Systemic Medical Treatment of Mucous Membrane Pemphigoid

Mucous membrane pemphigoid (MMP), also called ocular cicatricial pemphigoid (OCP), is an autoimmune disease that causes scarring of mucous membranes such as the conjunctiva, cornea, the lining of the mouth and throat, and the skin. Severe dry eye, painful corneal abrasions from in turned eyelashes (trichiasis) and eyelid margins (entropion), adhesions of the lining of the inside of the eyelid to the surface of the eyeball (symblepharon), and damage to the cornea all are common in MMP. Although ocular involvement in MMP “only” affects the surface of the eye, secondary complications inside the eye such as cataract and glaucoma are common.

MMP is almost always bilateral, but often asymmetric. Roughly two-thirds of MMP patients have scarring in sites other than the eye, most commonly the mucus membrane lining of the mouth. The disease has been found in patients as young as 20, but the vast majority are >60 years of age.

The ophthalmologists in the Pemphigoid Clinic at Wills strive to treat every patient individually; there is no “cookie cutter” approach to the management of this complex disease. In all cases, however, the goal of therapy is to maximize control of the inflammation and minimize side effects of therapy. Once the disease has been diagnosed (based on careful history and a complete eye examination, often but not always confirmed by biopsy of the conjunctiva), treatment is based on the severity of the disease. Mild cases may respond to steroid eye drops and/or the oral antibiotic doxycycline. If the disease is progressive and/or there is involvement of the cornea, more potent therapy is usually necessary. Furthermore, many necessary ocular surgeries (such as cataract surgery and repair of abnormal eyelids and eyelashes) cannot be safely undertaken without control of the underlying MMP.

It is important for patients to understand that the medications to treat MMP have side effects. As with many diseases, drug-induced side effects tend to be greater with more potent medications used to treat more advanced MMP. The chances of side effects occurring are less, and their severity minimized, when there is good communication between patients, their family, and the doctors in the Pemphigoid Clinic as well as the patient’s other health care providers. Thus, it is essential that patients bring in relevant health records when they are seen in the clinic, including their medical conditions, medications, allergies or drug intolerances, and names and addresses of other treating physicians (e.g., ear/nose/throat specialist, dermatologist, and primary care physician). Treatment of MMP requires a multi-disciplinary approach; for example, the presence of conditions such as diabetes, liver disease, or blood disorders has a big impact on which medications are the best choices for a given patient.

Oral steroids (e.g., prednisone) are sometimes used to treat acute MMP, but are not an effective long-term treatment. In addition, oral steroids may have numerous long-term side effects (including diabetes, hypertension, osteoporosis, bone fractures, stomach ulcers) and they are rarely used as sole treatment for MMP. Instead, MMP is often treated with “immunosuppressive” drugs. These are non-steroid anti-inflammatory medications that, as the name suggests, are designed to dampen down the body’s overactive immune system and prevent further scarring on the surface of the eye. Roughly 70% of patients require immunosuppression at some point during the course of disease.

These immunosuppressive drugs come from four different categories: antimetabolites, T cell inhibitors, B cell inhibitors, and cytotoxic agents (B cells and T cells are types of white blood cells that are part of the immune system; abnormalities in both B and T cell function are involved in the development of MMP). Most patients tolerate these medications well, but all of them may cause serious side effects. As a general guideline, these medications are used for 1-2 years (depending on the drug) at the minimum. If they are working well AND they are well tolerated by the patient over that time, consideration is given to tapering and stopping the drugs. However, many patients require longer, even lifetime therapy for severe MMP.
All immunosuppressants may increase the risk of infection, ranging from relatively mild upper respiratory infections to life-threatening pneumonia, urinary tract infections, and sepsis (blood infections). The doctors in the Pemphigoid Clinic will arrange for patients to get periodic blood tests to monitor for possible toxicity. We strongly encourage patients to take advantage of the patient portals now offered by most hospitals and labs (such as Quest Diagnostics and LabCorps) that provide access to test results. We find it helpful when patients become an active participant in their own care and learn to recognize what the important blood tests mean. At each visit the team will discuss the most recent lab results and make adjustments in the medications if necessary.

The risk of infection in patients taking immunosuppressants can be reduced by regular handwashing or use of alcohol-based gel cleaners and avoiding exposure to sick individuals (as is recommended for everyone during flu season, for example). We strongly recommend that patients get proper vaccinations, including a yearly flu shot, the pneumonia vaccine, and shingles vaccine (Shingrix). It should be noted that these vaccinations are routinely recommended for ALL patients over the age of 60 or 65 as part of general preventive health care. However, “live” or attenuated vaccines (such as the nasal flu spray) should not be used by patients who are immunosuppressed. Smoking is a strong risk factor for infections in any patient, but is particularly discouraged in patients taking immunosuppressive drugs.

T cell inhibitors are rarely used to treat MMP but may be important in the management of other scarring disorders that mimic MMP, such as atopic disease such as severe eczema/asthma. These drugs can increase the risk of hypertension and kidney disease. They may also cause tremors, particularly at higher doses.

Antimetabolites include methotrexate and mycophenolate. The most common side effect of these drugs is gastrointestinal, including nausea, diarrhea, and decreased appetite. Other side effects include fatigue, thinning of the hair, and general malaise. More severe side effects include liver damage, decreases in the white blood cells, and anemia. It is important to minimize (or in some cases avoid altogether) the concurrent use of alcohol or drugs such as acetaminophen that may increase the risk of liver disease in patients taking immunosuppressants. Mycophenolate is usually taken twice a day, whereas methotrexate is a once-a-week medication. However, mycophenolate may be better tolerated, and is the most commonly used immunosuppressant in the Pemphigoid Clinic.

Cytotoxics (cyclophosphamide and chlorambucil) are the most potent of the immunosuppressants. They are the most likely drugs to induce a permanent cure of MMP, but also have the highest rate of short- and long-term side effects. These include nausea, hair loss, and diarrhea, as well as liver disease, severe anemia and other blood abnormalities, infections, and malignancies such as leukemia and lymphoma. Cyclophosphamide can also increase the risk of urinary tract bleeding and bladder cancer. For these reasons, cytotoxic agents are rarely used as “first-line” therapy in MMP and are only used in the most advanced cases of disease with a high potential for blindness.
The most recent advance in MMP treatment is the development of drugs that act against B cells. Rituximab is a drug that helps to block B cells and has been used increasingly in the treatment of MMP. It is given as an intravenous infusion, sometimes as little as once every six months. Potential side effects are similar to the antimetabolites.

Finally, intravenous immunoglobulin (IVIG) may be helpful in some cases. IVIG is made up of antibodies (immunoglobulins) pooled from many blood donors. It is usually given as an intravenous infusion once a month. Side effects include muscle pain, allergic reactions, blood clots, anemia and blood vessel inflammation (vasculitis).

All immunosuppressants may increase the risk of certain types of cancer, especially skin cancer. The risk varies with different drugs, and is lowest with methotrexate and mycophenolate and greatest with the cytotoxic agents. Thus, patients on immunosuppression should see a dermatologist at least yearly for a thorough checkup. There is also a small risk of “blood cancers” such as leukemia and lymphoma.
While MMP is almost always a disease that occurs in patients past the age of child-bearing (women taking immunosuppressants should not get pregnant), there is some concern about the risk to the fetus in men who take these drugs. If a man taking immunosuppressants is considering fathering a child, he should have a careful discussion with the woman’s gynecologist.

A final note: MMP is a rare disease and there are no drugs that are FDA-approved for its treatement. While immunosuppressants are often the mainstay of treatment and critically necessary to avoid blindness, insurance companies may not cover the cost of such drugs (which tend to be quite expensive). Your doctors will work with you and your insurance company to obtain coverage to the greatest extent possible.