tretinoin and Pemphigoid--Benign-Mucous-Membrane

This review is in two sections. The first section summarises 35 conditions, both common and infrequent, causing cicatrising conjunctivitis. Guidelines for making a diagnosis are given together with the use of diagnostic tests, including direct and indirect immunofluorescence, and their interpretation. The second section evaluates our knowledge of ocular mucous membrane pemphigoid, which is the commonest cause of cicatrizing conjunctivitis in most developed countries. The clinical characteristics, demographics, and clinical signs of the disease are described. This is followed by a review and re-evaluation of the pathogenesis of conjunctival inflammation in mucous membrane pemphigoid (MMP), resulting in a revised hypothesis of the autoimmune mechanisms causing inflammation in ocular MMP. The relationship between inflammation and scarring in MMP conjunctiva is described. Recent research, describing the role of aldehyde dehydrogenase (ALDH) and retinoic acid (RA) in both the initiation and perpetuation of profibrotic activity in MMP conjunctival fibroblasts is summarised and the potential for antifibrotic therapy, using ALDH inhibition, is discussed. The importance of the management of the ocular surface in MMP is briefly summarised. This is followed with the rationale for the use of systemic immunomodulatory therapy, currently the standard of care for patients with active ocular MMP. The evidence for the use of these drugs is summarised and guidelines given for their use. Finally, the areas for research and innovation in the next decade are reviewed including the need for better diagnostics, markers of disease activity, and the potential for biological and topical therapies for both inflammation and scarring.

Topics: Aldehyde Dehydrogenase 1 Family; Autoantibodies; Autoimmune Diseases; Cicatrix; Conjunctivitis; Fibroblasts; Fluorescent Antibody Technique, Indirect; Humans; Immunosuppressive Agents; Inflammation; Isoenzymes; Pemphigoid, Benign Mucous Membrane; Retinal Dehydrogenase; Tretinoin

Topics: Biopsy; Conjunctiva; Conjunctival Diseases; Echothiophate Iodide; Epinephrine; Humans; Idoxuridine; Immunosuppression Therapy; Pemphigoid, Benign Mucous Membrane; Pilocarpine; Quaternary Ammonium Compounds; Skin Diseases, Vesiculobullous; Timolol; Tretinoin

Mucous membrane pemphigoid (MMP) is a systemic mucosal scarring disease, commonly causing blindness, for which there is no antifibrotic therapy. Aldehyde dehydrogenase family 1 (ALDH1) is upregulated in both ocular MMP (OMMP) conjunctiva and cultured fibroblasts. Application of the ALDH metabolite, retinoic acid (RA), to normal human conjunctival fibroblasts in vitro induced a diseased phenotype. Conversely, application of ALDH inhibitors, including disulfiram, to OMMP fibroblasts in vitro restored their functionality to that of normal controls. ALDH1 is also upregulated in the mucosa of the mouse model of scarring allergic eye disease (AED), used here as a surrogate for OMMP, in which topical application of disulfiram decreased fibrosis in vivo. These data suggest that progressive scarring in OMMP results from ALDH/RA fibroblast autoregulation, that the ALDH1 subfamily has a central role in immune-mediated ocular mucosal scarring, and that ALDH inhibition with disulfiram is a potential and readily translatable antifibrotic therapy.

Topics: Adult; Aged; Aged, 80 and over; Aldehyde Dehydrogenase; Animals; Cells, Cultured; Cicatrix; Conjunctiva; Disulfiram; Female; Fibroblasts; Fibrosis; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mucous Membrane; Pemphigoid, Benign Mucous Membrane; Tretinoin

Despite the diverse causes of dry-eye disorders, the ocular surface epithelia in these diseases all undergo squamous metaplasia, manifested by loss of goblet cells, mucin deficiency, and keratinization. These changes account for tearfilm instability, which leads to various ocular symptoms and corneal complications. This article reviews research in the use of topical tretinoin to treat severe dry-eye disorders. To classify squamous metaplasia into stages, a modified impression cytology technique was used to monitor the therapeutic effect of topical tretinoin ointment (0.01% or 0.1%, w/w) in 22 patients. This population had severe dry-eye disorders, including keratoconjunctivitis sicca, Stevens-Johnson syndrome, inactive ocular pemphigoid, drug-induced pseudopemphigoid, and surgery- or radiation-induced dry eyes. After treatment, clinical improvements were correlated with the reversal of squamous metaplasia as evidenced by the impression cytology technique. Tretinoin may also be effective in treating conjunctival keratinization without dry eyes, as illustrated by a case study. This may represent the first reported attempt to treat ocular surface disorders by reversing diseased epithelium.

Topics: Administration, Topical; Adolescent; Eye Diseases; Female; Humans; Keratoconjunctivitis; Keratoconjunctivitis Sicca; Pemphigoid, Benign Mucous Membrane; Postoperative Complications; Radiotherapy; Skin Diseases, Vesiculobullous; Stevens-Johnson Syndrome; Tretinoin

A case of drug-induced ocular cicatricial pemphigoid with pronounced keratinizing squamous epithelium metaplasia was treated for 5 months with all-trans retinoic acid ointment. Keratinization reversed completely and the cicatricial process was stabilized in one eye and slowed down in the other eye. The treatment was well tolerated.

Topics: Aged; Aged, 80 and over; Conjunctivitis; Female; Humans; Ointments; Pemphigoid, Benign Mucous Membrane; Skin Diseases, Vesiculobullous; Tretinoin

We evaluated the clinical efficacy of treating various dry-eye disorders using 0.01% and 0.1% (weight/weight) topical all-trans retinoic acid ointment. Twenty-two patients were selected and classified into four major groups: keratoconjunctivitis sicca (6 patients; 11 eyes), Stevens-Johnson syndrome (9 patients; 17 eyes), ocular pemphigoid or drug-induced pseudopemphigoid (3 patients; 6 eyes), and surgery or radiation-induced dry eye (4 patients; 4 eyes), based on the criterion that they remained symptomatic even under maximum tolerable conventional medical and/or surgical therapies. The results indicated that squamous metaplasia with mucin deficiency secondary to goblet cell loss and keratinization may be the basis for the development of clinical symptoms and morbidities, as these epithelial abnormalities were invariably present before treatment. After treatment, all patients demonstrated clinical improvements in symptoms, visual acuity, rose Bengal staining, or Schirmer test. Most importantly, this topical vitamin A treatment caused the reversal of squamous metaplasia as evidenced by impression cytology. Therefore, this treatment may represent the first nonsurgical attempt to treat these disorders by reversing diseased ocular surface epithelium.

Topics: Administration, Topical; Adolescent; Adult; Aged; Child; Child, Preschool; Eye; Female; Humans; Keratoconjunctivitis; Lacrimal Apparatus Diseases; Male; Metaplasia; Middle Aged; Ointments; Pemphigoid, Benign Mucous Membrane; Postoperative Complications; Radiotherapy; Stevens-Johnson Syndrome; Tretinoin; Visual Acuity; Xerophthalmia