We welcome Mashiah and Brenner's cogent comments. The fact that 2 cases of pemphigus localized at sites of topical
Aldara / imiquimod treatment have now been reported makes one wonder how many cases have gone unreported. It is
critical for any additional cases to be reported so that the ever increasing number of patients being treated with this
medication can be informed of this permanent and severe adverse effect, however rare it may be.
As we all know, pemphigus requires lifelong treatment with systemic immunosuppressive agents. These agents increase
the risk of opportunistic infections and cancers. As dermatologists counseling our patients on how to best treat their skin
cancers and precancers, we would be wise to mention pemphigus foliaceous as a possible adverse effect of topical
imiquimod therapy and the long-term comorbidities associated with its treatment, which could actually increase
the chance of getting cancer in the future.
While imiquimod is a powerful immunologic weapon against skin cancer and precancer, it can obviously work
just as powerfully against our patients. While cryosurgery. electrodessication and curettage, routine excision, and Mohs
micro graphic surgery may be older and thus viewed as somewhat "less sophisticated" than topical imiquimod, we are
far more familiar with their long-term adverse effects. Clearly, more reporting of "pemphigus imiquimodious" is
needed to assess the incidence of this adverse effect of topical imiquimod treatment.
Daniel J. Ladd, Jr, DO Rick J. Lin, DO
herpes simplex virus (HSV)
Topical Imiquimod Therapy for Cutaneous T-Cell Lymphoma
Jennifer Do, MA, MD - Susan S. McLaughlin, MA, MD - Anthony A. Gaspari, MD
Medscape – WEBMD posted 10/29/2003
A 74-year old Caucasian woman was being treated for cutaneous T-cell lymphoma (CTCL). The Aldara/imiquimod
she was using in her treatment of this incurrable CTCL disease triggered the activation and out-break of herpes simplex
virus (HSV), a known side-effect of Aldara.
Excerpts
from Article:
Adverse skin reaction included (among others)
scarring as a consequence of cytokine induced inflammation……..
…imiquimod has been shown to increase levels of
prostaglandin E2 , which has been associated with
the activation of herpes simplex virus (HSV).
Imiquimod therapy has been associated with
recurrences of HSV in patients with a history of facial HSV.
Chronic neuropathic pain associated with imiquimod
J AM ACAD DERMATOLOGY
FEBRUARY 2005
ABSTRACT
Imiquimod is known to stimulate
the production of interferon-
a
and other
cytokines that have been linked to the development of distal peripheral
neuropathies and focal neuropathies.
The
mechanism of action of interferon associated
nerve damage may be mediated by the induction of HLA-DR expression in
Schwann cells making them potential targets for immunologic attack.
(Normally, nerve cells do not express HLA-DR on the surface.) In
neuropathy of small myelinated and unmyelinated nerves, standard
electrodiagnostic studies may be normal. In the cases reported
above, it
is notable that factors, such as erosion or daily use with paring and
tape occlusion, may have led to an increase in penetration of imiquimod
through the skin.
B. Alexander Yi, PhDa
Melissa J. Nirenberg, MD, PhDb
B. Alexander Yi, PhD
- Melissa J. Nirenberg, MD, PhD
- Sanford M. Goldstein, MD
- Timothy
G. Berger, MD
-
We report
the provocation of localized psoriasis at the sites of application of
topical imiquimod, possibly evolving into a generalized flare. A patient
with pre-existing psoriasis that had been stable for 14 years was treated
with imiquimod 5% cream daily for 6 weeks to three superficial basal cell
carcinomas. During treatment one of the lesions developed severe local skin
reactions necessitating rest periods, and received only 18 applications in 6
weeks. The other two lesions were treated for all 42 days. Psoriasiform
changes developed at all three application sites. Nine-and-a-half weeks
after completing treatment the patient developed disseminated small
psoriatic lesions. Other recognized triggers of psoriasis were not
identified. The psoriasis resolved slowly with conventional treatment.
Pityriasis rubra
pilaris exacerbation with topical use of
imiquimod
F.
Clarissa Yang MD,
Chad
Jessup MD, MS,
Madhu
Dahiya MD,
Rachel Reynolds MD
Article first
published online: 24 SEP 2008
DOI:
10.1111/j.1365-4632.2008.03729.x
Abstract
The role of
immune response modifiers is increasing in
the treatment of dermatologic diseases.
Imiquimod, a toll-like receptor agonist,
results in up-regulation of proinflammatory
cytokines for improved immune surveillance.
Although topical use is generally
well-tolerated, imiquimod can potentially
result in systemic effects and exacerbate
generalized inflammatory papulosquamous
diseases of the skin. We report the case of
a 67-year-old man who was treated with
imiquimod for actinic keratosis and
developed fever and a progressive
erythematous papulosquamous eruption that
was histologically consistent with
pityriasis rubra pilaris.
DRUG INDUCED VASCULITIS
by Marta Lucia Cuellar, MD – Tulane University Medical Center
ABSTRACT
With the increasing therapeutic use of cytokines and hematopoietic growth
factors (both found in the family of proteins induced by Imiquimod) in a
variety of clinical disorders, a large body of evidence is accumulating to
support the notion that activation of the immune response may result at
times in deleterious consequences. A large clinical spectrum of adverse
events, have been described as a direct consequence of the immune activation
induced by cytokines (eg, flu-like illness, vascular leak syndrome, frank
leuko-cytoclastic vasculitis). This may occur in addition to development of
several types of auto-antibodies, and the development or exacerbation of
autoimmune disorders (ie, thyroiditis, SLE, RA, autoimmune hematologic
diseases, insulin-dependent diabetes mellitus, nephritis, psoriasis,
colitis).
Interferon-alpha may induce auto-antibodies and autoimmune disorders such
as nephritis, pneumonitis, colitis, and SLE.
How Interferon
Ruins Your Brain
By Russel L.
Blaylock, M.D.
Board Certified Neurosurgeon
Practitioner, Author & Lecturer
ABSTRACT
The mechanism
of this injury to the brain appears to involve the brain's special immune
cell called the microglia. Normally, these cells remain dormant in the
brain. That is, they are sleeping. Microglia cells can be activated by
numerous factors, including mercury, aluminum, iron, over-vaccination, and
brain trauma, strokes, infections (viruses, bacteria, rickettsia) and
cytokines such as interferon's.
Once
activated, microglia can move about the brain secreting very toxic
compounds, which include two excitotoxins (glutamate and quinolinic acid).
These excitotoxins dramatically increase free radical generation in the
brain as well as oxidation of lipids (called lipid peroxidation). These
radicals, damage synaptic connections, interfere with neurotransmitters and
can even kill neurons. In addition, these activated microglia, generate
other toxic compounds such as prostaglandins (PGE2), which increase brain
inflammation.
If the
microglia activation is short lived, the damage to the brain is minimal and
recovery takes place. Yet, should the activation continue, which would occur
with high-dose and long-term use of interferon's, the damage could be
substantial and irreversible.
Immune-mediated side-effects of cytokines in
human's.
Vial T, Descotes J.Laboratoire d'Immunotoxicologie Fondamentale et Clinique, INSERM U80,
Faculté de Médecine Alexis Carrel, Lyon,France.
Toxicology. 1995 Dec
20;105(1):31-57.
Abstract
A large body of clinical experience on the adverse consequences of cytokine
administration has accumulated since the last decade. Side-effects reported
after the therapeutic use of cytokines has provided evidence that activation
of the immune response may sometimes have deleterious consequences. Several
effects appeared as a direct consequence of the immune activation induced by
cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced
exacerbation of underlying diseases or immune dysregulation were other
complications of growing concern. Interferon-alpha (IFN-alpha) treatment has
now been clearly linked with the exacerbation or the occurrence of several
types of auto-antibodies or autoimmune diseases ( thyroiditis, systemic
lupus erythematosus, hematologic disorders, insulin-dependent diabetes
mellitus) or diseases involving altered cell-mediated immune functions
(inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By
contrast immunological side-effects of IFN-beta and IFN-gamma have been
seldom reported. However, the extent of clinical experience with both of
these cytokines is still very limited. Interleukin-2 (IL-2) has also been
implicated in various conditions that may involve immuno-pathological
processes (thyroid disorders, rheumatoid arthritis, dermatological diseases,
interstitial nephritis). Growth factors have been more specifically linked
with the development or the exacerbation of dermatological inflammatory
diseases through neutrophils, monocytes / macrophages or eosinophils
activation (e.g. cutaneous vasculitis and generalized cutaneous eruption,
Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune
thyroiditis was described with granulocyte-macrophage colony-stimulating
factor (GM-CSF) only.
Peripheral
cytokines profile in Parkinson's disease
.
Reale
M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M.
Department of Oncology and Neuroscience, University G. D'Annunzio
Chieti-Pescara, Italy. mreale@unich.it
Abstract
Higher levels of proinflammatory cytokines
are found in Parkinson's disease (PD) patient's brains and inflammation is
thought to be a major contributor to the neurodegeneration. During the
inflammatoryprocess, microglial release of proinflammatory cytokines
act on the endothelium of blood-brain barrier(BBB) cells to stimulate
upregulation of adhesion molecules. Consequently, this upregulation leads to
the recruitment of passing T cells and monocytes, which express the counter
receptors, that then go on to release more cytokines [Whitton, P.S., 2007.
Inflammation as a causative factor in the aetiology of Parkinson's disease,
Br. J. Pharmacol. 50, 963-976; Kortekaas, R., Leenders, K.L., Van Oostrom,
J.C.,Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005.
Blood-brain barrier dysfunction in parkinsonian midbrain in vivo, Ann.
Neurol. 57, 176-179]. In addition, a systemic inflammatory response results
in the production of cytokines which circulate in the blood and communicate
with neurons within the brain. Thus, a central inflammatory reaction
interacts with peripheral blood mononuclear cells (PBMCs) modulating immune
activity. The present study investigates levels of production and expression
ofcyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of
MCP-1, RANTES, MIP-1alpha, IL-8, IFNgamma, IL-1beta and TNFalpha were
significantly higher in PD patients than in HCsubjects (p<0.001), as
determined by RT-PCR and Elisa methods. Cyto/chemokine levels were
significantly correlated with UPDRS III and H/Y stage (p<0.001). The
Pearson's correlation coefficient (R)was also used to assess the strength of
the relationship between NF-kappaBp65 levels and all studie dcyto/chemokines
and between NF-kappaBp65, UPDRS III and H/Y score in PD patients. The
overall results strengthen and extend the knowledge of the peripheral
dysregulation in the cytokine network associated with PD.
Development of vitiligo-like
hypopigmentary lesions associated with topical imiquimod has been
reported. We hypothesized that mode of action of imiquimod in
melanocytes may include triggering of apoptosis resulted in loss of
cells, which may be a possible mechanism of imiquimod-induced
hypopigmentary lesions. Therefore, we investigated whether imiquimod
induces apoptosis of human melanocytes and also whether it modulates
expression of apoptosis-related molecules in human melanocytes.
Imiquimod treatment induced apoptosis of melanocytes, which was
observed by TUNEL assay and Hoechst 33258 staining.
Imiquimod-induced apoptosis was further shown by measuring
mitochondrial membrane potential in melanocytes. The apoptotic
activity of imiquimod was associated with caspase-3, Bcl-2 and
mitogen-activated protein kinase expression in melanocytes. These
results indicated that imiquimod induces apoptosis of melanocytes.
These findings may provide a clue to understand pathogenesis of
imiquimod-induced vitiligo-like hypopigmentary lesions.
Development of
subacute cutaneous lupus erythematosus associated with the use of imiquimod
to treat actinic keratoses.
Burnett TJ
,
English JC 3rd, Ferris LK.
United
States Air Force, WPAFB, OH, USA.
Abstract
The immunomodulating drug imiquimod
is approved by the U.S. Food and Drug Administration (FDA) to treat actinic
keratoses, non-facial superficial basal cell carcinomas and genital warts.
This drug elicits its immunological response by binding to toll-like
receptor 7 (TLR-7) on dendritic cells inducing the production of interferon
alpha (IFN-alpha) and other inflammatory cytokines. The authors report the
case of a 56-year-old female who developed subacute cutaneous lupus
erythematosus (SCLE), as well as severe autoimmune retinitis following a
vigorous response to imiquimod 5% cream that was prescribed to treat actinic
keratoses. Given the important role of IFN-alpha in the pathogenesis of
cutaneous lupus, it is likely that imiquimod either induced or unmasked an
autoimmune tendency in this patient.
