According to The Global Burden of Disease Project, acne is one of the ten most common diseases, ranking 8th [1]. It affects 9.4% of the world’s population [1, 2]. Starting at puberty, the disease resolves spontaneously in 60% of patients as they grow older, but in 40% of patients it can proceed up to the third decade of life and longer [3]. The chronic nature of the course of dermatosis, the resolution of rashes with the formation of scars and pigmentation, the impact on the quality of life dictate the strategy for its treatment: it should be effective, timely (early), long-term with a transition to maintenance therapy and carried out with the interaction of dermatologists with other specialists, including gynecologists, endocrinologists, and psychiatrists [4—7].
Approximately 20% of people suffering from acne, primarily adolescents, the disease is severe and is represented by widespread papulopustular and nodular (conglobate) acne [8]. The drug of choice for the treatment of patients with such forms of the disease is isotretinoin [9–12].
Buy Isotretinoin Online is a monoaromatic retinoid (13-cis isomer of retinoic acid). It was first approved for the treatment of acne by the U.S. Food and Drug Administration (FDA) in 1982. Since 2001, isotretinoin generics have begun to appear.
Since that time, vast experience has been accumulated in the use of isotretinoin for the treatment of acne. It has been proven to be highly effective in patients with severe forms of the disease: resolution of rashes is observed after 4 months of treatment in 85% and after another 1 month in 3% of patients [13, 14]. At the same time, the number of pustules decreases most rapidly – their number decreases by 50% already in the first 2–4 weeks of treatment [13]. The number of other inflammatory elements – papules and nodes decreases somewhat later, and finally, the number of comedones decreases last.
The basis of the high efficiency of the drug is its effect on the main links in the pathogenesis of acne – hyperproduction of sebum, impaired horn formation, inflammation and colonization of Propionibacterium acnes [13]. The main target for the drug are sebocytes. In vivo studies have shown that when isotretinoin is taken at a dose of 0.5–1.0 mg/kg for 6 weeks, sebum production decreases by almost 90% [15]. Subsequent in vitro studies have shown that this is due to suppression of proliferation and differentiation of basal sebocytes, their apoptosis, and inhibition of sebum production [20, 21]. The mechanisms of regulation of keratinocyte proliferation processes remain the subject of study, however, the inhibitory effect of the drug on the processes of keratinization and comedogenesis is obvious [22].
The anti-inflammatory effects of isotretinoin are associated with the regulation of the antigen-nonspecific immune response to P. acnes, including suppression of overexpression of Toll-like receptors-2 (TLR-2) and increased production of pro-inflammatory cytokines by monocytes, as well as normalization of the expression of antimicrobial peptides [23, 24] . Although the mechanisms of these effects remain unclear, it is important that they last at least 6 months after the end of treatment and ensure the duration of the clinical effect of the drug.
Although isotretinoin does not have a direct antimicrobial effect, its use leads to a significant log3 decrease in the number of P. acnes [21]. This effect exceeds that of antibiotics for external and systemic use, develops in relation to bacteria resistant to antimicrobial drugs, and is supposed to be a consequence of a change in the bacterial microenvironment [25–27].
Thus, the clinical efficacy of isotretinoin, due to its complex effect on the processes of proliferation and differentiation of sebocytes and keratinocytes, and cell apoptosis, is beyond doubt. Nevertheless, there are a number of unresolved problems associated with the prescription of the drug. This concerns the choice of an adequate dose of the drug, its safety, as well as the persistence of remission of the disease after the end of treatment.
Isotretinoin dosage. The optimal daily and cumulative dose of isotretinone is still a matter of debate. The individual daily dose of the drug is determined depending on the patient’s body weight, acne severity, the presence of other chronic diseases and ongoing treatment, as well as the development of side effects [13, 14]. The recommended starting dose of isotretinoin is 0.5 mg/kg for up to 4 weeks. With good tolerability of the drug, it is increased to 1.0 mg / kg. The cumulative dose of the drug is at least 110-120 mg/kg and is achieved in about 5 months of treatment in this mode. To reduce the risk of side effects B. Amichai et al. [28] proposed to prescribe the drug in low daily doses of 0.1–0.3 mg/kg. Another alternative use of the drug is its use at a dose of more than 1.0 mg/kg/day to achieve a cumulative dose of at least 150 mg/kg [29].
Features of dosage in patients with concomitant pathology. Patients suffering from acne and with severe comorbidities often require adjustment of the daily and cumulative dose of isotretinoin [27].
According to experts [27-30], these patients should be divided into three groups, taking into account the increased risk of side effects of the drug. Patients of the 1st group include patients suffering from diabetes mellitus, Crohn’s disease, ulcerative colitis, epilepsy. In this group of patients, isotretinoin for the treatment of acne can be administered at usual doses. The 2nd group includes patients suffering from chronic renal failure, manic-depressive psychosis, multiple sclerosis, who are on dialysis, with immunosuppression. Data on the safety of isotretinoin in these diseases are sparse, but suggest that the drug does not cause any significant changes in the course of their disease. These patients are recommended to start treatment with isotretinoin at a daily dose of 0.25–0.5 mg/kg, which can be increased after 2 months from the start of treatment, if the drug is well tolerated, up to 0.5 mg/kg or even higher. Treatment should be continued for 24 weeks. As for patients suffering from Behçet’s disease, cerebellar spongioform encephalopathy, idiopathic thrombocytopenic purpura, leukemia, mitochondrial degeneration, paroxysmal nocturnal hemoglobinuria, polymyalgia rheumatica, data on the safety of prescribing isotretinoin to them are practically not presented in the literature. In these cases, it is possible to start treatment with 20 mg of isotretinoin per week, the dose of the drug is gradually increased by 20 mg per week so that at the end of the 7th week, patients take 20 mg / day. If necessary and well tolerated, it is allowed to increase the daily dose to 40 mg / day, which the patient can take for another 7 weeks.
In all these cases, patients are subject to careful clinical and laboratory observation by a dermatologist and related specialists [27].
The frequency of relapses and prognostic factors for their development. When using the drug, almost 80% of patients experience stable remission [32, 33]. However, recurrence of the disease is not uncommon. Thus, in the course of a meta-analysis by F. Wessels et al. [32] found that the frequency of relapses varies, according to different authors, from 19 to 22% and averages 21.2%. Other researchers provide similar data. So, J. Strauss et al. [31] and J. Stainforth et al. [32] indicate that the need for a second course of the drug within 18 months after the end of treatment occurs in 20% of patients, and 9.5% of patients require more than two courses of isotretinoin (within 60 months). During a 10-year follow-up of 88 patients treated with isotretinoin, A. Layton et al. [15] showed that 16% of patients require additional treatment with antibacterial drugs, and 23% – a repeated course of isotretinoin, and recurrence of the disease occurs in 96% of these patients within 3 years after full treatment.
In this regard, the issue of identifying unfavorable prognostic factors for the development of relapses after treatment with isotretinoin seems to be very important. Among them are severe acne with localization on the skin of the trunk, very severe acne and its long course, the presence of macrocomedones, smoking, age up to 14 years or over 25 years, lack of correction of hormonal disorders [15, 33, 36, 38]. At the same time, all authors unanimously point to the presence of a direct relationship between the development of relapses and a low cumulative dose of isotretinoin, as well as the duration of remission and a cumulative dose of the drug more than 120-150 mg per 1 kg of body weight.
R. Blasiak et al. [29] observed 180 patients with acne resistant to other therapies. Patients received isotretinoin at a cumulative dose of less than 220 mg/kg and more than 220 mg/kg. The researchers found that the recurrence rate was significantly less in the 2nd group. In patients of both groups, cheilitis and xerosis were equally often observed, retinoic dermatitis was more typical for patients of the 2nd group (53.8% compared to 31.6%; p=0.02), the frequency of other side effects did not differ.
According to J. Strauss et al. [31] and J. Stainforth et al. [32] relapses after treatment with the drug at low doses were observed in 42% of patients, and more than two courses of isotretinoin were required in 88% of patients. On the contrary, against the background of the use of high doses of isotretinoin, the relapse rate does not exceed 10%, and standard doses – 20%. It is interesting that the clinical efficacy of isotretinoin, prescribed in low, standard and high doses, is comparable in the first 20 weeks of treatment, i.e., does not depend on the daily dose of the drug. Thus, the effectiveness of the drug in the first months of treatment does not guarantee a long-term remission, especially when prescribing low doses of isotretinoin.
Thus, in 80% of patients receiving isotretinoin for severe acne, there is a stable remission of the disease. Relapses develop in about 20% of patients. A number of reasons for relapses are associated with the regimen of the drug – its insufficient cumulative dose and low daily dose. The second group of causes is related to the course of the disease and includes severe acne localized on the skin of the trunk, its long course, the presence of macrocomedones, smoking, age under 14 years or over 25 years of age, and lack of correction of hormonal disorders.
Side effects. Despite its high efficacy, the use of isotretinoin may be limited by a wide range of possible side effects. Since the introduction of the drug, its safety has been actively studied. A large number of studies are being conducted on the spectrum and frequency of side effects, highlighting the most common of them and developing methods for their prevention and correction. Nevertheless, data on the teratogenic effects of the drug, the likelihood of developing depression, inflammatory bowel disease and some other complications (including rare ones such as pseudotumor cerebri) remain controversial. Remains a subject of discussion and the relationship of some of them directly with the effects of isotretinoin. In the review, we focused on the most significant and severe effects of the drug in clinical practice.
Teratogenic action. The teratogenic effect of the drug is not in doubt. So, E. Lammer et al. [41] provide data according to which up to 20-35% of children whose mothers took isotretinoin during pregnancy have congenital defects – craniofacial, cardiovascular, neurological, thymus lesions, and 60% of children have neurocognitive disorders in the absence of organic lesions. brain. Embryopathies are often the causes of preterm birth, spontaneous abortion and intrauterine death of the fetus. In the United States between 1983 and 2003, more than 2,000 women who took isotretinoin became pregnant. The outcome of most pregnancies was its termination or spontaneous abortion, 160 children were born with birth defects. It is assumed that most of the teratogenic effects are due to the effects of metabolites on neural crest cells, especially at the 4th week of gestation [13].
Due to the high risk of embryopathies while taking isotretinoin in Europe, the Pregnancy Prevention Program (hereinafter referred to as the “Program”) has been approved, the goals of which are to educate patients and specialists, as well as control treatment. All women of childbearing age taking isotretinoin are included in this program. In accordance with the provisions of the Program, patients and physicians must be fully aware of the teratogenicity of isotretinoin. Patients must sign informed consent and receive detailed counseling before and during treatment. A pregnancy test should be performed before, during and after 5 weeks of isotretinoin treatment. When prescribing isotretinoin, it is assumed that a prescription is issued for a period not exceeding 30 days, valid for 7 days. Reception of isotretinoin must be combined with effective methods of contraception. However, given the possible side effects of oral contraceptives, it is not always advisable to insist on their use, despite the risk of pregnancy. In the United States, the Pregnancy Prevention Program (iPLEDGE), approved by the FDA in 2005, requires all women and men taking isotretinoin to be listed on the National Registry.
In the clinical guidelines of the Russian Society of Dermatovenereologists for the treatment of acne (2010), it is recommended to conduct a pregnancy test (laboratory determination of the level of human chorionic gonadotropin in blood serum) 2 times – no later than 11 days before the start of the drug and in the first 2-3 days menstrual cycle. Treatment with isotretinoin should be initiated within the first 2-3 days of a normal menstrual cycle (in parallel with the exclusion of pregnancy) and combined with effective contraceptive methods.
However, even a single pregnancy test is not carried out by up to 56% of women, and a two-time one by 95 to 99%. 7% of patients do not use contraceptive methods [42-44]. In the course of the analysis of 17 publications by H. Crijns et al. [40] found that isotretinoin was prescribed in full accordance with the recommendations of the European pregnancy prevention program in only 6-26% of cases. The pregnancy rate was 0.2-1.0 cases per 1000 women of childbearing age taking isotretinoin, from 65 to 87% of pregnancies were terminated. According to other data, pregnancy is terminated in 29–63% of patients, and 13–19% have spontaneous abortion [43, 44].
Currently, the problem of isotretinoin teratogenicity is very relevant, therefore, the appointment of this drug to women of childbearing age requires special additional attention and monitoring.
Depression and suicidal thoughts. Another side effect of isotretinoin that has been under scrutiny for many years is the risk of depression. For the first time, symptoms of depression and suicidal ideation while taking isotretinoin were described in cancer patients (25%) taking isotretinoin [45]. A year later, similar publications appeared about patients with acne — in 5.5% of patients [46]. According to the FDA, the incidence of suicidal ideation among 4992 acne patients treated with isotretinoin between 1982 and 2004 is 3.8% (n=192). However, a large number of epidemiological studies have not confirmed the direct relationship between isotretinoin use, depression and suicidal thoughts [14, 15]. Most of these studies consider acne as an independent risk factor for the development of depression. Moreover, mental disorders associated with acne are an indication for the prescription of isotretinoin, including patients with moderate papulopustular acne [47]. At the same time, early and effective treatment of the disease is often accompanied by an improvement in the emotional and mental state of patients [45], as well as an increase in the quality of life. For example, according to Yu.N. Perlamutrov and K.B. Olkhovskaya, an improvement in the quality of life is observed during treatment with Sotret in more than 80% of patients (from 82.74% to 93.53%, depending on the initial severity of the disease) [17].
On the other hand, research undertaken by neuropathologists and psychiatrists does not completely rule out the relationship between isotretinoin and depression. So, in the course of studies of metabolism in brain tissues by the method of positron emission tomography, J. Bremner et al. [49] found a decrease in the volume of the cortex of the orbitofrontal zone after 4 months of treatment in 21% of patients compared with 2% of patients receiving antibiotics, and proved a direct relationship between headaches and drug intake. Although the connection of these zones responsible for the development of depression with the use of the drug has not been proven.
Thus, two polar points of view have now developed: dermatologists consider acne to be an independent risk factor for depression; psychiatrists – isotretinoin. Patients and physicians should be informed about this side effect of isotretinoin.
Inflammatory bowel disease. Another complication that has attracted attention relatively recently is the association of isotretinoin and inflammatory bowel disease [50]. In the FDA report on the side effects of isotretinoin for 1997-2002. there are data on 85 cases of inflammatory bowel disease, in 4 (5%) cases of which it is assumed that the connection with taking the drug is “highly probable”. In the first population-based study, which included 8189 patients, including 60 patients with acne, who received isotretinoin, it was found that the risk of developing ulcerative colitis increased by 5 times during treatment with the drug (OR = 4.36, 95% CI 1.97 – 9.66), while the risk of Crohn’s disease remains comparable to that in the general population (OR = 0.68, 95% CI 0.28–1.68) [48]. Among the risk factors, the authors indicated a daily dose of 20 mg (OR = 1.50, 95% CI 1.08-2.09) and duration of treatment for more than 2 months (OR = 5.63, 95% CI 2.10-15, 03). However, a number of studies conducted in subsequent years [52-55] found no relationship between isotretinoin intake and the development of inflammatory bowel diseases. Moreover, some authors [56] found a reduced risk of Crohn’s disease in patients receiving isotretinoin for acne.
Thus, the assumption of an association between the use of isotretinoin and the risk of developing inflammatory bowel diseases is not confirmed. However, for the final conclusion about the absence of such a dependence, an analysis of a larger number of observations is required.
Increased levels of enzymes and triglycerides. An increase in the level of triglycerides and cholesterol in the blood serum during treatment with isotretinoin is observed quite often – in 44 and 31% of patients, respectively, transaminases – somewhat less frequently (up to 11%). According to various authors [47, 48, 56], they are transient, reversible and, as a rule, are not an indication for discontinuation of treatment. As for Sotret, an increase in cholesterol levels is noted according to different authors in 13–36% and triglycerides in 16% of patients [16]. These changes, as a rule, are not significant, do not exceed the threshold of 30% of the initial values [17] and require special correction. Patients may be advised to reduce their intake of animal fats. Compliance with these recommendations by patients leads to the normalization of indicators [18].
Another common finding when examining patients treated with isotretinoin is an increase in the level of creatine phosphokinase. It is detected in 16–51% of patients [59]. A significant increase in the enzyme (more than 5000 IU / l) is observed relatively rarely (no more than 1.5% of patients). Moreover, the latter, as a rule, have a high level of physical activity, as well as myalgia [60]. It is important that the increase in creatine phosphokinase is transient and normalizes within 2 weeks with a decrease in the level of physical activity [56, 57]. In this regard, researchers recommend to study its serum level only in patients with myalgias [58].
Thus, an increase in the level of liver enzymes, according to the literature, is often clinically insignificant and transient. However, according to some authors [56, 63], it may be associated with an increased risk of liver and cardiovascular diseases. That is why it is recommended to study the serum level of enzymes before treatment, after 1 month, and then every 3 months. An increase in triglycerides and cholesterol is a more common side effect of isotretinoin and requires monitoring and sometimes correction. It is also recommended to determine the level of total cholesterol and triglycerides before, 1 month after the start of treatment and at the end of the course of therapy.
Acne exacerbation. Acne exacerbation during the initiation of isotretinoin treatment is observed in 6% of patients, and in half of them (3% of the total number) this exacerbation is clinically significant [51, 57]. Macrocomedones and large nodes are considered risk factors. In earlier studies [63], experts recommended short courses (3–6 weeks) of prednisolone at a daily dose of 0.5–1.0 mg/kg to relieve exacerbations. Currently, the main recommendation is to increase the daily dose of isotretinoin to 1.0 mg/kg.
More than 30 years of use of isotretinoin convincingly proves its high clinical efficacy in the treatment of patients with severe forms of acne. Nevertheless, the data accumulated to date demonstrate that a number of patients experience an exacerbation of the disease after a full course of treatment. Potential complications, some of which seem to be very serious (depression, inflammatory bowel disease, etc.), can also significantly limit the use of the drug in clinical practice.
The choice of a patient for whom isotretinoin therapy is indicated, taking into account the prediction of the effectiveness of the drug, the development of side effects, remains one of the topical issues of modern dermatology.