Cross-Disciplinary Research Has Increased Our Understanding of Oral Mucosal Diseases
The classical cycle of investigation, hypothesis and experimentation in clinical research
2.2 What Is Research in Medical and Dental Schools?
It can be argued that research in dental schools is actually a philosophyof investigation at a number of different levels (Table 2.1). At the clinical level, research may be the detached analysis of response to therapies, the continuous audit of outcomes of treatments, the analysis of patients and the division into clinical phenotypes, epidemiology, etc. The second area is that of applied research which is looking at the clinical trials, the disease groups, the classification of disease and the investigations using patients. This often leads on from basic research which until recently has been hypothesis-based investigation often of mechanisms of disease or cell interactions but not necessarily with an obvious clinical benefit (see Table 2.1). Thus ideally there is a continuous cycle of basic science research leading to disease process understanding and models which lead to clinical diagnosis investigation and audit which lead to hypothesis, mechanisms and samples which lead to basic research to understand these and so on (Fig. 2.1). This is a modification of the classical cycle of hypothesis to experimentation to observation to preliminary data and back to hypothesis.
What is reseach in medical and dental schools?
A Philosophy of investigation
Detached analysis of response to therapies, outcomes of treatments, analysis of patients, epidemiology, etc.
Disease groups, classification. Clinical trials, investigation using patients
Hypothesis-based investigation but not necessarily with obvious clinical benefit
Thus clinical and translational research progresses from basic research using cell molecules and genes, to clinical research using human research participants and materials, (having investigated the mechanisms, markers, drug devices and interventions) (see Fig. 2.2) and then on to the application to health and populations. This requires understanding the barriers, the feasibility, the strategy, the effectiveness and the safety as well as the quality of the translation of this research. The ideal translation is from bench to bedside, i.e. laboratory to human but then from bedside to community with the evidence allowing this to be translated into practice.
2.3 Multidisciplinary Clinics
Multidisciplinary clinics can allow the collection of large numbers of patients with similar clinical diseases and make much more efficient the journey from applied research to changes in clinical practice. At Guy’s Hospital Dental School (now King’s College London Dental Institute), multidisciplinary clinics were established in the 1990s for (a) Sjögren’s syndrome with the Departments of Rheumatology, Ophthalmology and Immunology; (b) orofacial granulomatosis with the Departments of Gastroenterology, Immunology and Nutrition; (c) bullous diseases with the Departments of Dermatology and with Moorfields Eye Hospital, Ophthalmology; and (d) Behcet’s syndrome with the Department of Ophthalmology and Rheumatology. These multidisciplinary clinics have led to the Dental School being host to regional centres in each of these conditions and have led to changes in the management of several due to research, application of findings and assessment of clinical outcomes. It can be argued that without a robust system of disease severity measures and of measurement of clinical outcomes to management, any research leading to clinical application is unlikely to fulfil its full potential.
2.4 Assessment of Disease Severity and Treatment Responses in Oral Mucosal Disease
It is a sad truism and reflection on the field that few oral medicine treatments are evidence-based, even those regarded as standard therapies. Until the last few years, there had been a lack of any method to routinely assess disease severity and thus of quantifying responses to therapies. This led to the obvious need to devise and validate oral disease severity scores for a variety of conditions seen in routine clinical practice which could also be used for assessing treatment responses.
The benefits of a scoring system for mucosal disease severity are that (a) they can indicate the severity of disease, (b) they are needed to indicate the efficacy of any treatments, (c) they may distinguish between or reveal between disease subgroups, (d) they may assist in deciding to implement or withhold treatment and (e) they are a routine clinical audit tool which can also be used for research.
Any such oral disease severity scoring systems (ODSS) must be objective and must be reproducible; they should be easy to use and they should be widely applicable. Fortunately such ODSS have been created and validated and are used for recurrent aphthous ulceration , lichen planus , pemphigus , mucous membrane pemphigoid , orofacial granulomatosis  and dry mouth assessment .
2.5 Bullous Diseases
A joint clinic with the Institute of Dermatology was established in 1994 with the Oral Medicine Department at Guy’s Hospital. The dermatologists from the Institute were Dr. Martin Black and Dr. Jane Setterfield and from the Department of Oral Medicine Professor Stephen Challacombe and Dr. Pepe Shirlaw. Monthly clinics alternated between the Dental Institute at Guy’s Hospital and those held in the Institute of Dermatology at St Thomas’ Hospital. Later strong connections were made with Dr. John Dart in the Moorfields Eye Hospital, Ophthalmology Department, with a special interest in mucous membrane pemphigoid. This led in due course to the joint clinic becoming part of a Biomedical Research Centre leading on to clinical trials and a European collaboration. The establishment of a joint clinic led in due course to its recognition as a regional centre and to wide geographical referral to the centre resulting in the largest series of patients with mucous membrane pemphigoid (MMP) and patients with pemphigus vulgaris (PV) in the UK (Fig. 2.3a, b).
Such richness in clinical material carries with it an obligation to perform basic research, which might lead to identification of clinical phenotypes and improvement in patient management. Greater than 20 peer-reviewed research papers have emanated from this clinic along with Master students in Oral Medicine and five higher degrees (MD/PhDs).
Notable achievements coming from this research include the establishment and validation of an oral disease severity scoring systems for both MMP and PV (Fig. 2.4) , identification of different clinical phenotypes of MMP [4, 7], establishment of new assays to monitor serum antibodies to epitopes of BP180 in MMP [8, 9] and desmogleins 1 and 3 in PV , establishment of saliva as an alternative diagnostic fluid in both MMP and PV and the discovery of secretory IgA antibodies in saliva in MMP [8, 9].
This multidisciplinary research clinically was supported by laboratory-based investigations in immunology, immunopathology and ophthalmology. This has led to the definition of the clinical spectrum, identification of disease subgroups, the study of isotype specificity and of the role of IgA antibodies in disease severity, HLA associations and antigen specificity. The recognition that a B-cell- and antibody-mediated disease is driven by T-cell responses to antigens and epitopes has also been studied .
The main laboratory and clinical studies in MMP utilising a multidisciplinary approach are outlined in Table 2.2 (laboratory and clinical studies in MMP), and some key findings in MMP derived from a multidisciplinary clinic are summarised in Table 2.3.
Cross-discipline laboratory and clinical studies in mucous membrane pemphigoid (see [4, 7–9, 11])
• Laboratory studies with immunology, immunopathology
– Target antigens in MMP in relation to clinical phenotype: BP180, a6b4, NC16a, laminin 5
– Antibody isotypes: IgG, IgA, secretory IgA
– Use of saliva as diagnostic fluid
• Clinical studies with dermatology
– Distinct clinical phenotypes of oral MMP
– Oral disease severity scoring
– Different clinical phenotypes may respond to different therapies
Key findings in MMP derived from a multidisciplinary clinic (see [4, 7–9])
• Three main clinical oral phenotypes of MMP
• Two main immunofluorescent types relating to target antigens (BP180 and a6b4, laminin 5)
• Serum IgG antibody titre correlates with disease severity
• Serum IgG and IgA antibodies combined lead to a more severe disease
• Different clinical phenotypes respond to different drugs
• Salivary IgA and IgG antibodies to BP180-NC16a are diagnostic biomarkers in mucous membrane pemphigoid
In pemphigus vulgaris, laboratory-based research has allowed development of sensitive ELISAs and optimisation of substrates, while the development of an intraoral disease severity scoring system has allowed an evidence base to treatments for the first time and the translation of these findings to the clinic. For example, where the serum antibodytitres have fallen and the clinical severity score has fallen, patients can be maintained on local therapy and do not need systemic immunosuppression. Key findings in pemphigus vulgaris derived from a multidisciplinary clinic are summarised in Table 2.4.
Key findings in PV derived from a multidisciplinary clinic (see [3, 8–13])
• The severity of cutaneous and oral pemphigus is related to desmoglein 1 and 3 antibody levels
• The transition of pemphigus vulgaris into pemphigus foliaceus related to Dsg antibodies
• Oral and genital lichenoid reactions associated with circulating autoantibodies to desmoplakins I and II
• Serum and salivary IgG and IgA antibodies to Dsg3 in mucosal pemphigus vulgaris
2.6 Orofacial Granulomatosis
A multidisciplinary clinic looking after patients with orofacial granulomatosis (OFG) and oral Crohn’s was first established at Guy’s Hospital in 1995. This was a joint clinic involving Oral Medicine and Pathology, Gastroenterology (Dr. Jeremy Sanderson and colleagues), Nutrition (Dr. Lomer and colleagues), Immunology (Professor Jo Spencer) and Psychology. This clinic became a referral centre for not only oral medicine and oral maxillofacial surgery consultants around the UK, but also gastroenterologists and dermatologists as a UK regional referral centre. This led in due course to the largest series of characterised OFG in the UK and possibly the world. The first 250 patients were examined in detail both in vivo and in vitro, and the majority had colonoscopies as well as oral biopsies. Clinical trials and national collaborations (Liverpool, London and Newcastle) followed, and the findings have changed clinical practice in OFG (see Fig. 2.5 and Table 2.5).