Pharmacological Management and Potentially Inappropriate Prescriptions for Patients with Acne

J Clin Aesthet Dermatol. 2024;17(6):43–49.

by Luis Fernando Valladales-Restrepo, MD, MSc; Laura Sofia Serna-Echeverri, MD; Juan Darío Franco-Ramírez, MD; Katherine Vargas-Diaz, MD; Nathalia Marcela Peña-Verjan, MD; and Jorge Enrique Machado-Alba, MD, PhD

Drs. Valladales-Restrepo, Serna-Echeverri, Franco-Ramírez, and Machado-Alba are with the Grupo de Investigación en Farmacoepidemiologia y Farmacovigilancia at the Universidad Tecnológica de Pereira-Audifarma SA in Pereira, Colombia. Dr. Valladales-Restrepo is additionally with the Grupo de investigación Biomedicina of the Faculty of Medicine at the Fundación Universitaria Autonoma de las Americas in Pereira, Colombia. Drs. Vargas-Diaz and Peña-Verjan are with Semillero de Investigación en Farmacología Geriátrica, and the Grupo de investigación Biomedicina of the Faculty of Medicine at the Fundación Universitaria Autonoma de las Americas in Pereira, Colombia.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors have no conflicts of interest relevant to the content of this article.

ABSTRACT: Objective. Acne is a chronic inflammatory disease that involves the pilosebaceous follicle. Its pharmacological treatment involves topical and systemic medications, but a heterogeneous group of drugs may exacerbate or induce skin lesions. The aim of this study was to identify the pharmacological management and medications related to the exacerbation of skin lesions in patients diagnosed with acne.

Methods. This was a cross-sectional study that identified the outpatient medication prescription patterns of patients with acne from a dispensing database of 8.5 million members of the Colombian Health System. Sociodemographic and pharmacological variables and the identification of prescriptions that were potentially inappropriate due to the risk of worsening acne were considered.

Results. A total of 21,604 patients with acne were identified. Median age was 20.8 years (interquartile range: 17.3–27.3 years), and 60.7 percent were female. Treatment mainly involved antibiotics (79.9% of patients), especially doxycycline (66.0%), and retinoids (55.7%). A total of 17.2 percent of patients had potentially inappropriate prescriptions, predominantly progestogens with androgenic properties (8.9%). Female patients (odds ratio [OR]: 3.55; 95% confidence interval [CI]:3.24–3.90) and patients with pathologies such as systemic lupus erythematosus (OR: 18.61; 95% CI: 7.23–47.93) and rheumatoid arthritis (OR: 10.80; 95% CI: 5.02–23.23) were more likely to receive inappropriate prescriptions, and the risk increased with each year of life (OR: 1.02; 95% CI: 1.02–1.03).

Limitations. Access to medical records was not obtained to verify clinical characteristics of acne.

Conclusion. Patients with acne are excessively treated with systemic antibiotics, counter to clinical practice guidelines. Approximately one-fifth of these patients received some potentially inappropriate medication that could exacerbate their skin lesions.

Keywords: Acne vulgaris, antibacterial agents, retinoids, contraceptives, oral contraceptives, combined contraceptives, pharmacoepidemiology

Introduction

Acne is a very common inflammatory dermatological disease in adolescents and young adults.¹ It is estimated that between 80 and 90 percent of individuals in this age group have the disease, and in up to 50 percent, it may persist into adulthood. Due to its prolonged course and because periods of remission and relapse are common, it should be considered a chronic disease.^2,3 It has a significant impact on the quality of life of patients,⁴ is associated physical and mental health problems, and can affect social relationships.^4–6 It is estimated to affect 9.4 percent of the world population, which makes it the eighth most prevalent morbidity worldwide.⁷ In Colombia, its prevalence is 17.3 percent; it affects mainly women (11.1%) and is the most common dermatological disease in the country.⁸

Treatment is based on topical and systemic drugs that act on some of the pathophysiological factors responsible for acne, such as keratinization disorder, sebaceous hypersecretion, proliferation of Propionibacterium acnes, or in situ inflammatory activity.² Several groups of medications are used for treatment, including retinoids, combined hormonal contraceptives, and spironolactone, among others.^1,2,9 However, to be effective, they must be used regularly,⁴ and the management strategy depends on disease severity.^1,2,9

Various medications are associated with triggering or exacerbating skin lesions in patients with acne,^10–12 and they have been classified into three categories according to their ability to induce acne: drugs with an unquestionable relationship, which include corticosteroids, androgens, chloroquine, isoniazid, and lithium, among others; drugs with a considerable causal relationship but with insufficient evidence, which include cyclosporine, vitamin B12, barbiturates, azathioprine, quinidine, tricyclic antidepressants, and tacrolimus, among others; and medications that are occasionally reported to have an association with acne, including vitamins B1 and B6, propylthiouracil, voriconazole, rifampicin, and ethambutol, among others.¹⁰ The skin lesions resulting from these drugs are usually refractory to conventional acne therapy but disappear with discontinuation of the inducer drug.¹¹ However, when the drug must be continued, addressing adverse reactions with conventional treatment for acne vulgaris is recommended.¹⁰

The Colombian Health System offers universal coverage to the entire population through two regimens: the contributory system, which is paid by workers and employers, and a state-subsidized system whose benefit plan includes some drugs used for the treatment of acne and a large number of medications that may be associated with increased acne. The objective of this study was to determine pharmacological management and identify the frequency of potentially inappropriate prescriptions for patients diagnosed with acne.

Methods

An observational, cross-sectional study was conducted to determine the prescription patterns of medications used to treat patients diagnosed with acne and identify potentially inappropriate prescriptions used in these patients. Data were taken from a database of dispensing drugs that collects the information from approximately 8.5 million people affiliated with the Colombian Health System covered by six health insurance companies. This corresponds to approximately 30 percent of the population actively affiliated with the contributory or paid regimen and six percent of those actively affiliated with state-subsidized regimen, comprising 17.3 percent of the total Colombian population.

Patients were identified based on the International Classification of Diseases (ICD-10) codes consistent with an acne diagnosis (L700–L705, L708, L709, L730). All prescriptions received by patients between November 1, 2019, and October 31, 2020, were analyzed. Patients aged 12 years or older of male or female sex who were treated at an outpatient clinic and who had received some medication for the management of acne were selected. From the medication consumption information for the affiliated population, which was systematically obtained from the dispensing company (Audifarma SA), a database was designed that allowed the following groups of patient variables to be collected:

1. Sociodemographic information. Sex, age (adolescents: 12–25 years; adults: >25 years), city of dispensation, and health system regimen affiliation (contributory or state-subsidized).
2. Comorbidities. The main cardiovascular, endocrine, rheumatic, urological, kidney, psychiatric, neurological, digestive, respiratory, and neoplastic diseases were identified from the reported ICD-10 diagnostic codes.
3. Medications for the treatment of acne.^1,2,9 Retinoids. Topical (tretinoin, adapalene, tazarotene, isotretinoin, and trifarotene [not available]; and oral (isotretinoin) Antimicrobials. Topical (benzoyl peroxide, clindamycin, erythromycin, dapsone, and minocycline [not available]); Oral (tetracycline, doxycycline, minocycline, erythromycin, trimethoprim/sulfamethoxazole, azithromycin, and sarecycline [not available]) Hormonal agents. Spironolactone; combined oral contraceptives (estrogens/progestogens); and progestogens with antiandrogenic effects (cyproterone, dienogest, drospirenone, and chlormadinone) Others. Azelaic acid and salicylic acid.
4. Potentially inappropriate medications.¹⁰ Drugs with an undoubted causal relationship with acne. Systemic corticosteroids; androgens (anabolic steroids, testosterone); progestogens (levonorgestrel, etonogestrel, norethisterone, medroxyprogesterone); lithium; isoniazid; halogenated derivatives (iodides, bromides); antimalarials (chloroquine); antiepileptics (phenytoin); corticotropin; and epidermal growth factor receptor (EGFR) inhibitors (gefitinib, erlotinib, cetuximab). Drugs with a considerable causal relationship with acne but with insufficient data. Cyclosporin A; vitamin B6; vitamin B12; vitamin D2; barbiturates (phenobarbital); disulfiram; azathioprine; quinidine; infliximab; adalimumab; certolizumab; etanercept; and tricyclic antidepressants (amitriptyline, imipramine, nortriptyline). Drugs occasionally related to acne. Vitamin B1; propylthiouracil; sirolimus; voriconazole; dactinomycin; rifampicin; and ethambutol

The protocol was approved by the Bioethics Committee of the Technological University of Pereira in the category of risk-free research (endorsement code: 04-191020). The ethical principles established by the Declaration of Helsinki were respected.

Statistical analysis. The data were analyzed with the SPSS Statistics statistical package, version 26.0 for Windows (IBM; US). A descriptive analysis was performed using frequencies and proportions for the qualitative variables and measures of central tendency and dispersion for the quantitative variables, depending on their parametric behavior, which was established using the Kolmogorov-Smirnov test. Quantitative variables were compared using student’s t-test or Mann–Whitney U test; categorical variables were compared using Chi-squared or Fisher’s exact test. A multivariate binary logistic regression model was developed that included the associated variables determined in the bivariate analyses and those with sufficient plausibility or reported association after adjustment to suggest an association with potentially inappropriate prescriptions. A level of statistical significance of p less than 0.05 was determined.

Results

A total of 21,604 patients with a diagnosis of acne in 150 different cities were identified. A total of 60.7 percent (n=13,120) were female, and the median age was 20.8 years (interquartile range: 17.3–27.3 years; range: 12.0–92.5 years). A total of 94.3 percent (n=20,379) of the patients were affiliated with the contributory regimen, and 5.7 percent (n=1,225) were affiliated with the state-subsidized regime. Acne in adolescents (n=15,367; 71.1%) predominated over acne in adults (n=6,237; 28.9%). According to the ICD-10 codes, the most common type was acne not specified (n=12,205; 56.5%), followed by acne vulgaris (n=7,961; 36.8%), acne conglobata (n=1,037; 4.8%), acne necrotica (varioliformis) (n=181; 0.8%), keloid acne (n=117; 0.5%), acne excoriée (n=54; 0.2%), tropical acne (n=33; 0.2%), and childhood acne (n=16; 0.1%).

Pharmacological treatment of acne. Most of the patients with acne received management with antimicrobials (n=17,269; 79.9%), predominantly oral forms (n=17,073; 79.0%); the majority of the prescriptions were tetracyclines (n=15,582; 72.1%), followed by trimethoprim/sulfamethoxazole (n=1,886; 8.7%) and macrolides (n=428; 2.0%). The second most used pharmacological group was retinoids (n=12,023; 55.7%), mainly for topical use (n=10,648; 49.3%). Hormonal agents were dispensed for three percent of patients (n=648), with spironolactone prescribed for 2.6 percent (n=558) of them. Table 1 shows the oral and topical medications used in the management of acne.

A total of 59.6 percent (n=12,874) of the patients were prescribed one acne medication, 35.7 percent (n=7,713) were prescribed two, and 4.7 percent (n=1,017) were prescribed three or more. A total of 87.2 percent (n=18,835) of patients received one of the following treatment regimens: oral doxycycline (n=7,066; 32.7%), oral doxycycline and topical tretinoin (n=5,592; 25.9%), topical tretinoin (n=2,825; 13.1%), oral isotretinoin (n=1,142; 5.3%), oral tetracycline (n=737; 3.4%), oral trimethoprim/sulfamethoxazole (n=701; 3.2%), oral trimethoprim/sulfamethoxazole and topical tretinoin (n=404; 1.9%), and oral tetracycline and topical tretinoin (n=368; 1.7%).

Potentially inappropriate prescriptions for acne. A total of 17.2 percent (n=3,723) of all patients received a potentially inappropriate prescription; 13.9 percent (n=3,016) received one such prescription, and 3.3 percent (n=707) received two or more. The most used group of medications was progestogens with androgenic properties (n=1,921; 8.9%), particularly ethinyl estradiol associated with levonorgestrel (n=1,270; 5.9%) and estradiol valerate associated with norethisterone (n=466; 2.2%). The second most used pharmacological group was systemic corticosteroids (n=1,733; 8.0%), of which dexamethasone was predominant (n=1,051; 4.9%). Table 2 shows the potentially inappropriate prescriptions used for patients diagnosed with acne.

Comorbidities. A total of 21.3 percent (n=4,602) of patients with acne had some chronic pathology, predominantly cardiovascular (n=2,293; 10.6%), endocrine (n=1,187; 5.5%), neurological (n=722; 3.3%), digestive (n=581; 2.7%), psychiatric (n=567; 2.6%), rheumatic (n=267; 1.2%), or respiratory conditions (n=223; 1.0%). The 10 most common comorbidities were high blood pressure (n=2,271; 10.5%), hypothyroidism (n=575; 2.7%), migraine (n=507; 2.3%), chronic gastritis (n=452; 2.1%), anxiety disorders (n=350; 1.6%), diabetes mellitus (n=350; 1.6%), dyslipidemia (n=203; 0.9%), asthma (n=187; 0.9%), depressive disorders (n=184; 0.9%), and epilepsy (n=140; 0.6%).

Comparison of adolescent and adult acne. Statistically significant differences in some variables were found between adolescent and adult acne. There was a predominance of female patients among those with adult acne, and comorbidities were more frequent in this group. Regarding pharmacological management, topical therapy predominated in patients with adolescent acne, while oral therapy was predominant for those with adult acne. No differences in the general use of antibiotics were identified. A greater proportion of potentially inappropriate prescriptions was found among patients with adult acne (Table 3).

Multivariate analysis. The binary logistic regression showed that female sex; increasing age; residing in the cities of Cali, Medellín, or Manizales; and chronic comorbidities, such as systemic lupus erythematosus, rheumatoid arthritis, bronchial asthma, migraine, bipolar affective disorder, high blood pressure, depression, and anxiety, increased the probability of receiving potentially inappropriate medications, while living in Bogotá or Cartagena reduced this risk (Table 4).

Discussion

This study determined the pharmacological treatments prescribed for patients diagnosed with acne and identified potentially inappropriate prescriptions that can be associated with the exacerbation of dermatological lesions in a group of patients affiliated with the Colombian Health System. These findings can aid healthcare, academic, and scientific personnel in decision-making regarding pharmacological treatment and the risks faced by their patients.

The average age of the patients with acne was similar to that found in other studies (19.8–23.7 years),^13,14 and there was a predominance of women, as identified in other studies (65.4–80.0%);^13,15,16 however, in other countries, such as India, a higher proportion of men with acne was described.¹⁴ In addition, acne in adolescents predominated over acne in adults, which was also evident in Italy (58.7% vs. 41.3%, respectively),¹⁵ India (69.8% vs. 30.2%, respectively),¹⁷ and China (74.3% vs. 25.7%, respectively).¹⁸

Systemic antibiotics were prescribed for most patients (79.0%), in contrast with findings in India, where they were used for only 15.1 percent of patients with acne,¹⁷ and in the United Kingdom, where their use was documented in 45.3 percent of cases.⁴ It should be noted that according to clinical practice guidelines, the use of systemic antibiotics is indicated for the management of moderate and severe acne and forms of inflammatory acne that are refractory to topical management.^1,2,9 Within this therapeutic group, tetracyclines, especially doxycycline and minocycline, are the medications most frequently recommended for the management of patients with acne,^2,9 which was evidenced in both this study and other epidemiological investigations.^4,17 No statistically significant differences in the prescription of systemic antibiotics were found between adolescents and adults with acne, as was also documented in Singapore.¹⁹

It is likely that many of the prescriptions of systemic antibiotics for acne were inadequate since, according to a study conducted in several Latin American countries, Spain, and Portugal and another conducted in China, mild acne is the most common form of acne (47.8–68.4% of cases),^16,18 and systemic antimicrobial therapy is not indicated for mild acne.^1,9 The methodological design of this study did not allow us to characterize the severity of the pathology and thus failed to reliably establish the appropriateness of antibiotic therapy.

Among topical medications, tretinoin was the most used, consistent with what has been documented in other studies.^20,21 This treatment is indicated for the maintenance treatment of acne and can be used as monotherapy (mainly for comedones) or in combination with topical or oral antibiotics in patients with inflammatory lesions.^1,2 In addition, we found that the use of topical medications was significantly predominant in patients with adolescent acne, probably because younger patients tend to have less severe acne.²² For example, Zahra et al²³ documented that patients over 17 years of age had more than double the risk of developing severe acne (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.5–3.1) and therefore more frequently required systemic therapies.

Potentially inappropriate prescriptions were documented in almost one-fifth of all patients with acne. No pharmacoepidemiological studies were found for comparison purposes. However, it has been documented that various drugs can be associated with skin lesions, including androgens, some progestins, corticosteroids, and antimalarials, among others.^10–12 In this analysis, 8.9 percent of all patients (14.6% of all women) received some progestogen with androgenic properties (levonorgestrel, norgestrel, and norethisterone, among others), which are included in the Pediatrics: Omission of Prescriptions and Inappropriate Prescriptions (POPI) criteria as inadequate prescriptions for patients with acne²⁴ that should be avoided.^24,25 The use of these medications is frequent, as evidenced in a study of Australian women in which the prescription of hormonal contraceptives containing levonorgestrel or norethisterone predominated (67.1%),²⁶ which is consistent with the findings of this report.

Systemic corticosteroids were the second most frequently prescribed pharmacological group among the potentially inappropriate prescriptions. This finding is consistent with those published by Pathak et al²⁷ in a study conducted in India in which corticosteroids were prescribed for 13 percent of patients with dermatological pathologies, including those diagnosed with acne. However, it is important to note that on some occasions, prednisolone is recommended by clinical practice guidelines for the management of local and systemic manifestations of acne fulminans induced or not induced by isotretinoin.^9,28 In such circumstances, this prescription would not be considered potentially inappropriate, but this condition occurs very rarely, with less than 200 cases reported in the literature.²⁸ Therefore, in this study, corticosteroids were considered potentially inappropriate medications. A limitation of the study was the inability to identify patients who may have had this indication, since acne fulminans is not included among the ICD-10 codes.

Age, sex, city of prescription, and the course of some pathologies were associated with an increased probability of potentially inappropriate prescriptions, as has been evidenced in pharmacoepidemiological studies of other clinical conditions,^­ such as erectile dysfunction,²⁹ psoriasis,³⁰ and constipation.³¹ Women have a higher risk of receiving these prescriptions because they are most often the users of medications that contain progestogens with androgenic properties;²⁶ in addition, since rheumatic pathologies are most frequent in women,³² women are more often exposed to medications such as corticosteroids and antirheumatics, which are widely used in these comorbid conditions.³³ The rheumatic pathologies that were most associated with potentially inappropriate prescriptions in patients with acne were systemic lupus erythematosus and rheumatoid arthritis, which are very commonly treated with prednisolone, deflazacort, chloroquine, azathioprine and cyclosporine, among others, which are recommended in the clinical practice guidelines for the management of these conditions.^34,35 On the other hand, variations in the dispensing of medications among cities depend on factors such as where the physician was trained and the academic training they received, the availability of the medication, and the local epidemiology of the different pathologies.

Limitations. Some limitations in the interpretation of the results are recognized. Access to medical records was not obtained to verify the clinical characteristics of acne, the type of acne, its severity, the number of lesions, and the extent of the pathology; similarly, medications prescribed outside the health system and those that are not delivered by the dispensing company were unknown. In addition, it was not possible to establish whether prednisolone was prescribed for the management of acne fulminans, in which case it would not be potentially inappropriate. Finally, only the potential risk of triggering skin reactions was considered with the use of this group of drugs; therefore, it is necessary to develop studies of possible causality. However, the study includes a significant number of patients distributed throughout most of the national territory and covered by both the contributory and state-subsidized regimes.

Conclusion

With these findings, we can conclude that some patients with acne are likely excessively treated with systemic antibiotics against clinical practice guidelines. Approximately one-fifth of patients receive some potentially inappropriate medication that could exacerbate their skin lesions; some of these medications, such as corticosteroids, immunosuppressants, or rheumatic disease modifying drugs, cannot be withdrawn in patients with rheumatologic pathologies, but androgenic progestogens should be avoided in favor of those with antiandrogenic properties.

Acknowledgements

We thank Soffy Claritza López Lucero at Audifarma SA for her work in obtaining the database.

Author Contributions

JEMA participated in the drafting, data collection, data analysis, description of results, discussion, critical revision of the article, and evaluation of the final version of the manuscript. LFVR participated in the drafting, data collection, data analysis, description of results, and discussion of the article. LSSE participated in the drafting, description of results, and discussion of the article. JDFR participated in the drafting, description of results, and discussion of the article. KVD participated in the drafting, description of results, and discussion of the article. NMPV participated in the drafting, description of results, and discussion of the article.

Availability of data and materials

Data repository: dx.doi.org/10.17504/protocols.io.bu2bnyan

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