Included in the theme issue:

ATOPIC DERMATITIS, URTICARIA AND ITCH

Acta Derm Venereol 2012; 92: 455-461 Acta Derm Venereol 2012; 92: 449–581

REVIEW ARTICLE

Relieving the Pruritus of Atopic Dermatitis: A Meta-analysis

Lindsay G. Sher1, Jongwha Chang2, Isha B. Patel3, Rajesh Balkrishnan3 and Alan B. Fleischer Jr1
1
Department of Dermatology, Wake Forest School of Medicine, Winston-Salem, NC, 2Public Health Sciences, Penn State College of Medicine, Hershey,
PA, and 3Health Management & Policy, University of Michigan, Ann Arbor, MI, USA

The goal of this study was to perform a meta-analysis on agents, autoallergens, foods, and emotional stress (2).
randomized controlled trials of topical therapies compa- In addition to physical modalities such as ultraviolet
red against their vehicles, and systemic therapies com- therapy, many classes of medications are widely used
pared against their placebos, and to record how these in the management of AD, including topical cortico­
therapies changed the magnitude of pruritus associated steroids, topical calcineurin inhibitors, antihistamines,
with atopic dermatitis. A systematic search of the lite- immunosuppressants, probiotics, and herbal remedies
rature was performed using Medline, Embase, and the (3). In order to guide clinicians in evidence-based
Cochrane Controlled Clinical Trials Register, as well as medicine, we undertook a meta-analysis of medications
follow-up references in retrieved articles. Data regarding used for AD and their effect on relieving the symptom
the magnitude of the change in pruritus was extracted of pruritus.
from eligible publications and categorized according to It is important to recognize the substantial “placebo
the type of treatment modality. Standard inverse vari- effect” that patients can experience from inactive forms
ance fixed-effects meta-analysis was used to calculate the of therapy. This concept was nicely illustrated in a
pooled estimates for randomized controlled trials falling landmark study by Epstein & Pinski (4) in which 12
under each type of treatment. Overall, the topical treat- patients suffering from pruritic dermatoses, including
ments were more successful at reducing atopic pruritus atopic dermatitis, were given 4 tablets placed in diffe-
compared to the systemic treatments. Calcineurin in- rent envelopes, and were instructed to take the tablets
hibitors were the most effective antipruritic agent. Key in rotation until all 4 types of pills were consumed. In
words: pruritus; atopic dermatitis; eczema; meta-analysis. 66% of the cases, patients experienced an improvement
in their symptoms from one or more of the tablets. On
(Accepted January 18, 2012.) the other hand, 16% of patients suffered from adverse
Acta Derm Venereol 2012; 92: 455–461 side effects. Unbeknownst to the patients, all 4 types
of pills were lactose-containing placebos.
Alan B. Fleischer, Jr., M.D., Department of Dermatology, This meta-analysis reviews the randomized controlled
Wake Forest School of Medicine, Medical Center Bou- trials that have tested various topical therapies against
levard, Winston-Salem, NC 27157-1071, USA. E-mail: their vehicles and systemic therapies against their pla-
[email protected] cebos. It also assesses the effectiveness of the topical
and systemic therapies on the magnitude of the pruritus
associated with AD.
Atopic dermatitis (AD) is a chronically relapsing inflam-
matory skin disease associated with a family history of
atopy, xerosis, epidermal barrier dysfunction, and immu- MATERIALS AND METHODS
noglobulin E reactivity. AD has increased in prevalence
Search strategy
over the past 30 years, currently affecting 15–20% of
children and 1–3% of adults in industrialized nations (1). A systematic literature search was performed in June 2011 using
Medline, Embase, Cochrane Central Register of Controlled
Irrespective of its cause, the cardinal symptom of AD is Trials, and Academic Search Premier, as well as the follow-up
pruritus, a cutaneous sensation that provokes scratching references in retrieved articles to find randomized clinical trials
of the skin. Severe pruritus negatively affects the quality for the treatment of AD published from 1977 to 2011. Search
of life of the afflicted patients. The ideal treatment for AD terms included “atopic dermatitis”, “eczema”, “pruritus”, “itch”,
should not only alleviate the objective symptoms of the “randomized”, and “double-blind”.
disease such as erythema, induration/papulation, excoria-
tion, and lichenification, but should also ameliorate the Inclusion and exclusion criteria
subjective symptoms such as pruritus and insomnia. Study inclusion criteria were: 1) trials must have used between-
An effective treatment for AD requires a systematic patient (parallel group), crossover, or left-right comparison
design; 2) the study must have included at least 20 human
regimen that incorporates skin hydration, pharmaco- participants in each of the treatment arms irrespective of the
logic therapy, and the identification and elimination dropout rates; 3) the study compared a topical therapy compared
of exacerbating factors such as inhalants, microbial to its vehicle, or a systemic therapy compared to its placebo,

© 2012 The Authors. doi: 10.2340/00015555-1360 Acta Derm Venereol 92

Journal Compilation © 2012 Acta Dermato-Venereologica. ISSN 0001-5555
456 L.G. Sher et al.

for the treatment of AD; 4) the study must have specifically meta-analysis was used to calculate the pooled estimates for
measured the reduction in pruritus from the baseline compared RCTs falling under each type of treatment. The mean effect
to the end of the treatment for each of the treatment groups. was determined by combining the pooled estimates of the dif-
We included trials with ≥ 20 subjects in each treatment arm as ferent types of treatments and 95% confident interval (CI) for
this was the cutoff proposed by Columbia University in their each RCT.
Quality of Study Rating Form for Evidence Based Practice For visually examining heterogeneity, forest plots were con-
(5). For studies in which the change in pruritus was not made structed. Heterogeneity was also examined between the trials
explicit but instead displayed graphically without clear labels, using the subgroup analyses, i.e. stratifying trials based on types
the pruritus scores were estimated as best as possible from the of treatments. In order to quantify heterogeneity, the I2 statistic
graph (6–14). Patient selection was based on inclusion criteria was used. This statistic describes the percentage of variation
developed by Hanifin & Rajka (15). Studies were not limited across studies attributable to heterogeneity.
by the severity of the disease at baseline, the area of skin in- A funnel plot was constructed by plotting the inverse of the
volvement or the area of the body undergoing treatment. We standard error against the log RR. The funnel plot summary
did not take into account any patient demographic information approach was used to assess publication bias qualitatively.
such as age, gender or race. We included one study that was To examine the publication bias quantitatively, the Begg and
published in Turkish (16), one that was published in German Mazumdar rank correlation (the Begg test) was used. In order
(17), and one that was published in Korean (18). to disentangle different causes of funnel asymmetry other than
Study exclusion criteria were: 1) studies that only assessed publication bias, the Confunnel test was performed. Contour-
pruritus in a composite score, such as SCORAD, that inclu- enhanced funnel plots were also constructed by adding contours
ded measurements for other symptoms of AD as these scales of statistical significance.
made it impossible to assess the change in pruritus itself; 2) The p-values set as less than 0.05 for pooled effect estimates were
randomized clinical trials that studied UV therapy for the tre- considered statistically significant. All the analyses were conducted
atment of pruritus as this type of treatment could not clearly using STATA version 10.0 (Stata Corp., College Station, TX).
be categorized as topical or systemic; 3) studies in which the
patient population suffered from other pruritic dermatoses,
such as chronic urticaria, in addition to AD; 4) studies in which RESULTS
concomitant therapies were administered simultaneously with
the active treatment, as it contaminated the effect on pruritus The selection process
by the active treatment in question. Other scales such as the
Eczema and Severity Index (EASI) and the International Global Out of the 205 peer-reviewed full text scientific articles
Assessment (IGA) of AD that assess the objective symptoms whose titles and/or abstracts were screened from this
of AD were also excluded, as these scales did not specifically meta-analysis study, 71 non-RCT were excluded. Out
measure the change in magnitude of pruritus. of the 134 remaining studies, after excluding another
82 RCT, 42 studies met the inclusion criteria for topical
Outcome measures treatment and 10 studies met the inclusion criteria for
The primary outcome measure was the pruritus score at the end oral treatment. The 42 studies using topical treatment
of the study. Pruritus was assessed by either the visual analogue as an intervention had a total of 7,011 study subjects
scale (VAS) from 0–100 mm in which 0 indicated ‘no pruritus’ whereas the 10 studies using oral treatment as an in-
and 100 mm indicated ‘the worst pruritus imaginable’, or by the
patient’s assessment of pruritus using a 4-point ordinal scale tervention had a total of 647 study subjects. The 52
in which 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. For studies were dated from January 1, 1990 to December
the latter, results were dichotomized such that a final score of 31, 2009. Fig. 1 represents a flow diagram detailing the
0 or 1 was considered a “success” and a score of 2 or 3 was process leading to the inclusion of studies for topical
considered a “failure.” The change in pruritus was recorded for and oral treatment respectively. A summary of the RCTs
each treatment arm in each study we included.
included in the meta-analysis can be found in Tables
SI–SIII (available from http://www.medicaljournals.se/
Data extraction
acta/content/?doi=10.2340/00015555-1360).
Data was extracted from eligible publications and compiled
in a Microsoft Excel® spreadsheet. When recording the data,
trials were categorized according to the type of therapy, such
as corticosteroid, anti-histamine, calcineurin inhibitor, or
immunosuppressant. A single eligible randomized controlled Potentially relevant publications
trial (RCT) using sodium cromoglycate, a mast cell stabilizer, identified from search strategy
was functionally incorporated into the topical anti-histamine (n=205)
group. Similarly, a single eligible RCT using montelukast, a Papers excluded (non-randomized
leukotriene receptor antagonist, was functionally incorporated controlled trials) (n=71)
into the systemic immunosuppressant group. The duration of
Randomized controlled trials
the study in days, sample size in each treatment arm, baseline retrieved for detailed evaluation Randomized controlled trials excluded:
pruritus score, final pruritus score, p-value, and instrument used (n=134) Sample size too small (n=29)
to assess pruritus were recorded for each study. Composite score (n=13)
Did not assess pruritus (n=32)
Patient had other dermatoses (n=5)
Concomitant treatment given
Data synthesis Randomized controlled trials simultaneously with active treatment
included (n=52) given throughout duration of study (n=2)
The binary outcomes for each study were expressed as risk RCT was testing UV therapy (n=1)
ratios (RRs) in order to achieve similarity in the outcomes and
pool them together. Standard inverse variance fixed-effects Fig. 1. Consort diagram of search strategy.

Acta Derm Venereol 92

 Relieving the pruritus in AD 457

Topical treatment prednicarbate 0.25% ointment, one tested hydrocorti-

Calcineurin inhibitor. Among topical therapeutic sone 1%, and one tested methylprednisolone aceponate
agents, calcineurin inhibitors were used in 22 RCTs. 0.1% cream. The pooled relative risk of treatment ef-
Of these trials, 16 tested pimecrolimus 1% cream, 3 fect of corticosteroids versus vehicle was 0.66 (95%
tested tacrolimus 0.3% ointment, one tested tacroli- CI, 0.58–0.75 [p < 0.001]). The use of corticosteroids
mus 0.1% ointment, one tested 0.03% ointment, and as therapeutic agents significantly reduced the pruri-
one tested tacrolimus 0.01%. The pooled relative risk tus of AD by 34% in patients compared to the use of
of treatment effect of calcineurin inhibitor versus ve- vehicle.
hicle was 0.64 (95% CI, 0.61–0.68 [p < 0.001]). The Anti-histamine. Topical anti-histamines were used in
evidence of heterogeneity in a random effects model 4 RCTs. Three RCTs tested doxepin 5% cream and
was not found to be significant. The use of calcineurin one RCT tested sodium cromoglycate 4% lotion.
inhibitors as therapeutic agents significantly reduced The pooled relative risk of treatment effect of anti-
the pruritus of AD by 36% in patients compared to the histamines versus vehicle was 0.73 (95% CI, 0.65–0.83
use of vehicle. [p < 0.001]). The use of anti-histamines as therapeutic
Corticosteroid. Topical corticosteroids were used in agents significantly reduced the pruritus of AD by 27%
6 RCTs. Of these trials, one tested desonide hydrogel in patients compared to the use of vehicle.
0.05%, one tested clobetasol proprionate lotion, one A summary of the effectiveness of the topical
tested fluticasone proprionate 0.05% cream, one tested therapies in their effects on the magnitude of ato-

Study %
ID RR (95% CI) Weigh

Calcineurin Inhibitors
Leung, DYM et al. 2009 (19) 0.93 (0.72, 1.20) 1.22
Staab, D et al. 2005 (7) 0.35 (0.26, 0.46) 3.53
Hoeger, P et al. 2009 (20) 0.22 (0.10, 0.47) 1.53
Murrell, DF et al. 2007 (21) 0.48 (0.35, 0.65) 3.11
Aschoff, R et al. 2009 (22) 0.42 (0.18, 0.96) 0.56
Langley, RG et al. 2008 (8) 0.64 (0.53, 0.76) 5.70
Kaufmann, R et al. 2006 (23) 0.58 (0.43, 0.77) 2.97
Fowler, J et al. 2007 (24) 0.65 (0.51, 0.83) 3.05
Baskan, EB et al. 2007 (25) 1.00 (0.07, 15.12) 0.05
Kaufmann, R et al. 2004 (26) 0.57 (0.47, 0.70) 3.53
Ho, VC et al. 2003 (9) 0.43 (0.31, 0.59) 2.60
Schulz, P et al. 2007 (27) 0.50 (0.26, 0.97) 0.65
Eichenfield, LF et al. 2002 (10) 0.67 (0.56, 0.80) 5.70
Meurer, M et al. 2004 (11) 0.46 (0.31, 0.70) 2.01
Kapp, A et al. 2002 (28) 0.60 (0.39, 0.94) 1.37
Rahman, MF et al. 2008 (29) 0.60 (0.41, 0.89) 1.17
Chapman, MS et al. 2005 (30) 0.64 (0.56, 0.73) 11.01
Wollenberg, A et al. 2008 (31) 1.61 (1.29, 2.01) 2.52
Luger, T et al. 2001 (32) 0.66 (0.50, 0.89) 1.72
Boguniewicz, M et al. 1998 (33) 0.53 (0.34, 0.83) 1.40
Schachner, LA et al. 2005 (34) 0.57 (0.46, 0.69) 5.64
Reitamo, S et al. 2010 (12) 1.63 (1.27, 2.09) 1.81
Subtotal (I-squared = 87.9%, p = 0.000) 0.65 (0.61, 0.68) 62.83

Topical Corticosteroids
Hebert, AA et al. 2007 (35) 0.20 (0.15, 0.27) 6.35
Breneman, A et al. 2005 (36) 0.49 (0.37, 0.63) 2.02
Abramovits, A et al. 2010 (37) 0.71 (0.46, 1.11) 1.34
Lawlor, F et al. 1995 (38) 0.22 (0.10, 0.47) 1.14
Gehring, W et al. 1996 (39) 0.88 (0.60, 1.28) 1.00
Peserico, A et al. 2008 (40) 3.15 (2.30, 4.30) 1.42
Subtotal (I -squared = 97.1%, p = 0.000) 0.66 (0.58, 0.76) 13.26

Anti-histamines
Drake, LA et al. 1994 (41) 0.70 (0.52, 0.95) 2.92
Lee, HJ et al. 2006 (42) 0.63 (0.42, 0.93) 0.94
Stainer, R et al. 2004 (43) 0.90 (0.74, 1.10) 2.19
Breneman, D et al. 1997 (36) 0.85 (0.76, 0.96) 2.75
Subtotal (I-squared = 43.0%, p = 0.154) 0.79 (0.70, 0.89) 8.80

Others
Lee, J et al 2008 (16) 0.82 (0.43, 1.55) 0.51
Griffiths, C et al. 2002 (6) 0.66 (0.51, 0.85) 2.20
Patzelt, WR et al. 2000 (44) 0.96 (0.67, 1.37) 1.20
Mayser, P et al. 2006 (45) 1.08 (0.50, 2.33) 0.31
Patrizi, A et al. 2008 (46) 0.40 (0.23, 0.70) 0.93
Abramovits,W et al. 2006 (47) 0.26 (0.18, 0.38) 3.23
Boguniewicz, M et al. 2008 (48) 0.26 (0.17, 0.40) 2.84
Giordano, LF et al. 2006 (49) 0.84 (0.52, 1.36) 0.91
Klovekorn, W et al. 2007 (50) 1.09 (0.75, 1.60) 1.49
Gueniche, A et al. 2008 (51) 0.42 (0.26, 0.66) 1.48
Subtotal (I-squared = 85.1%, p = 0.000) 0.55 (0.48, 0.63) 15.11

Overall (I-squared = 90.7%, p = 0.000) 0.65 (0.62, 0.68) 100.00

.1 Favors Treatment 1 Favors Placebo 10

Fig. 2. Topical treatment of atopic pruritus. The dotted line indicates the mean anti-pruritic effect for all of the agents included in the figure.

Acta Derm Venereol 92

458 L.G. Sher et al.

Study %
ID RR (95% CI) Weight

Immunosuppressants
Leung, DY et al. 1990 (52) 0.81 (0.65, 1.02) 16.09
Stiller, MJ et al. 1994 (53) 0.95 (0.75, 1.21) 6.64
Friedmann, PS et al. 2007 (54) 1.12 0.95, 1.30) 9.90
Oldhoff, J et al. 2005 (55) 0.70 (0.45, 1.10) 6.38
Hanifin, JM et al. 1993 (14) 0.85 (0.64, 1.12) 12.12
Subtotal (l-squared = 62.3%, p = 0.031 0.88 (0.79, 0.99) 51.13

Anti-histamines
Hannuksela, M et al. 1993 (56) 0.71 (0.50, 1.01) 11.67
Subtotal (l-squared = .%, p = .) 0.71 (0.50, 1.01) 11.67

Others
Senapati, S et al. 2008 (17) 0.23 (0.11, 0.46) 11.22
Cheng, HM et al. 2011 (57) 0.60 (0.46, 0.78) 11.60
Fölster-Holst, R et al. 2006 (58) 1.30 1.03, 1.64) 7.47
Koch, C et al. 2008 (59) 0.75 (0.51, 1.10) 6.91
Subtotal (l-squared = 92.8%, p = 0.000) 0.65 (0.55, 0.78) 37.20

Overall (l-squared = 84.4%, p = 0.000) 0.78 (0.71, 0.86) 100.00

.1 1 10
Favors Treatment Favors Placebo
Fig. 3. Systemic treatment of atopic pruritus. The dotted line indicates the mean anti-pruritic
effect for all of the agents included in the figure.

pic pruritus can be found in Fig. 2, and Table SIV DISCUSSION

(available from http://www.medicaljournals.se/acta/
content/?doi=10.2340/00015555-1360). There are a wide variety of pharmacologic agents
used to treat pruritus associated with AD. Although
topical corticosteroids have long been the mainstay of
Systemic treatment
treatment for AD, usage of these drugs is accompanied
Immunosuppressant. Among systemic therapeutic by certain drawbacks including atrophy of the skin,
agents, immunosuppressants were used in 5 RCTs. Of and they are not recommended for chronic use. In ad-
these trials, 2 tested thymopentin, one tested montelu- dition, there is limited evidence suggesting that these
kast, one tested mepolizumab, and one tested rIFN-γ. agents are effective in reducing pruritus as opposed
The pooled relative risk of treatment effect of im- to the calcineurin inhibitors, which have been shown
munosuppressants versus placebo was 0.88 (95% CI, to be safe and effective in reducing atopic pruritus in
0.78–0.99 [p = 0.037]). The evidence of heterogeneity both children and adults (60). While topical and oral
in a random effects model was not found to be signi- anti-histamines can be prescribed to treat the objec-
ficant. The use of immunosuppressants as therapeutic tive symptoms of AD, their effectiveness at reducing
agents significantly reduced the pruritus of AD by 12% pruritus has not been well measured. Similarly, anti-
in patients compared to the use of placebo. microbial agents, such as fusidic acid (61) which was
Anti-histamine. Oral anti-histamine was included in not included in our meta-analysis, are widely used for
only one RCT that tested the effectiveness of cetiri- the treatment of AD despite any evidence illustrating
zine. The pooled relative risk of treatment effect of anti-pruritic effects. For the cases that do not respond
the anti-histamine versus placebo was 0.71 (95% CI, to topical treatment, oral immunosuppressants such as
0.49–1.01 [p = 0.058]). The evidence of heterogeneity cyclosporine (62), azathioprine, and methotrexate have
in a random effects model was not found to be signi- been shown to be effective at relieving atopic pruritus
ficant. The use of the anti-histamine as a therapeutic (63), although these agents were not included in our
agent did not significantly reduce the pruritus of AD meta-analysis.
in patients compared to the use of placebo. In general, topical agents have fewer side effects
A summary of the effectiveness of the systemic thera- than systemic agents. Common side effects of topical
pies in their effects on the magnitude of atopic pruritus agents are skin application site reactions, such as for
can be found in Fig. 3, and Table SV (available from the calcineurin inhibitors, or atrophy of the skin, for
http://www.medicaljournals.se/acta/content/?doi=10.2 the corticosteroids. On the other hand, systemic agents
340/00015555-1360). such as cyclosporine have the potential for systemic

Acta Derm Venereol 92

 Relieving the pruritus in AD 459

side effects such as hepatotoxicity, nephrotoxicity and In addition, our group of systemic immunosuppres-
electrolyte imbalances, and thus require closer moni- sants are a relatively heterogeneous group that inclu-
toring during the course of treatment. des thymopentin, montelukast (a leukotriene receptor
The purpose of this study was to perform a meta- antagonist), mepolizumab (a humanized monoclonal
analysis on the various topical and systemic treatments antibody), and rIFNγ. As these agents all have varying
for AD in order to determine which method of treatment structures, mechanisms of action, and routes of admi-
was the most effective at reducing atopic pruritus, and nistration, and because there are very few published
how superior these active forms of treatment were clinical trials per each of these agents, it is difficult to
compared to their vehicles and placebos. In general, the compare their efficacies to one another and draw any
results of our analysis show that topical treatments are formal conclusions.
more effective at reducing pruritus than systemic treat­
ments when comparing the two methods against their
ACKNOWLEDGEMENT
controls. The topical calcineurin inhibitors were the
most effective in reducing the pruritus of AD. However, All financial interests for Alan Fleischer (including pharmaceu-
tical and device products): Employment: Merz, Consultancies:
in two separate RCTs that tested tacrolimus 0.01% and Allergan, Best Doctors, Gerson Lehrman, Intendis, Kikaku
0.1% ointments, the active form of treatment was found America International, Novan, Speakers bureau: Astellas,
to be no more effective than its vehicle alone in reducing Eisai, Upsher Smith.
pruritus. The second most effective antipruritic therapy
was the corticosteroids. The one RCT which tested
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