1.
British Journal Of Dermatology
Moderator- Dr. Puneet Agarwal Sir
Presenter- Dr. Mehul Choudhary

2.
Self-applied topical interventions for melasma:
a systematic review and meta-analysis of data
from randomized, investigator-blinded clinical
trials

3.
Introduction
• Melasma is a common skin condition characterized by an acquired
symmetrical cutaneous hypermelanosis.
• Its pathogenesis is complex, involving not only melanocytes, but also
keratinocytes, fibroblasts and endothelial cells along with an altered
basement membrane.
• Risk factors include exposure to ultraviolet (UV) and visible light, genetic
predisposition, oral contraceptives, pregnancy and female sex.
• Melasma is most common in Asian and Latin women of reproductive age
with Fitzpatrick skin types II–IV.

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• Occurs most commonly on the central face, forehead, temple and cheeks.
• Treatments include a broad range of medical and cosmetic interventions,
albeit characterized by inconsistent results and frequent relapses.
• This paper aims to systematically assess the evidence from randomized
controlled trials (RCTs) on self-applied topical interventions for melasma.

5.
Materials and Methods
Eligibility criteria-
• The study included RCTs assessing the efficacy and safety of topical, self-
administered interventions in patients diagnosed with melasma.
• Included RCTs are that explicitly stated in their methods section or study
protocol-
1. How they generated their random allocation sequence?
2. That the study outcome assessor was blinded towards the participants’
group allocation.

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• Population, intervention, comparator and outcomes framework is
provided in following table-

7.
Results
Triple combination cream and its individual components-
• One RCT compared triple combination cream (TCC) [fluocinolone
acetonide 0.01%, hydroquinone (HQ) 4% and tretinoin 0.05%] with
placebo.
• TCC was superior with respect to participants rated as ‘cured or greatly
improved’.
• However, significantly more patients in the intervention group
experienced AEs, which included eye pain and stabbing pain.
• Another RCT compared TCC with HQ 4% alone
• TCC was superior, both with respect to patients with no or only mild
hyperpigmentation. The number of patients with AEs was significantly
higher in the TCC group.

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Combination cream containing hydroquinone and glycolic acid
• One RCT compared a combination cream containing HQ 4%, glycolic acid
10%, and vitamins C and E vs. placebo in 35 patients.
• There was no significant difference in improvement of melasma according
to the physician’s evaluation. However, the authors reported that the
combination cream was superior with respect to Mexameter readings and
MASI score.
Cysteamine cream
• One RCT compared cysteamine 5% cream with vehicle.
• Participants who received cysteamine cream achieved a score of ‘clear’ or
‘mild’ on the Melasma Severity Score significantly more often, and had a
better improvement of MASI and Mexameter melanin index. However,
more participants in the cysteamine group experienced AEs

9.
• One RCT compared cysteamine 5% with TCC (HQ 4%, retinoic acid 0.05%
and betamethasone 0.1%) in 50 patients. At 4 months, no significant
differences were seen between the two groups with respect to modified
MASI (mMASI) or Investigator’s Global Assessment.
Methimazole
• One RCT compared methimazole 5% with HQ 4% in 40 patients. There was
no significant difference between groups with respect to the physician’s
evaluation .Patients in the HQ 4% group had a greater reduction in MASI.
Undecylenoyl phenylalanine
• One RCT compared topical undecylenoyl phenylalanine 2% with vehicle in
37 patients. Significantly more patients in the undecylenoyl phenylalanine
group had a complete or partial response. There was no significant
difference with respect to Aes.

10.
Isobutylamido thiazolyl resorcinol (Thiamidol)
• One split-face RCT compared isobutylamido thiazolyl resorcinol (ITR) 0.2%
applied to one side of the face with the untreated half in 31 patients.
Patients in the ITR group had a greater improvement of mMASI.
• Another intra-individual RCT reported in the same publication compared
ITR 0.2% with HQ 2% in 28 patients. The reduction in mMASI was
significantly greater with ITR than with HQ.
• One Study included one three-armed RCT with 30 participants per arm
comparing the combination of ITR 0.15% and hyaluronic acid (HA) vs. ITR
0.15% and HA alone. With respect to MASI, the combination of ITR plus
HA was superior to HA alone and ITR alone was superior to HA alone,
whereas there was no significant difference between combination
treatment and ITR alone.

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• Ultraviolet- and visible light-spectrum sunscreen
• Study included one RCT that compared sunscreen protecting both from
UV and visible light (VL) (SPF 60) with sunscreen protecting from UV light
only (SPF 50+) in 61 patients with high sunlight exposure.
• Participants in both groups were additionally treated with HQ 4% cream.
• After 8 weeks of treatment, patients in the UV + VL-protective sunscreen
group had a significantly greater percentage reduction in MASI
• According to the physician’s global assessment, significantly more patients
had an ‘excellent’ or ‘good’ improvement

12.
Tranexamic acid-
• One study included RCT that compared tranexamic acid (TXA) 2.5%
cataplasm to vehicle in 81 patients.
• Patients who received TXA had a lower MASI score at the end of
treatment. No patients in either group reported AEs.
• Two RCTs compared TXA 5% with HQ 2% and 3%, respectively.
• No significant difference in MASI was seen. There was no significant
difference with respect to pigmentation at the end of treatment.
• Significantly more participants receiving HQ experienced AEs
• One RCT that compared TXA with TCC (HQ 2%, tretinoin 0.05% and
fluocinolone 0.01%). With respect to mean difference in MASI from
baseline to week 8, TXA was inferior to TCC.

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Discussion
• TCC, which consists of HQ, tretinoin and corticosteroids, remains the gold
standard and first-line topical, selfapplied therapy in treating melasma.
• TCC is more effective in lightening melasma than placebo or HQ alone.
• Topical TXA proved to be more effective than placebo and equally effective
as HQ in treating melasma. However, TXA was inferior to TCC with respect
to MASI.
• Cysteamine was also more effective than vehicle and as effective as TCC,
and could potentially be an alternative to TCC and its individual
component.

14.
• Some herbal products, particularly Rumex occidentalis and mulberry
extract, were superior to placebo with respect to some outcomes.
• Common AEs across all included studies were mild and transient
erythema, burning, irritation and pruritus. No SAEs and only few cases of
dropouts due to AEs were reported.
• The use of sunscreen is of great importance in managing melasma and
was recommended in most studies. Current recommendations advise
using a broad-spectrum sunscreen protecting against UVB, long-wave UVA
and high-energy visible light.

15.
Limitations
• Firstly By including only RCTs that explicitly reported in their methods
section how the randomization was performed and that the investigators
were blinded, the Study restricted the eligibility to higher-quality RCTs.
Which may have overlook studies that included evidence on other
relevant interventions.
• Secondly the language restrictions can lead to language bias, particularly
considering that the prevalence of melasma is especially high in Asian and
Latin American countries

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Conclusion
• In conclusion, melasma is a frequent dermatological disease that can
severely affect patients’ wellbeing and quality of life. Aside from the
frequently prescribed topical agents, many nonstandardized treatments
were evaluated in clinical studies. Current evidence suggests that TCC or
HQ alone are effective in treating melasma. Apart from these and other
medical treatments, some over-the-counter cosmetic and herbal products
showed promising results in randomized trials.
• Overall, topical treatments for melasma are well tolerated. Patients should
be encouraged to use a broad-spectrum sunscreen protecting from both
UV and visible light during treatment and thereafter because evidence
suggests that this might improve treatment efficacy

17.
A systematic review and network meta-analysis
of topical pharmacological, oral
pharmacological, physical and combined
treatments for acne vulgaris

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Introduction
• Acne vulgaris is an inflammatory disorder of pilosebaceous unit, which
runs a chronic course and it is self-limiting.
• Acne vulgaris is triggered by propionibacterium acnes in adolescence,
under the influence of normal circulating dehydroepiandrosterone.
• Acne vulgaris is the eighth most common disease globally, affecting over
0.5 billion people.
• Acne can have a detrimental physical, psychological and social impact.

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• Various treatments for acne vulgaris exist, but little is known about their
comparative effectiveness in relation to acne severity.
• Objective of this study is to identify best treatments for mild-to-moderate
and moderate-to severe acne, as determined by clinician-assessed
morphological features.

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Materials and Methods
Search strategy-
• Searches for RCTs of treatments for acne vulgaris were conducted in
Embase, MEDLINE, the CENTRAL and the Cochrane Database of Systematic
Reviews (CDSR).The search was undertaken in August 2019 and reruns
were performed in May 2020
Selection criteria for the systematic review and the network meta-analysis
• The review included people with acne vulgaris of all ages (except neonatal
acne) and severity levels.
• Populations with postinflammatory dyspigmentation, polycystic ovary
syndrome (PCOS), refractory acne or receiving maintenance treatment
were excluded.

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• The study was categorized as mild-to-moderate acne if each participant
had only noninflammatory lesions, or < 35 inflammatory lesions, or if the
average number of inflammatory lesions per study participant was ≤ 30.
• Whereas the study was categorized as moderate-to-severe acne if each
participant had ≥ 3 nodules (regardless of the number of other
inflammatory lesions), or ≥ 35 inflammatory lesions, or if the average
number of inflammatory lesions per study participant was ≥ 40.
• Topical pharmacological treatments included retinoids, antibiotics, benzoyl
peroxide (BPO), azelaic acid and other interventions.
• Oral pharmacological treatments included antibiotics, isotretinoin,
hormonal contraceptives and hormone-modifying agents (e.g. metformin,
spironolactone).

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• Physical treatments included chemical peels (e.g. salicylic acid, mandelic
acid, Jessner’s peel), and light therapies including photochemical therapies
(blue, red or combined blue/red light), photodynamic therapy (i.e. therapy
comprising a light source, e.g. red light, blue light, daylight, and a
photosensitizing chemical, e.g. 5-aminolaevulinic acid, methyl
aminolaevulinate) and other phototherapies.
• Three outcomes at treatment endpoint were analyzed using NMA
techniques-
1. Efficacy, expressed as percentage change in total acne lesion count from baseline
(%CFB).
2. Treatment discontinuation for any reason (reflecting acceptability).
3. Treatment discontinuation owing to side-effects (reflecting tolerability).

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Efficacy of each treatment class relative to placebo is shown in Table 1 for
mild-to-moderate acne and Table 2 for moderate to-severe acne.
Results

24.
Results
• In each analysis, treatment classes have been ordered from best to worst
using their mean ranking for females.
• In mild-to-moderate acne, topical retinoids, BPO and their combination
showed higher discontinuation owing to side-effects compared with
placebo
• In moderate-to-severe acne, topical retinoids alone or combined with an
oral tetracycline, cocyprindiol alone or combined with an oral tetracycline,
and oral tetracycline alone showed higher discontinuation owing to side-
effects compared with placebo.

25.
Discussion
• The study compared a wide range of treatments for acne vulgaris.
• For mild-to-moderate acne, topical and physical treatments (chemical
peels and photochemical therapy) were shown to be effective compared
with placebo.
• Among topical treatments, combinations of BPO with clindamycin, BPO
with a retinoid, BPO with a macrolide, clindamycin with a retinoid, and a
macrolide with an antifungal appeared to be the most effective.
• Adapalene combined with BPO was the most effective topical treatment,
but had a slightly higher incidence of withdrawal than monotherapy.
Followed by topical antibiotics and BPO.

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• Overall, single topical agents (e.g. retinoids, BPO, macrolides) ranked
lower than topical treatment combinations.
• Topical retinoids and BPO were less well tolerated than placebo.
• Topical antibiotics combined with BPO and chemical peels, and topical
antibiotics combined with topical retinoids, were another two good
options for noninflammatory lesions, while light devices were good for
inflammatory lesions.
• Azelaic acid combined with an oral tetracycline was considered a good
alternative for people with moderate-to-severe acne who have irritation
to topical retinoids; moreover, azelaic acid has a possible effect in reducing
the risk of hyperpigmentation in people with darker skin and acne.

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• For moderate-to-severe acne, the most effective treatments in ranking
included oral isotretinoin, oral tetracyclines combined with topical
treatments (azelaic acid, retinoid, or combined retinoid with BPO), and
topical treatment combinations (e.g. retinoid with clindamycin or BPO,
retinoid with clindamycin and BPO, BPO with clindamycin or with a
macrolide).
• Overall, monotherapies of oral tetracyclines or topical treatments ranked
lower than combined treatments.
• No evidence was identified for hormone-modifying agents (metformin,
spironolactone).
• Hormonal contraceptives (combined oral contraceptives and cocyprindiol)
showed evidence of a small effect in reducing acne lesions in mild-to-
moderate acne.

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• Based on the NMA findings guideline on acne vulgaris management
recommends-
first-line treatments-
• Fixed topical treatment combinations (adapalene with BPO, clindamycin
with BPO, or tretinoin with clindamycin) for mild-to-moderate acne.
• Fixed topical treatment combinations (adapalene with BPO, tretinoin with
clindamycin) or oral tetracyclines (doxycycline or lymecycline) combined
with topical treatments (fixed combination of adapalene with BPO; or
azelaic acid) for moderate-to severe acne.
• Where oral doxycycline not tolerated or are contraindicated, alternative
oral antibiotics such as trimethoprim or an oral macrolide (e.g.
erythromycin) might be considered.

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• BPO alone may be considered as an option across all acne severity levels if
other recommended first-line treatments are contraindicated (e.g. during
pregnancy).
• Topical retinoids and BPO should be initiated with alternate-day or short-
contact application because of their increased risk of discontinuation
owing to sideeffects there is a patient preference against their use
• Photodynamic therapy may be considered as an option for adults with
moderate-to-severe acne if other treatments are ineffective, not tolerated
or contraindicated.
• Further research was recommended for chemical peels, photochemical
and photodynamic therapies (for which the evidence was promising but
limited), for hormone-modifying agents, e.g. metformin and
spironolactone (for which no evidence was identified), and for oral
isotretinoin in reduced dosage or reduced-dose regime.

30.
Limitations
• Dietary interventions (e.g. milk-free diet, low glycaemic load diet), which
may have an effect on acne vulgaris and its response to treatment,were
not included in this review.
• Although the study searched for treatments for acne vulgaris at any body
site, the majority of the RCTs included in the review focused on facial
acne.
• Another potential limitation of the review was its focus on evidence
published in the English language only.

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Conclusion
• Topical pharmacological treatment combinations, chemical peels and
photochemical therapy were most effective for mild-to-moderate acne.
Topical pharmacological treatment combinations, oral antibiotics
combined with topical pharmacological treatments, oral isotretinoin and
photodynamic therapy were most effective for moderate-to-severe acne.
Further research is warranted for chemical peels, photochemical therapy
and photodynamic therapy for which evidence was more limited.

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