Interventions for Mooren's ulcer

  • Review
  • Intervention

Authors


Abstract

Background

Mooren's ulcer is a chronic, painful peripheral ulcer of the cornea. Its cause is unknown but it can or will lead to loss of vision if untreated. Severe pain is common in patients with Mooren's ulcer and the eye(s) may be intensely reddened, inflamed and photophobic, with tearing. The disease is rare in the northern hemisphere but more common in southern and central Africa, China and the Indian subcontinent. There are a number of treatments used such as anti-inflammatory drugs (steroidal and non-steroidal), cytotoxic drugs (topical and systemic), conjunctivectomy and cornea debridement (superficial keratectomy). There is no evidence to show which is the most effective amongst these treatment modalities.

Objectives

The aim of this systematic review is to assess the effectiveness of the various interventions (medical and surgical) for Mooren's ulcer.

Search methods

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 4 June 2013.

Selection criteria

We planned to include randomised controlled trials (RCTs) or discuss any prospective non-RCTs in the absence of any RCTs. The trials included would be of people of any age or gender diagnosed with Mooren's ulcer and all interventions (medical and surgical) would be considered.

Data collection and analysis

Two authors screened the search results independently; we found no studies that met our inclusion criteria.

Main results

As we found no studies that met our inclusion criteria, we highlighted important considerations for conducting RCTs in the future in this area.

Authors' conclusions

We found no evidence in the form of RCTs to assess the treatment effect for the various interventions for Mooren's ulcer. High quality RCTs that compare medical or surgical interventions across different demographics are needed. Such studies should make use of various outcome measures, (i.e. healed versus not healed, percentage of area healed, speed of healing etc.) as well as ensuring high quality randomisation and data analysis, as highlighted in this review .

Résumé scientifique

Interventions pour l'ulcère de Mooren

Contexte

L'ulcère de Mooren est un douloureux et chronique ulcère périphérique de la cornée. Sa cause reste inconnue mais, s'il n'est pas traité, il risque d'entrainer une perte de vision. Les patients présentant un ulcère de Mooren souffrent souvent de douleurs violentes et leurs yeux peuvent être extrêmement rouges, enflammés et photophobiques, avec larmoiement. Cette pathologie est rare dans l'hémisphère nord, mais plus fréquente dans le sud et le centre de l'Afrique, la Chine et le sous-continent indien. Un certain nombre de traitements sont employés, comme les médicaments anti-inflammatoires (stéroïdiens et non-stéroïdiens), les médicaments cytotoxiques (topiques et systémiques), la conjonctivectomie et le débridement de la cornée (kératectomie superficielle). Il n'y a pas de données permettant d'établir quelle est la plus efficace de ces modalités de traitement.

Objectifs

L'objectif de cette revue systématique est d'évaluer l'efficacité des différentes interventions (médicales et chirurgicales) pour l'ulcère de Mooren.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans CENTRAL (qui contient le registre des essais du groupe Cochrane sur l'œil et la vision) (Bibliothèque Cochrane 2013, numéro 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (de janvier 1946 à juin 2013), EMBASE (de janvier 1980 à juin 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (de janvier 1982 à juin 2013), le méta-registre des essais contrôlés (mREC) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) et le système d'enregistrement international des essais cliniques (ICTRP) de l'OMS (www.who.int/ictrp/search/en). Nous n'avons appliqué aucune restriction concernant la langue ou la date dans les recherches électroniques d'essais. Nous avons effectué les dernières recherches dans les bases de données électroniques le 4 juin 2013.

Critères de sélection

Nous avions prévu d'inclure des essais contrôlés randomisés (ECR) ou, en l'absence d'ECR, d'examiner d'éventuels essais non-ECR. Les essais inclus devaient porter sur des personnes de tous âges et sexes atteintes d'un ulcère de Mooren et sur tous types d'interventions (médicales et chirurgicales).

Recueil et analyse des données

Deux auteurs ont passé au crible les résultats de recherche de façon indépendante ; nous n'avons trouvé aucune étude répondant à nos critères d'inclusion.

Résultats principaux

N'ayant trouvé aucune étude répondant à nos critères d'inclusion, nous avons mis l'accent sur des considérations importantes pour la réalisation à l'avenir d'ECR dans ce domaine.

Conclusions des auteurs

Nous n'avons pas trouvé de données sous forme d'ECR permettant d'évaluer l'effet thérapeutique des différentes interventions pour l'ulcère de Mooren. Il y a un besoin d'ECR de bonne qualité comparant des interventions médicales ou chirurgicales dans différents contextes démographiques. De telles études devraient employer divers critères de résultats (proportion de patients guéris, pourcentage de la zone ayant cicatrisé, rapidité de la guérison, etc.) tout en garantissant une randomisation et une analyse des données de qualité élevée, comme souligné dans cette revue.

Plain language summary

Interventions for Mooren's ulcer

Mooren's ulcer is inflammation that occurs at the edge of the cornea (clear part of the front of the eye). Its cause is unknown. It is very painful and can or will lead to loss of vision if untreated. It occurs worldwide and affects all age groups. It is diagnosed by excluding other causes of ulcerations at the edge of the cornea such as chronic inflammation of the joints due to rheumatoid arthritis. Mooren's ulcer can be treated both medically and surgically. Medical treatment includes the use of drugs such as steroids and non-steroidal anti-inflammatories. Surgical methods include resection of the conjunctiva (the thin clear tissue that covers the surface of the eye) from the cornea, removal of dead cornea tissue and cornea transplant. We set out to determine the best available intervention for the treatment of Mooren’s ulcer by looking for randomised controlled trials (RCTs) comparing one form of treatment to another; and treatment versus no treatment. The electronic database searches did not find any RCTs on the treatment of Mooren’s ulcer. This review recommends the need for well conducted RCTs for both medical and surgical interventions for Mooren’s ulcer. These trials should look at outcomes such as number of participants that healed against those that did not, what percentage of area healed and the speed at which healing took place.

Résumé simplifié

Interventions pour l'ulcère de Mooren

L'ulcère de Mooren est une inflammation qui se développe en bordure de la cornée (la partie transparente à l'avant de l'œil). Sa cause reste inconnue. Il s'agit d'une pathologie très douloureuse qui, si elle n'est pas traitée, risque d'entrainer une perte de vision. On l'observe dans le monde entier et à tous les âges. Son diagnostic consiste en l'exclusion des autres causes possibles d'ulcération en bordure de la cornée, comme l'inflammation chronique des articulations causée par la polyarthrite rhumatoïde. L'ulcère de Mooren peut être traité médicalement et chirurgicalement. Le traitement médical fait notamment usage de médicaments comme les stéroïdes et les anti-inflammatoires non-stéroïdiens. Les principales méthodes chirurgicales sont la résection de la conjonctive (la fine membrane transparente qui recouvre la surface de l'œil) au niveau de la cornée, l'élimination des tissus cornéens nécrosés et la transplantation de cornée. Nous avons cherché à déterminer la meilleure des interventions disponibles pour le traitement de l'ulcère de Mooren en recherchant des essais contrôlés randomisés (ECR) comparant une forme de traitement à un autre traitement ou à l'absence de traitement. Les recherches dans les bases de données électroniques n'ont débouché sur aucun ECR portant sur le traitement de l'ulcère de Mooren. Cette revue souligne le besoin d'ECR bien menés sur les interventions tant médicales que chirurgicales pour l'ulcère de Mooren. Ces essais devraient s'intéresser à des critères tels que la proportion de participants guéris, le pourcentage de la zone ayant cicatrisé et la vitesse de guérison.

Notes de traduction

Traduit par: French Cochrane Centre 26th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Streszczenie prostym językiem

Interwencje stosowane we wrzodzie Moorena

Wrzód Moorena jest stanem zapalnym występującym na brzegu rogówki (przezroczystej przedniej części oka). Jego przyczyna nie jest znana. Jest bardzo bolesny i może prowadzić lub doprowadzi do utraty wzroku, jeżeli nie będzie leczony. Występuje na całym świecie i dotyka wszystkich grup wiekowych. Rozpoznaje się go przez wykluczenie innych przyczyn owrzodzeń brzeżnych rogówki, takich jak przewlekle zapalenie stawów spowodowane reumatoidalnym zapaleniem stawów. Leczenie wrzodu Moorena może być zarówno zachowawcze, jak i chirurgiczne. W ramach farmakoterapii stosuje się leki takie jak steroidy oraz niesteroidowe leki przeciwzapalne. Metody chirurgiczne obejmują wycięcie spojówki (cienka, przezroczysta tkanka pokrywa powierzchnię oka) z rogówki, usunięcie martwej tkanki rogówki i przeszczep rogówki. Autorzy przeglądu postawili sobie za cel określenie najlepszych dostępnych interwencji w leczeniu wrzodu Moorena, poprzez poszukiwanie badań z randomizacją (RCT; badania, w których uczestnicy przydzielani są losowo do grupy badanej i kontrolnej - przyp. tłum.) porównujących różne formy leczenia pomiędzy sobą oraz leczenie z nieleczeniem. W wyniku przeszukiwania elektronicznych baz danych nie odnaleziono żadnych badań klinicznych z randomizacją (RCT) dotyczących leczenia wrzodu Moorena. Niniejszy przegląd wskazuje na potrzebę przeprowadzenia dobrze zaprojektowanych badań klinicznych z randomizacją (RCT) zarówno dla zachowawczego, jak i chirurgicznego leczenia wrzodu Moorena. Badania te powinny koncentrować się na punktach końcowych takich jak liczba uczestników wyleczonych w porównaniu do osób niewyleczonych, procent powierzchni wyleczonej oraz szybkość gojenia.

Uwagi do tłumaczenia

Tłumaczenie: Monika Storman Redakcja: Agnieszka Ole

Background

Description of the condition

Mooren's ulcer is a chronic, painful, peripheral ulcerative keratitis (PUK) (peripheral ulcer of the cornea). It is bilateral in approximately one-third of cases and the cause is unknown.

Epidemiology

The prevalence of Mooren's ulcer and the blindness caused by it worldwide is unknown. The disease is rare in the northern hemisphere but more common in southern and central Africa, China and the Indian subcontinent (Tuft 2003). It is more common in males (1.3:1) than females (1.6:1) and very rare in children (Tuft 2003). In a three-year retrospective review in a hospital in Nigeria, amongst 18 people (25 eyes) with Mooren's ulcer, the age range was 12 to 42 years (average 27.9 years) (Alhassan 1999).

The incidence varies from one case per year seen in specialist clinics in Europe and North America, to between one in 350 and one in 2200 clinic visits in India and Nigeria (Zegans 1998). A large case series from China (715 eyes treated in 36 years) put the incidence at 0.03% of the study population (Chen 2000).

Risk factors

Although the cause is unknown, it has been suggested that there is a genetic as well as an environmental basis for the disease. The likely environmental factors include antecedent history of accidental trauma or surgery and exposure to viral and parasitic infections. However, an increase in the rate of hepatitis C infection has not been found in patients from India with Mooren's ulcer (Tuft 2003). An association with helminthiasis (intestinal worm infestation) has also been noted, but the disease can develop in the absence of helminthiasis. Even where helminthiasis is endemic, Mooren's ulcer is still rare (Tuft 2003). Human leukocyte antigens (HLAs) can confer susceptibility to several autoimmune disorders and in Asian and black African patients the presence of HLA-DR17 or DQ2 (histocompatibility antigens) may confer susceptibility to Mooren's ulcer (Taylor 2000). Zhao 1993 also reported increased expression of HLA DR in patients with the disease.

Presentation and diagnosis

Classification

There are various forms of classifications of the disease. A recent and more often used classification groups Mooren's ulcer into three distinct types on the basis of clinical features, fluorescein angiographic evidence of capillary closure or leakage and response to treatment (Watson 1997).

  1. Unilateral Mooren's ulceration (UM) is a painful progressive corneal ulceration in elderly patients and is associated with non-perfusion of the superficial vascular plexus of the anterior segment.

  2. Bilateral aggressive Mooren's ulceration (BAM) occurs in young patients and progresses circumferentially then centrally in the cornea. There is vascular leakage and new vessel formation extending into the base of the ulcer.

  3. Bilateral indolent Mooren's ulceration (BIM) usually occurs in middle-aged patients and presents with progressive peripheral corneal guttering in both eyes, with little inflammatory response. There is no change from normal vascular architecture except an extension of new vessels into the ulcer.

Another common classification is based on laterality and age of onset. The disease is grouped into two types.

  • A unilateral type common amongst older age groups with same sex distribution, and slow progression.

  • A type that occurs mostly in Africa, as a bilateral rapidly progressive disease, that is less responsive to treatment (Wilhelmus 2001).

Clinical manifestation

Severe pain is common in Mooren's ulcer and the eye(s) may be intensely reddened, inflamed and photophobic, with tearing. The disease is characterised by a crescent-shaped, peripheral corneal ulcer, with an extensively undermined central edge that results in the characteristic 'overhanging' edge of the cornea (Bouchard 1998; Foster 1999; Kanski 2003; Wilhelmus 2001; Young 1982). The ulcer typically progresses with an anterior stromal yellow-white infiltrate 2 mm to 3 mm from the limbus at the advancing margin of the ulcer, often in the interpalpebral zone (Kanski 2003; Tuft 2003). An overlying linear epithelial defect then develops often at the central margin. This is followed by progressive stromal melting, which affects the deeper stroma first and subsequently the anterior stroma. The ulcer progresses circumferentially and centrally. A re-epithelialised, conjunctivalised, thinned cornea may remain.

Chronic Mooren's ulcer ultimately results in a central island of hazy stromal tissue with severe peripheral thinning. Topography demonstrates significant irregular astigmatism and peripheral steepening. No scleral involvement occurs, although associated conjunctival and episcleral inflammation may be seen. Visual loss as a result of irregular corneal astigmatism and scarring is common.

Clinical grading

Mooren's ulcer can be graded as follows (Sharma 2005).

  1. The extent of corneal thinning in one or more quadrants, subdivided into a) mild - thinning affecting less than 25% of corneal circumference; b) moderate - thinning affecting 25% to 50% of corneal circumference; and c) severe - thinning affecting more than 50% of corneal circumference.

  2. Impending corneal perforation.

  3. Corneal perforation of more than 2 mm.

Diagnosis

Mooren's ulcer is diagnosed by its typical clinical features as described above (in 'Clinical manifestation') and exclusion of any systemic disease. This distinguishes it from other, more common types of PUK associated with collagen vascular disease, which must be excluded in order to diagnose Mooren's ulcer.

Description of the intervention

Treatment options

Some investigators advocate 'the stepladder approach' in the treatment of aggressive Mooren's ulcer. This includes medical (local and systemic) and surgical therapy (Brown 1984).

Medical treatment
Local

It has been suggested that initial treatment should be with topical corticosteroids, followed by limbal conjunctival resection if the inflammation is not controlled. Topical cyclosporine 1% drops have been used in some cases (Zhao 1993). In addition, bandage contact lenses (to reduce discomfort and promote epithelial healing); tissue adhesive; subconjunctival heparin injections; artificial tears and topical collagenase inhibitors, such as acetylcysteine (Mucomyst 10%) and L-cysteine 0.2 molar have been used. Lecinthinated superoxide dismutase use has also been reported (Shimmura 2003).

Systemic

Immunosuppression with cyclophosphamide followed by azathioprine may be initiated if treatment with conjunctival resection fails, and may be considered earlier in bilateral cases or in cases where the disease is advanced at first examination, with extensive corneal thinning (Foster 1985). Systemic immunosuppressive treatment of the more aggressive bilateral disease has included the use of oral corticosteroids, cyclosporine A, and methotrexate (Brown 1984). The use of high-dose cyclosporine A has been reported (Foster 1985). Plasma exchange has also been tried. Systemic interferon alfa-2b has been used in the treatment of patients positive for the hepatitis C virus who have Mooren's ulcer (Moazami 1995; Wilson 1994). Two case reports showed favourable responses to monoclonal antibodies campath- 1H and infliximab (Fontana 2007; Van der Hoek 2003).

Surgical treatment

Surgical interventions include conjunctival resection, lamellar keratoplasty, epikeratoplasty, delimiting keratotomy, conjunctival flap and patch grafts of periosteum or fascia lata (Kinoshita 1991). Some investigators advocate "removal of the presumed antigenic corneal source (central lamellar keratectomy)" in an attempt to mediate a more rapid resolution of the inflammation (Brown 1984).

Although initial corneal surgery is usually contra-indicated, some authors have reported good results with a primary lamellar keratoplasty combined with topical cyclosporine A. Using this regimen Chen 2000 achieved a cure of 74% for the first procedure, and a final cure rate of 95%.

How the intervention might work

The local and systemic immunosuppressives act by mitigating the immune response to inciting antibodies while the surgical interventions like conjunctival resection act by preventing the delivery of immune complexes to the cornea stroma.

Why it is important to do this review

The multiplicity of therapeutic strategies employed for Mooren's ulcer underscores the relative lack of knowledge about effective treatment. The outcome of management is difficult to determine because of the different treatments and different patient characteristics. Thus, it is imperative to identify the most effective modality or modalities for the treatment of this condition, for different patient characteristics, so that informed decisions can be made for optimal management of the disease.

Objectives

The aim of this systematic review is to assess the effectiveness of the various interventions (medical and surgical) for Mooren's ulcer.

Methods

Criteria for considering studies for this review

Types of studies

Only RCTs were eligible for inclusion. However, as there were no eligible RCTs, we presented a narrative summary of other forms of prospective studies on the disease.

Types of participants

We planned to include people of any age and gender, clinically diagnosed with Mooren's ulcer as a PUK, epithelial defect with over-hanging edges. The diagnosis had to exclude other causes of PUK such as collagen vascular diseases by laboratory examinations. We had planned to exclude trials which enrolled people with a history of eye infections in the affected eye prior to the diagnosis of Mooren's ulcer, unless data for these participants could be separated. We had planned to exclude trials that enrolled people with other systematic diseases, unless data for these participants could be separated.

Types of interventions

We considered the following comparisons.
1. Any single intervention for Mooren's ulcer against no intervention.
2. One form of intervention for Mooren's ulcer against another.
3. A combination of interventions for Mooren's ulcer against another intervention or another combination of interventions.

Intervention refers to any type of measure either medical, surgical or otherwise used for the treatment of the disease.

Types of outcome measures

Primary outcomes
  1. Complete healing - present or not, after eight weeks of follow-up.

Fluorescein staining or slit-lamp examination may be used to ascertain healing. Complete healing is defined as non-progression of the ulcer and filling of ulcer crater, with no fluorescein staining.

Secondary outcomes
  1. Speed of healing as determined by a) the period (days or weeks) taken to complete healing; and (b) the percentage/proportion/length/area of the ulcer healed after a period (days or months).

  2. Number of ulcers that have reoccurred after healing.

  3. Visual outcomes: level of visual acuity change before treatment and after treatment. Any measure of visual acuity that can be converted to a LogMAR chart.

Healed portions of the ulcer refers to parts of the ulcer crater with no fluorescein staining and progressive filling of the crater.

Adverse effects (severe, minor)

1. Severe adverse effects of interventions - local effects or systemic effects or both, defined as life threatening conditions.
2. Minor adverse effects of interventions - local effects or systemic effects or both, defined as non-life threatening conditions.

Quality of life measures
We planned to examine any measure of quality of life used by the trialists.

Economic data

We collected information about costs of treatments where available.

Follow-up

We planned to consider a minimum follow-up period of eight weeks.

Search methods for identification of studies

Electronic searches

We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) 2013, Issue 5, part of The Cochrane Library. www.thecochranelibrary.com (accessed 4 June 2013), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 4 June 2013.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We planned to search the Science Citation Index to identify further studies. We planned to search the reference lists of included studies to find further trials. We specifically did not handsearch journals or conference proceedings for this review. We planned to contact companies and pharmaceutical firms that produce medications used in Mooren's ulcer treatment which includes, but is not limited to immunosuppressive agents (e.g. cyclophosphamide, azathioprine, methotrexate and topical and systemic steroids). We planned to contact companies such as Alcon, GlaxoSmithKline, Novartis, Pfizer, Troge, Baxter oncology and Duopharma for any unpublished data they may have, or further information on any company that may have information to give on this subject.

Data collection and analysis

Selection of studies

Two authors (MA and IA) independently assessed all titles and abstracts. We retrieved full-text copies of all possibly or definitely relevant articles. Two authors (MA and IA) independently assessed the articles to determine whether they met the inclusion criteria.

As we did not find any trials, we did not collect any data.

Future updates of this review

For future updates, we will continue to follow the method set out above for screening the search results from the electronic databases and will complete the following processes for any trials that meet our inclusion criteria.

We will contact the authors of articles with inadequate information for further details of their studies. If we do not receive a response within a given time, we will send reminders and may contact co-authors. We will resolve disagreements in the included articles by consulting the third author (MR).

Data extraction and management

Two authors will independently extract data from all included studies. The third author will settle any differences between the two authors. We will extract the following Information from the included studies.

  • Methods: method of allocation of participants; masking (participant, provider, outcome); exclusions after randomisation; losses to follow-up; compliance; unusual study design such as randomisation by persons but analysis by eyes.

  • Participants: country where participants enrolled; participant's racial/ethnic background; number randomised; age; sex; main inclusion and exclusion criteria.

  • Interventions: treatment; comparison intervention (control); duration of intervention.

  • Outcomes: primary and secondary outcomes as reported.

We will contact the authors of studies with missing data to ask for more information.

We will group together similar outcomes (units of measurements) for analysis.

Assessment of risk of bias in included studies

Two authors will independently assess the methodological quality of studies for inclusion in the review. We will use the criteria for assessing risk of bias, as stated in Chapter 8 of The Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), for each of the following domains. Each parameter will be graded as: low risk, high risk or unclear risk of bias.

  • Random sequence generation (selection bias).

  • Allocation concealment (selection bias).

  • Blinding of participants and personnel (performance bias).

  • Blinding of outcome assessment (detection bias).

  • Incomplete outcome data (attrition bias).

  • Selective reporting (reporting bias).

  • Other biases.

Measures of treatment effect

We will calculate and pool risk ratios (RRs) and their 95% confidence intervals (CIs) for dichotomous data (such as healed/not healed). For continuous data we will calculate mean differences (MDs) and their 95% CIs for each included study and pool the data to derive the mean difference (MD). If the scales vary, we will calculate and pool the standardised mean difference (SMD). If possible, we will calculate a hazard ratio (HR) and 95% CI for time-to-event data.

Unit of analysis issues

If the unit of analysis differs from the unit of randomisation (for example analysis by eyes but randomisation done per individual) then we will ensure that the correct denominator is used for analysis, or else we will adjust for the non-independence between the two eyes.

Dealing with missing data

We plan to contact primary authors for missing data. If we do not get a response from the primary author, we will address missing data by using replacement values (assuming that the data were missed at random and that the missing values signify poor outcomes). We will perform sensitivity analysis using various assumptions.

Assessment of heterogeneity

We will assess statistical heterogeneity using a P value of  less than 0.10 to determine significant heterogeneity (Chi2 test). We will use a random-effects model and subgroup analysis to address significant heterogeneity.

Assessment of reporting biases

We plan to assess for reporting bias if at least 10 papers are included in the review. We also plan to include unpublished studies. We have not restricted the electronic database searches by language (see 'Search methods for identification of studies'). We will also examine the funnel plot for asymmetry by visual inspection. For continuous data we will use linear regression of the intervention effect estimate on their standard error to test for funnel plot asymmetry. For dichotomous data we will use linear regression of the log odds ratio (OR) on its standard error by the inverse of the variance of the log OR.

Data synthesis

If meta-analysis is deemed appropriate we will combine studies using a fixed-effect model where there are three or less studies, or a random-effects model where there are more than three studies.

If meta-analysis is not possible, we will report included studies in a narrative synthesis. We will group the studies according to study design and intervention with consideration of variation in recruited participants, outcome measures and methodological validity. If possible, we will present RRs, HRs or WMDs and 95% CIs in graphical format, without statistical pooling of data.

Subgroup analysis and investigation of heterogeneity

If data permit, and included studies are sufficiently similar, we will perform exploratory subgroup analyses according to the following variables that may affect the prognosis of the disease.

  • Severity of disease at presentation, using the clinical grading mentioned above or any other used by the trialists.

  • Racial disposition of participants.

  • Whether the participants have unilateral or bilateral Mooren's ulcer.

  • Age of participants at diagnosis (child - age 15 years and below; adult - older than 15 years).

Sensitivity analysis

If data permit, we will perform sensitivity analyses to explore the impact of the study design and methodological quality on the summary estimate. We will repeat the analysis excluding unpublished studies and studies that have assumed that eyes within an individual are independent.

Results

Description of studies

The electronic searches yielded a total of 1312 titles and abstracts (Figure 1). After deduplication the Trials Search Co-ordinator scanned 1019 records and discarded 351 records as they were not relevant to the scope of the review. We screened the title and abstracts of the remaining 668 references. We rejected a further 649 abstracts as not eligible for inclusion in the review. We obtained and screened full-text copies of 19 references, however none of these were reports of RCTs.

Figure 1.

Results from searching for studies for inclusion in the review.

An update search run in June 2013 identified 283 references. The Trials Search Co-ordinator removed 55 duplicates, scanned 228 references and removed 225 records which were not relevant to the scope of the review. We screened the remaining three references but none of these were relevant for inclusion in the review.

Included studies

We did not find any RCTs that met our inclusion criteria.

Excluded studies

We excluded 19 studies as they were not RCTs. See the 'Characteristics of excluded studies' table for details.

Risk of bias in included studies

We did not assess any studies for risk of bias as no RCTs were included.

Effects of interventions

As we did not include any trials, we could not measure the effects of the interventions.

Discussion

The electronic searches did not find any prospective RCTs that met our inclusion criteria. We did not find any prospective non-randomised studies comparing various interventions for Mooren's ulcer. We found either case reports or retrospective case series studies which we have discussed in the 'Characteristics of excluded studies' table.

The available evidence of treatment effects for Mooren’s ulcer are level 4 (intervention case series) (Wormald 2004) (case series: Brown 1975; Chen 2000; Hill 1987; Karegelopolous 2004; Sharma 2005) and level 5 (intervention case reports: Chen 2004; Erdem 2007; Tiev 2002).

In a traditional literature review, Chow 1996 discussed extensively the various treatment modalities available for Mooren’s ulcer. These include topical steroids, conjunctival resections, keratoepithelioplasty, systemic immunosuppression with cyclophosphamide, methotrexate and azathioprine and topical immunosuppression with cyclosporine A.

Other surgical procedures that have been tried in the treatment of Mooren’s ulcer included superficial lamellar keratoplasty, conjunctival flaps, penetrating keratoplasty and periosteal grafts.

Zegans 1998 has summarised the various strategies into four as follows: local immunosuppression, systemic immunosuppression, removal of local stimulatory antigens and removal of distant stimulatory antigens.

A combination of these strategies has been used in many of the studies cited above. Chen 2000 used a combination of conjunctival excision, lamellar keratoplasty and topical 1% cyclosporine A with some success. This is the largest case series reported.

Sharma 2005 used a step ladder approach, selecting the type of intervention for each case of Mooren’s ulcer. The classification is based on the degree of cornea thinning at time of commencement of treatment.

Definition of success also seems to vary in the literature. Some studies used ‘healed’(Brown 1975; Chen 2000; Erdem 2007; Tiev 2003; Zhao 1993) while others used 'visual acuity' (Chen 2004; Hill 1987). Failure was defined as progression of corneal melting leading to perforation and loss of the eye.

Any RCT design for the measurement of treatment effect for Mooren’s ulcer needs to take into consideration the above factors i.e. combination of modalities, step ladder approach and clear definitions of outcome measures such as visual acuity, healing, cornea thinning/perforation, time to healing and adverse events. Case definition has to be clearly stated including how the other causes of PUK were ruled out. All interventions compared should be well defined. We suggest any RCT on interventions for Mooren's ulcer should consider the following points.

Participants' selection

Selection of participants must ensure that the mechanism for exclusion of PUK from systemic conditions is followed. The panel of tests to be carried out will include the following: antinuclear antibody (ANA); antiphospholipid antibodies; rheumatoid factor (Rh); erythrocyte sedimentation rate (ESR); serum antibodies to hookworm; C-reactive protein (CRP); and stool microscopy for hookworm (Van der Gaag 1983; Zelefsky 2007). Adequate concealment of allocation must also be insured. The Wilhelmus 2001 classification of Mooren's ulcer is suggested in any planned RCT.

Assessment

Masking of participants and the care giver should be effected in trials involving use of drugs.

Adequate masking of the assessors needs to be made for all interventions. This may easily be effected by assessing quality photographs of the ulcer instead of the patient.

The following intervention combinations can be used in an RCT on Mooren's ulcer treatment: topical immunosuppressives (topical steroids, topical cyclosporine and topical cyclophosphamide); systemic immunosuppressives (steroids, cyclosporine and cyclophosphamide); and conjunctivectomy with superficial keratectomy.

Outcome measures

Types of outcome measures that should be considered include:

1. Primary outcomes (fluorescein staining and/or slit-lamp examination may be used to ascertain healing).

  • Complete healing present or not present.

  • Percentage/proportion of ulcer healed.

  • Rate (proportion/length/area of defect healed per unit time).

2. Secondary outcomes

  • Pain assessments using 0 to 100 score, visual analogue score or any form of pain measurement.

  • Visual outcomes using the visual acuity chart.

  • Analgesia use; use of topical cycloplegics.

  • Other symptoms e.g. photophobia.

  • Quality of life measures.

  • Daily living activities assessments.

  • Insomnia assessments.

Adverse effects

1. Severe adverse effects of interventions - local effects or systemic effects or both, defined as life threatening conditions.

2. Minor adverse effects of interventions - local effects or systemic effects or both, defined as non-life threatening conditions.

Economic data

Information about costs of treatments.

Authors' conclusions

Implications for practice

There are no RCTs available to measure the effectiveness of the various modalities for the treatment of Mooren's ulcer. For now the routine practice of selective treatment or step ladder approach, judged clinically to be most appropriate for the patient characteristics, will have to continue.

Implications for research

Mooren's ulcer is potentially a blinding condition. High-quality RCTs are needed comparing the various treatment modalities (medical or surgical) for the treatment of Mooren's ulcer among the different demographic status of patients. Such studies should make use of various outcome measures such as (healed versus not healed, percentage of area healed, speed of healing etc.) as well as ensuring high quality randomisation and data analysis as highlighted in this review.

Acknowledgements

The Cochrane Eyes and Vision Group (CEVG) created and ran the search strategies. We thank Catey Bunce, Steve Tuft, Swaroop Vedula and Kirk Wilhelmus for their comments on the protocol and/or review. We thank Anupa Shah, Managing Editor for the CEVG for her help throughout the review process.

Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor Corneal Ulcer
#2 mooren*
#3 (ulcer* or peripheral) near/3 (keratitis)
#4 (cornea* or marginal*) near/3 (ulcer*)
#5 ulcus rodens
#6 (#1 OR #2 OR #3 OR #4 OR #5)

Appendix 2. MEDLINE (OvidSP) search strategy

1 randomized controlled trial.pt.
2 (randomized or randomised).ab,ti.
3 placebo.ab,ti.
4 dt.fs.
5 randomly.ab,ti.
6 trial.ab,ti.
7 groups.ab,ti.
8 or/1-7
9 exp animals/
10 exp humans/ )
11 9 not (9 and 10)
12 8 not 11
13 exp corneal ulcer/
14 mooren$.tw.
15 ((ulcer$ or peripheral) adj3 keratitis).tw.
16 ((cornea$ or marginal$) adj3 ulcer$).tw.
17 ulcus rodens.tw.
18 or/13-17
19 12 and 18

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Appendix 3. EMBASE (OvidSP) search strategy

1 exp randomized controlled trial/
2 exp randomisation/
3 exp double blind procedure/
4 exp single blind procedure/
5 random$.tw.
6 or/1-5
7 (animal or animal experiment).sh.
8 human.sh.
9 7 and 8
10 7 not 9
11 6 not 10
12 exp clinical trial/
13 (clin$ adj3 trial$).tw.
14 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15 exp placebo/
16 placebo$.tw.
17 random$.tw.
18 exp experimental design/
19 exp crossover procedure/
20 exp control group/
21 exp latin square design/
22 or/12-21
23 22 not 10
24 23 not 11
25 exp comparative study/
26 exp evaluation/
27 exp prospective study/
28 (control$ or prospectiv$ or volunteer$).tw.
29 or/25-28
30 29 not 10
31 30 not (11 or 23)
32 11 or 24 or 31
33 exp corneal ulcer/
34 mooren$.tw.
35 ((ulcer$ or peripheral) adj3 keratitis).tw.
36 ((cornea$ or marginal$) adj3 ulcer$).tw.
37 ulcus rodens.tw.
38 or/33-37
39 32 and 38

Appendix 4. LILACS search strategy

keratitis or mooren$ or cornea$ or marginal and ulcer$ or peripheral

Appendix 5. metaRegister of Controlled Trials search strategy

keratitis or mooren

Appendix 6. ClinicalTrials.gov search strategy

Keratitis OR Mooren

Appendix 7. ICTRP search strategy

keratitis or mooren

What's new

DateEventDescription
12 December 2013New citation required but conclusions have not changedIssue 12, 2013: No new studies identified for inclusion
12 December 2013New search has been performedIssue 12, 2013: Electronic searches were updated

History

Protocol first published: Issue 3, 2006
Review first published: Issue 6, 2011

DateEventDescription
9 October 2008AmendedConverted to new review format.

Contributions of authors

Conceiving the review: MR
Designing the review: MR, MA, IA
Co-ordinating the review: MR, MA, IA
Undertaking manual searches: IA
Screening search results: MR, MA
Organising retrieval of papers: MR
Screening retrieved papers against inclusion criteria: MR, MA
Appraising quality of papers: MR, MA, IA
Abstracting data from papers: MR, IA
Writing to authors of papers for additional information: MR
Obtaining and screening data on unpublished studies: IA, MR
Data management for the review: MR
Entering data into RevMan: MR, MA
Analysis of data: MA
Interpretation of data: MR
Writing the review: MR, MA, IA

Declarations of interest

None known.

Differences between protocol and review

The review ended with a discussion of the published case series or case reports on Mooren's ulcer treatment.

Notes

None

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Brown 1975Not a randomised controlled trial, case report
Chen 2000Not a randomised controlled trial, retrospective case series
Chen 2004Not a randomised controlled trial, case report
Chow 1996Not a randomised controlled trial, conventional literature review
Erdem 2007Not a randomised controlled trial, case report
Fontana 2007Not a randomised controlled trial, case report
Hill 1987Not a randomised controlled trial, case report
Kalogeropulous 2004Not a randomised controlled trial, case report
Mavrakanas 2007Single case report
Miyazaki 2008Case report
Sangwan 1997Not a randomised controlled trial, literature review
Sharma 2005Not a randomised controlled trial, case report
Shimmura 2003Case reports
Spelsberg 2007Not a randomised controlled trial, retrospective case report of three patients
Tandon 2008Retrospective case series
Tiev 2003Not a randomised controlled trial, case report
Van der Hoek 2003A case report
Xie 2003Not a randomised controlled trial, retrospective case series
Zegans 1998Literature review
Zhao 1993Not a randomised controlled trial, case report

Ancillary