussed.12,13,25,26 However, the issue is particularly acute for dermatology
because oral antibiotics are vital to the treatment of skin conditions. 

While dermatologists represent about 1% of the nation’s physician population, reports suggest they order nearly 5% of antibiotic prescriptions.27 From 2003 through 2013, US dermatologists prescribed antibiotics 8 to 9 million times annually, accounting for at least 20% of all prescriptions written by dermatologists.28-30

Dermatologists continue to prescribe oral antibiotics because the most effective ones to treat skin conditions are only available in oral formulations.31 For example minocycline, a commonly prescribed oral antibiotic that is also the least resistant of the tetracycline class of antibiotics, is currently not commercially available as a topical.31

Meanwhile, many of the available topical formulation of antibiotics, including clindamycin and erythromycin, have high resistance rates. This makes them marginally effective.31

Antibiotic resistance is a serious, global problem. In Spain, the Propionibacterium acnes resistance rate to erythromycin/clindamycin is 91%.32 In India, P acnes resistance rates are 90% for clindamycin, 98% for erythromycin, and 100% for azithromycin.33 A US study found resistance rates to erythromycin and clindamycin of 100%, to tetracycline 97%, and to doxycycline 83%.34 In the end, this is why dermatologists have been forced to embrace a standard of care using combination therapies that alternate the use of oral antibiotics and topical products.  

Promising New Drugs in Development

Recognizing the need for improved rosacea therapies, significant research and development is underway. As of July 2018, www.ClinicalTrials.gov lists 140 rosacea studies, of which 39 focus on papulopustular rosacea,35 which some view as a gateway to more serious phenotypes. And most of these papulopustular studies are evaluating drugs to supplement or replace current treatments, which have significant shortcomings. 

Several companies are researching new twists on existing therapies, such as azelaic acid, an FDA-approved drug found to be effective for papulopustular rosacea.36 Bayer and Novum Pharmaceutical are studying different formulations of azelaic acid and combinations with other therapies. Galderma is conducting a combination trial with ivermectin 1% topical cream + doxycycline 40 mg modified release capsules (Soolantra and Oracea in combination). The company has also been studying the role of brimonidine tartrate therapy, as well as the relative effectiveness of ivermectin vs metronidazole cream. 

Two companies are researching new delivery systems to treat rosacea with a topical formulation of minocycline. BioPharmX is conducting trials with a topical minocycline gel that may provide both the antibiotic and anti-inflammatory benefits of this common tetracycline derivative without the systemic adverse effects associated with oral minocycline. Foamix has been researching a foam formulation of the same antibiotic. These topical products have not been approved by the FDA and are still considered investigational (available only for use in clinical trials).

Minocycline is particularly attractive to dermatologists because it is generally well tolerated and has a lower resistance rate than many other antibiotics. Compared with first-generation tetracyclines, minocycline has a better pharmacokinetic profile and compared with doxycycline, it is not phototoxic.37

All these products that are currently in clinical trials may significantly change the way dermatologists treat rosacea in coming years—and could potentially reduce adverse effects associated with the treatment. 

 

Dr Bhatia is director of clinical dermatology at Therapeutics Clinical Research in San Diego,CA, is board certified, has a background in immunology, and has interests in mechanisms of therapy, skin cancer, and medical dermatology.

Disclosure: Dr Bhatia is an advisor and investigator for Bayer, BioPharmX, Foamix, and Galderma.

References

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2. Mikkelsen CS, Bjerring P, Lirvall M, et al. Rosacea: Time for a new approach. Forum Nord Derm Ven. 2017;22(1):3-12.

3. Drake L. New survey shows rosacea tends to evolve beyone one subtype. Rosacea Review. Fall 2004. https://www.rosacea.org/rr/2004/fall/article_4.php. Accessed July 24, 2018.

4. Schwab VD, Sulk M, Seeliger S, et al. Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J Invest Dermatol Symp Proc. 2011;15(1):53-62.

5. Seeliger S, Buddenkotte J, Schmidt-Choudhury A, et al. Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo. Am J Pathol. 2010;177(5):2563-2575.

6. Sulk M, Seeliger S, Aubert J, et al. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol. 2012;132(4):1253-1262.

7. Wladis EJ, Iglesias BV, Adam AP, et al. Molecular biologic assessment of cutaneous specimens of ocular rosacea. Ophthal Plast Reconstr Surg. 2012;28(4):246-250.

8. Tan J, Blume-Peytavi U, Ortonne JP, et. al. An observational cross-sectional study of rosacea: clinical associations and progression between subtypes. Br J Dermatol. 2013;169(3):555-62.

9. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics. Exp Dermatol. 2017;26(8):659-667.

10. Gallo RL, Granstein RD, Kang S, et. al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2017;78(1):148-155.

11. Gallo RL, Granstein RD, Kang S, et al. Rosacea comorbidities and future research: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78(1):167-170.

12. Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J Invest Dermatol Symp Proc. 2011;15(1):2-11.

13. Trivedi NR, Gilliland KL, Zhao W, Liu W, Thiboutot DM. Gene array expression profiling in acne lesions reveals marked upregulation of genes involved in inflammation and matrix remodeling. J Invest Dermatol. 2006;126(5):1071-1079.

14. Buhl T, Sulk M, Nowak P, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015;135(9):2198-2208.

15. Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic inflammation. J Invest Dermatol Symp Proc. 2011;15(1):33-39.

16. Lonne-Rahm SB, Fischer T, Berg M. Stinging and rosacea. Acta Derm Venereol. 1999;79(6):460-461.

17. Steinhoff M, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev. 2014;94(1):265-301.

18. Tan J, Blume-Peytavi U, Ortonne JP, et. al. An observational cross-sectional study of rosacea: clinical associations and progression between subtypes. Br J Dermatol. 2013;169(3):555-562.

19. Holmes AD, Steinhoff M. Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics. Exp Dermatol. 2017;26(8):659-667.

20. Weinkle AP, Doktor V, Emer J. Update on the management of rosacea. Clin Cosmet Investig Dermatol. 2015;8:159-177. doi:10.2147/CCID.S58940

21. Dreno B, Thiboutot D, Gollnick H, et al. Antibiotic stewardship in dermatology: limiting antibiotic use in acne. Eur J Dermatol. 2014;24(3):330-334. 

22. Del Rosso JQ. Report from the scientific panel on antibiotic use in dermatology: introduction. Cutis. 2007;79(suppl 6):6-8. 

23. Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in acne vulgaris and other inflammatory skin disorders: focus on antibiotic resistance. Cutis. 2007;79(suppl 6):9-25. 

24. Woolhouse M, Farrar J. Policy: An intergovernmental panel on antimicrobial resistance. Nature. 2014;509(7502):555-557. 

25. Struelens MJ, Monnet D. Prevention of methicillin-resistant Staphylococcus aureus infection: is Europe winning the fight? Infect Control Hosp Epidemiol. 2010;31(suppl 1):S42-S44. 

26. Allerberger F, Lechner A, Wechsler-Fördös A, et al. Optimization of antibiotic use in hospitals—antimicrobial stewardship and the eU project ABS international. Chemotherapy. 2008;54(4):260-267. 

27. Jesitus J. Dermatologists contribute to overuse of antibiotics. Dermatology Times. Published October 31, 2013. http://www.dermatologytimes.com/dermatology-times/content/tags/acne/dermatologists-contribute-overuse-antibiotics. Accessed July 24, 2018.

28. Kim S, Michaels BD, Kim GK, Del Rosso JQ. Systemic antibacterial agents. In: Wolverton SE, ed. Comprehensive Dermatologic Drug Therapy. 3rd ed. Philadelphia, PA: Elsevier-Saunders; 2013:61-97. 

29.. Get smart  https://www.cdc.gov/antibiotic-use/week/index.htmlabout antibiotics week 2015. Centers for Disease Control and Prevention website. https://www.cdc.gov/antibiotic-use/week/index.html. Accessed July 24, 2018.

30. Sanchez G. Presented at Scientific Panel on Antibiotic Use in Dermatology (SPAUD); September 6, 2014; Las Vegas, Nevada.

31. Del Rosso JQ, Webster GF, Rosen T, et al. Status report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society Part 1: antibiotic prescribing patterns, sources of antibiotic exposure, antibiotic consumption and emergence of antibiotic resistance, impact of alterations in antibiotic prescribing, and clinical sequelae of antibiotic use. J Clin Aesthet Dermatol. 2016;9(4):18-24.

32. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. 2003;148(3):467-478.

33. Sardana K, Gupta T, Kumar B, Gautam HK, Garg VK Cross-sectional pilot study of antibiotic resistance in Propionibacterium acnes strains in Indian acne patients using 16S-RNA polymerase chain reaction: A comparison among treatment modalities including antibiotics, benzoyl peroxide, and isotretinoin. Indian J Dermatol. 2016;61(1):45-52.

34. Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis. 2008;82(6):417-421.

35. ClinicalTrials.gov website. https://www.clinicaltrials.gov/ct2/results?cond=Rosacea%2C+Papulopustular&term=&cntry=&state=&city=&dist=. Accessed July 24, 2018.

36. Johnson AW, Johnson SM. The role of topical brimonidine tartrate gel as a novel therapeutic option for persistent facial erythema associated with rosacea. Dermatol Ther (Heidelb). 2015;5(3):171-181. 

37. Oschendorf F. Minocycline in acne vulgaris: benefits and risks. Am J Clin Dermatol. 2010;11(5):327-341.



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