Ngati and healthy: translating diabetes prevention evidence into community action.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a major health issue in New Zealand Maori. Clinical trials have demonstrated potential for the prevention of T2DM, but whether community public health programmes aiming to prevent diabetes are effective is untested. OBJECTIVE: To describe the planning and design of an intervention aiming to translate T2DM prevention clinical trial evidence into a community-wide population health intervention in a high risk predominantly Maori community. APPROACH: Community concerns about the diabetes burden were heard by the local diabetes nurse, herself a tribal member, and discussed with a locally raised academic. Project planning ensued. The intervention and its evaluation were designed using a participatory community development model. The planned intervention had three components: community-wide health promotion initiatives conveying healthy lifestyle messages, community education and monitoring for identified high-risk individuals and their extended families, and a structural strategy aimed at adapting local environments to support lifestyle changes. The evaluation plan involved interrupted time series surveys coupled with formative and process evaluations rather than a randomised control trial design. DISCUSSION: Consulting communities, validating community concerns and prioritising cultural and ethical issues were key steps. Time spent developing good relationships amongst the health provider and academic research team members at the outset proved invaluable, as the team were united in addressing the project planning and implementation challenges, such as funding obstacles that arose because of our ethically and culturally appropriate non-randomised control trial evaluation design. The pre-intervention survey demonstrated high rates of diabetes (13%), insulin resistance (33%) and risk factors, and provided evidence for positive, as opposed to negative, lifestyle intervention messages. CONCLUSION: Community-wide lifestyle interventions have the potential to reduce rates of type 2 diabetes and other chronic diseases in high-risk communities, but require a high level of commitment from the health sector and buy-in from the community. Adequate commitment, leadership, planning and resources are essential.

Insulin resistance and impaired glucose metabolism in a predominantly Maori community.

We sought to identify lifestyle behaviours which influence risk of impaired glucose metabolism, IGM (newly diagnosed type 2 diabetes, impaired glucose tolerance [IGT] or impaired fasting glycemia [IFG]) or insulin resistance (IR) in a predominantly Maori community, and applied the McAuley formula to determine whether it predicts high risk individuals amongst this community. Three hundred and seventy one participants completed a lifestyle and dietary behaviour questionnaire and oral glucose tolerance test. Clinical variables, microalbuminuria, fasting glucose, insulin and lipids were measured. Diabetes, IFG and IGT were defined according to WHO criteria. IR was defined using the McAuley formula. Those with IGM and those with IR showed similar risk factor attributes. Odds ratios (95% CI) for development of IGM and IR were 0.43 (0.21-0.88) and 0.51 (0.33-0.80), respectively, for regular physical activity, and 0.55 (0.26-1.15) and 0.59 (0.37-0.96), respectively, for two or more dietary behaviours characterized by a high intake of fibre. Regular physical activity and a diet characterized by a high intake of dietary fibre were found to reduce risk of newly diagnosed IGM or IR. The McAuley formula appears to predict high-risk individuals in a predominantly Maori population as it does in European populations.

Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients.

In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor κB (NF-κB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.

Cardiovascular disease is increased prior to onset of rheumatoid arthritis but not osteoarthritis: the population-based Nord-Trøndelag health study (HUNT).

INTRODUCTION: Patients with rheumatoid arthritis (RA) have increased risk of cardiovascular (CV) events. We sought to test the hypothesis that due to increased inflammation, CV disease and risk factors are associated with increased risk of future RA development. METHODS: The population-based Nord-Trøndelag health surveys (HUNT) were conducted among the entire adult population of Nord-Trøndelag, Norway. All inhabitants 20 years or older were invited, and information was collected through comprehensive questionnaires, a clinical examination, and blood samples. In a cohort design, data from HUNT2 (1995-1997, baseline) and HUNT3 (2006-2008, follow-up) were obtained to study participants with RA (n = 786) or osteoarthritis (n = 3,586) at HUNT3 alone, in comparison with individuals without RA or osteoarthritis at both times (n = 33,567). RESULTS: Female gender, age, smoking, body mass index, and history of previous CV disease were associated with self-reported incident RA (previous CV disease: odds ratio 1.52 (95% confidence interval 1.11-2.07). The findings regarding previous CV disease were confirmed in sensitivity analyses excluding participants with psoriasis (odds ratio (OR) 1.70 (1.23-2.36)) or restricting the analysis to cases with a hospital diagnosis of RA (OR 1.90 (1.10-3.27)) or carriers of the shared epitope (OR 1.76 (1.13-2.74)). History of previous CV disease was not associated with increased risk of osteoarthritis (OR 1.04 (0.86-1.27)). CONCLUSION: A history of previous CV disease was associated with increased risk of incident RA but not osteoarthritis.

Trajectory of intensive treat-to-target disease modifying drug regimen in an observational study of an early rheumatoid arthritis cohort.

OBJECTIVES: Studies of early rheumatoid arthritis (RA) cohorts have analysed treatment response and prognostic factors at fixed time points. However, in treat-to-target protocols, therapeutic decision-making is dynamic and responsive to disease activity over time. To determine when a minimal residual disease response target should be expected, our primary objective was to identify the time-dependent therapeutic response to combination disease modifying antirheumatic drugs (DMARDs) for 12 months. Our secondary objective determined factors affecting this response trajectory. DESIGN: Observational cohort. SETTING: Treat-to-target early RA clinic in Australian tertiary referral hospital. PARTICIPANTS: We enrolled consecutive patients attending an early arthritis clinic with symptom duration less than 12 months, who were diagnosed with RA for the first time between 2004 and 2008. 101 met these eligibility criteria and data were available at baseline through 12 months. INTERVENTIONS: intensive DMARDs according to a treat-to-target protocol. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured disease activity scores (DAS) at each visit, then analysed therapeutic response and associated factors in a time-dependent fashion over 12 months. RESULTS: The median DAS4vESR of 4.46 at baseline decreased 12 weeks later by 24%, while the proportion with DAS4v ≤ 2.6 increased (p<0.01). DAS4v continued to decrease over 52 weeks. DAS4v reduction of at least -0.45 at 4 weeks was predictive of DAS4v at 28 and 52 weeks. Female gender, current smoking, primary education and an interaction between baseline weight and C reactive protein (CRP) negatively impacted DAS4v reduction over 4 and 52 weeks. Time-varying effects of blood pressure, neutrophils, erythrocyte sedimentation rate and CRP also significantly influenced DAS4v over 52 weeks. CONCLUSIONS: Time-dependent data suggest that the largest reduction of DAS4v to combination DMARDs occurs in the first month of therapy, and this predicts subsequent response. Variables known to impact long-term treatment response in RA also impacted early DAS4v response to combination DMARDs.

T-cell autoreactivity to citrullinated autoantigenic peptides in rheumatoid arthritis patients carrying HLA-DRB1 shared epitope alleles.

INTRODUCTION: Anti-citrullinated peptide antibodies are found in rheumatoid arthritis (RA) patients with HLA-DRß chains encoding the shared epitope (SE) sequence. Citrullination increases self-antigen immunogenicity, through increased binding affinity to SE-containing HLA-DR molecules. To characterise T-cell autoreactivity towards citrullinated self-epitopes, we profiled responses of SE+ healthy controls and RA patients to citrullinated and unmodified epitopes of four autoantigens. METHODS: We compared T-cell proliferative and cytokine responses to citrullinated and native type II collagen 1,237 to 1,249, vimentin 66 to 78, aggrecan 84 to 103 and fibrinogen 79 to 91 in six SE+ healthy controls and in 21 RA patients with varying disease duration. Cytokine-producing cells were stained after incubation with peptide in the presence of Brefeldin-A. RESULTS: Although proliferative responses were low, IL-6, IL-17 and TNF were secreted by CD4+ T cells of SE+ RA patients and healthy controls, as well as IFNγ and IL-10 secreted by RA patients, in response to citrullinated peptides. Of the epitopes tested, citrullinated aggrecan was most immunogenic. Patients with early RA were more likely to produce IL-6 in response to no epitope or to citrullinated aggrecan, while patients with longstanding RA were more likely to produce IL-6 to more than one epitope. Cytokine-producing CD4+ T cells included the CD45RO+ and CD45RO- and the CD28+ and CD28- subsets in RA patients. CONCLUSION: Proinflammatory cytokines were produced by CD4+ T cells in SE+ individuals in response to citrullinated self-epitopes, of which citrullinated aggrecan was most immunogenic. Our data suggest that the T-cell response to citrullinated self-epitopes matures and diversifies with development of RA.

Two-year results from a community-wide diabetes prevention intervention in a high risk indigenous community: the Ngati and Healthy project.

We describe changes in markers and prevalence of glucose metabolism disorders following a 2-year community-wide intervention aimed at reducing insulin resistance (IR) prevalence in a high risk community. Surveys were undertaken before and 2 years after implementation of a community developed and led diabetes prevention program. Proportions and means were calculated and compared by sex and age groups: 25-49 years and 50+ years. A process evaluation contributed to interpretation of results. Response rates were around 50% and demographic characteristics similar in both surveys. Overall, IR prevalence decreased markedly from 35.5% to 25.4% (p=0.003). Most changes were observed amongst 25-49 years old women for whom there was a significant change in prevalences of IR and glucose metabolism disorders (p=0.015), largely due to reduced IR prevalence (38.2-25.6%). In 2006, 60.3% achieved minimum recommended exercise levels and 65.4% ate wholegrain bread compared with 45.1% (p=0.002) and 42.2% (p=0.044), respectively, in 2003. Participation in a community diabetes prevention intervention appeared to reduce IR prevalence after 2 years in those with the highest level of participation and most marked lifestyle changes.

Insulin resistance in a rural Maori community.

AIM: To determine the prevalence of insulin resistance, impaired fasting glycaemia, impaired glucose tolerance, and diabetes mellitus in a rural Maori community, and to compare different methods for identifying individuals with insulin resistance. METHODS: 589 randomly selected individuals from the Ngati Porou Hauora Register aged 25 years and over and resident on New Zealand's East Coast north of Gisborne were invited to participate in the study. A questionnaire was administered, anthropometric measures made, and blood samples taken for an oral glucose tolerance test and biochemical analysis. Impaired fasting glycaemia, impaired glucose tolerance, and diabetes mellitus were defined according to World Health Organization (WHO) diagnostic criteria, and among those persons with normal glucose tolerance, insulin resistance was calculated according to the McAuley formula and three other recognised methods for calculating insulin sensitivity. RESULTS: The overall age-standardised prevalence of diabetes (both known and newly diagnosed) was 10.6% and the age-standardised prevalence of insulin resistance was 37.0%. Age-specific diabetes rates were high among the older age groups, peaking at 34.1% for 60-69 year olds, whereas age-specific insulin resistance rates were high among the young age groups with the highest rate (44.3%) occurring among 30-39 year olds. Persons identifying as insulin-resistant reported higher rates of gout and family history of diabetes--and were found to have a higher waist circumference, blood pressure, and lower high-density lipoprotein (HDL) cholesterol than those without a glucose metabolism disorder. CONCLUSION: Diabetes is a common disorder among this population, but insulin resistance is even more prevalent, especially among young age groups. This is considerable cause for concern given that insulin resistance is believed to be the underlying cause of most cases of type 2 diabetes mellitus, and is confirmed by these data to be associated with a high degree of cardiovascular risk.