Abstract
Oral chronic graft-versus-host disease (cGVHD) is a frequent, clinically significant sequela of allogeneic hematopoietic stem cell transplant (HSCT). This study was designed to elucidate relationships among clinical characteristics of oral cGVHD and related oral pain and oral dryness, salivary proinflammatory cytokine IL6 and IL1α concentrations, and health-related quality of life (HRQL). An understanding of the characteristics and correlates of oral cGVHD manifestations and related symptoms such as dryness is fundamental to the development of therapeutic interventions. Methods: Oral cGVHD severity was assessed with the Oral Mucositis Rating Scale (OMRS). Oral pain and perceived oral dryness intensity were self-reported via a visual analogue scale and a numeric rating scale respectively. HRQL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G). Salivary IL1α and IL6 concentrations were measured by enzyme-linked immunosorbent assay (R & D Systems, Minneapolis, MN). Results: All 42 adult subjects (male 59%) had clinician-assessed oral cGVHD by OMRS scale (mean = 18.38 ± 12.99; range = 2 to 46). Oral dryness (43%) (mean = 2.56 ± 3.45; range = 0 to 10) was more prevalent than oral pain (8%) (mean = 0.13 ± 0.47). Salivary IL6 was associated with oral cGVHD severity (r = .49; p < .01), oral ulceration (r = .38; p = .04), and erythema (r = .63; p < .01). FACT-G total, and physical and emotional well-being subscale scores were meaningfully lower than US population normative values. Participants with more severe oral cGVHD manifestations had significantly inferior social/family well-being (r = −.49; p < .01). Oral dryness was associated with higher salivary IL1α (r = .41; p = .04), and controlling for cGVHD severity, with lower health-related quality of life (r = −.41; p = .03). Subjects with moderate to severe oral dryness tended to report the poorest overall HRQL. This study provides preliminary evidence of the relationship between oral dryness and HRQL, the contribution of oral cGVHD to inferior HRQL, and the association between IL6 and oral cGVHD overall severity, ulceration and erythema. The high prevalence of oral dryness and its relationship to HRQL in a sample of patients with oral cGVHD underscores the importance of improving our evaluation and management of this symptom in long-term survivors of allogeneic HSCT. The positive association seen between IL6 and oral sGVHD overall severity, and erythema, as well as the positive trend seen with oral ulceration, warrant further exploration of this cytokine as a potential biomarker of active oral cGVHD.
Keywords: Oral Chronic Graft-versus-Host Disease, Symptoms, Quality of Life
INTRODUCTION
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) (1-4) and results from an exaggerated inflammatory mechanism as donor lymphocytes encounter foreign antigens on host cells and mount an inflammatory reaction. Approximately 50% of patients who undergo allogeneic HSCT develop cGVHD (5), with increasing incidence related to lower transplant-related mortality and changing HSCT utilization patterns (1). Approximately 45% of patients with cGVHD live with these late treatment effects for a prolonged period of time (1), and our limited knowledge of their supportive care needs impedes delivery of quality care.
Animal and human models suggest that the underlying immunologic mechanisms of cGVHD include: (a) donor-derived alloreactive T lymphocytes; (b) autoreactive T-lymphocytes that evade thymic deletion (6,7); (c) alterations in absolute numbers, ratios or kinetics of lymphocyte subpopulations (8,9) such as regulatory T lymphocytes (10,11,12,13,14); and (d) dysregulated cytokine expression (15,16,17). Elevations in interleukin 6 (IL6) IL1β, IL1α, IL1 receptor antagonist, tumor necrosis factor alpha (TNFα), soluble TNF-receptor II, monocyte chemoattractant protein-1, and soluble B cell activating factor are associated with autoimmune or chronic inflammatory diseases that clinically parallel cGVHD (18,19,20,21,22,23,24,25). Several of these immune activity mediators are candidate biomarkers of cGVHD activity (15, 16).
Approximately 80% of patients with cGVHD have oral involvement including tissue atrophy and edema, erythema, lichenoid changes, and oral ulcerations. Xerostomia, immunosuppressant side effects, and viral or fungal infection can exacerbate the severity of discomfort caused by oral cGVHD (4, 26, 27) (Figure 1). Significant reduction in stimulated submandibular and sublingual gland saliva flow rates is observed in cGVHD patients (28). A decrease in salivary volume results in decreased salivary immunoglobulin secretion (IgA, IgG, and EGF) (28) which may place the patient at risk for infection.
Figure 1.
Erythema, and ulceration/pseudomembrane in an oral cGVHD patient.
Chronic GVHD-related oral pain is prevalent (4, 27), and may occur in association with oral ulceration(s). Chronic GVHD-related xerostomia, oropharyngeal pain, and heightened oral sensitivity may also contribute to decreased nutritional intake and weight loss (29). Although candidate serum biomarkers of cGVHD are being actively explored (17), little is known about cytokine expression in oral tissues involved with cGVHD. Exploration of oral tissue cytokine milieu could yield important insights into the pathobiology of oral cGVHD and inform the rational development of targeted interventions.
Observational studies have demonstrated that patients with cGVHD experience impairments in health status and health-related quality of life (HRQL) (1, 30,31). The extent to which oral cGVHD is a contributor to these impairments is unknown. Xerostomia induced by radiation therapy has a significant negative impact on HRQL in patients with head and neck cancer (32, 33, 34) and lymphoma (35, 36). However, the relationship between oral cGVHD-related symptoms and HRQL has not been examined. Patients with oral cGVHD may live the remaining years of their lives with this disease, thus making effective management essential.
In this descriptive study we examined the oral symptom experience, health-related quality of life (HRQL), and salivary proinflammatory cytokines in a sequentially accrued cohort of patients (N = 42) with oral cGVHD. The specific aims of this study were to describe: i) clinical characteristics of oral cGVHD; ii) cGVHD-related perceived oral dryness and oral pain intensity; iii) HRQL; iv) concentrations of salivary IL6 and IL1α; and e) associations between characteristics of oral cGVHD, oral dryness, HRQL, and salivary cytokine expression. Elucidating components of the symptom experience of patients with oral cGVHD, as well as their associations with HRQL and the cytokine milieu, is a preliminary step in designing studies to test novel treatments and supportive care strategies for this oral disease (37).
MATERIALS AND METHODS
This study analyzed cross-sectional data from a sequentially accrued subsample of patients with oral cGVHD who were participants enrolled in the National Cancer Institute (NCI) sponsored cGVHD Natural History Protocol, “Prospective Assessment of Clinical and Biological Factors Determining Outcomes in Patients with cGVHD” (clinicaltrials.gov #NCT00331968). The study was approved by the NCI Institutional Review Board, National Institutes of Health (NIH). Patients were referred by their primary transplant physician for evaluation by the NIH cGVHD Study Group. Written informed consent was obtained from all participants. Oral examination was performed to confirm oral cGVHD diagnosis, and self-reported oral pain and oral dryness data were obtained by the study dentist (J P-G) during one protocol visit in the Dental Clinic, Clinical Center, NIH. Stimulated submandibular/sublingual saliva samples were also obtained at this visit. Submandibular/sublingual saliva samples were also obtained from a comparison sample of healthy adult volunteers (mean age = 43.74 (range = 21 to 72); male 57%; n = 31). Using standardized criteria, a summative cGVHD severity score was derived based on a clinical and diagnostic evaluation of multiple organ systems including the skin, mouth, eyes, liver, lungs and gastrointestinal systems, as well as functional capacity, and gynecologic disease manifestations in women (38). The Functional Assessment of Cancer Therapy-General (FACT-G) (44) was completed within ± 48 hours of the Dental Clinic visit.
Research Instruments
Oral cGVHD Characteristics
The Oral Mucositis Rating Scale (OMRS) was constructed through selection of clinical descriptors of oral mucosal changes following bone marrow transplantation (39), and was found to be reliable and valid in classifying oral changes related to cGVHD (27). The tool divides the oral cavity into seven distinct anatomic areas: lips (upper and lower); labial mucosa (upper and lower); buccal mucosa (right and left); tongue (dorsal, lateral, ventral); floor of mouth; palate (hard and soft); and attached gingiva. These 13 oral cavity areas are clinician-assessed for erythema, atrophy, hyperkeratosis, lichenoid changes, and edema, and rated on a scale of 0 to 3 for these oral tissue changes as compared to normal oral tissue (0 = normal/no change; 1 = mild change; 2 = moderate change; 3 = severe change). The extent of ulceration/pseudomembrane is estimated based on the surface area involved (0 = none; 1 = > 0 but ≤ 1cm2; 2 = > 1cm2, but ≤ 2cm2; and 3 = > 2cm2). The total score is the sum of all OMRS items with a possible range of 0 to 273.
Oral Symptom Intensity
Current oral pain intensity was reported by subjects using a 10 cm visual analogue scale (VAS) anchored with 0 = “no pain” to 10 = “worst possible pain” (40). In past research, high test-retest reliability for the VAS has been demonstrated (40). Current oral dryness intensity was measured using a verbally administered 10 cm numeric rating scale consisting of a 1-item, 11 point scale with the anchors measuring extremes of the oral dryness continuum (0 = “no dryness” and 10 = “worst possible dryness”). A written numeric rating scale has been shown to be valid in the measurement of dyspnea (41), and has shown evidence of reliability, validity, and responsiveness for pain assessment (42).
Health Related Quality of Life
Health-related quality of life was measured with the FACT-G version 4 (43). The 27 items evaluate aspects of physical, social/family, emotional and functional well-being on a scale of 0 = “not at all” to 4 = “very much”. Scores are summed for a total FACT-G score with a possible range of 0 to 108. Four subscales - physical well-being; social/family well-being; emotional well-being; and functional well-being - are included within the FACT-G. Higher total FACT-G and subscale scores indicate better HRQL and better well-being within these domains. Normative values for the general US population and for adults with cancer are available to aid interpretation (44). A 2-point difference in the FACT-G subscale scores and a 5-point difference in the FACT-G total score represent the minimum clinically important difference (44). More than 50% of the items on the FACT-G assess symptoms, underscoring the importance of symptoms within the HRQL experience. Evidence of reliability and construct validity for the FACT-G has been demonstrated across a wide range of chronically ill populations (43, 45, 46).
Saliva Sample Collection, Processing, and Analysis
Submandibular/sublingual saliva was stimulated by the bilateral application of 2% citric acid to the tongue using a cotton-tipped swab. After isolation of the parotid gland with cotton gauze, saliva was suctioned from the sublingual area for a total of one minute, with 30-second intervals between applications. The saliva was then put into 1.5 ml polypropylene microcentrifuge tubes on ice, and transported to the research laboratory. Saliva was aliquoted to 300μl samples in 0.6 ml tubes which were stored at −80°C. The saliva was thawed to room temperature, centrifuged at 4000rpm for 10 minutes at 4°C, and supernatant was retained. Salivary concentrations of IL1α and IL6 in both subjects and healthy volunteers were measured by enzyme-linked immunosorbent assay (ELISA) (R & D Systems, Minneapolis, MN).
STATISTICAL ANALYSIS
Descriptive statistics were used to characterize the demographic and clinical profile of the sample. The strength and direction of linear relationships between total OMRS score and clinical characteristics, oral dryness intensity, FACT-G and subscale scores, and salivary cytokine concentrations were assessed with Pearson Product Moment Correlations. Significance of the correlation between oral dryness and FACT-G was tested controlling for the overall severity of cGVHD. Significance was established as p < .01 to accommodate an adjustment for multiple comparisons. The Exact Wilcoxin Two-Sample Test was used to test for differences in oral dryness and HRQL between subjects with and without opioid use. Scatter plots were used to evaluate oral dryness and HRQL data by symptom intensity for linear and non-linear trends (Figure 2). Data were analyzed with SAS 9.1.3 (47).
Figure 2.
Scatterplots of Individual Scores of the A) Functional Assessment of Cancer Therapy-General (FACT-G) Total version 4; and B) FACT-G Physical (PWB), Emotional (EWB), Social (SWB), and Functional (FWB) Well-Being Subscales by Oral Dryness Classified as None (0), Mild (1-3), Moderate (4-6) or Severe (7-10). N = 29. Higher FACT-G total scores (range 0-108) and higher PWB, SWB, FWB and EWB scores represent better health-related quality of life.
RESULTS
Demographic Characteristics
Subjects (N = 42) ranged in age from 22 to 61 years with a median age of 48.5 years (Table 1). The majority were male (59%) and Caucasian (88%). Subjects had a median of 36.9 months (range 5-201) from peripheral blood stem cell (94%) or bone marrow (7%) transplantation, used primarily to treat a hematologic malignancy (Table 2). A median of 11 months (range 1-196) had elapsed since participants had received their cGVHD diagnosis (Table 2). Subjects had predominantly moderate (47%) or severe (50%) cGVHD per the NIH cGVHD Global Rating, with a median of three organ systems involved (range = 1-6) (Table 2). Approximately two thirds of the sample was receiving moderate or high levels of systemic immunosuppression (Table 2) Nineteen patients were receiving one or more systemic opioids, including oxycodone (n=13), oxycontin (n=4), methadone (n=2), and percocet (n=1), morphine (n=1), transcutaneous fentanyl (n=1), acetaminophen with codeine (n=1), and dilaudid (n=1).
Table 1.
Clinical and Demographic Characteristics of the Sample (N=42)
| N | % | Mean(SD) | Median | Range | |
|---|---|---|---|---|---|
| Age | 42 | 46.1(12.4) | 48.5 | 20-62 | |
| Gender | |||||
| Male | 25 | 60% | |||
| Female | 17 | 40% | |||
| Race | |||||
| Caucasian | 38 | 90% | |||
| Non-Caucasian | 4 | 10% | |||
| Marital Status | |||||
| Single | 8 | 19% | |||
| Married | 28 | 67% | |||
| Divorced/Widowed/Separated | 6 | 14% | |||
| Diagnosis | |||||
| Acute leukemia/myelodysplastic syndrome | 15 | 36% | |||
| Chronic leukemia/lymphoma | 18 | 43% | |||
| Multiple myeloma | 6 | 14% | |||
| Other | 3 | 7% | |||
| Conditioning | |||||
| Myeloablative | 17 | 40% | |||
| Reduced intensity | 25 | 60% | |||
| Donor type | |||||
| Related | 34 | 81% | |||
| Unrelated | 8 | 19% | |||
| Stem cell source | |||||
| Bone marrow | 8 | 19% | |||
| Peripheral blood | 33 | 79% | |||
| Unspecified | 1 | 2% | |||
| Karnofsky Performance Scale | |||||
| <50 | 2 | 5% | |||
| 50-60 | 2 | 5% | |||
| 70-80 | 26 | 62% | |||
| <80 | 12 | 28 | % |
Table 2.
Chronic Graft-Versus-Host Disease Characteristics of the Sample
| n/N | % | Mean (SD) | Median | Range | |
|---|---|---|---|---|---|
| Time since transplant (months) | 38.6 (46.2) | 36.9 | 5-201 | ||
| Time since cGVHDa diagnosis (months) | 30.9 (44.3) | 11 | 1-196 | ||
| cGVHD onset | |||||
| De novo | 18/42 | 43% | |||
| Quiescent | 6/42 | 14% | |||
| Progressive | 18/42 | 43% | |||
| NIH cGVHD Global Rating | |||||
| Mild | 1/40 | 2% | |||
| Moderate | 19/40 | 48% | |||
| Severe | 20/40 | 50% | |||
| Organ systems involved with cGVHDb | |||||
| Oral | 42/42 | 100% | |||
| Skin | 30/40 | 75% | |||
| Ocular | 29/40 | 73% | |||
| Gastrointestinal Tract | 15/40 | 38% | |||
| Liver | 23/40 | 58% | |||
| Lungs | 14/40 | 35% | |||
| Joints/Fascis | 17/40 | 43% | |||
| Genital (women only) c | 9/16 | 56% | |||
| Number of organs (other than oral) involved with cGVHD | 3.4 (1.4) | 3 | 1-6 | ||
| Platelets < 100,000 | 4/42 | 9% | |||
| Platelets > 100,000 | 38/42 | 91% | |||
| Intensity of immunosuppression | |||||
| None | 9/42 | 21% | |||
| Mild (single agent prednisone < 0.5 mg/kg/day) |
4/42 | 10% | |||
| Moderate (single agent prednisone ≥ 0.5 mg/kg/day, or single agent/modality ± prednisone ≥ 0.5 mg/kg/day) |
16/42 | 38% | |||
| High (two or more agents/modalities ± prednisone ≥ 0.5 mg/kg/day) |
13/42 | 31% |
cGVHD = Chronic graft-versus-host disease;
NIH scores are missing for two patients who enrolled into the cGHVD Natural History Protocol before scoring system implementation;
One woman declined gynecological exam.
Oral cGVHD, Oral Symptoms, and HRQL
Our sample of patients with oral cGVHD had erythema (91%), lichenoid changes (72%), and ulceration (56%) (Table 4). Oral dryness (43%) (mean = 2.56 ± 3.45; range = 0 to 10) was more prevalent than oral pain (8%) (mean = 0.13 ± 0.47) (Table 3). Previous acute GVHD had little association with oral dryness (r =0.16; p = .03). Subjects receiving opioids did not have significantly greater oral dryness (Exact Wilcoxon Two-Sample Test, p = .71) or more impairment in HRQL (p = .85) compared to those who were not receiving these agents. No other demographic factors were associated with oral dryness. FACT-G scores and all subscale scores were below the US norm data, with the exception of social/family well-being scores (Table 3).
Table 4.
Associations Among Oral cGVHD Severity, Health-Related Quality of Life, and Salivary Cytokine Concentrations (n = 30)
| Variable | OMRSa | Lichenoid | Erythema | Ulceration | Oral Dryness |
IL1αSg | IL6S | FACT-Gb | PWBc | SWBd | EWBe | FWBf |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age | −0.08425 | 0.148605 | −0.00897 | 0.083346 | −0.35519 | −0.06659 | 0.223991 | 0.357699 | 0.20507 | 0.345739 | 0.4087* | 0.267128 |
| OMRS | 1 | 0.52971** | 0.92127*** | 0.61427** | 0.190347 | 0.126738 | 0.494027** | −0.30353 | 0.021231 | −0.49221** | −0.24163 | −0.30822 |
| Lichenoid | 1 | 0.360538* | 0.507305** | 0.060984 | −0.34064 | 0.195994 | −0.07682 | 0.053615 | −0.17345 | 0.043233 | −0.15849 | |
| Erythema | 1 | 0.545079** | 0.18994 | 0.279536 | 0.628402** | −0.20068 | 0.01839 | −0.31585 | −0.16786 | −0.21075 | ||
| Ulceration | 1 | 0.259602 | −0.02234 | 0.378025* | 0.009007 | 0.296871 | −0.30228 | 0.17447 | −0.10633 | |||
| Oral Dryness | 1 | 0.407659* | 0.305972 | −0.4114* | −0.4207* | −0.3998* | −0.36535 | −0.2007 | ||||
| IL1αSg | 1 | 0.333071 | −.18558 | −0.24574 | −0.13323 | −0.26923 | 0.034808 | |||||
| IL6Sh | 1 | −0.03401 | 0.077317 | −0.16336 | 0.00009 | −0.02881 |
01 ≤ p < .05;
p < .01;
p < .001;
Prob > |r| under H0: Rho=0
OMRS = Oral Mucositis Rating Scale;
FACT-G = Functional Assessment of Cancer Therapy-General;
PWB = Physical Well-Being;
EWB = Emotional Well-Being;
FWB = Functional Well-Being;
SWB = Social/Family Well-Being;
ILlαS = interleukin1 alpha concentration in submandibular/sublingual saliva;
IL6s = interleukin 6 concentration in submandibular/sublingual saliva.
Table 3.
Oral Mucositis, Oral Symptoms, and Quality of Life Scores (N = 42)
| Variables | Subscale/Domain | Mean (SD) | Median | Range |
|---|---|---|---|---|
| Oral Mucositis | 18.38 (12.99) | 12 | 2 - 46 | |
| Rating Scale | ||||
| Erythema | 6.19 (4.75) | 5 | 0 - 17 | |
| Lichenoid Changes | 3.45 (3.27) | 3 | 0 - 12 | |
| Ulceration/ Pseudomembrane |
1.83 (2.55) | 1 | 0 - 11 | |
| Oral Pain Visual | 0.13 (0.47) | 0 | 0 - 2 | |
| Analogue Scale | ||||
| Oral Dryness Numeric Rating Scale |
2.56 (3.45) | 0 | 0 - 10 | |
| Functional Assessment of Cancer Therapy- General (n=40) |
74.22 (19.30) | 74.5 | 17-104 | |
| Physical Well-Being | 18.08 (6.77) | 6 - 27 | ||
| Emotional Well-Being | 17.83 (4.84) | 2 - 24 | ||
| Functional Well-Being | 17.15 (6.79) | 3 - 28 | ||
| Social/Family Well-Being | 20.97 (6.50) | 4 - 28 |
Oral Mucositis Rating Scale (OMRS) score range = 0-273. Higher OMRS scores denote more severe oral chronic graft-versus-host disease. Oral pain visual analogue scale score range = 0-10; oral dryness numeric rating scale range = 0-10. Higher oral pain and oral dryness scores denote more severe symptoms. Functional Assessment of Cancer Therapy-General (FACT-G) version 4 possible score range = 0 - 108. Physical well-being (PWB), social/family well-being (SWB), and functional well-being (FWB) subscales have score ranges of 0-28; and emotional well-being (EWB) subscale has a score range of 0-24. Higher subscale scores indicate better physical, social/family, emotional, and functional well-being. FACT-G scores greater than 80.1, PWB scores above 22.7, SWB scores above 19.1, EWB scores above 19.9, and FWB scores above 18.5 are interpreted as above the general United States (US) adult population norm data (N ~ 1600) (49). FACT-G scores greater than 80.9, PWB scores above 21.3, SWB scores above 22.1, EWB scores above 18.7, and FWB scores above 18.9 are interpreted as above the US adult patients with cancer norm data (N = 2226) (49).
Salivary Cytokine Concentrations
Despite the presence of oral dryness, 31 (73%) of subjects were able to produce an adequate amount (≥400μL) of stimulated submandibular/sublingual saliva for ELISA analysis. In submandibular/sublingual saliva, mean IL1α concentration was 85.2 pg/mL (median = 68; range = 13 to 250; n = 29), and mean IL6 concentration was 2.48 pg/mL (median = 1.29; range = 0.100 to 10; n = 29). In submandibular/sublingual saliva of healthy volunteers, mean IL1α concentration was 31.97 pg/mL (range = 6 to 48.7; n = 23), with 20/23 values below the assay detection limit of 3.9 pg/mL. Mean IL6 concentration in submandibular/sublingual saliva of healthy volunteers was 0.93 pg/mL (range = .08 to 5.14), with 11/23 values below the assay’s detection limit of 0.156 pg/mL. When the salivary IL6 or the IL1α levels were not detectable by the ELISA assay kit, the lowest detectable level was used. There were statistically significant differences between the subjects’ and healthy volunteers’ submandibular/sublingual saliva IL1α concentrations (p < .05) and IL6 concentrations (p < .001).
Associations Among Oral cGVHD, Oral Dryness, HRQL, and Salivary Cytokines
Total OMRS score had a low negative association with the social/family well-being subscale of the FACT-G (r = −0.49; p =< .01) (Table 4). IL6 had a low positive association with OMRS (r= .49; p < .01) and a moderate positive association with erythema (r = 0.63, p < .01), and a positive trend was seen with oral ulceration (r = .38; p = .04). However, no association was found between clinician-assessed erythema, lichenoid, or ulcerative cGVHD manifestations and FACT-G total or subscale scores. Oral pain was not included in the association analysis because only three subjects had oral pain greater than 0. Oral dryness had a low positive association with IL1α (r = 0.41; p = .04). Oral dryness was also associated with lower total FACT-G scores (r = −.41; p = .03) and with lower physical well-being (r + −0.42; p = .03) and lower social/family well- being (r = −0.40; p = .04), at trend levels. Scatter plots (Figure 2) showed that subjects with moderate to severe oral dryness tended to report the lowest HRQL. The association between oral dryness and impaired HRQL remained when cGVHD severity was controlled in the analysis (p=.03).
DISCUSSION
This study described clinical characteristics and severity of oral cGVHD, prevalence and intensity of related oral pain and oral dryness, salivary IL6 and IL1α concentrations, HRQL, and associations among these findings in a sample of adult patients diagnosed with oral cGVHD. Clinician-assessed oral cGVHD characteristics and patient reported symptoms were studied separately as recommended by the NIH cGVHD Study Group Response Criteria Working Group Report (48). Accurate assessment of cGVHD oral lesions is critical in both clinical research and practice settings because these lesions may be the only observed indicator of cGVHD, and are a highly predictive index of the presence of systemic cGVHD (49). The low association observed in this sample between oral cGVHD severity and oral dryness underscores the importance of objective clinical evaluation of oral cGVHD clinical characteristics.
Although more than 50% of the subjects had oral ulceration(s) present, only two subjects with oral ulcers reported oral pain. Possible explanations for these results include cross sectional assessment of oral pain without swallowing, accommodation to the symptom experience in chronically ill patients, and use of opioids. Oral sensitivity was not assessed in this study and would be a useful addition to future symptom research in patients with oral cGVHD. Although prescribed medications may have contributed to perceived oral dryness in this sample, subjects receiving opioids did not have significantly greater perceived oral dryness compared to those who were not receiving these agents. Oral dryness is also accompanied by a decrease in factors available to protect the oral mucosa (28) and maintain oral cavity homeostasis (50). The negative trends seen between oral dryness and overall HRQL, physical well-being and social/family well-being, as well as the trend of an association between dryness and higher IL1α, should be explored in a larger sample. Cytokines play a dynamic role in regulating and modulating immunologic and inflammatory processes (51) via cooperative networks that control normal physiologic activity and disease-related threats to homeostasis. The positive association seen between erythema and salivary IL6, an essential mediator of inflammatory response to localized mucosal inflammation (51, 52), should be evaluated empirically as a potential biomarker of oral cGVHD activity and severity. Associations between oral cGVHD severity and IL6 gene polymorphisms have been previously reported (53). Significant redundant functionality and temporality exist with cytokines such that no single cytokine is likely to be responsible for controlling a specific cellular function or physiologic process (51). Therefore, exploration of the cytokine pathways and crosstalk involved in the pathogenesis of oral cGVHD should be explored to elucidate pathogenesis of oral cGVHD and molecular mechanisms of related symptoms (53, 54, 55). To date, few studies have examined candidate biomarkers of organ-specific disease activity in cGVHD, including disease activity in the oral cavity. Saliva is easy to procure during clinic visits, and salivary cytokine profiles may also offer a marker of overall cGVHD activity because oral manifestations are often associated with the presence of systemic cGVHD presenting in the eye, liver, and skin (17).
Although studies have described HRQL in HSCT survivors without cGVHD (56), the impact of cGVHD on HRQL has not been well characterized in the published literature (57). Our sample reported FACT-G scores and physical well-being subscale scores below both general US adult and adult cancer population normative values, and emotional well-being subscale scores below US norm data (44) (see Table 4). The fact that these differences exceeded the threshold of minimally important difference of 2 points on the subscale scores and 5 points on the FACT-G (49) suggests that these differences may be clinically meaningful.
Although generalization of these results is limited by the small sample size drawn from a single institution, the high prevalence of oral dryness (43%) observed in our sample is in accord with previous research. Our observation that oral cGVHD severity was negatively associated with social/family well-being, and the trends observed between oral dryness and inferior physical well-being and social/family well-being deserve further exploration in larger, prospective samples. However, that the association between oral dryness and inferior HRQL remained even when overall cGVHD severity was controlled, suggests that oral cGVHD and its symptoms may contribute to impairments in HRQL, and this hypothesis should be empirically tested using longitudinal or comparative designs.
This study also elucidates the association between immunobiology of oral cGVHD and the patient symptom experience. Examining relationships among clinician-assessed characteristics of oral cGVHD, related oral symptoms, HRQL, and the local proinflammatory cytokine milieu is critical to improve our understanding of the pathobiology and sequelae of this oral disease. Although candidate serum biomarkers of cGVHD are being actively explored (17), continued study of the oral tissue cytokine milieu and its association with clinician-assessed and patient reported features of oral cGVHD is needed to inform the rational development of targeted interventions to test in clinical trials.
Acknowledgements
The authors thank Dr. Mary E. Kerr, National Institute of Nursing Research (NINR), National Institutes of Health, and Dr. Joan K. Austin, Indiana University School of Nursing, for useful discussions regarding manuscript development. Also thanked are Dr. Matin Imanguli, DDS, formerly Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI) for saliva sample acquisition, and Sherri Gollins, BS, and Sharon Mitchell, National Institute of Dental and Craniofacial Research (NIDCR), NIH for assistance with the saliva collection. Dr. Gabor Illei, NIDCR, NIH, is thanked for submandibular/sublingual saliva samples from healthy volunteers. We also acknowledge with gratitude the subjects in the NCI-sponsored Chronic Graft-versus-Host Disease Natural History Protocol (clinicaltrials.gov #NCT00331968).
Footnotes
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Contributor Information
Jane M. Fall-Dickson, Mucosal Injury Unit, Symptom Management Branch National Institute of Nursing Research National Institutes of Health.
Sandra A. Mitchell, Nursing Research and Translational Science Clinical Center, National Institutes of Health.
Susan Marden, Office of Extramural Programs, National Institute of Nursing Research National Institutes of Health.
Edward S. Ramsay, National Institute of Nursing Research, Symptom Management Laboratory National Institutes of Health.
Jean-Pierre Guadagnini, Dental Service, National Institute of Dental and Craniofacial Research National Institutes of Health.
Tianxia Wu, Center for Information Technology National Institutes of Health.
Lena St. John, National Institute of Nursing Research, Symptom Management Laboratory National Institutes of Health.
Steven Z. Pavletic, NIH Chronic GVHD Study Group Experimental Transplantation and Immunology Branch, National Cancer Institute National Institutes of Health.
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