Sufferers of Little Understood Disease May Soon Have New Treatment Options by G

Rosacea: Sufferers of Little Understood Disease May Soon Have New Treatment Options by G. Scott Herron, M.D., Ph.D.

osacea is an elusive skin condition that is not well understood. Until R now, there has been no guaranteed method to eradicate it. However, recent advancements could offer new treatment options for the condition.

62 DERMASCOPE | March 2018 March 2018 | DERMASCOPE 63 survey of 600 rosacea patients found 42 percent were of Irish, German, or English ancestry. The disease can, however, occur in individuals of any race or skin color. There is also evidence that rosacea may be hereditary.8 NRS research found that 52 percent of rosacea patients had a relative who suffered from the condition. Age is also a factor. Unlike acne, which typically initially presents in adolescence, 80 percent of cases are di- agnosed in people who are at least 30.10 While women are two to three times more likely than men to get rosacea, men tend to experience more severe cases.11 Since the onset of the condition tends to occur in adulthood, rosacea achieves highest prevalence in later years. For example, women experience highest prevalence between the ages of 61 and 65. For men, highest prevalence occurs between the ages of 76 and 80. One early warning sign of rosacea may be frequent blushing. Some researchers think rosacea occurs when blood vessels expand too easily, causing blushing.12 More than one in 20 American ruddiness of the facial skin, thickening adults – approximately 16 million of the skin, and even enlargement of NEW UNDERSTANDING people – suffer from rosacea, but this the nose. OF ROSACEA common skin disease is often misdi- New research shows that rosacea’s There has been an abundance of agnosed as acne.1 As with acne, there different symptoms and features may research since 2002, when the initial is no simple test to diagnose rosacea. all be part of a continuum of inflam- classification system of rosacea was -de Dermatologists generally identify mation that may only be detectable veloped. At that time, the skin disease the condition by observing persistent histologically and biochemically.3, 4, 5, 6 was thought to fall into four distinct erythema of the skin in a patient or the For these reasons, rosacea’s impact clinical subtypes with apparently differ- emergence of papules or pustules. goes beyond the physical. NRS surveys ent symptoms. In October 2017, a new Unlike acne, people suffering from found that more than 90 percent of classification system was published by rosacea are often unaware or confused patients say the condition has lowered the NRS’ panel of experts. This new about the condition. A recent National their self-confidence and self-esteem, grouping system is based on current Rosacea Society (NRS) survey of 1,459 while 41 percent say it has caused them understanding of the pathophysiology patients2 found that 95 percent knew to avoid public contact or cancel social of rosacea and identifies four major little or nothing about rosacea’s signs engagements. Among patients with se- phenotypes and three secondary phe- and symptoms prior to their diagnosis vere symptoms, 88 percent say rosacea notypes of rosacea, all of which appear and 47 percent said they had never has hurt their professional interactions to be interrelated.13 heard of the disease. and more than half say it has led them This lack of awareness increases to miss work.7 MAJOR PHENOTYPES the threat rosacea poses because some These major phenotypes may oc- over-the-counter acne treatments that WHO IS AT RISK? cur independently or concurrently. confused rosacea sufferers might use to Fair-skinned adults, especially Papules and pustules: Dome- treat their condition can actually aggra- those with blond hair and blue eyes, shaped, red, acne-like pimples, some- vate it. If left untreated, rosacea tends are more likely to get rosacea. Particu- times accompanied by white heads, to become more severe with time and larly susceptible are adults from Celtic often surface in crops across the cheeks can lead to symptoms like permanent or Scandinavian ancestry.8 An NRS and nose. Nodules may also occur.3, 13, 14, 15, 16 14, 15, 16

64 DERMASCOPE | March 2018 Flushing: Frequent and prolonged burning, stinging, light sensitivity, and flushing (sometimes blushing) is com- foreign object sensation.13 mon, except in darker skin tones, where flushing may be experienced without SECONDARY PHENOTYPES obvious erythema. Unlike other ery- Burning or stinging: These sensa- thematous changes, in rosacea, flushing tions may occur, normally on ery- can occur within seconds to minutes in thematous skin without scales, although response to neurovascular stimulation scaling may also occur.13,18 Pruritus is by trigger factors.3, 4, 5, 13, 14, 17 not a typical characteristic of rosacea, Telangiectasia: Telangiectasias, but may also occur. sometimes known as spider veins, are Edema: Facial swelling may ac- common signs of rosacea and are company or follow prolonged erythema predominantly centrofacial. Use of or flushing as a result of postcapillary a dermatoscope may allow for detec- extravasation during inflammation.19 tion of telangiectasias in patients with Soft edema may last for days or be darker skin types.13 aggravated by inflammatory changes. Ocular manifestations: Ocular Solid facial edema (persisting hard, rosacea can occur in mild, moderate, nonpitting edema) can occur with or severe cases and may also appear rosacea and independently of red- when no other phenotypes are appar- ness, papules, pustules, or phymatous ent. Signs of ocular rosacea include lid changes. Commonly, rosacea-related margin telangiectases, interpalpebral edema involves a combination of blood conjunctival injection, spade-shaped and lymphatic vessels.3, 13 infiltrates in the cornea, and scleritis Dry appearance: Central facial and sclerokeratitis. Common symptoms skin may be rough and scaly, resem- that may suggest ocular rosacea include bling dry skin and suggesting an

March 2018 | DERMASCOPE 65 eczematous dermatitis. Rosacea may coexist 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.13 Rosacea’s different phenotypes may appear in different combinations and at different times, but research sug- gests that all may be manifestations of the same underlying inflammatory con- tinuum3, 4, 5, 6 and that individual cases may progress in severity and worsen to include additional phenotypes.20, 21 The NRS’ panel of experts wrote that, “recent studies point to a multivariate set of pathogenic pathways, including defects in the innate and adaptive immune systems, mast cells and related biochemical mechanisms, and the neurovascular system. It now appears likely that initial erythema and vascular manifestations such as telangiectasia may be in a continuum initiated by a combination of both neurovascular dysregulation and innate immune responses.”13 The phenotype designations are meant to replace the four subtypes widely used clinically to identify the nature of each patient’s rosacea and treat each case. The classical subtypes – vascular, inflammatory, rhinophymatous, and ocular rosacea – are still used clinically by many dermatologists. However, as the NRS panel’s report indicated, they are not accurate diagnostic categories, given the transient and progressive signs and symptoms exhibited by rosacea patients. Earlier research by the NRS had already shown that more than half of rosacea patients suffer from a combination of different subtypes.22 An NRS survey of 1,231 patients found that 72 percent experienced some kind of progression. Overall, 77 percent of patients in the study said they experienced more than one subtype at a time.23 What remains clear is that untreated cases of rosacea generally worsen. CAUSES Beyond the apparent genetic con- nection, the causes of rosacea are not well understood. Researchers believe there is a relationship between triggers

66 DERMASCOPE | March 2018 The classical subtypes – vascular, inflammatory, rhinophymatous, and ocular rosacea – are still used clinically by many dermatologists. However, as the NRS panel’s report indicated, they are not accurate diagnostic categories, given the transient and progressive signs and symptoms exhibited by rosacea patients.

of rosacea, flushing reaction, and the scientists cannot prove it can permanent swelling of blood vessels cause rosacea. close to the skin surface (telangiectasis). • A mite that lives on everyone’s Inflammation appears to be linked to skin, demodex, may play a the flushing reaction, but it is not clear role. This mite likes to live on how. NRS experts have called for the nose and cheeks, where additional study.13 Meanwhile, the rosacea often appears. In American Academy of Dermatology normal skin, demodex found reports that researchers are finding in small numbers feeds on important clues about the causes sebaceous gland contents and of rosacea:25 is considered part of normal • The immune system may play skin microbiome. Studies a role. Researchers have found found that people with rosacea that most people with acne- have much larger numbers of like rosacea react to a bacte- demodex mites on their skin. rium called bacillus oleronius. However, some people who The reaction causes their do not have rosacea also pos- immune systems to trigger an sess increased facial demodex exaggerated inflammatory re- populations, again indicat- sponse. Scientists are not sure ing it may not cause rosacea, this can cause rosacea. but rather could contribute • A bug that causes intestinal to abnormal skin physiology infections may play a role. characteristic of rosacea. This bug, Helicobacter pylori, • A protein that protects skin or H. pylori, is common in from infection, cathelici- people who have rosacea. din, may cause the redness However, because many and swelling. How the body people who do not suffer processes this protein may from rosacea may have determine whether a person an H. pylori infection, gets rosacea.

March 2018 | DERMASCOPE 67 AVAILABLE TREATMENTS ARE NOT CONSISTENT Rosacea medications provide inconsistent results; and treatment remains aligned with the four clinical Subtype 1 subtypes physicians have used to identify erythematotelangiectatic and treat the skin disorder since the (or vascular) rosacea early 2000s: Subtype 1, erythematotelangiectatic (or vascular) rosacea: Primary symptoms include flushing and facial redness. Patients of this traditional subtype tend to be sensitive to topical products and cosmetics; so it is best treated by staying out of the sun or using sunscreen. Recently, the FDA approved two topical agents that constrict superficial capillary blood vessels – 0.33 percent brimonidine gel and 1 percent Subtype 2 oxymetazoline cream. Both agents show temporary improvement in facial red- papulopustular or ness in rosacea. inflammatory rosacea Subtype 2, papulopustular or inflammatory rosacea: Primary symptoms include persistent redness, papules, or pustules. This subtype has typically been treated with topical or systemic antibiotics or a combination of both. Clinicians usually start with metronidazole cream or gel or topical sulfur/sulfacetamide wash or lotion. Other topical agents found to be effective include azelaic acid (cream and foam) and ivermectin. Two derivatives of tetracycline, minocycline and doxycycline, are the most Subtype 3 common systemic treatments for inflam- phymatous rosacea matory rosacea. Subtype 3, phymatous rosacea: Primary symptoms include thickening of the skin and excess tissue that enlarges the nose, a condition known as rhinophyma. This severe form of rosacea generally requires more aggres- sive therapy and systemic antibiotics, sometimes with isotretinoin. Typically, after maximizing the drug regimen, patients are best served by surgical resurfacing of the rosacea-affected area. Electrosurgery can be used to sculpt the Subtype 4 rhinophymatous nose, as can use of a laser. ocular rosacea Subtype 4, ocular rosacea: Pri- mary symptoms include eye irritation. Ocular rosacea can only be treated with the use of systemic antibiotics, such as oral tetracycline (250 to 500 milligrams), minocycline (40 to 100 milligrams), or

68 DERMASCOPE | March 2018 doxycycline (100 milligrams). In some cases, topical corticosteroid eyedrops may help to alleviate symptoms. Most therapies are associated with adverse side effects. For example, in the case of common topicals, patients often complain of itching, burning, and other discomfort. Rosacea sufferers tend to be especially sensitive to skin irritations. In the case of systemic antibiotics, steady use puts patients at risk of antibiotic resistance and adverse systemic events. THE FUTURE Significant research is currently being conducted in rosacea, particularly in papulopustular or inflammatory rosacea, which is, in many ways, a gateway subtype that can lead to more severe cases. Most of the research, 28 of the 43 rosacea studies currently listed on ClinicalTrials.gov, focuses on papulopustular rosacea. Some of these studies are looking at how medical devices may be useful in treating this subtype, but most are evaluating drugs to supplement or sup- plant existing treatments, which are not curative and often require patients to try several different medications and drug combinations to find an effective treatment.27 Many drugs currently used to treat papulopustular rosacea have significant shortcomings. Metronidazole, a

March 2018 | DERMASCOPE 69 cornerstone therapy, has an unknown mechanism of action, but seems to have antimicrobial, antioxidant, and anti-inflammatory properties.28, 29 It is used topically, but is not as effective as some newer agents. Ivermectin, a recent FDA-approved topical agent to treat papulopustular rosacea, is thought to reduce papules by killing demodex mites that live in the sebaceous glands.30, 31, 32 However, adverse effects associated with the topical cream include burning, itching, and dryness at the application site.33 Because of the limitations of current treatments, several companies are researching new twists on existing Does a proven antibacterial offer therapies, such as azelaic acid, an FDA- fresh promise for rosacea sufferers? approved drug found to be effective for papulopustular rosacea.1, 34 Bayer, No- vum Pharmaceutical, and Galderma hile most drug-related clinical trials in rosacea are are researching various formulations focused on existing treatments, two clinical stage com- of azelaic acid and combinations with panies are researching the efficacy of a proven, widely other therapies. Galderma is trialing Wavailable, systemic drug reformulated into a treatment for this com- Soolantra and Oracea in combina- mon skin disease. tion (Ivermectin 1 percent topical BioPharmX and Foamix are conducting trials on novel deliv- cream and doxycycline 40 milligrams ery of minocycline, an antibiotic in the tetracycline family that is in modified release capsules). Cutanea widely used to treat bacterial and inflammatory skin diseases. While is researching the efficacy of a topical minocycline is less likely to cause bacterial resistance than other -cy- gel formulation of omiganan – a novel, clines, physician concern for the growing problem has made many antimicrobial peptide. dermatologists reluctant to rely too heavily on oral antibiotics, which Two companies are looking at a tend to flood the body with medicine and have been known to cause new approach to rosacea treatment adverse effects ranging from nausea to diarrhea. using different delivery systems for Minocycline, which was first commercialized in 1971, is particu- minocycline. BioPharmX is conduct- larly interesting to dermatologists because it has both antibacterial ing trials with a topical minocycline gel and anti-inflammatory properties – a combination that is useful in that may provide both the antibiotic the treatment of several skin diseases, including rosacea. However, and anti-inflammatory benefits of this minocycline has only been available in an oral formulation because common tetracycline derivative without drug developers have not been able to stabilize minocycline in a topi- the systemic adverse effects associated cal formulation, which would allow for targeted delivery directly to with oral minocycline. Foamix has been the skin. researching a foam formulation of the BioPharmX and Foamix are taking different approaches to ef- same antibiotic. These topical products fectively deliver minocycline through the skin. BioPharmX solubi- have not been approved by the FDA lizes the minocycline in an anhydrous hydrophilic gel formulation. and are still considered investigational Clinical trials completed to date suggest the minocycline reaches (available only for use in clinical trials). the pilosebaceous unit in the skin where diseases like rosacea and While oral doxycycline is com- acne form. Foamix, whose formulation suspends minocycline in an monly used to treat rosacea, oral oil-based foam, dosed its latest phase 3 clinical trial patient last year. antibiotics are often associated with Previous trials have shown their drug also reaches the problem area. systemic adverse effects, such as upset Research from BioPharmX and Foamix is particularly interest- stomach, diarrhea, dizziness, photosen- ing because it shows both products dramatically reduce the amount sitivity, and headaches. In higher doses, of antibiotic that is measurable in the bloodstream. If ongoing trials doxycycline also has a greater rate of confirm the research, the new products may offer significant promise antibiotic resistance than minocycline. to dermatologists and their patients. The novel topical formulations of minocycline may have the potential to deliver the efficacy of a tetracycline-

70 DERMASCOPE | March 2018 class drug without the undesireable 13 Gallo RL, Granstein RD, et. al. Standard classification and for rosacea: a chronic vascular and inflammatory skin disease. J pathophysiology of rosacea: The 2017 update by the National Manag Care Spec Pharm. 2014;20(6):623-629. systemic effects. Rosacea Society Expert Committee. J Am Acad Dermatol. 2017 29 McClellan KJ, Noble S. Topical metronidazole: a review of Oct 28. pii: S0190-9622(17)32297-1. its use in rosacea. Am J Clin Dermatol. 2000;1(3):191-199. doi: 14 Steinhoff M, Buddenkotte J, Aubert J, et al. Clinical, cellular, 10.2165/00128071-200001030-00007. Products that are currently in and molecular aspects in the pathophysiology of rosacea. J Invest 30 Abokwidir M, Fleischer AB. An emerging treatment: topical clinical trials may significantly change Dermatol Symp Proc. 2011;15:2-11. ivermectin for papulopustular rosacea. J Dermatolog Treat. 15 Trivedi NR, Gilliland KL, Zhao W, et al. Gene array expression 2015;26(4):379-380. doi:10.3109/09546634.2014.991672. the way dermatologists treat rosacea profiling in acne lesions reveals marked upregulation of genes -in 31 Brooks M. FDA clears ivermectin cream (Soolantra) for rosacea. in coming years and could potentially volved in inflammation and matrix remodeling. J Invest Dermatol. Medscape website. medscape.com/viewarticle/837230. Published 2006;126:1071-1079. December 24, 2014. Accessed December 29, 2015 reduce adverse effects associated with 16 Buhl T, Sulk M, Nowak P, et al. Molecular and morpho- 32 Jarmuda S, O’Reilly N, Zaba R, Jakubowicz O, Szkaradkiewicz the treatment. logical characterization of inflammatory infiltrate in rosacea A, Kavanagh K. Potential role of Demodex mites and bacteria in reveals activation of Th1/Th17 pathways. J Invest Dermatol. the induction of rosacea. J Med Microbiol. 2012;61(pt 11):1504- 2015;135:2198-2208. 1510. doi: 10.1099/jmm.0.048090-0. References: 17 Aubdool AA, Brain SD. Neurovascular aspects of skin neuro- 33 Del Rosso JQ. Management of cutaneous rosacea: em- 1 https://www.rosacea.org/rr/2010/winter/article_1.php genic inflammation. J Invest Dermatol Symp Proc. 2011;15:33-39. phasis on new medical therapies. Exert Opin Parmacother. 2 https://www.rosacea.org/weblog/rosacea-awareness-month- 18 Lonne-Rahm S-B, Fischer T, Berg M. Stinging and rosacea. 2014;15(14):2029-2038. doi: 10.1517/14656566.2014.945423. highlights-warning-signs Acta Derm Venereol. 1999;79:460-461. 34 Johnson AW, Johnson SM. The role of topical brimonidine 3 Schwab VD, Sulk M, Seeliger S, et al. Neurovascular and 19 Steinhoff M, von Mentzer B, Geppetti P, et al. Tachykinins and tartrate gel as a novel therapeutic option for persistent facial neuroimmune aspects in the pathophysiology of rosacea. J Invest their receptors: contributions to physiological control and the erythema associated with rosacea. Dermatol Ther (Heidelb). Dermatol Symp Proc. 2011;15:53-62. mechanisms of disease. Physiol Rev. 2014;94:265-301. 2015;5(3):171-181. doi: 10.1007/s13555-015-0078-1. 4 Seeliger S, Buddenkotte J, Schmidt-Choudhury A, et al. 20 Tan J, Blume-Peytavi U, et. al. An observational cross-sectional Pituitary adenylate cyclase activating polypeptide: an impor- study of rosacea: clinical associations and progression between tant vascular regulator in human skin in vivo. Am J Pathol. subtypes. Br J Dermatol. 2013 Sep;169(3):555-62. 2010;177:2563-2575. 21 Holmes AD, Steinhoff M. Integrative concepts of rosacea 5 Sulk M, Seeliger S, Aubert J, et al. Distribution and expression Dr. Herron is a physician sci- pathophysiology, clinical presentation and new therapeutics. Exp of non-neuronal transient receptor potential (TRPV) ion channels Dermatol. 2017;26:659-667. entist with nearly three decades in rosacea. J Invest Dermatol. 2012;132:1253-1262. 22 https://rosacea-support.org/wp-content/uploads/2017/05/ of dermatology experience and 6 Wladis EJ, Iglesias BV, Adam AP, et al. Molecular biologic as- Rosacea-Time-for-a-New-Approach.pdf sessment of cutaneous specimens of ocular rosacea. Ophthal Plast an active clinical practice in 23 https://www.rosacea.org/rr/2004/fall/article_4.php Reconstr Surg. 2012;28:246-250. 24 https://www.uspharmacist.com/article/rosacea Palo Alto, California. As a 7 https://www.rosacea.org/ 25 https://www.aad.org/public/diseases/acne-and-rosacea/ member of the Stanford Univer- 8 Mikkelsen C, et. al. Rosacea: Time for a new approach. Forum rosacea#causes for Nord Derm Ven. (2017) 22:1 sity School of Medicine faculty, 26 Kligman AM, Christensen MS. Demodex folliculorum: require- 9 https://www.rosacea.org/weblog/can_rosacea_be_inherited ments for understanding its role in human skin disease. J Invest he conducted biomedical research, consulted with the 10 Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study of the Dermatol. 2011 Jan;131(1):8-10. epidemiology of rosacea in the U.K. Br J Dermatol. (2012) biopharmaceutical industry, authored or co-authored 27 Weinkle AP, Doktor V, Emer J. Update on the management of Sep;167(3):598-605. rosacea. Emer Clin Cosmet Investig Dermatol. 2015;8:159-177. more than 30 peer-reviewed papers, and secured 11 Brownlee C. Rosacea. Modern Drug Discovery. (2003) Jan;40. doi: 10.2147/CCID.S58940 several patents in the biomedical field. He serves as 12 https://www.niams.nih.gov/health-topics/rosacea#tab-causes 28 Feldman SR, Huang WW, Huynh TT. Current drug therapies medical director for BioPharmX Corporation.

March 2018 | DERMASCOPE 71