Pemphigus: An Acronym for a Disease with Multiple Causes

Pemphigus is generally considered to stem from a genetic predisposition to the disease triggered and/or aggravated by one or more external factors. An acronym has been suggested from the name of the disease, PEMPHIGUS, to encompass those factors:

PE=Pesticides
M= Malignancy
P= Pharmaceuticals
H=Hormones
I=Infectious agents
G=Gastronomy
U=UV radiation
S=Stress

Pesticides

Gardening materials and pesticides are a major group of agents implicated in the development of the disease. The medical literature documents numerous cases provoked by pesticides all over the world. Organochlorine pesticides, and organophosphates, a new generation of pesticides, have been tied to the disease.

How pesticides work on the skin is unclear. It is speculated that the immune system is activated via contact or systemic exposure, resulting in the generation of autoantibodies targeting desmosomal antigens. Interestingly, in most of the reported cases the patients had a first-time, long-duration exposure to the offending substance, and developed the disease only after a massive additional exposure, resembling the induction and elicitation phases of allergic contact dermatitis.

Malignancy

Pemphigus has been associated with malignant processes, mainly hematolymphoproliferative diseases such as Hodgkin's lymphoma, chronic lymphocytic leukemia, Castelman's disease, and others. These constitute a specific clinicopathological variant called paraneoplastic pemphigus. A few reports on cases of pemphigus associated with malignant diseases that did not meet the above criteria raised the possibility of simple co-existence. In both events, the physician should perform a malignancy-directed work-up on a pemphigus patient.

Pharmaceuticals

Drugs reported to induce pemphigus are divided into three main groups according to their chemical structure: drugs containing a sulfhydryl radical such as penicillamine; phenols such as rifampin, levodopa and aspirin; and nonthiol nonphenol drugs, such as calcium channel blockers, angiotensin converting enzyme inhibitors, NSAIDS, dipyrone, and glibenclamide.

Again, speculated mechanisms are chemical insult and immune system activation by a complicated mechanism involving diverse molecules (autoantibodies, cytokines). Calcium channel blockers are emphasized in view of the fact that the calcium ion is critical to maintaining an intact epithelium.

Hormones

Pregnancy is closely related to autoimmune diseases and thus to immunoblistering diseases, an association seen in the aggravation of pemphigus vulgaris during pregnancy, and pregnancy- or postnatally-induced herpes gestationis and neonatal pemphigus. These diseases are attributed to the passage of pathogenic autoantibodies via the placenta that target different placental antigens or skin antigens in the newborn. The role of sex hormones, mainly estrogen, in the pathogenesis of pemphigus has not yet been established.

Infection

Different infectious agents and immunizations can induce or exacerbate pemhigus, mainly by activating the cellular immune system. The most frequently incriminated infectious agents are the viruses of the herpetoviridae family, namely herpes simplex, EBV, CMV, and even HH8.

Despite the confusing clinical similarities of viral diseases and pemphigus, and because of the different outcomes of the two conditions, it is important to diagnose viral infection in a pemphigus patient and initiate early antiviral therapy, often as an adjunct to immunosuppressive therapy. Viral isolation remains the most reliable laboratory means for viral diagnosis, followed by molecular biology techniques, which are more sensitive but less reliable and indicated only in cases in which the results of the former are not conclusive.

In addition, bacteria such as coagulase positive staph aureus are capable of inducing pemphigus. Gram negative bacteria and even Actinomyces have been cultured in patients before the pemphigus becomes manifest, and were therefore described as its possible triggers.

Gastronomy

Although rarely mentioned in the literature, recent studies indicate that certain foods can induce or trigger pemphigus. Some nutritional components are chemically similar to known causative drugs, and may act in the same way. The following chemicals and related foodstuffs have been associated with pemphigus:

Pemphigus Vulgaris

Pemphigus is a particularly difficult disease to treat. Anti-desmoglein antibodies are produced in all forms of pemphigus. These antibodies bind to adhesion molecules on the epithelial cell surface, which leads to separation of keratinocytes from each other and to blister formation. The exact mechanism by which this occurs is uncertain but likely involves inflammatory pathways triggered by binding of antibodies to the adhesion molecules. Therefore, therapy is intended to reduce the production of pathogenic antibodies and to inhibit the other pathways involved in the disease process (aa). It is unclear at this time, whether drug therapy's effect on reducing autoantibody synthesis is more or less significant than the effect of decreasing the inflammatory response. Pemphigus occurs in various parts of the body and often looks like these photos.

A recent analysis of therapeutic approach identified the following patterns and opportunities for improving care:

Early expert evaluation: as "the long delay from onset of symptoms to expert evaluation is quite striking". In PV, similarly to other autoimmune diseases, if the process is not promptly and appropriately controlled, the disease becomes more resistant, making the condition more difficult to treat.
Confirmation of the clinical diagnosis: by tissue biopsy specimen for histopathologic and both indirect and direct immunofluorescence examination.
Although still under evaluation, consideration of early adjuvant immunosuppression in moderate and severe cases: e.g. azathioprine or mycophenolate mofetil.
Review of the length of adjuvant immunosuppressant use: The vast majority (82%) of experts use adjuvant immunosuppressants for 2 years or less (bb).

Types of Pemphigoid

All types of pemphigoid are caused by an immune system malfunction. They create rashes and fluid-filled blisters. The types of pemphigoid differ in terms of where on the body the blistering occurs and when it occurs.

Bullous Pemphigoid - In cases of bullous pemphigoid, the skin blistering occurs most commonly on the arms and legs where movement occurs, that is, around the joints and on the lower abdomen.

Cicatricial Pemphigoid - Cicatricial pemphigoid refers to blisters that form on the mucous membranes. This includes the mouth, eyes, nose, throat, and genitals. The rash and blistering may begin in one of these areas and spread to the others if left untreated.

Pemphigoid Gestationis - When blistering occurs during or shortly after pregnancy, it is called pemphigoid gestationis. It is also called herpes gestationis, although it is not related to the herpes virus. The blistering typically develops during the second or third trimester, but may occur at any time during pregnancy or up to six weeks after delivery. Blisters tend to form on the arms, legs, and abdomen.

Causes

The cause of bullous pemphigoid is not well understood. The blisters occur because of a malfunction in the immune system.

Your body's immune system normally produces antibodies to fight bacteria, viruses or other potentially harmful foreign substances. For reasons that are not clear, the body may develop an antibody to a particular tissue in your body.

In bullous pemphigoid, the immune system produces antibodies to the skin's basement membrane, a thin layer of fibers connecting the outer layer of skin (epidermis) and the next layer of skin (dermis). These antibodies trigger inflammatory activity that produces the blisters and itching of bullous pemphigoid.

Contributing factorsullous pemphigoid usually appears randomly with no clear factors contributing to the onset of disease. A small percentage of cases may be triggered by certain medical treatments, such as:

Medications. Prescription drugs that may cause bullous pemphigoid include penicillin, etanercept (Enbrel), sulfasalazine (Azulfidine) and furosemide (Lasix).
Light and radiation. Ultraviolet light therapy to treat certain skin conditions may trigger bullous pemphigoid, as can radiation therapy to treat cancer.

Associated diseases

Pemphigus is associated with other autoimmune diseases. It has been reported in association with myasthenia gravis.

What can I do to help manage my Pemphigus & Pemphigoid symptoms?

Avoid these foods and food additives as they may contribute and/or trigger an outbreak episode.

PHENOLS

Fruits: mango, bananas, potatoes, tomatoes
Nuts: pistachio, cashew
Pinenes: baked goods, smoked and grilled food, candy, chewing gum, ice cream, black pepper
Cow's milk
Food additives: aspartame, sodium benzoate, tartrazine, vanillin, eugenol, caffeic acid, cinnamic acid, vitamis C and E

TANNINS

Nuts: Kola, betal, walnuts
Fruits: cassava, cranberry, raspberry, blackberry, cherry, banana, apple, pear, grape skins, peach avocado
Drinks: tea, mate, fruit juice, beer, wine, liquors, water, coffee, guarana
Food additives: vanillin
Spices: ajowan, coriander, cumin, black pepper, red chilies, rosemary, garlic, ginger

THIOLS

Vegetables: garlic, onion, shallot, chive, leek

Assuming that foods containing thiol, phenol, and polyphenolic compounds may contribute to pemphigus, avoidance of certain foods may lead to remission.

Ultraviolet radiation

Pemphigus is considered a photosensitive disease, especially the superficial variant pemphigus erythematosus. Ultraviolet radiation, either occupation- or leisure-related, can induce or exacerbate the clinical manifestation. Whether the phototoxic reaction is a simple one or entails specific immune system stimulation remains to be determined.

Physical factors such as x- ray radiotherapy, burns, major surgery and cosmetic procedures have also been reported capable of inducing pemphigus.

Stress

The well-known connection between the immune and nervous systems raises the possibility that a psychoneural disorder can influence the onset and course of autoimmune disease. Several studies and case reports point to the possible contribution of emotional stress as a precipitating factor in pemphigus. Hence, avoiding emotional stress may be therapeutic in pemphigus patients, hastening the healing process and reducing or stopping the use of immunosuppressive drugs.

In summary, while the myriad causes of pemphigus complicate the differential diagnosis and course of the disease, it also points to the numerous factors that can help in its diagnosis and treatment. These factors have been documented in the studies cited here. The acronym is suggested to give clinicians a tool to pinpoint possible causes and prevent flare-ups in every newly diagnosed pemphigus patient.

DHEA
Low levels of DHEA are seen in many of the autoimmune diseases, and higher daily intake of DHEA is associated with improvement of symptoms in many. A typical daily dose of DHEA for autoimmunity would be 50-200mg per day. However, since DHEA is a hormone, doses in excess of 50mg per day should be supervised.

Chinese Rhodiola

Stress is the #1 antagonizer in autoimmune diseases and the effects of this are devastating.
Rhodiola rosea, literally reduces the cortisol in your body. This is the hormone that is released from your adrenal glands in a cyclic manner during the day or during times of stress -- most of us exist in a state of nearly constant exposure to this compound, resulting in lowered blood sugar response, abdominal weight gain, decreased memory, reduced cellular energy production, and diminished immunity.

References:
DermIS. http://www.dermis.net/dermisroot/en/29935/diagnose.htm
International Pemphigus & Pemphigoid http://www.pemphigus.org
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