Erosive Lichen Planus Affecting the Vulva

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Erosive Lichen Planus Affecting the Vulva EROSIVE LICHEN PLANUS AFFECTING THE VULVA: Defining the disease, developing outcome measures and designing a randomised controlled trial Rosalind C Simpson BMedSci, BMBS, MRCP(UK) Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy December 2014 Abstract Erosive lichen planus (ELP) is a chronic, inflammatory, scarring skin condition that occurs predominantly on the mucosal surfaces of the mouth and genital region. It is believed to be an autoimmune condition although the exact pathogenesis remains unclear. This thesis focuses on ELP affecting the vulvovaginal region (ELPV). This is a rare condition with unknown incidence and prevalence. It causes painful raw areas at the vaginal entrance and subsequent scarring leads to anatomical changes with narrowing of the vaginal canal. Symptoms lead to difficulty in normal daily activities such as walking/sitting, washing, going to the toilet and can prevent normal sexual function. There is risk of cancerous change in affected skin of 1-3%. A Cochrane Systematic Review of interventions for mucosal erosive lichen planus, published in 2012, found no randomised controlled trials (RCT) on which to base treatment for ELPV. Evidence for treatments has historically been based upon retrospective case- series and case reports. Retrospective case series suggest that super-potent topical corticosteroids an effective first-line therapy, although one third of patients fail to respond adequately and require I Abstract escalation of therapy. There is no agreement for which second-line agents should be used and this is where the greatest clinical need for therapeutic guidance exists. The objective of this PhD was to begin to standardise practice for the management of people with ELPV and then develop a pragmatic protocol for those individuals who had failed to adequately respond to first line therapy with super-potent topical corticosteroids. Initial work focused on current practice in the management of lichen planus, how response to therapy was documented and which outcome measures were routinely used. The following steps were taken to finally inform the design of an RCT to determine optimal second-line therapy for EVLP resistant to topical steroids A multi-centre retrospective review and audit of case notes to assess current clinical management in the UK. Variation in practice was found and uncertainties were identified. These uncertainties comprised methods of diagnosing the condition, outcome measures used to assess severity and impact of the disease and therapeutic choices. A qualitative investigation into UK clinicians’ views and principles of management of vulval erosive lichen planus. This involved interviews with 25 UK clinicians and aimed to begin to address the uncertainties identified by the retrospective case note study. II Abstract An international multi-disciplinary consensus exercise. This was performed to agree a set of diagnostic criteria for ELPV that are acceptable to the clinical community. A systematic review of the literature to assess existing outcome measure tools that have been used in randomised controlled trials of vulval skin disorders. A survey of a national patient group, the UK Lichen Planus Society which identified preliminary information about living with ELPV from the patient’s perspective. Focus groups with patients. The themes identified from the UK Lichen planus Society survey, plus findings from the systematic review of outcome measures, were subsequently explored in greater detail through focus group work with patients. Focus groups were also used to obtain patient input into the proposed future RCT protocol Evidence from this work has informed a randomised controlled trial (RCT) developed with input from patients and clinicians to pragmatically answer an important question of clinical significance The resulting trial is a multi-centre, four-armed, open-label, pragmatic randomised controlled trial which will run in the secondary care setting. The trial will compare the medications hydroxychloroquine, methotrexate and mycophenolate mofetil against a standard care group of clobetasol propionate 0.05% plus a short course of oral prednisolone. These therapies were identified by III Abstract clinicians as likely to be most effective in clinical practice. However, amongst expert clinicians, there was no clearly preferred agent and insufficient data existed within the literature to demonstrate efficacy of any of these medications. It was therefore impossible to pick one comparator alone to test in a two-armed, placebo controlled RCT. As the disease is rare but chronic and resources limited in it was decided that a four-armed study would be the most appropriate as it would conserve patient numbers compared to running separate trials, and would give information on the three of the most commonly used systemic agents likely to be most effective. The primary outcome measure will be the proportion of participants responding to therapy at 6 months. This will be measured by a Patient Global Assessment score of 0 or 1 on a 4-point scale, and an Investigator Global Assessment of improvement from baseline judged by clinical images. The randomised controlled trial protocol has received ethical approval by the National Research Ethics Committee and the necessary regulatory documentation has been completed for the trial to commence in summer 2014. Impact of this research: This will be the first randomised controlled trial to test systemic agents for patients with vulval erosive lichen planus and will add to the existing evidence base. The impact of this work will potentially IV Abstract extend beyond improving care for patients with ELPV as the methodologies employed to develop the RCT protocol, and the trial design itself, may act as a template for clinical research into the therapeutic management of other rare inflammatory conditions. V Publications and presentations arising from this work Peer reviewed publications Simpson RC, Thomas KS, Murphy R. Comment on "management of vulvovaginal lichen planus: a new approach”. J Low Genit Tract Dis. 2014 Jan;18(1):E23-4. Simpson RC, Thomas KS, Murphy R. Outcome measures for vulval skin conditions: A systematic review of randomised controlled trials. Br J Dermatol. 2013 Sep;169(3):494-5 Simpson RC, Thomas KS, Murphy R. Vulval Erosive Lichen Planus: A qualitative investigation of UK clinician views and principles of management. Br J Dermatol. 2013 Jul;169(1):226-7. Simpson RC, Thomas KS, Leighton P, Murphy R. Diagnostic Criteria for Erosive Lichen Planus Affecting the Vulva: An international electronic-Delphi Consensus Exercise. Br J Dermatol. 2013 Aug;169(2):337-43 Simpson RC, Murphy R. Critically Appraised Topic - Is vulval erosive lichen planus a premalignant condition? Arch Dermatol. 2012 Nov 1;148(11):1314-6. VII Publications and presentations Simpson RC, Murphy R et al. Real life experience from a UK multi- centre case note audit; management of vulval erosive lichen planus. Br J Dermatol. 2012 Jul;167(1):85-91. Simpson RC, Murphy R. Considerations for Disease Impact and Outcome Measures in Vulvar Disease. J Low Genit Tract Dis. 2012 Oct;16(4):460-3. Book chapter Simpson RC, Murphy R, Nunns D: Vulval lichen sclerosus, erosive lichen planus and vulvodynia. In Williams HC , Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B (eds) Evidence Based Dermatology 3rd Edition Chapter 72, Wiley Blackwell Publishers 2014. Conference abstracts Simpson RC, Thomas KS, Leighton P, Murphy R. Diagnostic criteria for erosive lichen planus affecting the vulva: An electronic-Delphi consensus exercise. Br J Dermatol 2013;169 (Suppl 1):4 Simpson RC, Thomas KS, Leighton P, Murphy R. Diagnostic criteria for erosive lichen planus affecting the vulva: An electronic-Delphi consensus exercise. Journal of Investigative Dermatology 2013; 133 (Suppl.):S38 VIII Publications and presentations Cheng S, Simpson R, Kirtschig G, Cooper S, Silcocks P, Thornhill P, Murphy R. A Systematic Review of Interventions for Erosive Lichen Planus Affecting Mucosal Sites. J Low Gen Tract Dis Oct 2011; (Suppl): S5. Oral presentations British Society for the Study of Vulval Disease (BSSVD) Biannual Meeting, Glasgow, March 2014 Update on vulval erosive lichen planus randomised controlled trial School of Clinical Sciences Research Committee Workshop, Nottingham, July 2013 Patient and Public Involvement in the Clinical Research Cycle British Association of Dermatologists Annual Meeting, Liverpool, July 2013 Diagnostic criteria for erosive lichen planus affecting the vulva: An electronic-Delphi consensus exercise. Sue Watson Postgraduate Oral Presentation Event, University of Nottingham, July 2013 IX Publications and presentations Diagnostic criteria for erosive lichen planus affecting the vulva: An electronic-Delphi consensus exercise. THESIS’ (The Skin Investigation Society) Annual Meeting, London, June 2012 (Invited speaker) ‘Dreams, creams and aspirations’ British Society for the Study of Vulval Disease (BSSVD) Biannual Meeting, Newcastle, March 2012 Audit of current UK practice in the Diagnosis and Management of Vulval Erosive Lichen Planus; Results, Lessons and Future Work International Society for the Study of Vulval Disease (ISSVD) Biannual Meeting, Paris, September 2011 Vulval Erosive Lichen Planus. Results of a Cochrane Systematic review and subsequent Multi-centre case note audit X Grant awards and prizes arising from this work Year Award Role 2013 British Association of Presenter (oral Dermatologists 93rd Annual presentation)
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