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ACNE BRIEFS

VOL. 1 NO. 2

PUBLISHED UNDER AN UNRESTICTED EDUCATIONAL GRANT FROM GALDERMA

COMBINATION THERAPY IS THE BEST APPROACH FOR MILD TO MODERATE ACNE

In this issue of Acne Briefs, Gary M. White, MD, chief of dermatology at Kaiser Permanente in San Diego, shares his experience treating acne with what he calls the "two pillars of conventional therapy": a comedolytic agent to open the pores and an antimicrobial to kill the bacterium Propionibacterium acnes, which infects the follicles of acne patients. Recent advances in acne therapy, including the development of new, less irritating topical retinoids that successfully resolve and prevent comedones, have given this two-pillared approach an extra punch. Dr White explains how best to integrate these drugs into effective acne therapy for patients of any age or skin type.

Q. Can you review the various types of acne therapies available, and delineate which part of the pathogenesis of acne they each affect?

Dr White: One of the two pillars of conventional therapy is killing the bacterium P acnes with antimicrobials (Table 1, page 2). We have both topical and oral agents. There is topical benzoyl peroxide, which is probably the best topical agent to kill P acnes, and then we have topical erythromycin and clindamycin. In the past, tetracycline was used topically, but that's not really used much anymore. We have combination therapies, like Benzamycin®, which is a combination of 5% benzoyl peroxide and 3% erythromycin. There are also some products that contain sodium sulfacetamide, like Klaron®, that can be used to kill P acnes.

In terms of oral antibiotics, I usually use tetracycline, at a dose of 500 mg twice a day, doxycycline, 50 to 100 mg twice a day, and minocycline, 50 to 100 mg once or twice a day. Those are the drugs that kill P acnes.

As the second pillar, to open up the follicle, to get rid of those comedones, I rely on the retinoids. Retinoids are just fabulous topical agents to do that, and the newer, less irritating retinoids are definitely my favorite. I like Differin® (adapalene) gel, which is excellent for almost any patient, but in particular those with a little oilier complexion or maybe during the summertime. I also like Avita® (tretinoin) cream for patients with sensitive skin or during the wintertime, when the air can be a little drying. I find both of those very

effective. Retin-A Micro® (tretinoin) is another one you might consider. Tazorac® (tazarotene) tends to be a little more irritating and more costly, and so I usually don't use tazarotene.

Azelex® (azelaic acid) has been marketed to have both P acnes-reducing and comedolytic effects, but I think the data don't support its effectiveness in killing P acnes, and its comedolytic effect is not quite as good as that of the retinoids. So, in general, to open up those pores, the retinoids are really the best.

Q. Are there any drawbacks with the drugs used in this "two-pillar" approach?

Dr White: Benzoyl peroxide is very effective in killing P acnes, but the main drawback is the drying effect. Some patients don't tolerate it well, especially if you go to 10%. We modulate that by trying to go with the 5% preparations. Patients can even use it every other day, if they need to. If that still doesn't work, Benzamycin is an excellent product that reduces the irritation of benzoyl peroxide and has, perhaps, even greater efficacy. The one downside to Benzamycin is it's a little more expensive than an over-the-counter drug or even many of the prescription benzoyl peroxides. In terms of sodium sulfacetamide, it probably doesn't kill P acnes as well as benzoyl peroxide, but it may be appropriate for patients with really sensitive skin. Clindamycin is an excellent topical product, though it doesn't kill the P acnes quite as well as benzoyl

peroxide. Also, the bacterium can develop resistance to both topical clindamycin and erythromycin, but we still use a lot of that.

Oral antibiotics: Tetracycline is a good first-line agent for moderate inflammatory acne. It can cause a yeast infection in about 3% of women, so we always have to let them know about that. There's a theoretical interaction with birth control pills, so as doctors, we always feel obligated to mention that, but it's not been proven. Doxycycline is very effective and can be taken with food, but it has quite a bit of photosensitivity, so we don't like doxycycline in the summertime. Minocycline is probably the most effective of all our oral

antibiotics, but it has some long-term side effects that you have to think about, like blue patches on the skin and even blue teeth. And sometimes, early on, women can get vertigo or dizziness with the first couple of doses. It is also more expensive than tetracycline and doxycycline.

With regard to the retinoids, there are very few drawbacks to either the Differin® (adapalene) gel or Avita® (tretinoin) cream. I find those products to be very well tolerated by patients. Tazarotene, as I mentioned, is more irritating.

Q. What is the normal therapeutic regimen you prescribe for the average patient with acne?

Dr White: The average patient with acne gets topical therapy as a fundamental starting point. So, they always get a topical retinoid and a topical antimicrobial. My favorite is Differin gel or the Avita cream, along with a benzoyl peroxide-containing product. That's my foundation. If in addition to that they have moderate inflammatory acne with some nodules, I'll add an oral antibiotic, either tetracycline or doxycycline, to that topical regimen. If they are resistant to that treatment, I'll switch the oral antibiotic to minocycline and give that another 6 weeks. If that doesn't work, then I put them on

isotretinoin (Accutane®).

Q. What prompts you to change therapies?

Dr White: I usually like to see patients back in about a month to 6 weeks, to see how any regimen they're on is doing. If they have improved significantly, by maybe 40% to 60%, I'll stay on it and see them back in another month to 6 weeks. If they haven't budged one bit after a month to 6 weeks, then I usually think it's time to switch to something different.

Q. What can the dermatologist do to reduce the risk for the patient's P acnes developing resistance when using antibiotics?

Dr White: The resistance of the bacterium P acnes to various antibiotics is on a significant rise, and I think it will continue to go in that direction and be a problem for our patients. But the good news is that benzoyl peroxide is not subject to that; P acnes will not develop resistance to benzoyl peroxide, plus there's no resistance in any way to the retinoids and their action. Therapy with adapalene gel and benzoyl peroxide, for example, is not at all subject to any

P acnes resistance problems. And when you add an oral antibiotic, such as tetracycline, you still have that benzoyl peroxide on board to help kill the P acnes. A strain of P acnes that's fully resistant to tetracycline will be just as easily killed by benzoyl peroxide as one that's not resistant to tetracycline. So this topical regimen of benzoyl peroxide and retinoids is not going to be affected by any P acnes resistance.

Q. Should two different antibiotics ever be used simultaneously?

Dr White: That question, I think, would apply to a regimen of, perhaps, tetracycline orally and clindamycin topically, along with a retinoid. I don't use that as much, because you get into the issue of P acnes resistance. That's why I like an oral antibiotic, such as a tetracycline, with benzoyl peroxide, because you don't have that problem, and if irritation is a problem, I'll use Benzamycin. But there are some patients who just don't tolerate a benzoyl peroxide, but they had used clindamycin or erythromycin in the past and

they had liked it. So I do, sometimes, have a very small percentage of my patients on an oral tetracycline and a topical antibiotic, but

it's not my first choice.

Q. How many times in your practice have you used a single agent for acne therapy and obtained good results?

Dr White: The only time we use monotherapy is with the systemic retinoid isotretinoin. If you exclude that and look just at conventional therapy, I use one medication just 2% or 3% of the time; 97% or 98% of the time, I use multiple medications.

Q. Why do you need to use more than one drug?

Dr White: The whole reason we use combination therapy is because acne, probably fundamentally, has two problems that we try to address: one is the closing up of the pore, the comedone formation, and the second is the growth of the bacterium P acnes. We don't have any topical agents that fight both. Sometimes, if a patient is very young and the main thing that bothers him or her is the

inflammatory papules and pustules, benzoyl peroxide would be very appropriate. The patient can get that over the counter and do pretty well. Sometimes adult women in their 20s or 30s who are mainly bothered by the inflammatory papules do pretty well with nightly benzoyl peroxide.

If a young patient has mainly comedones and hasn't started to develop the inflammatory acne phase, then a topical retinoid might be good. Those are the kinds of situations where I might use a single agent.

Q. Why is it important to include an agent that corrects keratinization defects when treating acne?

Dr White: The follicular opening, the pore, closes up or gets clogged because of a variety factors, but one of the key ones is the thickening of the follicular lining, which results from abnormal keratinization. That, together with the oil and the debris from the P acnes, forms the plug. Anything that can improve the

keratinization and normalize the follicular opening will help unclog that pore.

There is some benefit to using keratolytics, such as salicylic acid, that peel the skin, but those are not nearly as effective as the topical retinoids, which act through the retinoic acid receptors to normalize that follicular opening. We don't fully understand why retinoids normalize the opening, but we do know they do that very well.

Q. Is there anything else that can help eliminate or prevent comedones?

Dr White: Whenever I encounter patients with a lot of comedones, the first thing I want to know is whether they are putting anything on their face that's greasy or comedogenic. I always go through a quick question-and-answer session about what they put on their face, and then try to eliminate any greasy substances that might be causing the comedones to occur. If I want to get rid of comedones, I use the topical retinoids almost exclusively. It's interesting that almost

anything that reduces P acnes will also reduce comedones to some extent, so when you use benzoyl peroxide, when you give oral antibiotics, the reduction of P acnes actually will help to a small extent to reduce the comedones. So that's one benefit of combination therapy.

Also, acne surgery can be an adjunct to retinoid therapy. We have patients see our nurse for acne surgery, to take out some comedones.

Q. What about azelaic acid and the ?-hydroxy acids?

Dr White: Azelaic acid probably has some comedolytic effect, though it is not nearly as effective as the retinoids. It might be a good adjunct in a patient with darker skin who has some postinflammatory hyperpigmented macules.

The ?-hydroxy acids continue to be agents that people would like to use for acne, but the data are really quite sparse. The best study, published in Cosmetic Dermatology, used glycolic acid with or without tretinoin, and the tretinoin was far superior to the glycolic acid. We need more studies in the area of -hydroxy acids, but I continue to think that retinoids are clearly superior in their comedolytic effect.

Q. Are there any combination treatments for acne that do not work and shouldn't be used?

Dr White: Absolutely. Obviously, we have only a certain number of interventions we can expect our patients to use. I think three medications is getting to be about the limit. If you focus all your efforts on either killing P acnes or opening up the pore, and not both, then you're missing the boat. So, for example, I don't like tetracycline plus benzoyl peroxide. That therapy kills P

acnes, but it doesn't open up the pore. I don't like a topical retinoid therapy plus salicylic acid as the only approach. It doesn't do anything for P acnes. Azelaic acid, as I've mentioned, is only a little better in its comedolytic effect, so I wouldn't combine it with a retinoid.

Q. Have the newer, less irritating retinoids changed the way you treat acne, and if so, how?

Dr White: The newer retinoids, like adapalene (Differin), and the newer packaging of tretinoin, like Avita, have definitely changed the way I practice dermatology in the area of treating acne by making it much easier for me. I am more willing to give the retinoids to almost every patient with acne. In the past, because Retin-A was fairly irritating, I would sometimes try to get by with not giving a retinoid to some patients who didn't have as many comedones, whereas now I'm able to give retinoids to almost any patient.

Q. What about the patient with sensitive skin? Do you have any patients who still have problems with irritation?

Dr White: In the past, we often had a significant percentage of patients whom we couldn't get to stay on a daily regimen of retinoids. But now, with the newer, less irritating retinoids, almost every patient will stay on retinoid therapy and do very well.

In the past, we used to have the patients wash their face and wait 20 minutes before they put the retinoids on; we don't have to do that anymore. The new retinoids have simplified the approach for our patients. They just wash their face, put the medication on, and go do their thing.

Q. Do you ever encounter patients who have tried a retinoid before and don't want to try one again?

Dr White: It's interesting how educated many of our patients are. Many of the lay publications have correctly encouraged patients to see their doctors for these newer retinoids. Everyone knows that Retin-A can be very irritating, and these new medications are really a nice advance. I do have some patients that I

have to tell about the new retinoids, but many patients come to me knowing that there's something different, something new, and maybe they don't have to use that old Retin-A.

Q. What do you tell those few patients who require persuasion?

Dr White: I just tell them, "Medical science has made an advance here. Retin-A was the old product. We've got some newer, improved medications. They really are better. If you'll just try them, I think you'll do very well and you won't get the irritation that you used to get with Retin-A."

Q. How do these new retinoids compare in efficacy with all-trans-retinoic acid (Retin-A)?

Dr White: In the largest multicenter trial comparing Differin gel with Retin-A .025% gel, Differin gel was actually more effective than Retin-A. There were some other studies that showed that they were equally effective. The bottom line, I think, that most dermatologists should take away from the studies with retinoids is that in general, either Differin or Retin-A will get you to the same point at 12 weeks. It's very hard to prove any significant difference in terms of efficacy. The main benefit is the reduction in irritation. The patients

can use Differin much more easily.

Q. What kind of daily regimen do you recommend to maximize the efficacy of using topical retinoids and antimicrobials in the two-pillared approach to acne therapy?

Dr White: In general, we like the patients to wash their face twice a day: morning and night (Table 2). We want them to be careful about what they put on their face and use products from reputable, well-known companies, like Clinique, Estée Lauder, or any of the major companies. We like products that say "noncomedogenic" or "nonacnegenic" - something that shows that the company thinks they're okay for acne skin. I discourage a lot of moisturizers if the patient has acne. In the morning, they may want to use a light moisturizer with sunscreen, or they may want to use a light moisturizer if they're getting some drying or peeling from the regimen.

Other than that, the key points that I go over with patients for their regimen is that we're trying to prevent acne. Probably the number-one mistake that patients make with their topical therapies is trying to "spot treat." They want to put a little something here, a little something there on the acne that's already broken out. I tell patients that's like closing the barn door after the cow got out. It doesn't prevent acne; they need to put the medications all over to prevent acne.

Benzoyl peroxide can bleach carpets and clothing, so that's important for patients to know. Many patients do better with benzoyl peroxide at nighttime, especially women, because sometimes it leaves a visible white residue that doesn't look good at school or work.

Although it's not in the package insert, Differin gel does very nicely in the morning. Many women like to put Differin on in the morning and then put makeup on afterwards, as needed. It's very light and goes well with makeup.

I work in San Diego, and we've used Differin gel on thousands of patients. I have not seen a single case of photosensitivity from it. I do confess that I usually like patients to use some moisturizer with a little sunscreen in the summertime, but I'd say that this regimen works very well.

Q. What kind of sunscreens should acne patients use when they are at the beach or in the sun for prolonged periods of time?

Dr White: Sun-protection factor (SPF) 15 is probably not sufficient for several hours out in the sun. I recommend at least an SPF 30 for my patients with acne who will be outside for prolonged periods of time. Many of the sunscreens with SPF 30 claim to be noncomedogenic, or okay for acne, but I have found in general that a patient just has to go and try them. If you use something for a week, and your acne flares up, even if the product says "nonacnegenic," it's not good for you. I tell the patient to get two or three different sunscreens and try them for a week in the summertime. I've never had a patient who couldn't figure out

which ones flare up their acne and which ones don't.

Q. Do you recommend any special acne cleansers or soaps?

Dr White: I'm not really into spending money on a whole regimen that's not nearly as effective as benzoyl peroxide and a topical retinoid. There are, in general, two types of cleansers: the salicylic acid-containing cleanser and the benzoyl peroxide-containing cleanser. The benzoyl peroxide-containing cleanser is not nearly as effective at killing P acnes as the benzoyl peroxide that you put on and leave on. But if patients are on a topical retinoid and an antimicrobial, and they still have some inflammatory lesions, then you could add a cleanser with benzoyl peroxide. Or, if they have a few more comedones, you could add a salicylic acid-containing cleanser.

Q. How can patients be educated to maximize the value of their acne therapy?

Dr White: In terms of educating patients about acne therapy, there are a few things I always try to do in the time that I have them in my office. The first is to stress that if a regimen works, we have got to stay on it. If it works for 6 weeks, then we stay on it for 3 months, 6 months, etc; we don't wait until it improves and then stop. That's one of the key things.

The second is that we use combination therapy in acne for a reason. We are trying to affect at least two different causes of acne, so we're using medications with two different purposes. Many times, if you don't prepare patients appropriately, if you give them two medications, they'll try to figure out which one works better. And I've never understood how patients can think they've figured out that one works and the other one doesn't. But invariably, they will, and they'll stop one medication and come back to you and they're

just on one topical.

I prep them by saying "We've got to use these medications daily for a prolonged period of time. I want you to use them both; don't stop just one, use them both. And if you have any side effects or problems, call me." You want to head off the patient who's going to come back to your office who used the medication for 1 week, had some sort of problem, and then just stopped. Then you've wasted that whole period of time, and you've got to get him or her back on the regimen. Those are the things that I tell patients as a kind of preemptive strike.

Q. How do you manage the patient who continues to have macrocomedones underneath the skin, despite otherwise successful acne therapy?

Dr White: The macrocomedones are an interesting variant of the comedone. They're these 1- to 2-mm white balls right under the skin that you can see best by stretching the skin (Figure). They often become apparent during isotretinoin therapy, but you may notice them in patients on conventional therapy as well.

Oftentimes, the tried-and-true method of acne surgery is best at eliminating these. You take a number 11 blade, make a small incision, and then use a comedone extractor to remove them.

In the United Kingdom, they have reported using EMLA cream applied first, and then electrocautery if there are maybe 50 to 100 lesions. I myself haven't done that, but Dr Cunliffe and others recommend that approach for treating multiple lesions.

Q. How often do you use acne surgery as an adjunct to acne therapy?

Dr White: I think we have a duty to do what's best for our patients. If you can get them on a topical retinoid that keeps their pores clear, they probably won't have to return to you month after month for extractions; that's a service we do for our patients. But in those few patients on a topical retinoid who are

not fully clear of comedones - blackheads and whiteheads - then I utilize my acne surgery nurse to clear out those pores, and have the patients come back as often as they need. So I use it as an adjunct to topical retinoid therapy.

Q. What role do hormones play in acne, and do you take that into account when prescribing therapies?

Dr White: We know that hormones are a significant part of the process of acne, because it only occurs when the pubertal hormones start to increase. But that's a normal process.

It's in the area of young adult women with acne that we really think that hormones are related, although we're not quite sure of all the details. We see a lot of young adult women who have acne that flares with their menstrual cycle, and that is benefited by hormonal therapy. It's interesting, but in this group of patients, the hormone levels are usually normal. If you take 100 young adult women with acne, their average hormone levels might be slightly higher than those in a normal group, but for the individual patient, you don't find a specific abnormality. Oftentimes, for young adult women - especially those who

have relapsed after Accutane - we'll want them to go on birth control pills, such as Ortho-Tri-Cyclen®. If a woman has a relapse after a second course of Accutane, I'll give spironolactone therapy, which I've found to be effective in this subset of patients with acne.

Q. Are there any precautions that pregnant or nursing women who are being treated for acne should take?

Dr White: We have a greatly limited armamentarium for pregnant women with acne. Erythromycin is okay topically, as is benzoyl peroxide. That allows them to use Benzamycin, benzoyl peroxide, topical erythromycin, or even oral erythromycin, although I must say that I always have the patient or myself check with the obstetrician before I start any oral medications.

Azelex (azelaic acid) is pregnancy category B, and even though it's not as comedolytic as the retinoids, we in general don't use topical retinoids in our pregnant patients. Azelex is also appropriate for nursing mothers. So, in general, a lot of women just have to wait until they're done with their pregnancy.

Many times, the acne will improve with pregnancy, but sometimes it will worsen, and for those patients, they just have to wait.

Q. What about treating the pediatric patient? Is it safe to use your normal combination of benzoyl peroxide and retinoids, or topical antibiotics and retinoids?

Dr White: The child with acne can be treated with all of these regimens. There's certainly no problem with benzoyl peroxide with all of the topical retinoids. The main concern that we think about is with tetracycline, because it can damage the teeth.You shouldn't use tetracycline in kids 8 years or younger. It's

rare to need tetracyclines in patients until they're 12, 13, or 14. So there's rarely any problem with kids and using these sort of therapies.

Q. How does the cost of therapies influence the regimens you prescribe?

Dr White: In a perfect world, I would like to ignore costs in treating patients. I would like to give them the absolute best therapy possible. Sometimes the cost is very important to the patient, especially if they're paying for it, and so they want to know how much it's going to cost; if it's too expensive, they can't afford it. But if a health plan is paying for the medication, then I think the doctor is more free to give what's absolutely best for the patient.

Now, having said that, I think that the good news is that many of the most effective therapies that I recommend are relatively inexpensive, compared with alternatives. For example, benzoyl peroxide is very inexpensive, and yet it's a great topical medication for acne. In the area of retinoids, Differin gel is also a good drug for its cost. Avita is the least expensive. Tazarotene is more expensive and it's also more irritating, so I don't usually use it. The oral antibiotics - tetracycline and doxycycline - are very inexpensive, and of course Accutane is very expensive.

Q. How long after their acne clears should patients remain on their regimen?

Dr White: If a patient is on this topical regimen of a retinoid plus benzoyl peroxide or an antimicrobial and an oral antibiotic, then I'll usually give the oral antibiotic for a 3- to 6-month period and then tell the patient to stop it and see if the topical regimen will do. I usually see the topical program as something for long-term maintenance, but I try to get patients off antibiotics orally if I can.

If they have gone a long time with the topical regimen, then invariably I don't have to tell patients. On their own, they will stop one agent and see how they do. If they ask me first, if they have more inflammatory lesions, I'll say, "Stop the retinoid and just go with the topical antimicrobial." If they have more comedonal disease, I'll say, "Stay on the retinoids, stop the antimicrobial, and just see how you do over time."

Q. What are some of the changes in lifestyle and self-image that people experience after being on successful combination acne therapy?

Dr White: A lot has been said about the psychological problems, concerns, or issues that patients have when they have a face full of acne, and I think that's absolutely warranted. These poor kids - they're trying to become adults and create their own personality and life, and if they're plagued with a face full of acne, it really causes them a lot of harm.

You'll see patients when they first come in with bad acne: they're not talking, they're not looking at you in the eye, they're looking down at the floor, they let Mom do most of the talking, etc. You get a sense that their self-esteem is low, they don't feel good about themselves. And then, when you do treat them

effectively, and their face is clear, they come in, they're smiling, they're looking at you, they're interacting much more. And that is one of the rewards that I have in treating acne. When the patients get better, you can just see, psychologically, how much better they feel.

Q. Do you ever have to recommend adjunctive psychologic counseling?

Dr White: You know, I never have. The acne therapy that we have available is so good - the topical retinoids, the Accutane - we have such good therapy these days, that if a patient has a face full of acne, then it's almost always because he or she is not seeing a doctor. The old story is told about the psychologist

who is treating a patient who is standing out in the rain and the psychologist is trying to help him to accept all the problems associated with standing in the rain, and another psychologist comes by and just says, "Come in out of the rain!" So, we could try to treat all of these psychological issues, or we could just fix the acne. And that's really what I focus on.

Q. So you never use psychotropic drugs in your practice?

Dr White: I never do. I tell the patients, and I can be very honest about it, "If you'll stick with me, if you'll do what I recommend, if you come to see me every 4 to 6 weeks, we will fix your acne, one way or the other."

Q. How important for effective therapy is the relationship of trust that you establish with the patient?

Dr White: The most important thing for effective therapy is that patients use what you give them. And this applies not just for acne, but for any skin disease.

You have to have a certain bonding with patients so that they know that you have personalized your therapy for them, that you know their concerns, and you address them appropriately. If you don't do that, then you get into a situation where the patient ends up not using what you recommend. For example, if the

patient is there only because Mom wants him to be there, and you don't sense that and pick up on that, then he's probably not going to use what you recommend. In that situation, you have to talk to the patient, have Mom be quiet, and find out what he's willing to do. And if he's willing to use only one therapy, which is a retinoid or benzoyl peroxide, then that's what you do.

If you don't find out that a patient has a summer job that requires work outdoors, you might give doxycycline, which would have too many side effects. Or, if you don't find out that patients have really sensitive skin, or they're allergic to benzoyl peroxide, then you may give benzoyl peroxide and have it not work.

It's really important to try to find out what patients have used, the characteristics of their skin, their activities, etc, so you can tailor something that's just right for them.

Q. Will the newer retinoids continue to be a part of your armamentarium?

Dr White: Differin is so good that I can't imagine treating acne without it. At the current time, I can't imagine not having the topical retinoids in my therapy.

Q. Do you have any advice for new dermatologists who are just starting to treat acne?

Dr White: For the medical student, or the new dermatology resident, or the new dermatologist who has not really thought much about acne therapy, I would say it's different from other therapies, in the sense that we try to treat two things. We try to open the pore and kill the bacteria. So think about combination therapy when you treat acne, and just get very comfortable with these topical retinoids and benzoyl peroxide, because they'll be very beneficial in your practice.

Q. Can you review the various types of acne therapies available, and delineate which part of the pathogenesis of acne they each affect?

Dr White: One of the two pillars of conventional therapy is killing the bacterium P acnes with antimicrobials (Table 1, page 2). We have both topical and oral agents. There is topical benzoyl peroxide, which is probably the best topical agent to kill P acnes, and then we have topical erythromycin and

clindamycin. In the past, tetracycline was used topically, but that's not

really used much anymore. We have combination therapies, like Benzamycin®, which is a combination of 5% benzoyl peroxide and 3% erythromycin. There are also some products that contain sodium sulfacetamide, like Klaron®, that can be used to kill P acnes.

In terms of oral antibiotics, I usually use tetracycline, at a dose of 500 mg twice a day, doxycycline, 50 to 100 mg twice a day, and minocycline, 50 to 100 mg once or twice a day. Those are the drugs that kill P acnes.

As the second pillar, to open up the follicle, to get rid of those comedones, I rely on the retinoids. Retinoids are just fabulous topical agents to do that, and the newer, less irritating retinoids are definitely my favorite.

I like Differin® (adapalene) gel, which is excellent for almost any patient, but in particular those with a little oilier complexion or maybe during the summertime. I also like Avita® (tretinoin) cream for patients with

sensitive skin or during the wintertime, when the air can be a little drying. I find both of those very effective. Retin-A Micro® (tretinoin) is another one you might consider. Tazorac® (tazarotene) tends to be a little more irritating and more costly, and so I usually don't use tazarotene.

Azelex® (azelaic acid) has been marketed to have both P acnes-reducing and comedolytic effects, but I think the data don't support its effectiveness in killing P acnes, and its comedolytic effect is not quite as good as that of the retinoids. So, in general, to open up those pores, the retinoids are really the best.

Q. Are there any drawbacks with the drugs used in this "two-pillar" approach?

Dr.White: Benzoyl peroxide is very effective in killing P acnes, but the main drawback is the drying effect. Some patients don't tolerate it well, especially if you go to 10%. We modulate that by trying to go with the 5% preparations. Patients can even use it every other day, if they need to. If that still doesn't work, Benzamycin is an excellent product that reduces the irritation of benzoyl peroxide and has, perhaps, even greater efficacy. The one downside to Benzamycin is it's a little more expensive than an over-the-counter drug or even many of the prescription benzoyl peroxides.

In terms of sodium sulfacetamide, it probably doesn't kill P acnes as well as benzoyl peroxide, but it may be appropriate for patients with really sensitive skin.

Clindamycin is an excellent topical product, though it doesn't kill the P acnes quite as well as benzoyl peroxide. Also, the bacterium can develop resistance to both topical clindamycin and erythromycin, but we still use a lot of that.

Oral antibiotics: Tetracycline is a good first-line agent for moderate inflammatory acne. It can cause a yeast infection in about 3% of women, so we always have to let them know about that. There's a theoretical interaction with birth control pills, so as doctors, we always feel obligated to mention that, but it's not been proven. Doxycycline is very effective and can be taken with food, but it has quite a bit of photosensitivity, so we don't like doxycycline in the summertime. Minocycline is probably the most effective of all our oral

antibiotics, but it has some long-term side effects that you have to think about, like blue patches on the skin and even blue teeth. And sometimes, early on, women can get vertigo or dizziness with the first couple of doses. It is also more expensive than tetracycline and doxycycline.

With regard to the retinoids, there are very few drawbacks to either the Differin® (adapalene) gel or Avita® (tretinoin) cream. I find those products to be very well tolerated by patients. Tazarotene, as I mentioned, is more irritating.

Q. What is the normal therapeutic regimen you prescribe for the average patient with acne?

Dr White: The average patient with acne gets topical therapy as a fundamental starting point. So, they always get a topical retinoid and a topical antimicrobial. My favorite is Differin gel or the Avita cream, along with a benzoyl peroxide-containing product. That's my foundation.

If in addition to that they have moderate inflammatory acne with some nodules, I'll add an oral antibiotic, either tetracycline or doxycycline, to that topical regimen. If they are resistant to that treatment, I'll switch the oral antibiotic to minocycline and give that another 6 weeks. If that doesn't work, then I put them on isotretinoin (Accutane®).

Q. What prompts you to change therapies?

Dr White: I usually like to see patients back in about a month to 6 weeks, to see how any regimen they're on is doing. If they have improved significantly, by maybe 40% to 60%, I'll stay on it and see them back in another month to 6 weeks. If they haven't budged one bit after a month to 6 weeks, then I usually think it's time to switch to something different.

Q. What can the dermatologist do to reduce the risk for the patient's P acnes developing resistance when using antibiotics?

Dr White: The resistance of the bacterium P acnes to various antibiotics is on a significant rise, and I think it will continue to go in that direction and be a problem for our patients. But the good news is that benzoyl peroxide is not subject to that; P acnes will not develop resistance to benzoyl peroxide, plus there's no resistance in any way to the retinoids and their action. Therapy with adapalene gel and benzoyl peroxide, for example, is not at all subject to any P acnes resistance problems. And when you add an oral antibiotic, such as

tetracycline, you still have that benzoyl peroxide on board to help kill the P acnes. A strain of P acnes that's fully resistant to tetracycline will be just as easily killed by benzoyl peroxide as one that's not resistant to tetracycline. So this topical regimen of benzoyl peroxide and retinoids is not going to be affected by any P acnes resistance.

Q. Should two different antibiotics ever be used simultaneously?

Dr White: That question, I think, would apply to a regimen of, perhaps, tetracycline orally and clindamycin topically, along with a retinoid. I don't use that as much, because you get into the issue of P acnes resistance. That's why I like an oral antibiotic, such as a tetracycline, with benzoyl peroxide, because you don't have that problem, and if irritation is a problem, I'll use Benzamycin. But there are some patients who just don't tolerate a benzoyl peroxide, but they had used clindamycin or erythromycin in the past and

they had liked it. So I do, sometimes, have a very small percentage of my patients on an oral tetracycline and a topical antibiotic, but it's not my first choice.

Q. How many times in your practice have you used a single agent for acne therapy and obtained good results?

Dr White: The only time we use monotherapy is with the systemic retinoid isotretinoin. If you exclude that and look just at conventional therapy, I use one medication just 2% or 3% of the time; 97% or 98% of the time, I use multiple medications.

Q. Why do you need to use more than one drug?

Dr White: The whole reason we use combination therapy is because acne, probably fundamentally, has two problems that we try to address: one is the closing up of the pore, the comedone formation, and the second is the growth of the bacterium P acnes. We don't have any topical agents that fight both.

Sometimes, if a patient is very young and the main thing that bothers him or her is the inflammatory papules and pustules, benzoyl peroxide would be very appropriate. The patient can get that over the counter and do pretty well. Sometimes adult women in their 20s or 30s who are mainly bothered by the inflammatory papules do pretty well with nightly benzoyl peroxide.

If a young patient has mainly comedones and hasn't started to develop the inflammatory acne phase, then a topical retinoid might be good. Those are the kinds of situations where I might use a single agent.

Q. Why is it important to include an agent that corrects keratinization defects when treating acne?

Dr White: The follicular opening, the pore, closes up or gets clogged because of a variety factors, but one of the key ones is the thickening of the follicular lining, which results from abnormal keratinization. That, together with the oil and the debris from the P acnes, forms the plug. Anything that can improve the

keratinization and normalize the follicular opening will help unclog that pore.

There is some benefit to using keratolytics, such as salicylic acid, that peel the skin, but those are not nearly as effective as the topical retinoids, which act through the retinoic acid receptors to normalize that follicular opening. We don't fully understand why retinoids normalize the opening, but we do know they do that very well.

Q. Is there anything else that can help eliminate or prevent comedones?

Dr White: Whenever I encounter patients with a lot of comedones, the first thing I want to know is whether they are putting anything on their face that's greasy or comedogenic. I always go through a quick question-and-answer session about what they put on their face, and then try to eliminate any greasy substances that might be causing the comedones to occur.If I want to get rid of comedones, I use the topical retinoids almost exclusively. It's interesting that almost

anything that reduces P acnes will also reduce comedones to some extent, so when you use benzoyl peroxide, when you give oral antibiotics, the reduction of P acnes actually will help to a small extent to reduce the comedones. So that's one benefit of combination therapy.

Also, acne surgery can be an adjunct to retinoid therapy. We have patients see our nurse for acne surgery, to take out some comedones.

Q. What about azelaic acid and the ?-hydroxy acids?

Dr White: Azelaic acid probably has some comedolytic effect, though it is not nearly as effective as the retinoids. It might be a good adjunct in a patient with darker skin who has some postinflammatory hyperpigmented macules.

The ?-hydroxy acids continue to be agents that people would like to use for acne, but the data are really quite sparse. The best study, published in Cosmetic Dermatology, used glycolic acid with or without tretinoin, and the tretinoin was far superior to the glycolic acid. We need more studies in the area of hydroxy acids, but I continue to think that retinoids are clearly superior in their comedolytic effect.

Q. Are there any combination treatments for acne that do not work and shouldn't be used?

Dr White: Absolutely. Obviously, we have only a certain number of interventions we can expect our patients to use. I think three medications is getting to be about the limit.

If you focus all your efforts on either killing P acnes or opening up the pore, and not both, then you're missing the boat. So, for example, I don't like tetracycline plus benzoyl peroxide. That therapy kills P acnes, but it doesn't open up the pore. I don't like a topical retinoid therapy plus salicylic acid as the only approach. It doesn't do anything for P acnes. Azelaic acid, as I've mentioned, is only a little better in its comedolytic effect, so I wouldn't combine it with a retinoid.

Q. Have the newer, less irritating retinoids changed the way you treat acne, and if so, how?

Dr White: The newer retinoids, like adapalene (Differin), and the newer packaging of tretinoin, like Avita, have definitely changed the way I practice dermatology in the area of treating acne by making it much

easier for me. I am more willing to give the retinoids to almost every patient with acne. In the past, because Retin-A was fairly irritating, I would sometimes try to get by with not giving a retinoid to some patients who didn't have as many comedones, whereas now I'm able to give retinoids to almost any patient.

Q. What about the patient with sensitive skin? Do you have any patients who still have problems with irritation?

Dr White: In the past, we often had a significant percentage of patients whom we couldn't get to stay on a daily regimen of retinoids. But now, with the newer, less irritating retinoids, almost every patient will stay on retinoid therapy and do very well.

In the past, we used to have the patients wash their face and wait 20 minutes before they put the retinoids on; we don't have to do that anymore. The new retinoids have simplified the approach for our patients. They just wash their face, put the medication on, and go do their thing.

Q. Do you ever encounter patients who have tried a retinoid before and don't want to try one again?

Dr White: It's interesting how educated many of our patients are. Many of the lay publications have correctly encouraged patients to see their doctors for these newer retinoids. Everyone knows that Retin-A can be very irritating, and these new medications are really a nice advance. I do have some patients that I

have to tell about the new retinoids, but many patients come to me knowing that there's something different, something new, and maybe they don't have to use that old Retin-A.

Q. What do you tell those few patients who require persuasion?

Dr White: I just tell them, "Medical science has made an advance here. Retin-A was the old product. We've got some newer, improved medications. They really are better. If you'll just try them, I think you'll do very well and you won't get the irritation that you used to get with Retin-A."

Q. How do these new retinoids compare in efficacy with all-trans-retinoic acid (Retin-A)?

Dr White: In the largest multicenter trial comparing Differin gel with Retin-A .025% gel, Differin gel was actually more effective than Retin-A. There were some other studies that showed that they were equally effective. The bottom line, I think, that most dermatologists should take away from the studies with retinoids is that in general, either Differin or Retin-A will get you to the same point at 12 weeks. It's very hard to prove any significant

difference in terms of efficacy. The main benefit is the reduction in irritation. The patients can use Differin much more easily.

Q. What kind of daily regimen do you recommend to maximize the efficacy of using topical retinoids and antimicrobials in the two-pillared approach to acne therapy?

Dr White: In general, we like the patients to wash their face twice a day: morning and night (Table 2). We want them to be careful about what they put on their face and use products from reputable, well-known companies, like Clinique, Estée Lauder, or any of the major companies. We like products that say

"noncomedogenic" or "nonacnegenic" - something that shows that the company thinks they're okay for acne skin. I discourage a lot of moisturizers if the patient has acne. In the morning, they may want to use a light moisturizer with sunscreen, or they may want to use a light moisturizer if they're getting some drying or peeling from the regimen.

Other than that, the key points that I go over with patients for their regimen is that we're trying to prevent acne. Probably the number-one mistake that patients make with their topical therapies is trying to "spot treat." They want to put a little something here, a little something there on the acne that's already broken out. I tell patients that's like closing the barn door after the cow got out. It doesn't prevent acne; they need to put the medications all over to prevent acne.

Benzoyl peroxide can bleach carpets and clothing, so that's important for patients to know. Many patients do better with benzoyl peroxide at nighttime, especially women, because sometimes it leaves a visible white residue that doesn't look good at school or work.

Although it's not in the package insert, Differin gel does very nicely in the morning. Many women like to put Differin on in the morning and then put makeup on afterwards, as needed. It's very light and goes well with makeup.

I work in San Diego, and we've used Differin gel on thousands of patients. I have not seen a single case of photosensitivity from it. I do confess that I usually like patients to use some moisturizer with a little sunscreen in the summertime, but I'd say that this regimen works very well.

Q. What kind of sunscreens should acne patients use when they are at the beach or in the sun for prolonged periods of time?

Dr White: Sun-protection factor (SPF) 15 is probably not sufficient for several hours out in the sun. I recommend at least an SPF 30 for my patients with acne who will be outside for prolonged periods of time. Many of the sunscreens with SPF 30 claim to be noncomedogenic, or okay for acne, but I have found in

general that a patient just has to go and try them. If you use something for a week, and your acne flares up, even if the product says "nonacnegenic," it's not good for you. I tell the patient to get two or three different sunscreens and try them for a week in the summertime. I've never had a patient who couldn't figure out which ones flare up their acne and which ones don't.

Q. Do you recommend any special acne cleansers or soaps?

Dr White: I'm not really into spending money on a whole regimen that's not nearly as effective as benzoyl peroxide and a topical retinoid. There are, in general, two types of cleansers: the salicylic acid-containing cleanser and the benzoyl peroxide-containing cleanser. The benzoyl peroxide-containing cleanser is not nearly as effective at killing P acnes as the benzoyl peroxide that you put on and leave on. But if patients are on a topical retinoid and an antimicrobial, and they still have some inflammatory lesions, then you

could add a cleanser with benzoyl peroxide. Or, if they have a few more comedones, you could add a salicylic acid-containing cleanser.

Q. How can patients be educated to maximize the value of their acne therapy?

Dr White: In terms of educating patients about acne therapy, there are a few things I always try to do in the time that I have them in my office. The first is to stress that if a regimen works, we have got to stay on it. If

it works for 6 weeks, then we stay on it for 3 months, 6 months, etc; we don't wait until it improves and then stop. That's one of the key things.

The second is that we use combination therapy in acne for a reason. We are trying to affect at least two different causes of acne, so we're using medications with two different purposes. Many times, if you don't prepare patients appropriately, if you give them two medications, they'll try to figure out which one works better. And I've never understood how patients can think they've figured out that one works and the other one doesn't. But invariably, they will, and they'll stop one medication and come back to you and they're

just on one topical.

I prep them by saying "We've got to use these medications daily for a prolonged period of time. I want you to use them both; don't stop just one, use them both. And if you have any side effects or problems, call me." You want to head off the patient who's going to come back to your office who used the medication

for 1 week, had some sort of problem, and then just stopped. Then you've wasted that whole period of time, and you've got to get him or her back on the regimen. Those are the things that I tell patients as a kind of preemptive strike.

Q. How do you manage the patient who continues to have macrocomedones underneath the skin, despite otherwise successful acne therapy?

Dr White: The macrocomedones are an interesting variant of the comedone. They're these 1- to 2-mm white balls right under the skin that you can see best by stretching the skin (Figure). They often become apparent during isotretinoin therapy, but you may notice them in patients on conventional therapy as well.

Oftentimes, the tried-and-true method of acne surgery is best at eliminating these. You take a number 11 blade, make a small incision, and then use a comedone extractor to remove them.

In the United Kingdom, they have reported using EMLA cream applied first, and then electrocautery if there are maybe 50 to 100 lesions. I myself haven't done that, but Dr Cunliffe and others recommend that approach for treating multiple lesions.

Q. How often do you use acne surgery as an adjunct to acne therapy?

Dr White: I think we have a duty to do what's best for our patients. If you can get them on a topical retinoid that keeps their pores clear, they probably won't have to return to you month after month for extractions; that's a service we do for our patients. But in those few patients on a topical retinoid who are

not fully clear of comedones - blackheads and whiteheads - then I utilize my acne surgery nurse to clear out those pores, and have the patients come back as often as they need. So I use it as an adjunct to topical retinoid therapy.

Q. What role do hormones play in acne, and do you take that into account when prescribing therapies?

Dr White: We know that hormones are a significant part of the process of acne, because it only occurs when the pubertal hormones start to increase. But that's a normal process.

It's in the area of young adult women with acne that we really think that hormones are related, although we're not quite sure of all the details. We see a lot of young adult women who have acne that flares with their menstrual cycle, and that is benefited by hormonal therapy. It's interesting, but in this group of patients, the hormone levels are usually normal. If you take 100 young adult women with acne, their average hormone levels might be slightly higher than those in a normal group, but for the individual patient, you don't

find a specific abnormality. Oftentimes, for young adult women - especially those who have relapsed after Accutane - we'll want them to go on birth control pills, such as Ortho-Tri-Cyclen®. If a woman has a relapse after a second course of Accutane, I'll give spironolactone therapy, which I've found to be effective in this subset of patients with acne.

Q. Are there any precautions that pregnant or nursing women who are being treated for acne should take?

Dr White: We have a greatly limited armamentarium for pregnant women with acne. Erythromycin is okay topically, as is benzoyl peroxide. That allows them to use Benzamycin, benzoyl peroxide, topical erythromycin, or even oral erythromycin, although I must say that I always have the patient or myself check with the obstetrician before I start any oral medications.

Azelex (azelaic acid) is pregnancy category B, and even though it's not as comedolytic as the retinoids, we in general don't use topical retinoids in our pregnant patients. Azelex is also appropriate for nursing mothers. So, in general, a lot of women just have to wait until they're done with their pregnancy.

Many times, the acne will improve with pregnancy, but sometimes it will worsen, and for those patients, they just have to wait.

Q. What about treating the pediatric patient? Is it safe to use your normal combination of benzoyl peroxide and retinoids, or topical antibiotics and retinoids?

Dr White: The child with acne can be treated with all of these regimens. There's certainly no problem with benzoyl peroxide with all of the topical retinoids. The main concern that we think about is with tetracycline, because it can damage the teeth.You shouldn't use tetracycline in kids 8 years or younger. It's

rare to need tetracyclines in patients until they're 12, 13, or 14. So there's rarely any problem with kids and using these sort of therapies.

Q. How does the cost of therapies influence the regimens you prescribe?

Dr White: In a perfect world, I would like to ignore costs in treating patients. I would like to give them the absolute best therapy possible. Sometimes the cost is very important to the patient, especially if they're paying for it, and so they want to know how much it's going to cost; if it's too expensive, they can't afford it. But if a health plan is paying for the medication, then I think the doctor is more free to give what's absolutely best for the patient.

Now, having said that, I think that the good news is that many of the most effective therapies that I recommend are relatively inexpensive, compared with alternatives. For example, benzoyl peroxide is very inexpensive, and yet it's a great topical medication for acne. In the area of retinoids, Differin gel is also a good drug for its cost. Avita is the least expensive. Tazarotene is more expensive and it's also more irritating, so I don't usually use it. The oral antibiotics - tetracycline and doxycycline - are very inexpensive, and of course Accutane is very expensive.

Q. How long after their acne clears should patients remain on their regimen?

Dr White: If a patient is on this topical regimen of a retinoid plus benzoyl peroxide or an antimicrobial and an oral antibiotic, then I'll usually give the oral antibiotic for a 3- to 6-month period and then tell the patient to stop it and see if the topical regimen will do. I usually see the topical program as something for long-term maintenance, but I try to get patients off antibiotics orally if I can.

If they have gone a long time with the topical regimen, then invariably I don't have to tell patients. On their own, they will stop one agent and see how they do. If they ask me first, if they have more inflammatory lesions, I'll say, "Stop the retinoid and just go with the topical antimicrobial." If they have more comedonal disease, I'll say, "Stay on the retinoids, stop the antimicrobial, and just see how you do over time."

Q. What are some of the changes in lifestyle and self-image that people experience after being on successful combination acne therapy?

Dr White: A lot has been said about the psychological problems, concerns, or issues that patients have when they have a face full of acne, and I think that's absolutely warranted. These poor kids - they're trying to become adults and create their own personality and life, and if they're plagued with a face full of acne, it really causes them a lot of harm.

You'll see patients when they first come in with bad acne: they're not talking, they're not looking at you in the eye, they're looking down at the floor, they let Mom do most of the talking, etc. You get a sense that their self-esteem is low, they don't feel good about themselves. And then, when you do treat them

effectively, and their face is clear, they come in, they're smiling, they're looking at you, they're interacting much more. And that is one of the rewards that I have in treating acne. When the patients get better, you can just see, psychologically, how much better they feel.

Q. Do you ever have to recommend adjunctive psychologic counseling?

Dr White: You know, I never have. The acne therapy that we have available is so good - the topical retinoids, the Accutane - we have such good therapy these days, that if a patient has a face full of acne, then it's almost always because he or she is not seeing a doctor. The old story is told about the psychologist

who is treating a patient who is standing out in the rain and the psychologist is trying to help him to accept all the problems associated with standing in the rain, and another psychologist comes by and just says, "Come in out of the rain!" So, we could try to treat all of these psychological issues, or we could just fix the acne. And that's really what I focus on.

Q. So you never use psychotropic drugs in your practice?

Dr White: I never do. I tell the patients, and I can be very honest about it, "If you'll stick with me, if you'll do what I recommend, if you come to see me every 4 to 6 weeks, we will fix your acne, one way or the other."

Q. How important for effective therapy is the relationship of trust that you establish with the patient?

Dr White: The most important thing for effective therapy is that patients use what you give them. And this applies not just for acne, but for any skin disease.

You have to have a certain bonding with patients so that they know that you have personalized your therapy for them, that you know their concerns, and you address them appropriately. If you don't do that, then you get into a situation where the patient ends up not using what you recommend. For example, if the

patient is there only because Mom wants him to be there, and you don't sense that and pick up on that, then he's probably not going to use what you recommend. In that situation, you have to talk to the patient, have

Mom be quiet, and find out what he's willing to do. And if he's willing to use only one therapy, which is a retinoid or benzoyl peroxide, then that's what you do.

If you don't find out that a patient has a summer job that requires work outdoors, you might give doxycycline, which would have too many side effects. Or, if you don't find out that patients have really sensitive skin, or they're allergic to benzoyl peroxide, then you may give benzoyl peroxide and have it not work.

It's really important to try to find out what patients have used, the characteristics of their skin, their activities, etc, so you can tailor something that's just right for them.

Q. Will the newer retinoids continue to be a part of your armamentarium?

Dr White: Differin is so good that I can't imagine treating acne without it. At the current time, I can't imagine not having the topical retinoids in my therapy.

Q. Do you have any advice for new dermatologists who are just starting to treat acne?

Dr White: For the medical student, or the new dermatology resident, or the new dermatologist who has not really thought much about acne therapy, I would say it's different from other therapies, in the sense that we try to treat two things. We try to open the pore and kill the bacteria. So think about combination therapy when you treat acne, and just get very comfortable with these topical retinoids and benzoyl peroxide, because they'll be very beneficial in your practice.

-------------------------------------------

ACNE BRIEFS REVIEW:

COMBINATION THERAPY IS THE BEST APPROACH

Summarized here are the key points made by Gary M. White, MD,

in his discussion of why most patients with mild to moderate acne

will need more than one acne agent to clear their skin.

The "Two-Pillared Approach" to Acne Treatment

• The first pillar of conventional therapy is killing the bacterium Propionibacterium acnes with antimicrobials. Topical antimicrobials include benzoyl peroxide, erythromycin, clindamycin, tetracycline (rarely used), sodium sulfacetamide, and Benzamycin®. Effective oral antibiotics are tetracycline, doxycycline, and minocycline.

• The second pillar is opening the follicles. Retinoids, such as Differin® (adapalene) gel, are excellent for almost any patient. Other topical retinoids include Avita® (tretinoin) cream for patients with sensitive skin, Retin-A Micro® (tretinoin), and Tazorac® (tazarotene).

Combining Agents for Effective Therapy

• The average patient with acne shou

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