Acne Vulgaris and Isotretinoin – Science aspects and Clinical aspects
Currently, isotretinoin is the drug of choice for the management of severe, treatment-resistant acne vulgaris. Treatment with isotretinoin can lead to both marked improvement and long-lasting remission. Essentially, isotretinoin has the capacity to “cure” acne. In a field where physicians are usually resigned to suppressing inflammatory skin disorders until they “burn out,” this power of isotretinoin is astounding.
The scientific community has long known that vitamin A significantly impacts proliferation and differentiation of skin (1). Thus, retinoids, or natural and synthetic analogues of vitamin A, have long been studied for the treatment of various dermatologic diseases (2). However, synthesizing an effective, though relatively safe, retinoid proved formidable. From the late 1960s to the 1980s, at least 1500 retinoids were synthesized and tested by Bollag and collaborators (2). The model that they used to test retinoids was chemically induced cutaneous papillomas of mice. These studies were undertaken to find retinoids that were antikeratinizing for the treatment of psoriasis and antineoplastic for the treatment and prevention of skin cancer.
It was not until 1979 when Peck et al. conducted an open label trial in which 13/14 patients with treatment-resistant cystic and conglobate acne ach-ieved complete clearance at four months when administered isotretinoin at an average dose of 2 mg/kg/day (3). A few years later, a randomized placebo control trial was conducted that confirmed the remarkable efficacy of iso-tretinoin in the treatment of severe acne vulgaris (4). Shortly thereafter in that same year, the Food and Drug Administration (FDA) approved isotretinoin for the treatment of severe nodulocystic acne. Now with 30 years of experience with this drug, our purpose in this post is to focus on the basic properties of isotretinoin as well as the principles of its use for acne.
BASIC SCIENCE ASPECTS
Isotretinoin, though a vitamin A derivative, is a relatively water-soluble mole-cule. Small amounts are found in the blood naturally, and one month following discontinuation of isotretinoin, levels within the body return to background levels. This rapid clearance from the body is the rationale for prevention of pregnancy for one month after discontinuing isotretinoin in women of child-bearing potential.
Peak isotretinoin plasma levels are achieved between 1 4 hours (5). Importantly, the magnitude of this peak level is increased by coadministration with lipids. Thus, patients are instructed to take their doses with a small, fatty meal. Given the half-life of 10 to 20 hours, it is best to take isotretinoin twice a day (5 7). Finally, isotretinoin is metabolized in the liver, where it is oxidized to 4-oxo-isotretinoin via CYP450 3A4 substrate and then excreted in urine and feces.
Mechanism of Action in Acne
The primary mechanism of isotretinoin is its effect on sebaceous glands. Isotretinoin dramatically inhibits sebaceous gland activity, proliferation, differ-entiation, function, and production of sebum (8 10). In vitro studies conclude that isotretinoin induces apoptosis and cell cycle arrest of human sebocytes (11 13). This effect seems to persist indefinitely upon completion of a full course (120 150 mg/kg) of isotretinoin, and this is thought to be the mode by which treatment with isotretinoin can cure acne.
Precisely how isotretinoin molecularly renders its effect is uncertain. Unlike other retinoids used in dermatology, isotretinoin does not bind retinoic acid receptors (RARs), rather isotretinoin functions via an RAR/RXR-indepen-dent mechanism. Secondary mechanisms that contribute to the efficacy of iso-tretinoin include anti-inflammatory, antibacterial (secondary to sebum reduction/ alteration), and antikeratinizing effects.
Per FDA guidelines, isotretinoin is indicated for the treatment of severe recal-citrant nodular acne. Its use for less severe acne is often indicated provided such cases are treatment resistant and especially if the disease is leading to scarring, whether physical or emotional. In only the severest cases should it be considered initial therapy.
Isotretinoin should be dosed at 0.5 to 1 mg/kg/day divided BID. In the typical acne patient requiring treatment with isotretinoin, we start at 0.5 mg/kg/day for the first month to acclimate the patient to mucocutaneous xerosis, minimize initial inflammatory response, and monitor for any adverse effects. If after the first month the patient is not experiencing excess dryness or other adverse effects, the dose should then be increased to approximately 1 mg/kg/day.
In patients with severe acne in which explosive flares may occur, we often pretreat for one or two weeks with daily prednisone to minimize this risk. After this pretreatment, we initiate isotretinoin at 0.5 mg/kg/day, or even less if necessitated by severity. The prednisone dose should then be gradually decreased as the isotretinoin dose is increased toward a goal of 1 mg/kg/day.
In general, most patients are treated with 1 mg/kg/day. However, more important than the daily dose is achieving a total cumulative dose of 120 to 150 mg/kg, which ensures the greatest likelihood of prolonged remission of acne (14). Calculating this dosage permits flexibility and minimizes adverse reactions.
Relapses do occur and most investigators agree that relapses are more common in younger patients, males, and truncal acne. However, acne that recurs after isotretinoin therapy is more responsive to less aggressive acne treatments such as topical agents or oral antibiotics. If still severe, a repeat course of isotretinoin can be tried with success rates similar to that of initial treatments.
Purported relapse rates following treatment of acne with isotretinoin varies between 5.6% and 65.5% (15 26). The most likely reasons for this large dis-crepancy are small sample size, short follow-up, retrospective design, and/or subtherapeutic cumulative dosage. Perhaps the most convincing study to date showed a relapse rate of 41% and a need for a second course of isotretinoin at 26% (19). We usually communicate to our acne patients that approximately 1/3 will be “cured,” 1/3 will be better, and 1/3 will be unimproved following a full course of isotretinoin.
Absolute contraindications include pregnancy, breast-feeding, and hypersensi-tivity to parabens, soybean oil, or other retinoids.
Relative contraindications include psychiatric disorders, skeletal disorders, seizure disorder, hyperlipidemia, pancreatitis history, diabetes mellitus, hyperuricemia, gout, and anorexia nervosa.
Since lists of various drug interactions can easily be obtained from various drug references, we will only comment on the possible interaction of concomitant use of isotretinoin and tetracycline class medications. Both isotretinoin and tetra-cyclines can cause idiopathic intracranial hypertension (IIH), that is, pseudotu-mor cerebri. The mechanism of this rare adverse effect is believed to be an idiosyncratic reaction. Therefore, when starting isotretinoin in patients with very severe nodulocystic acne, we occasionally continue/start minocycline or dox-ycyline and/or systemic corticosteroids to reduce a severe inflammatory response in the patient. After a month or two, we then discontinue the minocycline or doxycycline and continue isotretinoin. Obviously, symptoms of IIH (e.g., headache, visual changes, and tinnitus) should be closely monitored.
Treatment with isotretinoin can have various adverse effects since RARs are ubiquitous throughout the body. Many of these adverse effects are common and dose dependent, though some are rare and idiosyncratic. These side effects mimic the effects of hypervitaminosis A, albeit in a much attenuated presenta-tion, and almost all are reversible upon discontinuation of isotretinoin.
The first, and essentially universal, side effect of isotretinoin is cheilitis. Chapped and cracking lips are so expected that its absence is often considered a marker of noncompliance or insufficient dosage. In addition to the lips, any mucocutaneous site can be affected including the skin, conjunctiva, oropharynx, nasopharynx, and genitalia. Treatment for mucocutaneous dryness is straight-forward and consists of artificial tears for the eyes, petrolatum for the lips, and bland emollients for the body. In severe cases, topical corticosteroids may also be employed. Other rarely reported cutaneous side effects of isotretinoin include photosensitivity, exuberant granulation tissue, and abnormal wound healing. Telogen effluvium, nail plate fragility, paronychia, and onycholysis are adverse effects that can affect the hair and nails.
Because of xerophthalmia, patients who wear contact lenses should be informed that it may be uncomfortable to wear contact lenses while being treated with isotretinoin. Other reported ocular side effects due to progressive xeroph-thalmia include night blindness, conjunctivitis, keratitis, corneal opacities, and cataracts.
Reversible alterations in blood lipids are another frequent side effect of isotretinoin. Hypertriglyceridemia is the most common dyslipidemia secondary to isotretinoin and is generally seen in about 20% of acne patients treated with isotretinoin (27 29). LDL may also be increased, while HDL may be decreased. These alterations typically occur early in treatment during the first month or two, stabilize, and then revert to pretreatment levels promptly upon discontinuation of isotretinoin. The long-term effect of relatively brief alterations in lipid levels is thought to be negligible. However, substantially increased triglyceride levels can have immediate risks including pancreatitis and eruptive xanthomas (28). Triglyceride-induced pancreatitis is usually not seen unless triglyceride levels are greater than 800 mg/dL, a level infrequently caused by isotretinoin (30).
Treatment of slight to moderate elevations in triglycerides (300 500 mg/dL) consists of lifestyle changes including weight loss, increased exercise, and incorporation of a healthy diet with increased consumption of fruits, vegetables, whole grains, and lean meat. Decreased consumption of fatty foods, processed foods, carbohydrates, and alcohol should also be emphasized. For triglyceride levels in the 500 to 800 mg/dL range, more immediate intervention may be indicated, particularly if triglyceride levels continue to rise. Since triglyceride elevations are dose related, one can decrease the dose of isotretinoin. If dose reduction is not sufficient, pharmacologic therapy is indicated. The drug of choice for isotretinoin-induced hypertryglyceridemia is gemfibrozil, a fibrate lipid-lowering agent. The standard dose of gemfibrozil is 600 mg twice daily, taken 30 minutes prior to breakfast and dinner. For triglyceride levels greater than 800 mg/dL, discontinuation of isotretinoin is appropriate.
Long-term implications of altered blood lipid levels during treatment with isotretinoin may actually be profound. A relatively recent prospective study makes a strong argument that individuals treated with isotretinoin who develop lipid abnormalities may be at an increased risk for future development of the metabolic syndrome. This is characterized by central obesity, hypertension, hyperglycemia, and dyslipidemia (31). Dermatologists can play a pivotal role in preventing the long-term complications by referring these patients to primary care physicians and specialists for early intervention to prevent obesity, hyper-tension, hyperlipidemia, and diabetes mellitus. Importantly, this study suggests that treatment with isotretinoin may unmask susceptibility to the metabolic syndrome but in no way suggests causality.
Besides mucocutaneous xerosis and transient dyslipidemia, the incidence of other adverse effects due to isotretinoin is much less frequent. Increased trans-aminase levels are seen in some 11% to 15% of acne patients treated with isotretinoin (32). However, the development of severe hepatotoxicity is exceed-ingly rare. Nevertheless, it is a standard of care to check baseline liver enzymes with consideration of foregoing treatment with isotretinoin if levels are sub-stantially elevated. Other occasionally reported gastrointestinal adverse effects of isotretinoin include nausea, diarrhea, abdominal pain, acute gastritis, and acute proctocolitis. Rare reports of decreased white blood cell count, hemoglobin, and platelets compel most physicians to check these levels at baseline.
Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is an exceedingly rare idiosyncratic reaction of isotretinoin. It is characterized by severe and persistent headaches, classically worse in the morning, associated with nausea, vomiting, and blurred vision (33). Additional manifestations include pulsatile tinnitus, retrobulbar pain, and focal neurologic deficits. Any of these findings should prompt a fundoscopic exam to evaluate for papilledema, or swelling of the optic disc. Isotretinoin should be immediately discontinued and a neurologist should be consulted for further management. Concurrent treatment with tetracyclines, another class of medications associated with IIH, is generally avoided. However, given that IIH is an idiosyncratic reaction rather than a dose-related side effect, concurrent treatment with isotretinoin and a tetracycline may, on rare instances, be appropriate. Musculoskeletal complaints, such as arthralgias or myalgias, may be reported by some 30% of acne patients treated with iso-tretinoin, though significant elevations in creatine kinase are much rarer (34). It is thought that patients who engage in strenuous physical activity are at greater risk for the development of muscle pains. We recommend patients continue their normal activities and decrease the intensity should they experience myalgias.
Clearly, the most serious side effect of isotretinoin is teratogenicity. Iso-tretinoin affects organogenesis; therefore, its greatest risk to a fetus is early in pregnancy (during the first trimester) (35). However, isotretinoin is contraindicated throughout pregnancy and even one dose is thought to be able to induce congenital defects. Some 18% to 22% of pregnancies exposed to isotretinoin end in spon-taneous abortion (35,36). Of those exposed pregnancies not ending in spontaneous abortion or elective abortion, the rate of birth defects ranges from 18% to 28% (35,36). These birth defects include craniofacial, cardiac, central nervous system, thymic, and various other abnormalities (35 37). Furthermore, it is thought that fetal exposure to isotretinoin can also cause impaired neuropsychological func-tioning and mental retardation, manifesting later in childhood (38).
To minimize the risk of congenital defects, in March 2006, the FDA mandated that all prescribing physicians, patients, and pharmacies distributing isotretinoin must be enrolled in the iPLEDGE program, an Internet-based dis-tribution system that interconnects physicians, patients, and pharmacies. Simply put, iPLEDGE links a monthly negative pregnancy test, conducted at a physi-cian’s office or laboratory, to a prescription for a one-month supply of iso-tretinoin. Prior to starting isotretinoin, a patient must be enrolled in the system, select and adhere to two means of contraception (or may elect for abstinence), and have two negative urine pregnancy tests separated by at least 30 days. If these obligations are met, a patient can then be provided a prescription for a one-month supply of isotretinoin. Every month this process must be repeated with a new negative pregnancy test and counseling on the risks of isotretinoin, both of which must be officially documented in the iPLEDGE program. This program, albeit in a somewhat more lenient form, is also required for women without childbearing potential and males (though there is no evidence of any adverse pregnancies from men treated with isotretinoin). Further details of the iPLEDGE program can be obtained at http://www.ipledgeprogram.com.
Altered bone mineralization is another controversial aspect of isotretinoin. Long-term treatment with isotretinoin can affect bone mineral density (BMD) (39 41). However, these effects probably do not apply to the short-term treat-ment of acne with a standard course of isotretinoin. At least four studies have demonstrated that short courses of isotretinoin for treatment of acne do not decrease BMD (34,42 44), though two of the four studies did find a decreased BMD at Ward’s Triangle (34,43). Still, measurements at this site are notoriously unreliable and should not be used to determine, or monitor, BMD (45,46). Rather, the preferred site to measure BMD is the lumbar spine and, if not feasible there, then the total hip region should be used (34,35).
The development of hyperostosis, or osteophytes, and diffuse idiopathic skeletal hyperostosis (DISH) (calcification of interosseous tendons and liga-ments), is another controversial possible toxicity of isotretinoin. Whether brief courses of isotretinoin for the treatment of acne do cause hyperostosis or DISH-like changes is debatable. Further uncertain is the consequences of hyperostosis and DISH-like changes.
There are two putative adverse effects of isotretinoin treatment that are currently the topic of courtroom battles. We feel that the verdicts of these legal proceedings are not founded by evidence-based medicine. The first of these concerns psychiatrics events. The first case report suggesting a relationship between the use of isotretinoin and the development of depression was in 1983 (47). Since that time, perhaps no other issue in dermatology has been more controversial and divisive. Nevertheless, there is no evidence that there is a causal relationship between mood disturbances such as depression, anxiety, or suicidal ideation and the use of isotretinoin.
To date, numerous large, valid studies have demonstrated that there is no increased risk of depression in patients treated with isotretinoin (48 51). On the contrary, there have actually been numerous studies showing improved mood or reduced anxiety in patients treated with isotretinoin (52 56). In 2008, a study was published alleging an association between isotretinoin and depression (57). However, this study was flawed for many reasons and has been disproven (58). Confounding factors included the similar age of onset of acne and depression and that acne itself is a well-established cause of depression (59,60).
Given the serious nature of depression and suicidal ideation, we do recommend close psychological monitoring of patients treated with isotretinoin. At this time, there does not appear to be a causal relationship between the use of isotretinoin and depression. However, this does not mean that some patients may not develop an idiosyncratic reaction to isotretinoin.
The second adverse effect to be considered is the alleged relationship between treatment of acne with isotretinoin and the development of inflamma-tory bowel disease (IBD). The two major diseases of IBD are Crohn’s disease and ulcerative colitis. Since the approval of isotretinoin for the treatment of acne in the 1980s, there have been scattered case reports and case series that associate isotretinoin use and onset or flaring of IBD (61,62). A systematic review was conducted evaluating whether isotretinoin may trigger IBD (63). Using the Naranjo adverse drug reaction probability scale, they determined that of the 85 cases reported to the FDA MedWatch program from 1997 to 2002, 4 cases (5%) scored in the “highly probable” range for isotretinoin as the cause of IBD, 58 cases (68%) were “probable,” 23 cases (27%) were “possible,” and no cases were “doubtful” (63).
There is just as much evidence that suggests there is no causal link between isotretinoin and IBD. Similar to the study cited above, though using different criteria of causality, it was concluded that there is insufficient evidence to confirm or refute a causal association between isotretinoin and IBD (64). In the most powerful study to date examining isotretinoin and IBD, a population-based, matched case-control study showed that IBD patients were no more likely to use isotretinoin than the general population (65). Patients with known IBD have been treated with isotretinoin for acne. In one study, only one of the four patients with IBD developed a flare in IBD when his/her acne was treated with isotretinoin, further supporting the concept that there is no casual link between isotretinoin and IBD (66).
It is our opinion at this time that there is insufficient evidence to conclude that isotretinoin can cause IBD. Perhaps the greatest confounding factor that leads to this erroneous conclusion is the overlap between the age of onset of acne and IBD. Similar to acne, the age of onset of IBD begins in the second decade and peaks in the third decade (65,67). Acne vulgaris similarly rises in incidence and peaks at the same time. Thus, it seems to be more of an incidental occur-rence, rather than causal, that patients treated with isotretinoin develop IBD.
Nevertheless, it would be foolish to ignore the case reports suggesting a link between the use of isotretinoin and the development of mental disturbances or IBD. However, coassociation does not equal causation. Larger studies investigating these occurrences have failed to establish any increased incidence of either of these problems in patients treated with isotretinoin. Therefore, it is our opinion that isotretinoin should continue to be employed, albeit with caution and informed consent, when appropriately necessary.
At time of publication, the isotretinoin package insert recommends checking fasting lipids and liver function tests (LFTs) at baseline, then every one to two weeks until stable. Given the minimal immediate risk of elevated lipid levels and the exceedingly rare incidence of dangerously high LFTs, in our practice we check lipids and LFTs at baseline and then lipids monthly for the first two months. If no abnormalities are found and the dose unchanged, we do not check any further labs unless there are reasons to be concerned based on history of rising or unstable laboratory values. Of course, one should check labs more frequently if abnormalities are encountered.
As per iPLEDGE requirements, women of child bearing potential require two negative in-office urine or serum pregnancy tests separated by at least 28 days before starting therapy. Thereafter, they will need monthly in-office neg-ative urine or serum pregnancy tests throughout therapy and for one month after treatment is finished.
Finally, it is recommended that all patients receiving isotretinoin be evaluated for signs or symptoms of suicidality or any unusual behavior changes every month. If any concerns arise, psychiatric consultation should be immediately obtained and discontinuing isotretinoin should be considered.
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