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Ocular Cicatricial Pemphigoid: Symptoms, Causes, Diagnosis, Treatment, Hypothesis and Progression

Updated on August 27, 2016
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Trained in dentistry, Sree is currently pursuing lab sciences. She loves researching and sharing information on various health topics.

Ocular Cicatricial Pemphigoid: An In-depth Look at a Rare Autoimmune Condition

In the relatively uncommon disease cicatricial pemphigoid, blisters that may result in scarring appear on the mucous membranes of the human body. While common sites include the genitals, the gums, and the sinuses, this condition may also affect the eye - specifically its outermost layer, called the cornea, as well as the mucous membranes surrounding the eye. When this condition manifests in the eye, it is referred to as ocular cicatricial pemphigoid.

As it manifests in the mucous membranes of the eye and in other places in the body, this condition is characterized as an autoimmune disease.

Autoimmunity and Autoimmune Disease
The human body has a built-in defense system against incoming disease or infection. This defense system is known as the immune system. Various cells, tissues, and organs within the body are incorporated into the immune system. The chemicals secreted by these components are also counted as part of the immune system - or, more accurately, these chemicals are part of the immune response.

The skin serves as the first line of defense against disease. It acts as a physical barrier that protects the internal organs from bacteria, viruses, and other disease-causing agents.

In and around the openings of the body, such as the mouth and the nose, the mucous membranes perform the same barrier function as the skin itself. At the same time, these membranes secrete and are covered by mucus, which traps particles and possible disease-causing agents before they have a chance to get further into the body.

Should any one of these disease-causing agents manage to get past the skin, different actions and different systems are activated in order to expel it. Irritants in the respiratory tract may be caught in the mucous membranes, and then physically ejected through the actions of sneezing, blowing the nose, or coughing. Irritants getting in through the mouth may be prevented from reaching the stomach by the action of vomiting; if these irritants reach the stomach, they may be neutralized once they come into contact with gastric acid. And irritants that get into the eyes may be literally washed away by tears.

A disease-causing agent that does manage to get past the physical barriers and expelling actions may now become the center of an inflammatory response. Inflammation is one of the key immune responses, when the body secretes protective and healing substances in response to the presence of injured or infected cells. These substances include cytokines and eicosanoids.

While we normally see inflammation in terms of its seemingly negative outer manifestations - redness, swelling, pain, or heat at the affected areas - the main purpose of inflammation is to attract infection-fighting cells to the affected site, and to promote the healing or replacement of damaged tissues.

Foreign cells that make their way into the body can be recognized by the body as such. If a foreign cell or molecule should get past the body's different protective systems, various proteins can bind to the surfaces of this cell or molecule. The effect of these proteins is to identify the foreign cell or molecule as an antigen, which is a substance that causes the body to have an immune response. Once the immune system has correctly identified the antigen, it can then respond by sending in the specific proteins that will work to destroy those foreign cells.

If the immune system is at peak condition, then it is capable of putting together a tailored response depending on the antigen that has entered the body, regardless of whether that antigen has been encountered before or not. Under regular conditions, a person can only catch chickenpox once. Should that person be exposed to chickenpox again, the immune system will be able to recognize the antigens and act specifically against them, thereby preventing a recurrence of that sickness.

The immune system also acts against dead and worn-out cells in the body. Dying cells, for example, display specific antigens, and as a result, the immune system makes sure that these dying cells are properly eliminated and disposed of.

A key component of these disease-fighting and cleaning-up actions is the white blood cell. There are different types of white blood cells. They all share the same general function, which is to kill disease-causing agents. If these agents are relatively small, white blood cells can physically engulf them; if these agents are relatively large, white blood cells can attack them starting from their surfaces.

Ocular Cicatricial Pemphigoid: An In-depth Look at a Rare Autoimmune Condition
Ocular Cicatricial Pemphigoid: An In-depth Look at a Rare Autoimmune Condition | Source
Type of White Blood Cell
Primary Functions
Neutrophil
Fights bacteria and fungi
Eosinophil
Fights large parasites
Basophil
Releases histamine
Lymphocyte
Releases antibodies; Fights virus-infected and tumor cells
Monocyte
Clean up broken and spent body cells

Additionally, white blood cells play important roles in the allergic response.

One kind of white blood cell serves as a long-standing record of responses by the immune system. These white blood cells display pieces of neutralized antigens and disease-causing agents on their surfaces, so that the body can “recognize” them in the future, and deploy the correct disease-fighting substances.

In general, the immune system can and does recognize the cells that belong to its own host body: it doesn't attack the cells or tissues that make up its host body's systems, since those cells do not commonly display any markers that show them to be foreign or able to cause disease. This is called autoimmunity.

Should there be an abnormal response from the immune system, causing it to attack its host body's cells, then this response can be looked at in terms of an autoimmune condition, or an autoimmune disease.

Taken another way, an autoimmune condition or disease arises when the body mistakes its own cells for antigens. The immune system attacks the cells inside its own host body, giving rise to the different manifestations and symptoms of the different autoimmune conditions.

Broadly speaking, autoimmune conditions affect the body in three ways:

  • The tissues of the body are destroyed
  • The affected organs of the body grow abnormally
  • The affected organs of the body function abnormally or differently

Autoimmune diseases are not limited to the rare or to the uncommon. Some relatively common conditions are actually rather familiar or commonplace, but people don't immediately associate them with problems of autoimmunity.

For example: spot baldness, known medically as alopecia areata, has to do with the loss of hair from specific areas of the body, and results from the body attacking its own hair follicles. Psoriasis is characterized by areas of abnormal skin on the body, and is again a result of the body attacking its own skin cells.

In recent years, coeliac disease has been under intense scrutiny. In this autoimmune condition, ingesting gluten - a specific combination of proteins that is commonly found in products made from wheat, oats, rye, or barley - triggers an abnormal immune response, including inflammation in the small intestine. Over the long term, coeliac disease may cause problems in the absorption of nutrients from food and beverages, and may result in malnutrition.

Even one of the types of diabetes involves some form of autoimmune response: diabetes mellitus type 1, or, simply, type 1 diabetes. Everyone knows that in diabetes, there are abnormalities in the production of insulin - the hormone that promotes the movement of glucose from the blood into fat, muscle, and liver cells. Insulin stops the secretion of glucose into the blood.

What people might not easily realize about type 1 diabetes is that it's classified as an autoimmune condition. In this type of diabetes, the body doesn't recognize its own insulin-producing cells, which are the beta cells located in the pancreas - so it destroys them. As a result, the body doesn't produce enough insulin, leading to high levels of glucose in the blood, and the health problems that result from those high levels.

Autoimmune diseases are often chronic - meaning they are long-term conditions - and in the vast majority of cases, they are incurable. After all, these conditions are caused by underlying problems with the immune system, and to get rid of these conditions might well mean taking out the immune system altogether. Not only is this patently impossible, it is also unreasonable - it doesn't make sense to expose the human body to all other possible disease-causing agents just to get rid of one autoimmune condition.

Increasingly, modern medicine is evolving newer and better regimens to alleviate the symptoms of various autoimmune conditions.

Cicatricial Pemphigoid

If a disease or condition is described as cicatricial, it forms or leaves scars; if a disease or condition is referred to as pemphigoid, it causes blisters or other forms of swelling to develop.

The general condition of cicatricial pemphigoid is known by many names, including mucous membrane pemphigoid (MMP) and benign mucous membrane pemphigoid. As might be inferred from these names, it primarily affects the mucous membranes associated with the mouth, nose, esophagus, trachea, and the genital openings (including the vagina and the rectum).

Cicatricial pemphigoid is an autoimmune disease. The body's immune system attacks what is known as the basement membrane. The basement membrane, a fibrous tissue composed of extracellular matrix, separates epithelial, mesothelial, or endothelial cells from their underlying connective tissues. In the case of the skin, the basement membrane separates the outermost layer of the skin, known as the epidermis, from the inner layers of the skin, which are referred to as the dermis.

Cicatricial pemphigoid arises when the immune system attacks the basement membrane, primarily by producing antibodies against it. These antibodies have the effect of dissolving the basement membrane. This causes the affected areas of the skin to lift away from the dermis, resulting in fluid coming in to fill the spaces, thus resulting in blisters. If these blisters burst, they leave behind scars.

It's actually not possible to determine when this autoimmune condition was first described, as cicatricial pemphigoid has been observed since ancient times. However, systematic and organized records on the ocular manifestation of this condition date from the 18th century.

Ocular Cicatricial Pemphigoid: Symptoms, Causes, Diagnosis, Treatment, Hypothesis and Progression
Ocular Cicatricial Pemphigoid: Symptoms, Causes, Diagnosis, Treatment, Hypothesis and Progression | Source

Ocular Cicatricial Pemphigoid - Characteristics

At its onset, this condition often manifests as a form of conjunctivitis.

Conjunctivitis is the general medical term for an inflammation of the conjunctiva, which are the mucous membranes associated with the eye. These membranes cover the front of the eye, and they are also found lining the inner eyelids. The conjunctival membranes produce mucus and tears, which help in protecting the eye from dirt, flying insects, and disease-causing agents.

The initial signs of this condition can also include trichiasis and/or madurosis. Trichiasis is a condition of abnormal growth of the eyelashes, in which they grow inwards instead of outwards. Madurosis refers to the condition in which the eyelashes, and sometimes the eyebrows, fall off.

Ocular cicatricial pemphigoid usually appears in patients over the age of 60, but increasingly, cases have also been reported in patients in their thirties. It is thought that there may be twice as many female patients affected by this condition as males.

In terms of geographical distribution, no worldwide or region-specific patterns have been observed - meaning that anyone anywhere in the world might find out that they have this condition only when it gets triggered.

In majority of patients, this autoimmune condition is accompanied by ulcers in the mouth.

Hypothesis
In 2001, researchers proposed the two-hit hypothesis to account for the manifestation of symptoms in vulnerable patients. They proposed that the potential sufferer possesses one or more underlying genetic predispositions, which constitutes the “first hit”. The “second hit”, which actually triggers the manifestation of symptoms, is caused by some stimulus or other environmental factor.

The onset of the condition has been observed in patients after using different kinds of drugs, including but not limited to epinephrine (administered as a medication for anaphylactic shock), pilocarpine (a treatment for glaucoma and for dry mouth), timolol (a possible treatment for hypertension and migraines), and others. Researchers are still looking into other possible triggering medications.

Progression
The condition usually progresses according to a series of stages.

At the onset, ocular cicatricial pemphigoid usually affects only one eye. The typical symptoms of conjunctivitis are first observed. These symptoms include irritation, a burning sensation in the affected eye, and the discharge of mucus or of tears. Red eye, in which the blood vessels of the eye may be observed to become more prominent, may also develop. The same goes for photophobia, a condition in which the eyes exhibit an abnormal intolerance to light.

Within the following three or four years, the conjunctivitis symptoms are often observed to spread to the previously unaffected eye.

The second stage involves the namesake cicatrices, or scars, appearing on the conjunctiva. These membranes may also begin to show signs of shrinkage.

Sub-epithelial fibrosis may be observed in patients who are at this stage of progression, as well as exposure keratitis. In sub-epithelial fibrosis, the basement membrane may be observed to undergo the processes of thickening and scarring, usually because of the repeated blistering and rupture of those same blisters. In exposure keratitis, the cornea becomes inflamed because of lack of lubrication.

In the third stage, symblepharons develop. These are spots where adhesion takes place between the mucous membranes of the eyelids and of the eyeball.

If left untreated, the fourth and final stage results in chronically dry eyes. Adhesion of the eyelid membranes to each other, known as ankyloblepharon, takes place, resulting in the inability to move the eyelids. The movement of the eyeballs themselves may also be severely limited at this stage, owing to continuing development of symblepharons. In addition, a keratinization process may take place in the outermost cells of the cornea, meaning that the contents of those outermost cells are replaced with the protein keratin.

The drying-out of the eyes and the blisters that are inherent to the condition may lead to extensive corneal scarring as the condition progresses. Should that scarring become widespread and extensive, blindness in both eyes may ensue.

It may take up to twenty years for the condition to progress through all four stages.

Diagnosis and Testing

When presented with a possible case of ocular cicatricial pemphigoid, all other possible diagnoses must first be ruled out. A complete medical history is mandatory, as is a thorough examination of the patient who is presenting possible symptoms.

One of the difficulties in diagnosing this autoimmune disease arises from the similarity of some of the initial symptoms to relatively common eye conditions. In fact, some studies estimate that because of this initial confusion with other diseases, most cases are not correctly diagnosed until the patient has progressed into stage 3 (as detailed above).

Blood tests may be recommended during the process of diagnosis in order to rule out other causes of conjunctival scarring, such as topical medications that are being used to treat other eye-related ailments; or medications that are used to treat systemic diseases, such as sarcoidosis.

In the great majority of cases, the final diagnosis can be confirmed through a biopsy of the affected mucous membranes.

Treatment

Once the patient has been confirmed to be suffering from ocular cicatricial pemphigoid, the treating physician can now consider courses of treatment.

As the condition stems from a problem with autoimmunity, therapies must go the immunosuppressive or immunoregulatory route. These kinds of therapies inhibit the self-destruction of the tissues of the body, and stop white blood cells from attacking the affected organs.

A key component of modern treatment and management regimens is a type of drug known as chronic steroid-sparing immunomodulators. Steroids and steroid-related drugs were once used as the major line of treatment, but these have since been shown to have adverse effects on the body, so they are now being phased out. Advice and assistance from other doctors, such as an internist or rheumatologist, can help the treating physician in making decisions related to treatment.

Other treatments will address the manifested symptoms. To treat dry eyes, ointment lubricants can be used, together with artificial tears and tear conservation measures. If there is inflammation of the eyelid, recommended eyelid hygiene measures must be undertaken, and oral antibiotics may also be prescribed. If the patient is prone to ingrowing eyelashes, these may need to be removed or extracted, so they don't damage the cornea.

In some cases, surgical intervention may be considered. The transplantation of mucous membranes from the hard palate and the nose may help in reversing the continuing scarring of the cornea and the eyelids.

Should the patient require surgical intervention in stage 4 of this condition, the physician may have to resort to using a type-II Boston keratoprosthesis. An opening is made in the patient's upper eyelid before the upper and lower eyelids are permanently sutured shut. The prosthesis, which is fitted to the opening, provides a clear window through which the patient can see.

Ocular Cicatricial Pemphigoid - Prognosis
It is rare, but possible, for this condition to spontaneously go into permanent remission. Early diagnosis and early intervention are critical. While treatments for the symptoms may be prescribed for the short term, treatment of the condition itself may go on for longer. Remember that this is an autoimmune condition, and if there is no longer-term treatment regimen, the patient's own immune system will once again attack the conjunctiva, resulting in the recurrence of symptoms and possibly blindness.

Ongoing Research
Current studies into cicatricial pemphigoid are showing promise. These investigations are centered on the genes and antigens that may contribute to the defective autoimmune response. The results of these investigations may help in developing better diagnostic techniques, as well as therapeutic interventions.

Tip!

Make sure to provide your treating physician with a complete medical history, especially with regards to eye problems. Report everything, from repeated incidents of conjunctivitis to difficulties with opening and closing your eyes. It is easy to confuse the initial symptoms of ocular cicatricial pemphigoid with the symptoms of other diseases.

Ocular cicatricial pemphigoid, if left untreated, may ultimately end up causing which condition?

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