Sue Pavitt

Tooth loss and osteoporosis: the OSTEODENT Study

AIM To determine the cross-sectional association of the osteoporotic status of patients with the number of their teeth, with and without taking into account age and/or smoking. MATERIAL & METHODS At four centres, the study recruited 665 females aged 45-70 years and the number of teeth was counted for 651 subjects. Bone density was measured at the total hip, femoral neck and lumbar spine. RESULTS The mean number of teeth in the osteoporotic subjects was 3.3 fewer than normal subjects and 2.1 fewer if those with no teeth were excluded. The association between osteoporosis and having <6 or having <28 teeth remained significant after adjusting for age, smoking and centre with p-values of 0.016 and 0.011, respectively. A single regression model for tooth count with normal errors would not fit all the data. By fitting mixture regression models to subjects with tooth count >0, three clusters were identified corresponding to different degrees of tooth loss. The overall effect of osteoporosis was as follows: -1.8 teeth before and after adjusting for smoking, -1.2 teeth after adjusting for age, and -1.1 teeth after adjusting for both age and smoking. CONCLUSIONS We have established a significant association between osteoporosis and tooth loss after adjusting the effect for age and smoking.

The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis.

BackgroundPsoriatic Arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, “tight control” intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone.Methods/designTICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks.DiscussionThe TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients’ disease activity and a reduction in radiological joint damage.Trial registrationISRCTN30147736, NCT01106079

Effects of Vitamin D on Cardiac Function in Patients With Chronic HF: The VINDICATE Study

Background Patients with chronic heart failure (HF) secondary to left ventricular systolic dysfunction (LVSD) are frequently deficient in vitamin D. Low vitamin D levels are associated with a worse prognosis. Objectives The VINDICATE (VitamIN D treatIng patients with Chronic heArT failurE) study was undertaken to establish safety and efficacy of high-dose 25 (OH) vitamin D3 (cholecalciferol) supplementation in patients with chronic HF due to LVSD. Methods We enrolled 229 patients (179 men) with chronic HF due to LVSD and vitamin D deficiency (cholecalciferol <50 nmol/l [<20 ng/ml]). Participants were allocated to 1 year of vitamin D3 supplementation (4,000 IU [100 μg] daily) or matching non−calcium-based placebo. The primary endpoint was change in 6-minute walk distance between baseline and 12 months. Secondary endpoints included change in LV ejection fraction at 1 year, and safety measures of renal function and serum calcium concentration assessed every 3 months. Results One year of high-dose vitamin D3 supplementation did not improve 6-min walk distance at 1 year, but was associated with a significant improvement in cardiac function (LV ejection fraction +6.07% [95% confidence interval (CI): 3.20 to 8.95; p < 0.0001]); and a reversal of LV remodeling (LV end diastolic diameter -2.49 mm [95% CI: -4.09 to -0.90; p = 0.002] and LV end systolic diameter -2.09 mm [95% CI: -4.11 to -0.06 p = 0.043]). Conclusions One year of 100 μg daily vitamin D3 supplementation does not improve 6-min walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes. (VitamIN D Treating patIents With Chronic heArT failurE [VINDICATE]; NCT01619891)

Serial Change in Health-Related Quality of Life Over 1 Year After Transcatheter Aortic Valve Implantation: Predictors of Health Outcomes

OBJECTIVES The goal of this study was to assess serial changes in patient health-related quality of life (HRQOL) over time and identify predictors of patient benefit. BACKGROUND Severe aortic stenosis reduces the length and quality of a patients life. Transcatheter aortic valve implantation (TAVI) is superior to standard medical therapy and noninferior to surgical aortic valve replacement for 1-year mortality. HRQOL is an important outcome measure for which there is limited evidence in TAVI populations. METHODS A total of 102 patients (mean age 80 ± 0.6 years; 49% male) undergoing TAVI consented to participate. Two HRQOL questionnaires-the social functioning (SF)-12v2 with physical component summaries (PCS) and mental component summaries (MCS) and the EQ-5D (with a visual analog scale [VAS])-were completed at baseline, 30 days, 6 months, and 1 year according to the recommendations of the Valve Academic Research Consortium. A SF-6D utility measure was calculated from the SF-12 survey. RESULTS HRQOL significantly improved over 1 year (PCS p = 0.02; EQ-5D p = 0.02; VAS p = 0.01; SF-6D p = 0.03), becoming similar to age-adjusted U.S. population norms. The greatest change occurred from baseline to 30 days (p < 0.001), with further significant improvements to 6 months (p < 0.01). An insignificant decline occurred between 6 months and 1 year (p > 0.05), but a linear pattern of change remained for PCS, EQ-5D, and VAS (p < 0.05). Male sex (SF-6D p = 0.01) and increased operator experience (PCS, EQ-5D, and VAS p < 0.05) were independent predictors of a greater improvement in HRQOL. CONCLUSIONS HRQOL significantly improved early after TAVI and was maintained out to 1 year. Patient factors, procedural complications, and operator experience are predictors of health benefit at 1 year.

Attaining Surgical Competency and Its Implications in Surgical Clinical Trial Design: A Systematic Review of the Learning Curve in Laparoscopic and Robot-Assisted Laparoscopic Colorectal Cancer Surgery

BackgroundLaparoscopic surgery is increasingly used in the treatment of colorectal cancer and more recently robotic assistance has been advocated. However, the learning curve to achieve surgical proficiency in laparoscopic surgery is ill-defined and subject to many influences. The aim of this review was to comprehensively appraise the literature on the learning curve for laparoscopic and robotic colorectal cancer surgery, and to quantify attainment of surgical proficiency and its implications in surgical clinical trial design.MethodsA systematic review using a defined search strategy was performed. Included studies had to state an explicit numerical value of the learning curve evaluated by a single parameter or multiple parameters.ResultsThirty-four studies were included, 28 laparoscopic and 6 robot assisted. Of the laparoscopic studies, nine defined the learning curve on the basis of a single parameter. Nine studies used more than one parameter to define learning, and 11 used a cumulative sum (CUSUM) analysis. One study used both a multiparameter and CUSUM analysis. The definition of proficiency was subjective, and the number of operations to achieve it ranged from 5 to 310 cases for laparoscopic and 15–30 cases for robotic surgery.ConclusionsThe learning curve in laparoscopic colorectal surgery is multifaceted and often ill-defined, with poor descriptions of mentorship/supervision. Further, the quantification to attain proficiency is variable. The use of a single parameter to quantify this is simplistic. Multidimensional assessment is recommended; as part of this, the CUSUM model, which assesses trends in multiple surgical outcomes, is useful and appropriate when assessing the learning curve in a clinical setting.

The use of visual assessment of dental radiographs for identifying women at risk of having osteoporosis: the OSTEODENT project

OBJECTIVE The objective of this study was to investigate the diagnostic accuracy of visual assessment of the trabecular pattern in intraoral periapical radiographs to identify female subjects at risk of having osteoporosis. STUDY DESIGN Six hundred female subjects underwent intraoral periapical radiography of the maxillary and mandibular premolar region. Five observers assessed the trabecular pattern as dense, heterogeneous, or sparse, with the aid of reference images. All patients received a central dual energy x-ray absorptiometry (DXA) examination of the hip and lumbar spine. RESULTS With sparse trabecular pattern as indicative of osteoporosis, mean specificity was high (91.6 for the upper jaw and 90.8 for the lower jaw) while the sensitivity was low (28.2 for the upper and lower jaw). The mean intraobserver agreement was comparable for radiographs of the upper and lower jaw (median kappa(w) 0.53 and 0.57, respectively). CONCLUSION Visual assessment of the trabecular pattern in intraoral periapical radiographs of premolar regions is a potential method to identify women at risk of having osteoporosis.

No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine

Objective: To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS). Methods: Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test. Results: Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546). Conclusions: Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.

Osteoporosis detection using intraoral densitometry

OBJECTIVES To determine the diagnostic accuracy of mandibular and maxillary bone density in detecting osteoporosis using receiver operating characteristic (ROC) analysis. METHODS 671 women between 45 years and 70 years of age underwent dual energy X-ray absorptiometry (DXA) of the hip and lumbar spine. This was the gold standard for diagnosing osteoporosis. Intraoral radiography of the upper and lower right premolar region was performed, using an aluminium wedge as a densitometric reference. Jaw bone density was determined using dedicated software. Observer differences and ROC curves were analysed. RESULTS For detecting osteoporosis using jaw bone density, the area under the ROC curve (A(z)) was 0.705. For separate analysis of mandibular and maxillary films, sensitivity varied from 33.9% to 38.7% and specificity from 83.5% to 85.3% when using a threshold of 4.3 mm Al equivalent. CONCLUSIONS Density of the premolar region reaches a fair diagnostic accuracy, which might improve when including additional factors in the analysis and refining the densitometric tool.

The role of the dental surgeon in detecting osteoporosis: the OSTEODENT study

Objective To determine if thinning (<3 mm width) of the lower cortical border of the mandible on dental panoramic radiographs, as well as other clinical risk factors, may provide a useful diagnostic test for osteoporosis in young postmenopausal women.Design Six hundred and fifty-two subjects (age range 45-70 years) were involved in this multi-centre, cross-sectional study.Setting Patients were recruited from centres in Leuven (Belgium), Athens (Greece), Manchester (UK), and Malmo (Sweden).Subjects and methods The subjects age, body weight, whether the patient took hormone replacement therapy or had a history of low trauma fracture were used to form a clinical osteoporosis risk assessment (the OSteoporosis Index of RISk or OSIRIS index). Each patient also received a dental panoramic radiographic examination.Results One hundred and forty subjects had osteoporosis involving at least one of the measurement sites (lumbar spine, femoral neck or total hip). Those with osteoporosis tended to have a low OSIRIS score and a thinned cortical mandibular border. The area under the ROC curve for using both cortical width and OSIRIS to predict osteoporosis was 0.90 (95% CI = 0.87 to 0.92). There was a significant improvement in the diagnostic ability of the combined OSIRIS and cortical width test over both tests applied separately (p <0.001). The cost effectiveness of the cortical width and OSIRIS model was improved by using a high specificity threshold rather than high sensitivity. However, this analysis ignores the costs associated with missed cases of osteoporosis.Conclusion Dentists have a role to play in the detection and referral of patients at high risk of osteoporosis.

The TRACTISS Protocol: a randomised double blind placebo controlled clinical TRial of Anti-B-Cell Therapy In patients with primary Sjögren's Syndrome

BackgroundPrimary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 – 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.Methods/designTRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.DiscussionThe TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.Trial registrationUKCRN Portfolio ID:9809 ISRCTN65360827.