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Ocular Mucous Membrane Pemphigoid

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Mucous Membrane Pemphigoid (MMP) is an autoimmune disease which affects the skin and mucous membranes. When the eyes are affected, it is called ocular MMP (OMMP). The cause of MMP is not clearly understood, but it is known to have a genetic predisposition although this probably only plays a minor role. The disease is rarely associated with cancers when it is called paraneoplastic pemphigoid. Autoantibodies can be identified in most patients except for those with ocular only MMP (no other sites affected). The antibodies are directed at the subsurface layer (basement membrane) of the mucous membranes and, in some cases, of the skin causing inflammation and ulceration or blistering which lead to scarring. The scarring component is why the disease used to be called cicatricial pemphigoid. Another older term for the disease was “Benign MMP”; so called because it rarely causes death unlike pemphigus which historically had a high mortality, before the advent of immunosuppressive therapies. Although it can affect the skin it is only diagnosed when mucous membranes are involved. The mucous membranes targeted by the disease, for reasons that are not understood, are those at our orifices; mouth, eyes, nose, throat, genitals, anus and less often the tracheal region and oesophagus. MMP rarely affects all of these sites in any one person, more often 1-3 sites are involved. The most affected sites are the mouth (gums and oral mucosa) followed by the eyes, nose and throat and then other sites. When the eyes are affected both are usually involved.

The disease causes variable inflammation, often with ulceration and scarring at affected sites. Inflammation is usual at all sites and causes pain, as does ulceration, although the development of ulceration and scarring varies from site to site. For example, ulceration is common in the mouth but infrequent in the eyes whereas scarring is infrequent in the mouth but a hallmark of eye disease. Scarring does not cause pain but the effects of scarring may result in loss of function such as difficulty swallowing and speaking, or lead to ingrowing eyelashes and loss of tear production.

When the disease affects the eyes, it results in inflammation (conjunctivitis) and scarring of the conjunctiva. The illustration shows the conjunctiva which is the thin membrane (0.25 mm) that covers both the white of the eyeball and which extends into the sacs (fornices) behind the lids (a) and (b) and which lines the back surface of the eyelids to the lash margin (b). Conjunctival scarring occurs in the thin layer behind the surface (where it is called subepithelial fibrosis) and results in contraction with shortening of this large area of thin lining tissue causing loss of the fold of conjunctiva adjacent to the nose (the plica semilunaris) (c) and shortening of the fornices (d) followed by the formation of bands of tissue between the eyeball and eyelid called symblepharon (e). In more advanced cases this process results in the loss of all of the conjunctival tissue between the eyeball and eyelid, so that the two appear to have stuck together.

A image containing five smaller pictures of eyes showing different symptoms of OMMP

The shortening of the conjunctiva on the back surface of the lid may also cause the eyelid(s) to turn inward (called entropion) which often results in the lashes rubbing on the surface of the eye (called trichiasis). The conjunctival scarring may also cause damage to the accessory lacrimal (tear) glands in the conjunctiva, the mucous producing cells, and the very fine ducts that bring the tears from the lacrimal gland (situated under the outer end of the upper eyelid and eye socket) causing a dry eye.

OMMP progresses at different rates in different patients, a small proportion get a rapid onset of severe inflammation and scarring which can lead to blindness in months whereas in most patients the inflammation is initially mild and/or intermittent resulting in a slower onset over years. In both groups a lack of appropriate treatment can cause severe visual debility or even blindness. Diagnosis and appropriate treatment at an early stage can largely prevent or greatly slow down disease progression. Correct diagnosis, as quickly as possible, is important for the reasons outlined below.

How is OMMP Diagnosed?

For patients with MMP already diagnosed at other sites such as the mouth or nose, then disease is relatively easy to confirm or exclude in the eyes. This is because the disease at the non-ocular sites more often tests positive (in biopsies and blood) than when MMP is limited to the eyes. In patients, with known MMP at non-ocular sites, any eye inflammation (conjunctivitis) or any of the early signs of scarring (as in the illustration) must be assumed to be caused by ocular MMP and diagnosis without conjunctival biopsies is accepted by international guidelines. All patients with MMP at other sites should be referred to an ophthalmologist for an eye examination, whether or not they have these symptoms and signs of eye disease, because early signs of OMMP may be present without symptoms. If there are signs of inflammation or scarring needing treatment, as mentioned above, there is no requirement for further tests on the eyes to make the diagnosis of OMMP, providing the tests at any other sites have confirmed that MMP is present and that the eye signs are typical. However, the ophthalmologist may want the results of additional eye biopsies, or other investigations, to exclude other conjunctival scarring diseases that can co-exist with MMP or be confused with it.

For those patients with OMMP and no involvement of other sites (ocular only MMP) the path to diagnosis has been difficult and may continue to be so for a time as not all clinicians will be aware of the recently published (2021) European Guideline (European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II E. Schmidt, H. Rashid, A. V. Marzano, A. Lamberts, G. Di Zenzo, G. F. H. Diercks, et al. J Eur Acad Dermatol Venereol 2021 Vol. 35 Issue 10 Pages 1926-1948); these give criteria for the diagnosis of ocular only MMP when both conjunctival and biopsies from other sites  (typically skin or oral mucosa), as well as blood tests for autoantibodies, are all negative. There are over 20 causes of conjunctival inflammation and scarring although, in the UK, MMP is the most common of these. In addition, most of the other causes are associated with easily identified diseases with the exception of surface tumours (usually affecting only one eye whereas MMP usually affects both), sarcoidosis and other autoimmune bullous diseases (e.g. pemphigus); the latter may very rarely show up in the eye before developing at other sites. Diagnosis of ocular MMP requires one small (2-3 mm) biopsy, ideally from each eye, taken from the conjunctiva, often from the loose conjunctival tissue on the ball of the eye under the upper lid, using local anaesthetic eye drops, together with blood tests. It is optimal to take an additional biopsy from another site, even though there are no symptoms at that site, usually the mouth mucosa or the skin because these sites may test positive when the ocular samples test false negative. The eye biopsies are processed for both the direct immunofluorescence test (as are the biopsies from the apparently uninvolved sites) and for routine histopathology to exclude other potential causes of the inflammation and scarring. Blood is taken to detect pemphigoid antibodies using a variety of tests.

Why may it be difficult to make a diagnosis?

When MMP affects the eye, with no other sites of involvement, the tests described above, that have been considered necessary for diagnosis, are negative in about 50% of cases. Until the 2021 European Guideline was published (as described above) this caused a lot of problems for OMMP patients because effective treatment for OMMP requires quite different treatment than that for the other causes of scarring conjunctivitis, for which the standard of care is local treatment, often with steroid eyedrops. Unfortunately, local steroid eyedrops are ineffective at controlling the inflammation in OMMP and do not prevent the progression of the conjunctival scarring, both of which usually require oral, or intravenous, anti-inflammatory medication.

What should I do if my tests are negative?

It is now increasingly accepted by specialists in MMP (see the European Guidelines mentioned above) is that in OMMP, particularly when no other sites are involved by MMP, a diagnosis does not require positive test results but can be made after the tests have been used to exclude the other potential causes and using clinical findings. Your specialist should be told about the European Guidelines if you think you may have MMP affecting the eyes and your tests are negative.

Why are my eyes so painful?

The inflammation of the conjunctiva itself can be very painful and irritating. Inturned eyelashes (trichiasis) can also scratch the surface of the eye and damage the cornea, and dry eyes compound the discomfort.

Are there many people with OMMP?

MMP is a rare disease, occurring in about 2.5 per 100,000 in Europe.

Can other parts of my body be affected?

About 60-70% of MMP patients have some level of eye involvement in their condition. Half of these have OMMP without involvement of other sites and the remainder have MMP involving other mucous membranes such as mouth, nose, larynx, oesophagus and the genital and anus areas affected. It can also cause blistering on the skin. The degree of scarring varies by the location. You will probably be referred to a variety of medical specialists to monitor the extent of your disease.

How am I going to be treated?

About 20% of patients with MMP and ocular involvement have minimal inflammation with slowly progressive scarring and will need no treatment or simple topical therapies.However, topical treatments – those that you put directly in your eye – haven’t been found to be effective in controlling inflammation or the progression of scarring in the other 80% of cases which require treatment with oral therapy. The ophthalmologist, or another specialist working with the ophthalmologist, will usually start treating milder cases with the least risky drugs – those with the least severe side effects - such as dapsone and sulfasalazine. But in cases where the disease progresses quickly, more “aggressive” (but better termed “effective”) treatments will be deployed. These treatments may involve drugs such as steroids to get short term control of severe inflammation but which, to avoid steroid side effects, must be used with non-steroidal “immunosuppressive” drugs. Steroids are generally only needed for a few months while the immunosuppressive drugs take effect. These will reduce your immune system response and therefore the autoimmune activity which is causing the damage to your eyes. Commonly used drugs for moderate disease are: azathioprine, mycophenolate, and (occasionally) methotrexate.

If your eye disease is particularly severe then cyclophosphamide and steroids, or steroids before courses of intravenous “biological” anti-CD20 treatments (e.g. Rituximab or Truxima) or intravenous immunoglobulin (IVIG) will be used.

Where the disease has also caused entropion (the eyelids turning in) and the eyelashes are scratching the cornea, then you may be recommended to have the eyelashes removed (epilation) either in the clinic or by self-removal. For occasional individual lashes electrolysis may be useful. For large numbers of lashes, for which epilation has proved difficult to manage, both electrolysis and freezing therapy (cryotherapy) have been used in the past. However as these latter may cause increased lid scarring and disease flare ups respectively, they have been superseded by surgery to turn the eyelids out to reposition the lashes away from the eye or by surgery to totally remove all the lashes.

Can I be cured?

MMP and, specifically OMMP, are not curable. But with the right treatment at the right level, it is possible to halt the progress of the disease and “remission” can be achieved. It is vital that there is an early diagnosis and effective treatment is given to control inflammation and slow the progress of scarring. Currently, there is no reversing the blindness that very bad or untreated OMMP can cause with the exception of the use of artificial corneal replacements – treatments that carry a high risk of loss of all vision (no light perception) but which can offer the prospect of long periods of good vision. The best established of these treatments is the osteo-odonto-keratoprosthesis (OOKP) and its variants which should only be carried out in accredited centres.

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