David A. Sirois

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury

This study explored the feasibility of developing an animal model for radiation-induced salivary gland injury with a radiation protocol identical to current clinical practice. Three male Hanford minipigs were subjected to fractionated daily irradiation with a total dose of 70 Gy; structural and functional measures were compared with those of a control group of minipigs. We found that irradiated submandibular and parotid glands were one-third to one-half the gross size of control glands. Whereas no pathologic changes were noted in control glands, irradiated glands consistently demonstrated significant parenchymal loss with extensive acinar atrophy and interstitial fibrosis, enlarged nuclei in remaining acinar cells, and ductal dilatation and proliferation. Stimulated salivary flow was reduced by 81% in irradiated animals compared with preirradiation flow (P <.001); salivary flow in the control group increased by 30% during the same period (P <.001). The observed radiation-induced structural and functional salivary gland changes are comparable in every respect to those observed following irradiation of human salivary glands.

Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination. Cancer Prev Res; 3(9); 1093–103. ©2010 AACR.

EDNRB and DCC Salivary Rinse Hypermethylation Has a Similar Performance as Expert Clinical Examination in Discrimination of Oral Cancer/Dysplasia versus Benign Lesions

Purpose: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. Experimental Design: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR. Results: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60–0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51–0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58–0.76). Conclusions: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. Clin Cancer Res; 19(12); 3268–75. ©2013 AACR.

World Workshop on Oral Medicine VI: a systematic review of the treatment of mucocutaneous pemphigus vulgaris

OBJECTIVE To determine the efficacy and safety of interventions for pemphigus vulgaris (PV). STUDY DESIGN We conducted a systematic review from 2003 to 2013 according to the Cochrane Collaboration methodology. Randomized controlled trials (RCTs) or controlled clinical trials (CCTs) and observational studies were conducted along with diagnosis confirmed by clinical, histopathologic, and immunofluorescence criteria. Primary outcomes were disease remission and mortality; several relevant secondary outcomes were also included. RESULTS Fourteen RCTs or CCTs and 110 observational studies were included in the final analyses. RCTs or CCTs demonstrated considerable heterogeneity in outcome measures, and all had a high risk of bias for at least 1 of 8 domains. Of the studies, 96.8% (120) described the use of oral corticosteroids. Azathioprine and mycophenolate-mofetil were the most commonly cited treatments. An increasing number of studies described biologic therapies (rituximab, intravenous immunoglobulin [IVIg]). Evidence supporting recent comprehensive treatment guidelines was reviewed. CONCLUSIONS We found persisting wide variations in treatment practice and inadequate quality of research supporting optimal PV treatment.

Development of a Disease Registry for Autoimmune Bullous Diseases: Initial Analysis of The Pemphigus Vulgaris Subset

Pemphigus vulgaris (PV) is a rare, potentially life threatening, autoimmune blistering skin disease. The International Pemphigus and Pemphigoid Foundation (IPPF) has recently developed a disease registry with the aim to enhance our understanding of autoimmune bullous diseases with the long-term goal of acquiring information to improve patient care. Patients were recruited to the IPPF disease registry through direct mail, e-mail, advertisements, and articles in the IPPF-quarterly, -website, -Facebook webpage, and IPPF Peer Health Coaches to complete a 38-question survey. We present here the initial analysis of detailed clinical information collected on 393 PV patients. We report previously unrecognized gender differences in terms of lesion location, autoimmune comorbidity, and delay in diagnosis. The IPPF disease registry serves as a useful resource and guide for future clinical investigation.

Generating Consensus Research Goals and Treatment Strategies for Pemphigus and Pemphigoid: The 2010 JC Bystryn Pemphigus and Pemphigoid Meeting

The third international meeting cosponsored by the International Pemphigus and Pemphigoid Foundation (IPPF) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases was attended by approximately 130 scientists and clinicians representing the international pemphigus and pemphigoid community.* The intent of this meeting, organized by Sergei Grando (University of California–Irvine), Victoria Werth (University of Pennsylvania, Philadelphia), Luis Diaz (University of North Carolina at Chapel Hill), and the late Jean-Claude Bystryn (New York University), was to assemble an international group of researchers and clinicians involved in pemphigus and pemphigoid research and treatment. This report highlights the research presentations, group discussions, and recommendations for future work (see the meeting program at http://www.pemphigus.org/files/2010PP-MeetingProgram.pdf and accompanying presentations at http://www.pemphigus.org/index.php?option=com_content&view=article&id=396). In addition, an overview of barriers to international collaborations and multicenter trials was presented along with recommendations for the development of a consensus algorithm for treatment of pemphigus and pemphigoid.

Thermal temporal summation and decay of after-sensations in temporomandibular myofascial pain patients with and without comorbid fibromyalgia

Introduction Chronic myofascial temporomandibular disorders (TMD) may have multiple etiological and maintenance factors. One potential factor, central pain sensitization, was quantified here as the response to the temporal summation (TS) paradigm, and that response was compared between case and control groups. Objectives As previous research has shown that fibromyalgia (FM) is diagnosed iñ20% of TMD patients, Aim 1 determined whether central sensitization is found preferentially in myofascial TMD cases that have orofacial pain as a regional manifestation of FM. Aim 2 determined if the report of after-sensations (AS) following TS varied depending on whether repeated stimuli were rated as increasingly painful. Methods One hundred sixty-eight women, 43 controls, 100 myofascial TMD-only cases, and 25 myofascial TMD + FM cases, were compared on thermal warmth and pain thresholds, thermal TS, and decay of thermal AS. All cases met Research Diagnostic Criteria for TMD; comorbid cases also met the 1990 American College of Rheumatology criteria for FM. Results Pain thresholds and TS were similar in all groups. When TS was achieved (~60%), significantly higher levels of AS were reported in the first poststimulus interval, and AS decayed more slowly over time, in myofascial TMD cases than controls. By contrast, groups showed similar AS decay patterns following steady state or decreasing responses to repetitive stimulation. Conclusion In this case–control study, all myofascial TMD cases were characterized by a similar delay in the decay of AS. Thus, this indicator of central sensitization failed to suggest different pain maintenance factors in myofascial TMD cases with and without FM.

Bidirectional Impact of Oral Health and General Health

Oral manifestations of systemic disease or its treatment have been the subject of an extensive body of biomedical literature; several textbooks cover the subject in great detail (1,2). More recently, the impact of oral health on systemic health and disease has been the subject of intense investigation, leading to provocative ideas about oral risk factors for systemic disease and novel approaches to health promotion and disease prevention. This collective understanding of the reciprocal oral and systemic risks for disease will require, more than ever before, an expanded scope of dental, medical, and nutrition professional training to achieve competency in risk assessment and risk reduction. Translation into practice will require consultation among and collaboration between clinicians and should lead to innovative health care delivery systems that efficiently bring these caregivers and services to the patient.

Depressive Symptoms Account for Differences between Self-reported Versus Polysomnographic Assessment of Sleep Quality in Women with Myofascial TMD

Patients with temporomandibular disorder (TMD) report poor sleep quality on the Pittsburgh Sleep Quality Index (PSQI). However, polysomnographic (PSG) studies show meagre evidence of sleep disturbance on standard physiological measures. The present aim was to analyse self-reported sleep quality in TMD as a function of myofascial pain, PSG parameters and depressive symptomatology. PSQI scores from 124 women with myofascial TMD and 46 matched controls were hierarchically regressed onto TMD presence, ratings of pain intensity and pain-related disability, in-laboratory PSG variables and depressive symptoms (Symptoms Checklist-90). Relative to controls, TMD cases had higher PSQI scores, representing poorer subjective sleep and more depressive symptoms (both P < 0·001). Higher PSQI scores were strongly predicted by more depressive symptoms (P < 0·001, R2 = 26%). Of 19 PSG variables, two had modest contributions to higher PSQI scores: longer rapid eye movement latency in TMD cases (P = 0·01, R2 = 3%) and more awakenings in all participants (P = 0·03, R2 = 2%). After accounting for these factors, TMD presence and pain ratings were not significantly related to PSQI scores. These results show that reported poor sleep quality in TMD is better explained by depressive symptoms than by PSG-assessed sleep disturbances or myofascial pain. As TMD cases lacked typical PSG features of clinical depression, the results suggest a negative cognitive bias in TMD and caution against interpreting self-report sleep measures as accurate indicators of PSG sleep disturbance. Future investigations should take account of depressive symptomatology when interpreting reports of poor sleep.