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Cicatricial Pemphigoid - Causes, Symptoms, Diagnosis and Treatment

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Cicatricial pemphigoid is a rare autoimmune disorder that can affect the body's mucous membrane. Read the article below to know more.

Written byDr. Sowmiya D

Medically reviewed byDr. Kumari Monalisa

Published At March 24, 2022
Reviewed AtMay 30, 2024

What Is Cicatricial Pemphigoid?

Cicatricial pemphigoid, also known as mucous membrane pemphigoid, is a chronic autoimmune disorder that results in blisters that predominantly affect the mucous membranes, including the skin and the conjunctiva. If only the eyes are involved, it is referred to as ocular pemphigoid. It usually scars; hence, if left untreated, it can even result in blindness when it affects the eyes. The risk of scarring depends on the location of disease activity.

What Is the Etiology of Cicatricial Pemphigoid?

The exact etiology is unknown, but according to the existing evidence, it supports a type 2 hypersensitivity response by our own body (autoantibody) against the epithelium of the basement membrane. Thus, the normal structure and function of the basement membrane are disrupted. This allows the epidermis to separate from the dermis, which manifests clinically as blisters and erosions. The oral cavity is the common site of involvement, extending up to the pharynx posteriorly. There are severe cases that can affect mucous membranes anywhere in the body, such as the sinuses, genitals, anus, and cornea.

What Is the Epidemiology Behind Cicatricial Pemphigoid?

Cicatricial pemphigoid is rare, and its exact prevalence and incidence remain unknown. However, some studies have estimated its annual incidence at 1.16 and 0.87 cases per million, respectively. One study indicated that cicatricial pemphigoid typically begins around the age of 66, with a higher prevalence among females, especially noted in a German population study with a female-to-male ratio as high as 7:1.

A retrospective study involving 162 mucous membrane pemphigoid patients found that 67 percent had ocular involvement at presentation. The risk of developing ocular mucous membrane pemphigoid was estimated at 0.014 per person-year for those without initial ocular involvement. Also, HLA-DQB1*0301 has been identified as a susceptibility marker for cicatricial pemphigoid.

What Is the Pathophysiology of Cicatricial Pemphigoid?

Cicatricial pemphigoid is a condition where antibodies attack molecules responsible for sticking cells together in the mucosa and skin. This damages the basement membrane, causing the epidermis to separate from the dermis, leading to blisters and erosions.

Key target molecules include:

  1. Laminin 332: This protein connects the keratinocyte's hemidesmosome to collagen VII, which helps attach the epidermis to the dermis. It strengthens this attachment against shearing forces.

  2. BP180 (Collagen XVII): Found in the hemidesmosome of epithelial cells, BP180 binds keratin within the keratinocyte. It spans the lamina lucida, with its N-terminus near the cellular membrane and the C-terminus reaching into the lamina densa. Antibodies in cicatricial pemphigoid patients mainly target the C-terminus, leading to deeper separation and scarring.

  3. Alpha-6-Beta-4 Integrin: This hemidesmosome component binds to laminin 332, which attaches to collagen VII. Antibodies from cicatricial pemphigoid patients target the intracellular portion of alpha-6-beta-4 integrin, potentially playing a role in the disease's development.

What Are the Signs and Symptoms of Cicatricial Pemphigoid?

Eyes - Eye irritation, such as a burning sensation or excessive tearing. The fornices (permit freedom of movement of the eyelids) are shortened, which causes adhesions between the eyelid and the eyeball. Later, when the disease progresses, they fuse. Severe scarring can result in blindness. The lesion is initially present in one eye, and may progress to the other in a couple of years. There may be chronic tear deficiency when lacrimal glands (tear glands) are affected, which leads to dry eyes.

Clinically, the following are present:

  • Conjunctivitis (inflammation of the conjunctiva of the eye).

  • Keratinization (filled with keratin) of corneal epithelium.

  • Shortening of the corneal sulcus.

  • Entropion (eyelid rolled inward that irritates the eye caused by the lashes).

  • Symblepharon (bulbar and palpebral conjunctiva form an abnormal adhesion to one another).

  • Long-term ankyloblepharon (adhesion of the edges of the upper eyelid to the lower eyelid).

Oral Cavity - Recurrent painful erosions and desquamative (red, swollen, ulcerative appearance of the gums) gingivitis occur, and the lesions heal with scarring. Any mucosal site in the mouth may blister. When the pharynx is involved, it presents as hoarseness in voice or difficulty swallowing. Progressive scarring may lead to esophageal stenosis (narrowing of the esophagus). Supraglottic (upper part of larynx including epiglottis) involvement may lead to airway obstruction requiring emergency treatment.

Nasal Involvement - Nasal bleeding (epistaxis), nasal crusting, and bleeding after blowing the nose are seen.

Skin - Vesicles are small blisters or bulla are bleeding. Large blisters are seen. They may heal with scarring. Itchiness may be present at the blister site, or generalized itchiness may be present. Common sites include the scalp, head and neck, hands, or trunk. Scalp involvement may lead to hair loss.

Genitals - On the genitalia, painful erosions involving the clitoris, labia, glans, or shaft of the penis may be seen.

How to Diagnose Cicatricial Pemphigoid?

The recommended tests to diagnose cicatricial pemphigoid include:

  • Biopsy of the skin lesion.

  • Histopathological studies.

  • Direct immunofluorescence (DIF).

They are performed on uninvolved skin or mucous membranes around the lesion. Histopathological studies reveal subepithelial blisters, infiltrates containing plasma cells, eosinophils, and neutrophils.

DIF demonstrates a linear band of antibodies (IgG) and precipitates complement (C3) in the basement membrane of the epithelia. Indirect immunofluorescence (IIF) can show linear deposition of IgA antibodies along with IgG and C3, suggestive of mucous membrane pemphigoid. A salt split technique is used in IIF to evaluate the presence of both IgG and IgA. Western blot, immunoprecipitation, and immunoelectron microscopy are also used. There is a positive Nikolsky sign (when rubbed, the upper layer of skin slips away from the lower layers).

Imaging studies such as CT (computed tomography) scans and barium swallows may help evaluate the upper airway or the esophagus. Routine blood tests do not show any significant change from the normal range. Sometimes, there can be elevated immunoglobulins (antibodies), erythrocyte sedimentation rate (a test that measures how quickly the erythrocytes settle at the bottom of the test tube), and acute phase reactants (present during inflammation in the body).

What Is the Treatment for Cicatricial Pemphigoid?

  • Topical therapies can be effective in the case of mild oral mucosa and skin disease. If the topical treatments are ineffective, Dapsone (medicine to treat skin diseases) and systemic corticosteroids can be used. In addition, the importance of oral care has also been emphasized.

  • Proper eye care is essential. For mild to moderate eye lesions, only systemic corticosteroids or corticosteroids combined with Dapsone may be considered. Since dry eyes are familiar, lubricants such as artificial tear drops or petroleum jelly must be applied. Excess fluid from the eyes must be cleaned to prevent secondary bacterial infections.

  • A combination of systemic corticosteroids and immunosuppressive agents is recommended for severe or rapidly progressive cases. The recommended drugs are Azathioprine, Mycophenolate mofetil, and Cyclophosphamide.

  • In patients refractory to other therapies, high-dose intravenous immunoglobulin has been used.

What Are the Complications of Cicatricial Pemphigoid?

  • Oral mucosal lesions result in painful scarring that can limit movement. Gingival lesions can also result in the loss of gingival tissue, alveolar bone, and teeth.

  • Ocular complications include decreased tear and mucin production, secondary infection, symblepharon, ankyloblepharon, corneal ulcers, and blindness.

  • Nasal complications include discharge, epistaxis, crust formation, chronic sinusitis, scarring, and impaired airflow.

  • Pharyngeal complications include hoarseness or loss of voice, supraglottic stenosis, and airway compromise.

  • Esophageal complications include difficulty swallowing, aspiration, and narrowing of the air passage or food passage in the body (stricture formation).

  • Anogenital complications also include painful ulcerations, stenosis, and stricture formation.

Conclusion:

To provide adequate care, a multidisciplinary approach is recommended for patients with cicatricial pemphigoid. Intermittent exacerbations and a waning of disease activity characterize the disease. Due to its chronic nature and potentially severe complications, the patient should be counseled to remain compliant with medical therapy and have regular follow-up visits.

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Frequently Asked Questions

Pemphigoid cannot be permanently cured, but certain medications can relieve the symptoms and ease discomfort. Treatment prevents the condition from getting worse. The sores and blisters reduce and sometimes can resolve completely. Bullous type of pemphigoid may clear by itself but can take around five years to resolve completely. Popping blisters with infection can cause sepsis (overactive response to infection), which can be life-threatening.
Blood tests can be useful in identifying the antibodies associated with pemphigoid since it is an autoimmune (the body’s immune system detects self-tissues as foreign and attacks them) disorder. IIF and ELISA are common blood tests. IIF detects circulating antibodies and their pattern of deposition, while the ELISA test identifies and semi-quantifies antibodies to antigens present in bullous pemphigoid and other variants.
Sulfur-containing drugs, especially Furosemide, can trigger drug-induced pemphigoid. Other causative drugs include Amoxicillin, Ampicillin, Penicillin, Phenacetin, Penicillamine, Captopril, Tiopronin, beta-blockers, and Psoralen-ultraviolet-A light. Over 50 agents are considered responsible for causing drug-induced bullous pemphigoid, which includes diuretics (a drug type that increases the urine output), ACE inhibitors (drugs to treat hypertension), and antibiotics. 
Ocular cicatricial pemphigoid is a type of mucous membrane pemphigoid (a less common, autoimmune disorder that affects the mucous membranes of the body, particularly the mouth and the eyes), which affects the eye, and if left untreated, can cause blindness. Studies have shown that about 25 to 30 percent of patients can turn blind due to the mechanism of the condition and due to scarring or clouding of the cornea (the transparent membrane that permits light to pass through). 
When the rare, autoimmune cicatricial pemphigoid disorder affects the mucous membranes, then it is called mucous membrane pemphigoid. The mouth is commonly affected by cicatricial pemphigoid. Common sites in the oral cavity include all areas like buccal mucosa (the inner lining of the cheeks), gingiva (gums), tongue, vermilion lips (the reddish or pink margin of the lip), and the palate (the roof portion of the mouth in the inside).
Normally, the immune system of the body fights against harmful microorganisms like bacteria and viruses by producing antibodies. Pemphigoid is a type of autoimmune disease in which the immune system considers cells on the upper layer of the skin (epidermis) and mucous membranes as foreign substances and attacks them. When antibodies are produced against the protein-binding skin cells, the protein bonds break, skin becomes fragile, and fluid gets collected, forming blisters.
Bullous type of pemphigoid can resolve on its own but can take around five years to be cured completely. The long-term outlook for pemphigoid with proper treatment is good. It usually gets resolved after a few years but can relapse at any time, even with appropriate treatment. If any recurring blisters are noticed, one must consult a physician. The majority of the patients respond effectively to the treatment.
Usually, patients consult a general physician. Once the condition is identified as pemphigus, the physician may refer the patient to a dermatologist (a medical expert who specializes in treating the diseases of the hair, skin, and nails). Regular follow-up with the dermatologist is necessary to get relief from the condition.
Stress is the primary factor that can flare up a pemphigoid. Stress induces antibodies, which in turn can increase the number of blisters. Emotional stress or stressful life events can trigger and escalate pemphigus. Simple exercises, brisk walking, listening to music, deep breathing, meditation, yoga, and swimming can calm the mind, and reduce anxiety and prevent pemphigoid from getting worse.
Pemphigus can resolve on its own after a few years with proper treatment, but there are chances of relapse. The condition can be managed with certain medications. With supportive treatment, the patient can lead a normal life, but if untreated, it can be fatal. Infection of the blisters can result in sepsis (overactive response to infection), which can be life-threatening. With recent medications, the lifespan of these patients is normal. 
Though allopathy treatment is the primary mode of treatment for pemphigus, alternative medicine like Ayurveda has been successful in treating bullous pemphigoid. The side effects and high cost of allopathy push the patients to shift to alternative medicine. Studies show that bullous pemphigoid can be successfully treated with herbal medicines.
Pemphigus, if left untreated, can be fatal. The risk of death from bullous pemphigoid is high in patients with associated medical conditions, advanced age, and in those who are hospitalized. Infected blisters can lead to sepsis (overactive response to infection), which can be life-threatening. In severe cases of bullous pemphigoid, one-year mortality rates can be as high as 25 to 30 percent, even with medical care. 
The gold standard diagnostic test for bullous pemphigoid is direct immunofluorescence (DIF) microscopy of a perilesional biopsy (a type of biopsy in which the outer layer of the skin called epidermis is included). Skin samples from the affected areas may be obtained to detect the presence of antibodies. Blood tests will also be performed to identify the circulating antibodies.
The blisters can appear on the skin and can involve the mucosal surfaces like the inside of the mouth, nose, throat, eyes, and genitals. Bullous pemphigoid can occur in areas that bend, like the lower abdomen, armpits, and upper thighs. It initially starts as an itchy, elevated rash. As the disease progresses, large blisters are formed on the skin. It can also occur in a few pregnant women.
Bullous pemphigoid has been found to be linked with cerebrovascular disease (a disease that affects the blood flow in the brain) and dementia (a serious mental issue caused by brain disease or injury that can have an impact on the ability to think, remember, and behave normally). A study shows that psychiatric and neurological (nerve) disorders can have a connection with bullous pemphigoid. 
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Dr. Kumari Monalisa from iCliniq
Dr. Kumari Monalisa

Dermatology

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