Ocular Cicatricial Pemphigoid (OCP) 

Updated: Jul 16, 2019
Author: C Stephen Foster, MD, FACS, FACR, FAAO, FARVO; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Ocular cicatricial pemphigoid (OCP) is one of the subsets of mucous membrane pemphigoid (MMP), a group of systemic autoimmune diseases characterized by T-lymphocyte dysregulation, the production of circulating autoantibodies directed against a variety of adhesion molecules in the hemidesmosome-epithelial membrane complex, and the production of proinflammatory cytokines and immune system activation markers. OCP can affect the skin and other mucous membranes (eg, oral mucosa, pharynx, larynx, trachea, esophagus, vagina, urethra, anus), in addition to its hallmark feature, chronic cicatrizing conjunctivitis.[1]

See image below depicting stage II ocular cicatricial pemphigold.

Ocular cicatricial pemphigoid, stage II. Note the Ocular cicatricial pemphigoid, stage II. Note the fornix foreshortening.

Pathophysiology

The pathophysiologic mechanisms of ocular cicatricial pemphigoid (OCP), as well as conjunctival fibrosis, are not completely understood. Clearly, a defect exists in immunoregulation, with the production of autoantibodies directed against the beta 4 subunit of alpha 6 beta 4 integrin, and, reportedly, in some instances, against alpha 3, beta 3, or gamma 2 subunits of laminin 5.[2]

A triggering agent in the genetically susceptible individual, leading to clinical manifestations of the disease, may occur in a "2-hit" mechanism. It is probably operative in some patients. Human leukocyte antigen DR2 (HLA-DR2), human leukocyte antigen DR4 (HLA-DR4 [HLA-DR*0401]), and human leukocyte antigen DQw7 (HLA-DQw7 [DQB1*0301]) genotypes have been identified as conferring increased susceptibility to the development of OCP.

In some patients, systemic practolol therapy and topical antiglaucoma drugs, such as pilocarpine, timolol, epinephrine, Humorsol, idoxuridine, and phospholine iodide, have triggered the onset of OCP. The term pseudopemphigoid or drug-induced pemphigoid may be used to describe these cases. Whether or not these cases associated with medication use are identical to OCP is not completely clear.

On the molecular level, the initial trigger may be a process by which the OCP antigen undergoes a conformational change that provides antigenic stimulation. This signal results in the generation of B-cell clones that produce antibodies against antigens located at the basement membrane zone (BMZ), initiating a type II Gell and Coombs hypersensitivity reaction. The antibodies of immunoglobulin G (IgG), immunoglobulin A (IgA), and/or immunoglobulin M (IgM) bind to the antigen and initiate complement activation.

Circulating autoantibodies are difficult to demonstrate by classic indirect immunofluorescence technique in patients with OCP. Specialized radioimmunoassay and immunoblot techniques allow the circulating autoantibodies to be seen in all patients with OCP who have active conjunctivitis. The resultant inflammatory mediators that are produced induce migration of lymphocytes, eosinophils, neutrophils, and mast cells to the BMZ. The separation of the epithelium from the underlying tissues within the BMZ may be the result of direct cytotoxic action or the effect of lysosomal proteolytic enzymes.

Fibroblast activation secondary to inflammatory cytokine influences, with collagen production and subsequent cicatrization, is the end result in the conjunctiva. Progressive fibrosis causes profound tear insufficiency, meibomian gland dysfunction, and mucin deficiency. Symblepharon formation, trichiasis, distichiasis, and keratinization cause corneal epitheliopathy, persistent corneal epithelial defects, stromal ulcers, corneal scarring, neovascularization, and even perforation.

OCP is a chronic, slowly progressive, bilateral blinding, systemic autoimmune disease. Multiple antigens in the BMZ of squamous epithelia may serve as targets for a spectrum of autoantibodies observed in OCP. The molecular definition of these autoantigens facilitates the classification and characterization of subsets of OCP. Sera from patients with OCP have been shown to recognize beta 4 integrin, which is a 205-kDa protein, also known as CD104. A subset of patients with clinical features similar to OCP also has been shown to have autoantibodies against epiligrin, which is identified as laminin 5, a ligand for alpha 6 beta 4 integrin, and autoantibodies to the alpha 6 integrin subunit. OCP probably is a spectrum of several different diseases associated with different target antigens, different triggers, and different therapeutic responses.

Epidemiology

Frequency

United States

The incidence of ocular cicatricial pemphigoid (OCP) is estimated at between 1 in 8,000 and 1 in 46,000 ophthalmic patients. It is likely that the early stages of OCP are not reflected in these estimates because of difficulties in making the correct diagnosis. The real frequency of the disease is probably higher.

International

Distribution appears to be worldwide. No geographical predilection is reported.

Mortality/Morbidity

Oral lesions occur in 75-100% of patients with OCP. Skin involvement (eg, face, neck, scalp) occurs in approximately 25% of patients with OCP.

Race

OCP can occur in all races.

Sex

Females predominate patients diagnosed with OCP. The female-to-male ratio is estimated to be 1.5:1 to 3:1.

Age

Average age of onset is 50-60 years; however, the exact age of onset may be younger, since most patients with early stages of OCP remain undiagnosed. Some cases have been diagnosed as early as 12 and 19 years.

Prognosis

Based on the results of one study, slightly more than one third of patients with ocular cicatricial pemphigoid (OCP) receiving immunosuppressive therapy, according to the guidelines for use of immunosuppressive agents, respond to the therapy and remain free of inflammation following the cessation of therapy. Another one third of patients were free of disease activity, but they continued to receive chemotherapy because their disease had been controlled for only a short time (< 1 y) or because they had a history of relapse while on therapy. Nearly one third of patients only responded partially to treatment. Inability to control inflammation and to stop progression of cicatrizing conjunctivitis was seen only in a few individuals. In these patients, intravenous immunoglobulin seems to be effective.[3]

Patient Education

Patients with ocular cicatricial pemphigoid (OCP) should be educated about the disease, the potential consequences, and the therapy. It is a systemic disease affecting the eye; therefore, no topical medication can be curative.

It should be explained to patients that chemotherapy is currently the only available effective treatment of OCP, providing its safety by regular monitoring by an oncologist, rheumatologist, or other specialist familiar with immunosuppressive therapy.[4]

 

Presentation

History

The history of ocular cicatricial pemphigoid (OCP) is as follows:

  • Ocular symptoms

    • Red eye

    • Tearing

    • Dry eye

    • Blepharospasm

    • Itching

    • Grittiness

    • Heavy eyelid

    • Foreign body sensation

    • Decreased vision

    • Burn sensation

    • Photophobia

    • Diplopia

  • Other symptoms

    • Skin lesions

    • Oral lesions

    • Esophageal lesions

    • Pharyngeal lesions

    • Laryngeal lesions

    • Anal lesions

    • Tracheal lesions

    • Vaginal lesions

    • Urethral lesions

Physical

Physical examination of ocular cicatricial pemphigoid (OCP) is as follows:

  • External examination

    • Conjunctival hyperemia (red eye)

    • Quiet eye

    • Entropion

    • Skin lesions

    • Nasal lesions

    • Mouth lesions

    • Discharge (ie, catarrhal, mucous, membranous)

  • Slit lamp examination

    • Eyelids

      • Trichiasis

      • Distichiasis

      • Meibomian gland dysfunction

      • Blepharitis

    • Conjunctiva

      • Papillae

      • Follicles

      • Keratinization

      • Subepithelial fibrosis

      • Conjunctival shrinkage

      • Foreshortening of fornices

      • Symblepharon

      • Ankyloblepharon

    • Cornea

      • Superficial punctate keratitis

      • Epithelial defect

      • Stromal ulcer

      • Neovascularization

      • Keratinization

      • Limbitis

      • Conjunctivalization

      • Stromal opacity

      • Perforation

Based on clinical findings, progression of disease can be divided into 4 stages.

Stage I is characterized by chronic conjunctivitis with mild conjunctival and/or corneal epitheliopathy with subepithelial conjunctiva fibrosis, best seen at the tarsal conjunctiva as fine, white striae.

Stage II is characterized by cicatrization with conjunctival shrinkage, distorted anatomy, and foreshortening of fornices, as shown below.

Ocular cicatricial pemphigoid, stage II. Note the Ocular cicatricial pemphigoid, stage II. Note the fornix foreshortening.

Stage III is characterized by the presence of symblepharon (see image below). Subepithelial scarring alters the orientation of lashes, causing aberrant lash growth. In addition, cicatricial entropion may occur.

Ocular cicatricial pemphigoid, stage III. Note the Ocular cicatricial pemphigoid, stage III. Note the symblepharon.

Stage IV is the end stage, consisting of a dry eye with keratinization of the cornea and ankyloblepharon, which immobilizes the globe (see first image below). Profound keratopathy can develop secondary to eyelid disorders, tear insufficiency, and corneal exposure. Corneal epitheliopathy, persistent epithelial defects, stromal ulceration, and neovascularization may be present (see second image below). The cornea may become completely scarred, vascularized, and keratinized.

Ocular cicatricial pemphigoid, stage IV. Note the Ocular cicatricial pemphigoid, stage IV. Note the ankyloblepharon and ocular surface keratinization.
Corneal neovascularization with ulceration and str Corneal neovascularization with ulceration and stromal thinning after persistent epithelial defect in a patient with ocular cicatricial pemphigoid.

Causes

The cause of ocular cicatricial pemphigoid (OCP) is unknown. Genetic factors and several triggers can increase the likelihood of the onset of OCP.

Individuals with HLA-DR2, HLA-DR4 (HLA-DR*0401), and HLA-DQw7 (DQB1*0301) are more susceptible to OCP.

In some patients, systemic practolol therapy and topical antiglaucoma drugs (eg, pilocarpine, timolol, epinephrine, Humorsol, idoxuridine, phospholine iodide) have been identified as triggers of OCP.

Complications

Ocular complications of ocular cicatricial pemphigoid (OCP) include the following:

  • Corneal epithelial defects

  • Corneal stromal ulcers

  • Corneal perforation

  • Endophthalmitis

  • Glaucoma

Two types of lesions can occur. The most common lesion is a vesiculobullous eruption, similar to that of bullous pemphigoid. These lesions rupture spontaneously and heal without significant scarring. The second type of lesion is an erythematous localized plaque that evolves into recurring bullae, which can rupture and leave scars (ie, Brunsting-Perry dermatitis). Patients with OCP may present with skin lesions and lesions on other mucous membranes (eg, nose, mouth, esophagus, pharynx, larynx, urethra, vagina, anus).

Mouth involvement is the most common. Scarring of mucosa in the nose and the mouth can be debilitating. Nasopharyngeal involvement can manifest as ruptured vesicles of the nasal mucosa along with discharge, crusting, and epistaxis.

Patients with tracheolaryngeal lesions may present with hoarseness, dyspnea, and laryngeal stenosis. Aphonia can occur secondary to vocal cord involvement. Laryngeal stenosis and tracheal scarring with mucous accumulation may lead to fatal asphyxiation.

Progressive desquamative gingivitis typically results in bone loss and dental extraction.

Pharyngeal scarring can cause painful swallowing with subsequent malnutrition and weight loss. Patients suspected of having OCP must be questioned for the presence of dysphagia and difficulties in breathing. Endoscopic evaluation is required, if there is a possibility of tracheal or esophageal involvement.

Pain on defecation or rectal bleeding can manifest as a result of rectal involvement; however, esophageal involvement, typically is silent. Although the progressive scarring associated with esophageal inflammation results in esophageal strictures, which may produce dysphagia, even to the point of choking with attempted swallowing of food. As a consequence of this condition, death from asphyxiation is reported and is a major threat.

 

DDx

 

Workup

Laboratory Studies

Diagnosis of ocular cicatricial pemphigoid (OCP) is based on clinical presentation and immunohistochemical studies of the conjunctiva, which can reveal pathognomonic features of the disease.[5]

Currently, no specific laboratory assays are available to diagnose or monitor the activity of OCP; however, such assays are being developed. In one study, decreased serum levels of interleukin 6 and increased serum levels of tumor necrosis factor alpha were described in patients with active OCP, but the use of these tests is not common in clinical practice.[6]

Individuals receiving immunosuppressive agents require appropriate laboratory studies to monitor the therapy.

Procedures

Conjunctival biopsy

A definitive diagnosis of ocular cicatricial pemphigoid (OCP) is made by demonstration of linear deposition of immunoreactants (eg, IgG, IgA, complement component C3 or C4) at the BMZ of the biopsy specimen of inflamed conjunctiva using immunofluorescent or immunoperoxidase technique.

Other histologic techniques, such as hematoxylin and eosin staining, periodic-acid Schiff (PAS), and Giemsa staining, are not diagnostically specific.

Only experienced laboratory technicians should process conjunctival tissue to obtain the highest possible diagnostic yield and sensitivity. A negative or inconclusive biopsy result may be secondary to poor biopsy technique or poor handling of the specimen.[7] Indeed, two recent reports led the authors to abandon biopsy-proof efforts and to simply treat patients whom they believed had OCP.[8, 9] The authors of this article believe that this is ill-advised and recommend extra efforts at amplification strategies for definitive diagnosis.[10]

Histologic Findings

Hematoxylin and eosin staining shows the conjunctiva infiltrated with neutrophils, macrophages, and Langerhans cells. PAS goblet cells are decreased or absent in patients with advanced ocular cicatricial pemphigoid (OCP). Patients with active OCP have excess mucus production and strands of mucus-like material in the inferior fornix.

Observations with scanning and transmission electron microscopy indicate mucus present on the surface of the conjunctiva, even though goblet cells are not seen. Giemsa stain results show that the total mast cell number and ratio of connective tissue mast cells to mucosal mast cells are significantly higher than in normal conjunctiva.

The deposition of IgG, IgA, C4, or C3 is highlighted by fluorescein or rhodamine-labeled antibodies, which are directed against immunoglobulins and complement components. The diagnostic sensitivity of immunofluorescence alone is approximately 50-52%.

Immunoperoxidase technique is required when immunofluorescence study findings are negative, yet the clinical presentation strongly suggests OCP. The immunoperoxidase technique is approximately 1,000 times more sensitive than immunofluorescence. Immunoperoxidase can detect the deposition of immunoreactants at the BMZ in smaller amounts. The diagnostic sensitivity of immunoperoxidase is 83%, an increase of 31% compared to immunofluorescence technique.

 

Treatment

Medical Care

No topical agent is effective in stopping ocular cicatricial pemphigoid (OCP) activity. In selected patients, subconjunctival steroid injections or subconjunctival injections of mitomycin C may be used temporarily for slowing disease progression, while systemic therapy takes effect.

Adjuvant treatment with topical lubricants should be used in patients with dry eye symptoms. The use of topical cyclosporine and tacrolimus ointment has also been described in anecdotal reports to aid in the control of surface inflammation.[11]

Systemic corticosteroids can control the activity of the disease; however, they are not as effective as other immunosuppressive drugs, and the doses required have been shown to be very toxic. Additionally, tapering of systemic steroids has always been associated with recurrence of disease activity, suggesting the need of high doses for extended periods of time. Because of the toxicity of long-term corticosteroid use (eg, aseptic hip necrosis, pathological fractures, uncontrolled diabetes mellitus, hypertension), it is an unacceptable treatment. Corticosteroids should never be used as a sole agent. Their use should be reserved only for severely inflamed eyes that do not readily respond to immunosuppression alone. When administered, corticosteroids should be used for a limited period of time, preferably not longer than 3 months.[12]

Long-term use (>1 y) of systemic immunomodulators is the major therapeutic strategy in treating OCP. The current guidelines for using chemotherapy in treating OCP are as follows:

For mild-to-moderate inflammation, diaminodiphenylsulfone (Dapsone) is a first-line agent, provided the patient is not glucose-6-phosphate dehydrogenase deficient. Methotrexate may also be considered first-line therapy. If therapeutic response is not satisfactory, or if the use of Dapsone is contraindicated, or if the patient cannot tolerate the drug, mycophenolate mofetil or azathioprine can be substituted. If inflammation persists, cyclophosphamide can be used sequentially.

For severe inflammation, cyclophosphamide should be used initially, and systemic prednisone could be added with rapid taper for a limited period of time (3 mo).

Patients with active conjunctival inflammation refractory to chemotherapy or patients who do not tolerate the spectrum of immunosuppressive drugs can be treated with intravenous immunoglobulin (IVIg) or a combination of IVIg and rituximab infusions.[13, 14] Combination IVIg plus rituximab therapy may be the treatment approach with the highest likelihood of induction of durable remission and drug-free cure[15] ; the cost of such therapy may actually be less than the other therapeutic approaches, although such cost may appear to be the highest.[16] Additionally, since such therapy is not FDA-approved for labeling for treating OCP, obtaining insurance carrier coverage for such off-label use may require considerable effort.

Surgical Care

Ocular surgical procedures should only be performed when the inflammation is completely under control, and systemic corticosteroids should be used perioperatively, when the procedure involves the conjunctiva or the cornea. Once the inflammation is suppressed, such procedures as marginal rotation of the eyelid, mucous membrane grafting, retractor plication, fornix reconstruction, or cataract extraction can be performed without significant danger of excessive postoperative inflammation and cicatrization.

Epilation

Aberrant lash growth that produces damage to the ocular surface is common in ocular cicatricial pemphigoid (OCP). Extraction of these lashes and destruction of the follicles is important not only to prevent further irritation of the ocular surface but also to remove a factor that can mimic immunologically driven conjunctival inflammation, thereby hindering judgment regarding clinical response to chemotherapy and disease activity.

Mechanical epilation has only a temporary effect, and the lashes that regrow may be more deleterious than the original lashes. Gas permeable scleral contact lenses can be used to provide protection to the ocular surface from injury by aberrant lashes.

In case of trichiasis or distichiasis, permanent destruction of the lash follicles is ideal, although not easy to provide. Cryodestruction of lash follicles requires subsequent epilation in 10% of patients. The recurrences can be retreated.

Punctual occlusion

Treat dry eye syndrome with punctal occlusion and ocular lubricants without preservatives. Ocular hydration also can be increased with the use of twice daily mild steroid and topical cyclosporine.

Treat meibomian gland dysfunction with warm compresses and lid massages with eyelid hygiene, with or without systemic tetracycline therapy.

Lid surgery

Entropion surgery usually is avoided in patients with OCP because of the interference with the conjunctiva. Recently, several cases of lower lid entropion have been treated successfully with a retractor plication technique. The procedure is repeatable in case of undercorrection. Moreover, the conjunctiva remains intact during the surgery, which can avoid the exacerbation of conjunctival inflammation.

Tarsorrhaphy can be used in case of lagophthalmos, corneal hypoesthesia, or corneal epithelial defects.

Fornix reconstruction

Amniotic membrane transplantation or autologous oral mucosa can be used to reconstruct the conjunctival fornices in patients with OCP.

Mucous membrane grafting should not be performed when patients have severe keratoconjunctivitis sicca, advanced OCP, or active conjunctival inflammation. The procedure not only reconstructs the anatomy of fornices but also provides nonkeratinizing epithelium with goblet cells supplying mucous production to the ocular surface.

The beneficial long-term effect of this procedure is provided in approximately one third of the patients.[17]

Corneal surgery

The visual acuity in patients with OCP is impaired mostly by corneal pathology. Unfortunately, the spectrum of procedures on the cornea providing a satisfactory long-term visual outcome is very limited. Corneal transplantation on a dry eye with impaired lid function and limbal stem cell deficiency has a very poor prognosis; therefore, corneal grafting in patients with advanced OCP should be avoided. This procedure should only be performed in case of corneal perforation.

In patients with advanced corneal damage from OCP, keratoprosthesis may be the only feasible alternative for visual rehabilitation. Necrosis of the tissue surrounding the prosthesis is the major problem limiting the long-term outcomes. This process can lead to aqueous leak, retinal detachment, infection, and extrusion of the prosthesis. Recent advances in keratoprosthesis along with lifelong use of topical antibiotics have improved the outcome. At one facility, 5-8 patients had considerable improvement of visual acuity over a 5-year period.

Cataract surgery

The need for cataract surgery is common in patients with OCP. Cataract surgery performed on patients with OCP is followed by increased conjunctival inflammation, rapid progression of keratopathy, and conjunctival scarring, if the disease is not medically controlled.

The results of one study showed that a worse outcome of cataract surgery was associated with chemotherapy intolerance or the presence of any preoperative conjunctival inflammation. Similar to other surgical procedures for OCP, the use of perioperative systemic steroids is necessary in patients who are on systemic immunosuppressive therapy and in those patients whose inflammation is currently in remission without taking any immunosuppressive agents.[18]

Consultations

Consult an appropriate specialist in case of skin involvement or involvement of other mucous membranes. Patients who have difficulty swallowing or breathing require an immediate endoscopic examination looking for esophageal webs, as these patients are at risk of asphyxiation.

Patients receiving chemotherapy may require regular consultations with a chemotherapeutist.

Patients should be referred to an ear, nose, and throat specialist for laryngoscopy in case of recent onset of hoarseness, which may be caused by laryngeal stenosis and tracheal scarring. These patients are in a medical emergency because of the risk of mucous accumulation and subsequent fatal asphyxiation. A statim laryngoscopy is essential, and it may be a life-saving procedure.

Activity

Patients may be limited by visual acuity.

Long-Term Monitoring

Because relapse can occur in approximately one third of the ocular cicatricial pemphigoid (OCP) cases, lifelong follow-up care should be continued. Patients who relapsed were found to regain disease control readily on institution of therapy and did not deteriorate to more advanced cicatrization.[19] ​

 

Medication

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and to prevent complications. Combination therapy in a stepladder regimen is needed in many cases to improve disease control.

Antibiotics

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.

Dapsone (Avlosulfon)

Recommended as first-line agent for treatment of ocular cicatricial pemphigoid (OCP) if inflammatory activity is not severe, disease is not rapidly progressive, and patient is not glucose-6-phosphate dehydrogenase deficient. A response usually is observed within 4 weeks of initiation of therapy. Has both antimicrobial and anti-inflammatory activity. Mechanisms by which it influences inflammatory and immune systems are not clear. Able to penetrate bacterial cells and have both bactericidal and bacteriostatic activity against Mycobacterium leprae. Believed to mediate anti-inflammatory effects in cicatricial pemphigoid by a variety of mechanisms. Evidence suggests that dapsone stabilizes lysosomal membranes, decreasing release of contents, and interferes with myeloperoxidase halide-mediated cytotoxic system of neutrophils. May inhibit Arthus reaction and adjuvant-induced arthritis in a manner similar to that of corticosteroids and indomethacin.

Immunosuppressive agents

Class Summary

Inhibit cell growth and proliferation.

Methotrexate (Folex, Rheumatrex)

Chemical structure analogous to that of folic acid. Prevents conversion of dihydrofolate to tetrahydrofolate by competitively and irreversibly binding to enzyme dihydrofolate reductase. Tetrahydrofolate is an essential cofactor in production of 1-carbon units critical to synthesis of purine nucleotides and thymidylate. Less rapid, partially reversible competitive inhibition of thymidylate synthetase occurs within 24 h after methotrexate administration. Net effect is inhibition of DNA synthesis, DNA repair, RNA synthesis, and cell division at specific stages of the cell cycle.

Has little effect on resting cells. Exerts cytotoxic actions in actively proliferating tissues such as malignant cells, fetal cells, cells of GI tract, urinary bladder, buccal mucosa, and bone marrow. By inhibiting DNA synthesis in immunologically competent cells, methotrexate has some activity as immunosuppressive agent. Both B and T cells are affected, and primary and secondary antibody responses can be suppressed when administered during antigen encounter. To date, no controlled data in humans or animals indicate that methotrexate is carcinogenic.

Azathioprine (Imuran)

Prodrug quickly metabolized in liver to active form, 6-MP, which in turn interferes with purine metabolism and ultimately with DNA, RNA, and protein synthesis.

Shown to suppress both B and T lymphocytes. Effective in suppressing mixed lymphocyte reaction in vivo and recirculating T lymphocytes that are in the process of homing. Also can suppress development of monocyte precursors and thus participation of K cells (which themselves are derived from monocyte precursors) in antibody-dependent cytotoxicity reactions.

Reduce dose by 25% if allopurinol is administered concomitantly, since allopurinol interferes with metabolism of 6-MP8.

Cyclophosphamide (Cytoxan, Neosar)

Belongs to nitrogen mustard family of alkylating agents. Prodrug that must be converted in vivo by hepatic microsomal cytochrome P-450 mixed function oxidase system into its active metabolites, phosphoramide mustard and 4-hydroxy-cyclophosphamide. Products act through nucleophilic substitution reactions resulting in formation of covalent cross linkages (alkylation) with DNA, thereby mediating their major immunosuppressive activity.

At clinical doses, has profound effect on lymphoid cells. Both B- and T-cell function are depressed, although with acute administration of high doses of drug, B cells appear to be more affected.

It is preferred that patients take total daily dose in morning and maintain adequate oral fluids throughout rest of day, in an effort to induce frequent voiding. In this way, risk of hemorrhagic cystitis from prolonged contact of bladder mucosa with cyclophosphamide metabolites is minimized.

Intravenous administration of cyclophosphamide offers certain advantages overoral

administration and is useful in the following clinical situations: (1) permits rapid induction in patients with severe ocular inflammatory involvement; (2) avoids prolonged bladder exposure, allowing larger doses, yet less frequent dosing in patients with hemorrhagic cystitis induced from oral intake; and (3) induces only transient neutropenia, making intercurrent infections less likely

Mycophenolate mofetil (CellCept)

Has been shown useful in moderate OCP in several recent studies. Has generally been well tolerated and, in these studies, has been as effective (possibly more effective) as more traditional therapies, including dapsone, sulfasalazine, and azathioprine, with less toxicity.

Systemic steroids

Class Summary

To reduce inflammatory response; however, these are not useful drugs for this disease because of the necessity for long-term usage and the adverse effects. Reserve their use for the severely inflamed eyes that do not readily respond to immunosuppression alone.

Prednisone (Deltasone, Orasone, Meticorten)

Immunosuppressant that may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Aminosalicylic acid derivative

Class Summary

Used to reduce inflammation.

Sulfasalazine (Azulfidine, En-Tabs)

Sulfonamide derivative with anti-inflammatory properties. Decreases inflammatory response and systemically inhibits prostaglandin synthesis.

Immunomodulators

Class Summary

Interfere with cytokine actions responsible for inflammation. Some anecdotal reports and case series of OCP treatment with anti-TNF-alpha have been described with favorable results.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Reported in anecdotal case reports

Etanercept (Enbrel)

A recombinant human TNF-alpha receptor protein fused with Fc portion of IgG1 that binds to TNF-alpha, thereby neutralizing the effects of TNF-alpha. Reported in anecdotal reports and case reports.

Monoclonal antibodies

Class Summary

Found to be effective for OCP in uncontrolled small studies.

Rituximab (Rituxan)

Genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes.

Immunoglobulins

Class Summary

Used in cases resistant to conventional treatment.

Immune globulin intravenous (Gamimune, Gammagard, Sandoglobulin, Gammar-P)

Contains the pooled immunoglobulin G (IgG) immunoglobulins from the plasma of approximately a thousand or more blood donors. Acts by modulation of complement activation; suppression of idiotypic antibodies; saturation of Fc receptors on macrophages; and suppression of various inflammatory mediators, including cytokines, chemokines, and metalloproteinases.