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Treatments for alopecia areata: a network meta-analysis (Review)

Mateos-Haro M, Novoa-Candia M, Sánchez Vanegas G, Correa-Pérez A, Gaetano Gil A, Fernández-

García S, Ortega-Quijano D, Urueña Rodriguez MG, Saceda-Corralo D, Bennouna-Dalero T,
Giraldo L, Tomlinson J, Vaño-Galván S, Zamora J

Mateos-Haro M, Novoa-Candia M, Sánchez Vanegas G, Correa-Pérez A, Gaetano Gil A, Fernández-García S, Ortega-Quijano D,

Urueña Rodriguez MG, Saceda-Corralo D, Bennouna-Dalero T, Giraldo L, Tomlinson J, Vaño-Galván S, Zamora J.
Treatments for alopecia areata: a network meta-analysis.
Cochrane Database of Systematic Reviews 2023, Issue 10. Art. No.: CD013719.
DOI: 10.1002/14651858.CD013719.pub2.

www.cochranelibrary.com

Treatments for alopecia areata: a network meta-analysis (Review)

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

[Intervention Review]

Treatments for alopecia areata: a network meta-analysis

Miriam Mateos-Haro1,2a, Monica Novoa-Candia3a, Guillermo Sánchez Vanegas4, Andrea Correa-Pérez1,5, Andrea Gaetano Gil1, Silvia
Fernández-García6, Daniel Ortega-Quijano7, Mayra Gizeth Urueña Rodriguez8, David Saceda-Corralo7, Tayeb Bennouna-Dalero9, Lucia
Giraldo3, Jaqueline Tomlinson10, Sergio Vaño-Galván7, Javier Zamora11,12,13

1Clinical Biostatistics Unit, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, Spain. 2Doctoral programme in Clinical Medicine
and Public Health, Universidad de Granada, Granada, Spain. 3Paediatric Dermatology Department, Hospital San Jose-Fundación
Universitaria de Ciencias de la Salud-FUCS, Bogotá, Colombia. 4Hospital Universitario Mayor-Méderi, Universidad del Rosario, Bogotá,
Colombia. 5Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain. 6WHO Collaborating Centre for Global Women’s Health,
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK. 7Department of Dermatology, Hospital
Universitario Ramón y Cajal, Madrid, Spain. 8Department of Dermatology, Hospital San Jose-Fundación Universitaria de Ciencias de
la Salud-FUCS, Bogotá, Colombia. 9Preventive Medicine and Public Health Department, Hospital Universitario Ramón y Cajal, IRYCIS,
Madrid, Spain. 10c/o Cochrane Skin Group, The University of Nottingham, Nottingham, UK. 11Institute of Metabolism and Systems
Research, University of Birmingham, Birmingham, UK. 12Clinical Biostatistics Unit, Hospital Universitario Ramón y Cajal (IRYCIS). CIBER
Epidemiology and Public Health (CIBERESP), Madrid, Spain. 13Cochrane Associate Centre of Madrid, Madrid, Spain

aThese authors should be considered joint first author

Contact: Andrea Correa-Pérez, correaprez@gmail.com.

Editorial group: Cochrane Skin Group.

Publication status and date: New, published in Issue 10, 2023.

Citation: Mateos-Haro M, Novoa-Candia M, Sánchez Vanegas G, Correa-Pérez A, Gaetano Gil A, Fernández-García S, Ortega-Quijano D,
Urueña Rodriguez MG, Saceda-Corralo D, Bennouna-Dalero T, Giraldo L, Tomlinson J, Vaño-Galván S, Zamora J. Treatments for
alopecia areata: a network meta-analysis. Cochrane Database of Systematic Reviews 2023, Issue 10. Art. No.: CD013719. DOI:
10.1002/14651858.CD013719.pub2.

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background
Alopecia areata is an autoimmune disease leading to nonscarring hair loss on the scalp or body. There are different treatments including
immunosuppressants, hair growth stimulants, and contact immunotherapy.

Objectives
To assess the benefits and harms of the treatments for alopecia areata (AA), alopecia totalis (AT), and alopecia universalis (AU) in children
and adults.

Search methods
The Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO ICTRP were searched up to July 2022.

Selection criteria
We included randomised controlled trials (RCTs) that evaluated classical immunosuppressants, biologics, small molecule inhibitors,
contact immunotherapy, hair growth stimulants, and other therapies in paediatric and adult populations with AA.

Data collection and analysis

We used the standard procedures expected by Cochrane including assessment of risks of bias using RoB2 and the certainty of the evidence
using GRADE. The primary outcomes were short-term hair regrowth ≥ 75% (between 12 and 26 weeks of follow-up), and incidence of
serious adverse events. The secondary outcomes were long-term hair regrowth ≥ 75% (greater than 26 weeks of follow-up) and health-

Treatments for alopecia areata: a network meta-analysis (Review) 1

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
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related quality of life. We could not perform a network meta-analysis as very few trials compared the same treatments. We presented direct
comparisons and made a narrative description of the findings.

Main results
We included 63 studies that tested 47 different treatments in 4817 randomised participants. All trials used a parallel-group design except
one that used a cross-over design. The mean sample size was 78 participants. All trials recruited outpatients from dermatology clinics.
Participants were between 2 and 74 years old. The trials included patients with AA (n = 25), AT (n = 1), AU (n = 1), mixed cases (n = 31), and
unclear types of alopecia (n = 4).

Thirty-three out of 63 studies (52.3%) reported the proportion of participants achieving short-term hair regrowth ≥ 75% (between 12 and
26 weeks). Forty-seven studies (74.6%) reported serious adverse events and only one study (1.5%) reported health-related quality of life.
Five studies (7.9%) reported the proportion of participants with long-term hair regrowth ≥ 75% (greater than 26 weeks).

Amongst the variety of interventions found, we prioritised some groups of interventions for their relevance to clinical practice: systemic
therapies (classical immunosuppressants, biologics, and small molecule inhibitors), and local therapies (intralesional corticosteroids,
topical small molecule inhibitors, contact immunotherapy, hair growth stimulants and cryotherapy).

Considering only the prioritised interventions, 14 studies from 12 comparisons reported short-term hair regrowth ≥ 75% and 22 studies
from 10 comparisons reported serious adverse events (18 reported zero events and 4 reported at least one). One study (1 comparison)
reported quality of life, and two studies (1 comparison) reported long-term hair regrowth ≥ 75%.

For the main outcome of short-term hair regrowth ≥ 75%, the evidence is very uncertain about the effect of oral prednisolone or
cyclosporine versus placebo (RR 4.68, 95% CI 0.57 to 38.27; 79 participants; 2 studies; very low-certainty evidence), intralesional
betamethasone or triamcinolone versus placebo (RR 13.84, 95% CI 0.87 to 219.76; 231 participants; 1 study; very low-certainty evidence),
oral ruxolitinib versus oral tofacitinib (RR 1.08, 95% CI 0.77 to 1.52; 80 participants; 1 study; very low-certainty evidence), diphencyprone or
squaric acid dibutil ester versus placebo (RR 1.16, 95% CI 0.79 to 1.71; 99 participants; 1 study; very-low-certainty evidence), diphencyprone
or squaric acid dibutyl ester versus topical minoxidil (RR 1.16, 95% CI 0.79 to 1.71; 99 participants; 1 study; very low-certainty evidence),
diphencyprone plus topical minoxidil versus diphencyprone (RR 0.67, 95% CI 0.13 to 3.44; 30 participants; 1 study; very low-certainty
evidence), topical minoxidil 1% and 2% versus placebo (RR 2.31, 95% CI 1.34 to 3.96; 202 participants; 2 studies; very low-certainty
evidence) and cryotherapy versus fractional CO2 laser (RR 0.31, 95% CI 0.11 to 0.86; 80 participants; 1 study; very low-certainty evidence).
The evidence suggests oral betamethasone may increase short-term hair regrowth ≥ 75% compared to prednisolone or azathioprine (RR
1.67, 95% CI 0.96 to 2.88; 80 participants; 2 studies; low-certainty evidence). There may be little to no difference between subcutaneous
dupilumab and placebo in short-term hair regrowth ≥ 75% (RR 3.59, 95% CI 0.19 to 66.22; 60 participants; 1 study; low-certainty evidence)
as well as between topical ruxolitinib and placebo (RR 5.00, 95% CI 0.25 to 100.89; 78 participants; 1 study; low-certainty evidence).
However, baricitinib results in an increase in short-term hair regrowth ≥ 75% when compared to placebo (RR 7.54, 95% CI 3.90 to 14.58;
1200 participants; 2 studies; high-certainty evidence).

For the incidence of serious adverse events, the evidence is very uncertain about the effect of topical ruxolitinib versus placebo (RR 0.33,
95% CI 0.01 to 7.94; 78 participants; 1 study; very low-certainty evidence). Baricitinib and apremilast may result in little to no difference in
the incidence of serious adverse events versus placebo (RR 1.47, 95% CI 0.60 to 3.60; 1224 participants; 3 studies; low-certainty evidence).
The same result is observed for subcutaneous dupilumab compared to placebo (RR 1.54, 95% CI 0.07 to 36.11; 60 participants; 1 study;
low-certainty evidence).

For health-related quality of life, the evidence is very uncertain about the effect of oral cyclosporine compared to placebo (MD 0.01, 95%
CI -0.04 to 0.07; very low-certainty evidence).

Baricitinib results in an increase in long-term hair regrowth ≥ 75% compared to placebo (RR 8.49, 95% CI 4.70 to 15.34; 1200 participants;
2 studies; high-certainty evidence).

Regarding the risk of bias, the most relevant issues were the lack of details about randomisation and allocation concealment, the limited
efforts to keep patients and assessors unaware of the assigned intervention, and losses to follow-up.

Authors' conclusions
We found that treatment with baricitinib results in an increase in short- and long-term hair regrowth compared to placebo. Although we
found inconclusive results for the risk of serious adverse effects with baricitinib, the reported small incidence of serious adverse events in
the baricitinib arm should be balanced with the expected benefits. We also found that the impact of other treatments on hair regrowth is
very uncertain. Evidence for health-related quality of life is still scant.

PLAIN LANGUAGE SUMMARY

What are the benefits and risks of different treatments for alopecia areata (hair loss)?

Key messages

Treatments for alopecia areata: a network meta-analysis (Review) 2

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

-There are multiple treatment options for alopecia areata as systemic therapies such as immunosuppressants and local treatments such
as hair growth stimulants, but it is unclear how helpful they are in producing new hair growth in the affected area.

-Only one oral immunosuppressant treatment, baricitinib, showed an increment in hair regrowth.

-Therapies appear to be safe and serious side effects are rare.

-More good-quality studies are required to evaluate the therapies that appear to be useful.

What is alopecia areata?

Alopecia areata is a common condition characterised by localised or diffuse hair loss on the scalp or around the body. Almost half of the
patients have new hair growth without treatment, but a considerable number of them still require specific treatment.

How is alopecia areata treated?

Most patients get better spontaneously and, in some cases, the doctor and patient may choose to wait for new hair to grow. However,
spontaneous growth is rare in severe cases. For patients who need medication, there are multiple treatments, including topical therapies,
oral treatments, and localised corticosteroid injections.

Why did we do this Cochrane Review?

Due to the broad landscape of treatments for alopecia areata, we wanted to know the potential benefits and harms of the available
treatments and to see if some of them work better than others.

What did we do?

We searched for studies that tested therapies to treat alopecia areata (AA), alopecia totalis (AT) and alopecia universalis (AU). The therapies
we searched for included medicines administered orally or subcutaneously with systemic effects (that affect the body as a whole) such as
immunosuppressants, and local treatments (that affect the skin surface) such as hair growth stimulants or cryotherapy. These treatments
were compared with a placebo (a 'dummy' treatment that does not contain any drug) or with another medicine. We assessed the effect of
the treatments on significant hair regrowth (equal or greater than 75% and measured from 12 to 26 weeks after starting the treatment or
beyond 26 weeks), on well-being (quality of life), and if they are likely to cause serious adverse events (unwanted or harmful effects).

We also summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and
number of participants.

How up-to-date is this review?

We included evidence up to July 2022.

What did we find?

We found 63 studies that tested 47 different therapies in 4817 people with AA, AT or AU (participants were between 2 and 74 years old).

Within the 12 comparisons (one comparison means one treatment compared to another) considered more relevant to clinical practice,
short-term hair regrowth ≥ 75% (from 12 to 26 weeks of follow-up) was evaluated in 14 studies and long-term regrowth ≥ 75% (after 26
weeks of follow-up) was evaluated in two studies. Only one study assessed well-being (quality of life) and 22 studies assessed serious
adverse events (although only four of them reported at least one serious adverse event).

What are the main results of our review?

Baricitinib (an immunosuppressant medicine taken by mouth) compared to placebo increases hair regrowth ≥ 75% (both short and long-
term) and we are confident with these results. The evidence is very uncertain about the effect of topical hair growth stimulants (minoxidil)
on short-term hair regrowth ≥ 75% compared to placebo as the results largely varied from study to study. It is unclear if other treatments
compared to placebo or to other medicines have an effect on hair regrowth, and we are not confident of the evidence because the results
from the studies varied widely, and involved small numbers of people. Some studies did not clearly report how they were conducted, or
whether the people taking part knew what they had received which could have affected the study's results. Further research is likely to
change our results.

Four studies that assessed the immunosuppressant drugs dupilumab (administered subcutaneously), baricitinib, and topical ruxolitinib
reported 30 serious adverse events (23 in the treatment group and 7 in the placebo group) in a total of 1332 participants. In all cases, the
authors did not establish a direct relationship between serious adverse events and therapies. There were no deaths, serious infections, or
cancer cases. Based on the available evidence, those treatments may have little to no effect on serious adverse events.

It is unclear if oral cyclosporine (an immunosuppressant drug) has an effect on the quality of life.

Treatments for alopecia areata: a network meta-analysis (Review) 3

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews

Limitations of the evidence

Our confidence in the evidence is only high for one comparison (baricitinib compared to placebo) and, for the remaining identified
evidence, our confidence is generally low since most of the therapies have been evaluated in studies with weaknesses in their design, with
few patients, and that have not been replicated to evaluate the consistency of the results.

Treatments for alopecia areata: a network meta-analysis (Review) 4

Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.