pemphigus   foliaceous
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




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 -

Departments of Dermatology and Neurology

University of California

Department of Dermatology Kaiser Permanente

Psoriasis induced by topical imiquimod
Jason K Wu ; Greg Siller ; Geoff Strutton 

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.




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.



by Marta Lucia Cuellar, MD – Tulane University Medical Center


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



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.


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.




Brain Behav Immun. 2009 Jan;23(1):55-63. Epub 2008 Jul 17.

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.


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.



Imiquimod induces apoptosis of human melanocytes

Chul-Ho Kim, Joo Hee Ahn, Sung Un Kang, Hye Sook Hwang, Mi Hye Lee, Jung Hee Pyun and Hee Young Kang



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.


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.