This is a representative photograph of subepithelial fibrosis
This is a representative photograph of forniceal foreshortening . Note that traction on the eyelid puts tension on the bulbar conjunctiva
When these findings of cicatrizing conjunctivitis are discovered, the first diagnostic consideration is whether it is the result of a historical event or is reflective of an active process. Patients should be questioned about previous episodes of severe conjunctivitis, chemical injuries, a history of Stevens-Johnson syndrome (SJS) , or prior chronic use of topical glaucoma medications, particularly pilocarpine . These episodes can result in conjunctival scarring that, in general, is not progressive. A rare but important exception here is an autoimmune-mediated progressive scarring found in some patients with SJS long after resolution of the acute episode .
Active, progressive cicatrizing conjunctivitis has many reported etiologies. Of those with autoimmune etiologies, ocular cicatricial pemphigoid (OCP) is likely the most common with an estimated incidence of 1:12,000 to 1:60,000 . Rosacea with MGD and atopic disease are both common entities in general ophthalmic practice, but, in especially severe forms, each can be the primary cause of conjunctival cicatrization [4, 5]. Importantly, even mild to moderate MGD or atopy can combine with OCP to form a more refractory disease.
Several systemic inflammatory syndromes have also been described as rare causes of cicatrizing conjunctivitis. These include (but are not limited to) Sjögren’s syndrome , granulomatosis with polyangiitis (GPA) (formerly Wegener’s granulomatosis ), and sarcoidosis [1, 6–8]. Paraneoplastic cases have also been reported . Trachoma causes chronic conjunctival scarring resulting in a cicatricial entropion that then causes mechanical damage to the ocular surface. Worldwide, it is the most common infectious cause of blindness . While extremely rare in the USA, trachoma should be considered in recent immigrants from endemic areas.
OCP is defined as a slow but relentless progression of conjunctival scarring eventually leading to corneal involvement and blindness [11, 12]. It is a bilateral disease but in some cases can be markedly asymmetric. The four stages of the disease have been described (Table 12.1). It falls under the spectrum of diseases classified as mucous membrane pemphigoid (MMP) . In these disorders antibodies are formed to various glycoproteins in mucous membrane basement membrane zones (BMZ) resulting in chronic inflammation and scarring of mucous membranes. OCP can occur as an isolated condition or in combination with other mucous membrane involvement. The gold standard for diagnosis of OCP remains a conjunctival biopsy demonstrating immunoglobulin or complement deposition at the epithelial BMZ. False negatives are common and do not rule out the condition .
Evaluation and treatment of ocular cicatricial pemphigoid
Foster staging system for OCP
Stage 1—Chronic conjunctivitis accompanied by subconjunctival fibrosis
Stage 2—Conjunctival fornix foreshortening due to cicatrization
Stage 3—Presence of symblephara, entropion, trichiasis, keratopathy
Stage 4—Corneal keratinization, ankyloblepharon, severe dry eye
Cicatrizing conjunctivitis workup
1. Serologic evaluation for underlying disorder (GPA, Sjögren’s syndrome, sarcoidosis, atopy)
2. Conjunctival biopsy for histopathology and immunofluorescence
3. Collaborative investigation of other potentially involved mucous membranes
Early—antimetabolites (AZA, MTX, MMF)
Advanced or progressive—combination IVIg and rituximab (preferred) or CYC
Confounding and aggravating factors
Meibomian gland dysfunction
Topical medications, particularly preservatives
Though this patient’s current condition started with a presumed viral conjunctivitis, the conjunctivitis itself was never noted to be especially severe; rather it has simply lingered. Now identified as cicatrizing, a thorough history and review of systems should be performed to look for an occult underlying systemic inflammatory process with focus on involvement of other mucous membranes. Patients will often not mention oral or vaginal lesions without prompting. Special emphasis should be placed on dysphagia and breathing abnormalities as these may signal occult involvement in the esophagus or larynx. Involvement of these areas has been estimated to be 5–15% . Laryngeal strictures are of particular importance as they can be life-threatening if not diagnosed. Though uncommon, OCP has been reported as a manifestation of a para-neoplastic process; however, routine workup for occult malignancy is not indicated (beyond age-appropriate routine screening tests).
The patient denies a history of trauma, chemical injury, SJS, or previous severe conjunctivitis. Additional review of systems for this patient reveals mild dysphagia for which she underwent an endoscopy that showed mild idiopathic scarring of the esophagus. This was attributed to reflux and prompted treatment with esomeprazole. With this medication and some dietary modifications, no other treatment has been necessary. She has no other mucous membrane lesions. There are no signs or symptoms suggest an underlying connective tissue or vasculitic disorder. Baseline anterior segment photographs are taken.
What Are Your Next Diagnostic Steps?
Patients with cicatrizing conjunctivitis should have a serologic workup for baseline studies and mimicking etiologies (ESR, CBC, comprehensive metabolic panel, serum IgE, ANA, SS-A, SS-B, ANCA, ACE/lysozyme). A conjunctival biopsy can be performed on any part of the bulbar conjunctiva. Several specific reports of technique have been described [1, 14, 16]. Briefly, this can be done by using a bleb of subconjunctival lidocaine for both anesthesia and demarcation of the tissue from underlying Tenon’s capsule . The biopsy is taken using forceps and scissors after which antibiotic ointment and a pressure patch are applied. The biopsy needs to be large enough to allow proper pathologic interpretation.
Blood work is drawn, and the bulbar conjunctival biopsy is taken from the inferior nasal quadrant. It is completed on the same day given the patient’s travel distance. It is approximately 3 × 4 mm in size. Forceps are used to place the tissue on gauze soaked in normal saline.
In What Solution(S) Will You Deliver the Biopsy to Pathology? What Type of Pathologist Would Be Best Equipped to Read It? What Pathologic Studies Will You Request?
As with most biopsies done on ocular tissue, it is best to communicate with the pathologist in advance to make sure he/she is comfortable and experienced in conjunctival tissue processing and interpretation. In addition to ocular pathologists who have significant experience processing and interpreting conjunctival tissue, immunofluorescence is commonly performed by dermatopathologists.
As biopsy specimens are often reflexively placed in formalin, it is emphasized that immunofluorescence often cannot be performed well on specimens delivered in this solution. Michel’s solution or normal saline can be used. It is important to communicate with the pathologist regarding his/her individual preferences.
The histologic pattern of inflammation should be evaluated, specifically whether there are granulomatous features to suggest conditions such as sarcoidosis or GPA. The presence of goblet cells should be noted. The number/location of mast cells is also of importance, specifically if there are excessive numbers or excessive degranulation that might suggest an atopic component. Immunofluorescence should be used to evaluate for linear staining of immunoglobulins or complement at the epithelial basement membrane zone (BMZ).
The conjunctival tissue was large enough to be cut in half. Half was placed in formalin for histopathology and the other half in Michel’s solution for immunofluorescence. The specimen was brought to pathology promptly. As the appointment ends, the patient is perturbed that you have not made any modifications to her therapy nor have you extensively discussed the individual items on your differential diagnosis.
We inform our patients that there are many causes of cicatricial conjunctivitis and that we prefer to not go into extensive discussions on diagnosis or therapeutic decisions until the return of the serologies and biopsy. This sometimes frustrates patients, as they want immediate answers. As many patients have failed multiple therapies before being referred, we discuss the importance of having as much information as possible before deciding on the next step.
In 2 weeks, she returns. The serologic workup is negative for systemic disorders. Histopathologic evaluation of the conjunctiva reveals a mononuclear lymphocytic infiltrate in the stroma, decreased goblet cells, and a normal mast cell population without significant degranulation. There is no evidence of granulomatous inflammation. Immunofluorescence shows positive linear staining of IgG, IgA, and complement (C3) at the epithelial BMZ.
What Is the Most Likely Diagnosis?
The clinical exam and biopsy are consistent with ocular cicatricial pemphigoid (OCP). Given her history of esophageal scarring, you contact the GI specialist to make sure he is aware of the possibility of mucous membrane pemphigoid.
What If the Immunofluorescence Results Had Been Equivocal?
Avidin-biotin complex (ABC) staining has been shown to increase the sensitivity of biopsy results that are negative or equivocal on immunofluorescence . This is routinely done in our lab in instances where there is a high clinical suspicion.
If ABC staining is not available, a second biopsy could be considered. Yet, some patients are not excited about a second biopsy, and at times it can still be negative. For those biopsy-negative patients in whom the clinical condition looks and progresses in a manner typical for OCP, we offer systemic therapy. A common misconception is that negative results rule out OCP. Chronic cicatricial conjunctivitis, regardless of biopsy results, needs to be treated systemically to control the inflammation. Patients whose biopsy does not show classic pemphigoid are still at great risk of vision loss from chronic cicatrization.
Assuming no known drug allergies, what therapeutic options would you present to the patient? Is there an option that is contraindicated?
What can one do if one is not comfortable prescribing and monitoring immunomodulatory therapy (IMT) ? Is there a topical alternative?
How long will it take to know the full clinical effect of the medication? How will you know if the patient is in remission?
Systemic treatment is required for OCP. For non-vision threatening cases, we prefer the use of an antimetabolite with a proven track record in this disease: methotrexate (MTX), mycophenolate mofetil (MMF), or azathioprine (AZA) [17, 18]. In the past, we have used dapsone for mild cases, but this has fallen out of favor in our practice given the high incidence of hemolytic anemia while on this medication and the safety of alternatives . This patient’s thalassemia would be a relative contraindication to dapsone.
Many ophthalmologists are not experienced, comfortable, or motivated to prescribe and monitor IMT . Yet it is increasingly recognized how important these steroid-sparing therapies are for ocular inflammatory disease. In such cases, we recommend a close collaboration with a rheumatology or hematology colleague who can prescribe and monitor the medication. The ophthalmologist must take the leading role in communicating the status of the ocular inflammation and, if necessary, the need to increase or change therapy.
We monitor treatment efficacy by improvement in both subjective symptoms and objective conjunctival injection. We consider remission to be a white and quiet eye. This underscores the need for periodic anterior segment photography. We allow 6 weeks for an antimetabolite to reach full effect. After 3 weeks of therapy, we will attempt to taper any corticosteroids (oral or topical) that have been used as a bridge in therapy. In patients who only partially respond to the starting dose, the dose can be increased. Here we wait an additional 6 weeks to know the full effect of the increased dose. If a patient is not tolerating a medication, we will discontinue it and move along to another.
As she does not drink alcohol, she was started on 15 mg of methotrexate weekly with daily folic acid supplementation. After 1 month she reported clinical improvement, and Durezol was finally tapered. Off Durezol her IOP improved and so brimonidine was discontinued as well. At this time she tells you that her eyes feel “wonderful.” She reports she has not been using artificial tears and, if possible, would like to discontinue Restasis. She would also like to resume contact lens wear.
What Is the Relationship Between Dry Eye Syndrome and OCP? Can She Stop Restasis? What About Resuming Her Contact Lenses?
Often, tearing in patients with OCP is felt secondary to “dry eye” and is often treated reflexively as an aqueous deficiency. However, OCP itself does not cause a true aqueous deficiency until late stages . As she is doing so well, it is reasonable to trial off Restasis with restarting for worsening symptoms. There is no contraindication to contact lenses so long as they are well tolerated.
Now 3 months into remission, she returns for follow-up. Her glare symptoms have progressed, and she is extremely anxious for cataract surgery.
When Will You Perform This Surgery? What Perioperative Changes to Systemic Therapy Will You Make? How Will the OCP Affect Your Surgical Approach to the Cataract Surgery?
Ocular surgery should not be performed on patients with OCP until remission is achieved. For traditional extracapsular cataract surgery, we recommend waiting for 6 months at the very least . There are no data on optimal length of remission for patients undergoing phacoemulsification. Here we prefer a minimum of 3 months of remission. In all patients, no matter how long the remission, perioperative high-dose prednisone should be used. We typically start with 60 mg of prednisone for 3 days before surgery with a taper of 10 mg every 4 days after surgery. The patient should continue all current IMT as well.
Regarding surgical technique, exposure can be difficult in these patients, as a normal speculum may not fit. In such cases we use a 6-0 silk suture through the lid margins for retraction. If possible a clear corneal incision should be made to avoid manipulation of the conjunctiva .
Postoperatively these patients can develop abrupt but persistent corneal epithelial defects that, when finally resolved, leave the patient with poor vision secondary to corneal scarring and thinning [21, 22]. For this reason, we recommend reexamining these patients every 1–2 weeks postoperatively. If conjunctival scarring progresses, high-dose prednisone should be reinitiated and systemic therapy increased. If a corneal epithelial defect develops, amniotic membrane grafting or tarsorrhaphy should be considered early if there are no signs of improvement with aggressive lubrication . We do not recommend operating on the second eye until it is clear that the first eye is completely healed. Ultimately, despite best efforts, outcomes after cataract surgery in patients with OCP are not as favorable as in normal patients [20, 23]. Thus, the threshold to proceed with surgery should be higher and the patient well informed about a potentially difficult postoperative period.
She waits for an additional 3 months before having uneventful cataract surgery in both eyes (2 months apart). She has now achieved 1 year of remission. She is not having any side effects from the methotrexate but does not like the idea of being “on medication.”
These situations are common. We make sure patients know upfront that we intend to continue therapy for a minimum of 2 years following full steroid-free remission before attempting to taper. Attempting to taper medication earlier is a mistake and will almost inevitably result in a relapse. To address her concern of taking methotrexate, we discuss the long history of experience and safety (with proper monitoring) that the medical community has with this medication.
Once 2 years of steroid-free remission is achieved, medication is slowly tapered. Her methotrexate dose is reduced by 5 mg every 6–12 weeks. Once off medication, we monitor patients at 3-month intervals with slow extension over time. If there is a relapse, she will return to her previous dose for another 2 years before trying to taper again.
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CC is a 65-year-old female with bilateral chronic cicatrizing conjunctivitis that has been refractory to treatment. She is referred to you for assistance with a nonhealing corneal epithelial defect of the right eye. In addition to her work as an attorney, she has previously been employed as a model. She has not been able to work recently due to her chronic ocular injection. Her medical history is significant for hypertension controlled with lisinopril. Review of systems is negative for dyspnea, dysphagia, or lesions of other mucous membranes. She has occasional diarrhea and an occasional rash from rosacea. She does not recall ever having a herpes simplex (HSV) lesion.
About 15 years ago, she had an uneventful cosmetic blepharoplasty of all four lids. Three years ago she had cataract surgery of both eyes. About 18 months ago, she developed chronic tearing of the right eye with a sensation of dryness, irritation, and visible injection of both eyes. She was initially diagnosed with dry eye syndrome and MGD. Restasis and oral doxycycline (100 mg by mouth twice daily) were started, and punctual plugs were placed. She could not tolerate doxycycline due to nausea.
Despite these treatments, the conjunctival inflammation persisted, and she was referred to a cornea specialist whom she first saw 12 months ago. The specialist noted numerous inferior symblephara creating a significantly blunted fornix. A conjunctival biopsy was not performed given the high clinical suspicion of OCP. At that visit, the patient was started on mycophenolate mofetil (MMF) 1 gram twice daily that improved but did not resolve her symptoms. The irritation, dryness, and injection persisted bilaterally, albeit to a lesser extent.
Her corneas had no documented pathology until 6 months ago when epitheliopathy was seen on the right cornea. 3 months ago she developed a central epithelial defect of the right eye. This defect has persisted despite amniotic membrane grafts, a brief trial of oral prednisone, and valacyclovir. She recalls the oral prednisone helped her symptoms, but her epithelial defect continued. A bandage contact lens has been helpful to decrease her irritation. She is currently instilling prednisolone four times a day to the right eye.
On examination her vision is 20/400 OD, 20/30 OS. Her pupils are equal. Her IOP is 12 OU. The slit lamp examination reveals numerous symblephara in the inferior fornices ( Fig. 12.3 ), now only 25% of normal depth. There is 2+ conjunctival injection bilaterally. The right corneal epithelium has been replaced with hazy, irregular conjunctival epithelium. There is superficial neovascularization and a 2.5 mm epithelial defect centrally ( Fig. 12.4 ). There is no associated infiltrate or stromal thinning seen. The left cornea appears normal. The anterior chambers appear quiet and irides appear normal. She is pseudophakic bilaterally. The details of the right fundus are obscured by the corneal haze. The left fundus appears normal. B-scan ultrasonography of the right eye is normal.
Inflamed conjunctiva with inferior symblephara
Neovascularization of cornea (limbal stem cell failure) due to chronic inflammation and a central epithelial defect in the same patient