Systemic isotretinoin therapy remains the most effective treatment for severe acne and for patients with moderate acne who are refractory to other treatments. This article outlines the mechanisms of superior outcomes, describes how to optimize treatment, reviews recommended guidelines for monitoring, and outlines adverse events.
Systemic isotretinoin for acne
Oral isotretinoin (13-cis-retinoic acid) was approved by the U.S. Food and Drug Administration (FDA) in 1982 for the treatment of severe acne. After all these years, the effectiveness of isotretinoin has not been replaced by other treatments and remains the most effective clinical anti-acne treatment, providing long-term relief and/or improvement of acne in many patients.
Mechanism of action
Isotretinoin is the only treatment that acts on all the major pathogenic factors of acne. It achieves this remarkable effect by affecting cell cycle development, cell differentiation, cell survival and apoptosis. It significantly reduces sebum production, acne, surface and glandular ducts of P. acnes and has anti-inflammatory properties. 0.5-1.0 mg/kg/d significantly reduces sebum excretion by 90% in 6 weeks. Unlike retinoic acid (all-trans vitamin A), isotretinoin has smaller or no binding to cellular vitamin A binding proteins or vitamin A-like nuclear receptors (RARs and RXRs), but can activate RAR and RXR nuclear receptors by altering intracellular metabolites.
X isotretinoin has at least five biologically important metabolites: 13-cis-4oxo-retinoic acid (4-oxo-isotretinoin), all-trans RA (retinoic acid), all-trans-4-oxo-retinoic acid (4-oxo-retinoic acid), 9-cis-retinoic acid, and 9-cis-4-oxo-retinoic acid. The study found that the reduction in sebum production rate in patients with severe acne using 4-oxo-isotretinoin (30-60 mg/d orally) over 4 weeks was 70% of that of the same dose of isotretinoin taken orally for more than 4 weeks. Isotretinoin also inhibited sebum better than 9-cis-retinoic acid and all-trans-retinoic acid. Only the combination of retinoic acid and 4-oxo-retinoic acid was important for the treatment of acne with RAR-γ. Incubation of isotretinoin in SZ95 human cortical cells resulted in significantly higher intracellular retinoic acid concentrations than isotretinoin. Incubation with retinoic acid also produced very high intracellular retinoic acid concentrations and negligible isotretinoin concentrations. These data suggest that retinoic acid may be the active intracellular form of isotretinoin and that isotretinoin may be a drug precursor. The different plasma concentrations of these metabolites could explain the differences in the intensity of individual response to treatment and the occurrence of severe or general side effects. Recent studies have demonstrated that isotretinoin induces apoptosis in cortical cells and that these effects are dependent on the activation of the RAR receptor, suggesting that oral isotretinoin acts on the sebaceous glands leading to a decrease in sebum production.
Isotretinoin significantly reduces blackhead acne by reducing hyperkeratosis. The exact mechanism remains unclear, and there is no evidence that isotretinoin affects the metabolic activity of keratinocytes.
Isotretinoin has no direct anti-microbial activity, but by significantly reducing the size of SER and sebaceous ducts thus altering the microenvironment in the ducts makes it unsuitable for the colonization of Propionibacterium acnes. The result was a reduction of Propionibacterium acnes into Log3 that was more potent than the inhibitory effect of oral and topical antibiotics. This also suggests that, like all-trans retinoic acid, isotretinoin can increase host defense mechanisms and alter monocyte chemotaxis, which could partially explain the anti-inflammatory effects of this drug. The significant reduction of Propionibacterium acnes also contributed to the reduction of acne inflammation.
Clinical benefits of oral isotretinoin
Most patients treated with oral isotretinoin will be acne-free for 4-6 months after the end of treatment. One explanation is that isotretinoin is significantly used to treat less severe acne. These cases responded very well and wanted to remain free of recurrence, whereas patients with severe acne were initially treated and were less concerned about some rare recurrence. Thus, the early reports of “cures” may be due to the fact that the patients ended up with acceptable acne relative to the initial severe acne. These phenomena suggest that younger patients are more likely to relapse than older patients. Isotretinoin was originally approved for the treatment of severe acne and as a second-line agent for refractory acne that had failed to respond to other treatments, including antibiotics. Clinical experience over the years has been that isotretinoin is a first-line agent for the treatment of severe acne, and these poorer prognostic features are shared by a number of acne-related conditions.
European guidelines were recently introduced for the prescription of isotretinoin. The purpose of the guidelines is to (1) ensure that generic prescribing is coordinated and costs are appropriate in the EU and (2) minimize adverse effects including pregnancy. Table 1 summarizes the recommendations of this guideline and compares them with previous prescribing practices.
A pregnancy prevention program (PPP) was approved by each national authority. This program includes educational communication, therapeutic management, and dispensing of controlled substances
Patients and prescribers are educated so that they are well aware of the teratogenic effects. Patients are also required to sign an informed consent form acknowledging this issue and to be questioned in detail by the physician prior to and during clinical administration of the drug.
Treatment management includes a medically supervised pregnancy test prior to treatment, at 5 weeks of treatment, and the provision of effective contraception.
The distribution control states that only 30 days of oral isotretinoin should be given to female patients at a time and that prescriptions should only be valid for 7 days.
In addition, a pregnancy test is recommended once a month for the duration of treatment.
The recommendation also states that isotretinoin is not currently used as first-line therapy and is not to be used in children younger than 12 years of age. With increased clinical experience, the use of the drug has expanded worldwide to include long-term antibiotics and/or appropriate topical antibiotics or retinoids in patients with less severe acne who are less satisfied with conventional treatment.
There are many reasons for the failure of conventional treatment, including antibiotic resistance of Propionibacterium acnes. Table 2 summarizes the possible precursors and considers recommendations for prescribing oral isotretinoin.
The recommended dose of isotretinoin is 0.5 mg/kg/d to begin with, with a gradual increase if well tolerated. If the patient does not tolerate the recommended dose, intermittent therapy may be used. Strict contraception must be used during administration.
Although European guidelines recommend that isotretinoin should not be used in children <12 years of age, there are still many reports of successful treatment of children, some younger than 10 years of age, presenting with intractable scarring acne. Oral isotretinoin should be considered for pediatric acne patients if there are adequate clinical indications.
The most acne patients treated by dermatologists are at the age of 25 years. Although they are not as severe at this time as they were at 15-25 years of age, persistent acne leads to an increased risk of scarring and disproportionate psychological confusion. Isotretinoin has an important role in the treatment of this age group. Acne in adults aged 30 years and older often persists for more than 10 years. Low-dose, intermittent isotretinoin therapy may be appropriate for this patient subgroup, but is often prone to recurrence after treatment.
Isotretinoin can be used in patients with significant systemic disease. Patients with systemic disease were successfully treated with isotretinoin. These patients were divided into 3 subgroups and 3 appropriate regimens were recommended (Table 3) to minimize the adverse effects of concomitant disease. All patients were carefully examined on a monthly basis by a dermatologist and associated internist to ensure that there were no significant clinical or laboratory changes in systemic disease.
1, Group 1 patients represented those who could safely be given adequate amounts of isotretinoin.
2, Group 2 patients represent patients for whom there is limiting information, but the drug may not cause any changes in concomitant disease after equilibration. These patients usually start with a small dose of 0.25-0.5 mg/kg/d and if all is well, the dose can be increased to 0.5 mg/kg/d in 2-month intervals and the treatment can be maintained for 24 weeks if needed.
3. Group 3 includes patients with rare diseases or not much information exists.
In these uncommon cases, the recommended treatment is to start with isotretinoin 20 mg / week. The dose is then increased by 20 mg per week, with patients reaching a dose of 20 mg/d by the end of week 7. This cycle can be repeated if further dose increases are needed. In this disease group, it is important for the dermatologist to be in proper contact with the internist so that careful clinical and related laboratory examinations can be performed.
Isotretinoin can treat different types of acne. These diseases are rare and isotretinoin can be effective in treating these cases. These diseases include eruptive acne, eruptive rosacea, gram-negative folliculitis, scalp cellulitis, suppurative sweat glands, and convergent acne.
Recommended dose and duration of treatment. European guidelines recommend starting with 0.5 mg/kg/d and gradually increasing to 1.0 mg/kg/d based on tolerability and response. half-life is 22 hours and bioavailability is 25%. The absorption of isotretinoin is significantly affected by fat, and pharmacokinetic studies have shown that isotretinoin is twice as well absorbed when taken with or after meat consumption as when fasted. Therefore, isotretinoin capsules are taken at the same time of day with food. The dose is then adjusted according to the clinical response and the presence of side effects.
The duration of treatment varies depending on the dose administered during treatment. The range is often 16-30 weeks, with an average between 16-20 weeks, as patients receiving 0.5 mg/kg/d require long-term treatment to achieve adequate results. Studies of cumulative dosing for maximum benefit and reduced relapse rates have demonstrated a positive effect of both dose and treatment duration, but there is no pharmacokinetic rationale to support this idea of cumulative drug or dose effect accumulation. Relapse rates are minimized at a total dose of at least 120 mg/kg, but the benefit does not increase above a total dose of 150 mg/kg. Generally, this total amount is achieved at 0.5-1.0 mg/kg/d over 4-6 months. Treatment duration needs to be adjusted to achieve at least 90% clearance of acne lesions.
Skin factors such as age, gender, and duration of acne may have an effect on response rate and relapse rate. Eighty-five percent of patients receiving the 0.5-1.0 mg/kg/d dose cleared acne at 16 weeks, 13% took 5 to 6 months, and 3% took longer. Less than 1% of patients required 12 months of continuous treatment. Small doses of isotretinoin have been successful in treating persistent and late-onset acne in adults. The typical dosing regimen is 0.5 mg/kg/d given 4 days out of 1 week for 6 months. 91% of patients clear acne with this regimen, but relapse rates are also frequent. In addition, some patients receive very small amounts of isotretinoin and wish to maintain it in small doses over time. It is unclear whether this method causes long-term side effects, and it is important to clarify for patients that there are no data on this, and that fertility in women is not known.
Why does isotretinoin have a slow onset of action?
Analysis shows that the slow onset of action of isotretinoin is due to the presence of microcomedema in 70% of the main cases, and that hyperandrogenism may also play a part
Side effects
Isotretinoin has many side effects, but most are predictable and rarely interfere with patient treatment. The common dermal and mucosal side effects are dose-dependent and can be tolerated with dose changes and/or other symptomatic treatments.
Teratogenicity is the most important side effect. Informed consent and a pregnancy test are required for patients.
Mood changes including depression have been reported in adolescents.
Skin mucosal side effects are dose-dependent and can often be controlled by regular use of humidifying agents. Occasionally, vitamin A drug dermatitis occurs, often secondary to Staphylococcus aureus infection. These patients require potent steroid creams in combination with antimicrobial therapy. Table 4 summarizes common skin mucosal problems that may be caused by isotretinoin.
Overt systemic side effects are rare (Table 5), early features of benign intracranial pressure increase headache is rare, and arthralgia is common in patients with regular heavy physical activity. Tetracyclines are generally not used with isotretinoin because these drugs can cause benign intracranial pressure increases. Systemic side effects are well controlled by dose reduction and concomitant use of nonsteroidal anti-inflammatory drugs or aspirin.
Early acute acne exacerbation is a recognized problem in isotretinoin therapy. The physician needs to inform the patient. If the problem is severe, oral prednisolone 0.5-1.0 mg/kg/d may be given for 2-3 weeks and then tapered over the next 6 weeks. The dose of isotretinoin can be stopped or reduced depending on the severity
There is still much debate about the need to monitor liver function and lipids at the time of treatment. The literature demonstrates that laboratory tests do not need to be repeated unless there is a risk, such as diabetes and a known family history of hypertriglyceridemia. However, European guidelines recommend testing at baseline, 1 month post-treatment and every 3 months throughout treatment.Amichai et al. provide a good overview of the many side effects of oral isotretinoin.
Cost-effectiveness ratio
Oral isotretinoin is more effective than oral antibiotics for acne of all severity levels. However, its relative expense and side effects prevent some physicians from prescribing it. The cost-benefit ratio shows that a 4-6 month course of isotretinoin is much cheaper than a 3-year rotating regimen of antibiotics and topical applications. In fact, only patients treated with isotretinoin achieve complete acne clearance within 3-5 years. However, additional testing, monitoring and prescription control have a negative effect on this cost-benefit ratio.
Drug Interactions
The efficacy of isotretinoin can be diminished by heavy alcohol intake. Isotretinoin is metabolized by the cytochrome P450 enzyme, which can be induced by alcohol and inhibited by some drugs such as ketoconazole. Therefore, if used in combination with imidazole antifungal agents there may be an increase in the concentration of isotretinoin. Acidic drugs like salicylic acid and indomethacin have high affinity to albumin. If the concentration in the blood is too high it may displace the binding of isotretinoin to the protein leading to an increase in the unbound concentration of the drug. Plasma levels of carbamazepine decrease when carbamazepine is ingested with isotretinoin, so patients with epilepsy using carbamazepine who require isotretinoin need to consider monitoring plasma concentrations of carbamazepine. Tetracyclines need to be avoided in conjunction with isotretinoin, as both drugs cause benign intracranial pressure increases. There are reports in the literature that combining these 2 drugs can cause superimposed effects. Vitamin supplements containing vitamin A need to be avoided with isotretinoin because of the potential for superimposed toxic reactions.