眼類天疱瘡（ocular cicatricial pemphigoid; OCP）は、結膜基底膜に対する自己抗体によって引き起こされる慢性の瘢痕性結膜炎である。粘膜類天疱瘡（mucous membrane pemphigoid; MMP）の眼病変に相当し、両者の用語は互換的に用いられる。
粘膜類天疱瘡は口腔・眼・鼻咽頭・食道・喉頭・生殖器などの粘膜に水疱・びらんを生じる自己免疫性疾患である。口腔病変が最多（約90%）であり、眼病変は約61%に認められる1)。眼病変は粘膜類天疱瘡のなかでもハイリスクに分類され、口腔粘膜や皮膚のみの症例よりも予後が不良である。口腔疾患を持つ患者の最大3分の1が眼病変へ進行する。
Epidemiologically, the incidence is estimated at 1 in 12,000 to 60,000 people. The male-to-female ratio is 1:2, with a higher prevalence in women, and the age of onset is typically 60–80 years. Onset before age 30 is rare, and no racial differences have been reported.
They are different names for the same disease. In dermatology, it is called mucous membrane pemphigoid, while in ophthalmology, cases with ocular involvement are referred to as ocular pemphigoid. In addition to the eyes, mucous membranes of other organs such as the mouth, esophagus, and larynx can also be affected.
The initial symptoms of ocular pemphigoid are nonspecific and can easily be overlooked.
Foster classification and Mondino classification are used for staging ocular pemphigoid. The Foster classification is based on clinical signs and is useful for understanding the disease stage.
Stage I (Early stage)
Chronic conjunctivitis: Nonspecific findings mainly characterized by mild hyperemia.
Subepithelial fibrosis: Observed as fine white striae in the inferior conjunctival fornix.
Positive rose bengal staining: Reflects mucin deficiency.
Tear film dysfunction: Associated with meibomian gland loss and goblet cell depletion.
Stage II
Shortening of the conjunctival fornix: Decreased depth of the inferior fornix is observed. Normal inferior fornix depth is approximately 11 mm.
Stage III
Symblepharon: Adhesion between the bulbar and palpebral conjunctiva. Detected by pulling the eyelid during upward and downward gaze.
Corneal vascularization: Reflects damage to limbal stem cells.
Trichiasis: Eyelashes contact the cornea due to entropion.
Decreased tear secretion: Due to obstruction of the lacrimal gland ducts.
Stage IV (End stage)
Keratization of the ocular surface: The corneal surface becomes keratinized like skin.
Symblepharon: Extensive adhesion between the eyelid and eyeball restricts eye movement.
Limbal stem cell deficiency: Corneal epithelial stem cells are lost, and conjunctival tissue invades the cornea.
The Mondino classification is based on the percentage of obliteration of the inferior conjunctival fornix depth.
| Stage | Loss of fornix depth |
|---|---|
| I | Up to 25% |
| II | 25–50% |
| III | 50–75% |
| IV | 75% or more |
It can progress. Even conjunctiva that appears clinically quiet may show histological inflammatory cell infiltration, known as “white inflammation.” A UK study reported that 42% of cases progressed despite no apparent inflammation.
Ocular mucous membrane pemphigoid is an autoimmune disease classified as a type II hypersensitivity reaction (where autoantibodies attack tissues)1).
The main target autoantigens are as follows:
As a genetic predisposition, an association with HLA-DR4 is known. In particular, the HLA-DQB1*0301 allele shows a strong association with ocular pemphigoid and pemphigoid diseases.
The diagnosis of ocular pemphigoid is based on a combination of clinical findings and immunological tests.
It is characterized by slowly progressive bilateral chronic conjunctivitis with scarring. Suspect ocular pemphigoid in the following cases:
Impression cytology shows loss of conjunctival goblet cells. Serial photography is useful for monitoring clinical progression.
Direct immunofluorescence (DIF) of the conjunctiva is necessary for definitive diagnosis.
Ocular pemphigoid is a disease that destroys the conjunctiva, so biopsy should be performed carefully, taking only the minimum necessary tissue.
The differential diagnosis of cicatrizing conjunctivitis is broad.
Differentiation from Stevens-Johnson syndrome is based on history of systemic fever and rash. For differentiation from pseudopemphigoid, it is important to obtain a history of long-term use of eye drops.
Pseudopemphigoid results from long-term use of eye drops with epithelial toxicity, and its clinical findings are identical to ocular pemphigoid. Direct immunofluorescence may also show linear staining of the basement membrane zone. The key to differentiation is whether improvement occurs after discontinuation of the causative drug (e.g., pilocarpine, timolol).
Without treatment, the disease progresses in up to 75% of cases. Systemic immunosuppressive therapy is the mainstay of treatment; local therapy alone cannot prevent the progression of conjunctival scarring.
Local therapy is symptomatic treatment for ocular surface disease and is not a substitute for systemic therapy.
For acute exacerbations or progressive cases, systemic corticosteroids are used to quickly reduce inflammation, and immunosuppressants are started simultaneously. Once a response is achieved, corticosteroids are tapered.
If quiescence is maintained after several years of treatment, discontinuation of systemic therapy may be attempted, but recurrence occurs in up to 22%, so continuous monitoring is necessary.
If the disease remains quiescent with several years of systemic therapy, discontinuation of treatment may be attempted. However, recurrence is seen in up to 22%, so regular monitoring is important even after treatment is stopped.
The pathology of ocular cicatricial pemphigoid is based on a type II hypersensitivity reaction 1). In susceptible individuals, autoantibodies are produced against the β4 subunit of α6β4 integrin in hemidesmosomes located in the lamina lucida of the conjunctival basement membrane 1).
When autoantibodies bind to basement membrane antigens, complement is activated, leading to cytotoxic destruction of conjunctival epithelium. Basement membrane disruption results in blister formation, and inflammatory cell infiltration appears in the epithelium and lamina propria.
Changes over the time course of inflammation are as follows:
In conjunctival tissue of patients with ocular pemphigoid, multiple inflammatory cytokines are elevated 1).
In particular, interleukin-13 has pro-fibrotic and pro-inflammatory effects on conjunctival fibroblasts and may be involved in progressive conjunctival fibrosis even in clinically quiescent states.
In tear fluid, elevations of interleukin-8, matrix metalloproteinase-8, matrix metalloproteinase-9, and myeloperoxidase are observed, which are thought to originate from neutrophil infiltration.
James et al. (2021) reported that autoantibodies against the cytoplasmic domain of the β4 peptide of α6β4 integrin are involved in the pathogenesis of mucous membrane pemphigoid, and that elevations of interleukin-1, interleukin-6, interleukin-12, interleukin-13, and interleukin-17 are observed in affected tissues1). Since the JAK-STAT pathway is involved in these cytokine signals, it has been suggested that simultaneous suppression of multiple inflammatory pathways by Janus kinase inhibitors may provide therapeutic benefits.
In advanced cases, loss of goblet cells and obstruction of lacrimal ducts lead to deficiency of the aqueous and mucin layers of tears. This dryness, combined with subepithelial fibrosis and destruction of limbal stem cells, results in limbal stem cell deficiency and keratinization of the ocular surface.
Janus kinase (JAK) inhibitors are a novel therapeutic strategy that simultaneously suppresses multiple cytokine signaling pathways involved in the pathogenesis of mucous membrane pemphigoid1).
James et al. (2021) used the Janus kinase 1/3 inhibitor tofacitinib (11 mg extended-release tablet/day) in two cases of refractory ocular mucous membrane pemphigoid that had failed multiple prior treatments (methotrexate, mycophenolate mofetil, rituximab, cyclophosphamide, etc.)1). Both cases showed marked improvement in conjunctival inflammation within 8 weeks, and one case maintained disease activity remission with tofacitinib monotherapy for over 16 months. The other case relapsed after temporary discontinuation due to cost issues, but regained quiescence upon resumption.
Baricitinib (Janus kinase 1/2 inhibitor) has also been reported effective in refractory ocular mucous membrane pemphigoid1). It has been suggested that Janus kinase 1 inhibition, common to both tofacitinib and baricitinib, may be key to the therapeutic effect1).
Interventional trials of tofacitinib (NCT03580343), baricitinib (NCT04088409), and filgotinib (NCT03207815) for non-infectious uveitis are ongoing1).
Interleukin-8, matrix metalloproteinase-9, and myeloperoxidase in tears may be useful for monitoring treatment response. Systemic immunotherapy has been reported to reduce these levels. In particular, myeloperoxidase is considered to have high sensitivity and specificity as a quantitative marker of disease activity.
Cultured oral mucosal epithelial transplantation has shown efficacy in treating ocular surface diseases caused by limbal stem cell deficiency, including ocular cicatricial pemphigoid. Cultured mucosal epithelial sheet transplantation is also useful for epithelial repair in persistent epithelial defects and for preventing progression of symblepharon.
