Rheumatoid Arthritis: Brennan MT

von Bültzingslöwen I, Sollecito TP, Fox PC, Daniels T, Jonsson R, Lockhart PB, Wray D, Brennan MT, Carrozzo M, Gandera B, Fujibayashi T, Navazesh M, Rhodus NL, Schiødt M. · Department of Oral Medicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden. <> · Oral Surg Oral Med Oral Pathol Oral Radiol Endod. · Pubmed #17379156 No free full text.

Abstract: OBJECTIVES: The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia. STUDY DESIGN: Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005. RESULTS: Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient. CONCLUSIONS: These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.

Brennan MT, Shariff G, Lockhart PB, Fox PC. · Department of Oral Medicine, Carolinas Medical Center, Post Office Box 3280, Charlotte, NC 28232, USA. · Dent Clin North Am. · Pubmed #12436835 No free full text.

Abstract: The results of the present systematic review of randomized controlled trials published in peer-reviewed journals demonstrate the presence of a wide variety of biases and the weakness of the existing literature of xerostomia treatment. The report of statistically significant efficacy on an outcome measure is only meaningful in the setting of a well-controlled, appropriately designed clinical trial. This points to the importance of evaluating the quality of the clinical trial closely when deciding if study results are applicable to a specific patient population. Future studies in the management of xerostomia will require an increased effort on the part of investigators to eliminate easily recognized flaws during the planning stages of a clinical trial. Minimizing bias in clinical studies will allow for easier interpretation and comparisons of different studies. Better clinical trial design is vital to provide maximal confidence in the efficacy of xerostomia interventions.

Pillemer SR, Brennan MT, Sankar V, Leakan RA, Smith JA, Grisius M, Ligier S, Radfar L, Kok MR, Kingman A, Fox PC. · National Institute of Dental and Craniofacial Research, Bethesda, Maryland 28092, USA. · Arthritis Rheum. · Pubmed #15334433 links to  free full text

Abstract: OBJECTIVE: To screen for potential efficacy and assess feasibility and safety of dehydroepiandrosterone (DHEA) as a treatment for Sjögren's syndrome (SS). METHODS: A 24-week randomized, double-blinded, pilot trial of oral DHEA (200 mg/day) versus placebo was conducted. The primary comparison was to a hypothesized 20% placebo response rate. If 14 consecutive subjects on DHEA did not respond, a Phase III trial would be considered futile. A placebo group of 14 subjects was planned to verify placebo response rate and estimate sample size required for a definitive trial. Response criteria required 20% improvement in at least 2 of 3 domains. Analysis of covariance was used to adjust for baseline differences and for stratified randomization. Outcome measures included visual analog scale questionnaires for dry eye and dry mouth symptoms, lissamine green ocular dye staining and Schirmer I tests, stimulated salivary flow, IgG, and erythrocyte sedimentation rate (ESR). RESULTS: Randomization resulted in 14 DHEA and 14 placebo group subjects. At baseline, mean +/- SD for DHEA versus placebo groups were Schirmer I tests 4.5 +/- 4.5 versus 5.4 +/- 6.1 mm/5 minutes; Van Bijsterveld score 5.3 +/- 2.1 versus 5.5 +/- 2.2; unstimulated saliva 0.03 +/- 0.05 versus 0.04 +/- 0.10 ml/minute; IgG 1,699 +/- 749 versus 1,712 +/- 621 g/dl; and ESR 40 +/- 31 versus 44 +/- 28 mm/hour. Apart from changes over the trial in dry mouth symptoms, no significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow; IgG, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. Although 7 subjects met response criteria in the DHEA group, 5 met the criteria in the placebo group, and there was no significant difference between groups. CONCLUSION: DHEA showed no evidence of efficacy in SS. Without evidence for efficacy, patients with SS should avoid using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown.

Sankar V, Brennan MT, Kok MR, Leakan RA, Smith JA, Manny J, Baum BJ, Pillemer SR. · National Institutes of Health, Bethesda, Maryland, USA. · Arthritis Rheum. · Pubmed #15248223 links to  free full text

Abstract: OBJECTIVE: To assess the safety and potential efficacy of etanercept in the treatment of Sjögren's syndrome (SS). METHODS: This pilot study was a 12-week randomized, double-blind, placebo-controlled trial of etanercept, with 14 subjects in each group. Patients received 25 mg of etanercept or placebo (vehicle) by twice-weekly subcutaneous injection. Patients met the American-European Consensus Group criteria for SS. The primary outcome required at least 20% improvement from baseline values for at least 2 of the following 3 domains: subjective or objective measures of dry mouth, subjective or objective measures of dry eyes, and IgG level or erythrocyte sedimentation rate (ESR). RESULTS: Of the 14 patients taking etanercept, 11 had primary SS and 3 had SS secondary to rheumatoid arthritis. Baseline measures did not differ between the 2 groups. Three etanercept-treated patients and 1 placebo-treated patient did not complete the trial. Five etanercept-treated patients and 3 placebo-treated patients showed improvement from baseline in the primary outcome variable at 12 weeks, but the difference was not statistically significant. There were no significant differences between the groups for changes in subjective measures of oral or ocular symptoms (by visual analog scale), the IgG level, Schirmer I test result, van Bijsterveld score, or salivary flow. At 12 weeks, the ESR had decreased in the etanercept group compared with baseline (P = 0.004); however, the mean reduction was only 18.6%. CONCLUSION: We found no evidence to suggest that treatment with etanercept at a dosage of 25 mg twice weekly for 12 weeks was clinically efficacious in SS. A larger trial will be necessary to definitively address the efficacy of etanercept in the treatment of SS.

Pillemer SR, Leakan RA, Sankar V, Manny J, Baum BJ, Smith J, Chaudhry U, Fox PC, Radfar L, Ligier S, Brennan MT. · No affiliation provided · Arthritis Rheum. · Pubmed #15188341 links to  free full text

This publication has no abstract.

Brennan MT, Sankar V, Leakan RA, Grisius MM, Collins MT, Fox PC, Baum BJ, Pillemer SR. · Gene Therapy and Therapeutics Branch (GTTB), National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland, USA. · J Rheumatol. · Pubmed #12784401 No free full text.

Abstract: OBJECTIVE: To investigate the relationships between concentrations of sex hormones and measures of disease activity in patients with primary Sjögren's Syndrome (pSS). METHODS: Fifty-four women were evaluated: 39 patients (age, Q1,Q3: 57.0 yrs; 46, 66) diagnosed with pSS and 15 patients (49.0 yrs; 45, 60) who did not meet diagnostic criteria for pSS. The following measures of disease activity were assessed: serological data [antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin levels (IgG, IgA, IgM), serum protein, anti-SSA, and anti-SSB], labial minor salivary gland focus score, salivary flow rates, and objective measures of eye dryness (fluorescein corneal staining and unstimulated Schirmer's I test). Spearman correlations were calculated between these indices of disease activity and serum levels of sex hormones: dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, testosterone, dihydrotestosterone (DHT), estrone, estradiol, and sex hormone binding globulin (SHBG). RESULTS: Numerous differences were noted between cases and controls with disease activity measures. All median values of sex steroid hormones were within the range of normal for pSS cases. Positive correlations were noted between testosterone and ESR (r = 0.36, p = 0.03), testosterone and serum protein (r = 0.37, p = 0.05), and testosterone and focus score (r = 0.44, p = 0.007). Negative correlations were present between SHBG and anti-SSA (r = -0.33, p = 0.05), SHBG and anti-SSB (r = -0.43, p = 0.009), and DHT and CRP (r = -0.41, p = 0.05). No correlations were noted between estrogens and measures of pSS disease activity. CONCLUSION: Higher levels of disease activity (ESR, serum protein, and focus score) were associated with higher concentrations of testosterone. No correlation between disease activity and estrogens was found.

Sankar V, Brennan MT, Radfar L, Leakan RA, Pillemer SR. · Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA. · Oral Surg Oral Med Oral Pathol Oral Radiol Endod. · Pubmed #12221385 No free full text.

Abstract: OBJECTIVE: The purpose of this study was to determine whether systolic and diastolic blood pressures are associated with salivary flow, dry mouth, or dry eye symptoms in patients with primary Sjögren's syndrome as compared with xerostomic control subjects. STUDY DESIGN: One hundred forty consecutive patients seen at the Sjögren's Syndrome Clinic were categorized retrospectively with various classification schemes: (1) subjective dry mouth; (2) subjective dry eye; (3) European criteria; and (4) international criteria. Data collection included age, gender, systolic blood pressure, diastolic blood pressure, salivary flow rate, focus score, Schirmer's test, and laboratory findings, including antinuclear antibodies, anti-SSA, anti-SSB, IgG, IgA, IgM, erythrocyte sedimentation rate, and rheumatoid factor. RESULTS: No meaningful associations of salivary flow rates with systolic or diastolic blood pressures were found in patients with Sjögren's syndrome or in xerostomic control subjects. An inverse correlation was seen between salivary flow and elevated diastolic blood pressure in xerostomic control subjects only. CONCLUSION: Elevated blood pressure was not related to saliva flow in patients with Sjögren's syndrome.

Brennan MT, Sankar V, Leakan RA, Kleiner D, Atkinson JC, Wilkinson WE, Baum BJ, Pillemer SR. · National Institute of Dental and Craniofacial Research (NIDCR), NIH, Bethesda, Maryland, USA. · Arthritis Rheum. · Pubmed #11954013 No free full text.

Abstract: OBJECTIVE: To investigate risk factors for positive minor salivary gland biopsy results in Sjögren's syndrome (SS) and dry mouth patients. METHODS: A total of 289 patients with dry mouth symptoms were evaluated. Potential risk factors for positive minor salivary gland biopsy results (>1 focus of lymphocytes) were studied in 2 phases. In phase 1, predictor variable candidates were identified for the test study (phase 2). Odds ratios were calculated for predictor variables. RESULTS: IgG, IgA, keratoconjunctivitis sicca, and sex, identified as the best predictor variables from phase 1 data, were included in a logistic regression model using phase 2 data. Only IgG demonstrated association with biopsy results (chi(2) = 20.4, P = 0.0001). An elevated IgG level (>1,482 mg/dl) had a high specificity (97% and 97%), high positive predictive value (PPV) (97% and 97%), but poor sensitivity (40% and 45%) in predicting positive biopsy results and SS, respectively. CONCLUSION: Elevated serum IgG levels best predicted a positive biopsy result and SS with high PPV and specificities.

Brennan MT, Pillemer SR, Goldbach-Mansky R, El-Gabalawy H, Schumacher HR, Fox PC. · Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. · Clin Exp Rheumatol. · Pubmed #11491501 No free full text.

Abstract: OBJECTIVE: To investigate the frequency of sialadenitis on lip biopsy in patients with synovitis of recent onset (ES), and see how sialadenitis relates to clinical and laborator findings of ES. METHODS: Joint involvement, laboratory measures and biopsies of the minor salivary glands were evaluated in 10 ES patients. Diagnosis at a one-year follow-up exam was noted. RESULTS: Six ES patients (60%) had a positive lip biopsy (mononuclear cell focus score greater than 1). ES patients with a positive lip biopsy presented with oligoarthritis, while ES patients with a negative lip biopsy had a more polyarticular presentation. No differences in laboratory measures between patients with a positive and negative lip biopsy were present. Seven ES patients had a diagnosis of rheumatoid arthritis and three had undifferentiated arthritis at the end of one year. CONCLUSION: ES patients had a higher than expected frequency offocal sialadenitis.

Brennan MT, Fox PC. · Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. · J Rheumatol. · Pubmed #10555894 No free full text.

Abstract: OBJECTIVE: To examine the clinical and serologic characteristics of 14 men compared to 28 women with primary Sjögren's syndrome (SS) and contrast these findings with studies evaluating sex differences in primary SS. METHODS: Patient information was collected from patients seen at the National Institutes of Health Salivary Gland Dysfunction Clinic from 1987 to 1998. A total of 14 male patients were diagnosed with primary SS during this period. The control group consisted of 28 female patients matched according to focus score of the labial minor salivary gland biopsy. RESULTS: Women had significantly higher antinuclear antibody titers and erythrocyte sedimentation rate than men. A significant sex difference was also noted in extraglandular manifestations, with more women reporting fatigue compared to men (68 vs 21%, respectively). CONCLUSION: This study indicates that women may have more positive serological findings than men and a higher prevalence of fatigue. No sex differences could be established with other extraglandular manifestations of SS.