Ocular cicatricial pemphigoid is best described as which kind of disease?

An autoimmune conjunctivitis causing conjunctival scarring OCP is an autoimmune conjunctivitis that cicatrises the conjunctiva and is regarded as a subtype of mucous membrane pemphigoid; left untreated it can lead to blindness.

A chronic bacterial conjunctivitis of the fornices

A neoplastic proliferation of conjunctival epithelium

A toxic reaction to ultraviolet exposure

Which autoantigen is currently considered most likely in ocular cicatricial pemphigoid?

The beta-4 subunit of alpha-6 beta-4 integrin Although sera from OCP patients bind the bullous pemphigoid antigens, further work supports the beta-4 subunit of the hemidesmosomal alpha-6 beta-4 integrin as the more likely target.

Type VII collagen of the anchoring fibrils

Which HLA allele shows a strong association with ocular cicatricial pemphigoid?

HLA-DQB1*0301 HLA typing shows increased susceptibility with HLA-DR4, and HLA-DQB1*0301 in particular is strongly associated, being thought to bind the beta-4 integrin subunit.

What is the typical demographic profile of ocular cicatricial pemphigoid?

Women twice as often as men, with onset at 60 to 80 Women are affected twice as often as men, onset is usually between 60 and 80 years and rarely below 30, and there is no racial predilection.

Men predominate, with onset in the third decade

Both sexes equally, with onset in childhood

Women predominate, with onset under 30 years

How must conjunctival tissue be submitted when testing for ocular cicatricial pemphigoid?

Unfixed, for direct immunofluorescence Diagnosis rests on clinical signs plus positive direct immunofluorescence, and the conjunctival biopsy must be taken from an actively involved area and sent unfixed.

Fixed in formalin for routine histology

In saline for bacterial culture

In glutaraldehyde for electron microscopy

What does direct immunofluorescence show in ocular cicatricial pemphigoid?

Linear staining of the epithelial basement membrane zone Immunofluorescence reveals linear staining along the epithelial basement membrane zone, though sensitivity may fall as low as 50% in longstanding, heavily scarred disease.

Granular IgA deposits in the dermal papillae

Intercellular net-like staining of the epithelium

Perivascular complement deposition alone

Why should a conjunctival biopsy in ocular cicatricial pemphigoid remove only minimal tissue?

OCP is an obliterating disease of the conjunctiva Because OCP obliterates the conjunctiva, biopsy must be judicious and take only the minimum tissue needed; the inferior fornix is preferred when involvement is diffuse.

Large specimens dilute the immunofluorescence signal

Conjunctival tissue cannot be transported in bulk

Wider excision provokes corneal neovascularisation

Which condition is clinically identical to ocular cicatricial pemphigoid but drug-induced?

Pseudopemphigoid from long-term topical medication Pseudopemphigoid from agents such as pilocarpine, epinephrine, timolol, idoxuridine, echothiophate iodide or demecarium bromide can even show linear basement membrane staining, so resolution after stopping the drug is what makes the diagnosis.

Linear IgA disease of the conjunctiva

Chronic graft versus host disease

What role does topical therapy have in ocular cicatricial pemphigoid?

An adjunct for surface disease, never a substitute for systemic treatment Ocular involvement is a high-risk subset of mucous membrane pemphigoid that needs systemic therapy; topical and subconjunctival steroids relieve symptoms but do not treat the underlying disease.

The definitive treatment once scarring is established

Sufficient on its own when only one eye is involved

Reserved for patients who relapse after systemic therapy

In what proportion of untreated patients does ocular cicatricial pemphigoid progress?

Up to 75% Without treatment the disease progresses in up to 75% of patients; systemic therapy halts cicatrisation in most but fails in about 10%, and up to 22% relapse once it is withdrawn.

Ocular Cicatricial Pemphigoid (OCP): case study entity and management

CASE REPORT

A 58-year-old female presented to the ophthalmology clinic with a six-month history of persistent redness, irritation, tearing, and blurred vision in both eyes, initially attributed to seasonal allergies but worsening despite over-the-counter antihistamines and artificial tears.

She had a medical history significant for rheumatoid arthritis, hypothyroidism, and previous cataract surgery in both eyes.

Clinical examination revealed bilateral conjunctival injection, corneal erosions, symblepharon formation, and reduced visual acuity with bilateral conjunctival scarring and meibomian gland dysfunction.

A diagnosis of Ocular Cicatricial Pemphigoid (OCP) was made based on these findings.

DISEASE

Ocular Cicatricial Pemphigoid (OCP) is considered a subtype of Mucous Membrane Pemphigoid, and these terms are sometimes used interchangeably.

Ocular Cicatricial Pemphigoid

Ocular Cicatricial Pemphigoid (OCP) is a type of autoimmune conjunctivitis that leads to cicatrization (i.e. scarring) of the conjunctiva. If OCP is left untreated, it can lead to blindness.

The exact pathogenesis of OCP remains to be elucidated but the existing evidence supports a Type II hypersensitivity response caused by an autoantibody to a cell surface antigen in the basement membrane of the conjunctival epithelium and other similar squamous epithelia.

Investigations into the underlying target antigen have led to several possible suspects. The autoantigens responsible for bullous pemphigoid (BP230 (i.e. Bullous pemphigoid antigen I, a desmoplakin) and BP180 (i.e. Bullous pemphigoid antigen II, a transmembrane hemidesmosome)) were studied, and the sera of patients with OCP was shown to bind these antigens.

However, further investigation supports that the more likely autoantigen is actually the beta-4 subunit of the alpha-6 beta-4 integrin of hemidesmosomes.

Studies of HLA (human leukocyte antigen) typing have found an increased susceptibility to the disease in patients with HLA-DR4.

The HLA-DQB1*0301 allele in particular shows a strong association with OCP and other forms of pemphigoid disease.

HLA-DQB1*0301 is thought to bind to the beta-4 subunit of the alpha-6 beta-4 integrin (the suspected autoantigen in OCP).

Incidence rates vary between 1 in 12,000 to 60,000. A study in the UK found that Ocular Cicatricial Pemphigoid (OCP) represents 61% of cicatricial conjunctivitis and is estimated to occur with an incidence of 1 in 1 million.

Women are affected more than men by a ratio of 2:1. Age on onset is usually age 60 to 80 and rarely younger than 30. There is no racial predilection.

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Diagnosis

Diagnosis is based on clinical signs and positive direct immunofluorescence testing of the conjunctiva. Conjunctival biopsy of an actively involved area is needed and the conjunctival tissue must be submitted unfixed for analysis.

If involvement is diffuse, a biopsy of the inferior conjunctival fornix is recommended. A judicious biopsy is advisable as Ocular Cicatricial Pemphigoid (OCP) is an obliterating disease of the conjunctiva and only the minimal amount of tissue necessary should be removed.

Alternatively, a biopsy of an active oral mucosa lesion can be diagnostic as well. Immunofluorescence reveals linear staining of the epithelial basement membrane zone.

The sensitivity of immunofluorescence may be as low as 50%, especially for longstanding/severe cicatrization because of the loss of immunoreactants and the destruction of the basement membrane in longstanding disease.

Serological testing is not routinely used in diagnosis. Sequential photographs are useful to monitor clinical progression.

Differential Diagnosis

The differential diagnosis of Ocular Cicatricial Pemphigoid (OCP) is broad as it encompasses the differential for cicatricial conjunctivitis.

The differential includes infectious etiologies such as trachoma, inflammatory etiologies such as rosacea, autoimmune etiologies such as linear IgA disease, Graft Versus Host Disease (GVHD), and Stevens-Johnson Syndrome (SJS), allergic etiologies such as atopy, conjunctival trauma, chemical burns, medicaments, radiation, and neoplasia.

A common confounder of clinical diagnosis is medicamentosa, which results in a condition called pseudopemphigoid.

Pseudopemphigoid is clinically identical to OCP but is caused by the long-term use of certain offending topical medications.

Conjunctival biopsies may show linear staining of the conjunctival basement membrane zone. Differentiation from Ocular Cicatricial Pemphigoid (OCP) is difficult. Resolution with discontinuation of the offending agent is diagnostic.

Several topical medications have been implicated, including pilocarpine, epinephrine, timolol, idoxuridine, echothiophate iodide, and demecarium bromide.

Ocular Cicatricial Pemphigoid

MANAGEMENT

Without treatment, the disease progresses in up to 75% of patients. While systemic treatment stops the progression of cicatrization in most patients, it fails in approximately 10% of them.

Systemic therapy is necessary for Ocular Cicatricial Pemphigoid (OCP) as ocular involvement comprises a high-risk subset of MMP and is insufficiently treated with topical therapy alone.

Systemic treatment is best managed by a physician trained in the management of anti-inflammatory and immunomodulatory treatment given the significant risk of systemic complications necessitating frequent blood test monitoring.

Several drugs are effective in treating Ocular Cicatricial Pemphigoid (OCP) and a step-wise approach of escalation of therapy when there is insufficient response is recommended.

Topical therapy can be used as an adjunct for surface disease but should not be used in place of systemic therapy.

Topical therapy includes optimizing lubrication of the ocular surface with artificial tears and punctual plugging.

Topical and subconjunctival steroids can relieve symptoms but are ineffective for the treatment of the underlying disease.

Topical cyclosporine has been found to be ineffective while topical tacrolimus has been shown to be successful in small case series. Subconjunctival mitomycin-c has also been investigated in small case series with variable effects.

If the disease remains quiescent following a few years of systemic therapy, many practitioners are often able to discontinue systemic therapy successfully. However, it is important to continue to monitor the patient for recurrence of the disease as up to 22% of patients relapse.

REFERENCES

Arafat SN, Suelves AM, Spurr-Michaud S, et al. Neutrophil Collagenase, Gelatinase and Myeloperoxidase in Tears of Stevens-Johnson Syndrome and Ocular Cicatricial Pemphigoid Patients. Ophthalmology. 2014;121(1):79-87.
Ophthalmic Pathology and Intraocular Tumors. Basic and Clinical Science Course (BCSC). American Academy of Ophthalmology, 2014; pp54-56.
External Disease and Cornea. Basic and Clinical Science Course (BCSC). American Academy of Ophthalmology, 2014; pp344-345.
Tyagi S, Bhol K, Natarajan K, Livir-Rallatos C, Foster CS, Ahmed AR. Ocular cicatricial pemphigoid antigen: Partial sequence and biochemical characterization. Proc. Natl. Acad. Sci. 1996;93(25):14714-14719.
Zakka LR, Reche P, Ahmed AR. Role of MHC Class II Genes in the pathogenesis of pemphigoid. Autoimmunity Reviews. 2011;(11):40–47.
Bhol KC, Dans MJ, Simmons RK, et al. The autoantibodies to alpha 6 beta 4 integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human beta 4. J Immunol. 2000 Sep 1;165(5):2824-9.

Test yourself

A few questions straight from this article.

1 / 10 0 correct

Ocular cicatricial pemphigoid is best described as which kind of disease?
OCP is an autoimmune conjunctivitis that cicatrises the conjunctiva and is regarded as a subtype of mucous membrane pemphigoid; left untreated it can lead to blindness.
Which autoantigen is currently considered most likely in ocular cicatricial pemphigoid?
Although sera from OCP patients bind the bullous pemphigoid antigens, further work supports the beta-4 subunit of the hemidesmosomal alpha-6 beta-4 integrin as the more likely target.
Which HLA allele shows a strong association with ocular cicatricial pemphigoid?
HLA typing shows increased susceptibility with HLA-DR4, and HLA-DQB1*0301 in particular is strongly associated, being thought to bind the beta-4 integrin subunit.
What is the typical demographic profile of ocular cicatricial pemphigoid?
Women are affected twice as often as men, onset is usually between 60 and 80 years and rarely below 30, and there is no racial predilection.
How must conjunctival tissue be submitted when testing for ocular cicatricial pemphigoid?
Diagnosis rests on clinical signs plus positive direct immunofluorescence, and the conjunctival biopsy must be taken from an actively involved area and sent unfixed.
What does direct immunofluorescence show in ocular cicatricial pemphigoid?
Immunofluorescence reveals linear staining along the epithelial basement membrane zone, though sensitivity may fall as low as 50% in longstanding, heavily scarred disease.
Why should a conjunctival biopsy in ocular cicatricial pemphigoid remove only minimal tissue?
Because OCP obliterates the conjunctiva, biopsy must be judicious and take only the minimum tissue needed; the inferior fornix is preferred when involvement is diffuse.
Which condition is clinically identical to ocular cicatricial pemphigoid but drug-induced?
Pseudopemphigoid from agents such as pilocarpine, epinephrine, timolol, idoxuridine, echothiophate iodide or demecarium bromide can even show linear basement membrane staining, so resolution after stopping the drug is what makes the diagnosis.
What role does topical therapy have in ocular cicatricial pemphigoid?
Ocular involvement is a high-risk subset of mucous membrane pemphigoid that needs systemic therapy; topical and subconjunctival steroids relieve symptoms but do not treat the underlying disease.
In what proportion of untreated patients does ocular cicatricial pemphigoid progress?
Without treatment the disease progresses in up to 75% of patients; systemic therapy halts cicatrisation in most but fails in about 10%, and up to 22% relapse once it is withdrawn.