Pemphigus

Pemphigus is a group of rare autoimmune diseases that cause blistering of the skin and mucous membranes (mouth, nose, throat, eyes, and genitals). An autoimmune disease is a disease that occurs when the immune system begins to attack different parts of the body as if they were foreign. Some forms of pemphigus, including the most common form, may be fatal if left untreated. The disease can affect people of all ages and races but is most common in adult women and in certain ethnic groups.

Types

There are three main types of pemphigus:

• Pemphigus vulgaris
• Pemphigus foliaceus
• Paraneoplastic pemphigus

Signs and Symptoms

Pemphigus vulgaris

Pemphigus vulgaris is the most common type of pemphigus. Soft and limp blisters appear on healthy-looking skin and mucous membranes. The sores almost always start in the mouth. The blisters of pemphigus vulgaris form within the deep layer of the epidermis, and are often painful. Blistered skin becomes so fragile that it may peel off by rubbing a finger on it. The blisters normally heal without scarring, but pigmented spots may remain for a number of months.

Pemphigus foliaceus

Pemphigus foliaceus involves crusted sores or fragile blisters that often appear first on the face and scalp and later on the chest and other parts of the body. Unlike pemphigus vulgaris, blisters do not form in the mouth. The sores are superficial and often itchy, and are rarely as painful as pemphigus vulgaris blisters. There may also be loose, moist scales on the skin.

Paraneoplastic pemphigus

Paraneoplastic pemphigus is a rare disease that is distinct from pemphigus, but shares some features of it. It occurs in people with certain types of cancer, including some lymphomas and leukemias. It often involves severe ulcers of the mouth and lips, cuts and scarring of the lining of the eye and eyelids, and skin blisters. Because the antibodies also bind the airways, patients may develop life-threatening problems in the lungs. This disease is different from pemphigus, and the antibodies in the blood are different. Special tests may be needed to identify paraneoplastic pemphigus.

Other types of pemphigus

Pemphigus vegetans is a form of pemphigus with thick sores in the groin and under the arms.

IgA pemphigus is a blistering disorder in which a different type of antibody binds to the cell surface of epidermal cells. This disease is different from other forms of pemphigus because it involves a different type of antibody (called IgA) than other types. The disease may result in blisters similar to those seen in pemphigus foliaceus, or it may involve many small bumps containing pus. This is the most benign, or least harmful, form of pemphigus.

Pemphigoid is also a blistering disorder caused by autoimmune problems that result in an attack on the skin cells by a person’s own antibodies. Pemphigoid produces a split in the cells where the epidermis and dermis, the layer below the epidermis, meet, causing deep, tense blisters that do not break easily. Pemphigus, on the other hand, causes a separation within the epidermis, and the blisters are soft, limp, and easily broken. Pemphigoid is seen most often in the elderly and may be fatal. Usually, both pemphigus and pemphigoid are treated with similar medications. Severe cases may require different treatment.

Causes

Normally, the immune system produces antibodies that attack viruses and harmful bacteria. In people with pemphigus, however, the immune system mistakenly attacks the cells in the epidermis, or top layer of the skin, and the mucous membranes. The immune system produces antibodies against proteins in the skin known as desmogleins. These proteins form the glue that keeps skin cells attached to keep the skin intact. When desmogleins are attacked, skin cells separate from each other and fluid can collect between the layers of skin, forming blisters that do not heal. In some cases, these blisters can cover a large area of skin.

It is unclear what triggers the disease, although it appears that some people have a genetic susceptibility. Environmental agents may trigger the development of pemphigus in people who are likely to be affected by the disease because of their genes. In rare cases, pemphigus may be triggered by certain medications. In those cases, the disease usually goes away when the medication is stopped. Pemphigus is not contagious. It does not spread from person to person.

Though there can be a genetic predisposition to develop pemphigus, there is no indication the disease is hereditary.

Diagnosis

A diagnosis of pemphigus may require:

• Visual examination by a dermatologist. The doctor will take a complete history and physical exam, noting the appearance and location of the blisters.
• Blister biopsy. A sample of a blister is removed and examined under the microscope. The doctor will look for cell separation that is characteristic of pemphigus, and will also determine the layer of skin in which the cells are separated.
• Direct immunofluorescence. A biopsy of a skin sample is treated in the laboratory with a chemical compound to find the abnormal desmoglein antibodies that attack the skin. The specific type of antibodies that form may indicate what type of pemphigus exists.
• Indirect immunofluorescence. Sometimes called an antibody titre test, a sample of blood is tested to measure pemphigus antibody levels in the blood and help determine the severity of the disease. Once treatment begins, this blood test may also be used to find out if treatment is working.

Pemphigus is a rare disease of the skin; therefore, dermatologists are the doctors best equipped to diagnose and treat people with pemphigus. If there are blisters in the mouth, a dentist can provide guidance for maintaining good oral health. This is important for preventing gum disease and tooth loss.

Treatment

Medications

Treatment for pemphigus vulgaris involves using one or more drugs. High-dose oral corticosteroids, such as prednisone or prednisolone, are the main treatment for pemphigus. These are anti-inflammatory medicines that suppress the immune system. High doses are often required to bring pemphigus under control. To minimize the side effects patients may experience, once the disease begins to subside the corticosteroid levels are reduced slowly to the lowest level required to prevent new blisters or sores from appearing. Many patients will go into complete remission with treatment, although this may take a number of years. Other patients will need to continue to take small doses of medication to keep the disease under control. Prednisone is usually taken by mouth, but can also be injected into a vein, muscle, or directly into a blister. The route depends on the type and severity of disease. Usually, a corticosteroid cream will be used directly on the blisters.

To keep the levels of corticosteroid use to a minimum, immunosuppressive drugs are often added to a patient’s treatment. These are drugs that stop or slow down the immune system’s response to what it sees as an attack on the body. They include:

• Myco-phenolate mofetil
• Azathioprine
• Cyclophosphamide
• Methotrexate.

Other drugs that may be used include:

• Dapsone (DDS)
• Antibiotics such as tetracycline

All of these medications can cause serious side effects. With prolonged high-dose corticosteroid therapy, common side effects include susceptibility to life-threatening infections, delayed wound healing, osteoporosis, cataracts, glaucoma, type 2 diabetes, loss of muscle mass, peptic ulcers, swelling of the face and upper back, and salt and water retention. To reduce the risk of osteoporosis, bone density measurements are taken, and patients with low bone density are prescribed medications such as alendronate or risedronate. Extra calcium and vitamin D intake, exercise, and stopping smoking are also recommended. For diabetes caused by steroid use, patients must be on a low sugar diet and may need to take antidiabetic medications.

The immunosuppressive drugs that are used to treat pemphigus can also increase the chances of developing an infection and may cause anemia, a decrease in the white blood cells in the blood, inflammation of the liver, nausea, vomiting, or allergic reactions.

Therapies

People with severe pemphigus that cannot be controlled with corticosteroids may undergo plasmapheresis, a treatment in which the blood containing the damaging antibodies is removed and replaced with blood that is free of antibodies. Such patients can also be treated with intravenous immunoglobulin (IVIg), which is given daily for three to five days, every two to four weeks for one to several months. Plasmapheresis and IVIg are both very expensive treatments, since they require large amounts of donated and specially processed blood. Scientists have reported success in treating difficult cases of pemphigus vulgaris with a combination of IVIg and rituximab, a cancer medication.

Holistic and alternative treatments

It may take several months to years for the ulcers and blisters of pemphigus vulgaris to disappear after treatment has begun because circulating antibodies remain in the blood for a long time. Lesions in the mouth are particularly slow to heal. Blisters in the mouth can make brushing the teeth painful. As a result, gum disease and tooth loss can occur due to decreased brushing. A dentist can offer approaches that make it possible to maintain healthy teeth and gums. Avoiding spicy, hard, and acidic foods will help, since those foods can irritate or trigger the blisters. If taking corticosteroids, it is a good idea to get advice on maintaining a diet low in calories, fat, and sodium, and high in potassium and calcium.

Chances of Developing Pemphigus

Pemphigus affects people across racial and cultural lines. Research has shown that certain ethnic groups (such as the eastern European Jewish community and people of Mediterranean descent) are more susceptible to pemphigus. ^{[1] [2]} A particular type of pemphigus occurs more frequently in people who live in certain areas of Brazil. ^[3]

Men and women are equally affected. Research studies suggest a genetic predisposition to the disease. Although the onset usually occurs in middle-aged and older adults, all forms of the disease may occur in young adults and children.

Clinical Trials

A list of ongoing clinical trials is available at: pemphigus trials.

Research

Recent discoveries

• Etanercept (Enbrel), a drug used to treat rheumatoid arthritis and psoriasis, was studied for the treatment of pemphigus. ^[4]
• The addition of pulse therapy using oral steroids to conventional treatment for pemphigus was studied in Europe. This therapy was not found to be more beneficial than conventional therapy. ^[5]

Current research

• A comparison of two different protocols for the use of clobetasol propionate (Dermoval) in the treatment of bullous pemphigus. ^[6]
• A study is being performed to evaluate the response rate and one-year event free survival rate when high dose cyclophosphamide is used to treat refractory pemphigus. ^[7]
• Another study will assess the efficacy and safety of mycophenolate (CellCept} (a drug used to prevent transplant rejection) (1 g or 1.5 g orally taken twice a day for 52 weeks) in patients with pemphigus vulgaris receiving prednisone or other corticosteroids. ^[8]
• Phase II and phase III trials are ongoing regarding the use of rituximab (Mabthera), a monoclonal antibody used to treat leukemia, to treat pemphigus. ^[9]

Expected Outcome

The outlook for people with pemphigus has changed dramatically in the past 40 years. A person diagnosed with pemphigus vulgaris in the 1960s faced the reality that they had a disease that was rare, usually fatal, poorly understood, with no good treatment options. Today, through medical research supported by the National Institutes of Health (NIH), the picture is dramatically better. The disease is now rarely fatal, and the majority of deaths occur from infections. For most people with pemphigus, the disease can be controlled with corticosteroids and other medications, and these medications can eventually be completely discontinued. However, as described earlier, these medications can cause side effects that can sometimes be serious. Pemphigus and its treatments can be debilitating and cause lost time at work, weight loss, loss of sleep, and emotional distress. The International Pemphigus Foundation provides patient support services to help people with the disease cope with its effects.

References

1. ↑ Mimouni D, Bar H, Gdalevich M, Katzenelson V, David M. Pemphigus - analysis of epidemiological factors in 155 patients. J Eur Acad Dermatol Venereol. 2008 May 12. (Epub ahead of print) Abstract
2. ↑ Uzun S, Durdu M, Akman A, et al. Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol. 2006 May;45(5):523-8. Abstract
3. ↑ Friedman H, Campbell I, Rocha-Alvarez R. Endemic pemphigus foliaceus (fogo selvagem) in native Americans from Brazil. J Am Acad Dermatol. 1995 Jun;32(6):949-56. Abstract
4. ↑ ClinicalTrials.gov. Study of Etanercept (Enbrel) in the Treatment of Pemphigus Vulgaris
5. ↑ Mentink LF, Mackenzie MW, Tóth GG. Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial. Arch Dermatol. 2006 May;142(5):570-6. Abstract | Full Text
6. ↑ ClinicalTrials.gov. Comparison of Two Therapeutic Strategies of Dermoval in Treatment of Bullous Pemphigus
7. ↑ ClinicalTrials.gov. Phase II Study of High-Dose Cyclophosphamide in Patients With Refractory Pemphigus
8. ↑ ClinicalTrials.gov. A Study to Assess the Effect of CellCept (Mycophenolate Mofetil) and Reduced Corticosteroids in Patients With Active Pemphigus Vulgaris (PV)
9. ↑ ClinicalTrials.gov. Effect of Anti CD20 in Pemphigus Desease

External Images

DermAtlas

DermNetNZ

Skinsight

External Links

American Academy of Dermatology (AAD)

International Pemphigus & Pemphigoid Foundation

American Autoimmune Related Diseases Association, Inc

National Organization For Rare Disorders (NORD)