Vidya Sankar

New developments and opportunities in oral mucosal drug delivery for local and systemic disease

The oral mucosas accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.

Local drug delivery for oral mucosal diseases: challenges and opportunities

There are few topical formulations used for oral medicine applications most of which have been developed for the management of dermatological conditions. As such, numerous obstacles are faced when utilizing these preparations in the oral cavity, namely enzymatic degradation, taste, limited surface area, poor tissue penetration and accidental swallowing. In this review, we discuss common mucosal diseases such as oral cancer, mucositis, vesiculo-erosive conditions, infections, neuropathic pain and salivary dysfunction, which could benefit from topical delivery systems designed specifically for the oral mucosa, which are capable of sustained release. Each condition requires distinct penetration and drug retention profiles in order to optimize treatment and minimize side effects. Local drug delivery may provide a more targeted and efficient drug-delivery option than systemic delivery for diseases of the oral mucosa. We identify those mucosal diseases currently being treated, the challenges that must be overcome and the potential of novel therapies. Novel biological therapies such as macromolecular biological drugs, peptides and gene therapy may be of value in the treatment of many chronic oral conditions and thus in oral medicine if their delivery can be optimized.

Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor α and systemic immune activation

Objective: To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. Methods: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. Results: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFα were significantly increased after treatment. Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFα and other indicators of immune activation in this patient population. These data suggest that TNFα may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.

Fungal load and candidiasis in Sjögren’s syndrome

OBJECTIVE We sought to investigate the prevalence of Candida carriage and the relationships between salivary flow rates and oral Candida load in patients with Sjögrens syndrome (SS). METHODS The oral Candida load of patients with SS was evaluated by culturing oral rinse (swish and spit) samples. Culture, Gram stain, and wet-mount test results were reported. RESULTS One hundred three patients (96 women) met European criteria for SS (91 with primary SS and 12 with secondary SS). The mean age (95% confidence interval) was 55 years (range, 51-57 years). Oral rinse cultures were positive in 77% of subjects. The total stimulated salivary flow rate was inversely correlated with oral Candida load (r = -0.47; P </=.0001). The oral rinse samples yielded gram-positive results in 38% of patients with SS, and the Fungi-Fluor assay (wet mount) results were positive in 49%. CONCLUSIONS The prevalence of Candida carriage varies according to the methods used to determine the presence of the organism and is similar to that reported in the literature. A low stimulated salivary flow rate-not a low unstimulated flow rate-was associated with Candida carriage.

Cationic liposome-mediated gene transfer to rat salivary epithelial cells in vitro and in vivo

Previously we have shown that gene transfer to salivary gland epithelial cells readily occurs via recombinant adenoviruses, although the response is short‐lived and results in a potent host immune response. The aim of the present study was to assess the feasibility of using cationic liposomes to mediate gene transfer to rat salivary cells in vitro and in vivo.

Lack of efficacy of etanercept in Sjögren’s syndrome correlates with failed suppression of TNFα and systemic immune activation

Objective: To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. Methods: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. Results: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFα were significantly increased after treatment. Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFα and other indicators of immune activation in this patient population. These data suggest that TNFα may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.

Risk factors influencing antibody responses to kaposi's sarcoma-associated herpesvirus latent and lytic antigens in patients under antiretroviral therapy

Background:Kaposis sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposis sarcoma. Methods:We examined demographic, viral, and immunologic factors that influence KSHV latent and lytic antibodies in HIV-infected patients. Results:Detection rate of KSHV latent but not lytic antibodies was lower in patients with CD4 cells/mm3 less than 200 than greater than 200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11-0.61) and CD8 cells/mm3 less than 400 than greater than 400 (OR, 0.26; 95% CI, 0.07-0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 less than 200 than greater than 200 (OR, 2.34; 95% CI, 1.37-4.02) and HIV copies/mL greater than 400 than less than 400 (OR, 1.70; 95% CI, 1.09-2.65). Lytic antibody level was inversely correlated with CD4 count (P < 0.001). Lytic seropositivity (OR, 2.47; 95% CI, 1.35-4.50) and antibody level (adjusted difference mean optical density, 0.324; 95% CI, 0.16-0.46) were higher in patients with HIV infection greater than 15 than less than 15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07-2.73) and antibody level (adjusted difference mean optical density, 0.111; 95% CI, 0.03-0.18) than non-Hispanics. Conclusions:Lower CD4 and CD8 counts impair antibody response to KSHV latent antigens. Immune deterioration, long-term HIV infection, and Hispanic status are risk factors for Kaposis sarcoma predictors.

Adult heart block is associated with disease activity in primary Sjögren's syndrome

Objectives: Congenital heart block occurring in the foetus and neonate may be associated with maternal anti‐SS‐A/anti‐SS‐B autoantibodies (anti‐SSA/anti‐SSB). The adult atrioventricular node is generally thought to be resistant to the damaging effects of anti‐SSA/anti‐SSB. However, case reports suggest that heart block developing in adult Sjögrens syndrome (SS) patients may be associated with these autoantibodies. Therefore, we investigated the relationship between serum antibodies and heart block in adult SS patients. Methods: We abstracted data from clinic patient records. Diagnosis of primary SS was based on American–European classification criteria. Electrocardiograms (EKGs), laboratory immunology parameters, lipid profiles, and focus scores from labial salivary gland biopsies were available for 51 SS patients. Fifteen patients had follow‐up EKGs. PR interval⩾200 ms was considered to be first‐degree heart block. Results: Five patients showed prolonged PR intervals; the presence of heart block was not related to the presence of anti‐SSA antibodies. However, significant differences between patients with prolonged and normal PR intervals were seen for mean focus scores (p<0.0001), anti‐cardiolipin immunoglobulin IgG (p = 0.0009), age (p = 0.01), IgG (p = 0.02), anti‐SSB antibodies (p = 0.02), and high density lipoprotein (HDL) cholesterol levels (p = 0.03). These parameters correlated with prolonged PR intervals. Conclusions: These results suggest an association between disease activity, the presence of anti‐SSB antibodies, and the occurrence of first‐degree heart block in adults with primary SS.

Treatment Guidelines for Rheumatologic Manifestations of Sjögren's Syndrome: Use of Biologic Agents, Management of Fatigue, and Inflammatory Musculoskeletal Pain

The Sjögrens Syndrome Foundation clinical practice guidelines (CPGs) are designed to improve quality and consistency of care in Sjögrens syndrome by offering recommendations for management.

Diagnosis of Sjogren's Syndrome American-European and the American College of Rheumatology Classification Criteria

Classification criteria provide a formalized approach to studying course and management of rheumatic disease, as well as a measure of improvement in care. Understanding the purposes of classification criteria sets and the differences between different classification criteria is crucial for understanding rheumatic disease and for the design and conduct of clinical and epidemiologic investigations. In this article, the similarities and differences between the American-European Consensus Group Criteria (AECG) and the newly proposed American College of Rheumatology (ACR) classification criteria for Sjögrens syndrome and the clinical implications of switching to the ACR classification criteria from the AECG are described.