1.1. Objectives

The aim of the present study is to analyze the relationship between tolerance of ISO therapy and lifestyle assessed by physical activity, diet, body mass index (BMI), and smoking.

2.1. Study Design

A retrospective cohort study was conducted at the Chair and Department of Dermatology, Sexually Transmitted Diseases, and Clinical Immunology Collegium Medicum University of Warmia and Mazury in Olsztyn in Poland. The database was created using an anonymous online survey distributed using Google Forms as a tool and by doctors at our clinic and Facebook as the platform. We utilized collected information regarding adult patients diagnosed with acne vulgaris and treated with systemic ISO. The research included both patients undergoing ISO therapy (at least 30 days after the start of the treatment) and those who completed the treatment. Each patient submitted their informed consent to participate in the trial, and our institution also granted its approval. Participation was voluntary, and participants did not receive financial remuneration for participation. Due to the study design, it was not formally supervised by a University Bioethics Committee in line with its policy.

2.2. Outcomes Measurement

The following information was collected: patient’s biological sex, chronological age, body weight, height, education degree, domicile size, income, smoking status, and brand of administered ISO. According to previous systematic review, AEs were categorized into nine classes and 41 subclasses: whole skin changes (skin dryness, skin fragility, erythemal changes, sunburn, hypohidrosis, mucosal dryness, hair changes, hand changes, skin atrophy, and acne flare-up), ophthalmic changes (eye dryness or irritation, eye pain, vision changes, and conjunctival changes), nasopharyngeal changes (nasal dryness, nasopharyngitis, upper respiratory tract infections, epistaxis, and cough), oral changes (lips dryness, cheilitis, mouth dryness and sore, and excessive thirst), mood and neurological changes (hearing changes, headaches, mood swings, decreased appetite, increased appetite, fatigue, and tiredness), musculoskeletal changes (back pain, arthralgia, and musculoskeletal discomfort), gastrointestinal changes (gastrointestinal disorders and abdominal pain), infections (increased incidence of infections, herpes simplex symptoms, and fever), and others (Stevens–Johnson syndrome, morbilliform eruption, pyogenic granuloma, and menstrual cycle disorders) (Figure 1) [13].

The occurrence and severity of AEs were assessed using a five-point scale: no symptoms, mild symptoms, moderate symptoms, severe symptoms, and very severe symptoms. As a result of the small groups, the authors decided to combine some of the responses to establish a three-point scale of severity of AEs: none, low severity, and high severity.

Smoking status separated patients into two groups: smokers (including current smokers and ex-smokers) and nonsmokers (containing: never smokers, nondaily smokers, occasional, and social smokers). BMI was estimated according to a standard formula, and patients were divided into two groups: normal weight (18.5–24.9 kg/m²) and overweight (≥25 kg/m²). Respondents also completed two questionnaires: the PREDIMED validated 14-item Mediterranean Diet Adherence Questionnaire and the World Health Organization (WHO) Global Physical Activity Questionnaire (GPAQ) [14, 15]. Patients were separated into two groups based on the 14-item score: those who adhere to the Mediterranean diet (MD group) and those who do not (non-MD group), with five points or less. The GPAQ classified patients into two categories: active and inactive, with a cut-off of 600 metabolic equivalents-minutes per week (MET-min/week). Considering the smoking status, BMI, physical activity, and compliance with the Mediterranean diet, respondents were divided into two groups: those who followed healthy habits (a healthy lifestyle group) and those who did not (unhealthy lifestyle). The patient in the healthy lifestyle group demonstrates more healthy than hazardous patterns (>2) (Figure 2).

2.3. Statistical Analysis

Using descriptive statistics, the database was analyzed. All calculations were preceded by the Shapiro–Wilk and Levene tests. To compare the values of the same parameter between the groups, the t-Student test for independent groups or the Mann–Whitney U test (parametric data) and the chi-square test (nonparametric data) were used. A P value <0.05 was considered significant. The analysis was performed using Statistica (data analysis software system), version 13, https://statistica.io (accessed March 4, 2023) TIBCO Software Inc., Krakow, Poland (2017).

4.1. Physical Activity

A rare AE of ISO is rhabdomyolysis, which is usually triggered by the synergistic effect of a systemically administered drug and physical activity [17, 18]. Our finding is that there is no correlation in the exacerbation of musculoskeletal-related AEs and physical activity. This only underscores the conclusion that ISO is a safe drug. Moreover, it is worth considering that physical activity itself is a proven factor in the pathogenesis of acne. Physical activity helps maintain a proper body weight and reduces inflammation [19, 20]. Therefore, it is extremely important not to forbid patients from physical activity but rather to encourage it. The only statistically significant differences were observed in excessive thirst, which are predominated in the inactive group, and in mood swings in the active group. A potential paradigm could be that patients who exercise consume more fluids during physical activity, by which they moisten their mucous membranes, which in the case of dry mouth and lips may reduce the feeling of excessive thirst, while inactive patients experience it excessively. There does not appear to be a direct link between depression and ISO treatment. The appearance of mood disorders may be only a rare idiosyncratic side effect [21]. The positive correlation of physical activity and higher incidence and severity of mood swings for our results may be coincidental, independent of therapy, and is solely the subjective opinion of patients completing the questionnaire.

4.2. The Mediterranean Diet

The published literature, though sometimes limited in study design, shows inconsistent results on the role of diet in acne. However, a growing number of studies point to diet as a factor in acne severity. In studies, omega-3 fatty acids, low glycemic diets, and probiotics have been shown to have an effect on acne reduction, while products such as whey protein and casein-containing milk, among others, may exacerbate skin lesions by affecting insulinotropic and insulin-like growth factor 1 (IGF-1) pathways [22]. The Mediterranean diet is characterized by a low glycemic index due to its low carbohydrate content, high oil and vegetable content, and moderate fish consumption. Therefore, it provides a significant source of antioxidant vitamins and acts on the systemic IGF-1 pathway by reducing its levels. Thus, it may exhibit a protective role in acne pathogenesis [23, 24]. However, studies on the effect of diet on the occurrence and severity of AEs associated with ISO therapy are not available. According to our results, more common, among patients not adhering to the Mediterranean diet, was hyperhidrosis. Sweating plays a key role in regulating human body temperature, removing excess micronutrients, waste products of metabolic processes, and toxins from the body. Patients who did not adhere to the Mediterranean diet were more than likely simply eating unhealthy diets, which increased sweating to eliminate unnecessary metabolic waste products [25]. In addition, we observed a higher severity of the musculoskeletal discomfort among the non-MD group. Many studies have observed a reduction in musculoskeletal pain with nutritional interventions, among others, the Mediterranean diet [26]. To reduce and prevent discomfort, it would be worthwhile to educate patients about the impact of a healthy diet. In other AEs, there was no statistically significant difference between the groups.

4.3. BMI

Obesity itself has been positively linked to acne aggravation, as well as by increasing the secretion of IGF-1 in the body and affecting insulin resistance [19]. ISO therapy increases serum levels of adiponectin and leptin but does not affect ghrelin levels and thus does not change patients’ BMI or affect body weight [27]. Furthermore, ISO AEs do not increase according to patients′ BMI.

4.4. Smoking

Previous studies have proven a correspondence of acne severity in smokers and ex-smokers, which may be due to increased levels of inflammatory and proinflammatory cytokines. Controversial results show that severe acne appeared less frequently in smokers [13]. Smoking also increases the likelihood of acne recurrence after treatment, a slow response or apparent lack of response to ISO [28]. Nevertheless, smoking is a proven etiologically relevant factor in the origin of acne inversa (hidradenitis suppurativa) [29–31]. Moreover, it is well known that tobacco smoking has negative effects on the health outcomes of the musculoskeletal system [32]. The higher incidence and severity of musculoskeletal symptoms in the smoking group according to our results may not necessarily be related to the ISO intervention but to smoking per se.

4.5. Lifestyle

Considering that other AEs that occur with ISO treatment extremely rarely are attributed to individual predisposition to the rise of these syndromes rather than a direct drug-response relationship. Nevertheless, given that these events occurred more frequently in the unhealthy group, it would be worthwhile to conduct more research on a broader group of respondents, as simple lifestyle alterations could potentially prevent certain of them from manifesting. Studies confirm that menstrual cycle disorders are influenced by factors such as smoking, obesity, and stress. WHO outlines that 60% of factors related to individual health and quality of life are correlated with lifestyle [33]. Its modification should be a key measure in preventing this complication, rather than abandoning effective ISO therapy [34]. Changing lifestyle habits can be also useful in treating symptoms of dry mucous membranes. It is known that avoiding caffeine, tobacco, alcohol, and dry or hard-to-chew foods can reduce the unpleasant sensations associated with dryness [35].

4.6. Limitations

In our analysis, an important limitation was the study design. Collecting results online prevents the possibility of explaining ambiguities to the patient, and respondents with biases may select themselves into the sample. Furthermore, only patients who spoke Polish were included. The outcomes may also have been significantly affected by the small population. Hence, the results obtained may not correspond to the results if the cohort had been larger. Additionally, our study does not allow analysis of the gender effect on ISO side effects due to the significantly lower response of men to the questionnaire compared to the female population. That also limited the ability to analyze the difference in the effect of sex hormones related to acne on ISO AEs. In addition, a limitation is the lack of control for other medications taken by patients, which may have influenced AEs or targeted potential patient diseases that could have distorted the results. Due to the retrospective nature of the study design, it was impossible to establish a temporal relationship between exposure and outcome. Therefore, no dose-effect analysis was performed. As for assessing nutritional status, it is worth mentioning that BMI as an indicator is an unreliable tool.