The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

Abstract

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.

Figure 1

Portrait of Sir William Bowman by George Watts painted about 1865. I am grateful to Rachel Clarkson, Sir William's great-great-granddaughter, for providing this image.

Figure 2

Illustrations of some of the causes of cicatrising conjunctivitis (a) Mucous membrane pemphigoid, (b) Trachoma, (c) Adenovirus, (d) Sebaceous carcinoma, (e) Ocular surface squamous neoplasia, (f) Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (g) Glaucoma drops, (h) Atopic keratoconjunctivitis, (i) Stevens-Johnson syndrome, (j) Ocular rosacea, (k) Lichen Planus, (l) Sarcoid.

Figure 3

The diagnostic problem in cicatrising conjunctivitis. This Figure illustrates the classification of CC used in Table 2 with notes on the prevalence, which causes are often overlooked, which are usually known but which may co-exist with mucous membrane pemphigoid and causes associated with systemic diseases that may have their first manifestations in the eye.

Figure 4

The epithelial basement membrane structure and immunofluorescent tests. The cartoon describes the basement membrane (dermoepidermal junction) structure and its constituent proteins. The proteins that have been shown to be target antigens in MMP are listed. The position of the basement membrane (BM) is shown on a direct immunofluorescence (DIF) specimen which also shows positive immunofluorescence to IgG in the BM zone. An example of indirect immunofluorescence (IIF) on salt split skin is also shown demonstrating positive fluorescence to the floor (see Figure 5). The cartoon is reproduced with permission from Figure 1 Schmidt.

Figure 5

Autoimmune bullous dermatoses and lichen planus. Direct immunofluorescence (DIF) and indirect immunofluorescence. The illustrations in the top left panel shows pemphigus vulgaris (PV) with DIF on perilesional skin showing intraepithelial antibody binding. In the top right panel the skin lesions in bullous pemphigoid are shown for comparison with those in PV together with an example of a positive DIF in conjunctiva with antibody binding at the basement membrane. The pemphigus and pemphigoid diseases are listed separating those that may be associated with conjunctival scarring and those that are not. The panel on mucosal lichen planus shows the typical appearance of a ‘shaggy' fibrin staining band at the dermoepidermal junction. The bottom panel shows indirect immunofluorescence on human salt split skin from a patient with MMP.

Figure 6

Criteria for referral. Criteria for referral of patients with cicatrising conjunctivitis to a specialist ocular surface disease service. Adapted from Figure 5 in Williams et al.

Figure 7

The spectrum of disease in mucous membrane pemphigoid (MMP) (a) Gingival inflammation and ulceration, (b) Palatal inflammation and ulceration, (c) Supraglottic inflammation and scarring, (d) Oesophageal stenosis, (e) Skin ulceration and scarring, (f) Foreskin scarring, (g) Conjunctival inflammation and scarring, (h) Intraoperative photograph showing a normal subconjunctival space under incised severely scarred and shortened conjunctiva demonstrating that subconjunctival tissue is unaffected.

Figure 8

Ocular mucous membrane pemphigoid (MMP). Clinical signs in ocular MMP.

Figure 9

Factors contributing to progression of disease in ocular mucous membrane pemphigoid (MMP).

Figure 10

Summary of the pathogenesis of inflammation and scarring in ocular MMP. This illustrates the description in this section in the text, for which the evidence is summarised in Table 3. In brief a loss of tolerance to mucosal epithelial basement membrane proteins results in the development of pathogenic autoreactive T cells (aT) which help autoreactive B cells (aB) to proliferate in the regional lymph nodes, and differentiate into plasma cells. The latter produce circulating IgG and IgA autoantibodies to the mucosal basement membrane, which are detectable in the serum of some patients by indirect immunofluorescence (and other antibody specific assays). Plasma cells are also found in the conjunctival mucosal substantia propria where they may produce local antibody. In the mucosal epithelium direct immunofluorescence tests may show the presence of IgG and/or IgA fixed to the basement membrane where C3 (complement 3) is also identified in some patients. Activation of C3 at the basement membrane precipitates the complement cascade and acute inflammation at the basement membrane. This is the injury and inflammation phase of the disease causing an accumulation of inflammatory effector cells (neutrophils, dendritic cells, mast cells, eosinophils, macrophages and T cells) and the associated cytokines interleukin (IL) IL-2, IL-5, IL-13 and growth factors: IFNγ (interferon gamma, TNFα (tumour necrosis factor alpha), resulting in, often severe, inflammation and expansion of both T helper subset 1 and 2 cells into a chronic inflammatory response. An alternative effector pathway may be more important, in the absence of autoantibody, in some subsets of patients whereby autoreactive T cells to basement membrane components home in on the mucosa. Here they can create an inflammatory response, in the absence of antibody, through their cytokines and growth factors including IFNγ, TNFα, IL-4, IL-5 and IL-13. This inflammatory response results in fibrosis through the effects of profibrotic mediators released by macrophages, T cells, mast cells and eosinophils on fibroblasts, including PDGF (platelet derived growth factor), IL-13, TGFβ (transforming growth factor beta) and HSP47 (heat shock protein). Fibrosis also results from ALDH/RA (aldehyde dehydrogenase/retinoic acid) mediated paracrine effects of dendritic cells that activate a profibrotic phenotype in fibroblasts. During both active inflammation, and once inflammation has resolved, the activated MMP fibroblasts continue to scar as these remain profibrotic because of an ALDH/RA mediated autocrine effect. The latter probably results in RA dependent TGFβ activation and or induction, further driving fibrosis.

Figure 11

Sectoral conjunctival inflammation in ocular mucous membrane pemphigoid (MMP). The same eye of a patient showing the superior bulbar conjunctiva free of inflammation but a localised area of inflammation in the inferior bulbar conjunctiva.

Figure 12

Immunosuppression for ocular mucous membrane pemphigoid (MMP). This illustrates ‘step up' and ‘step down' therapy to control conjunctival inflammation as described in the section on ‘Evidence for the efficacy of different immunosuppressive regimens in controlling inflammation and guidelines for its delivery' and in Table 4 Row 34, and Saw VP 2008. (a) Drugs in different coloured boxes can be combined. The drugs in the dark red boxes (cyclophosphamide, mycophenolate, azathioprine and methotrexate) are all myelosuppressives: combining these results in unacceptable toxicity. Some authors have described the use of CD 20 inhibitors (such as Rituximab) with existing myelosuppressive therapy for unresponsive ocular MMP but this may be unsafe and we follow the recommendations of restricting adjunctive drugs to sulfas and stop the myelosuppressives immediately before the first CD20 monoclonal infusion. Prednisolone can generally be given for a short term effect with any of the other drugs listed but is usually needed in high doses, with its associated side effects. (b) In general, all of these drugs, except high dose steroids take 2-4 months to take effect. This period is probably shorter for the CD 20 monoclonals than the other drugs. A full effect will often take longer and for this reason, unless inflammation is deteriorating, I do not usually alter therapy for 12 weeks. (c) For mild/moderate ocular MMP use step up therapy. Start with a sulfa and, there is no effect, or toxicity, introduce mycophenolate. If the effect is limited but the drug is tolerated, add mycophenolate to the sulfa. Azathioprine (in grey typeface) is the second line drug when mycophenolate is not tolerated and methotrexate (in grey typeface) the third line drug in this situation because these are generally less well tolerated than mycophenolate and no more effective. If none of these drugs works switch to cyclophosphamide without using adjunctive steroid unless the patient is deteriorating. Failing these then a CD20 monoclonal is the next choice of drug and, if there is a lack of response to that 2 months after a second cycle of therapy, then start IV immunoglobulin therapy. (d) For severe MMP (severe conjunctival inflammation±limbitis±corneal ulceration) use step down therapy. Start oral Prednisolone 1 mg/kg WITH cyclophosphamide 1.0–1.5 mg/kg. Very severe cases will get a short term benefit from intravenous methylprednisolone 1 g IV daily for 3 days before starting oral prednisolone with cyclophosphamide (unpublished data). If cyclophosphamide and prednisolone are not effective within 2–3 months, add a sulfa and then switch to a CD20 monoclonal. If this fails, as in the previous example, then start IVIG. Once control of inflammation has been established the patient can start stepdown therapy. (i) For cyclophosphamide follow the toxicity guidelines in Table 4 row 19, I usually maintain therapy for up to 12 months in the hope that a longer period of therapy might induce a remission. Two months before discontinuing cyclophosphamide, introduce a sulfa, if tolerated. After discontinuing cyclophosphamide patients with full control of inflammation can discontinue sulfas after another 2–4 months therapy. For patients with partial control the sulfa is maintained and mycophenolate (azathioprine or methotrexate) added. Drugs can be discontinued as required dependent on disease control and the development of side effects. ii. After CD 20 monoclonals patients may be in remission and any sulfa therapy can be discontinued after 2–4 months therapy. In the event of a relapse a decision has to be made whether to control this with step up therapy or a further cycle of a CD 20 monoclonal. After IVIG patients will usually still be in myelosuppressive agents which can be stepped down or stepped up as described above.