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Oral Complications of Chronic Graft-Versus-Host Disease

Oral Complications of Chronic Graft-Versus-Host Disease Abstract The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and the leading cause of morbidity and nonrelapse mortality post-HSCT (1,2). The increasing clinical indications for HSCT and improved clinical care throughout the HSCT treatment process have led to not only long-term survival but also to an increasing incidence and prevalence of GVHD (2). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT (3), with increasing incidence in pediatric patients in parallel with increasing use of peripheral blood stem cell transplantation protocols (4). cGVHD is an alloimmune condition deriving from an immune attack mediated by donor T cells recognizing antigens expressed on normal tissues (5). This chronic disease occurs after HSCT due to disparities in minor histocompatibility antigens between donor and recipient inherited independently of HLA genes (5). Systemic corticosteroids are the primary treatment for cGHVD. The United States Food and Drug Administration has recently approved Imbruvica® (ibrutinib) for the treatment of adult patients with cGVHD following failure of one or more systemic treatments (IMBRUVICA, US Prescribing Information, August, 2017) (6). Emerging scientific technologies are refining our understanding of GVHD. Multiple organ sites, including the oral cavity, may be differentially affected in GVHD, and recent studies have addressed the underlying biology of this heterogeneity. Risk stratification of organ-specific GVHD based on single-nucleotide polymorphism (SNP) markers, including oral GVHD, was explored in a sample of 394 consecutive patients who underwent HSCT (7). Correlative markers of acute and cGVHD were found in several SNP markers from the cytokine-apoptosis-transforming growth factor-beta (TGF-β)-and Platelet-derived growth factor-mediated pathways. Although each organ-specific GVHD site did share some common biological pathways, specific SNP markers correlated with increased risk of organ-specific GVHD, including IL12RB1 (rs3746190) and donor FCGR2A (rs1801274) for oral GVHD (7). The FCGR2A genotype that was found to be very unique to oral cGVHD contrasted with the genotypes that were found strongly associated with the risk of cGVHD in the lung, including recipient TGFB2 (rs3746190) and donor 1L4R (re2057768), FAS (rs2234767), IL12B (rs3181226), and TGFB1 (rs1800469) (7). These results suggest that different biological pathways are associated with development of GVHD in different organs (7). Incorporating genetic risk factors into a clinical factors risk model thus improved stratification power for organ-specific GVHD including oral GVHD (7). Clinical Significance of Oral cGVHD Oral cGVHD has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children (2,8). Oral cGVHD is clinically diagnosed by history, context, and clinical assessment (1). Diagnostic clinical signs for oral cGHVD include lichen planus-like changes (Figure 1). Erythematous and ulcerative changes are distinctive but are not diagnostic for oral cGVHD (5,9). The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids and calcineurin inhibitors (10). Corticosteroids with and without cyclosporine are the most common systemic therapy (10). Mays et al. (2) and Fall-Dickson et al. (10) have presented comprehensive reviews of available therapies for oral cGVHD. Figure 1. View largeDownload slide Erythema, lichen-like changes, and ulceration and pseudomembrane in adult patient with oral chronic graft-versus-host disease. Figure 1. View largeDownload slide Erythema, lichen-like changes, and ulceration and pseudomembrane in adult patient with oral chronic graft-versus-host disease. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to considerable decreased oral intake and nutritional deficiency, oral infections, increased health service utilization, and may affect overall health and survival (11–14). Specific symptoms related to cGVHD manifesting in the oral mucosa include sensitivity to spicy, acidic, and salty foods, alcoholic beverages, and mouth rinses containing alcohol and flavoring agents (eg, mint). Symptoms reported related to cGVHD in the salivary gland include xerostomia; difficulty in speaking, swallowing, and chewing; and taste changes. Patients with cGVHD have reported multiple, concurrent symptoms, and research has reported significant relationships among these symptoms, cytokine levels, and quality of life (15). Bassim et al. (16) explored the interrelationships of mucosal lesions, salivary dysfunction, and limited mouth opening in a sample of 212 participants enrolled in the National Institutes of Health (NIH) cGVHD Natural History Protocol (NCT00331968). Results suggested that classifying oral cGVHD into three distinct diseases—mucosal lesions, salivary gland dysfunction, and mouth sclerosis—may improve clinical diagnosis and observational research data collection and yield a more precise definition of outcome measures in clinical trials (16). Fall-Dickson et al. (13) explored clinical characteristics and severity of oral cGVHD, prevalence and intensity of oral pain and oral dryness, salivary interleukin (IL) 6 and IL-1α concentrations, and health-related quality of life (HRQL) in 42 adult subjects with clinician-assessed oral cGVHD using the Oral Mucositis Rating Scale. Oral dryness was more prevalent than oral pain, and salivary IL-6 was positively associated with oral cGVHD severity (r = 0.49; P < .01), oral ulceration (r = 0.38; P = .04), and erythema (r = 0.63; P < .01). Negative trends were seen between oral dryness and overall HRQL and association of oral dryness and higher salivary IL1α. Positive associations between IL-6 and oral cGVHD overall severity and erythema, and the positive trend seen between IL-6 and oral ulcerations may warrant exploration of IL-6 as a potential biomarker for active oral cGVHD. Participants with more severe oral cGVHD had significantly inferior social/family well-being (r = 0.49; P < .01) as measured with the Functional Assessment of Cancer Therapy-General scale. Conversely, a recent clinical research study reported no significant association between salivary dysfunction and overall HRQL, although salivary dysfunction had a greater impact on oral cavity-specific quality of life scores than did observed oral disease (17). Oral Assessment for Oral cGVHD Accurate assessment of oral cGVHD clinical characteristics is critical in both clinical practice and clinical research to accurately rate the severity of the oral disease. The oral cavity may be the only clinical site affected by cGVHD in a subset of patients or may also be a highly predictive index of the presence of systemic cGVHD (18). The NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD reported standardized criteria for oral cGVHD diagnosis, clinical and histopathological scoring, and therapeutic response to promote valid and reliable score comparisons across studies and between clinical institutions first in 2005, with updated recommendation issued in 2014 (3,18–21). The original NIH Staging Score for Oral cGVHD is a subjective, four-point scale that combines assessment for oral clinical signs, symptoms, and impact on oral function into each individual score (Table 1). The ratings range from 0 = “no symptoms” to 3 = “severe symptoms with disease signs with major limitation of oral intake.” Limitations of this assessment tool to measure the severity of oral cGVHD severity include its subjectivity through lack of specific definitions for both the clinician ratings of “mild” (score = 1), “moderate” (score = 2), or “severe” (score = 3) severity and the ratings for limitation of oral intake of “partial” (score = 2) and “major” (score = 3). Combining clinical signs, symptoms, and impact on oral function yields a composite score that is not specific to measure the extent of oral cGVHD. Table 1. The National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease Oral Disease Staging Score Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake * The possible staging score ranging from 0 to 3 is based on subjective clinician assessment. View Large Table 1. The National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease Oral Disease Staging Score Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake * The possible staging score ranging from 0 to 3 is based on subjective clinician assessment. View Large The 2005 NIH Oral cGVHD Clinical Scoring Instrument (form A, chronic graft-versus-host disease activity assessment-clinician report) was developed as a more detailed, objective assessment tool for use in clinical and clinical trial settings when used by trained clinician raters to measure the extent of reticulation/lichenoid changes (0–3), severity and extent of edema (0–3), and extent of ulcerations (0–6) with a possible total score range of 0–15 (1) (Figure 2). Specific scoring criteria to rate severity extent of each of these clinical characteristics are clearly delineated. A multicenter pilot evaluation of the 2005 NIH cGVHD therapeutic response measures reported for the NIH Oral cGVHD Clinical Scoring Instrument a 2.1- to 2.6-points threshold for defining change exceeding measurement error (22). Psychometric evaluation studies of this Clinical Scoring Instrument have reported appropriate internal consistency reliability, need for further adjustment in ability to differentiate cGVHD patients based on their severity level, unacceptable interrater reliability for use in clinical trials, and need for formal trainings (23,24). The study reporting interrater reliability results used intraoral photographs with a range of oral cGVHD severity, which were assessed by clinician raters (24). A limitation of this study was the use of clinical photos that may not have been appropriate proxies for clinical observation needed to identify and discriminate specific findings (24). A comprehensive construct validity evaluation of the 15-point version of the 2005 NIH cGVHD Oral Mucosal Score instrument (OMS) was conducted with 198 post-autologous HSCT patients enrolled in a prospective cross-sectional study of cGVHD conducted at the NIH Clinical Center (clinicaltrials.gov identifier: NCT00331968) (25). Clinicians, who were experienced in assessing patients with cGVHD, performed the oral exams using the OMS. Findings supported clinical utility of the NIH OMS with the erythema, lichenoid, and ulceration components being independently associated with cGVHD relevant signs and/or symptoms (25). Fassil et al. (26) proposed the use of more than 2 points on the 2005 NIH OMS scale as a reproducible definition of clinically significant oral cGVHD that may be useful in clinical practice and also in clinical trials as an endpoint or criterion. The current NIH Oral cGVHD Clinical Scoring Instrument was the result of the 2014 Response Criteria Working Group’s recommendations for modification of the 2005 NIH OMS scale (Figure 2). Recommendations included removing the mucocele measurement because of reported unreliability of this clinical sign assessment and lack of mucoceles’ correlation with important clinical outcomes (27). Also, the term “hyperkeratosis” was removed and replaced with the term “lichen-like changes.” These changes resulted in a modified scale with a possible scoring range of 0 to 12 (27). Figure 2. View largeDownload slide The National Institutes of Health oral chronic graft-versus-host disease clinical scoring instrument (form A, chronic graft-versus-host disease activity assessment-clinician report). Figure 2. View largeDownload slide The National Institutes of Health oral chronic graft-versus-host disease clinical scoring instrument (form A, chronic graft-versus-host disease activity assessment-clinician report). Treister et al. (28) reported a summary of oral cavity data obtained from subjects enrolled in the Chronic GVHD Consortium-sponsored multicenter, prospective, longitudinal study (n = 458) designed to validate and refine recommendations of the NIH Consensus Conference regarding provision of valid and reliable clinical assessment tools for cGVHD. Three hundred and thirty-one participants had objective oral cGVHD involvement at enrollment, and multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinician and patients were erythema and lichenoid as well as NIH severity and symptom scores. The significant variability in presentation and range of severity in oral cGVHD makes assessment of treatment outcome challenging. Further research is needed to continue validation of these oral cGVHD assessment tools. Scientific Importance of Oral cGVHD Acute and chronic systemic GVHD entail characteristic pathologic processes. Specifically, acute GVHD is strongly inflammatory with no chronic component, whereas cGVHD may begin as an inflammatory process with progression to include more autoimmune and fibrotic features and may have a waxing and waning clinical phenotype. The pathologic process of acute GVHD includes three sequential phases: activation of antigen-presenting cells (APCs); effector cell activation, proliferation, differentiation and trafficking; and target tissue destruction that activates a positive feedback loop to perpetuate the process (29–31). Cells of the innate and adaptive immune systems including APCs (dendritic cells and macrophages), T helper cells (Th1, Th2, Th17), regulatory T cells (Treg), B cells, and natural killer cells (NK) cells have roles in the process. The specific immune process of cGVHD is less well understood, although there are similar pathophysiologic elements, such as antigen presentation and effector cell activation and effector cell-mediated tissue destruction that play key roles. Immunological mechanisms of GVHD suggested by animal and human models include: (1) autoreactive T-lymphocytes that evade thymic deletion; (2) donor-derived alloreactive T lymphocytes; (3) altered absolute numbers, ratios, or kinetics of lymphocyte subpopulations (32,33), for example, regulatory T lymphocytes; and (4) dysregulated cytokine expression (34,35). Oral cGVHD includes both the oral mucosa, which is the soft lining of the oral cavity, and the exocrine salivary glands. Although the specific process within the oral cavity is not fully understood, it is believed to parallel the understanding of GVHD in similar mucosal and exocrine tissues. The oral tissues have been directly examined, and some information is known regarding the character of the immune cell infiltrate in the oral tissues. Diffuse T-cell infiltration in the labial minor salivary glands (MSG) and subepithelial T-cell infiltration in the buccal mucosa (BM) have been reported as characteristic of oral cGVHD (36). Hayashida et al. (36) reported in a small sample of cGVHD patients (n = 16) a significant increase in Th1 and Th2 cytokine mRNA, and several cytokines and chemokines in the BM and the MSG from cGVHD patients vs control subjects. Also reported in this sample was the close association between mRNA expression of Th2 cytokines, macrophage-derived chemokine, and CC chemokine receptor 4 with a strong T-cell infiltration in the BM and the MSG. Diffuse T-cell infiltration has also been reported in autoimmune or chronic inflammatory diseases that clinically parallel cGHVD, and associated immune activity mediators and cytokines including IL-6, IL-1α, IL-1β, IL-1 receptor antagonist, tumor necrosis factor alpha (TNFα), soluble TNF-receptor II, monocyte chemoattractant protein-1, and soluble B cell activating factor (25,26,28,36–44). The oral mucosal inflammatory infiltrate is composed primarily of CD4+ and CD8+ T lymphocytes and CD68+ macrophages and Langerhans cells, with infrequent detection of B cells (45–51). In a comparative analysis of FoxP3+ regulatory T cells in target tissues and blood in 35 patients enrolled in the NIH Natural History Study of cGVHD (clinicaltrials.gov#NCT00092235), findings were consistent with Treg capacity to upregulate functional markers and traffic into cGVHD-involved tissue (52). Although several of these mediators are candidate biomarkers of cGVHD activity, examination of biomarkers in peripheral blood has not yielded tissue-specific cGVHD mechanisms (34). Bassim et al. (53) tested the feasibility of liquid chromatography tandem mass spectrometry to identify protein biomarkers of oral cGVHD and to elucidate salivary proteins affected by oral cGVHD in pooled unstimulated whole saliva (n = 5; moderate-severe oral cGVHD) vs a sex-age matched pool of five cGVHD patients with negative oral mucosal findings. Results included reduction of salivary lactoperoxidase, lactotransferrin, and several cysteine proteinase inhibitor family proteins, thus warranting testing in a larger sample as a potential screening, early detection, and monitoring tool for cGVHD. Kuzmina et al. (54) reported using a cohort of 280 patients with cGVHD characterized by NIH criteria that, despite the frequency with which circulating autoantibodies were seen in patients with advanced cGVHD signaling both dysregulated humoral immunity and better quantitative immune reconstitution, they did not show biomarker utility for cGVHD. Exploration of biomarkers related to oral cGVHD is fundamental to inform development of targeted therapies. Current Pathobiological Model for Oral cGVHD Histopathologic features of oral cGVHD include hyperkeratosis/epithelial thickening, interface submucosal lymphocytic infiltrate, epithelial atrophy, and basal cell apoptosis and degeneration (12,19,45–48,55,56). Based on the association of these histopathological features with specific clinical findings in mild, moderate, and severe oral cGVHD, a progressive model of oral GVHD pathobiology may be postulated, as illustrated in Figure 3. Damage from the pretransplant conditioning regimen is believed to activate APCs at the time of the graft and to damage the integrity of mucosal surfaces (29,31). In cGVHD specifically, the initial activation of APCs may occur via a respiratory infection or other inflammatory insult to the oral cavity; the initiating factors in oral cGVHD are not well defined. Plasmacytoid dendritic cells are active in oral cGVHD and are associated with local production of type I interferon. Mucosal surfaces including the gut and oral cavity are home to a rich microbiome, and when the integrity of the mucosa is breached, bacteria and microbial products that serve as pathogen-associated molecular patterns are allowed to translocate to the circulation which induces production of pro-inflammatory cytokines including IL-1 and TNF-α from macrophages (30). These cytokines, in turn, activate neutrophils and increase expression of Major histocompatibility complex and adhesion molecules on APCs, thereby increasing their antigen presenting capacity. Both donor and host APCs may be involved in this process (30). Once APCs activate CD4+ and CD8+ T cells, these cells initiate a strong cytokine response and migrate into GVHD target tissues. A mixed population of CD4+ and CD8+ T cells is found in early-stage oral mucosal GVHD. This is typically accompanied by the presence of apoptotic or dyskeratotic cells in the epithelium, which are presumably targets of effector CD8+ cells expressing the transcription factor Tbet (57). Once cellular mediators (T cells, activated macrophages, and NK cells) have chemotaxed into target tissues of GVHD, their production of chemokine and cytokine mediators acts synergistically to enhance target tissue destruction. In oral cGVHD, B cells are rarely found, although they have important roles systemically and in other tissues (58). However, both Tregs and Th17 cells are present, and it has been established that an imbalance of Tregs and Th17 cells contributes to the pathogenesis of cGVHD (30,59). In a pilot study, Motta et al. (60) presented data characterizing the immunohistopathology of oral cGVHD through examination of paired oral cGVHD biopsies pre- and at 1 month post-topical dexamethasone or tacrolimus treatment. Results showed high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3, thus showing that oral cGVHD was primarily T-cell driven with participation by macrophages. Imanguli et al. (57) proposed a model of cGVHD pathogenesis in which the production of type 1 interferon by plasmacytoid dendritic cells plays a central role in cGVHD initiation and continuation. Figure 3. View largeDownload slide Pathobiology model of oral chronic graft-versus-host disease (Courtesy of Jacqueline W. Mays, DDS, MHSc, PhD, National Institute of Dental and Craniofacial Research, National Institutes of Health). Figure 3. View largeDownload slide Pathobiology model of oral chronic graft-versus-host disease (Courtesy of Jacqueline W. Mays, DDS, MHSc, PhD, National Institute of Dental and Craniofacial Research, National Institutes of Health). Epithelial thickening is frequently observed on affected oral mucosa, and this may be a reactive change secondary to the inflammatory microenvironment generated by the effector cell infiltrate. In more severe clinical cases of oral cGVHD, the presence of basal cell apoptosis and degeneration in tissue biopsies may signal a preceding event to the development of pseudomembranous ulcerations, because it is often observed in oral biopsies taken at sites adjacent to oral ulcers. Tissue sclerosis and fibrotic processes are later events in oral cGVHD, and although they are clinically associated with long-standing oral inflammation, the molecular triggers for these processes are as yet undefined. Evidence Gaps Relative to This Current Pathobiological Model Despite ongoing work, it is unclear to what extent histopathological features and molecular mechanisms correlate with actual oral cGVHD-related clinical disease activity and patient-reported symptoms and how these parameters are influenced by systemic and local therapies. Research in autoimmune disorders with clinical features similar to oral cGVHD, such as lichen planus, psoriasis, and to some extent Sjogren’s syndrome, may enrich the pathobiological understanding of these clinical issues as informed by GVHD-specific research. Clinical Management: Successes and Barriers Current Clinical Management No optimum treatment option exists for oral cGVHD, and the current focus is on disease management through reduction of immune-based damage to target tissues and symptom management. Patients may live with oral cGVHD and related negative sequelae for prolonged periods of time, thus making effective management essential. Disease management for oral cGVHD continues until immune tolerance between the host and the grafted immune system is achieved, and then specifically focuses on (1) healing of oral ulcerations, (2) relieving oral pain and sensitivity, (3) improving or maintaining salivary function, and (4) maximizing oral function. The report from the 2011 International Consensus Conference on clinical practice in cGVHD stressed the importance of a comprehensive treatment approach for oral cGVHD involving multidisciplinary teams who focus on operationalizing the treatment plan tailored to the specific type of oral cGVHD manifestation (61). Although the majority of patients with oral cGVHD are managed with systemic immunomodulatory medications, this disease often persists despite aggressive systemic therapy (62). Topical treatments provide symptom management that may be more readily achieved than disease resolution, thus placing importance on accurate patient adherence to treatment and accurate reported outcomes (63). Pain management is a critical component of overall management strategies, and topical anesthetics such as viscous lidocaine may be effective in reducing oral pain as well as oral sensitivity before eating, oral hygiene, or applying topical therapies (64). Systemic analgesics, including opioids, are used to manage clinically significant oral pain. Although oral cGVHD therapy is not always tested via randomized clinical trials, expert consensus and the literature describe use of high-potency topical steroids as standard treatment (14,62,64–67). Steroid gels are easily applied to distinct oral areas and are generally more effectively absorbed than creams or ointments. Tacrolimus ointment (Protopic 0.1% and 0.03% ointment, Astellas Pharma US, Deerfield, IL) has been found efficacious for oral mucosal cGVHD with maximum benefit seen with the 0.1% ointment, although it is associated with measurable systemic uptake (68–70). Rinsing with a steroid elixir is well tolerated and often more effective than gel applications, especially when symptoms and/or lesions are widespread throughout the oral cavity. Dexamethasone oral suspension (0.1 mg/mL) is the first line of oral topical therapy; however, reported clinical response rates are low, with 29–58% of patients reaching a partial or complete response in the first month (71,72). Although numerous treatments have been proposed, including topical azathioprine and cyclosporine, budesonide rinse, dexamethasone rinse, triamcinolone ointment, clobetasol ointment, CO2 laser, low-level laser, phototherapy with PUVA, and broad-band and narrow-band UVB therapy, results have been reported mainly through case studies or small series with variable results (68,69,71–85). Regularly scheduled dental evaluations are critical for patients with oral cGVHD because of risk for dental caries and second malignancies (86–88). Castellarin et al. (89) characterized extensive dental caries as a severe late complication of oral cGVHD and stressed that more prospective studies are needed to describe incidence of dental carries, identify risk factors, and test efficacy of preventive intervention. The oral/dental exam is also important to assess for squamous cell carcinoma, which has a well-known association with oral cGVHD (90). Genomic instability of mucosal cells may lead to malignant transformation, and a significant association between history of oral cGVHD and number of microsatellites showing this instability in oral mucosa has been reported (90). Evidence Gaps Regarding Current Clinical Management Comprehensive reviews of the current evidence base for oral cGVHD and related symptom treatment using single agent or combined topical agents all recognized the need to test agents through multi-site randomized controlled clinical trials with sufficient sample sizes, defined treatment outcomes, and valid and reliable oral cGVHD assessment tools (2,61,91,92). Although the oral cavity is a readily visualized site from which to assess the presence and severity of oral cGVHD and to monitor the effects of novel therapeutics, poorly defined inclusion and exclusion criteria and use of nonstandardized measurement tools have made comparison of efficacy and toxicity data between studies difficult. Clinical trials for oral cGVHD require consistently applied and interpreted criteria for pathological diagnosis if needed for confirmation (19). Clinical management is affected by false-negative histopathological assessment of oral cGVHD related to (1) suboptimal tissue sampling of oral ulceration and not adjacent intact mucosa, (2) performing labial biopsies that do not include enough glandular lobules to differentiate between active disease and damaged tissue, and (3) incorrectly sectioned samples (19). No standard treatment exists for cGVHD that recurs or fails to respond to initial therapy (93). Thus, a critical need exists to develop well-tolerated adjuvant therapies that are both efficacious and avoid the long-term consequences of systemic corticosteroid therapies (94). The majority of treatment strategies for oral cGVHD, including severe oral disease occurring in the presence of severe systemic disease and as the only focus of active disease, have not been evidence based, resulting in modest advances in evidence-based treatment. Clinical trials, as proposed by the NIH cGVHD Consensus Development Project, are needed to test novel agents for oral cGVHD that target therapy to active oral disease and avoid systemic effects. Consistent assessment of oral cGVHD across clinical trials and in clinical practice settings is a key component of the clinical research efforts targeted at elucidating the pathogenesis of this disease and the effect of investigational and routinely used agents. Clinical and Translational Research With Promise for Clinical Future Applications There is a paucity of reported clinical research focused on supportive care needs of patients with oral GVHD to support evidenced-based practice. The design of prevention or treatment protocols is dependent on understanding the immunobiology of both acute and cGVHD. As we learn more about the immune-based attack of GVHD on specific tissues, targeted prevention and management strategies should improve. Opportunities exist now to apply molecular-genetic techniques to elucidate underlying mechanisms of oral GVHD. Gene expression studies, mapping of gene pathways, genome-wide association studies, and epigenetic studies will ultimately provide greater understanding of environmental influences in this disease and guide therapeutic clinical research. Better Understanding of the Impact of Oral cGVHD Manifestations Management of oral cGVHD currently depends primarily on systemic therapy with adjunctive topical therapies for symptom control. Although this is a useful strategy, future clinical research strategies should also focus on the improved prevention and treatment of mucosal damage. It is not known why although oral lesions are most common in patients with extensive cGVHD, patients rarely may present with isolated disease involving only the oral cavity. Although there is some evidence that subclinical cGVHD diagnosed through skin or BM biopsy may predict subsequent development of cGVHD, timing and severity of oral findings are not currently useful to predict overall incidence, extent, or progression of systemic cGVHD (95). Currently, there are no reliable clinical signs or related symptoms that predict the clinical course of oral involvement. Descriptive and interventional clinical research is needed that explores potential symptom clustering of taste changes, oral pain, oral sensitivity, and oral dryness in relation to severity of oral manifestations. Weight loss and malnutrition are also clinically significant problems in this population, and the effect of oral cGVHD and related symptoms on these clinically challenging problems needs to be elucidated. Strategies to Advance the Science Scientific advancement in the field of oral cGVHD has been promoted through national and international interdisciplinary study groups that have been formed over the last few decades to systematically address the clinical and research challenges of oral cGVHD. Consensus reached by these study groups has articulated the importance of standardized definitions of disease manifestations and response criteria as well as common assessment tools. These groups have widely disseminated their recommendations for clinical care of the patient with oral cGVHD as well as results of clinical research focused on advancing the science of oral cGVHD. Foci of these efforts are numerous, including elucidating pathogenesis of oral cGVHD through exploration of immunological and inflammatory pathways; identifying biomarkers with diagnostic significance to make cGVHD treatment preemptive (29); exploring the diagnostic and prognostic value of biomarkers; testing psychometrics and clinical utility of assessment tools; testing efficacy of novel immunological agents through multi-site randomized controlled clinical trials; evaluating impact of oral cGVHD severity on the patient symptom experience and HRQL; and disseminating results of this work, which is often conducted in academic medical centers, into the community health care setting. Although the challenges of conducting randomized clinical trials in the cGVHD setting are recognized as often similar to other clinical settings–participant recruitment and retention, loss to follow-up, financial constraints—there has been a recent increase in interest in conducting preclinical and clinical studies in the oral cGVHD clinical setting (96). Much interest has been generated by the emerging therapeutics that are available or in the pharmaceutical pipeline, including the JAK family of nonreceptor tyrosine kinases (96). Funding for the conduct of clinical and translational research for oral cGVHD is critical to promote evidence-based practice supported by outcomes of rigorous randomized clinical trials vs treatment recommendations based on clinical experience of experts and small controlled trials (61). Funding Work in JWM's laboratory is supported by the Intramural Research Program of the NIH, NIDCR. Notes Affiliations of authors: Department of Professional Nursing Practice, Georgetown University School of Nursing & Health Studies, Washington, DC (JMFD); Experimental Transplantation and Immunology Branch, National Cancer Institute (SZP) and Division of Intramural Research, National Institute of Dental and Craniofacial Research (JWM), National Institutes of Health, Bethesda, MD; Department of Oral Medicine, University of Washington, School of Dentistry and Seattle Cancer Care Alliance and Oral Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA (MMS). J. Fall-Dickson, S. Pavletic, J. Mays, and M. Schubert have no conflicts of interest to declare. For support see Funding Acknowledgement section of Monograph. References 1 Treister N , Schubert MS , Fall-Dickson JM. Oral chronic graft vs host disease. In: Vogelsang GB , Pavletic SZ , eds. Chronic Graft-Versus-Host Disease: Interdisciplinary Management . New York : Cambridge University ; 2009 : 182 – 198 . 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Oral Complications of Chronic Graft-Versus-Host Disease

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
DOI
10.1093/jncimonographs/lgz007
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Abstract

Abstract The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented. Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) and the leading cause of morbidity and nonrelapse mortality post-HSCT (1,2). The increasing clinical indications for HSCT and improved clinical care throughout the HSCT treatment process have led to not only long-term survival but also to an increasing incidence and prevalence of GVHD (2). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT (3), with increasing incidence in pediatric patients in parallel with increasing use of peripheral blood stem cell transplantation protocols (4). cGVHD is an alloimmune condition deriving from an immune attack mediated by donor T cells recognizing antigens expressed on normal tissues (5). This chronic disease occurs after HSCT due to disparities in minor histocompatibility antigens between donor and recipient inherited independently of HLA genes (5). Systemic corticosteroids are the primary treatment for cGHVD. The United States Food and Drug Administration has recently approved Imbruvica® (ibrutinib) for the treatment of adult patients with cGVHD following failure of one or more systemic treatments (IMBRUVICA, US Prescribing Information, August, 2017) (6). Emerging scientific technologies are refining our understanding of GVHD. Multiple organ sites, including the oral cavity, may be differentially affected in GVHD, and recent studies have addressed the underlying biology of this heterogeneity. Risk stratification of organ-specific GVHD based on single-nucleotide polymorphism (SNP) markers, including oral GVHD, was explored in a sample of 394 consecutive patients who underwent HSCT (7). Correlative markers of acute and cGVHD were found in several SNP markers from the cytokine-apoptosis-transforming growth factor-beta (TGF-β)-and Platelet-derived growth factor-mediated pathways. Although each organ-specific GVHD site did share some common biological pathways, specific SNP markers correlated with increased risk of organ-specific GVHD, including IL12RB1 (rs3746190) and donor FCGR2A (rs1801274) for oral GVHD (7). The FCGR2A genotype that was found to be very unique to oral cGVHD contrasted with the genotypes that were found strongly associated with the risk of cGVHD in the lung, including recipient TGFB2 (rs3746190) and donor 1L4R (re2057768), FAS (rs2234767), IL12B (rs3181226), and TGFB1 (rs1800469) (7). These results suggest that different biological pathways are associated with development of GVHD in different organs (7). Incorporating genetic risk factors into a clinical factors risk model thus improved stratification power for organ-specific GVHD including oral GVHD (7). Clinical Significance of Oral cGVHD Oral cGVHD has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children (2,8). Oral cGVHD is clinically diagnosed by history, context, and clinical assessment (1). Diagnostic clinical signs for oral cGHVD include lichen planus-like changes (Figure 1). Erythematous and ulcerative changes are distinctive but are not diagnostic for oral cGVHD (5,9). The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids and calcineurin inhibitors (10). Corticosteroids with and without cyclosporine are the most common systemic therapy (10). Mays et al. (2) and Fall-Dickson et al. (10) have presented comprehensive reviews of available therapies for oral cGVHD. Figure 1. View largeDownload slide Erythema, lichen-like changes, and ulceration and pseudomembrane in adult patient with oral chronic graft-versus-host disease. Figure 1. View largeDownload slide Erythema, lichen-like changes, and ulceration and pseudomembrane in adult patient with oral chronic graft-versus-host disease. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to considerable decreased oral intake and nutritional deficiency, oral infections, increased health service utilization, and may affect overall health and survival (11–14). Specific symptoms related to cGVHD manifesting in the oral mucosa include sensitivity to spicy, acidic, and salty foods, alcoholic beverages, and mouth rinses containing alcohol and flavoring agents (eg, mint). Symptoms reported related to cGVHD in the salivary gland include xerostomia; difficulty in speaking, swallowing, and chewing; and taste changes. Patients with cGVHD have reported multiple, concurrent symptoms, and research has reported significant relationships among these symptoms, cytokine levels, and quality of life (15). Bassim et al. (16) explored the interrelationships of mucosal lesions, salivary dysfunction, and limited mouth opening in a sample of 212 participants enrolled in the National Institutes of Health (NIH) cGVHD Natural History Protocol (NCT00331968). Results suggested that classifying oral cGVHD into three distinct diseases—mucosal lesions, salivary gland dysfunction, and mouth sclerosis—may improve clinical diagnosis and observational research data collection and yield a more precise definition of outcome measures in clinical trials (16). Fall-Dickson et al. (13) explored clinical characteristics and severity of oral cGVHD, prevalence and intensity of oral pain and oral dryness, salivary interleukin (IL) 6 and IL-1α concentrations, and health-related quality of life (HRQL) in 42 adult subjects with clinician-assessed oral cGVHD using the Oral Mucositis Rating Scale. Oral dryness was more prevalent than oral pain, and salivary IL-6 was positively associated with oral cGVHD severity (r = 0.49; P < .01), oral ulceration (r = 0.38; P = .04), and erythema (r = 0.63; P < .01). Negative trends were seen between oral dryness and overall HRQL and association of oral dryness and higher salivary IL1α. Positive associations between IL-6 and oral cGVHD overall severity and erythema, and the positive trend seen between IL-6 and oral ulcerations may warrant exploration of IL-6 as a potential biomarker for active oral cGVHD. Participants with more severe oral cGVHD had significantly inferior social/family well-being (r = 0.49; P < .01) as measured with the Functional Assessment of Cancer Therapy-General scale. Conversely, a recent clinical research study reported no significant association between salivary dysfunction and overall HRQL, although salivary dysfunction had a greater impact on oral cavity-specific quality of life scores than did observed oral disease (17). Oral Assessment for Oral cGVHD Accurate assessment of oral cGVHD clinical characteristics is critical in both clinical practice and clinical research to accurately rate the severity of the oral disease. The oral cavity may be the only clinical site affected by cGVHD in a subset of patients or may also be a highly predictive index of the presence of systemic cGVHD (18). The NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD reported standardized criteria for oral cGVHD diagnosis, clinical and histopathological scoring, and therapeutic response to promote valid and reliable score comparisons across studies and between clinical institutions first in 2005, with updated recommendation issued in 2014 (3,18–21). The original NIH Staging Score for Oral cGVHD is a subjective, four-point scale that combines assessment for oral clinical signs, symptoms, and impact on oral function into each individual score (Table 1). The ratings range from 0 = “no symptoms” to 3 = “severe symptoms with disease signs with major limitation of oral intake.” Limitations of this assessment tool to measure the severity of oral cGVHD severity include its subjectivity through lack of specific definitions for both the clinician ratings of “mild” (score = 1), “moderate” (score = 2), or “severe” (score = 3) severity and the ratings for limitation of oral intake of “partial” (score = 2) and “major” (score = 3). Combining clinical signs, symptoms, and impact on oral function yields a composite score that is not specific to measure the extent of oral cGVHD. Table 1. The National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease Oral Disease Staging Score Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake * The possible staging score ranging from 0 to 3 is based on subjective clinician assessment. View Large Table 1. The National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease Oral Disease Staging Score Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake Score 0* Score 1 Score 2 Score 3 No symptoms Mild symptoms with disease signs but not limiting oral intake significantly Moderate symptoms with disease signs with partial limitation of oral intake Severe symptoms with disease signs with major limitation of oral intake * The possible staging score ranging from 0 to 3 is based on subjective clinician assessment. View Large The 2005 NIH Oral cGVHD Clinical Scoring Instrument (form A, chronic graft-versus-host disease activity assessment-clinician report) was developed as a more detailed, objective assessment tool for use in clinical and clinical trial settings when used by trained clinician raters to measure the extent of reticulation/lichenoid changes (0–3), severity and extent of edema (0–3), and extent of ulcerations (0–6) with a possible total score range of 0–15 (1) (Figure 2). Specific scoring criteria to rate severity extent of each of these clinical characteristics are clearly delineated. A multicenter pilot evaluation of the 2005 NIH cGVHD therapeutic response measures reported for the NIH Oral cGVHD Clinical Scoring Instrument a 2.1- to 2.6-points threshold for defining change exceeding measurement error (22). Psychometric evaluation studies of this Clinical Scoring Instrument have reported appropriate internal consistency reliability, need for further adjustment in ability to differentiate cGVHD patients based on their severity level, unacceptable interrater reliability for use in clinical trials, and need for formal trainings (23,24). The study reporting interrater reliability results used intraoral photographs with a range of oral cGVHD severity, which were assessed by clinician raters (24). A limitation of this study was the use of clinical photos that may not have been appropriate proxies for clinical observation needed to identify and discriminate specific findings (24). A comprehensive construct validity evaluation of the 15-point version of the 2005 NIH cGVHD Oral Mucosal Score instrument (OMS) was conducted with 198 post-autologous HSCT patients enrolled in a prospective cross-sectional study of cGVHD conducted at the NIH Clinical Center (clinicaltrials.gov identifier: NCT00331968) (25). Clinicians, who were experienced in assessing patients with cGVHD, performed the oral exams using the OMS. Findings supported clinical utility of the NIH OMS with the erythema, lichenoid, and ulceration components being independently associated with cGVHD relevant signs and/or symptoms (25). Fassil et al. (26) proposed the use of more than 2 points on the 2005 NIH OMS scale as a reproducible definition of clinically significant oral cGVHD that may be useful in clinical practice and also in clinical trials as an endpoint or criterion. The current NIH Oral cGVHD Clinical Scoring Instrument was the result of the 2014 Response Criteria Working Group’s recommendations for modification of the 2005 NIH OMS scale (Figure 2). Recommendations included removing the mucocele measurement because of reported unreliability of this clinical sign assessment and lack of mucoceles’ correlation with important clinical outcomes (27). Also, the term “hyperkeratosis” was removed and replaced with the term “lichen-like changes.” These changes resulted in a modified scale with a possible scoring range of 0 to 12 (27). Figure 2. View largeDownload slide The National Institutes of Health oral chronic graft-versus-host disease clinical scoring instrument (form A, chronic graft-versus-host disease activity assessment-clinician report). Figure 2. View largeDownload slide The National Institutes of Health oral chronic graft-versus-host disease clinical scoring instrument (form A, chronic graft-versus-host disease activity assessment-clinician report). Treister et al. (28) reported a summary of oral cavity data obtained from subjects enrolled in the Chronic GVHD Consortium-sponsored multicenter, prospective, longitudinal study (n = 458) designed to validate and refine recommendations of the NIH Consensus Conference regarding provision of valid and reliable clinical assessment tools for cGVHD. Three hundred and thirty-one participants had objective oral cGVHD involvement at enrollment, and multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinician and patients were erythema and lichenoid as well as NIH severity and symptom scores. The significant variability in presentation and range of severity in oral cGVHD makes assessment of treatment outcome challenging. Further research is needed to continue validation of these oral cGVHD assessment tools. Scientific Importance of Oral cGVHD Acute and chronic systemic GVHD entail characteristic pathologic processes. Specifically, acute GVHD is strongly inflammatory with no chronic component, whereas cGVHD may begin as an inflammatory process with progression to include more autoimmune and fibrotic features and may have a waxing and waning clinical phenotype. The pathologic process of acute GVHD includes three sequential phases: activation of antigen-presenting cells (APCs); effector cell activation, proliferation, differentiation and trafficking; and target tissue destruction that activates a positive feedback loop to perpetuate the process (29–31). Cells of the innate and adaptive immune systems including APCs (dendritic cells and macrophages), T helper cells (Th1, Th2, Th17), regulatory T cells (Treg), B cells, and natural killer cells (NK) cells have roles in the process. The specific immune process of cGVHD is less well understood, although there are similar pathophysiologic elements, such as antigen presentation and effector cell activation and effector cell-mediated tissue destruction that play key roles. Immunological mechanisms of GVHD suggested by animal and human models include: (1) autoreactive T-lymphocytes that evade thymic deletion; (2) donor-derived alloreactive T lymphocytes; (3) altered absolute numbers, ratios, or kinetics of lymphocyte subpopulations (32,33), for example, regulatory T lymphocytes; and (4) dysregulated cytokine expression (34,35). Oral cGVHD includes both the oral mucosa, which is the soft lining of the oral cavity, and the exocrine salivary glands. Although the specific process within the oral cavity is not fully understood, it is believed to parallel the understanding of GVHD in similar mucosal and exocrine tissues. The oral tissues have been directly examined, and some information is known regarding the character of the immune cell infiltrate in the oral tissues. Diffuse T-cell infiltration in the labial minor salivary glands (MSG) and subepithelial T-cell infiltration in the buccal mucosa (BM) have been reported as characteristic of oral cGVHD (36). Hayashida et al. (36) reported in a small sample of cGVHD patients (n = 16) a significant increase in Th1 and Th2 cytokine mRNA, and several cytokines and chemokines in the BM and the MSG from cGVHD patients vs control subjects. Also reported in this sample was the close association between mRNA expression of Th2 cytokines, macrophage-derived chemokine, and CC chemokine receptor 4 with a strong T-cell infiltration in the BM and the MSG. Diffuse T-cell infiltration has also been reported in autoimmune or chronic inflammatory diseases that clinically parallel cGHVD, and associated immune activity mediators and cytokines including IL-6, IL-1α, IL-1β, IL-1 receptor antagonist, tumor necrosis factor alpha (TNFα), soluble TNF-receptor II, monocyte chemoattractant protein-1, and soluble B cell activating factor (25,26,28,36–44). The oral mucosal inflammatory infiltrate is composed primarily of CD4+ and CD8+ T lymphocytes and CD68+ macrophages and Langerhans cells, with infrequent detection of B cells (45–51). In a comparative analysis of FoxP3+ regulatory T cells in target tissues and blood in 35 patients enrolled in the NIH Natural History Study of cGVHD (clinicaltrials.gov#NCT00092235), findings were consistent with Treg capacity to upregulate functional markers and traffic into cGVHD-involved tissue (52). Although several of these mediators are candidate biomarkers of cGVHD activity, examination of biomarkers in peripheral blood has not yielded tissue-specific cGVHD mechanisms (34). Bassim et al. (53) tested the feasibility of liquid chromatography tandem mass spectrometry to identify protein biomarkers of oral cGVHD and to elucidate salivary proteins affected by oral cGVHD in pooled unstimulated whole saliva (n = 5; moderate-severe oral cGVHD) vs a sex-age matched pool of five cGVHD patients with negative oral mucosal findings. Results included reduction of salivary lactoperoxidase, lactotransferrin, and several cysteine proteinase inhibitor family proteins, thus warranting testing in a larger sample as a potential screening, early detection, and monitoring tool for cGVHD. Kuzmina et al. (54) reported using a cohort of 280 patients with cGVHD characterized by NIH criteria that, despite the frequency with which circulating autoantibodies were seen in patients with advanced cGVHD signaling both dysregulated humoral immunity and better quantitative immune reconstitution, they did not show biomarker utility for cGVHD. Exploration of biomarkers related to oral cGVHD is fundamental to inform development of targeted therapies. Current Pathobiological Model for Oral cGVHD Histopathologic features of oral cGVHD include hyperkeratosis/epithelial thickening, interface submucosal lymphocytic infiltrate, epithelial atrophy, and basal cell apoptosis and degeneration (12,19,45–48,55,56). Based on the association of these histopathological features with specific clinical findings in mild, moderate, and severe oral cGVHD, a progressive model of oral GVHD pathobiology may be postulated, as illustrated in Figure 3. Damage from the pretransplant conditioning regimen is believed to activate APCs at the time of the graft and to damage the integrity of mucosal surfaces (29,31). In cGVHD specifically, the initial activation of APCs may occur via a respiratory infection or other inflammatory insult to the oral cavity; the initiating factors in oral cGVHD are not well defined. Plasmacytoid dendritic cells are active in oral cGVHD and are associated with local production of type I interferon. Mucosal surfaces including the gut and oral cavity are home to a rich microbiome, and when the integrity of the mucosa is breached, bacteria and microbial products that serve as pathogen-associated molecular patterns are allowed to translocate to the circulation which induces production of pro-inflammatory cytokines including IL-1 and TNF-α from macrophages (30). These cytokines, in turn, activate neutrophils and increase expression of Major histocompatibility complex and adhesion molecules on APCs, thereby increasing their antigen presenting capacity. Both donor and host APCs may be involved in this process (30). Once APCs activate CD4+ and CD8+ T cells, these cells initiate a strong cytokine response and migrate into GVHD target tissues. A mixed population of CD4+ and CD8+ T cells is found in early-stage oral mucosal GVHD. This is typically accompanied by the presence of apoptotic or dyskeratotic cells in the epithelium, which are presumably targets of effector CD8+ cells expressing the transcription factor Tbet (57). Once cellular mediators (T cells, activated macrophages, and NK cells) have chemotaxed into target tissues of GVHD, their production of chemokine and cytokine mediators acts synergistically to enhance target tissue destruction. In oral cGVHD, B cells are rarely found, although they have important roles systemically and in other tissues (58). However, both Tregs and Th17 cells are present, and it has been established that an imbalance of Tregs and Th17 cells contributes to the pathogenesis of cGVHD (30,59). In a pilot study, Motta et al. (60) presented data characterizing the immunohistopathology of oral cGVHD through examination of paired oral cGVHD biopsies pre- and at 1 month post-topical dexamethasone or tacrolimus treatment. Results showed high expression of CD3, CD4, CD8, CD103, CD163, and FoxP3, thus showing that oral cGVHD was primarily T-cell driven with participation by macrophages. Imanguli et al. (57) proposed a model of cGVHD pathogenesis in which the production of type 1 interferon by plasmacytoid dendritic cells plays a central role in cGVHD initiation and continuation. Figure 3. View largeDownload slide Pathobiology model of oral chronic graft-versus-host disease (Courtesy of Jacqueline W. Mays, DDS, MHSc, PhD, National Institute of Dental and Craniofacial Research, National Institutes of Health). Figure 3. View largeDownload slide Pathobiology model of oral chronic graft-versus-host disease (Courtesy of Jacqueline W. Mays, DDS, MHSc, PhD, National Institute of Dental and Craniofacial Research, National Institutes of Health). Epithelial thickening is frequently observed on affected oral mucosa, and this may be a reactive change secondary to the inflammatory microenvironment generated by the effector cell infiltrate. In more severe clinical cases of oral cGVHD, the presence of basal cell apoptosis and degeneration in tissue biopsies may signal a preceding event to the development of pseudomembranous ulcerations, because it is often observed in oral biopsies taken at sites adjacent to oral ulcers. Tissue sclerosis and fibrotic processes are later events in oral cGVHD, and although they are clinically associated with long-standing oral inflammation, the molecular triggers for these processes are as yet undefined. Evidence Gaps Relative to This Current Pathobiological Model Despite ongoing work, it is unclear to what extent histopathological features and molecular mechanisms correlate with actual oral cGVHD-related clinical disease activity and patient-reported symptoms and how these parameters are influenced by systemic and local therapies. Research in autoimmune disorders with clinical features similar to oral cGVHD, such as lichen planus, psoriasis, and to some extent Sjogren’s syndrome, may enrich the pathobiological understanding of these clinical issues as informed by GVHD-specific research. Clinical Management: Successes and Barriers Current Clinical Management No optimum treatment option exists for oral cGVHD, and the current focus is on disease management through reduction of immune-based damage to target tissues and symptom management. Patients may live with oral cGVHD and related negative sequelae for prolonged periods of time, thus making effective management essential. Disease management for oral cGVHD continues until immune tolerance between the host and the grafted immune system is achieved, and then specifically focuses on (1) healing of oral ulcerations, (2) relieving oral pain and sensitivity, (3) improving or maintaining salivary function, and (4) maximizing oral function. The report from the 2011 International Consensus Conference on clinical practice in cGVHD stressed the importance of a comprehensive treatment approach for oral cGVHD involving multidisciplinary teams who focus on operationalizing the treatment plan tailored to the specific type of oral cGVHD manifestation (61). Although the majority of patients with oral cGVHD are managed with systemic immunomodulatory medications, this disease often persists despite aggressive systemic therapy (62). Topical treatments provide symptom management that may be more readily achieved than disease resolution, thus placing importance on accurate patient adherence to treatment and accurate reported outcomes (63). Pain management is a critical component of overall management strategies, and topical anesthetics such as viscous lidocaine may be effective in reducing oral pain as well as oral sensitivity before eating, oral hygiene, or applying topical therapies (64). Systemic analgesics, including opioids, are used to manage clinically significant oral pain. Although oral cGVHD therapy is not always tested via randomized clinical trials, expert consensus and the literature describe use of high-potency topical steroids as standard treatment (14,62,64–67). Steroid gels are easily applied to distinct oral areas and are generally more effectively absorbed than creams or ointments. Tacrolimus ointment (Protopic 0.1% and 0.03% ointment, Astellas Pharma US, Deerfield, IL) has been found efficacious for oral mucosal cGVHD with maximum benefit seen with the 0.1% ointment, although it is associated with measurable systemic uptake (68–70). Rinsing with a steroid elixir is well tolerated and often more effective than gel applications, especially when symptoms and/or lesions are widespread throughout the oral cavity. Dexamethasone oral suspension (0.1 mg/mL) is the first line of oral topical therapy; however, reported clinical response rates are low, with 29–58% of patients reaching a partial or complete response in the first month (71,72). Although numerous treatments have been proposed, including topical azathioprine and cyclosporine, budesonide rinse, dexamethasone rinse, triamcinolone ointment, clobetasol ointment, CO2 laser, low-level laser, phototherapy with PUVA, and broad-band and narrow-band UVB therapy, results have been reported mainly through case studies or small series with variable results (68,69,71–85). Regularly scheduled dental evaluations are critical for patients with oral cGVHD because of risk for dental caries and second malignancies (86–88). Castellarin et al. (89) characterized extensive dental caries as a severe late complication of oral cGVHD and stressed that more prospective studies are needed to describe incidence of dental carries, identify risk factors, and test efficacy of preventive intervention. The oral/dental exam is also important to assess for squamous cell carcinoma, which has a well-known association with oral cGVHD (90). Genomic instability of mucosal cells may lead to malignant transformation, and a significant association between history of oral cGVHD and number of microsatellites showing this instability in oral mucosa has been reported (90). Evidence Gaps Regarding Current Clinical Management Comprehensive reviews of the current evidence base for oral cGVHD and related symptom treatment using single agent or combined topical agents all recognized the need to test agents through multi-site randomized controlled clinical trials with sufficient sample sizes, defined treatment outcomes, and valid and reliable oral cGVHD assessment tools (2,61,91,92). Although the oral cavity is a readily visualized site from which to assess the presence and severity of oral cGVHD and to monitor the effects of novel therapeutics, poorly defined inclusion and exclusion criteria and use of nonstandardized measurement tools have made comparison of efficacy and toxicity data between studies difficult. Clinical trials for oral cGVHD require consistently applied and interpreted criteria for pathological diagnosis if needed for confirmation (19). Clinical management is affected by false-negative histopathological assessment of oral cGVHD related to (1) suboptimal tissue sampling of oral ulceration and not adjacent intact mucosa, (2) performing labial biopsies that do not include enough glandular lobules to differentiate between active disease and damaged tissue, and (3) incorrectly sectioned samples (19). No standard treatment exists for cGVHD that recurs or fails to respond to initial therapy (93). Thus, a critical need exists to develop well-tolerated adjuvant therapies that are both efficacious and avoid the long-term consequences of systemic corticosteroid therapies (94). The majority of treatment strategies for oral cGVHD, including severe oral disease occurring in the presence of severe systemic disease and as the only focus of active disease, have not been evidence based, resulting in modest advances in evidence-based treatment. Clinical trials, as proposed by the NIH cGVHD Consensus Development Project, are needed to test novel agents for oral cGVHD that target therapy to active oral disease and avoid systemic effects. Consistent assessment of oral cGVHD across clinical trials and in clinical practice settings is a key component of the clinical research efforts targeted at elucidating the pathogenesis of this disease and the effect of investigational and routinely used agents. Clinical and Translational Research With Promise for Clinical Future Applications There is a paucity of reported clinical research focused on supportive care needs of patients with oral GVHD to support evidenced-based practice. The design of prevention or treatment protocols is dependent on understanding the immunobiology of both acute and cGVHD. As we learn more about the immune-based attack of GVHD on specific tissues, targeted prevention and management strategies should improve. Opportunities exist now to apply molecular-genetic techniques to elucidate underlying mechanisms of oral GVHD. Gene expression studies, mapping of gene pathways, genome-wide association studies, and epigenetic studies will ultimately provide greater understanding of environmental influences in this disease and guide therapeutic clinical research. Better Understanding of the Impact of Oral cGVHD Manifestations Management of oral cGVHD currently depends primarily on systemic therapy with adjunctive topical therapies for symptom control. Although this is a useful strategy, future clinical research strategies should also focus on the improved prevention and treatment of mucosal damage. It is not known why although oral lesions are most common in patients with extensive cGVHD, patients rarely may present with isolated disease involving only the oral cavity. Although there is some evidence that subclinical cGVHD diagnosed through skin or BM biopsy may predict subsequent development of cGVHD, timing and severity of oral findings are not currently useful to predict overall incidence, extent, or progression of systemic cGVHD (95). Currently, there are no reliable clinical signs or related symptoms that predict the clinical course of oral involvement. Descriptive and interventional clinical research is needed that explores potential symptom clustering of taste changes, oral pain, oral sensitivity, and oral dryness in relation to severity of oral manifestations. Weight loss and malnutrition are also clinically significant problems in this population, and the effect of oral cGVHD and related symptoms on these clinically challenging problems needs to be elucidated. Strategies to Advance the Science Scientific advancement in the field of oral cGVHD has been promoted through national and international interdisciplinary study groups that have been formed over the last few decades to systematically address the clinical and research challenges of oral cGVHD. Consensus reached by these study groups has articulated the importance of standardized definitions of disease manifestations and response criteria as well as common assessment tools. These groups have widely disseminated their recommendations for clinical care of the patient with oral cGVHD as well as results of clinical research focused on advancing the science of oral cGVHD. Foci of these efforts are numerous, including elucidating pathogenesis of oral cGVHD through exploration of immunological and inflammatory pathways; identifying biomarkers with diagnostic significance to make cGVHD treatment preemptive (29); exploring the diagnostic and prognostic value of biomarkers; testing psychometrics and clinical utility of assessment tools; testing efficacy of novel immunological agents through multi-site randomized controlled clinical trials; evaluating impact of oral cGVHD severity on the patient symptom experience and HRQL; and disseminating results of this work, which is often conducted in academic medical centers, into the community health care setting. Although the challenges of conducting randomized clinical trials in the cGVHD setting are recognized as often similar to other clinical settings–participant recruitment and retention, loss to follow-up, financial constraints—there has been a recent increase in interest in conducting preclinical and clinical studies in the oral cGVHD clinical setting (96). Much interest has been generated by the emerging therapeutics that are available or in the pharmaceutical pipeline, including the JAK family of nonreceptor tyrosine kinases (96). Funding for the conduct of clinical and translational research for oral cGVHD is critical to promote evidence-based practice supported by outcomes of rigorous randomized clinical trials vs treatment recommendations based on clinical experience of experts and small controlled trials (61). Funding Work in JWM's laboratory is supported by the Intramural Research Program of the NIH, NIDCR. Notes Affiliations of authors: Department of Professional Nursing Practice, Georgetown University School of Nursing & Health Studies, Washington, DC (JMFD); Experimental Transplantation and Immunology Branch, National Cancer Institute (SZP) and Division of Intramural Research, National Institute of Dental and Craniofacial Research (JWM), National Institutes of Health, Bethesda, MD; Department of Oral Medicine, University of Washington, School of Dentistry and Seattle Cancer Care Alliance and Oral Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA (MMS). J. Fall-Dickson, S. Pavletic, J. Mays, and M. Schubert have no conflicts of interest to declare. For support see Funding Acknowledgement section of Monograph. References 1 Treister N , Schubert MS , Fall-Dickson JM. Oral chronic graft vs host disease. In: Vogelsang GB , Pavletic SZ , eds. Chronic Graft-Versus-Host Disease: Interdisciplinary Management . New York : Cambridge University ; 2009 : 182 – 198 . 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JNCI MonographsOxford University Press

Published: Aug 1, 2019

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