Imiquimod 5 % Cream for the Treatment of Skin Diseases

Imiquimod 5 % Cream for the
Treatment of Skin Diseases
M. Shane Chapnzan, M.D.
Associate Professor of Medicine (Dermatology),
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
Abstract
Imiquimod is an immune response modifier and toll-like receptor agonist approved in the United States for
the treatment of external genital warts, actinic keratoses and superficial basal cell carcinoma. In addition to
stimulating the innate immune system, imiquimod increases tissue interferon-alpha, interleukin-12, and
interferon-gamma, which promotes a Th-1 cellular imrnune response. These inflammatory cytokines and
chemokines modify and enhance the immune response which is beneficial in treating of a multitude of other
skin diseases, including viral infections (common warts, molluscum, herpes simplex), keloids, hemangiomas,
cutaneous T-cell lymphoma, extramammary Paget's disease, Bowen's disease, nodular basal cell carcinoma,
melanoma in-situ and cutaneous metastatic melanoma.
Introduction
Imiquimod is a toll-like receptor agonist
and topical immune response modifier
approved for the treatment of external
genital warts, actinic keratoses and
superficial basal cell carcinoma. Because
this medication seems to enhance a broad
range of cytokines and chemokines within
the skin, the immune response induced by
imiquimod has been beneficial for other
types of viral skin infections and skin
cancers, as well as many other varieties of
benign growths and epidermal processes.
From warts to hemangiomas to
melanoma, we are just beginning to
understand
the
pharmacology
of
imiquimod, re-discovering the innate
immune system and defining toll-like
receptor biology. In addition to improving
our basic science understanding of the
immune - system, the application of
imiquimod has been broad, and continues
to expand. Many niches have been
discovered where imiquimod is safe,
effective, and sometimes the best treatment
for certain skin diseases. While many of the
uses and successes of imiquimod are in
their infancy, our understanding of the
mechanism of action of imiquimod,
J Egypt worn Derrnatol Soc. Vol. 5, No. I , 2008
toll-like receptor biology, and immune
response modification have allowed us to
improve our dermatology practice and care
of our patients.
Basic Science and Mechanism of Action
of Imiquimod
The basic science of toll-like receptors is
rapidly evolving, due in large part to the
in-vitro and in-vivo experimentation with
imiquimod. Imiquimod is a toll-like 7
receptor agonist, which stimulates a
complicated cascade of reactions in the
cytoplasm, leading to activation of nuclear
factor kappa-beta, and eventually the
production of cytokines and chemokines
outside of the cell. The most important of
these cytokines and chemokines include
interferon-alpha,
interferon-gamma,
interleukin- 12, interleukin-8 and tumor
necrosis factor-alpha. The exact effect of
these proteins on the immune system is not
known with certainty. It is known that
these inflammatory cytokines promote the
innate immune system much earlier than
would otherwise occur. The cell-mediated
branch of the immune response is also
stimulated,
leading
to
an
overall
T-lymphocyte helper type- 1 response, and
lm"&i*~& Ciearnfor the
Treatment of Skin Diseases
la
1
:i
1
Most, recalcitrant, difficult-to-treat warts
may even inhibit at Th-2 response. .
kcur in areas with a thick epidermis,
These bits and pieces of immunologic #
information continue to be assimilated in an
require occlusion of imiquimod,
1 therefore
attempt to explain some basic scientific
or pre-treatment with a keratolytic agent.
principles about cytokines, the innate
of the time, keratolysis can be
immune response, and the acquired immune
accomplished with various preparations of
response. However, there is still much we
urea (preferably 40%) prior to imiquimod
do not ,know. What is known is that
application. Improved outcomes can also be
plasmacytoid dendritic cells, the primary
1 accomplished by pre-treating with topical
interferon producing cells, are stimulated by
tretinoin. Occlusion of imiquimod with a
toll-like receptor 7 activation, leading to a
1 "band aid" or gauze containing bandage is
Th- 1 cytokine profile production.(l) Also,
recommended. We suggest the use of
imiquimod is anti-angiogenic, which
'1I1 not
duct tape, electrical tape, or Duoderm for
contributes to its clinical efficacy in treating
occlusion.
hemangiomas, as well as pyogenic
- Imiquimod has also been successful in
granulomas and Kaposi's sarcoma. This may
!
f
1 treating recalcitrant warts, flat warts,
also help in prevention neovascularization
of other types of tumors."
Imiquimod,
1 plantar warts and periungual warts.(9~10.11.12~13)
through its interaction with dendritic cells
Imiqimod is also a viable option for wart
and downstream flow of pro-inflammatory
therapy in immunocompromised patients,
cytokines, leads to apoptosis within tumor
either transplant or HIV infected patients.
c e l l ~ . ( ~ 9The
~ . ~ )combination of plamacytoid
Combinatio of cryotherapy, curettage,
dendritic cell activation, anti-angiogenesis
haridin and other destructive methods,
and ability to cause apoptosis are just of few
imiquimod are commonly employed
of the cellular and immunologic alterations
ore likely to be effective.
induced by imiquimod. This broad range of
cellular changes is responsible for the many ;/!,;I
Contagiosurn
therapeutic applications of imiquimod on !A
1
Although
not approved for the treatment
skin diseases that will be discussed below.
1
molluscum contagiosum, imiquimod is a
Warts
icommonly used and effective therapy for
'molluscum. It is especially useful for facial
Imiquimod was first approved for the
use in external genital warts in 1998. Initial
1 and eyelid molluscum lesions, multiple
wart studies showed an overall efficacy of
lesions in large areas, treatment for infants
about 50%, with better clearance rates in 1 in whom painful destructive procedures are
women than men, perhaps due to anatomy
contraindicate&
and
in
and application on mostly mucosal skin.c7& " immunocompromised patients, including
Since then, almost every type of cutaneous
those with HIVIAIDS.
human papilloma virus (HPV) infections
? Studies evaluating the effectiveness and
has been successfully treated with
clearance rates of imiquimod for molluscum
ilk
imiquimod. (Fig. 1)
. range between 33% and 80% for complete
kj",
. .. '
clearance, and comparable numbers for
partial clearance rates when applied 3 times
a week for 12 weeks-(16917918)
Clearance rates
- 1 may be improved when applied in
combination with cantharidin, cryotherapy ,
, . curettage and topical retinoids.
I' Immunocompromised patients with large,
1
I
1'
/
I
"1 .
;
I
"
;i
,
8
.~
Fig. 1. Anogenital warts clearing with imi
cream after application 3 time
12 weeks.
I
1
/
#$ant lesions pose special treatment
Cibnsiderations.(I9)Application of imiquimod
J Egypt worn Dei-matol Soc. Vol. 5, No. 1,2008
can be inhanced with increasing the
frequency and length of application as well
as with o c c l ~ s i o n . ( ~ ~ ~ ~ ~ )
Herpes simplex
Early in its discovery, imiquimod
showed excellent effects against herpes
simplex virus (HSV) infections in guinea
pigs.(22) Less impressive effects were
observed when imiqui~nodwas used to treat
human HSV infection. Despite its lack of
overwhelming
anti-herpes
action,
imiquimod has been shown to be effective
in rare cases of
HSV, including
acyclovir-resistant HSV in an HIVIAIDS
patient .(23324) Perhaps
other
toll-like
receptors will be developed in the future
that will be more effective for the treatment
and prevention of HSV.
Keloids
Keloid scars are difficult to treat and
recur post-excision about 50% of the time.
Applying imiquimod directly to a keloid
scar is not effective. However, the
post-excision application of imiquimod to a
keloid wound, with or without additional
intralesional steroid or interferon-alpha,
can deter the recurrence of some of the
most recalcitrant keloids.
Small studies have shown a reduction to
keloid recurrence rates when irniquimod is
applied to a sul-gical wound post-excision.
Depending
on the
location, keloid
recurrence rates can be as low as 15% and
as high as 85%.(25)Keloids of the ear seem
to be the most responsive. Recurrence can
be higher on the shoulders and chest.
Usually, irniquimod is applied directly on
to the surgical wound about a week after
the excision, and continued daily to 5 times
per week, for 8 weeks, depending on the
inflammatory response .(26.27728)
There is a growing interest in using
irniquirnod prophylactically for keloid
prevention in high-risk areas and in high
risk patients. Imiquimod has been hinted to
have a cosmetic effect on the skin after
cancer treatment and has also bcen
J Egjpr worn Dermntol Soc. Vol. 5, No. 1, 2008
suggested to promote an anti-aging effect.
(2"
All of the above indicates that
imiquimod may have a more prominent role
in both preventing and treating keloids
scars as well as improving the cosmesis of
surgical wounds in the future.
Hemangiomas
Because infantile hemangiomas (IH)
typically resolve over time, observation is a
common treatment option. However, some
IHs can evolve rapidly, impinge on facial
structures,
inhibit
development
and
function, ulcerate and bleed and thus
require treatment. Imiquimod 5% cream has
been shown to be effective in these
s i t u a t i o n ~ . ( ~ ~ J The
' - ~ ~ ) exact dose and
duration are somewhat arbitrary and
long-term side effects are unknown.
Because
imiquimod
increases
tissue
interferon-alpha, the risk of spastic diplegia
is a major concern with this treatment in
young children.
A retrospective review of (IH) treated
with i~niquirnod 5% cream showed that
imiquimod
was
most
effective
for
superficial IH, but not mixed or deep
hemangiomas. They treated children as
young as 18 weeks. for up to 46 weeks
(mean 17 weeks), 3 to 5 times weekly,
without noticeable systemic symptoms.(33)
Other studies have consistently shown
about 25% cleararlce of lesions and another
50% with partial or incomplete r e ~ p o n s e . " ~ )
The depth of IH is not always measured or
recorded in these studies and in clinical
practice, but this may be the most important
predictor of response with imiquimod 5%
cream.
Cutaneous T-cell I.,ymphoma
Interferon-alpha,
IL- 12 and
tumor
necrosis factor-alpha (TNF-alpha) are
elevated in the skin after imiquimod
application, which is the basis for its
potential use and success in cutaneous
T-cell 1yrnph0rna.c)~)The majority of cases
and case series have applied imiquimod 5 %
cream to treat early or patch stage mycosis
Itniquitnod 5% Creclrn for the
Treatnzeilt of Skin Diseuses
fungoides (MF).
-<I:-":
w+;,:s~
Up to half of the MF patches treated
with imiquimod resolved with 3 times
weekly application for 12 weeks, in a 6
patient report by Deeths et a1.(36.3738)
Treatment of large areas of patch stage
MF with imiquimod is expensive, not
practical and may lead to systemic
interferon-related symptoms. However,
..
can be effective in treating
imiquimod
small areas of MF, localized or unilesional
MF, those lesions recalcitrant to psoralen
and UV-A (PUVA) therapy and MF of the
genitalia and skin f o l d ~ . ( ~ ~ ? ~As
O " ~with
)
many of the off-label uses of imiquimod,
we are discovering niches where the drug
can be most effectively, either alone or in
combination with standard topical and
systemic therapies or when standard
therapies are not effective.'")
Extramammary Paget's Disease
Perhaps the best non-approved indication
in which to use imiquimod is exramammary
Paget's disease (EMPD). This is not only
because imiquimod is effective, but also
because of the difficulty with visualizing
the tumor margins, difficulty in surgically
eradicating this particular tumor, the
morbidity with surgical excision and repair,
and tendency for EMPD to recur. For these
reasons,
other
therapeutic
options,
including imiquimod, continue to expand.
In our experience, and that reported in
the literature, imiquimod is extremely
successful in treating EMPD in the majority
of cases.(43fly4S,46fly48?49)Treatment regimens
range from 3 to 7 times per week and from
6 to 16 weeks of application, depending on
the degree of discomfort. 1.n every case,
patients should be evaluated for an
underlying internal malignancy, especially
urogenital and gastrointestinal carcinomas.
Imiquimod 5% cream can be considered
for mammary and EMPD, when localized,
not
associated with an underlying
carcinoma, or when surgery is deferred or
declined by the patient. Imiquimod has also
been used in combination with topical 5%
5-fluorouracil for EMPDY0) We have also
used retinoids in combination with
imiquimod for recalcitrant cases of EMPD
(unpublished data). Clearance rates are not
well-defined, but when considering the
morbidity
associated
with
surgery,
imiquimod seems to be good choice,
perhaps even a first-line choice, in some
situations.(51)
Actinic Keratoses
Imiquimod is approved for actinic
keratoses (AK) in the United States and
works well in the majority of patients.(52)
Despite its proven efficacy, imiquimod is
not always the primary choice for the
treatment AKs, for the physician or the
patient. Some of the deterrents to its use are
the cost when not covered by insurance, the
small packets which can be difficult to open
by some elderly patients, the variable
inflammatory responses (some severe) and
a long, twice weekly, 16-week course if
used ~ n - l a b e l . ( ~ ~ )
A
more
practical
approach
for
in~iquimod'suse in AK treatment is "cycle
therapy" or application 2-3 times a week, for
about 4 weeks, followed by rest periods for
up to a month, then retreatment if necessary.
This approach can decrease the
incidence of severe inflammatory responses,
allows some flexibility with application,
reduces the total length of application and
can be very effective for the most sun
damaged and difficult to treat patients.
Perhaps the best utilization of imiquimod
for AKs is when there are multiple lesions or
a "field of actinic damage and keratoses,"
higher risk-patients such as organ transplant
patients and those in whom other options are
declined, such as 5 % fluoruracil and
photodynamic therapy.(") As with all AK
therapies, combinations of treatment, with
cryotherapy, curettage, and other topicals is
common, and perhaps more effective than
monotherapy .(59960)
Through
our
knowledge
of
the
mechanism of action of imiquimod, there is
(5495535657)
J Egypt worn Dernzatol Soc. Vol. 5, No. 1, 2008
M. Shane Chapman, M. D.
a belief that this medication is the best
treatment for AKs because it should
actually prevent future AKs via its immune
& ~ )of now,
mechanism and m e m ~ r y . ( ~ l As
this has yet to be proven, but the evidence
for this is accumulating.
Squamous Cell Carcinoma in-situ
(Bowen's Disease)
Bowen's disease or squamous cell
carcinoma (SCC) in-situ, while not
life-threatening, can offer many therapeutic
challenges. Topically applied imiquimod
5% cream can eradicate SCC in-situ in a
majority of cases. Pate1 et a1 have shown a
73% clearance rate of SCC in-situ when
imiquimod is applied daily for 16 weeks.(63)
Imiquimod seems to be particularly
effective for genital SCC in-situ lesions,
and frequently used to treat such lesions as
initial therapy and avoiding surgical
morbidity .(6476566767768969)
Kossard has also
applied imiquimod effectively for large
facial SCC in-situ lesions.(70)
rates range from 62% to 80% depending
on the length of application and tumor size.
(75J6) In general, longer durations of therapy
(up to 12 weeks) and smaller lesions (less
than lcm) respond better. There is about a
10% a discrepancy between clinical
clearance
and
histologic
resolution.
Occlusion may not have a beneficial effect.
Superficial Basal Cell Carcinoma
Imiquimod is effective for superficial
basal cell carcinoma in 85% of cases when
used 3-5 times weekly for 6 w e e k ~ . ( ~ l . ~ ~ )
There can be significant inflammation, but
minimal discomfort. Many patients choose
this option over traditional destructive
methods because of the improved cosmesis,
larger lesions, avoidance of surgical
Fig. 2. Nodular basal cell carcinoma eradicated with
procedures and the ability to self-treat.""
imiquimod 5% cream after daily application for 12
weeks.
This is especially important in some younger
patients equally concerned with cosmetic
outcome as they are with tumor eradicaiton,
While there is no specific study looking
in elderly patients with multiple medical
strictly at sclerotic BCCs, when they are
problems such as defibrillators and in those
included in studies, imiquimod can clear
with the basal cell nevus syndrome.(74)
these t ~ m o r s . ( ~ The
~ J ~ )efficacy rate and
recurrence
rate
is
unknown.
A
Nodular and Sclerotic Basal Cell
post-treatment biopsy should be performed
Carcinoma
for confirmation of clearance of sclerotic
There are various small studies
BCCs.
supporting the efficacy of imiquimod for
In attempt to further improve outcome
nodular and sclerotic basal cell carcinoma
and cosmesis, the combination of initial
(BCC). (Fig. 2) Nodular BCC clearance
curettage
followed
by
imiquimod
J Egypt worn Demzatol Soc. Vol. 5, No. 1, 2008
1
Zmiquimod 5% Creamfor the
Treatment of Skin Diseases
application can optimize both of&&.wa
parameters. Neville et a1 showed 100%
clearance of nodular BCCs following this
c~mbination.(~~,~O)
Melanoma in-situ
,I
Melanoma in-situ is a controversial
topic when considering non-surgical
treatment such as imiquimod. Surgical
excision remains the standard of care.
However, our
surgical dermatology
literature describes a 5 to 20% recurrence
rate of melanoma in-situ (lentigo maligna)
after surgical excision. Recurrence rates
may be lower when considering Mohs
micrographic
surgery and MART- 1
staining, but some argue that narrow
margins may not be appropriate when
considering melanoma in-situ, especially
1'
on sun damaged skin.
Because
imiquimod
induces
an
immunologic response led by an increase in
interferon-alpha, it works well for
melanoma in-situ, and may clear the
peripheral margins equally or better than
surgery, especially when considering the
theory of "skip areas" in melanoma. The
combination of surgical excision along with
adjuvant topical treatment with imiquimod
may be the best option.
Imiquimod has been successful as a
primary treatment for melanoma in-situ,
(Fig. 3) but many of the case reports and
case report series have had various
treatment schedules and clearance criteria.
A single prospective study exists,
showing a clearance rate of 93% (26 of 28
patients) when imiquimod was applied
daily for 12 weeks.(85) However, 5-year
follow up and comparison to surgical
excision has not been done, and the true
recurrence rate within a 5- year period
remains unsettled.
At present,
imiquimod may be
considered for large facial melanoma
in-situ tumors, poor surgical candidates, in
combination with surgical excision, and
should be applied at least 5 days a week for
(81782783,84)
12 weeks, with rest periods for
significant
discomfort
and
extreme
inflammatory responses. The clearance rate
with imiquimod is approximately 90%.
1
I
Fig. 3. Melanoma in-situ clearance with irniquimod 5%
cream after daily application for 6 weeks.
Metastatic Melanoma
Because the mechanism of action of
imiquimod promotes a Th- 1 cytokine,
interferon-alpha reaction, and because of
its known success with primary melanoma
in-situ, treatment with imiquimod for
metastatic melanoma to the skin has been
investigated. Patients with melanoma
metastatic melanoma to the skin have been
completely cleared with imiquimod 5 %
cream, either in combination with
interferons and interleukins or imiquimod
alone
Although, imiquimod will not cure
stage 4 melanoma, it does offer a
non-surgical,
palliative
option
for
metastatic melanoma to the skin, and this
can be a very welcome treatment option
for patients with visible metastatic
melanoma to the skin (Fig. 4).
.(869g7)
J Egypt wom Dermatol Soc. Vol. 5, No. 1,2008
M. Shane Chapman, M.D.
REFERENCES
-M
I
Fig. 4. Metastatic melanoma to the skin, clearing with
irniquimod 5% cream after daily application for 16
weeks, with residual depigmentation.
Conclusion
Imiquimod is the first generation of
immune response modifiers. It has shown
us the importance of cytokines, toll-like
receptors and the innate immune system in
fighting a multitude of skin diseases. The
potential benefits of immune response
modification with
toll-like receptor
agonist and antagonists have the ability to
change the way we deliver health care. In
the future, more specific, toll-like
receptors will be developed to improve
vaccines, prevent toxic shock, improve
immunity and fight internal cancer from
within. This type of immune enhancement
will also be a part of the future of
dermatology.
J Egypt worn Dermatol Soc. Vol.5,No. 1, 2008
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