Rosacea: A Tiered Approach to Therapy
`
`Joseph B. Bikowski, MD, Pittsburgh, Pennsylvania
`
`Remission of rosacea can be achieved with a mul(cid:173)
`
`tilevel th erapeutic approach involving patient
`education along with oral and topical antibi(cid:173)
`otics. 1 A tiered method of treatment ensures that
`the patien t receives maximum benefit from systemic
`4
`and topical agents.2 There is no cure for rosacea,3
`•
`but long-term, positive results are possible and re(cid:173)
`mission can be maintained with ongoing use of top(cid:173)
`ical antibiotics.
`
`Overview
`6
`Rosacea is a highly prevalent, chronic skin disorder5
`•
`affecting up to 13 million Americans. It is most
`commonly seen in fair-skinn ed persons, particularly
`Caucasian women 30 to 50 years of age. While less
`commonly seen in men, rosacea is generally more se(cid:173)
`vere in males and may be accompanied by rhino(cid:173)
`phyma. Rosacea generally appears on the central area
`of the face, particularly the nose, medial cheeks,
`glabella, upper lip, and chin. Involvement may also
`be present elsewhere to include the scalp, neck, chest,
`shoulders, and back. Rosacea is characterized by flush (cid:173)
`ing/blushing, papules, pustules, eryth ema, and telang(cid:173)
`iectasias. It is differentiated from acne vulgaris in its
`age of onset (ie, younger than 25 years for acne and
`older than 25 years for rosacea) and presence of
`comedones (blackheads and whiteheads are the sine
`qua non of acne vulgaris). Rosacea is differentiated
`from post-adolescent female adult-onset acne by the
`typical flushing/blushing pattern and no comedones.
`As the disease worsens, edema is more persistent,
`telangiectasias enlarge, and the facial pores become
`more pronounced. As rosacea progresses, patien ts may
`develop large inflammatory nodules, tissue hyperpla(cid:173)
`sia, and distortion of facial features.
`
`Assessment
`Before in itiating treatment, a thorough evaluation of
`the patient's rosacea is in order. Determine the stage
`of rosacea (Table I), as well as th e extent and sever(cid:173)
`ity. A lthough rosacea is classically localized to the
`face, it may extend beyond the face with involvement
`of the scalp, neck, or torso. The severity of rosacea
`
`Or. Bikowski is Clinical Assistant Professor, University of Pittsburgh,
`Department of Dermatology, Pittsburgh, Pennsylvannia, and is in
`private practice in Sewickley, Pennsylvania.
`
`Table I.
`Stages of Rosacea
`
`Stage 1
`
`• Mild, persistent erythema
`
`• Some telangiectases
`
`Stage 2
`
`• Persistent erythema
`
`• Plentiful papules, pustules, and telangiectases
`
`Stage 3
`
`• Deep, persistent erythema
`
`• Masses of telangiectases, predominantly on
`the nose
`
`• A variety of edema, with plaque-like character(cid:173)
`istics, on papules, pustules, and nodules
`
`ranges from mild, with 2 or 3 inflammatory lesions
`and minimal flushing and blushing, to a more severe
`presentation with greater than 15 to 20 inflammatory
`lesions and extensive flushing and blushing. Also be(cid:173)
`fore initiating therapy, ascertain the length of time that
`the patient has been symptomatic and the type and du(cid:173)
`ration of any previous rosacea management ( eg, both
`prescribed and self-care remedies). In particular, ques(cid:173)
`tion patients on the use of topical steroids, over-the(cid:173)
`counter remedies, and nutritional interventions. Once
`the aforementioned is complete, it is important to
`elucidate from patients their current therapeutic ex(cid:173)
`pectations. In particular, find out how patients rank the
`importance and annoyance of rosacea and how much
`time, energy, and effort they are willing to exert to im(cid:173)
`prove their symptoms. Helping patien ts to focus on a
`clear, realistic goal of therapy facilitates compliance
`with the therapeutic regimen.
`
`Treatment
`Step 1: Skin Care- First, discuss skin care (Table II)
`an d instruct patients to use a mild non -soap cleanser
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`VOLUME 66, OCTOBER 2000 3
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`1
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`Galderma Laboratories, Inc. Ex 2014
`Dr. Reddy's Labs v. Galderma Labs., Inc.
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`
`

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`ROSACEA: A TIERED APPROACH TO THERAPY
`
`Table II.
`Skin Care-Facial Cleansing2
`
`• Use lukewarm water
`• Wash with a mild, non-soap cleanser
`• Use fingertips rather than washcloth or sponge
`•
`Blot the skin dry rather than rubbing it dry
`
`Table Ill.
`Common Rosacea Triggers 10
`
`• Ultraviolet light, sun exposure
`•
`Alcoholic drinks
`•
`Spicy foods
`• Hot beverages
`•
`Skin care produc~s
`
`( eg, Cetaphil®, Aquanil ™, or Neutrogena®) and to
`avoid the use of soaps, astringents, cleansers, fresh(cid:173)
`eners, toners, facial scrubs, facial masks, or cosmetic
`skin care programs. Remind patients that if these
`products had provided relief they would not be seek(cid:173)
`ing care. With regard to cosmetics, most patients
`have personal preferences and want to use products
`they like. Steering patients toward one product and
`away from another is not necessarily beneficial. In(cid:173)
`struct patients that they may use any makeup prod(cid:173)
`uct that th ey ch oose, including foundation , setting
`powder, blush , eye color, and lip color, as long as it
`does not cause any skin irritation and they can eas(cid:173)
`ily afford it.
`Teaching makeup camouflage techniques (eg, green,
`beige, or yellow to mask red in fair-skinned people and
`the use of lavender as a masking color in those with
`darkly pigmented skin) may improve their outlook. Ad(cid:173)
`vise patients to use a sunscreen on a daily basis that
`they like the Look, feel, and smell of with an SPF of at
`least 15 and both UVA and UVB protection .7
`Step 2: Trigger Avoidance and Diary- T he patho(cid:173)
`genesis of rosacea is unknown, h owever various
`factors are recognized to trigger its characteristic
`
`symptoms.4•8 Patients should be taught to avoid fac(cid:173)
`tors that trigger their rosacea.9 A lthough the list is
`longer (Table III) , there are basically 3 primary of(cid:173)
`fenders: hot beverages, spicy foods, and alcoholic
`drinks. The most common trigger is h ot beverage con(cid:173)
`sumption (eg, hot tea, coffee, cocoa). Contrary to
`popular belief, th e culprit is not the caffeine but the
`temperature of the drink that causes the flush and the
`blush. The secon d most frequent trigger is hot spicy
`foods. Although the mechanism of action for this is
`unclear, it does seem to be a constant. Alcoholic
`
`4 CUTIS"
`
`drinks are the third offender, with reaction to it
`being extremely common and individualized. Some
`individuals worsen with scotch and some may find
`gin the culprit.
`Maintaining a daily diary of the frequency and du(cid:173)
`ration of flushing/blushing is a revelation for many
`patients. This provides objective evidence of the
`severity of the disorder at the beginning of treat(cid:173)
`ment, and then after 6 weeks of therapy, another un(cid:173)
`biased Look at the degree of improvement. For the
`first 4 to 6 weeks of therapy, patients are requested
`to keep a daily record of how often and how long
`they flush/blush. Patients are asked to bring their di(cid:173)
`aries to follow-up visits. Initially, patients may not
`notice any improvement and say that they have not
`experienced notable positive results. They are then
`surprised wh en they examine the diary. A typical sce(cid:173)
`nario involves someone with flushing/blushing 2 to 3
`times a day, lasting up to an hour at the beginn ing of
`treatment, which decreases to once daily, for a max(cid:173)
`imum of 30 minutes after 6 weeks of therapy. The di(cid:173)
`ary documentation provides objective validation and
`helps patients to realize the value of the therapeutic
`regimen in improving their rosacea.
`Step 3: Antibiotics- Successful rosacea therapy is a
`12
`combination of systemic and topical antibiotics.11
`•
`The symptoms of rosacea are brought under control
`by means of the anti-inflammatory properties of the
`drugs. Both oral and topical antibiotics are started si(cid:173)
`multaneously, with the expectation that the sys(cid:173)
`temic antibiotic begins to yield results in 2 to 4
`weeks, whereas the topical medication takes 3 to 12
`weeks. Patients are generally anxious to see results
`and should be instructed of the timeline of results.
`Advance notice of this may reduce disappointment
`an d enhance compliance with the prescribed regi(cid:173)
`men. Reinforce that th ere is no cure fo r rosacea,
`but th at it can be successfully treated and that the
`patient's appearance can be enhanced and symp(cid:173)
`toms improved.
`Oral Antibiotics- The first-tier, least expensive
`medication regimen generally begins with a course
`of either tetracycline 13 or erythromycin base en(cid:173)
`teric-coated (each dosed at 500 mg orally twice a
`day). The cost/benefit ratios are quite advanta(cid:173)
`geous; the typical cost for tetracycline is about 25
`cen ts per day, whereas erythromycin costs about 50
`to 60 cents per day. A lthough tetracycline is reported
`to be a photosensitizer, its occurrence is infrequent,
`and th ere are no double-blind controlled studies that
`verify this adverse effect.
`The primary side effect of either medication is gas(cid:173)
`trointestinal upset. To minimize th is, patients are in (cid:173)
`structed to take the medication with food. Those who
`do not tolerate tetracycline are switch ed to enteric-
`
`2
`
`Galderma Laboratories, Inc. Ex 2014
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782
`
`

`
`ROSACEA: A T IERED APPROACH TO THERAPY
`
`coated erythromycin. About 5% of patients complain
`of nausea or vomiting and cannot tolerate the eryth(cid:173)
`romycin at the 1000 mg/day dosing. For these pa(cid:173)
`tients, discontinuing the medication for several days
`until side effects abate, and then resuming it at a low(cid:173)
`ered dose (250 mg/day, taken with dinner) usually
`provides good resolution to this problem.
`Patients who cannot take tetracycline or eryth(cid:173)
`romycin may be prescribed the second-tie r oral
`antibiotic, doxycycline. This medication is also an
`appropriate ch oice for daily dosing to increase com(cid:173)
`pliance or for patient preference. Patient compliance
`is one of the most important factors in obtaining
`good therapeutic results, and thus it is often n eces(cid:173)
`sary to adjust dosing patterns to achieve the desired
`outcome. Once-daily dosing can be achieved with
`doxycycline, minocycline,
`or
`trimethoprim(cid:173)
`sulfamethoxazole. Doxycycline hyclatc and doxycy(cid:173)
`cline monohyG!rate can both be successfully used at a
`once-daily dose of 100 mg. When choosing between
`doxycycline hyclate and doxycycline monohydrate,
`Monodox® (Oclassen Dermatologies) is preferred
`because of its neutral pH (close to 7) results in less
`gastrointestinal tract upset or esophageal irritation.
`Although the incidence is rare ( < 1%), doxycycline
`is a photosensitizer.
`Irrespective of the antibiotic prescribed, photo(cid:173)
`sensitization is very rarely seen in patients with
`rosacea. Those who develop photosensitivity usually
`present with a classic erythema of the dorsum of the
`h ands, of the dorsum of the fingers, and in the promi(cid:173)
`nences of the face (ie, forehead, nose, checks, and
`chin). This reaction is usually seen when treating
`teenagers receiving the drugs for acne, who are ex(cid:173)
`posed to excessive or prolonged sun ( eg, working as
`lifeguards in the summertime).
`The third-tier oral antibiotic is minocycline 100
`mg, once daily. It is the most expensive and patients
`may experience vertigo, hypersensitivity, a lupus-like
`syndrome, or blue-gray pigmentation at areas of cu(cid:173)
`taneous inflammation. The pigmentation may be of
`long duration. (This author has one patient that is 1
`year post-minocycline treatment and still has an 8 X
`12-cm area of h yperpigmentation on the lateral as(cid:173)
`pect of her thigh.) On the positive side, there is no
`evidence that minocycline is a photosensitizer.
`Trimethoprim-sulfamethoxazole is the last choice
`for oral antibiotic treatment. It is advantageous be(cid:173)
`cause of its rapid results. The other medications yield
`outcomes in 14 to 28 days, whereas trimethoprim(cid:173)
`sulfamethoxazole ( 1 to 2 tablets daily) may result in
`a marked resolution of inflammatory lesions in 7 to
`10 days. However, the drug is not problem-free and
`has two important possible adverse effects. First, it
`may decrease the white blood cell count. Although a
`
`rare occurrence, it may be evident at the end of the
`first month of medication. The second concern is
`toxic epidermal necrolysis. If this occurs, it is mani(cid:173)
`fest between days 7 and 21 of therapy. Patien ts re(cid:173)
`ceiving the medication for 30 days without evidence
`of toxic epidermal necrolysis do not experience it
`later. Irrespective of this medication's rapid results, it
`is advisable to reserve its use after tetracycline, eryth(cid:173)
`romycin, doxycycline, and minocycline because of
`the potential and serious problem of toxic epidermal
`necrolysis.
`Regardless of the type of antibiotic the patient is
`taking, th e goal of therapy is to taper off the systemic
`antibiotics 3 to 6 months after the patient's skin
`clears and to maintain the usc of topical medication
`to sustain remission. The typical patient receives
`tetracycline that is tapered to 250 mg twice daily and
`then to a once-daily dose. Patients receiving doxy(cid:173)
`cycline or minocycline decrease their dose to 100 mg
`every other day.
`Topical Medications- The first tier of topical med(cid:173)
`ication is metronidazole 0.75 %, which is available as
`MetroGcl®, MetroCream TM, and MetroLotion TM (Gal(cid:173)
`21 These various products
`derma Laboratories, L.P.).14
`'
`facilitate the ability to specifically target each patient's
`individual skin type (eg, patients with combination
`skin can use MetroLotion; those with dry skin, Metro(cid:173)
`Cream; or those with oily skin, MetroGel). The sec(cid:173)
`ond tier is sodium sulfacetamide, Klaron® (Dermik
`Laboratories, Inc.) lotion. This is a clear, cosmetically
`elegant product. One drop of Klaron covers a large area
`of skin. It may be used to treat both rosacea and seb(cid:173)
`orrheic dermatitis when they occur together. The third
`tier of topical medication is metronidazole 1%, N ori(cid:173)
`tate TM (Dermik Laboratories, Inc.) creamY The base
`of this cream is quite thick, and thus may be of greater
`benefit in patients who have really dry skin. However,
`sebotTheic dermatitis is a very common disorder in pa(cid:173)
`tients who have a lot of redness and dryness or greasy,
`oily, scaling in the central third of the face. Therefore,
`if a patient has seborrheic dermatitis in combination
`with the rosacea, treatment for both disorders may be
`needed. The fourth choice for topical treatment is an
`old standby, sodium sulfacetamide 10% with 5% sulfa
`
`(Sulfacet-R49, Dermik Laboratories, Inc.; Novace~,
`GenDerm) lotion. These products are not the most
`cosmetically elegant, but they do have a longstanding
`track record of efficacy.
`
`Conclusion
`The first step in treating rosacea is teaching patients
`about good skin care, which products to use, and which
`to eliminate. The next step is to instruct patients to
`avoid trigger factors as much as possible and to keep a
`daily diary. The third component of treatment consists
`
`VOLUME 66, OCTOBER 2000 5
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`3
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`Galderma Laboratories, Inc. Ex 2014
`Dr. Reddy's Labs v. Galderma Labs., Inc.
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`
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`
`ROSACEA: A TIERED APPROACH TO THERAPY
`
`of a tiered regimen with combination drug therapy, start(cid:173)
`ing simultaneously with oral and topical antibiotics. Pa(cid:173)
`tients are instructed about the use of systemic antibiotic
`therapy concomitant with the use of topical medication
`to clear the rosacea. Results are usually seen in 4 to 6
`weeks, but may take as long as 12 weeks. Systemic an(cid:173)
`tibiotics are slowly tapered once the desired results are
`obtained and the patient is in remission. Long-term,
`low-dose oral antibiotics are generally continued only if
`needed to maintain remission. Patients are generally
`maintained on long-term topical antibiotics to preserve
`the positive effects. Although there is no cure for
`rosacea, an approach including skin care, trigger avoid(cid:173)
`ance, and tiered oral and topical antibiotics ameliorates
`its adverse effects and minimizes the symptoms.
`
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`6 CUTIS"
`
`4
`
`Galderma Laboratories, Inc. Ex 2014
`Dr. Reddy's Labs v. Galderma Labs., Inc.
`IPR2015-01782