Chapter 8 The vast body of writing on the three acnes has been heavy weighted toward medical and surgical management until the past 15 years. Gradually, the mechanisms of formation of the acnes are becoming understood, and that in turn is allowing us to look toward prevention, in the hope of avoiding the expense and side effects of the traditional lines of attack. The management of any disorder should start with prevention, and that should look at all preventable aspects of all the causes of the disease. The classical approach is to discuss primary, secondary, and tertiary prevention. Quaternary prevention has been added, as have universal, selective, and indicated prevention. Even further, environmental prevention is worth considering. Looking at this chart as it applies to acne, it is apparent that accepting diet as the prime cause of acne in the majority of cases means we have a lot of work to do. The evidence that diet is indeed the prime modifiable cause of acne has accumulated steadily over the past decade (Figure 2.16). The recent review by Melnik [1], discussed in this section, illustrates the mechanisms involved with a precision never achieved before (Figure 2.15). Universal primary prevention would be the ideal way to eliminate acne. That would involve the entire population stopping dairy and high-glycemic-index foods. It is an impossibly impractical undertaking in a free and unregulated society because “regulated avoidance” is not a viable option. Universal voluntary avoidance is also likely a pipe dream—unless the idea and its implementation suddenly “go viral.” That means that public education, where possible, and gradual recruitment patient by patient (and physician by physician) will remain the prime methods of prevention for now. For practical clinical purposes, it is sufficient to discontinue all dairy products that are provided in bulk or used as a major portion of a food. That means no milk or cream of any sort, no butter, cheese, cream cheese, yogurt, ice cream, cottage cheese, sour cream, raw milk, pasteurized milk, goat milk, or indeed anything that comes “from the south end of the cow”, or from any other mammal for that matter. Derivatives of dairy products are also eliminated. This particularly includes any of the protein products that contain whey or casein, which have been documented increasingly [2] but noted clinically to be a problem around the world. Unfortunately, we are not sure exactly what hormones and growth factors are present in these derivatives, but the whey alone seems to be a sufficient threat. These protein sources are commonly used by bodybuilders and in weight training. The question arises, given the involvement of this hormone-infiltrated industry, whether these supplements are adulterated with steroids. At the moment, there is no published material touching on the hormone content of these materials, so this comment is speculative. There are no publicly available assays; indeed, even the US Food and Drug Administration has not studied the existence and quantities of hormones in dairy products, nor was there any plan to do so as of the FDA response to me July 2012 [3]. Besides diet, there is little one can do as primary prevention to avoid the acnes. Genetics play a well-defined role but choosing new parents is not an option. We note the close relationship between the rise in insulin-like growth factor 1 (IGF-1) during the teens and the incidence of acne [4], but stopping puberty to control one’s elevated level of IGF-1 is likewise not an option, because that would mean stopping normal growth and development as well as stopping acne vulgaris. Total avoidance of the sun to prevent acne rosacea by minimizing the risk of sun damage to blood vessels and the collagenous support tissues of the folliculopilosebaceous unit (FPSU) during one’s entire early life is likewise unlikely to happen. Although the concept of pre-rosacea has been suggested, rosy cheeks are not generally considered a pre-disease state, even though this may actually be the case for patients with actinic telangiectasia and with true acne rosacea. On the other hand, careful sun avoidance and the use of effective sunscreens or sun blocks makes the use of vitamin D3 supplements mandatory to avoid the numerous adverse effects of vitamin D3 deprivation. Sunscreens and sun blocks are of two basic types, absorptive and reflective. The chemical para-amino benzoic acid (PABA) was used in the earliest absorptive sunscreens that achieved general use in the 1970s. Its disadvantages were several and it is rarely used now, but one major problem with PABA is still with us today. Because PABA’s capacity to protect against ultraviolet B’s (UVB) burning rays minimized sunburn, the public was led to believe that stopping the burn from the sun would stop the damage from the sun. That misconception has allowed a couple of generations to stay out in the sun longer than unprotected exposure would have allowed. We were robbed of our warning system (the redness and sensation of burning from UVB) and so we were able to remain too long in the sun. That extra exposure allowed us to accumulate far too much of the UVA that slipped right past the UVB blockade. In Europe, as early as the 1970s, broad-spectrum chemical sunscreens were available. The best sun protection products are still available there, while the products in the United States play catch-up. New FDA guidelines insist on documented adequate protection up to 370 nm to earn the broad-spectrum label, and that should clear the playing field of the deceptive labels on many sunscreens. The classic zinc oxide paste used on the 1955 beach lifeguard’s nose provided superb reflective protection but was an aesthetic joke. It has been improved upon over the years and now we have zinc oxide, titanium dioxide, and mineral pigments like ferric oxide that have been developed to provide newer physical blocks that are much more socially acceptable. They also provide the broad- to full-spectrum protection the general public thought it had enjoyed for the last 40 years or so. Gradually, over the past decade, these products have shown slow but steady acceptance by the public. Addition of silicone derivatives to several of these products has minimized the irritating features that made many products unacceptable to patients with combined acne rosacea and actinic telangiectasia [5]. Stopping smoking is always wise. The only better idea is to not start in the first place. Smoking’s likely influence in adult-onset acne [6], and particularly its influence in acne inversa/hidradenitis suppurativa (AI/HS) [7, 8], emphasizes the need to avoid not only smoking but all sources of nicotine. The challenge of stopping smoking without nicotine substitution is significant, but using nicotine substitutes just prolongs the problem. The only other general preventive advice that would be worth offering, particularly with regard to universal prevention, would be universal maintenance of ideal weight. Saving $3 billion per year in the United States on acne care would be a drop in the bucket compared to the savings achievable throughout the entire health care industry if maintenance of a normal-range Body Mass Index (BMI) or ideal weight became a national pastime. Certainly this would impact on many cases of AI/HS as well as the incomes of bariatric surgeons. That leaves us with diet as the single most effective means of preventing acne vulgaris and AI/HS, and sun avoidance as the major means of avoiding acne rosacea. Diet is discussed in Section 8.3 in much greater depth. Because almost all of my patients are referred, they and their referring physicians are expecting my best efforts to clear them as quickly as possible. They are not referred by their primary care physicians to serve as experimental subjects. This means that my observations, not being part of a randomized clinical trial (RCT), will never rise to the level of evidence of such formal work, so they cannot be considered EBM (evidence-based medicine). This allows me freedom to customize treatments, learning as I go, and my patient and I can explore therapy “outside the box” to the best of our combined abilities. This flexibility is essential to comprehensive management, but systematically reporting on such nonstandardized treatment courses is problematic. One winds up with broad impressions, a personal practice pattern, and what I call XBM (or experienced-based medicine). The advantage of this method of practice is that it is truly patient oriented—and the newest term is patient driven. Every patient gets a customized approach. The disadvantage (if it really is a disadvantage) is the simple fact that XBM cannot be plugged into a drop-down menu or treatment template. It takes thought, and experience, to guide one’s patients through the complexities of acne. The encumbrances and hurdles set up by restrictive guidelines (even those that claim to be nonrestrictive), “preferred drug” lists (which actually are the opposite of preferred), restrictions on use of drugs for non-FDA-approved indications, limited and self-serving formularies, “branded” but still expensive generics, highly inefficient government-level dictates such as iPLEDGE, and the imposition of “step therapy” that disallows the proper treatment until the improper treatment has been proven to fail—all these meddlesome economic barriers tend to produce a counterproductive and anti-intellectual practice environment. It is really quite wonderful to see clinical trials showing up from other countries where the legal system has not developed a pervasive, extensive, and expensive stranglehold on research productivity. Their work is much appreciated. The other side of the problem with referred patients is that they have usually been previously treated. Not only does this create numerous variables not of my (or my patients’) making, but also the patients or their parents have often invested significant money in therapy, often failed therapy. I usually take advantage of that fact to have them continue to use, when reasonable, the therapy from the past. Doing so helps maintain their relationship with their primary care providers (even though some doubts sometimes remain), and helps to retain or even build confidence in that physician, when possible, to encourage the patient to return eventually to primary care. As a former general practitioner, I am sensitive to the need to minimize criticism of prior attempts to treat. Inexplicable failures? Nothing ever works 100%. Unscientific successes? Never argue with success. Why didn’t my other doctor (or dermatologist) know (or do) that? We all have different training and experience paths. And so on … If the patient is having significant symptoms, or they are distressed, I press forward with the most aggressive therapy possible but insist that patients adopt a full zero-dairy and low-glycemic-load diet from the beginning, no matter which of the acnes is present. There are two reasons. The first is that prevention must start as soon as possible, and the first visit is the best time for a full review of causes and consequences. Secondly, prevention of new lesions takes time, so the earlier the start, the earlier the clearing. When patients are actually in trouble, they tend to remember better what is necessary to prevent the acne from coming back. Nevertheless, constant reminding is wise. It sometimes borders on nagging. I tell them I know that I’m nagging. I tell them I get paid to nag, that it is part of my job, but they can get it for free from their parents if they prefer. There are three reasons to modify diet in managing acne vulgaris. The first is to lower insulin levels, the second is to lower levels of IGF-1, and third is to avoid the steroid and polypeptide hormones and the growth factors that are present in dairy products. High-glycemic-load diets impact on only one of these three factors—they open the androgen receptor by perpetuating chronically high insulin levels. Restricting dairy intake has a profound effect on acne vulgaris. This is usually more obvious in teenage boys than teenage girls. The girls have the disadvantage of cyclical menstrual hormones that confuse the picture, and they seem to be more impacted by stress than most boys. This is not to say that simply stopping all dairy clears all acne within a couple weeks. It does not. It takes months. The patient needs to know this right up front. While it is possible to clear acne with nothing but dairy restriction, I have encountered only a few patients over the years who had the patience to follow that course. The most memorable are described elsewhere in this book. The low-glycemic-load (low-carbohydrate-load) diet should be introduced early as well. This restrictive diet is best maintained for a full six months. During that time, with or without isotretinoin, one can usually clear acne almost 100%. There may be some scarring or post-inflammatory hyperpigmentation (PIH), and perhaps a few residual lesions, but the war is pretty much won by six months. After six months, or after the patient is clear, more liberal dietary choices may be offered. The better choice would be to continue the restricted diet, and generally this is a wise lifelong choice. Alternatively, the patient can begin slowly liberalizing the diet. I generally discourage them from going back to the fluid milk. That includes not using it on breakfast cereal. There are many alternatives: milk substitutes made from soy, rice, almonds, coconut, and hemp. One can find, on the Internet, ways of making one’s own “milk” from nuts by using a blender. As far as cheese is concerned, the less the better, and zero is best. But to keep the patient “on side,” I permit the occasional nibble of small amounts of whatever dairy they particularly miss. There is a large population of cheese lovers among acne vulgaris patients and hidradenitis suppurativa patients, and they are some of my most recalcitrant patients. They tell me they are “addicted to cheese.” I tell them they can have one ounce of cheese per week, or that they may have a taste on occasion, but they must no longer consider cheese to be a food. It is just an occasional “taste treat.” It is interesting that, in the Harvard study, pizza did not show up as a risk factor [9]. On a speculative basis, I suggest to my patients that it may be that the high temperatures in the pizza ovens (750° F average and up to 900° for some cooks) will almost certainly cook and therefore destroy the activity of (denature) the polypeptide hormones and growth factors. Having said that, I have no proof whatsoever that this is true. The reproductive hormones, the steroids, have significant resistance to high temperatures and are likely not destroyed, but this also needs investigation. Unfortunately, this lack of data on hormone content is almost universal. I have looked into the costs of defining all the different hormones in all different types of dairy products from all the different breeds of cows, on many varied fodders, prepared as raw milk, organic milk, and pasteurized or unpasteurized milk; soft or hard and cream or cottage cheeses; yogurts (Greek or not); and other derivatives. It would take years, and several millions of dollars. The dairy industry does not seem interested; nor, as I have learned, does the US Food and Drug Administration (FDA). For now, a blanket avoidance rule is the safest approach, much like the FDA’s approach to contaminated food. The recall is general, and does not require the testing of each sample before excluding it from the diet. That brings up one of the major objections I hear every day—is it safe to NOT drink milk? The fact is that there are hundreds of millions of individuals who grow up quite healthy in this world without milk. It simply is not part of their diet for reasons of economics, geography, religion, custom, or choice. There are millions who are allergic to it and fully 65% of the entire world population is lactose intolerant and generally avoids the volume of fluid milk consumed here in the United States. Although estimates vary, 85–95% of African-Americans are lactose intolerant, as are almost 100% of Asians. Both groups are quite capable of developing serious acne when exposed to a Westernized diet. AI/HS in particular is a major problem when it occurs in African-Americans. Then there is the question of “organic milk.” Even the definition of organic milk leads to confusion. For a specific group of organic-conscious American consumers, this means milk produced without injecting the cow with recombinant bovine growth hormone (rBGH or rbGH), also called bovine somatotropin (BST). In some areas milk from such non-injected cows has been marketed as “hormone-free milk,” a concept that advertises ignorance of the facts more than anything else. Monsanto’s Posilac® injection, which is illegal in Canada and Europe (and too expensive for most of the rest of the world), is fading away, unmourned by most, thanks in particular to the marketing power of several major grocery retailers who in 2008 refused to sell milk and milk derivatives produced this way. I thank them, and so do the cows. And, just to be perfectly clear, there is no such thing as hormone-free milk. Actually, milk could be legitimately considered a specialized, highly evolved, and species-specific hormone delivery system that happens also to have the fats, proteins, and carbohydrates needed to do the hormones’ bidding [10]. For other consumers, organic means a generally more expensive product that has been produced with extra care by cows that are fed healthy, natural diets and are exposed to no unapproved pesticides, herbicides, fungicides, or antibiotics. It also means no exposure to the fodder that had in the past been formulated by recycling pieces of cows that had already gone to market, as ground-up bits of protein. That was the problem with “mad cow disease” (bovine spongiform encephalopathy). While such fodder was in a strict sense “organic,” it was a far cry from the sense intended. To the farmer, organic means extra expense, greater care, and adherence in the United States to a list of permissible chemicals published in the Federal Register. In the United States, the National Organic Program sets the standards at http://www.ams.usda.gov/nop. In Europe, extensive Council Regulations are in place. Straying beyond those guidelines means loss of the organic certification for the farm and an expensive few years of waiting to have the farm recertified. Interestingly, organic milk in the United States has been shown to have higher levels of estrogen and progesterone—evidence of healthier animals, we presume [11]. This is not a positive selling point when dealing with a set of disorders like the acnes that are postulated to be made worse by these same hormones. The next most common concern I hear from parents is that their offspring will not get enough calcium if they don’t drink their milk. It is worth pointing out that human beings are the only species who believe they must rely on dairy products for calcium. Cows have huge bones, they never take calcium supplements, they eat mostly grass, and they never drink milk after they are weaned. There is also a widespread belief that the major source of vitamin D3 should be from milk. The fact of the matter is that milk contains very little natural vitamin D3. Calves get their vitamin D3 from the sun. For generations, vitamin D3 has been added to milk one way or another during the manufacturing (dairying) process as a public health measure to minimize the risk of rickets. The only reason why humans need to take vitamin D supplements is that they do not spend their days standing in the sun in a pasture without clothing, having their own vitamin D made by the action of sun on the cholesterol in their skin. We dermatologists are forever cautioning patients to avoid excessive sun and to use sunscreens, so we bear some responsibility for the fact that the population in general is low on vitamin D3. The major responsibility for low levels of 25-hydroxy vitamin D3, however, must be borne by our weather, our clothing, and our indoor lifestyle. Just as we use iodized salt to provide an appropriate level of iodine in our diets, we really do need adequate daily supplements of vitamin D3. Thus, it is entirely responsible and wise to recommend and take vitamin D3 supplements. The question arises “How much?” Although the highly respected US Institute of Medicine (IOM) has placed an upper limit of safety at 2000 international units (IU) of vitamin D daily, the real experts in the field are comfortable with doses well in excess of that number; indeed, an informal 2009 survey of such experts’ own consumption came up with “an average of 5,000 IU” daily [12]. Why the discrepancy? The IOM is composed of a broad range of experts chosen from the tops of many fields, but they are not experts in vitamin D3 metabolism. That means they relied on a vast number of scientific papers, some reaching back decades to the days when the only known value of vitamin D was to provide the small amount needed to prevent rickets. They were basically looking for data to support their eventual published opinion. Unfortunately, no large population studies have been done, using the higher doses recommended by the real experts, to demonstrate the benefits that active vitamin D researchers are now learning about. For instance, it is standard to recommend both calcium and vitamin D, combined, to treat osteoporosis. This is despite there being no large study, of adequate length, of osteoporosis, whether for prevention or therapy, in which fully adequate doses of Vitamin D have been provided in the range of 2000–5000 IU per day without supplemental calcium. Lacking such studies, the IOM experts simply could not recommend the higher doses. Their understandably obsessive “evidence-based medicine” criteria were fulfilled only for what many now consider suboptimal doses. Their view was crystal clear but it was, of necessity, a look in the rear-view mirror. Two points on closing. Note that Vitamin D3 is a fat-soluble vitamin and should be taken with food, preferably fatty food, to assist and permit full absorption. And note that vitamin D2 is far less effective than vitamin D3 [13]. The only reason that weekly capsules of 50,000 IU of vitamin D2 are used seems to be that it is the only prescription preparation of vitamin D available, so it may be covered by insurance plans and it also offers prescribers a sense of control over the dose. I would be happy to see vitamin D2 disappear, taking with it the confusion it causes. Calcium supplements are another story, because taking extra calcium at the same time as vitamin D supplementation can cause hypercalcemia (a high level of calcium in the blood), hypercalciuria (excess calcium in the urine), and kidney stones [14]. To look at this from a physiological point of view, vitamin D supplementation restores to normal what would be normally obtained by sun exposure if modern clothing, housing, sun protection, and geographic location did not interfere with this natural process. Calcium supplementation, on the other hand, corrects no such deficiency or physiological process. I can find no evidence that taking calcium supplements alone (without vitamin D supplementation) improves bone mineralization. There is no doubt, however, that ensuring that normal blood and therefore tissue levels of vitamin D are maintained is the most physiological means of enabling the body to absorb the correct amount of calcium from food. A year’s supply of this very inexpensive vitamin costs less than the single blood test needed to determine your personal blood level of 25-hydroxy vitamin D3; it requires no visit to the physician and no needle stick at the lab, and the risk of side effects from hypervitaminosis D at this dose is essentially nil (as long as you stay away from calcium supplements). Ms. Bleu came to me with extensive nodular acne that involved her lower face, jawline, and upper neck literally from ear to ear. A few years previously she had inherited some money and after college, she decided that she would like to open a restaurant on the very small Atlantic coast of New Hampshire. She wanted to understand the whole operation and decided to spend her inheritance on further education. She headed to France and spent 2 years in a famous cooking school. Finishing that, and having seen how restaurants are run in France and elsewhere in Europe, she decided that it would be good to have a delicatessen associated with the restaurant. She travelled all over Europe learning everything she could about the products she planned to sell. During history taking at her first visit, I was discussing her diet over the past couple of years and of course she had a very broad experience of a wide range of fabulous foods. When I asked about dairy, she almost exploded, “Oh, my God, it’s the cheese!” She had specifically concentrated in the previous several months on sampling the “best of the best” cheeses in Holland, Denmark, France, Belgium, Germany, Italy, and Switzerland. She had never had acne as a teen but it was during the cheese-sampling months that her acne developed and blossomed. She was a certain candidate for Accutane, but for two problems. She was uninsured and didn’t have any money left, and she didn’t want (or need) to go on birth control pills (BCPs). Her acne had set her social life aside. Perfect! I explained that she was exactly the case I was looking for—someone I could treat with diet alone, who was mature enough to adhere to dietary rules, had dairy-induced acne, and would be willing to try management with no medications. As a bonus, she was an accomplished and willing professional chef who could design her own diet with care and taste. We agreed to meet at three-month intervals. No charge. She was essentially 60–70% improved by three months and 95% clear by six months, with no medications whatsoever. Patients like Ms. Bleu are hard to find, and even harder to convince to manage their acne with diet alone. But when they follow the rules, the rewards are self-evident. The purists will of course insist that only by returning to the dairy, and having the acne return and then disappear again on withdrawal, can one “prove” the relationship. I’m a pretty good salesman, but I have been unsuccessful in selling that approach to patients who have just escaped from the grip of years of acne. They don’t want to go back and, to my mind, it borders on the unethical to suggest that they should take the risk of further recurrences. But there is no doubt in my mind, or Ms. Bleu’s, that simple withdrawal of all dairy works wonders. Much of the content of this book has been shared over the years in various venues from Jaipur, India, to Copenhagen, Denmark, and from Cuzco, Peru, to Whistler, Canada. As it has evolved, I’ve regularly presented the story at Focus sessions at annual meetings of the American Academy of Dermatology. While most lectures are a concentrated one-way delivery of information to the audience, I sometimes learn fascinating things during the informal question period that follows when the presentation is over. After one session a few years ago, a pharmaceutical executive volunteered a story that made me just shake my head in amazement. He was never a patient of mine, but I had known him for years, and his career and company has impacted on millions of acne sufferers. I had been talking about the relationship of milk to acne, and he related the following: “My brother and I and some friends used to play basketball two or three nights every week for a couple of years during our teens. We played hard and were pretty tired and sweaty after every session, and I remember I would always down almost a quart of milk after the game. Listening to you, I realized that I had really bad acne during those years but when I went to college and the basketball and the milk stopped, my acne cleared up. I never connected the two until now.” This man is a very senior executive, highly respected in the industry, and has built and grown a huge multinational drug company, with his core products being an anti-acne line of topical preparations. My colleagues would likely recognize both his company and his product line. What would his life have been like if he had made the connection between his milk intake and his acne 50 years ago? We can only wonder. The word glycemic simply refers to sugar, specifically glucose, in blood (heme). If the level of glucose in blood is high, that is hyperglycemia. A high-glycemic-load diet is one that causes higher elevations in blood glucose than a low-glycemic-load diet. Hyperglycemia leads to a compensating elevation in blood insulin levels, which forces the blood glucose levels back down toward normal. If the levels go too low, that is hypoglycemia, low blood sugar, and you get hungry. The tendency is to eat at that point, to increase the level of sugar in your blood, and then you are no longer hungry. The result is that there is a constant attempt by your body to control the level of sugar in your blood by trying to control the amount and the timing of insulin produced by and then released from your pancreas into your blood. All diets contain elements from various food groups and types. In general, the foods that cause high-glycemic-index ratings are those that contain highly refined carbohydrates such as the sugar refined from sugarcane and the fine white flour refined from wheat. All will push sugar up in the blood quickly, causing insulin to be released. This elevated insulin level (hyperinsulinemia) is one of the two factors that open the androgen receptor, allowing it to accept androgenic molecules like testosterone (T) and dihydrotestosterone (DHT). They stimulate growth in tissues that are dependent on androgen signaling. This is one of the major links between diet and acne. Quite unexpectedly, it has been shown that another cause of hyperinsulinemia is the ingestion of milk itself [15, 16]. We knew that the lactose in milk (a mixture of glucose and galactose) raised blood glucose, but the effect on insulin levels in the blood of drinking whole milk is independent of this sugar. It is also about four times as powerful. This hyperinsulinemic reaction is caused by a small polypeptide called glucose-dependent insulinotropic polypeptide (GIP) and appears to be “purpose-built.” Whey proteins in milk are the most potent inducers of GIP, which is secreted by the baby’s enteroendocrine K cells. GIP, working together with essential amino acids from hydrolyzed whey protein, stimulates insulin secretion by the baby’s pancreatic beta cells [17]. The reason for this reaction is actually quite simple, and is quite natural at this stage of life. Milk is designed as a hormone-signaling messenger to be consumed in the early stages of life. At that point, it is essential to activate the androgen receptor so that the powerful anabolic (growth-enhancing) effect of milk on infant growth and development can be fully expressed. That is, after all, why babies drink milk. It is designed to make them grow. So the whey portion of milk, acting through GIP, really does open the throttle that controls the growth of babies, by providing part of the stimulus to open the androgen receptor. This, combined with the impact of IGF on the androgen receptor, adds to the overall de-repression (activation) of this important receptor. With the androgen receptor open, ready, and waiting, milk is also ready, loaded with the anabolic androgenic steroids that provide the stimulus to growth. The attention of the acne research community was drawn to low-glycemic-load diets by Professor Loren Cordain’s 2002 paper [18]. The complete absence of acne in the remote populations studied in New Guinea and Paraguay was attributed by the Lindeberg research team to the low-glycemic-load diet consumed by both these tribes of hunter-gatherers. Cordain has subsequently substantially developed and elucidated the science and the human dietary history behind the low-glycemic-load diet consumed by our distant ancestors. His publications are widely read and explain the basis for promoting a diet consisting of food that was available to our forebears during the millions of years prior to the availability of refined flour and sugar and the development of herding practices that introduced regular dairy intake to our diets. This is generally referred to as the caveman, Paleolithic, or Paleo diet. It is apparent that the lack of dairy plus the low level of simple-carbohydrate elements combine to provide a very healthy diet. The testimonials are positive, the effort is definitely worth it for most who adhere to the diet, but adherence to any strict diet can be a challenge on an individual basis. It remains to be seen whether such a diet could be the subject of universal and environmental primary prevention measures. Such measures would require a widespread change in attitude toward nutrition, business practices, farming methods, and the products produced. No discussion of sugar and insulin response is complete without an understanding of HFCS. Because it is cheaper to make and sweeter than regular table sugar (sucrose), fructose-containing corn syrup is the preferred sweetener for soda-type drinks. In 2004, the American Journal of Nutrition noted that HCFS represented “more than 40 percent of caloric sweeteners added to foods and beverages and (was) the sole caloric sweetener in soft drinks in the United States” [19]. So, that means cheaper drinks, right? So what’s the problem? Well, there are two main problems with fructose. The first concern is that fructose does not stimulate the release of insulin. This is important because insulin controls leptin, a hormone that tells you when you are full. So you get no “full feeling” from fructose. That means that you are likely to drink or eat more of the fructose-containing drink or food before your body tells you that you are full. This is not good for weight control. The second problem is that fructose is not handled in the body like other sugars. Instead of being broken down like glucose to produce energy in a process called glycolysis, it tends to produce the building blocks of fatty acids, setting us up for fat deposition. In animal studies, but less so in humans, fructose also raises blood pressure, raises triglycerides, impairs glucose tolerance, and promotes insulin resistance. Although a moderate amount of fructose intake in fresh fruit is a natural part of a healthy diet, consuming the excessive amounts available in artificial man-made “foodstuffs” (including sweetened drinks) is neither physiological nor natural. The impact of HFCS on acne occurs because of a mass effect. Normal sugars raise insulin levels to a normal degree. That triggers leptin and the appetite is satisfied, shutting down your wish to drink or eat more. When fructose is a part of the sugar mix, the signal to cease eating or drinking is diminished. You tend to consume more and that eventually boosts the insulin levels higher (from the other sugars, not the fructose), and that helps to de-repress the androgen receptor. That turns up the throttle on androgen-dependent processes from acne to hair growth to increased muscle and bone mass. This, combined with the tendency of fructose to store as fat, may be a significant player in the obesity epidemic that is driving up health care costs at a frightening rate. Limiting fructose to natural sources, taken in moderation, seems to be the best way to limit its impact on acne or other unwanted metabolic effects. As we have learned over the past few years, anything that can be done to normalize the everyday levels of glucose and insulin in our acne patients’ blood will reduce the tendency toward insulin resistance and will also assist in reducing the availability of the androgen receptors to androgens of whatever source. Metformin has recently been recognized to assist in this regard, and positive reports of its effective use in AI/HS have appeared [20]. It has been assigned FDA Pregnancy Category B so is worth consideration in the patient trying to achieve pregnancy (especially if she is overweight or has a diagnosis of polycystic ovarian disorder or metabolic syndrome). There is also reasonable evidence that metformin would be a wise addition to the anti-acne regimen [21]. The most common side effect is nausea and vomiting, so metformin’s introduction would be best done prior to achieving pregnancy, given the risk of morning sickness. Start low and go slow. There is a massive crossover in the influences of dairy and high-glycemic-load foods between acne and several other diseases and disorders of modern man and woman [22–24]. Prevention of the acnes presents lifelong dietary challenges, and these challenges are shared by the entire population exposed to processed foodstuffs, not just those with the genetic predisposition to the acnes. Acne vulgaris is linked with obesity, obesity is linked with polycystic ovaries (PCO), and PCO is linked with excessive facial hair growth. That is linked with balding in women and is also linked with obesity. Obesity links with AI/HS, acne inversa is linked to smoking, and smoking links to adult acne in women. The links through hyperinsulinemia and diabetes to insulin resistance and the metabolic syndrome are well established, and all appear to be related to dairy and increased glycemic load. There is recent evidence [25] that part of the blame may be shared by meat consumption, but we have (at the moment) no epidemiologic or clinical evidence that meat consumption is part of the problem in acne. Insulin resistance is a challenging problem, and its story is thoroughly interwoven into the pathogenesis of the acnes. Chronically elevated blood levels of diet-sourced glucose induce chronically elevated levels of insulin. The insulin attempts to lower glucose by storing it as glycogen in the liver and in other peripheral tissues. This chronically elevated insulin is one of the triggers of the de-repression of the androgen receptor, and is therefore a persistent pro-acne influence. The most effective product so far to counter this situation is metformin, a biguanide that decreases intestinal absorption of glucose and stimulates glucose’s entry into muscle and liver cells, where it is converted to and stored as glycogen, thus lowering the blood level. It has other useful metabolic effects (plus some side effects) and has proven of value in both acne and AI/HS [21, 26]. It is likely to see greater use in these conditions as we continue to search for alternatives to isotretinoin, and should probably be regularly used hand in hand with the dietary regimen. Other diseases and health problems that share dairy as a potential cause include prostate and breast cancer, decreased female fertility, overweight neonates, increased risk of Caesarean sections, increased fetal mortality, and increased rates of twinning [27]. Numerous other dairy-related problems that are mediated by allergy, lactose intolerance, and other factors that do not depend on the insulin mechanism, so they are not included here. The science is not yet complete, but the messages are clear. If you suffer from one or more of the acnes, you should: Some patients still show up believing the blackheads are dirt caught in the pores. They need to know that these plugs are made of keratinocytes, the cells that line the duct, and they are “stuck in a traffic jam” at the opening of the duct or just under the skin. The color is due to the same chemical, melanin, that gives our skin color or makes us tan. Each and every comedo in a case of acne needs to be emptied out of the follicular duct. Leaving it behind invites future trouble. While gentle cleanliness to remove the oil and makeup and other surface material at the end of the day is wise, it is impossible to scrub out comedones below the skin surface. Scrubbing just adds insult to injury and is to be discouraged, whether with wash cloth, loofah, or “complexion brush” (manual or electric). Soap and detergent selection alone will not clear acne, but on general principles I recommend the gentlest products possible, basically because I will be using other irritating chemicals on the face and I want to “reserve the irritation” for the medications the patient really needs. Unscented and pH-balanced synthetic detergent (syndet) cleansing bars are preferred, but gentle liquid facial cleansers or mild “super-fatted” soaps are usually sufficient. They should be applied with bare hands, warm water, and a gentle circular motion with fingertips only, and followed by a gentle rinse in clear warm water. No face cloths or washrags are permitted. Especially oily faces may need a second wash to get “squeaky clean.” The face is patted or blotted dry with a clean terrycloth towel, preferably laundered in an enzyme-free detergent and not exposed to dryer sheets or fabric softeners. This is all the preparation needed for the application of the products discussed throughout this section. Antibacterial soaps have been recommended for mild acne [28], but that recommendation was made before the realization that such products are likely partly responsible for the biotropic effect that shifts the balance of the facial flora toward production of Malassezia yeast by killing off the “easy-to-kill” bacteria. I have patients avoid such products unless there is clear evidence of bacterial infection, which is rare. Comedones (the plural) can be physically forced out by pressure (Section 8.7.1) or dissolved (lysed) by the action of a comedolytic. Some comedolytics do nothing but dissolve or unplug pores. Others have additional roles. These chemicals have long histories as valuable and effective products. The retinoids originated as drugs derived from vitamin A, whose chemical name is retinol. The first to be introduced was vitamin A acid, technically all-trans retinoic acid, which was available originally as a very effective but very irritating liquid, applied topically (Figure 8.1). Patients were warned that there would be redness, irritation, and peeling. It was easy to tell 40 years ago if your patient was using the medicine or not. Because there was little else available at the time, most put up with it, mainly because it really worked if used as directed, not only on open comedones (Figure 8.2) but on closed comedones as well (Figure 8.3 and see “Practical Acne Therapy”). Figure 8.1 The original liquid preparation in the mid-1970s was a challenge to tolerate, but alternatives were few. Figure 8.2 These comedones developed in a 16-year-old while he was on a full anti-inflammatory dose of doxycycline as successful treatment for pityriasis lichenoides chronica. Figure 8.3 This variety of fine closed comedonal acne with hundreds of lesions is a challenge, but proper use of topical retinoids will clear the tiny milia-like folliculopapules. With time, gentler formulations were developed with different strengths, different vehicles, different indications (including fine wrinkles), and numerous different names. Dermatologists generally pride themselves on being able to juggle drugs and fine-tune them to match their patients’ skins and needs, so the variety is welcome. As a starting point today, the generic vitamin A acid 0.05% cream is reasonable, perhaps three nights a week to the entire involved area. The frequency of use is increased as tolerated. My pre-printed prescription forms indicate that the applications may vary “from 3 to 14 times per week,” and patients are instructed and encouraged to gradually increase (or decrease) the frequency to tolerance. The use of these products over the entire involved area is highly important in a population that is used to “spot treatments.” Patients must understand that comedolytics work by doing two jobs at the same time: These applications are continued until all is clear and then the frequency is reduced to more tolerable maintenance levels, which (with luck and gentle skin care) are often below the level that causes redness and peeling or flaking. The next retinoid to reach the market, adapalene, is similar in effect to retinoic acid but was not based on the vitamin A molecule, even though it is called a retinoid. Adapalene was originally introduced as Differin® 0.1% cream, and a gel followed shortly. It had the advantage of being somewhat gentler than retinoic acid/vitamin A acid [29] but was just as effective. In addition, it is stable when exposed to sunlight so it can be used in the morning even in sunny locations. As a result of competition from generics and from a stronger product, Differin’s strength was boosted to 0.3% in the gel vehicle and it is a stable, reliable, albeit expensive product. The third retinoid, tazarotene, was introduced as a topical for psoriasis but in the hands of the dermatology community, always experimenting, it found a place as a comedolytic and that is now its preferred use. It is available in a cream and a gel, as both 0.1 and 0.05% Tazorac®. It is photostable and rates above the Differin 0.3% gel both as a comedolytic and as an irritant. I find it particularly useful as a supplemental tool to clean out the most resistant comedones that may be refusing to leave with low-dose isotretinoin (the oral retinoid—see Section 8.4.3.2). Using any of these to get out the last resistant comedo always requires persistence and tolerance. Persuading patients to remain adherent to a long-term preventive maintenance program is almost as difficult. A potent oxidizing agent, benzoyl peroxide (BP), has been in use as a solo ingredient and in various combinations for decades. It works to dry and peel the top layers of the skin, gradually thinning and flaking away the keratin that makes up the comedonal material plugging the pores, qualifying it as one of the earliest true comedolytics. It is also a moderately effective bactericidal (killing bacteria) and bacteriostatic (slowing their reproduction) agent. As such, it has been especially useful in the decades that saw the worldwide spread of antibiotic-resistant Propionibacterium acnes. Because its mode of action is not susceptible to induction of bacterial resistance, it has been and still is an ally against the antibiotic-resistant P. acnes strains [30]. It penetrates well into sebum, so it is capable of reaching not only the skin surface but also the follicular portions of the FPSU [31]. In the animation available at http://www.acnemilk.com/acne_animation, you can see how the low oxygen content of the follicular structure is produced by pressure from the overgrowth of the lining keratinocytes. The oxygen content is so low that P. acnes, which grows best in a low-oxygen (or no-oxygen) location, multiplies happily in these anoxic (no-oxygen) ducts. It is happy to do so as long as there is enough food. Fortunately, the same hormones that turn on the keratinocytes are equally busy producing lots of sebum. It is no accident that sebum is the preferred food of both P. acnes and Malassezia, so they are quite happy to take up residence in this sebum-saturated niche in the skin, at least until BP is added to the mix. Consider that BP, just like hydrogen peroxide, releases fresh oxygen as it reacts with other substances. And remember that it is quite soluble in sebum. So if you rub it on your skin, there is a pretty good chance that it will dissolve in the sebum, penetrate the pores, and then travel down into the duct to flood the deeper parts of the follicle with oxygen. This is likely to slow the growth of P. acnes, dropping the population of that organism. This has always been thought to be a bactericidal effect but it may be due simply to the inhibitory effect of the fresh input of oxygen flooding the living space of the anaerobic P. acnes. Although speculative and unproven, there is reason to wonder if one reason for its effectiveness may be the provision of sufficient oxygen to the depths of the follicle that the formation of hypoxia-inducible factor 1 (HIF-1; see Section 7.3) may be prohibited. BP has been used in concentrations from 2% to 20%, and both the effectiveness and the amount of irritation experienced by the patient are quite variable. This depends upon the concentration of the drug itself, the vehicle (cream, gel, lotion, wash, shower bar, shower gel, etc.), the length of application time (from a wash on–rinse off 2% shower gel to an overnight 10% spot treatment), and individual patients’ sensitivity. The last is somewhat unpredictable. Some patients may become truly allergic to BP; the estimates vary from 1% to 10% of patients exposed. More common is simple primary irritant contact dermatitis, which is dose or frequency related and so can be managed by varying the product used and the frequency and exposure time. There is also a population of extra-sensitive individuals, often atopics (patients with personal or family histories of allergies, eczema, hives, hay fever, etc.), who cannot tolerate using this (or many other topicals) at all. They have the sensitive skin syndrome [32], for which the only effective therapy is avoidance of irritants. Basically, they are best treated only with systemic medications unless they are prepared to put up with stinging, burning, itching, and general irritation during a prolonged course of gentle-as-possible topicals. BP is available both alone and as a combination with other medications. As Sulfoxyl 5 Lotion®, a mixture of 5% precipitated sulfur and 10% BP, it was a mainstay of therapy during the 1970s. The sulfur may have been responsible for the lack of problems with Malassezia during those years. Subsequently, BP was added to erythromycin and clindamycin topicals when studies showed that this decreased the incidence of resistant strains of P. acnes. The combination was marginally better than the topical antibiotics alone but did have the advantage of concurrent comedolytic therapy while the P. acnes was being treated. Like the retinoids, the BP products should be applied to the entire involved area for their preventive effect. Higher strength (10%) products may be used as “spot treatment” to dry up specific lesions. This is especially useful overnight, for example following “acne surgery” (Section 8.7.1). This simple relative of acetylsalicylic acid (Aspirin®) has been used for decades in low concentrations and is remarkably safe, cheap, and gently effective as a comedolytic for clearing mild acne. It is a beta-hydroxy acid; in fact, it is the only one used in acne care. This “beta” configuration means it is lipid soluble, so it can actually get down into the sebum (oil, lipid) in the follicular duct. It is available as a cream, cleansing bar, shower gel, lotion, body wash, and spot stick. As with BP, the effectiveness and tolerance vary from person to person. Salicylic acid is the only beta-hydroxy acid; all the others are alpha-hydroxy acids. The original one, promoted as an effective anti-aging facial peel by van Scott, was glycolic acid [33]. More than with other comedolytics, the variables of concentration, vehicle, pH, exposure time, skin “prep” preoperatively, “neutralization,” and aftercare determine the results with glycolic acid. At one extreme, the aggressiveness of the reaction is such that it is best monitored only by a cosmetically trained dermatologist with considerable experience, a well-trained staff, excellent handholding skills, and excellent liability insurance. At the low end of the potency scale, it can be rendered so gentle that it is sold over-the-counter and self-administered, but it is almost as ineffective at low potency as the high potency is risky. It has gradually become an aesthetician’s tool, even when dispensed or used by dermatologists or their staff. Many chemical compounds have been tried over the years. Their method of action is not always well defined. Nevertheless, some of them work for some people, some do not, but most are worthy of mention. This rather gentle compound is found naturally in some grains. It is a mild bactericidal against P. acnes, and is a gentle comedolytic. It is also a mild anti-inflammatory and a tyrosinase inhibitor, so it finds use in treatment of PIH, especially in those with darker skin types. The vehicle in which it is used has a significant effect on its potency, and the 15% gel is most often prescribed. While it suffers from the disadvantage of having little effect on Malassezia [34], it is FDA category B, so it is safe for use in pregnancy. Sulfur, in its many forms, has been used for centuries in dermatology. It is a mild antibacterial, is quite effective against Malassezia, and is a gentle comedolytic. Overuse will cause irritation and peeling, but it is otherwise nontoxic when used topically. It is often combined with salicylic acid or sodium sulfacetamide in various strengths in topical lotions and creams [35]. Correction of a presumed zinc deficiency has recently been shown, in specimens taken from patients with active lesions of AI/HS, to appear to enhance the expression of all the markers of innate immunity that were depressed [36]. This observation may explain why various forms of zinc have been found useful in managing acne vulgaris, acne rosacea, and acne inversa. When used topically in antibiotic combinations, it has been shown to be as effective as oral tetracycline [37]. Zinc has been associated with a decreased systemic absorption of clindamycin from a topical preparation containing both, a possible protective effect. It has also been found to be sebosuppressive. An oral proprietary mixture of nicotinamide 750 mg, zinc 25 mg, copper 1.5 mg, and folic acid 500 μg [38] produced positive results comparable to the effect of oral antibiotics in patients with acne rosacea or acne vulgaris. In AI/HS, oral zinc has been found to be effective. While it has been suggested that zinc supplementation might be useful only in those who suffer from a zinc deficiency, defining this deficiency is expensive. From a pragmatic point of view it is much more cost-effective to supplement with the dose used in this last study, zinc gluconate 30 mg with each meal [39], administering zinc gluconate or chelate with meals (30 mg twice or three times per day in adults). Zinc may reduce copper absorption by displacing copper, so copper supplementation has been advised [40]. A proprietary capsule containing the recommended proportion of 50 mg zinc and 2 mg copper in an amino acid chelate used once or twice orally daily likely avoids problems. Resorcinol is a simple benzene ring molecule with two hydroxyl groups at the 1 and 3 positions. It is an antiseptic, disinfectant, analgesic, and hemostatic (stops bleeding). In low concentrations (2% or less), it has been an active ingredient in anti-acne products for decades. Paired with sulfur, it was present in Acnomel® and is still present in certain Clearasil® products. It is useful for both acne vulgaris and acne rosacea. A recent innovation is its use in a stable proprietary base at a fairly high 15% concentration. It is used to treat early or resistant lesions of HS/AI [41]. As formulated, it decreases the redness and swelling and helps dry up early inflammatory nodules. Even though it is not a classical comedolytic, it dries and peels the surface of such lesions. Note that extemporaneous mixtures at this concentration tend to disintegrate. A proprietary vehicle that allows compounding without subsequent breakdown of the mixture has been developed. Topical therapy depends upon the ability of the active molecule to gain access to the targeted areas of the follicle at an effective concentration. Systemic administration has proven more effective than topical for the most important retinoid comedolytics. The original retinoid, vitamin A (retinol), has been available in such bland and innocuous topical products as Vitamin A&D ointment for generations and is included in all multivitamin oral preparations. Its effect on any of the acnes when applied topically is essentially nil. In high doses (300,000–400,000 IU daily), given orally there is a significant acne-clearing effect, even before obvious toxic effects are approached. Kligman and others [42] worked with such doses prior to the arrival of isotretinoin on the scene. These high doses have been associated with documented teratogenicity, and so must be avoided where there is risk of pregnancy [43]. Although available in some countries as a topical in a gel base, isotretinoin works far better when introduced to the follicular unit through the bloodstream following oral administration. The same is true of the need for delivery to the sebaceous gland itself, a feat that cannot be achieved topically. Following Peck’s introductory article in 1979 [44], isotretinoin arrived on the scene in 1982 and the entire picture of acne therapy changed. As Accutane in North America and Roaccutane elsewhere, it was quickly recognized as the most effective therapy available. Despite significant side effects, almost all of which are easily managed with conservative dosing and careful monitoring, it retains pride of place as the most effective of all therapies for acne. Isotretinoin is a powerful drug and must be treated with respect, consideration being carefully given to the following five areas of concern. See also Box 8.1, “Isoretinoin, a Challenge to Prescribe.” The major concern over the years with the use of isotretinoin has been teratogenicity (physical and mental abnormalities developing in the unborn baby caused by its mother’s exposure to the drug in early pregnancy). Programs mandated by government and underwritten by the drugs’ manufacturers have been in place for years, the most recent being iPLEDGE [45]. The object is to minimize the risk, and careful adherence to protocols has been shown to stabilize but not eliminate the occurrence of unwanted pregnancies. Although contraceptive failures occur and patient failures are often to blame, prescribers share the blame, occasionally excusing patients from adherence to the protocol or inadvertently trusting the untrustworthy [46, 47]. Adherence to the birth control regimen is a matter of trust, and it is essentially impossible to enforce. Religious objections and personal commitment need to be discussed openly, a difficult prospect if mother and underage daughter have differing agendas. Frankness and honesty, even though uncomfortable, is the best policy. It can be very helpful to view the newer progestins as being used for acne control, rather than exclusively as conception control. By presenting acne in all its variations as a disorder triggered by hormones, one can lead the discussion naturally to the use of hormonal control as a medical decision, not open to religious or moral concerns. This is admittedly a “sidelong glance at reality,” but it may allow the patient and her parents to see “the Pill” in a different light, as a valuable part of the therapy, and therefore as an acceptable choice. From the opposite side of the question, the physician always retains the right, indeed the responsibility, to withhold any medication that he or she suspects may be used inappropriately, putting an unborn child at risk. A patient who deceives the prescriber, accepts a prescription for a BCP, then sets it aside for religious or other reasons and takes the isotretinoin that was prescribed by the physician in good faith may create a very difficult situation. If a pregnancy occurs in the face of the physician’s misplaced faith in the patient, an innocent life is threatened. The iPLEDGE program assists in guiding, recording, and documenting the informed consent process, but the ultimate risk is the patient’s, or the unborn child’s. The question that is presently preoccupying and enriching lawyers in North America is whether or not isotretinoin may cause inflammatory bowel disease (IBD). Several cases have reached court. The financial settlements have been monumental. Nevertheless, the science is unsettled. One problem is that most patients who have been treated with isotretinoin have had their acne previously treated with broad-spectrum antibiotics. The incidence of IBD among patients who have taken isotretinoin may actually be lower [48] than that among those treated with broad-spectrum antibiotics [49], but this is insufficient evidence to totally exonerate isotretinoin. The only way to obtain data unconfounded by previous antibiotic therapy (topical or systemic) would be to identify a population with severe acne but no prior experience of broad-spectrum antibiotics and no family or personal history of gastrointestinal symptoms suggestive of (and so predisposing to) IBD. They could be treated with isotretinoin prospectively in a randomized clinical trial, but now that the drug is “off patent” there is no interest from the manufacturers in funding such expensive studies. That leaves standing the question of whether acne and IBD, both being inflammatory diseases (whether primary or secondarily), occur in individuals who have a genetic or acquired predisposition to inflammatory disease itself. It is possible that some individuals, like atopics, are simply more prone to certain kinds of disease driven by certain types of mediators, such as tumor necrosis factor alpha (TNFα) and others. And, of course, IBD existed long before isotretinoin came on the scene in 1982. To complicate matters, a pre-authorization policy of some pharmacy benefit managers in the United States insists on a failed trial of broad-spectrum antibiotics prior to the introduction of isotretinoin. A European directive on the use of isotretinoin mandates a similar approach (see Box 8.1, “Isotretinoin, a Challenge to Prescribe”). These “trial of antibiotics first” protocols (financially influenced by insurance companies in the United States) ignore the pathogenesis of the disease, encourage the overgrowth and influence of both Candida in the bowels and Malassezia in the FPSUs, put patients at further risk from scarring and perhaps even induction of IBD, hinder investigative science, and so are profoundly counterproductive, in my opinion. The fourth problem we need to consider is the question of the induction of depression by isotretinoin. The drug remains under suspicion as a true, if infrequent, idiosyncratic cause of depression. While the studies of depression and isotretinoin therapy generally support the lack of association, it is essential that we recognize the risk and possibility of depression occurring in rare individual patients. There is no denying that there are cases in which a temporal relationship exists between isotretinoin and depression or isotretinoin and suicide. The question is whether isotretinoin itself is the cause. Over the past 30 years, I’ve seen four patients in whom the depression question arose. The first was a young woman who was so severely depressed after 6 weeks on isotretinoin that she required admission to a psychiatric unit. This occurred before the question of depression associated with isotretinoin had been raised. She had, in order to take the isotretinoin safely, been started on a BCP. At the time (the early 1980s), the estrogen level in BCPs was higher and the potential for depression from the BCP far outweighed our concern regarding isotretinoin. Her depression was attributed to the BCP. She remained off both drugs subsequently, and no challenge was performed. The next two cases were patients, one male and one female, who reported depressive symptoms shortly after starting the isotretinoin. Both were interviewed in depth about their diet. Both habitually avoided vitamin A–containing vegetables and took no supplements. Both stopped the isotretinoin for two weeks and were placed on vitamin A supplements (8000–10,000 IU) for 10 to 14 days. Both then returned to isotretinoin and completed the course without incident [51]. I learned about the fourth patient from his parents, who reported his suicide four months after the very successful completion of the course of isotretinoin. There were extenuating personal problems in his case, and the call was to thank me for helping provide the young man with what they called “the best few months of his teens” before his passing. In the first case, there is no doubt that BCPs cause depression in a fair percentage of women, opening the possibility of simple coincidence. In the second and third cases, I suspect (but cannot prove) that vitamin A–deficient individuals have numerous vitamin A receptor sites in their bodies that are unoccupied by their natural ligand, vitamin A itself. This may leave these receptors open to accept isotretinoin, an unintended ligand, with unpredictable results, including the possibility of night blindness. There is unfortunately no practical way of proving this theoretical suspicion. Nevertheless, there is little risk of additional vitamin A toxicity if one simply advocates a daily dose of 10,000 IU vitamin A for a week or 10 days prior to starting isotretinoin therapy in any patient with a poor history of vitamin A intake. The admonition in the June 2000 Accutane package insert, “Because of the relationship of Accutane to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects,” was written without apparent regard to the relative safety of 400,000 IU of vitamin A in Kligman’s series [52]. There was no evidence in support of the warning in the product insert, written long before “evidence-based medicine” was invented. My experience with the two patients who suffered depression, then had vitamin A supplementation followed by successful isotretinoin therapy, suggests that vitamin A deficiency may predispose to isotretinoin toxicity [53, 54]. This is anecdotal, so the idea is probably an insurmountable distance from clinical proof, and it will likely never see the Cochrane stamp of approval of “evidence-based medicine.” Nevertheless, I occasionally supplement an isotretinoin candidate whose dietary history suggests inadequate vitamin A intake, and I offer it as a practical and low-cost preventive approach whenever the question of depression is raised. With regard to the fourth patient, it is becoming apparent with more reports that there is a population of individuals who appear well adjusted, normal, productive, and happy in every way, but who suffer from covert depression. A recent review states, Psychological disturbances, including depression and other suicidal tendencies, are extremely common during adolescence and are clearly increased by acne, particularly where it is severe. Isotretinoin does not appear to increase this risk. Routine screening should be performed for psychological disturbance in adolescents, particularly among those presenting acne. Prescription of isotretinoin is not contraindicated in subjects presenting depression. [55] So what is the practical approach to isotretinoin in the face of psychological or psychiatric worries? If the patient is already depressed, under psychiatric care, and taking appropriate medications, I explain the vitamin A deficiency hypothesis, take a dietary history, and recommend two weeks of 10,000 IU of oral vitamin A. Because isotretinoin is a derivative of vitamin A and vitamin A is a fat-soluble vitamin, both are taken daily with fatty food. Here in the United States, I recommend a tablespoon of peanut butter—but not cow or goat butter. Olive oil works well, but is harder to use. A square “pat” of (oleo) margarine spread on toast or a cracker will do, as will a couple of gelatin capsules of fish oil. The vitamin A is recommended irrespective of the food history, to eliminate doubt. If the patient (or parent) wishes, or if my concerns are high, I communicate with the psychiatric therapist. I explain that the use of isotretinoin in patients already under treatment for depression is normal and accepted and that most psychiatrists are well aware of this and welcome the help that isotretinoin provides. Indeed, as I tell my patients and their parents, “I would also likely be depressed if I had to come to work with acne like this. I hope we can get rid of one of the major causes of depression for you.” This may sound “promissory,” and with any other drug it would be a risk to make such a statement, but isotretinoin has passed the test of time and can deliver superb results when used properly. When all involved are counseled, consented, and comfortable, I then proceed with a low dose (20–40 mg isotretinoin daily with peanut butter) and the solid (sometimes written) understand that if there appears to be any adverse response, the drug is stopped and I am to be notified immediately—I provide my cell/mobile number for that purpose. If there is a family history of depression or bipolar disorder, but there is no clinical depression, I explain the situation. The explanation is communicated to the primary care physician. Again, the vitamin A supplementation is highly recommended, despite the iPLEDGE proscription against it. To repeat, there was no evidence provided in support of that warning, which was written long before evidence-based medicine was invented. If the concern springs from the patient’s or the family’s reading of the Internet or the iPLEDGE booklet, in the absence of depression, the approach is the same, with the vitamin A offered as an option. In an obviously depressed patient, or the rare patient with body dysmorphic disorder or obsessive-compulsive disorder (anything from destructive self-manipulation to obsessive use of the magnifying mirror), I recommend professional psychiatric help before we go further. As an aside, from a practical point of view, patients who are obsessive pickers will stop “obsessing” and picking if they run out of targets to pick at—and there is no drug that eliminates those targets better than isotretinoin. In ALL cases, the question needs to be asked about self-destructive thoughts. The additional psychological burden added to patients’ lives by the iPLEDGE program does have benefits, but we do lose patients who would benefit from a less heavy-handed administrative approach. And that, of course, prolongs the problem. On the other hand, if the negative power of the iPLEDGE program could be used to persuade all parents and professionals who care for acne patients to manage them from the first contact according to the principles set out in this book, aggressive prevention could lead to much less need for isotretinoin. The iPLEDGE process is uncomfortable for all concerned. This is one reason that in my practice I never prescribe isotretinoin to females, and very rarely in males, to a new patient on the first visit. I insist they take 48 hours, or a weekend or a week, to review the iPLEDGE booklet in detail. If aged less than 18, the review is also done by parents (mandatory when a parent’s signature is required), or with a trusted second or third party. This booklet is available online [45] and raises the question of depression and suicide in some detail, preparing patients and parents (assuming they read the whole booklet) for my eyeball-to-eyeball question before I sign off on the iPLEDGE consent form and write the prescription. My script is simple: “You have read the manual, you are aware that there are concerns about depression and suicide, do you have any further questions or concerns?” To the general public, the iPLEDGE pamphlets and the consent forms that go with them are scary documents. They pull no punches. They are designed to protect. They help to protect the patient against a lack of informed consent, they help to protect the physician against claims of failure to provide informed consent (when used as part of the full informed consent process), and they help to prevent exposure of an unborn child to a known teratogen. The documents are a “heavy read” for many patients and their parents. Indeed, of those who are sent home with the iPLEDGE documents for review, approximately 15% never come back to the office. Often this is a vote against the need for birth control, judging from the conversation when the question is introduced, rather than a vote against isotretinoin itself. Another 10% or so come back, but wish to avoid the drug for various other reasons. Alternative therapies, initially presented as options at the earlier visit, are then detailed. That leaves us with the physical side effects. Prior to its commercial introduction, and during the early years, the dosage of isotretinoin was often as high as 2 mg per kg per day. As a result of experience elsewhere [56], I now rarely go beyond 0.8 mg per kg per day. I explain to patients that we once used a fairly high dose over a short period of time, but that we now use a lower dose over a longer period of time. The total dose (and the effectiveness) of the medication is approximately the same, but the side effects are far less [57]. The long list of cutaneous and mucous membrane side effects that were such a challenge in the early years (see table) have diminished significantly with this lower dose regimen. The chapped lips and dry skin remain, and are very valuable in judging the patients’ adherence, but the peeling of upper lip and eyelid from waxing is now seldom seen (Figures 8.4, 8. 5). We still discourage waxing (in any area) for isotretinoin users for at least two months after finishing the drug. There are other side effects, once quite common, such as the pyogenic granuloma-like lesions around toenails that I have not seen for over 10 years. We still hear the occasional complaint about aching backs, we rarely hear about sore muscles at this dose, and the incidence of hypertriglyceridemia is so low on the zero-dairy, low-glycemic-load diet that blood tests are ordered on my patients only when there is a strong positive family history of diabetes or blood lipid anomalies. The exception is a strong parental presence that is insistent upon testing. In essence, the management of acne with isotretinoin in low doses is a much simpler process than it was in the early years. Figure 8.4 One of the earliest cases of a very upset bridesmaid whose waxing while on isotretinoin took off a strip of upper lip epidermis. Figure 8.5 Her eyebrows also lost a layer—fortunately, the wedding was over a week away. The major surprise has been the excellent response achieved over a 120-day course at the low dose. My bias is to attribute this to the zero-dairy, low-glycemic-load diet that I encourage all patients to follow. Certainly, those with significant lesions on the back, neck, and chest often require an additional 30- or 60-day course to achieve full clearance, but that is certainly not an excessive total dose. All are taught to consider isotretinoin as a means to clear their dairy-induced disease faster than avoidance of dairy alone will permit. All know that even the worst acne will clear over time with diet alone—but that it will be a much faster clearance (and with less scarring) with isotretinoin. As always in medicine, opinions and protocols change with time and there is now new evidence that a higher dose produces better long-term results [58], and discussion at a recent symposium pointed out some interesting facts about the guidelines being used. I’m not sure I wish to revisit the high-dose days. The reactions were sometimes quite impressive (Figures 8.6, 8. 7). Figure 8.6 High-dose Accutane. Note the (pre-existing) facial scarring as well as the extensive cheilitis (chapped lips). Figure 8.7 Same patient—a peeled heel. There is a problem created when a strict dosing schedule is used in setting up the clinical trial of a new drug. If the drug is successful in reaching the market, it comes with some baggage—the dosing schedule used in the trial usually becomes part of the FDA-regulated package insert. While useful as a guideline, the daily doses, the total doses, and the length and timing of treatment courses are subject to evolution and modification and individual patient sensitivity over years. Patients and physicians are both presented with choices every day, and there is now a background of 30 years of “experience-based” advice as well as “evidence-based” advice to consider on all sides of the discussion [59]. Before isotretinoin was introduced as Accutane® in 1982, it was available on a select basis to some investigators for clinical use. I had several patients on this early program, the most memorable being an inmate in a local penitentiary. This was in the days when inmates could earn “time off for good behavior,” and one of the good behaviors was to assist with clinical trials of drugs. This is now considered an unethical practice—times change—but it was mutually beneficial to all concerned in many cases. Even taxpayers benefitted, long before “Win, win, win” was ever invented. If you’ve seen the movie One Flew Over the Cuckoo’s Nest, you will remember Chief, the massive aboriginal basketball player whose declared love of Juicy Fruit® gum was a highlight of the film. My patient was cut from the same cloth; he could have been Chief’s twin, but he had horrible bleeding nodular acne that made him a prime candidate for the trial. He was involved from just beneath his ponytail down his back to his beltline, and his face, neck, shoulders, and upper chest were almost totally submerged in nodular acne. In isotretinoin’s early days, the dose was high and the side effects were a major concern. Because this was a clinical trial, no adjunct therapy was permitted by the protocol, so we saw the full major initial flare; peeling, cracked, and swollen lips; peeling and dry face; and even calluses peeled off feet and particularly off the heels. Special appeals for extra linen, extra issues of clothing, extra shower time, and excuses from manual labor—all were honored by his keepers, but he was still pretty uncomfortable. By six weeks, he could see some improvement and his natural stoicism carried him forward. He steadily improved, and the side effects became tolerable. By 16 weeks, he was essentially clear of active lesions. He was still putting up with peeling, swollen split lips, and dry skin but could get through the nights with no bleeding, and the nodules had almost all disappeared. His last appointment was for the four-week post-therapy follow-up. He failed to show. Clinical trial managers really frown on incomplete records, so my staff called the institution to check on him. It seems he was sufficiently happy with the results that he had decided to “take it to the streets.” One satisfied customer, he had “gone over the wall,” and that was the last I ever heard of him. Another retinoid is available for use in the acnes, but it was actually introduced for the management of conditions in which there is a “disorder of keratinization.” This occurred at a time when acne was considered to be due to overproduction of sebum and the role of disordered keratin metabolism took a back seat. Acitretin has the disadvantage of a very long half-life, and because it is teratogenic (like isotretinoin) and because its long half-life can be extended even further if it is taken concurrently with alcohol, it is normally avoided in women, especially those of childbearing capacity. Acitretin is not approved for use in acne vulgaris, nor is it used in acne rosacea. It is, however, quite useful in managing the abnormal keratinization of the follicular ductal canal that is the cause of the follicular rupture in AI/HS [60]. In managing this disease, all involved must be aware that the time frame is extended because patient and physician are looking for prevention of new lesions while the old lesions are managed with antibiotics, anti-inflammatories, and surgical approaches as each case dictates. If I were asked to design the most cost-effective therapy for acne, even non-inflammatory comedonal acne, it would consist of a zero-dairy, low-glycemic-load diet and an initial course of low-dose isotretinoin, accompanied in women by a non- or low-androgenic progestin-based oral contraceptive, preferably using the “extended” 84/7 regimen and likely supplemented with spironolactone. This would achieve both effective secondary prevention and effective treatment. It would eliminate the need for aggressive and risky long-term broad-spectrum antibiotics, expensive topicals that now run into the hundreds of dollars per packaged unit in the United States, and would have the added benefit of teaching a dietary lifestyle that could produce a lifetime of healthier choices. While we still do not have any epidemiological evidence that diet is important in true papulopustular acne rosacea, it is not unreasonable to expect that it is developed by the same processes that trigger acne vulgaris, so I make parallel recommendations to my acne rosacea patients regarding both diet and isotretinoin use. Increasing experience in my personal group of HS/AI patients has likewise shown the value of diet, but isotretinoin is of less value here. Acitretin is more effective and deserves broader use. Until all comedones are prevented, comedolytics are an essential part of acne care. The first tetracycline, Aureomycin®, was originally brought to bear on acne vulgaris over 60 years ago as a topical ointment in a case of a highly inflammatory acne known then as acne varioliformis [61]. The initial intent was to use the tetracycline as an antibiotic, to kill the “acne bacillus,” then called Corynebacterium acnes, now P. acnes. Twenty years later, we learned that tetracycline and other antibiotics, even in doses below the concentration needed for lethal or static antibacterial effect, were fairly potent as suppressors of inflammatory activity, at least as measured by neutrophil chemotactic activity [62]. Subsequently, other antibiotics employed in managing acne have showed varying degrees of anti-inflammatory activity, and varying degrees of success. The problem throughout this discussion over the years has been deciding to what degree the anti-inflammatory response is purely anti-inflammatory and what response is due to the elimination of the organisms. The problem that has evolved, and has not received adequate discussion, is the fact that reducing or eliminating P. acnes does away with one enemy, but tends to enhance the activity of another, or of several others. (See Sections 6.1 and 6.2.) The short story here is that every antibiotic that has been used for managing acne vulgaris has anti-inflammatory properties [63, 64]. That said, the choice of antibiotic is based more on overall clinical effect on inflammatory acne lesions and on safety than on a rating of the drug’s anti-inflammatory capacity. Topical dapsone, a moderately effective anti-inflammatory when applied topically, is much safer when administered this way than by mouth. Topical clindamycin, on the other hand, has been known to cause its major side effect, pseudomembranous colitis, even when applied topically [65]. Tetracycline applied on the skin surface has never been very effective in acne and is generally not used. Erythromycin ointment, on the other hand, does have some limited topical use, but mainly for its antibacterial capacity rather than its anti-inflammatory properties. In managing acne with tetracycline prior to the arrival of Accutane® in 1982, I regularly used 1–4 g of tetracycline daily. That high dose has not been much used since isotretinoin became available. Now that tetracycline, after disappearing temporarily from the American scene, has reemerged at approximately 100 times its cost of a few years ago, the emphasis will be on the continued use of doxycycline (also subject to a significant price rise) and minocycline. Both are normally used in a dose of 50 to 200 mg daily, in a divided dose, and either may be taken with food and water (minocycline) or must be taken midmeal with 8 oz. of water (doxycycline) despite the inaccurate instructions provided by pharmacists’ computerized handouts in the United States. Because of side effects [66], minocycline has been used less than doxycycline, but the new prices may change these practices. With the arrival of azithromycin, erythromycin has faded into the background. Numerous regimens have been suggested for azithromycin, one of the 500 mg tablets taken daily for 3 days every 10 days being one of my favorites because of improved compliance, limited side effects, and gentle efficacy. Amoxicillin and ampicillin have their advocates, as do clindamycin and trimethoprim–sulfisoxazole. In unusual situations such as Gram-negative folliculitis, the antibiotic selection will be determined by culture. In managing acne rosacea, almost all the same antibiotics used in acne vulgaris have been tried at various times. Nevertheless, topical metronidazole has held pride of place for a few decades now. In spite of the fact that even the manufacturer denies knowing how it works, it has recognized anti-inflammatory activity. There is little clinical difference between the efficacy of the cream, gel, or lotion. Personal preference of the patient seems to dictate the choice of vehicle. Likewise, there appears to be little difference between the 0.75% and 1% preparations, and between the brands and the generics. I tell patients that 80% of cases respond almost completely to the original 0.75% gel applied topically twice a day for 8 weeks. It works so well that I rarely see an untreated acne rosacea because primary care providers look after that 80%. That leaves 20% that will require a different type of therapy. Interestingly, about 40% of patients (half of the original 80%) who are clear upon discontinuation of the initial 8-week trial will stay that way, sometimes indefinitely. Certainly, topical metronidazole should be the first thing tried. Beyond that, things get complicated. (See Section 1.2.) Antibiotics have been leaned upon quite heavily in this disease. While many authors freely admit that bacterial cultures may bear little relevance to the pathogenesis of the disease, just about everyone admits that antibiotics are useful [67]. While they may be very effective in getting rid of secondary infection, escalation to more and more powerful combinations seems more likely to rely upon the anti-inflammatory capacity of these antibiotics than their ability to eliminate the organisms. Certainly, when an inflamed acne inversa nodule or sinus is unroofed and allowed to granulate in from below, there is usually no need for any antibiotic whatsoever. This strongly suggests that the inflammatory component of the disease is driven by something other than the bacterial load. (See 1.3) If I were convinced that AI/HS is due to a bacterial infection, I likely would be inclined to use antibiotic on a regular basis. In general, however, it is better to address the cause of the problem than it is to expose the patient to the risk of long-term, broad-spectrum antibiotic therapy. Nevertheless, when there is secondary infection obviously present, antibiotics are warranted. Really hot solitary nodules can also be cooled to a certain extent using the anti-inflammatory capacity of antibiotics, but they clear more quickly and heal faster and with much less pain if unroofed. Grossly infected sinuses are rare but do require antibiotics, and the choice varies from simple full-dose doxycycline to trimethoprim–sulfamethoxazole to rifampicin. They may be used preoperatively to cool the inflammation, making the surgery easier, and then for a short period postoperatively to calm residual inflammation. That said, the healing response without antibiotics, and without the risks of antibiotic resistance and allergic reactions and secondary yeast, is an argument in favor of avoiding them unless cellulitis is apparent. The risk of secondary yeast infection, especially if the genital areas are involved, is significant. Fluconazole given weekly in a dose of 150–200 mg is normally quite satisfactory to control yeast, and is best used weekly until the signs of infection have disappeared. Once again, unroofing would be preferred, thereby eliminating the need for the antibiotics and for the covering antifungal. Patients suffering from the extensive sinuses and hypertrophic scarring of Hurley Stage III disease need far more than broad-spectrum antibiotics. They need surgery, and that may be accomplished either by aggressive widespread staged unroofing or by en bloc excision with grafting. See Sections 8.7.3.3 and 8.7.3.4. These recalcitrant disorders require a “full court press,” treatment that addresses all potential contributors to the problem. Concurrent anti-Malassezia, antibiotic, anti-inflammatory, comedolytic, and intralesional steroid therapy plus diet are used to settle the process. I have not found surgery necessary in DTF if the patient will accept the risk of some residual scarring, but wide excision in acne keloidalis does give remarkably good results. When dealing with acne vulgaris, acne rosacea, or AI/HS, there will be times when true hot secondary infection needs aggressive culture-guided antibiotic therapy. The practitioner’s experience-based best ‘educated guess’ as to the offending agent should lead to initial antibiotic therapy while awaiting culture results. The need to switch to a different antibiotic is unusual, but one certainly does not wish to compromise the result by ignoring the availability of culture and sensitivity. In addition, it is essential to keep in mind that inflammation does not always mean infection. That hot red nodule on the back may be a sterile epidermoid cyst, requiring no antibiotic whatsoever, but simple evacuation instead. The hot red nodule in the middle of the cheek may look the same as the back lesion but may contain no cyst whatsoever, and an attempt to excise or evacuate the lesion may lead to a cosmetic disaster. In the latter situation, intralesional triamcinolone is far better therapy. The same hot red nodule in the inguinal area or under a breast in a patient with other signs of AI/HS may respond to intralesional triamcinolone (a steroid) but more likely needs unroofing as definitive care. Not antibiotics. Not excision. Not “I&D” (incision and drainage). If the lesion is fresh, and especially if solitary, then biopsy punch mini-unroofing is best. (See 8.7.3.1.) Lastly, remember that the biotropic effect of antibiotics is always there. Antibiotics encourage yeast to grow, whether Candida below the navel or Malassezia above. Watch for these predictable side effects, and treat with fluconazole or ketoconazole, respectively. Their effective spectra of antifungal activity are reasonably specific with little overlap. Lipophilic ketoconazole for lipophilic Malassezia and hydrophilic fluconazole for hydrophilic Candida. Ketoconazole, like most of the azoles, is both anti-inflammatory and antimicrobial. It is very useful in acne vulgaris and acne rosacea, but I’ve not tried it in AI/HS other than dealing with the remote side effects of excessively long courses of broad-spectrum antibiotics. When it was first introduced, it was dosed on a daily basis, and soon earned the reputation of causing liver problems. Shuster, an early fan, studied its use in seborrheic dermatitis using ketoconazole 200 mg per day for 4 weeks and then 400 mg daily for 4 weeks. He set it aside in 1984 with these words: “ketoconazole may occasionally produce hepatotoxicity … the drug is not suitable for prolonged treatment of seborrheic dermatitis and dandruff, its minor manifestation. It is to be hoped that an equally effective topical preparation or derivative will be developed” [68]. Professor Shuster’s hopes for an alternative have not been realized but ketoconazole, despite its reputation, can be used with remarkable safety at one-seventh of its original dose. One needs to realize that the primary impact of the drug on the liver is its ability to compromise the cytochrome P450 3a4 enzyme system. If this interference occurs on a regular daily basis, at the dosage approved at its introduction, general hepatic metabolic function is severely compromised. On the other hand, given once a week or less, ketoconazole in a dose of 400 mg is remarkably well tolerated. I have used it with patients for almost 20 years. Of course, working in a consulting practice, one does not double blind the treatment. Referred patients expect active treatment, the best available. That is what they are paying for, and that is exactly what they get with this drug. But a challenge has arisen. (See Box 8.2, “Ketoconazole Warning July 2013.”)
Management
8.1 Prevention
Primary
To avoid occurrence of the disease. This can be done on a universal, selective, or indicated population.
Secondary
To diagnose and treat early to prevent significant marking and both physical and psychological scarring.
Tertiary
To treat to reduce existing scarring, post-inflammatory hyperpigmentation, and psychological trauma.
Quaternary
To avoid unnecessary or excessive healthcare interventions.
Universal
This involves the whole population.
Selective
This involves the population at risk, those with a personal or family acne history.
Indicated
This identifies populations at risk, aiming at early identification.
Environmental
Regulated avoidance of an identified cause of the disorder.
8.2 General principles of management
8.3 Diet
8.3.1 Dairy
8.3.1.1 The deli-planning heiress
8.3.1.2 The pharmaceutical executive
8.3.2 Carbohydrates, glycemic load, and hyperinsulinemia
8.3.3 The paleolithic diet
8.3.4 High-fructose corn syrup (HFCS)
8.3.5 Metformin
8.3.6 Synthesis and summary
8.4 Comedolytics and other topicals
8.4.1 Standard topical comedolytics
8.4.1.1 Retinoids
8.4.1.2 Benzoyl peroxide
8.4.1.3 Salicylic acid
8.4.1.4 Alpha and beta-hydroxy acids
8.4.2 Unclassified topicals
8.4.2.1 Azelaic acid
8.4.2.2 Sulfur
8.4.2.3 Zinc compounds
8.4.2.4 Resorcinol
8.4.3 Systemic comedolytics
8.4.3.1 Vitamin A
8.4.3.2 Isotretinoin
8.4.3.2.1 Teratogenicity
8.4.3.2.2 Contraception
8.4.3.2.3 Inflammatory bowel disease
8.4.3.2.4 Depression
8.4.3.2.5 Other side effects
acne fulminans
alopecia (which may persist)
bruising
cheilitis (dry lips)
dry mouth
dry nose
dry skin
epistaxis (nose bleeds)
eruptive xanthomas
erythema multiforme
flushing
fragility of skin
hair abnormalities
hirsutism
hyperpigmentation and hypopigmentation
infections (including disseminated herpes simplex)
nail dystrophy
paronychia
peeling of palms and soles
photoallergy or photosensitivity
pruritus (itch)
pyogenic granuloma
rash (including facial erythema, seborrhea, and eczema)
Stevens–Johnson syndrome
sunburn susceptibility
increased sweating
toxic epidermal necrolysis
urticaria
vasculitis (including Wegener’s granulomatosis)
abnormal wound healing (delayed healing or exuberant granulation tissue)
8.4.3.2.6 The convict who looked like chief
8.4.3.3 Acitretin
8.4.3.4 Summary
8.5 Anti-inflammatories and antimicrobials
8.5.1 Antibiotics as anti-inflammatories
8.5.1.1 In acne vulgaris
8.5.1.2 In acne rosacea
8.5.1.3 In acne inversa
8.5.1.4 In dissecting terminal folliculitis (DTF) and acne keloidalis
8.5.2 Antibiotics as antibiotics
8.5.3 Ketoconazole, ivermectin, and crotamiton
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