Perspectives on oral chronic graft-versus-host disease from immunobiology to morbid diagnoses

Chronic Graft-versus-Host Disease (cGVHD) is a major long-term complication, associated with morbidity and mortality in patients following allogenic hematopoietic cell transplantation (HCT) for immune hematopoietic disorders. The mouth is one of the most frequently affected organs after HCT (45-83%) and oral cGVHD, which may appear as the first visible sign. Manifestations present with mucosal lichenoid lesions, salivary gland dysfunction and limited oral aperture. Diagnosis of oral cGVHD severity is based on mucosal lesions with symptoms of sensitivity and pain and reduced oral intake. However, diagnostic difficulties arise due to subjective definitions and low specificity to cover the spectrum of oral cGVHD. In recent years there have been significant improvements in our understanding of the underlying oral cGVHD disease mechanisms. Drawing upon the current knowledge on the pathophysiology and biological phases of oral cGVHD, we address oral mucosa lichenoid and Sjogren’s Syndrome-like sicca syndromes. We consider the response of alloreactive T-cells and macrophages to recipient tissues to drive the pathophysiological reactions and biological phases of acute inflammation (phase 1), chronic inflammation and dysregulated immunity (phase 2), and subsequent aberrant fibrotic healing (phase 3), which in time may be associated with an increased malignant transformation rate. When formulating treatment strategies, the pathophysiological spectrum of cGVHD is patient dependent and not every patient may progress chronologically through the biological stages. As such there remains a need to address and clarify personalized diagnostics and management to improve treatment descriptions. Within this review, we highlight the current state of the art knowledge on oral cGVHD pathophysiology and biological phases. We address knowledge gaps of oral cGVHD, with a view to facilitate clinical management and improve research quality on lichenoid biology and morbid forms of oral cGVHD

Dental health of patients with X-linked hypophosphatemia: A controlled study

ObjectiveThe present study compared the dental health of patients with X-linked hypophosphatemia (XLH) with healthy age- and gender-matched controls to increase our knowledge of the impact of XLH on oral health.Materials and methodsTwenty-two adult patients with XLH in the Stockholm region of Sweden were referred to the Department of Orofacial Medicine at Karolinska Institutet for an extended clinical and radiological examination. Pre-existing radiologic examinations of 44 healthy age- and gender-matched controls were retrieved from the Department of Oral Radiology, at Karolinska Institutet.ResultsThe 22 patients with XLH (15 females, median age 38 years, range 20–71; 7 males, median age 49 years, range 24–67) had a significantly higher number of root-filled teeth compared to healthy controls (p = .001). In the XLH group, females had significantly better oral health than males, especially concerning endodontic and cariological status (p's = .01 and .02, respectively). Periodontal status differed non-significantly between the XLH and control groups.ConclusionPatients with XLH had a significantly lower oral health status compared to a healthy population especially concerning endodontic conditions. Male patients with XLH had a higher risk of poor oral health compared to female patients with XLH

Conditioning associated effects on oral mucosa and salivary function in allogeneic stem cell recipients

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with a range of disorders of the immunohematopoietic system. In HSCT recipients, acute complications in the oral cavity are common. They are related to the disease itself, its treatment, the pre-transplant status of the oral cavity, and nutritional problems during the neutropenic phase. As the results of treatment improve and survival rates increase, not only cure of the disease but also a variety of delayed side effects become apparent that make the compromised patient require special oral care. In order to improve the patient’s quality of life, this problem must be solved. The aim of this thesis was to investigate conditioning related effects on salivary function and on the oral mucosa, and also the impact of other risk factors for salivary dysfunction and oral mucositis in allogeneic HSCT recipients. In patients conditioned with fractionated total body irradiation (fTBI) or singledose total body irradiation (sTBI), we found that fTBI resulted in less reduction of salivary secretion rate one year after HSCT than sTBI, despite the higher total dose of radiation. In addition, we found that risk factors for a low stimulated salivary secretion rate (SSSR) one year after HSCT were sTBI and seropositivity of recipients for 3–4 herpes viruses. A cumulative increase in risk factors resulted in less salivary output. We found no difference in long-term salivary function after HSCT in 15-yearolds who received conditioning with sTBI, fTBI, or busulfan (Bu). There was a negative correlation between age at conditioning with sTBI and salivary function. This correlation was not seen using fTBI or Bu. We also found a negative correlation between total systemic exposure to Bu and the SSSR. Female sex was a risk factor for salivary dysfunction at 15 years of age after HSCT. Comparing myeloablative conditioning (MAC) to reduced intensity conditioning (RIC), we found that MAC was associated with a higher prevalence of oral mucositis (OM). Severe OM prolonged hospitalization. The introduction of a new intensive oral hygiene protocol was associated with lower OM score and the two scoring systems used for grading of OM showed good correlation.We also identified several risk factors for OM. In multivariate analysis, all donor-recipient gender combinations except the female-donor-male-recipient situation and year of transplantation—especially before the year 2011 when oral care was intensified—was significantly associated with a higher OM score. In HSCT recipients, we found no difference in volume of gingival crevicular fluid (GCF) before, during, or after HSCT. When monitoring pro-inflammatory cytokines, we observed that cytokines are activated in the GCF. Patients conditioned with MAC or RIC had different patterns of pro-inflammatory cytokines, both in GCF and serum. There was a correlation between oral mucositis and an increase in IL-6 in the serum. Finally, we found no correlations between GCF and serum levels of cytokines at any time point. In conclusion, both acute and long-term oral side effects are common after allogeneic HSCT. There is a lack of comprehensive and effective oral management regimens. By developing evidence-based recommendations that might improve the appropriateness of clinical practice, the acute oral complications might be reduced, patient outcomes would be better, and cost-effectiveness and quality of life would improve. Our findings also suggest that it is necessary to have long-term follow-up after allogeneic stem cell transplantation because some children will have permanently reduced salivary function. These people may require additional preventive measures throughout their lives in order to maintain proper oral health

Oral mucositis after tacrolimus/sirolimus or cyclosporine/methotrexate as graft-versus-host disease prophylaxis

Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation. Subjects and methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day -3 to day 24 post-transplant. Results: Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found. Conclusions: The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate

Dental health of patients with X-linked hypophosphatemia : A controlled study

ObjectiveThe present study compared the dental health of patients with X-linked hypophosphatemia (XLH) with healthy age- and gender-matched controls to increase our knowledge of the impact of XLH on oral health.Materials and methodsTwenty-two adult patients with XLH in the Stockholm region of Sweden were referred to the Department of Orofacial Medicine at Karolinska Institutet for an extended clinical and radiological examination. Pre-existing radiologic examinations of 44 healthy age- and gender-matched controls were retrieved from the Department of Oral Radiology, at Karolinska Institutet.ResultsThe 22 patients with XLH (15 females, median age 38 years, range 20-71; 7 males, median age 49 years, range 24-67) had a significantly higher number of root-filled teeth compared to healthy controls (p = .001). In the XLH group, females had significantly better oral health than males, especially concerning endodontic and cariological status (p's = .01 and .02, respectively). Periodontal status differed non-significantly between the XLH and control groups.ConclusionPatients with XLH had a significantly lower oral health status compared to a healthy population especially concerning endodontic conditions. Male patients with XLH had a higher risk of poor oral health compared to female patients with XLH.Peer reviewe

Histopathological Grading of Oral Mucosal Chronic Graft-versus-Host Disease : Large Cohort Analysis

Graft-versus-host disease (GVHD) can manifest as acute or chronic complications in patients after hematopoietic cell transplantation (HCT). Oral chronic GVHD (cGVHD) occurs in approximately 70% of HCT recipients and includes lichenoid-like mucosal reactions, restricted mouth opening, and salivary gland dysfunction. However, the underlying histopathological presentation remains to be validated in large cohorts. We characterized the histopathological features of oral mucosal cGVHD and devised a scoring model in a large patient cohort (n = 112). Oral mucosal biopsy sections (n = 303) with and without oral cGVHD were identified from archived and current HCT recipients with additional healthy controls. Histological screening was performed on hematoxylin and eosinstained and periodic acid-Schiff-stained sections. A points-based grading tool (0 to 19, grade 0 to IV) was established based on intraepithelial lymphocytes and band-like inflammatory infiltrate, atrophic epithelium with basal cell liquefaction degeneration, including apoptosis, as well as separation of epithelium and pseudo-rete ridges. Validation involved 62 biopsy specimens, including post-HCT (n = 47) and healthy (n = 15) specimens. Remaining biopsy specimens (n = 199) were blindly graded by 3 observers. Histological severity was correlated with clinical diagnostic and distinctive features, demonstrating a spectrum of individual patient severity, including frequent signs of subclinical GVHD in healthy mucosa. However, oral cGVHD presented with significantly higher (P < .001) scores compared with HCT controls, with moderate to high positive likelihood ratios for inflammatory infiltrate, exocytosis, and basal membrane alterations. The grade II-IV biopsy specimens demonstrated a histopathological diagnosis of active mucosal lichenoid-like cGVHD, highlighting the importance of correlating clinical presentation with the dynamic histopathological processes for improved patient stratification. In addition, this tool could be used for assessing treatments, pathological processes, and immune cellular content to provide further insight into this debilitating disease

Grading of minor salivary gland immuno-histopathology post-allogenic hematopoietic cell transplantation

Objectives: The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) patho-physiology's. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0-16 points, Grade (G) 0 to IV). Second, a modified Sjo center dot gren's Syndrome focus-score with parenchymal damage was also adapted, (0-10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the his-topathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of "likely" sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclu-sions: Both schemes were verified as being suitable for histological grading to improve assess-ment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of "no/inactive", "possible" or "likely" cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD