10.5826/dpc.1302a121
Introduction: Systemic isotretinoin is the most effective treatment modality in acne vulgaris; however, both patients and physicians hesitate to use it due its side effects.
Objectives: The aim of this study is to determine the prevalence of fatigue, myalgia and low back pain during systemic isotretinoin treatment; and to determine their relationship with age, gender, treatment duration, daily isotretinoin dose and isotretinoin-naiveness of the patient.
Methods: This is a cross sectional study including the acne vulgaris patients, aged between 13 to 40 years, who have at least received one month of oral isotretinoin treatment. Patients were questioned for side effects during their follow-up visits; a physical therapy and rehabilitation specialist further evaluated patients complaining of low back pain.
Results: Fatigue was reported by 4.4% of the patients, myalgia by 2.8% and low back pain by 25% of the patients; 2.2% had inflammatory and 22.8% had mechanical low back pain. None of the patients had sacroiliitis. All the side effects that were examined were found to be independent of age, gender, isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness.
Conclusions: The side effects are not as common as feared; thus, patients and physicians should not hesitate to use systemic isotretinoin in indicated cases. 
text/xml
2160-9381
2776
en
Ayşe Nilhan Atsü
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
low back pain
Skeletal Side Effects of Systemic Isotretinoin Treatment: Do They Depend on Age, Gender, Treatment Duration, Daily Dose and Isotretinoin-Naiveness?
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-04-29
2022-08-23
2023-04-29
2023-06-05
e2023121
Dermatol Pract Concept
Introduction: Systemic isotretinoin is the most effective treatment modality in acne vulgaris; however, both patients and physicians hesitate to use it due its side effects.
Objectives: The aim of this study is to determine the prevalence of fatigue, myalgia and low back pain during systemic isotretinoin treatment; and to determine their relationship with age, gender, treatment duration, daily isotretinoin dose and isotretinoin-naiveness of the patient.
Methods: This is a cross sectional study including the acne vulgaris patients, aged between 13 to 40 years, who have at least received one month of oral isotretinoin treatment. Patients were questioned for side effects during their follow-up visits; a physical therapy and rehabilitation specialist further evaluated patients complaining of low back pain.
Results: Fatigue was reported by 4.4% of the patients, myalgia by 2.8% and low back pain by 25% of the patients; 2.2% had inflammatory and 22.8% had mechanical low back pain. None of the patients had sacroiliitis. All the side effects that were examined were found to be independent of age, gender, isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness.
Conclusions: The side effects are not as common as feared; thus, patients and physicians should not hesitate to use systemic isotretinoin in indicated cases. 
Ayşe Nilhan Atsü
2023/04/29
10.5826/dpc.1302a121
e2023121
İstanbul Kent University, Department of Dermatology and Venerology, İstanbul, Turkey
2160-9381
low back pain
en
e2023121
Bauer L, Ornelas J, Elston D, Alikhan A. Isotretinoin: controversies, facts, and recommendations. Expert Rev Clin Pharmacol. 2016;9(11):1435-1442. DOI: 10.1080/17512433.2016.1213629. PMID: 27414637.
Skeletal Side Effects of Systemic Isotretinoin Treatment: Do They Depend on Age, Gender, Treatment Duration, Daily Dose and Isotretinoin-Naiveness?
https://dpcj.org/index.php/dpc/article/download/2776/2115
         Skeletal Side Effects of Systemic Isotretinoin
         Treatment: Do They Depend on Age, Gender,
             Treatment Duration, Daily Dose and
                    Isotretinoin-Naiveness?
    Defne Özkoca1, Nazlı Caf2, Nazan Nur Alacagöz Yılmaz3, Tuğba Kevser Uzunçakmak4,
                             Ayşenur Özdil5, Ayşe Nilhan Atsü6


1 Zonguldak Atatürk State Hospital, Dermatology and Venerology Clinic, Zonguldak, Turkey
2 Diyarbakır Dağkapı Military Hospital, Dermatology and Venerology Clinic, Diyarbakır, Turkey
3 Zonguldak Atatürk State Hospital, Physical Therapy and Rehabilitation Clinic, Zonguldak, Turkey
4 Şişli Memorial Hospital, Dermatology and Venerology Clinic, İstanbul, Turkey
5 İstanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Department of Public Health, İstanbul, Turkey
6 İstanbul Kent University, Department of Dermatology and Venerology, İstanbul, Turkey



Key words: acne vulgaris, fatigue, low back pain, isotretinoin, myalgia
Citation: Özkoca D, Caf N, Alacagöz Yılmaz NN, Uzunçakmak TK, Özdil A, Atsü AN. Skeletal Side Effects of Systemic Isotretinoin
Treatment: Do They Depend on Age, Gender, Treatment Duration, Daily Dose and Isotretinoin-Naiveness? Dermatol Pract Concept.
2023;13(2):e2023121. DOI: https://doi.org/10.5826/dpc.1302a121
Accepted: November 14, 2022; Published: April 2023
Copyright: ©2023 Özkoca et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Defne Özkoca, MD, Zonguldak Atatürk Devlet Hastanesi, Site Ek Binası, Bahçelievler, Zonguldak, Turkey.
Phone: 00905366561000 E-mail: defneozkoca@yahoo.com




  ABSTRACT             Introduction: Systemic isotretinoin is the most effective treatment modality in acne vulgaris; however,
                       both patients and physicians hesitate to use it due its side effects.
                       Objectives: The aim of this study is to determine the prevalence of fatigue, myalgia and low back pain
                       during systemic isotretinoin treatment; and to determine their relationship with age, gender, treatment
                       duration, daily isotretinoin dose and isotretinoin-naiveness of the patient.
                       Methods: This is a cross sectional study including the acne vulgaris patients, aged between 13 to
                       40 years, who have at least received one month of oral isotretinoin treatment. Patients were questioned
                       for side effects during their follow-up visits; a physical therapy and rehabilitation specialist further
                       evaluated patients complaining of low back pain.
                       Results: Fatigue was reported by 4.4% of the patients, myalgia by 2.8% and low back pain by 25% of
                       the patients; 2.2% had inflammatory and 22.8% had mechanical low back pain. None of the patients




Original Article | Dermatol Pract Concept. 2023;13(2):e2023121                                                                    1
                     had sacroiliitis. All the side effects that were examined were found to be independent of age, gender,
                     isotretinoin dosage (mg/kg/day), treatment duration and isotretinoin-naiveness.
                     Conclusions: The side effects are not as common as feared; thus, patients and physicians should not
                     hesitate to use systemic isotretinoin in indicated cases.



Introduction                                                      consultations. The age, gender, isotretinoin dosage (mg/kg/
                                                                  day), treatment duration (weeks) and whether the patient is
Systemic isotretinoin (13-cis retinoic acid) is the most ef-      using isotretinoin the first or the second time for acne vul-
fective treatment modality for acne vulgaris given that it is     garis were noted during the monthly consultations. The pa-
the only treatment method that targets all four of the major      tients were questioned for the presence of fatigue, myalgia
etiological factors of acne vulgaris. The US Food and Drug        or low back pain; and the patients with low back pain were
Administration have approved its use for the treatment of         referred to the physical therapy and rehabilitation outpatient
severe acne vulgaris in 1982 [1]. The common side effects of      clinic for further evaluation.
systemic isotretinoin treatment are cheilitis, xerosis, xeroph-      The physical therapy and rehabilitation specialist has
thalmia, and myalgias. Its tendency for causing depression,       evaluated the patients to determine the character of low back
and suicidal ideation still remains controversial [2]. Arthral-   pain (inflammatory or mechanical) along with performing
gia may also be experienced by the patients during systemic       physical examination of the range of motion, muscle power
isotretinoin therapy; 20% of the patients complain of either      and lordosis. Magnetic resonance imaging of the lumber ver-
myalgia or arthralgia [3]. Inflammatory low back pain is a        tebrae was performed on the patients who had inflammatory
very common side effect of systemic isotretinoin therapy;         low back pain in order to evaluate sacroiliitis.
sacroiliitis and tendinitis may also occur although much
rare. The low back pain ceases with dose reduction [4,5].         Statistical Analysis
                                                                  SPSS version 21 was used for the statistical analyses.
Objectives                                                        Mann-Whitney U test was used to determine the relation-
                                                                  ship of age, isotretinoin dosage and treatment duration to
The aim of this study is to determine the incidence of fatigue,   all of the side effects studied (fatigue, myalgia and low back
myalgia and low back pain (inflammatory or mechanical)            pain). Pearson chi-square test was used to determine the re-
in acne vulgaris patients receiving oral isotretinoin therapy;    lationship of gender to fatigue and low back pain; and of
and to determine the relationship of these side-effects to the    isotretinoin-naiveness to low back pain. Fisher exact test was
age and the gender of the patient, the isotretinoin dosing reg-   used to determine the relationship of gender to myalgia; and
imen, the duration of isotretinoin therapy and the isotreti-      of isotretinoin-naiveness to fatigue and myalgia.
noin-naiveness of the patient.
                                                                  Ethics
Methods                                                           The approval of İstanbul Kent University Ethics Committee
                                                                  was obtained before the initiation of the study (27.05.2022).
Patient Selection                                                 Informed consent was taken from all of the patients who
Acne vulgaris patients, aged between 13 to 40 years, who have     were willing to participate in this study; and the study was
at least received one month of oral isotretinoin treatment in     conducted in accordance with the Helsinki Declaration.
the dermatology outpatient clinic of Zonguldak Atatürk State
Hospital and who were willing to participate in this study
                                                                  Results
were included in this cross-sectional study. Patients with al-
ready diagnosed rheumatic diseases, musculoskeletal diseases,     Patient Characteristics and Side Effects
inflammatory bowel disease, hormonal disturbances, psychi-        A total of 180 patients were included in this study. The mean
atric comorbidities and who were using non-steroidal anti-in-     age of the patients was 20.3 years with a standard deviation
flammatory drugs regularly were excluded from this study.         of 5 years. Of all the patients, 57 (31.7%) were male and
                                                                  123 (68.3%) were female. Fatigue was reported by 8 (4.4%)
Data Acquisition                                                  of the patients, myalgia by 5 (2.8%) and low back pain by
The blood chemistry including lipids and beta-human cho-          45 (25%) of the patients. Four (2.2%) of the patients were
rionic globulin (for female patients only) of the patients        diagnosed with inflammatory low back pain by the physical
receiving oral isotretinoin were evaluated during monthly         therapy and rehabilitation specialist; and 41 (22.8%) were



2                                                                     Original Article | Dermatol Pract Concept. 2023;13(2):e2023121
diagnosed with mechanical low back pain. The mean isotreti-                 Conclusions
noin treatment duration was 9.6 weeks with a standard devi-
ation of 6.7 weeks; the mean isotretinoin dosage was 0.582                  Systemic isotretinoin therapy is known to have side effects in
mg/kg/day with a standard deviation of 0.18 mg/kg/day; and                  many organ systems, including the musculoskeletal system
144 (80%) of the patients were isotretinoin-naïve, whereas                    Table 1. Patient characteristics and side effects.
36 (20%) were using isotretinoin for the second time. Patient
                                                                                    Patient characteristics                     N=180
characteristics and side effects are summarized in Table 1.
                                                                              Age
                                                                              Mean ± SD                                         20.3 ± 5
Relationship of Side Effects to Patient                                       Median (IQR)                                    20 (17 – 22)
Characteristics                                                               Gender, N (%)
Fatigue, myalgia and low back pain were the side effects                      Male                                             57 (31.7)
that were examined in this study. All of the side effects that                Female                                          123 (68.3)
were examined were found to be independent of age, gen-                       Side Effects, N (%)
der, isotretinoin dosage (mg/kg/day), treatment duration and                  Fatigue                                           8 (4.4)
isotretinoin-naiveness. The relationships of side effects to the              Myalgia                                           5 (2.8)
                                                                              Low Back Pain                                     45 (25)
patient characteristics are summarized in Table 2.
                                                                              Character of Low Back Pain, N (%)
                                                                              Inflammatory                                      4 (2.2)
Character of the Low Back Pain                                                Mechanical                                       41 (22.8)
The patients with low back pain were further examined for                     Treatment Duration (Weeks)
the character of low back pain by the physical therapy and                    Mean ± SD                                        9.6 ± 6,7
rehabilitation specialist. Within the patients with low back                  Median (IQR)                                     8 (4 – 12)
pain, only 4 (8.9%) had inflammatory low back pain. There                     Isotretinoin Naiveness, n (%)
was no statistically significant relationship between the age                 Naive                                            144 (80)
of the patient, gender of the patient, isotretinoin dosage                    Not Naive                                         36 (20)
                                                                              Isotretinoin dosage (mg/kg/day)
(mg/kg/day), treatment duration (weeks) and isotretinoin-­
                                                                              Mean ± SD                                   0.582 ± 0.18
naiveness of the patient; and the character of low back pain.
                                                                              Median (IQR)                             0.565 (0.5 – 0.695)
Table 3 summarizes the relationship of the character of low
back pain to the patient characteristics.                                   IQR = interquartile range; SD = standard deviation.


                              Table 2. Relationship of side effects to patient characteristics.
                                                FATIGUE                             MYALGIA                        LOW BACK PAIN
                                         Present             Absent           Present              Absent        Present              Absent
    Mean Age ±,SD                       19.8 ± 2           20.3 ± 5.1         21.6 ± 2         20.3 ± 5.1       19.3 ± 4.2         20.6 ± 5.3
    Median (Range) in years            20 (18 -21)        20 (17 – 22)     21 (20 – 23,5)     20 (17 – 22)     19 (16 – 21)       20 (17 – 22)
    P                                              0.906a                               0.162 a                              0.1 a
    Gender
    Male                                  2 (25)            55 (32)            0 (0)              57 (32.6)     14 (31.1)            43 (31.9)
    Female                                6 (75)            117 (68)          5 (100)             118 (67.4)    31 (68.9)            92 (68.1)
    P                                              0.678 b                              0.181 c                            0.926 b
    Isotretinoin dosage (mg/           0.625 ± 0.2         0.58 ± 0.2       0.582 ± 0.2       0.582 ± 0.2      0.599 ± 0.2        0.576 ± 0.2
    kg/day)                               0.58                0.57              0.6               0.56             0.6                0.5
                                      (0.46 – 0.73)       (0.5 – 0.68)      (0.4 – 0.76)      (0.5 – 0.68)     (0.5 – 0.69)       (0.44 – 0.7)
    P                                              0.608 a                              0.951 a                             0.23 a
    Treatment duration (weeks)           9.9 ±8.7          9.6 ± 6.7        13.6 ± 9.2            9.5 ± 6.7     8.9 ± 6.7            9.8 ± 6.8
                                        4 (4 – 19)         8 (4 – 12)       16 (4 – 22)           8 (4 – 12)    8 (4 – 12)           8 (4 – 12)
    P                                              0.583 a                              0.324 a                            0.391 a
    Isotretinoin-naiveness
    Naive                                7 (87.5)         137 (79.7)          5 (100)             139 (79.4)    38 (84.4)            106 (78.5)
    Not Naive                            1 (12.5)          35 (20.3)           0 (0)               36 (20.6)     7 (15.6)             29 (21.5)
    P                                                1c                                 0,585 c                            0,389 b
a
    Mann Whitney U test; 2Pearson chi-squared test; c Fisher exact test.



Original Article | Dermatol Pract Concept. 2023;13(2):e2023121                                                                                    3
                Table 3. Relationship of the character of low back pain to patient characteristics.
                                                                  Character of low back pain
                                                      Inflammatory (N = 4)                 Mechanical (N = 41)                P
    Age                                                     22.8 ± 9.7                            19 ± 3.4
                                                                                                                           0.631a
                                                          19 (16.3 – 33)                        19 (16 – 21)
    Gender
    Male                                                     3 (21.4)                            11 (78.6)
                                                                                                                           0.082 b
    Female                                                    1 (3.2)                            30 (96.8)
    Isotretinoin dose (mg/kg/day)                          0.593 ± 0.1                          0.599 ± 0.2
                                                                                                                           0.967 a
                                                       0.585 (0.5 – 0.693)                   0.6 (0.5 – 0.695)
    Treatment Duration (weeks)                              6.3 ± 6.7                            9.2 ± 6.7
                                                                                                                           0.234 a
                                                          4 (1.75 – 13)                          8 (4 – 12)
    Isotretinoin Naiveness
    Naive                                                     3 (7.9)                            35 (92.1)
                                                                                                                           0.505 b
    Not naive                                                1 (14.3)                             6 (85.7)
a
    Mann Whitney U test; b Fisher exact test.


[6,7]. Low back pain has been reported to be a common            average doses prescribed in the literature: 0.6 mg/kg/day,
side effect of systemic isotretinoin therapy in the literature   0.55 mg/kg/day and 0.53 mg/kg/day[4,11,12]. There was no
[5,8]. Low back pain can be categorized into two groups:         relationship between the daily dose of systemic isotretinoin
inflammatory, and mechanical low back pain [9]. Approxi-         treatment and the prevalence of the side effects. In alignment
mately 16 percent of the patients receiving systemic isotreti-   with this result, Karaosmanoğlu and Mülkoğlu also con-
noin therapy develop musculoskeletal side effects including      cluded that there is no correlation between the cumulative
myalgia, arthralgia and low back pain. Although rare, sac-       dosage of isotretinoin and the severity of low back pain [8].
roiliitis can also be observed in patients receiving systemic       Previously in the literature, Acar et al reported that low
isotretinoin therapy, which can be classified as a cause of      back pain was more common in male patients and pain
inflammatory low back pain [10].                                 severity increased with increasing age [4]. In contrast, this
      In this study, 45 patients (25%) have reported low back    study revealed that the side effects of systemic isotretinoin
pain; of which 4 (2.2%) have been diagnosed with inflam-         treatment are independent of age and gender. Our study also
matory low back pain and 41 (22.8%) have been diagnosed          revealed that side effects of systemic isotretinoin are inde-
with mechanical low back pain by the physical therapy and        pendent of the treatment duration and isotretinoin naiveness
rehabilitation specialist. None of the patients were diag-       of the patient.
nosed with sacroiliitis. Previous studies on this subject have      Although systemic isotretinoin treatment is the most ef-
reported a prevalence of low back pain, among patients re-       fective treatment modality for acne vulgaris, both patients
ceiving systemic isotretinoin treatment, of 78.7%, 46.9%,        and prescribing physicians express fear about the side ef-
49.3% and 10.4% [4,5,11,12]. Among the patients with             fects [13]. Compared to the previous literature, we report a
                                                1
low back pain, 60.3%, 54.7% and 44% had inflamma-                lower prevalence of fatigue and musculoskeletal side effects
tory low back pain [4,11,12]. We report a lower prevalence       (namely myalgia and low back pain) and no case of sacro-
of low back pain and inflammatory low back pain due to           iliitis in our patient population, which supports the use of
systemic isotretinoin use compared to most of the studies in     systemic isotretinoin in indicated cases of acne vulgaris. Fur-
the literature.                                                  thermore, we also report that side effects of isotretinoin treat-
      In our patient population, the prevalence of fatigue       ment are independent of age, gender, daily isotretinoin dose,
was 4.4% and of myalgia was 2.8%. In the literature, fa-         treatment duration and isotretinoin naiveness of the patient.
tigue has been reported to have a prevalence of 54% and of          Fatigue, myalgia and low back pain can be observed
50.7% [11,12]; myalgia has been reported to have a preva-        during systemic isotretinoin treatment. These side effects
lence of 46.9% and 42.5% [11,12] Again, we report a lower        are independent of the patient age, gender, daily systemic
prevalence of fatigue and myalgia due to systemic isotreti-      isotretinoin dosage, treatment duration and isotretinoin-na-
noin therapy compared to the literature.                         iveness of the patient. The side effects are not that common;
      The average daily dose of systemic isotretinoin pre-       thus, patients and physicians should not hesitate to use sys-
scribed in our study (0.582 mg/kg/day) is similar to the         temic isotretinoin in indicated cases.




4                                                                       Original Article | Dermatol Pract Concept. 2023;13(2):e2023121
References                                                                      Int J Environ Res Public Health. 2022;19(11):6463. DOI:
                                                                                10.3390/ijerph19116463.         PMID:      35682048.      PMCID:
 1. Layton A. The use of isotretinoin in acne. Dermatoendocri-                  PMC9180136.
    nol. 2009;1(3):162-169. DOI: 10.4161/derm.1.3.9364. PMID:              8.   Karaosmanoğlu N, Mülkoğlu C. Analysis of musculoskele-
    20436884. PMCID: PMC2835909.                                                tal side effects of oral Isotretinoin treatment: a cross-sectional
 2. Leyden JJ, Del Rosso JQ, Baum EW. The use of isotretinoin in                study. BMC Musculoskelet Disord. 2020;21(1):631. DOI:
    the treatment of acne vulgaris: clinical considerations and future          10.1186/s12891-020-03656-w. PMID: 32977793. PMCID:
    directions. J Clin Aesthet Dermatol. 2014;7(2):S3-S21. PMID:                PMC7519514.
    24688620. PMCID: PMC3970835.                                           9.   Ledford C. Spine Conditions: Mechanical and Inflammatory
 3. Kaplan G, Haettich B. Rheumatological symptoms due to ret-                  Low Back Pain. FP Essent. 2017;461:15-20. PMID: 29019640.
    inoids. Baillieres Clin Rheumatol. 1991;5(1):77–97. DOI:              10.   Aydog E, Ozturk G, Comert A, Tasdelen N, Akin O, Kulcu
    10.1016/s0950-3579(05)80297-3. PMID: 2070429.                               DG. Sacroiliitis during isotretinoin treatment: Causal asso-
 4. Acar EM, Şaş S, Aybala Koçak F. Evaluation of musculoskele-                 ciation or coincidence? North Clin Istanb. 2018;6(1):75-80.
    tal adverse effects in patients on systemic isotretinoin treatment:         DOI: 10.14744/nci.2018.93798. PMID: 31180372. PMCID:
    A cross-sectional study. Arch Rheumatol. 2022;37(2):223-229.                PMC6526982.
    DOI: 10.46497/ArchRheumatol.2022.8645. PMID: 36017204.                11.   Taheri A, Sabouhi S, Farazmand F. Incidence of low back pain
    PMCID: PMC9377170.                                                          and sacroiliitis in military families with acne vulgaris under
 5. Civelek U, Baykal L, Aksu Arica D, Capkin E, Yayli S. Isotreti-             isotretinoin therapy. Am J Clin Exp Immunol. 2020;9(2):6-9.
    noin-induced inflammatory back pain and sacroiliitis in patients            PMID: 32419981. PMCID: PMC7218680.
    with moderate to severe acne vulgaris. J Cosmet Dermatol.             12.   Baykal Selçuk L, Aksu Arıca D, Baykal Şahin H, Yaylı, ­Bahadır S.
    2022;21(10):4846-4851. DOI: 10.1111/jocd.14807. PMID:                       The prevalence of sacroiliitis in patients with acne vulgaris using
    35092165.                                                                   isotretinoin.. Cutan Ocul Toxicol. 2017;36(2):176-179. DOI:
 6. Agarwal US, Besarwal RK, Bhola K. Oral isotretinoin in different            10.1080/15569527.2016.1237521. PMID: 27764978.
    dose regimens for acne vulgaris: A randomized comparative trial.      13.   Bauer L, Ornelas J, Elston D, Alikhan A. Isotreti-
    Indian J Dermatol Venereol Leprol. 2011;77(6):688-694. DOI:                 noin: controversies, facts, and recommendations. Ex-
    10.4103/0378-6323.86482. PMID: 22016276.                                    pert Rev Clin Pharmacol. 2016;9(11):1435-1442. DOI:
 7. Kapała J, Lewandowska J, Placek W, Owczarczyk-Saczonek A. Ad-               10.1080/17512433.2016.1213629. PMID: 27414637.
    verse Events in Isotretinoin Therapy: A Single-Arm Meta-Analysis.




Original Article | Dermatol Pract Concept. 2023;13(2):e2023121                                                                                  5
