Interventions for erosive lichen planus affecting mucosal sites
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of interventions in the treatment of erosive lichen planus affecting the oral, anogenital, and oesophageal regions.
Background
Description of the condition
Definition
Lichen planus (LP) is an inflammatory condition which affects the skin and the squamous epithelium of mucosal surfaces lining the mouth, ears, eyes, and nose as well as the gastrointestinal and anogenital tracts. There are predominantly two patterns of inflammation described: the plaque (raised) type and the erosive (raw) type, although bullous, blistering, or hypertrophic (thickened) types also occasionally occur.
The plaque type occurs most commonly and is estimated to affect up to 2% of the population (Boyd 1991,Carrozzo 2008). It presents as purple raised areas with a surface made of a lacy white network known as Wickham’s striae. The lesions are predominantly distributed on the inner aspect of the wrists and ankles, although they may occur on any body surface lined with squamous epithelium (Boyd 1991, Breathnach 2004). Plaques of LP are often itchy and without treatment may take up to 2 years to settle. Occasionally the lesions are present without many symptoms and may remain for years (Boyd 1991, Breathnach 2004).
In contrast, erosive lichen planus (ELP) is a very painful and debilitating condition. The prevalence of ELP is unknown. It occurs predominantly, but not exclusively, on the mucosal surfaces of the mouth and genitals (oral, vulval, and penile lichen planus). Other less commonly affected sites include the eyes (Neumann 1993) and oesophagus (Abraham 2000). There may also be bladder, nasal, laryngeal, gastric, and anal involvement (Eisen 1999). Erosive lichen planus can be accompanied by classical cutaneous LP or other forms of mucosal LP – namely reticular (lacy), papular (solid raised bumps less than 5mm in diameter), plaque (raised), atrophic (thinned), and bullous (blisters) variants.
A severe variant of ELP in women involving both the genital and oral mucosa was described by Pelisse et al (Pelisse 1982 and Pelisse 1989) as the vulvovaginal‐gingival (VVG) syndrome. This syndrome is a triad of (erosive or desquamative) vulvitis, vaginitis, and gingivitis. The equivalent condition in men is known as the peno‐gingival (PG) syndrome, described by Cribier et al in 1993 (Cribier 1993).
Since ELP can affect different body sites, a number of healthcare specialists are involved in managing affected individuals such as oral medicine physicians, dermatologists, gynaecologists, and if the oesophagus is involved, gastroenterologists.
Impact of Erosive Lichen Planus
ELP is a chronic painful condition which is often difficult to treat. The psychological, emotional, and physical distress associated with ELP affecting any mucosal site can be significant with affected individuals suffering low moods with or without treatment. This has economic consequences both to the people affected and the health system. Affected individuals frequently attend hospital complaining of pain and loss of function which interferes with their personal and working life. It is important that healthcare providers are able to identify and treat any psychological issues arising as a result of ELP. Engaging a counsellor, as part of the multidisciplinary team, may be beneficial in these instances.
Symptoms vary according to the site involved. Individuals with erosive oral LP present with pain and difficulty eating. With milder disease the discomfort is mainly from spicy or acidic foods and fizzy drinks. With more extensive disease there are painful, persistent erosions on the gingivae (gums), and ulcers on the buccal (inside of cheek), tongue, and labial (lip) mucosae. Difficulty eating results in weight loss and nutritional deficiencies such as iron deficiency (Eisen 1999). Painful erosions lead to suboptimal dental hygiene and increased tooth decay.
The areas commonly affected in the vulva are the labia minora (inner lips), introitus (entrance to the vagina), and vaginal vault (arched roof of vaginal cavity). The affected areas may be erythematous, atrophic, and eroded. This makes them tender and extremely painful to light touch such as pressure from sitting and walking. Individuals complain of pain and stinging on passing urine, sometimes only able to urinate with comfort sitting or standing in water in the bath or shower. Anatomical alterations, such as due to inflammation and fusion of the labia minora, may cause impaired urine flow.
Sexual intercourse can be impossible due to pain and anatomical changes. In addition, the eroded vagina bleeds easily on contact, hence postcoital bleeding (bleeding following sexual intercourse) is typical. Inflammation higher up in the vagina (desquamative vaginitis) presents as a yellow discharge. With ongoing inflammation, the clitoral hood typically disappears, the labia minora adheres to the labia majora and the introitus closes over. Scarring in the vagina leads to narrowing and a fibrosed vaginal vault making cervical smears either impossible or difficult. Next to organic dysfunction the architectural disfigurement will cause psychological distress.
In men, ELP characteristically affects the glans penis, producing similar painful, tender, red and raw lesions, and reduced sexual function.
Risk of Malignant Transformation
Lesions of LP are thought to have an increased risk of development of malignancies and it is therefore mandatory to follow up these people. Approximately 1% to 5% of oral LP lesions will undergo malignant changes into squamous cell carcinoma (SCC) of the mouth (Silverman 1985, Holmstrup 1988, Lo Muzio 1998, Gandolfo 2001). Approximately 1% to 3% of vulval LP lesions develop into SCC (Lewis 1994, Cooper 2006) and a small but unknown percentage of penile LP lesions transform into SCC (Bain 1989, Leal‐Khouri 1994). High risk factors for malignant transformation in oral LP include smoking, excessive alcohol ingestion, erosive or atrophic clinical types, presence of erythroplakic lesions (reddened patches with a velvety surface found in the mouth), and sites involving the tongue, gingival, or buccal mucosa (Scully 2008). No risk factors are known for progression of vulval LP into carcinoma of the vulva. It is unknown if early treatment of ELP reduces the risk of malignancy.
Description of the intervention
The management of ELP is challenging and there is no clear agreement with respect to the best first line management in oral or genital disease or indeed as to whether first line therapy should be the same at both sites. People often respond poorly to the available treatments. The treatments for both oral and genital LP are similar but they have never previously been considered together in a systematic review. However, it is likely from work with clinics in oral medicine and dermatology that effective treatment for ELP in the oral region is likely to be beneficial in the genital region and vice versa.
The first‐line treatment for both genital and oral lesions is usually topical or intralesional steroid. A short course of systemic steroids may be administered for rapid control of symptoms. Steroid‐sparing agents such as azathioprine, methotrexate (Jang 2008), or ciclosporin can be used. Topical or systemic retinoids, anti‐malarials, dapsone, Psorolen + UVA treatment (PUVA) (Lundquist 1995), thalidomide (Camisa 2000), aloe vera gel (Rajar 2008), topical tacrolimus (Kaliakatsou 2002), or topical rapamycin (Soria 2009) may be considered in refractory cases. Surgical management, such as carbon dioxide laser, cryotherapy, and excision, is not recommended due to the possibility of triggering lesions (Koebner’s phenomenon) and recurrence of the inflammatory condition.
More recently reports are emerging on the use of biological therapies such as efalizumab (Cheng 2006, Heffernan 2007). However, the European Medicines Agency (EMEA), the European Union (EU) body which is responsible for monitoring the safety of medicines, has recommended the suspension of marketing authorisation for efalizumab (raptiva) over possible links between the drug and progressive multifocal leucoencephalopathy (PML). Hence we shall not consider efalizumab as a treatment intervention in this review.
How the intervention might work
The exact cause of ELP is poorly understood. It is thought to be autoimmune and idiopathic in most cases. Studies suggest that T‐cell‐mediated immunity plays a major role (Boyd 1991, Porter 1997, Thornhill 2001, Scully 2008), resulting in apoptosis of epithelial cells and chronic inflammation. Most interventions that are reported to improve ELP as described above have immunomodulatory or immunosuppressive effects.
Why it is important to do this review
For years the accepted first‐line therapy for ELP has been the use of ultra‐potent topical steroids (Carbone 2008). Whilst there appears to be symptomatic improvement for some people (Cooper 2006), the condition rarely goes into complete remission. In addition to assessing whether treatments can improve symptoms in the short‐term, it is important to assess the long‐term management of ELP since it is a chronic condition and because long‐term use of some treatments like potent topical steroids can have side‐effects such as skin thinning.
In recent years there has been the emergence of newer therapies such as tacrolimus (Lozada‐Nur 2006) and more recently efalizumab (Heffernan 2007). In such a painful and disabling condition it is important that affected individuals are given the most therapeutically efficacious treatments.
A Cochrane review on "Interventions for oral lichen planus" has been published (Chan 1999). Our review is different because it concentrates on the erosive type of LP and includes all mucosal sites. There is a recent systemic review focusing on treatments used in oral LP (Zakrzewska 2005). The authors concluded that due to small study sizes, lack of standardised outcome measures, and high likelihood of publication bias, the results are not reliable. It is possible that our proposed review will reach similar conclusions. If this is the case, this review will highlight the urgent need for more randomised controlled trials on a larger scale with standardised outcome measures, for the treatment of ELP.
Objectives
To assess the effects of interventions in the treatment of erosive lichen planus affecting the oral, anogenital, and oesophageal regions.
Methods
Criteria for considering studies for this review
Types of studies
We will consider all randomised controlled trials (RCTs) that evaluate the effectiveness of either topical or systemic interventions for ELP affecting either the mouth, genital region, or both areas. We will include cross‐over studies, but we will not include split body part designs because it is not possible to apply two topical treatments to either half of the oral mucosa or vulva without cross‐contamination.
Types of participants
Any individual of any age, gender, or race who has been diagnosed by either a dermatologist, oral medicine physician, genitourinary physician, or a gynaecologist as having ELP affecting the mouth, oesophagus, and/or anogenital regions. A clinical diagnosis stating specifically "erosive lichen planus" alone from an experienced physician will be considered diagnostically sufficient.
Any study including individuals with idiopathic plaque‐like LP (non‐erosive) or individuals with lichenoid drug eruptions will be excluded.
Types of interventions
We will include all types of interventions including topical treatments such as potent topical steroids, ciclosporin, retinoids and tacrolimus; oral medications such as prednisolone, azathioprine, methotrexate, retinoids, ciclosporin, mycophenolate, anti‐malarials; and biologics, phototherapy, and surgical management.
We will also include trials of different doses of the same intervention, comparison trials between different interventions, intervention versus placebo trials, intervention versus “no treatment” trials, and cross‐over studies. We will also explore intervention strategies such as intermittent therapies that are designed to maintain remission and prevent further flares.
Types of outcome measures
Outcome measures in ELP will mainly be based on scale‐rating of improvement of clinical signs (e.g. erythema, reticulation or lacy network pattern, ulceration) and symptoms (e.g. pain, discomfort) by investigators and participants as well as restoration of normal functions such as sexual activity and a varied diet (ability to eat) as reported by participants.
Primary outcomes
(a) Pain reduction using a visual analogue scale (e.g. 0 to 10) rated by participants
(b) Physician global assessment (e.g. 5 point)
(c) Participant global self‐assessment
Secondary outcomes
(a) Complete clinical response defined as the percentage of participants with complete resolution of clinical signs or symptoms
(b) Partial response defined as the percentage of participants with at least 50% improvement
(c) Reduction in severity of flares
(d) Reduction in number of flares
(e) Relapse rate when medications are stopped or reduced
(f) Dermatology quality of life measures
(g) Restoration of sexual activity (of most relevance to genital sites)
(h) Eating a normally varied diet (most relevant to oral involvement)
Timing of outcome assessment
We will record outcomes in the short‐term (less than 6 months) and long‐term (6 months or more) from the beginning of treatment.
Search methods for identification of studies
Electronic searches
We shall search for relevant trials in:
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The Cochrane Skin Group Specialised Register
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The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last update)
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MEDLINE (from 2005)
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EMBASE (from 2007)
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LILACS (Latin American and Caribbean Health Service Information Database, from 1982)
The UK Cochrane Centre has an ongoing project to systemically search MEDLINE and EMBASE for reports of trials which are then included in the Cochrane Register of Controlled Trials. Searching has currently been completed in MEDLINE to 2004 and in EMBASE to 2006. Further searching will be undertaken for this review by the Cochrane Skin Group to cover the years that have not been search by the UKCC.
We shall use the MEDLINE draft search strategy which is displayed in Appendix 1. This will be modified to include additional search terms where necessary and will be used as the basis for the search strategies for the other databases listed.
Ongoing trials
We shall search for ongoing trials in the following registers using the term "erosive lichen planus":
The metaRegister of Controlled Trials www.controlled‐trials.com
The U.S. National Institutes of Health Ongoing Trials Register www.clinicaltrials.gov
The Australian and New Zealand Clinical Trials Registry www.anzctr.org.au
The World Health Organisation International Clinical Trials Registry platform www.who.int/trialsearch
The Ongoing Skin Trials Register on www.nottingham.ac.uk/ongoingskintrials
Searching other resources
Unpublished and Grey literature
We will try to obtain unpublished trials through correspondence with authors.
Reference lists
We will examine reference lists of the relevant trials and reviews identified.
Correspondence
We will write to trial authors to clarify trial details.
Language
We will not impose language restrictions when searching for trials and we will seek translations where necessary.
Adverse Effects
We will search the included studies for reports of adverse effects. We will also collect data on adverse events from interventions for erosive lichen planus by running separate searches looking specifically for adverse effects of treatments used. Any reports from the latter will not be randomised controlled trials so will only be reported in the discussion section.
Data collection and analysis
Selection of studies
Two authors (SCh and RM) will independently review the titles, abstracts, and key words of all records retrieved in the searches. SCh and RM will obtain full articles of all relevant or possibly relevant references.
Data extraction and management
A paper data extraction form will be designed according to the pre‐defined selection criteria. Two authors (SCh and RM) will independently extract data. Differences in opinion will be resolved by discussion with a third author until a consensus is met. Logs of excluded studies with reasons for exclusion will be kept. Data will be entered into Review Manager 5.0.
Assessment of risk of bias in included studies
Two authors (SCh and RM) will independently assess quality by doing an assessment of the Risk of Bias (selection bias, performance bias, attrition bias, and detection bias) using the new features of Review Manager 5.0 and as described in Table 8.5c of the Cochrane Handbook (Higgins 2008).
Measures of treatment effect
We will present binary data as risk ratios (RR) and risk differences (RD). Risk differences will permit calculation of numbers needed to treat for a range of plausible baseline event rates. We will present continuous data (e.g. severity scores, duration of symptoms) as mean difference (MD) for the same scales or standardised difference in means (SDM) for similar but different scales. Ordinal outcome data (e.g. pain/disability scales) may be analysed as continuous or binary data if appropriate and necessary for the purposes of meta‐analysis. When trials are sufficiently homogeneous in terms of interventions, outcome measures and methods of analysis, we will pool these data for meta‐analysis.
Unit of analysis issues
We do not anticipate unit of analysis issues since all studies are likely to randomise whole participants.
Dealing with missing data
We shall contact the trial authors to try to obtain trial‐level data not originally reported. As we do not expect to have access to individual patient‐level data, we shall not perform any imputation procedures. Studies for which no response is obtained for trial‐level data will be down‐weighted in the analysis. Likewise studies will be down‐weighted in accordance with the reported level of missing patient‐level data.
Assessment of heterogeneity
We will use the Chi² test and I² statistic to assess variability among studies for statistical heterogeneity. If extreme levels of heterogeneity exists between studies (I² > 75%), we will report the results of the studies individually and explore further using subgroup analyses.
Assessment of reporting biases
We will assess publication bias using a funnel plot if enough studies are identified. If asymmetry is detected, we will perform formal tests for asymmetry (such as Egger's or Begg's test).
Data synthesis
Where appropriate, pooling of data for meta‐analysis of trials will be performed using random‐effects models. We will present data using forest plots and funnel plots.
Subgroup analysis and investigation of heterogeneity
We will perform subgroup analysis to explore treatment effect differences between ELP of the mouth and genitals.
