An Integrative Medicine Approach to Immunobullous (Blistering) Diseases

Immunobulluos diseases include blistering conditions of the skin that are caused by an autoimmune process. Some autoimmune bullous dermatoses include pemphigus vulgaris, bullous pemphigoid, and dermatitis herpetiformis.

In these conditions, the body mistakenly produces antibodies that target different proteins within the skin, resulting in different types of blistering and ulcerations depending on the location and function of the protein. These chronic skin disorders are most common in older adults and can cause significant discomfort and complications. 

An integrative approach to immunobullous diseases investigates underlying factors contributing to the autoimmune process using clinical assessment and functional medicine testing. Based on this evaluation, an individual management plan can be developed utilizing diet, supplementation, and lifestyle approaches to improve quality of life.  

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What Are Immunobullous (Blistering) Diseases?

The skin is the body’s largest organ and plays key roles in protecting you from the outside world, helping you maintain a constant body temperature, and allowing you to feel sensations. It is made up of several layers that help it maintain its structure and function. The epidermis is the outermost layer in contact with the outside world. Beneath the epidermis is a basement membrane that separates it from the middle layer known as the dermis. Below the dermis is a layer of fat called the hypodermis.

In immunobullous diseases, the immune system produces auto-antibodies directed at different proteins within the skin. These antibodies can bind to different parts of the skin, such as the epidermis, epidermal basement membrane, or dermis. Depending on the target of the antibodies, the skin develops different types of blisters and/or ulcerations. For example, if antibodies bind to proteins within the epidermis, flaccid blisters and erosions can develop. When antibodies bind to the epidermal basement membrane, this results in tense bullae. Bullae are large blisters filled with clear fluid that form in the skin.

Pemphigus Vulgaris 

Pemphigus vulgaris occurs due to antibodies that target proteins in desmosomes, the junction that helps to hold adjacent cells together. These proteins are found mostly in the outermost layers of the epidermis and mucosal tissues. Therefore, pemphigus vulgaris generally causes flaccid blisters or crushed erosions on the head, upper trunk, areas of skin folds like the groin and armpits, and mucosa. This can be painful, with oral involvement causing hoarseness. This disease most commonly begins between 40 and 60 years of age and is most common in those of Jewish or Mediterranean descent. While this skin condition is rare, there is a chance of infection, and it can be fatal if untreated.

Bullous Pemphigoid 

Bullous pemphigoid often starts out as localized or generalized red hives and itchy plaques on the lower legs, forearms, thighs, groin, and abdomen and evolves into tense bullae with clear fluid or erosions. Unlike pemphigus, it rarely impacts the mucosa. It generally begins in older age, between the ages of 60 and 80. Even when left untreated, this condition is usually self-limited. 

Dermatitis herpetiformis

Dermatitis herpetiformis causes grouped (herpetiform) itchy and burning vesicles or crusted erosions most commonly appearing symmetrically on the extensor forearms, elbows, and buttocks. It is associated with celiac disease and is almost always accompanied by signs of gastrointestinal disease. In addition to celiac disease, people with dermatitis herpetiformis have an increased risk of having other autoimmune disorders, including thyroid disease, type 1 diabetes mellitus, systemic lupus erythematosus, vitiligo, and Sjögren's syndrome. This immunobullous disease is more likely than the others to arise at a younger age, most commonly between 20 and 40 years of age, but it can also be seen in children. 

What Are The Possible Causes of Immunobullous (Blistering) Diseases?

Immunobullous diseases develop due to the immune system mistakenly forming antibodies that target proteins in the skin. The autoimmune attack that occurs in immunobullous diseases is due to the interaction of genetics and environmental factors, including a possible role for infectious diseases, imbalances in the microbiome, medications, allergens, radiation therapy, diet, and emotional stress potentially inducing immune dysregulation in someone with a genetic predisposition.

In pemphigus vulgaris, antibodies bind to desmoglein (Dsg) 1 and 3, which causes keratinocytes to separate, allowing intraepithelial blisters to form. Thiol-containing drugs such as penicillin, cephalosporins, and captopril, and phenol-containing medications such as aspirin, rifampin, levodopa, heroin, and some cephalosporins (which can also contain thiol groups) can bind to keratinocytes, interrupt cell-to-cell cohesion, and stimulate autoimmune attack. Other medications, such as angiotensin-converting enzyme (ACE) inhibitors (other than captopril), vaccines, interferons, and nonsteroidal anti-inflammatory drugs (NSAIDs) may also result in tissue disruption and/or autoantibody production leading to pemphigus blistering. 

A similar disruption of immune tolerance can occur in susceptible individuals when consuming foods high in thiols, such as garlic, leeks, and onions, and polyphenols like black pepper, red chili pepper, cherry, and red wine. 

While the exact mechanisms are still under study, viral infections, especially herpesvirus, cause inflammation and epithelial damage that contribute to pemphigoid lesions.

Bullous pemphigoid results due to antibodies that bind to proteins within the basement membrane of the epidermis, resulting in subepithelial blister formation. In some cases, this autoimmune process appears to be associated with taking dipeptidyl-peptidase 4 (DPP-4) inhibitors such as linagliptin that are used in the treatment of type 2 diabetes or when taking aspirin.

Studies show that traumatic injuries to the skin from exposure to radiation or excessive sun damage may lead to blister and bullae formation since these insults expose self-antigens. In addition, people with neurologic and neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, have an increased risk of developing bullous pemphigoid.

Dermatitis herpetiformis is a rash that occurs due to the autoimmune process that occurs in celiac disease. The blisters of this condition arise due to pathogenic IgA transglutaminase antibody binding within the upper dermis of the skin and are most common in people with certain genetic predispositions (human leukocyte antigen haplotypes DQ2 and DQ8). 

Exposures to environmental chemicals and other factors can contribute to imbalances in the skin and gut microbiomes that further dysregulate the immune system and cause inflammation, contributing to the development of autoimmunity. Like the gut, the skin is inhabited by microorganisms, including bacteria, fungi, viruses, and mites, that make up the skin microbiome and interact bidirectionally with gut microbes in the gut-skin axis. A loss of protective microbiota and an increase in inflammatory species has been seen in immunobullous diseases.

Further, impaired intestinal barrier function (leaky gut) can lead to the activation of an autoimmune response, which may be induced through molecular mimicry between food ingredients and self-antigens, increased inflammation, and/or the passage of other foreign substances into the bloodstream. 

Functional Medicine Labs to Test for Root Cause of Immunobullous (Blistering) Diseases

Functional medicine laboratory testing can help to assess factors contributing to the autoimmune process that underlies immunobullous diseases. 

Comprehensive Gut Testing

Testing using the GI-MAP allows for a comprehensive evaluation of the gut to look at factors that may be contributing to autoimmunity and inflammation. This stool test assesses the composition of the gut microbiome and measures relative amounts of healthy and unbalanced gut bacteria, inflammation, and leaky gut markers to uncover imbalances that can trigger inflammation and contribute to the immune dysregulation underlying the development of autoimmune disease. 

Testing for Food Allergies

Food allergies and sensitivities can also contribute to increased intestinal permeability, inflammation, and autoimmunity. Foods to which an individual is allergic or sensitive can be identified through various tests, including blood spot or blood draw for both food sensitivity and food allergens.

Testing for Celiac Antibodies

Since dermatitis herpetiformis is usually the cutaneous manifestation of underlying celiac disease, these patients show typical celiac disease alterations on a small bowel biopsy. Given the invasive nature of duodenum biopsy, the risks involved, and the increasing accuracy of available blood testing, circulating auto-antibodies to tissue transglutaminase (tTG), endomysial, and deamidated gliadin peptide can be measured. Looking at both immunoglobulin-A (IgA) and -G (IgG) antibodies against t-TG2 increases accuracy.

Specialty testing while eating gluten can detect antibodies to gluten proteins using tests such as the Elisa LRA Gluten Hypersensitivity Block (IgG, IgM, IgA), and Genova Diagnostics Celiac Panel (IgG & IgA).

Vitamin D Levels

Patients with pemphigus vulgaris, bullous pemphigoid, and other immunobullous diseases have low levels of vitamin D, which might contribute to dysregulation of the immune system and worsening of their disease. Vitamin D levels can be measured in the blood to determine if repletion with supplementation may be needed. 

Micronutrient Testing

People with immunobullous diseases like pemphigus vulgaris and dermatitis herpetiformis are more likely to have vitamin and mineral deficiencies due to the disease process itself, accompanying gut issues, and/or side effects of medications. For example, pemphigus vulgaris depletes trace elements, including zinc, selenium, and copper, which have important roles in immune health, wound healing, and antioxidant defense.

The function of 31 vitamins, minerals, amino acids, and antioxidants can be measured with the SpectraCell Micronutrient test.

Additional Labs To Test 

A skin biopsy is used to determine the type of immunobullous skin disease. To do this, a small sample is taken from the skin and examined under a microscope. To diagnose immunobullous diseases, a technique known as direct immunofluorescence is used. This technique involves the application of a glowing substance (fluorophore) attached to a specific antibody that binds to abnormal depositions of proteins in skin samples. When a special light is applied, the fluorophore emits light in a pattern that can be identified with different conditions and seen with a microscope.

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Conventional Treatment for Immunobullous (Blistering) Diseases

The conventional treatment of immunobullous diseases generally involves suppressing the immune system. For example, pemphigus vulgaris and bullous pemphigoid are commonly treated with corticosteroids like prednisone to suppress the autoimmune attack on the skin with the addition of azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan), or mycophenolate mofetil (CellCept) in some cases. Plasmapheresis or plasma exchange is also sometimes used to remove harmful antibodies.

Since dermatitis herpetiformis is associated with celiac disease, the first-line treatment is a gluten-free diet. If this does not result in the rash resolving after several months, dapsone is sometimes added.

Functional Medicine Treatment for Immunobullous (Blistering) Diseases

An integrative dermatology approach to immunobullous diseases aims to uncover and address underlying factors contributing to the autoimmune process. An individualized management approach combining diet, lifestyle, supplements, and integrative therapies can then be used to tame autoimmunity and inflammation in order to bring the body back into balance and improve quality of life.

Nutritional Recommendations

Nutrition plays a key role in the development of the dysregulation of the immune system that occurs in inflammatory skin conditions and autoimmunity. People with immunobullous diseases often benefit from a gluten-free, individualized, anti-inflammatory diet to reduce inflammation and autoimmunity.

A personalized anti-inflammatory diet can help reduce inflammation and calm autoimmune responses. For example, a Mediterranean Diet that emphasizes whole fresh vegetables and fruits while limiting processed foods and additives, caffeine, and alcohol, as well as any foods you are allergic or sensitive to, can help to reduce excess inflammation and heal the gut. 

In particular, omega-3 fatty acids EPA and DHA favorably regulate inflammatory responses. These healthy fats are found in cold-water fish like mackerel and salmon, walnuts, flaxseeds, and chia seeds, which can be integrated into a Mediterranean diet.

People with pemphigus often do best when avoiding foods high in thiols, including garlic, leeks, and onions, as well as foods and beverages containing high amounts of polyphenols like black pepper, red chili pepper, cherry, and red wine since these can trigger an autoimmune attack.

With dermatitis herpetiformis, a strict gluten-free diet is essential, with the avoidance of wheat, rye, and barley. Some alternative starches and flours that are gluten-free include amaranth, buckwheat, corn, flax, millet, quinoa, rice, sorghum, soy, and tapioca. In addition, studies have shown that an elemental diet can help reduce these skin lesions. This involves consuming free amino acids, short-chain polysaccharides, and small amounts of triglycerides and can result in the resolution of the rash more quickly than with a gluten-free diet, within a few weeks, although this diet can be very difficult to tolerate.

Supplements & Herbs for Immunobullous Diseases

In addition to an anti-inflammatory diet that limits gluten and other foods to which an individual is allergic or sensitive, targeted supplements may help reduce autoimmunity and inflammation and improve quality of life.

Vitamin D

Vitamin D plays a crucial role in regulating the immune system, including reducing the risk of autoimmune disease. If vitamin D levels are insufficient with testing, supplementation may help to replenish levels and regulate the immune response. Studies show significant improvement in autoimmune attack in pemphigus vulgaris with vitamin D supplementation.

Omega-3 Fatty Acids

Your body needs omega-3 fats from diet or supplementation to carry out important processes, including keeping the skin healthy. Supplementation with omega-3 fatty acids has been shown to reduce autoimmune disease and improve oral ulcerations in patients with pemphigus vulgaris.

Nicotinamide (vitamin B3)

Nicotinamide (or niacinamide) is a form of vitamin B3 that has been shown to benefit bullous pemphigoid when used in combination with tetracycline antibiotics. Further studies are needed, but nicotinamide may be a useful alternative to systemic steroids, with similar efficacy and fewer side effects, especially among older patients who are more prone to developing serious adverse effects from corticosteroids.

Probiotics

Supplementing with probiotics tailored to individual needs and testing results can help restore gut health to help with reducing autoimmunity and improve digestion and absorption of nutrients. Certain strains of probiotics have been shown to help celiac patients, including Bifidobacterium infantis, Bifidobacterium longum, Bifidobacterium breve, Lactobacillus casei, and Lactobacillus plantarum. 

Complementary and Integrative Medicine for Immunobullous Diseases

Integrative medicine approaches can complement dietary and supplement approaches to help reduce autoimmunity and heal the skin.

Traditional Chinese Medicine (TCM)

Traditional Chinese medicine (TCM) incorporates various complementary modalities and herbal remedies to rebalance the immune system and address autoimmune conditions such as immunobullous diseases. According to TCM theory, immunobullous diseases are due to heart fire and spleen dampness and can be addressed by distinguishing the pattern of imbalances involved.

For example, licorice and tripterygium wilfordii Hook F have been used in TCM to reduce inflammation and modulate the immune response in order to decrease the need for steroid treatment. Similarly, TCM herbal preparations such as TianPaoChuang have been shown to be effective in treating pemphigus when combined with corticosteroids. 

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Summary

Immunobullous (blistering) diseases such as pemphigus vulgaris, bullous pemphigoid, and dermatitis herpetiformis cause blistering of the skin, which can be painful and severe in some cases. These conditions are due to auto-antibodies that attack different proteins within the skin’s layers, causing the separation of skin cells and fluid-filled blisters and bullae. The immune system can become dysregulated and attack itself due to several factors, including environmental exposures in genetically susceptible individuals. 

A conventional approach to immunobullous diseases generally relies on corticosteroids and other immune-modulating therapies. An integrative approach uses functional medicine testing to uncover factors contributing to autoimmunity and inflammation and develops an individualized treatment plan to help rebalance the body and heal the skin.