Acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit associated
with socialisation and mental health problems, may affect more than 80% of teenagers.
Isotretinoin is widely recognised as a very effective treatment for severe acne; however,
it may cause adverse effects. To assess efficacy and safety of oral isotretinoin for
acne vulgaris. We searched the following databases up to July 2017: the Cochrane Skin
Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and LILACS. We updated
this search in March 2018, but these results have not yet been incorporated in the
review. We also searched five trial registries, checked the reference lists of retrieved
studies for further references to relevant trials, and handsearched dermatology conference
proceedings. A separate search for adverse effects of oral isotretinoin was undertaken
in MEDLINE and Embase up to September 2013. Randomised clinical trials (RCTs) of oral
isotretinoin in participants with clinically diagnosed acne compared against placebo,
any other systemic or topical active therapy, and itself in different formulation,
doses, regimens, or course duration. We used standard methodological procedures expected
by Cochrane. We included 31 RCTs, involving 3836 participants (12 to 55 years) with
mild to severe acne. There were twice as many male participants as females. Most studies
were undertaken in Asia, Europe, and North America. Outcomes were generally measured
between eight to 32 weeks (mean 19.7) of therapy. Assessed comparisons included oral
isotretinoin versus placebo or other treatments such as antibiotics. In addition,
different doses, regimens, or formulations of oral isotretinoin were assessed, as
well as oral isotretinoin with the addition of topical agents. Pharmaceutical companies
funded 12 included trials. All, except three studies, had high risk of bias in at
least one domain. Attrition bias was high in 20 trials, selective reporting bias was
high in 12 trials, and performance bias was high in 11 trials. Oral isotretinoin compared
with oral antibiotics plus topical agents These studies included participants with
moderate or severe acne and assessed outcomes immediately after 20 to 24 weeks of
treatment (short‐term). Three studies (400 participants) showed no evidence that isotretinoin
decreases trial investigator‐assessed inflammatory lesion count more than antibiotics
(RR 1.01 95% CI 0.96 to 1.06), with only one serious adverse effect found, which was
Stevens‐Johnson syndrome in the isotretinoin group (RR 3.00, 95% CI 0.12 to 72.98).
However, we are uncertain about these results as they were based on very low‐quality
evidence. Isotretinoin may slightly improve (by 15%) acne severity, assessed by physician's
global evaluation (RR 1.15, 95% CI 1.00 to 1.32; 351 participants; 2 studies), but
resulted in more less serious adverse effects (67% higher risk) (RR 1.67, 95% CI 1.42
to 1.98; 351 participants; 2 studies), such as dry lips/skin, cheilitis, vomiting,
nausea (both outcomes, low‐quality evidence). Different doses/therapeutic regimens
of oral isotretinoin For our primary efficacy outcome, we found three RCTs, but heterogeneity
precluded meta‐analysis. One study (154 participants) reported 79%, 80% and 84% decrease
in total inflammatory lesion count after 20 weeks of 0.05, 0.1, or 0.2 mg/kg/d of
oral isotretinoin for severe acne (low‐quality evidence). Another trial (150 participants,
severe acne) compared 0.1, 0.5, and 1 mg/kg/d oral isotretinoin for 20 weeks and,
respectively, 58%, 80% and 90% of participants achieved 95% decrease in total inflammatory
lesion count. One 24‐week RCT of participants with moderate acne compared isotretinoin
at (a) continuous low dose (0.25 to 0.4 mg/kg/day), (b) continuous conventional dose
(0.5 to 0.7 mg/kg/day), and (c) intermittent regimen (0.5 to 0.7 mg/kg/day, for one
week in a month). Continuous low dose (MD 3.72 lesions; 95% CI 2.13 to 5.31; 40 participants;
one study) and conventional dose (MD 3.87 lesions; 95% CI 2.31 to 5.43; 40 participants;
one study) had a greater decrease in inflammatory lesion counts compared to intermittent
treatment (all outcomes, low‐quality evidence). Fourteen RCTs (906 participants, severe
and moderate acne) reported that no serious adverse events were observed when comparing
different doses/therapeutic regimens of oral isotretinoin during treatment (from 12
to 32 weeks) or follow‐up after end of treatment (up to 48 weeks). Thirteen RCTs (858
participants) analysed frequency of less serious adverse effects, which included skin
dryness, hair loss, and itching, but heterogeneity regarding the assessment of the
outcome precluded data pooling; hence, there is uncertainty about the results (low‐
to very low‐quality evidence, where assessed). Improvement in acne severity, assessed
by physician's global evaluation, was not measured for this comparison. None of the
included RCTs reported birth defects, but oral isotretinoin is contraindicated during
pregnancy due to known teratogenic effects. Evidence was low‐quality for most assessed
outcomes. We did not find any clear evidence from RCTs that isotretinoin improves
acne severity compared with standard oral antibiotic and topical treatment when assessed
by a decrease in total inflammatory lesion count, but it may slightly improve physician‐assessed
acne severity. Only one serious adverse event was reported in the isotretinoin group,
which means we are uncertain of the risk of serious adverse effects; however, isotretinoin
may result in increased minor adverse effects. Heterogeneity in the studies comparing
different regimens, doses, or formulations of oral isotretinoin meant we were unable
to undertake meta‐analysis. Daily treatment may be more effective than treatment for
one week each month. None of the randomised studies in this comparison reported serious
adverse effects, or measured improvement in acne severity assessed by physician's
global evaluation. We are uncertain if there is a difference in number of minor adverse
effects, such as skin dryness, between doses/regimens. Evidence quality was lessened
due to imprecision and attrition bias. Further studies should ensure clearly reported
long‐ and short‐term standardised assessment of improvement in total inflammatory
lesion counts, participant‐reported outcomes, and safety. Oral isotretinoin is a well‐established
treatment for severe acne, and for acne that has not responded to oral antibiotics
plus topical agents. The clinical trial evidence for oral isotretinoin conducted around
30 years ago was low quality. Further trials are needed to evaluate different dose/regimens
of oral isotretinoin in acne of all severities. How effective and safe is a drug called
'isotretinoin', taken via tablet, for acne vulgaris? Review question How effective
and safe is isotretinoin, taken in a tablet for people with acne? We reviewed the
evidence about the effect of isotretinoin when compared either to itself at a different
dose, to placebo (an identical but inactive treatment), or to other systemic (oral
or injected medicines that work throughout the entire body) or topical (applied to
the outside of the body) therapies. Eligible participants had to have been diagnosed
with acne by a doctor. Background Acne is a persistent inflammatory disease that can
affect more than 80% of teenagers. Acne (including blackheads, whiteheads, and pimples)
mostly appears on the face, but can also appear on the back and chest. Mental health
problems, depression, and suicidal thoughts have been associated with acne. Isotretinoin,
a currently widely used therapy derived from vitamin A, transformed acne treatment.
However, it may cause adverse effects and has been associated with still uncertain
psychiatric events and inflammatory bowel disease. Study characteristics We searched
the medical literature up to July 2017 and included 31 studies, involving 3836 dermatology
outpatients worldwide. There were twice as many males than females; their ages ranged
from 12 to 55 years old. Acne severity ranged from mild to severe, although most participants
had severe acne. The pharmaceutical industry funded 12 included studies. We found
studies that compared oral isotretinoin versus placebo or other treatments such as
antibiotics. In addition, different doses, regimens (course of medical treatment),
or formulations of oral isotretinoin were assessed, as well as oral isotretinoin with
the addition of topical agents. Key results Three studies compared oral isotretinoin
versus any oral antibiotic plus any topical agent given to participants with moderate
or severe acne for between 20 to 24 weeks. Their outcomes were measured straight after
treatment stopped. There was no difference between therapies in decreasing the number
of inflamed lesions (an area of an organ or tissue that has been damaged by disease
or trauma). In one participant, isotretinoin led to the development of Stevens‐Johnson
syndrome (a serious disease where skin reacts severely, often in response to medication);
there were no serious side effects in the other group. However, we are uncertain of
these results because they were based on very low‐quality evidence. When assessed
by a doctor, the severity of acne may be slightly improved by isotretinoin, but it
may cause more side effects such as inflamed lips, dry skin, or nausea (low‐quality
evidence). Fourteen studies compared different doses/courses of oral isotretinoin
between 12 to 32 weeks. Participants had mainly severe or moderate acne. Two studies,
each comparing three different doses of isotretinoin at 20 weeks, found a greater
improvement (measured by inflammatory lesion counts) with the higher dose (low‐quality
evidence). A third study showed that continuous (daily) low dose and continuous (daily)
conventional dose may improve acne more than intermittent therapy, measured at 24
weeks (low‐quality evidence). Conventional dose isotretinoin reduced inflammatory
lesion counts more than low dose, but this was based on very low‐quality evidence,
indicating uncertainty. During treatment (from 12 to 32 weeks) or follow‐up after
end of treatment (up to 48 weeks), no serious side effects occurred in 14 studies
analysing different doses of isotretinoin (low‐quality evidence). Doctor‐measured
severity of acne was not assessed in this comparison. Less serious side effects, including
skin dryness, hair loss, and itching, were assessed in 13 studies, but we are uncertain
if there were any differences between groups (low‐ to very low‐quality evidence, where
assessed). No study reported birth defects. Quality of the evidence The overall quality
of evidence for all of our key outcomes was low, due to serious limitations of study
design and the limited amount of data. Thus, the identified clinical trials neither
support nor challenge the established place of oral isotretinoin in acne treatment.