Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

Foster also showed that cyclophosphamide was more effective than dapsone in severe OCP [3]. The preferred route of cyclophosphamide administration is daily oral intake, although monthly intravenous pulse therapy has been tested [59,60]. No comparative studies of the cyclophosphamide route of administration in OCP are available; however, daily oral treatment seems most effective in other diseases such as uveitis [61] and Wegener’s granulomatosis [62]. Therefore, intravenous pulse therapy is usually reserved for patients with drug-induced bone marrow toxicity or in whom the oral route is contraindicated.

Two clinical situations are encountered in severe OCP. When the patient has already been receiving systemic anti-inflammatory medications, oral cyclophosphamide can be added to the preexisting therapy, which can be tapered if poorly tolerated (Fig. 4). The different anti-inflammatory drugs can act as reciprocal sparing agents, thereby decreasing their respective toxicity. Disease control required more than one systemic anti-inflammatory drug in 78% and 71% of patients in the series of 61 patients by Foster’s group [11] and in our unpublished series of 63 patients, respectively. Unfortunately, diagnosis of OCP is often only made when fibrosis is already associated with symblepharon formation (stage III) and is becoming sight-threatening (86% of eyes in our series). The prognosis is then worse [11,63]. Oral cyclophosphamide may be directly indicated in such cases, sometimes in combination with oral prednisone; the latter is gradually withdrawn after 1 month, once the therapeutic effect of cyclophosphamide has been obtained.

When cyclophosphamide monotherapy is not effective, dapsone, sulfasalazine, azathioprine, methotrexate, and mycophenolate mofetil, alone or in combination, can be added. These drugs, preferably given in combination, can replace cyclophosphamide if the latter is too toxic. Subcutaneous cytosine arbinoside (ara-C) is only partially effective and is highly toxic [11]. Preliminary results with intravenous immunoglobulin are encouraging. This therapy was recently successful in 10 treatment-resistant OCP patients, with no side effects [22]. The level of autoantibodies directed against β4 integrin may be a good marker of IVIG treatment efficacy [22].

XI. SURGERY TO CORRECT OCP

Surgery should only be attempted 3–6 months after the inflammatory and fibrotic processes have been controlled, in order to avoid inflammatory reactivation [64]. It is recommended to increase the level of immunosuppression for at least 2 weeks after surgery [65–68]. Despite the report that conjunctival scarring increased after cryotherapy in 77% of patients in the absence of immunosuppression [69], cryoepilation or lid surgery may be required when mechanical irritation of the ocular surface by malpositioned eyelashes or keratinized plaques at the lid margins prevents correct assessment of disease activity.

A.Lid Surgery

Cryotherapy is valuable only when few eyelashes are ectopic (see Chapter 15).

Results of one study showed a success rate of 40% during the first year [70]. Total destruction of lash follicles is obtained if they are frozen to –30°C in two cycles

[71]. Inferior retractor plication, eyelash transposition, marginoplasty combined with buccal mucosa grafting, and fornix reconstruction with buccal mucosa or amniotic membrane are preferred when lid abnormalities are more severe and associated with fornix foreshortening and extensive symblepharon formation.

B.Ocular Surgery

Restoration of corneal transparency is the main challenge in OCP. The visual prognosis of patients with advanced disease is usually poor, because of severe ocular dryness secondary to meibomian gland dysfunction, fibrosis-induced obliteration of the ductular orifices of the lacrimal gland, and destruction of goblet cells and limbal stem cells. Superficial keratectomy is indicated only for localized corneal pannus. The outcome of lamellar or penetrating keratoplasty performed for more extensive and deeper corneal scars has recently improved with the advent of limbal stem cell and amniotic membrane transplantation. Because conjunctival fibrosis in OCP usually is or becomes bilateral, it is not wise to graft autologous limbal stem cells. Allograft limbal transplantation from a living related donor is preferred, and the risks to the donor are minimal [72–74]. More recently, Tsubota et al. used corneal scleral buttons obtained from cadaveric donors, simultaneously grafting the central corneal button and the trimmed annular limbal tissue in order to provide more epithelial stem cells to the recipient. They also used amniotic membranes as a replacement substrate when the underlying stroma was damaged [73]. Other investigators find that the success rate of keratoplasty is higher when it is performed 3 months after limbal stem cell transplantation [75]. In all cases, even when the donor is a relative, systemic immunosuppression, usually consisting of cyclosporine or tacrolimus and a short course of corticosteroids, is required [73,76]. The optimal duration of this postoperative immunosuppression is not clearly established. If the ocular involvement is asymmetric, one could possibly transplant limbal cells taken from the less involved eye and expanded on an amniotic membrane [77].

However, when corneal lesions are too severe (e.g., major neovascularization and xerosis), the only surgical option is keratoprosthesis insertion. Recent progress in the biomaterials used for keratoprostheses suggests that human transplants may one day be unnecessary, but follow-up is too short to judge the results of the latest generation of keratoprostheses [78].

Cataract surgery should be performed only in a noninflammed eye and after the fibrosis has stabilized (Fig. 5). Phacoemulsification with clear corneal

Figure 5 Same patient as Fig. 4, cured by adjunction of oral cyclophosphamide (1.5 mg/kg/day). The patient underwent successful cataract surgery. (Reprinted with permission from Hoang-Xuan T: Inflammatory Diseases of the Conjunctiva. New York: Thieme, 2001, p. 85.)

incision appears to be the best technique to lower the risk of inflammatory reactivation [64].

The use of an antimetabolite such as mitomycin C or 5-fluorouracil should probably be combined with filtering surgery in patients with glaucoma who are not responding to medical therapy.

XII. SUMMARY

1.Ocular cicatricial pemphigoid (OCP) is an autoimmune disease characterized by subepithelial fibrosis due to immune deposits along the basement membrane zone of the conjunctiva and other mucosa. It leads to fornix foreshortening, symblepharon formation, and eyelid margin deformations associated with ectopic eyelash growth.

2.When OCP is associated with lesions at other sites, biopsy of those sites may be sufficient for diagnosis, making conjunctival biopsy unnecessary. Diagnosis can be difficult if only the eye is involved.

3.Because of adverse effects, systemic corticosteroid therapy should be restricted to initial control of severe inflammation, or to the lowest possible maintenance dose.

4.Dapsone alone, or in combination with cyclophosamide, is the first-line therapy for mild to moderate OCP. Sulfasalazine may substitute for dapsone.

5.For severe OCP, cyclophosamide combined with prednisone is beneficial.

6.Surgery should be delayed until 3–6 months after inflammation and fibrosis have been controlled.

7.Cryoepilation is useful for removal of a few ectopic eyelashes.

8.Restoration of corneal transparency may require keratoplasty or insertion of a keratoprosthesis.

ACKNOWLEDGMENTS

The author thanks Serge Doan, M.D., and Eric Gabison, M.D., for their contributions.

REFERENCES

1.Foster CS, Wilson LA, Ekins MB. Immunosuppressive therapy for progressive ocular cicatricial pemphigoid. Ophthalmology 1982; 89:340–353.

2.Mondino BJ, Brown SI. Ocular cicatricial pemphigoid. Ophthalmology 1981; 88:95–100.

3.Foster CS. Cicatricial pemphigoid. Trans Am Acad Ophthalmol Soc 1986; 84:527–663.

4.Tauber J, Melamed S, Foster CS. Glaucoma in patients with ocular cicatricial pemphigoid. Ophthalmology 1989; 96:33–37.

5.Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, Cooper KD, Elder MJ, et al. The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators. Arch Dermatol 2002; 138:370–379.

6.Hoang-Xuan T, Robin H, Heller M, Caux F, Prost C. Epidermolysis bullosa acquisita diagnosed by direct immunoelectron microscopy of the conjunctiva. Ophthalmology 1997; 104:1414–1420.

7.Pouliquen Y, Patey A, Foster CS, Goichot L, Savoldelli M. Drug-induced cicatricial pemphigoid affecting the conjunctiva. Light and electron microscopic features. Ophthalmology 1986; 93:775–783.

8.Chan RY, Bhol K, Tesavibul N, Letko E, Simmons RK, Foster CS, Ahmed AR. The role of antibody to human beta4 integrin in conjunctival basement membrane separation: possible in vitro model for ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci 1999; 40:2283–2290.

9.Bhol KC, Dans MJ, Simmons RK, Foster CS, Giancotti FG, Ahmed AR. 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; 165:2824–2829.

10.Kumari S, Bhol KC, Simmons RK, Razzaque MS, Letko E, Foster CS, Razzaque AA, Ahmed AR. Identification of ocular cicatricial pemphigoid antibody binding site(s) in human beta4 integrin. Invest Ophthalmol Vis Sci 2001; 42:379–385.

11.Miserocchi E, Baltatzis S, Roque MR, Ahmed AR, Foster CS. The effect of treatment and its related side effects in patients with severe ocular cicatricial pemphigoid. Ophthalmology 2002; 109:111–118.

12.Mondino BJ, Brown SI. Immunosuppressive therapy in ocular cicatricial pemphigoid. Am J Ophthalmol 1983; 96:453–459.

13.Tauber J, Jabbur N, Foster CS. Improved detection of disease progression in ocular cicatricial pemphigoid. Cornea 1992; 11:446–451.

14.Franke E. Pemphigus und die essentialle Schrumpfung der Bindehaut des Auges. Wiesbaden: Bergmann JF, 1900:111.

15.Bean SF, Furey N, West CE, Andrews T, Esterly NB. Ocular cicatricial pemphigoid (immunologic studies). Trans Am Acad Ophthalmol Otolaryngol 1976; 81:806–812.

16.Waltman SR, Yarian D. Circulating autoantibodies in ocular pemphigoid. Am J Ophthalmol 1974; 77:891–894.

17.Franklin R, Fitzmorris C. Antibodies against conjunctival basement membrane zone. Arch Ophthalmol 1983; 101:1611–1613.

18.Furey N, West C, Andrews T, Paul PD, Bean SF. Immunofluorescent studies of ocular cicatricial pemphigoid. Am J Ophthalmol 1975; 80:825–831.

19.Herron BE. Immunologic aspects of cicatricial pemphigoid. Am J Ophthalmol 1975; 79:271–278.

20.Mondino BJ, Ross AN, Rabin BS, Brown SI. Autoimmune phenomena in ocular cicatricial pemphigoid. Am J Ophthalmol 1977; 83:443–450.

21.Donnenfeld ED, Perry HD, Wallerstein A, Caronia RM, Kanellopoulos AJ, Sforza PD, d’Aversa G. Subconjunctival mitomycin C for the treatment of ocular cicatricial pemphigoid. Ophthalmology 1999; 106:72–78.

22.Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid: a preliminary study. Ophthalmology 1999; 106:2136–2143.

23.Hardy KM, Perry HO, Pingree GC, Kirby TJ, Jr. Benign mucous membrane pemphigoid. Arch Dermatol 1971; 104:467–475.

24.Lever WF, Schaumburg-Lever G. Immunosuppressants and prednisone in pemphigus vulgaris: therapeutic results obtained in 63 patients between 1961 and 1975. Arch Dermatol 1977; 113:1236–1241.

25.Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in ocular cicatricial pemphigoid. Br J Ophthalmol 1995; 79:264–266.

26.Thomas TP. The complications of systemic corticosteroid therapy in the elderly. A retrospective study. Gerontology 1984; 30:60–65.

27.Neumann R, Tauber J, Foster CS. Remission and recurrence after withdrawal of therapy for ocular cicatricial pemphigoid. Ophthalmology 1991; 98:858–862.

28.Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 2000; 130:492–513.

29.Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. American College of Rheumatology Task Force on Osteoporosis Guidelines. Arthritis Rheum 1996; 39:1791–1801.

30.Saag KG, Emkey R, Schnitzer TJ, Brown JP, Hawkins F, Goemaere S, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 1998; 339:292–299.

31.Tamesis RR, Rodriguez A, Christen WG, Akova YA, Messmer E, Foster CS. Systemic drug toxicity trends in immunosuppressive therapy of immune and inflammatory ocular disease. Ophthalmology 1996; 103:768–775.

32.Stendahl O, Molin L, Dahlgren C. The inhibition of polymorphonuclear leukocyte cytotoxicity by dapsone. A possible mechanism in the treatment of dermatitis herpetiformis. J Clin Invest 1978; 62:214–220.

33.Bozeman PM, Learn DB, Thomas EL. Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone. Biochem Pharmacol 1992; 44:553–563.

34.Tauber J, Sainz dlM, Foster CS. Systemic chemotherapy for ocular cicatricial pemphigoid. Cornea 1991; 10:185–195.

35.Person JR, Rogers RS III. Bullous pemphigoid responding to sulfapyridine and the sulfones. Arch Dermatol 1977; 113:610–615.

36.Lang PG Jr. Sulfones and sulfonamides in dermatology today. J Am Acad Dermatol 1979; 1:479–492.

37.Rogers RSI, Seehafer JR, Perry HO. Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone. J Am Acad Dermatol 1982; 6:215–223.

38.Raizman MB, Fay AM, Weiss JS. Dapsone-induced neutropenia in patients treated for ocular cicatricial pemphigoid. Ophthalmology 1994; 101:1805–1807.

39.Elder MJ, Leonard J, Dart JK. Sulphapyridine—a new agent for the treatment of ocular cicatricial pemphigoid. Br J Ophthalmol 1996; 80:549–552.

40.Doan S, Lerouic JF, Robin H, Prost C, Savoldelli M, Hoang-Xuan T. Treatment of ocular cicatricial pemphigoid with sulfasalazine. Ophthalmology 2001; 108:1565–1568.

41.Rains CP, Noble S, Faulds D. Sulfasalazine. A review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995; 50:137–156.

42.Harvath L, Yancey KB, Katz SI. Selective inhibition of human neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by sulfones. J Immunol 1986; 137:1305–1311.

43.Cronstein BN. The mechanism of action of methotrexate. Rheum Dis Clin N Am 1997; 23:739–755.

44.Luqmani RA, Palmer RG, Bacon PA. Azathioprine, cyclophosphamide and chlorambucil. Baillieres Clin Rheumatol 1990; 4:595–619.

45.Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. Arch Dermatol 1995; 131:193–197.

46.Hemminki K. Binding of metabolites of cyclophosphamide to DNA in a rat liver microsomal system and in vivo in mice. Cancer Res 1985; 45:4237–4243.

47.Ben Efraim S. Immunomodulating anticancer alkylating drugs: targets and mechanisms of activity. Curr Drug Targets 2001; 2:197–212.

48.Wei MX, Tamiya T, Rhee RJ, Breakefield XO, Chiocca EA. Diffusible cytotoxic metabolites contribute to the in vitro bystander effect associated with the cyclophosphamide/cytochrome P450 2B1 cancer gene therapy paradigm. Clin Cancer Res 1995; 1:1171–1177.

49.Kleta R. Cyclophosphamide and mercaptoethane sulfonate therapy for minimal lesion glomerulonephritis. Kidney Int 1999; 56:2312–2313.

50.Klaesson S, Ringden O, Markling L, Remberger M, Lundkvist I. Immune modulatory effects of immunoglobulins on cell-mediated immune responses in vitro. Scand J Immunol 1993; 38:477–484.

51.Reis A, Reinhard T, Sundmacher R, Althaus C, Voiculescu A, Kutkuhn B. [Mycophenolatemofetil in ocular immunological disorders. A survey of the literature with 3 case reports.] Klin Monatsbl Augenheilkd 1998; 213:257–261.

52.Tsubota K, Satake Y, Ohyama M, Toda I, Takano Y, Ono M, et al. Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome [see comments]. Am J Ophthalmol 1996; 122:38–52.

53.Nussenblatt RB, Fortin E, Schiffman R, Rizzo L, Smith J, Van Veldhuisen P, et al. Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. Proc Natl Acad Sci USA 1999; 96:7462–7466.

54.Braun J, Breban M, Maksymowych WP. Therapy for ankylosing spondylitis: new treatment modalities. Best Pract Res Clin Rheumatol 2002; 16:631–651.

55.Robertson SM, Lang LS. Leflunomide: inhibition of S-antigen induced autoimmune uveitis in Lewis rats. Agents Actions 1994; 42:167–172.

56.Fellner MJ, Katz JM, McCabe JB. Successful use of cyclophosphamide and prednisone for initial treatment of pemphigus vulgaris. Arch Dermatol 1978; 114:889–894.

57.Dave VK, Vickers CF. Azathioprine in the treatment of muco-cutaneous pemphigoid. Br J Dermatol 1974; 90:183–186.

58.Brody HJ, Pirozzi DJ. Benign mucous membrane pemphigoid. Response to therapy with cyclophosphamide. Arch Dermatol 1977; 113:1598–1599.

59.Musette P, Pascal F, Hoang-Xuan T, Heller M, Lok C, Deboise A, Dubertret L, Prost C. Treatment of cicatricial pemphigoid with pulse intravenous cyclophosphamide. Arch Dermatol 2001; 137:101–102.

60.Pandya AG, Warren KJ, Bergstresser PR. Cicatricial pemphigoid successfully treated with pulse intravenous cyclophosphamide. Arch Dermatol 1997; 133:245–247.

61.Rosenbaum JT. Treatment of severe refractory uveitis with intravenous cyclophosphamide. J Rheumatol 1994; 21:123–125.

62.Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 1997; 40:2187–2198.

63.Mondino BJ. Cicatricial pemphigoid and erythema multiforme. Ophthalmology 1990; 97:939–952.

64.Sainz dlM, Tauber J, Foster CS. Cataract surgery in ocular cicatricial pemphigoid. Ophthalmology 1988; 95:481–486.

65.Mondino BJ, Brown SI, Lempert S, Jenkins MS. The acute manifestations of ocular cicatricial pemphigoid: diagnosis and treatment. Ophthalmology 1979; 86:543–555.

66.Shore JW, Foster CS, Westfall CT, Rubin PA. Results of buccal mucosal grafting for patients with medically controlled ocular cicatricial pemphigoid. Ophthalmology 1992; 99:383–395.

67.Elder MJ, Dart JK, Collin R. Inferior retractor plication surgery for lower lid entropion with trichiasis in ocular cicatricial pemphigoid. Br J Ophthalmol 1995; 79:1003–1006.

68.Heiligenhaus A, Shore JW, Rubin PA, Foster CS. Long-term results of mucous membrane grafting in ocular cicatricial pemphigoid. Implications for patient selection and surgical considerations. Ophthalmology 1993; 100:1283–1288.

69.Wood JR, Anderson RL. Complications of cryosurgery. Arch Ophthalmol 1981; 99:460–463.

70.Elder MJ, Bernauer W. Cryotherapy for trichiasis in ocular cicatricial pemphigoid. Br J Ophthalmol 1994; 78:769–771.

71.Sullivan JH, Beard C, Bullock JD. Cryosurgery for treatment of trichiasis. Am J Ophthalmol 1976; 82:117–121.

72.Kwitko S, Marinho D, Barcaro S, Bocaccio F, Rymer S, Fernandes S, Neumann J. Allograft conjunctival transplantation for bilateral ocular surface disorders. Ophthalmology 1995; 102:1020–1025.

73.Tsubota K, Satake Y, Kaido M, Shinozaki N, Shimmura S, Bissen-Miyajima H, Shimazaki J. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N Engl J Med 1999; 340:1697–1703.

74.Rao SK, Rajagopal R, Sitalakshmi G, Padmanabhan P. Limbal allografting from related live donors for corneal surface reconstruction. Ophthalmology 1999; 106:822–828.

75.Croasdale CR, Schwartz GS, Malling JV, Holland EJ. Keratolimbal allograft: recommendations for tissue procurement and preparation by eye banks, and standard surgical technique. Cornea 1999; 18:52–58.

76.Dua HS, Azuara-Blanco A. Allo-limbal transplantation in patients with limbal stem cell deficiency. Br J Ophthalmol 1999; 83:414–419.

77.Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells. N Engl J Med 2000; 343:86–93.

78.Dohlman CH, Terada H. Keratoprosthesis in pemphigoid and Stevens-Johnson syndrome. Adv Exp Med Biol 1998; 438:1021–1025.