Time to onset of bisphosphonate-related osteonecrosis of the jaws: a multicentre retrospective cohort study.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American­European Consensus Group (AECG) criteria, a model-based "gold standard"obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

The effect of quitting smoking on the risk of unfavorable events after surgical treatment of oral potentially malignant lesions.

The aim of this study was to examine if cessation of smoking after surgical excision of oral potentially malignant lesions in smokers reduced the risk of recurrences, development of new lesions or malignancies. 51 patients with oral leukoplakia or erythroplakia were included. They were daily smokers at the time of diagnosis and were treated surgically. Patients were advised to quit smoking at each visit. The change of smoking habits and occurrence of unfavorable events were noted during follow-up. Descriptive statistics, Fischer's exact test, Kaplan-Meier curves with log-rank test, and Cox proportional hazards model were used for analysis. 16 patients (31%) quit smoking during the observation period. Only one quitter (6%) developed recurrence compared with 11 continuing smokers (33%) (p<0.05). There were no new lesions and no malignancies among quitters compared with 8 new lesions (p<0.05) and 5 carcinomas (p>0.05) in continuing smokers. Multivariate analysis showed continuing smoking to be the most significant factor for occurrence of unfavorable events, OR 23.7. In conclusion, cessation of smoking significantly reduced the risk of unfavorable events after surgical treatment of oral potentially malignant lesions in smokers.

Host pathogen interaction and the development of oral lesions.

The aetiologies of oral ulceration, disseminated interstitial lymphocytosis syndrome and oral lymphomas have been reviewed, with emphasis on the role of HIV infection in the primary causation or modification of the presentation of these entities. There is a paucity of evidence to explain why oral ulceration is so severe in HIV infection, and why major ulceration affects the oropharynx. A number of mechanisms have been proposed to account for the development of lymphomas in patients with HIV infection, including a genetic predisposition, decreased immunosurveillance due to HIV infection, alteration of endothelial cell function and dysregulation of cytokine networks. From this review, it was concluded that there is a need for a prospective multicentre study, to elucidate the aetiological mechanisms involved in lymphomas of the oral regions in this patient group. It was concluded that, although there is anecdotal evidence implicating tobacco use in the aetiology of the lesions reviewed, this is insufficient to allow definitive statements to be made and further systematic evaluation is indicated.

Periodontal disease in primary Sjögren's syndrome.

UNLABELLED: Occurrence of periodontal disease in Sjögrens's syndrome (SS) is still controversial. OBJECTIVE: To examine if the risk of gingival and periodontal conditions was increased in SS compared to the general population. MATERIALS AND METHODS: Fifty-seven patients (4 men, 53 women) with primary Sjögren's syndrome (Copenhagen criteria) and an age-matched representative sample of the general population of 80 controls (all women) were examined for gingival and periodontal disease. RESULTS: Gingival bleeding and supra-gingival calculus did not differ among SS patients and controls. Subgingival calculus occurred more often among the younger SS patients than controls, but did not differ among the older SS patients and controls. Periodontal pockets of 4-5 mm as well as pockets > 5 mm occurred with similar prevalences among the two groups. Smoking habits did not influence the results. The health status of the gingival and periodontal tissues were thus similar in SS and controls. CONCLUSION: Primary SS is not associated with increased risk of periodontal disease.

Rational drug therapy recommendations for the treatment of patients with Sjögren's syndrome.

The aetiology of Sjögren's syndrome (SS) is unknown, and consequently curative treatments are not available. The immunopathogenesis of SS is partly clarified and immune-regulating drugs (IR) may therefore be of therapeutic value. However, the present understanding of SS is still too unclear to allow an exact and evidence-based algorithm for therapeutic decision making. Rational drug recommendations for the therapy of SS must, therefore, rely mostly on empirical data. Several IR drugs have been shown to be able to downregulate the immunopathological activity of primary SS, but it is not certain whether the diagnostic and cardinal manifestations from the eyes and mouth can be improved. In primary SS the disease-modifying qualities of IR and cytotoxic drugs, therefore, largely apply to the treatment of severe internal organ involvement, inflammatory vascular disease and malignant B lymphocyte disease. In secondary SS the IR therapy is directed against the basic immunoinflammatory connective tissue disease. Symptom-modifying therapies include drugs to stimulate and substitute for exocrine functions, and drugs to treat complications of the exocrine disease manifestations and to improve the various nonexocrine disease manifestations. The main drugs available for increasing lacrimal and salivary gland output are bromhexine and pilocarpine, respectively. However, exocrine substitutes, and in particular eye drops, are still the most important means of alleviating the sicca symptoms. They are also indispensable local treatment measures which may help to prevent mucosal complications.

Can alterations in integrin and laminin-5 expression be used as markers of malignancy?

Development of squamous cell carcinomas (SCCs) involves alterations in the adhesive interactions in the epithelium and invasion through the basement membrane. Therefore, changes in the expression of receptors and ligands involved in cell-cell and cell-matrix adhesion may be essential for the transformation of a premalignant into a malignant lesion. The aim of this study was to examine if expression of specific cell adhesion molecules can be used as markers of malignant development. By immunohistochemistry, we examined the expression pattern of integrins alpha2beta1, alpha3beta1, alpha6beta4 and laminin-5 in biopsies from SCCs (n=18), premalignant lesions (leukoplakias, n=21) and non-premalignant tissue with chronic inflammation (n=11). In poorly differentiated SCCs, patchy loss of alpha3beta1, alpha6beta4 and laminin-5 expression was pronounced at the invasion front, whereas there was a tendency to increased expression of alpha2beta1. Analogous to the SCCs, biopsies from the leukoplakias and the non-premalignant inflammatory tissue showed alterations of the expression of alpha3beta1 and alpha6beta4 in the basal cell layers and of laminin-5. However, a characteristic finding in biopsies from leukoplakias was loss of alpha2beta1 and alpha3beta1 in the suprabasal cells. There was no unequivocal expression of the adhesion molecules distinguishing between inflammatory tissue, premalignant, and malignant lesions.

Less common oral lesions associated with HIV infection: prevalence and classification.

This paper deals with a number of group II and III lesions, ie lesions definitely but less commonly, and lesions possibly associated with HIV infection, respectively. Salivary gland disease includes dry mouth and/or swelling of major salivary glands, often as a part of CD8-lymphocytosis syndrome. Xerostomia occurs commonly (2-10%) in HIV-infected individuals. Enlargement of the major salivary glands occurs frequently (19%) among HIV-infected children, but rarely among adults (0.8%). The major salivary glands show lymphoepithelial lesions or cysts histopathologically. Hyperpigmentation of the oral mucosa was found in 2.2% of 1710 HIV+ individuals in seven studies. The hyperpigmentation has been ascribed to a number of medicaments, and possibly to HIV. The prevalence of pigmentation is not significantly higher among HIV+ than HIV- individuals. Thrombocytopenia frequently occurs in HIV infection. Oral petechiae were reported in 2% of 1121 HIV+ in five studies. Human papilloma virus (HPV) infection occurred in 1.1% of 989 HIV+ in seven studies. Drug reactions (white lichenoid lesions, ulceration, toxic epidermal necrolysis) have been reported in a number of cases, not allowing prevalence figures. However certain drugs, notably Foscarnet, Interferon and 2,3-dideoxycytidine, may frequently cause oral ulcerations. Oral neurologic manifestations such as peripheral facial paralysis and sensory neuropathy have been reported in a few cases or series only.

A new model for classification of disease manifestations in primary Sjögren's syndrome: evaluation in a retrospective long-term study.

OBJECTIVES: The clinical features of 80 patients with primary Sjögren's syndrome (PSS) were revised in order to evaluate the descriptive and analytical facilities of a newly proposed model for classification of the exocrine and nonexocrine disease manifestations in PSS. DESIGN: Retrospective, long-term (median 7.5 years follow-up) observational, clinical study. SETTING: Patients were recruited from our Department, which is a tertiary referral centre for PSS patients. SUBJECTS: Eighty patients fulfilling the Copenhagen criteria for keratoconjunctivitis sicca and/or xerostomia and followed between 1972 and 1991 were studied. RESULTS: All patients had 'surface exocrine disease' and in 31% this was the only disease manifestation. 'Internal organ exocrine disease' was found in 25% of the patients, whilst 2.5% developed 'monoclonal B lymphocyte disease' (non-Hodgkin's lymphoma). 28% displayed 'inflammatory vascular disease', 25% 'noninflammatory vascular disease', 41% "mediator-induced disease' and 2.5% 'autoimmune endocrine disease' (thyroiditis). In patients with 'internal organ exocrine disease' the frequencies of "mediator-induced disease' (70%; P < 0.01) and 'inflammatory vascular disease, (50%; P < 0.03) were significantly higher than expected by chance. The level of immunoinflammatory activity (assessed by plasma IgG, serum ANA and focus scoring of minor labial salivary gland biopsies) correlated with the extent of clinical disease as assessed by the model. CONCLUSIONS: We conclude that this theoretically based model for classification of disease manifestations in PSS contains descriptive and analytic powers which may assist the clinical handling of these patients.

Assessment of the European classification criteria for Sjögren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjögren's Syndrome.

OBJECTIVE: To assess the recently proposed preliminary criteria for the classification of Sjögren's syndrome (SS) in a multicentre European study of a new series of clinically defined cases. METHODS: The criteria included six items: I = ocular symptoms; II = oral symptoms; III = evidence of keratoconjunctivitis sicca; IV = focal sialoadenitis by minor salivary gland biopsy; V = instrumental evidence of salivary gland involvement; VI = presence of autoantibodies. Each centre was asked to provide five patients with primary SS, five with secondary SS, five with connective tissue diseases (CTD) but without SS, and five controls (patients with ocular or oral features that may simulate SS). The preliminary six item classification criteria set was applied to both the SS patients and the non-SS controls, and the performance of the criteria in terms of sensitivity and specificity was tested. RESULTS: The criteria set was tested on a total of 278 cases (157 SS patients and 121 non-SS controls) collected from 16 centres in 10 countries. At least four of the six items in the criteria set (limiting item VI to the presence of Ro(SS-A) or La(SS-B) antibodies) were present in 79 of 81 patients initially classified as having primary SS (sensitivity 97.5%), but in only seven of 121 non-SS controls (specificity 94.2%). When the presence of item I or II plus any two of items III-V of the criteria set was considered as indicative of secondary SS, 97.3% (71 of 73) of the patients initially defined as having this disorder and 91.8% (45 of 49) of the control patients with CTD without SS were correctly classified. CONCLUSION: This prospective study confirmed the high validity and reliability of the classification criteria for SS recently proposed by the European Community Study Group.

Oral hairy leukoplakia in an HIV-negative woman with Behçet's syndrome.

The first case of oral hairy leukoplakia in an HIV-negative patient with Behçet's syndrome is reported. The patient was a 47-year-old woman with bilateral lesions on the tongue. The clinic and histologic appearances were typical of hairy leukoplakia, and Epstein-Barr virus was demonstrated in the epithelial cells by DNA in situ hybridization. The patient had been on systemic steroid therapy for 15 years to control lesions of Behçet's syndrome. The literature now records 30 HIV-negative patients with hairy leukoplakia.

Characteristics of stably expressed human dopamine D1a and D1b receptors: atypical behavior of the dopamine D1b receptor.

Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines, two binding sites were observed with Kd values of 0.5 and 5 nM in CHO cells and 0.05 and 1.6 nM in BHK cells, respectively. Neither of the receptors affected Ca2+ metabolism whereas they both were coupled in a stimulatory fashion to adenylyl cyclase. The pharmacological profile of both the D1a and D1b receptors as assessed from inhibition of specific [3H]SCH 23390 binding was classical D1-like. Thus, benzazepine derivatives as well as the atypical neuroleptics, clozapine and fluperlapine, exhibited high affinity whereas D2 selective compounds like sulpiride and spiperone had low affinity for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments, dopamine was around 20 fold more potent in stimulating adenylyl cyclase via the D1b receptor as compared to the D1a receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Langerhans cells in oral mucosa of rhesus monkeys before and after infection by simian retrovirus-1 and simian immunodeficiency virus.

To study the influence of experimental infection with simian retrovirus-1 and simian immunodeficiency virus on the number and distribution of Langerhans cells in oral mucosa of rhesus monkeys, 10 monkeys were intravenously inoculated with simian retrovirus-1, 7 with simian immunodeficiency virus, and 2 were mock-inoculated. Biopsies were taken from gingiva and cheek pouch before infection and at 1 (simian immunodeficiency virus group only), 4, and 7 months after infection. Langerhans cells were detected in frozen sections by immunohistochemistry with monoclonal antibodies Leu-6 and HLA-DR. The mean number of Langerhans cells per surface millimeter and square millimeter of epithelium was calculated under blind conditions. The results showed no statistically significant differences in the number or distribution of Langerhans cells in the three groups at the various time points of examination. Similarly, no differences were detected within any group over the observation period. Thus systemic infection of rhesus monkeys with either simian retrovirus-1 or simian immunodeficiency virus does not lead to a significant change in the number of Langerhans cells in oral mucosal epithelium.

Natural history of HIV-associated salivary gland disease.

To describe the natural history of HIV-associated salivary gland disease, which is characterized by enlarged major salivary glands and/or xerostomia in HIV-infected persons, we assessed 22 patients at an initial and follow-up examinations (median span of examinations, 15 months). Sixteen patients (73%) had bilateral parotid gland enlargement, 17 had symptoms of dry mouth, and 11 had both conditions. Parotid gland enlargement remained unchanged in 10 patients, it progressed in 2, and it regressed in 4 during treatment with zidovudine or steroids. Those patients with parotid gland enlargement had a significantly lower mean stimulated parotid flow rate (0.27 ml/min/per gland) than a control group of HIV+ persons without salivary gland disease (0.48 ml/min/per gland) (p less than 0.05), whereas the mean unstimulated whole salivary flow rates did not did not differ significantly between the two groups. The mean salivary flow rate of the study group did not change during the observation period. When HIV-associated salivary gland disease was diagnosed, 5 patients (23%) had AIDS, and at follow-up 10 (46%) had AIDS. Seven of these had Kaposi's sarcoma. The mean peripheral blood CD4 cell count was 280 and 225 per mm3 at the initial and follow-up examinations, respectively. The corresponding CD8 counts were 1138 and 900. The pathogenesis of HIV-associated salivary gland disease may include hyperplasia of intra-parotid lymphoid tissue. Because HIV-associated salivary gland disease can clinically resemble Sjögren's syndrome, the differential diagnosis of bilateral parotid enlargement should include HIV infection.

Unusual oral presentation of non-Hodgkin's lymphoma in association with HIV infection.

In 4.4% of human immunodeficiency virus-associated non-Hodgkin's lymphoma the presenting lesion is seen in the mouth. Often the lesion may clinically resemble a less sinister process, and a definitive diagnosis of lymphoma may be delayed. We describe three unusual cases of non-Hodgkin's lymphoma, appearing intraorally in association with other oral lesions, in HIV-positive homosexual men. The three patients reported here were all diagnosed as having diffuse, large-cell malignant non-Hodgkin's lymphoma. We performed Epstein-Barr virus DNA in-situ hybridization on our cases and Epstein-Barr virus DNA sequences were not seen. We review the pertinent literature and stress the importance of including non-Hodgkin's lymphoma in the differential diagnosis of oral lesions in patients at risk of HIV infection.

HIV-associated salivary gland disease: a review.

Human immunodeficiency virus-associated salivary gland disease (HIV-SGD) is defined as the presence of xerostomia and/or swelling of the major salivary glands. It is common among children but uncommon among adults. HIV-SGD includes lymphoepithelial lesions and cysts involving the salivary gland tissue and/or intraglandular lymph nodes, and Sjögren's syndrome-like conditions, diffuse interstitial lymphocytosis syndrome, and other reported lesions of the major salivary glands. This article reviews the terminology, prevalence, symptoms, clinical features, diagnostic procedures, histopathology, serology, natural history, treatment, and pathogenesis of HIV-SGD.

Oral candidiasis and hairy leukoplakia correlate with HIV infection in Tanzania.

We report a detailed study on oral lesions and their association with the WHO revised provisional case definition of AIDS as well as serologic signs of HIV infection among 186 patients in Dar Es Salaam, Tanzania. The patient material consisted of 39 hospitalized suspected AIDS patients, 44 medical nonsuspected patients, 53 dental outpatients, and 50 patients with sexually transmitted diseases. The male:female ratio was 2.1:1 on average. Oral examination was done without knowledge of the HIV status of the patients. Among 39 suspected AIDS patients 97% had WHO AIDS criteria and 90% were seropositive for HIV. Among the 147 patients not suspected of having AIDS 18 (12%) had AIDS criteria and 15% had serologic evidence of HIV infection. The presence of WHO AIDS criteria correlated significantly with the presence of HIV antibodies, but not with HIV antigen. Oral lesions were found in 54% of those with AIDS criteria and 52% of HIV-infected patients, as compared to 3% and 6% of the patients without AIDS criteria and HIV infection, respectively (p less than 0.01). Among patients with AIDS atrophic candidiasis occurred in 21%, pseudomembranous candidiasis in 23%, hairy leukoplakia in 36%, herpetic stomatitis in 2%, Kaposi's sarcoma in 4%, and nonspecific ulcer in 4%. The presence of oral lesions had a high predictive value for presence of AIDS criteria as well as for presence of HIV infection in this hospital setting. All patients should have a thorough oral examination and the presence of the aforementioned oral lesions should lead to testing for HIV infection.

Does HIV cause salivary gland disease?

HIV-associated salivary gland disease (HIV-SGD) is characterized by enlargement of the major salivary glands and/or xerostomia. HIV does not appear to play a direct role in this disease since it was detected by immunohistochemistry in only occasional lymphocytes in labial salivary glands in two out of six patients; it was not found in the salivary gland epithelial cells. Moreover, HIV was not found in any of 21 saliva samples from seven patients. We conclude that HIV-SGD is not caused by direct infection of the salivary glands with HIV.

Non-pigmented oral kaposi's sarcoma (AIDS). Report of two cases.

In 90% of cases of AIDS-associated Kaposi's sarcoma (KS), the lesion is observed in the oral cavity. Oral KS usually reveals distinct clinical features characterized by a brown-bluish or otherwise pigmented appearance. The histological features are identical to classical KS. The occurrence of a non-pigmented oral KS in 2 male homosexual patients has prompted the present case reports. Clinicians should be aware that not all cases of AIDS-associated oral KS appear as brown or purplish tumors but may present without any discoloration.

Parotid gland enlargement and xerostomia associated with labial sialadenitis in HIV-infected patients.

Infection with human immunodeficiency virus (HIV) may be associated with enlargement of the major salivary glands or symptoms of dry mouth. We term this condition HIV-associated salivary gland disease (HIV-SGD). In this report we describe 12 patients with HIV-SGD. Nine patients (one child, eight adults) had enlargement of the parotid glands, and three had xerostomia alone. Symptoms of dry mouth, dry eyes or arthralgia occurred in 11, five and five patients, respectively. Salivary flow rates were normal or slightly reduced in seven patients and severely reduced in five. Labial salivary gland (LSG) biopsy specimens from patients contained lymphocytic infiltrates in focal and other patterns, whereas specimens from three HIV-infected patients without salivary gland symptoms did not. The inflammatory infiltrates in LSG specimens showed a preponderance of T8-positive cells and a tissue T4/T8 average ratio of 0.66. The mean T4/T8 ratio of peripheral blood lymphocytes was 0.4. Serum antinuclear antibodies were present in one patient, but rheumatoid factor, SS-A, and SS-B antibodies were absent in all. Search for Epstein-Barr virus and cytomegalovirus in the LSG tissue of the six patients tested did not reveal evidence of antigens or DNA. HIV-SGD patients show a number of similarities to and differences from patients with Sjögren's syndrome (SS). The similarities include the oral and salivary features, histopathology and possibly changes in other organs. The differences include the lower salivary gland T4/T8 ratio and the absence of autoantibodies in serum. The causes of HIV-SGD as well as of Sjögren's syndrome are unknown.