Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. METHODS: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. RESULTS: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs. CONCLUSIONS: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.

Outcomes of periodontal therapy in rheumatoid arthritis: The OPERA feasibility randomized trial.

AIM: Periodontitis is independently associated with rheumatoid arthritis (RA); however, there is limited data on whether periodontal treatment improves overall RA disease activity. We conducted a pilot feasibility randomized controlled clinical trial to test whether intensive periodontal therapy reduces RA disease activity in patients with active RA and periodontitis. MATERIALS AND METHODS: The following inclusion criteria were applied: patients with RA and periodontitis, aged 18+, stable on treatment with disease-modifying anti-rheumatic drugs for ≥3 months, disease activity score (DAS28) ≥3.2, and DAS28 >5.1 only if patient unwilling to take biologics. Participants meeting the inclusion criteria were randomized to immediate intensive periodontal therapy or to delayed therapy (control group) administered by a dental hygienist in a secondary care setting. Data were collected at baseline and at 3 and 6 months of follow-up. Participants randomized to the control group (delayed therapy) received the standard of care for the duration of the trial, including oral hygiene instructions delivered by a dental hygienist, and the same periodontal therapy as the intervention group after study completion (i.e., 6 months after randomization). The periodontal inflammation surface area was calculated using clinical attachment loss (CAL), periodontal probing pocket depth, and bleeding on probing. Cumulative probing depth was also measured. We examined the effect of periodontal therapy on periodontal outcomes and on clinical markers of disease activity in RA, as measured by the DAS28-C-reactive protein score as well as musculo-skeletal ultrasound grey scale and power Doppler scores. RESULTS: A total of 649 patients with RA were invited to participate in the study. Of these, 296 (46%) consented to participate in the screening visit. A sample of 201 patients was assessed for eligibility, of whom 41 (20%) did not meet the RA inclusion criteria and 100 (50%) did not meet the periodontal disease criteria. Among the 60 (30%) eligible participants, 30 were randomized to immediate periodontal therapy and 30 were allocated to the control group. The loss to follow-up was 18% at the end of the trial. There were no major differences with regard to baseline characteristics between the groups. Periodontal therapy was associated with reduced periodontal inflamed surface area, cumulative probing depths, RA disease activity scores, and ultrasound scores over the course of the trial. There was no change in CAL. CONCLUSIONS: Overall, the trial was feasible and acceptable to the study participants. Recruitment to and satisfactory retention in a randomized controlled trial on the effect of periodontal treatment on RA patients is possible, albeit challenging. In this feasibility study of patients with RA and periodontitis, periodontal treatment resulted in significant improvements in periodontal disease outcomes and overall RA disease activity, although complete resolution of periodontal inflammation was difficult to achieve in some cases.

The value of ultrasound-defined tenosynovitis and synovitis in the prediction of persistent arthritis.

OBJECTIVES: The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis. METHODS: One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months' follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables. RESULTS: At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis [odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002] provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis. CONCLUSION: US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development.

Systematic review of imaging tests to predict the development of rheumatoid arthritis in people with unclassified arthritis.

OBJECTIVE: To estimate and compare the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound, for the prediction of rheumatoid arthritis (RA) in unclassified arthritis (UA). METHODS: MEDLINE, Embase and BIOSIS were searched from 1987 to May 2019. Studies evaluating any imaging test in participants with UA were eligible. Reference standards were RA classification criteria or methotrexate initiation. Two authors independently extracted data and assessed validity using QUADAS-2. Sensitivities and specificities were calculated for each imaging characteristic and joint area. Summary estimates with 95% confidence intervals (CI) were estimated where possible. RESULTS: Nineteen studies were included; 13 evaluated MRI (n=1,143; 454 with RA) and 6 evaluated ultrasound (n=531; 205 with RA). Studies were limited by unclear recruitment procedures, inclusion of patients with RA at baseline, differential verification, lack of blinding and consensus grading. Study heterogeneity largely precluded meta-analysis, however summary sensitivity and specificity for MRI synovitis in at least one joint were 93% (95% CI 88%, 96%) and 25% (95% CI 13%, 41%) (3 studies). Specificities may be higher for other MRI characteristics but data are limited. Ultrasound results were difficult to synthesise due to different diagnostic thresholds and reference standards. CONCLUSION: The evidence for MRI or ultrasound as single tests for predicting RA in people with UA is heterogeneous and of variable methodological quality. Larger studies using consensus grading and consistently defined RA diagnosis are needed to identify whether combinations of imaging characteristics, either alone or in combination with other clinical findings, can better predict RA in this population.

Burden of chronic diseases associated with periodontal diseases: a retrospective cohort study using UK primary care data.

OBJECTIVES: To identify the association between periodontal diseases (gingivitis and periodontitis) and chronic diseases including cardiovascular disease, cardiometabolic disease, autoimmune disease and mental ill health. DESIGN: Retrospective cohort. SETTING: IQVIA Medical Research Data-UK between 1 January 1995 and 1 January 2019. PARTICIPANTS: 64 379 adult patients with a general practitioner recorded diagnosis of periodontal disease (exposed patients) were matched to 251 161 unexposed patients by age, sex, deprivation and registration date. MAIN OUTCOME MEASURES: Logistic regression models accounting for covariates of clinical importance were undertaken to estimate the adjusted OR (aOR) of having chronic diseases at baseline in the exposed compared with the unexposed group. Incidence rates for each outcome of interest were then provided followed by the calculation of adjusted HRs using cox regression modelling to describe the risk of outcome development in each group. RESULTS: The average age at cohort entry was 45 years and the median follow-up was 3.4 years. At study entry, the exposed cohort had an increased likelihood of having a diagnosis of cardiovascular disease (aOR 1.43; 95% CI 1.38 to 1.48), cardiometabolic disease (aOR 1.16; 95% CI 1.13 to 1.19), autoimmune disease (aOR 1.33; 95% CI 1.28 to 1.37) and mental ill health (aOR 1.79; 95% CI 1.75 to 1.83) compared with the unexposed group. During the follow-up of individuals without pre-existing outcomes of interest, the exposed group had an increased risk of developing cardiovascular disease (HR 1.18; 95% CI 1.13 to 1.23), cardiometabolic disease (HR 1.07; 95% CI 1.03 to 1.10), autoimmune disease (HR 1.33; 95% CI 1.26 to 1.40) and mental ill health (HR 1.37; 95% CI 1.33 to 1.42) compared with the unexposed group. CONCLUSIONS: In this cohort, periodontal diseases appeared to be associated with an increased risk of developing cardiovascular, cardiometabolic, autoimmune diseases and mental ill health. Periodontal diseases are very common; therefore, an increased risk of other chronic diseases represent a substantial public health burden.

Association Between Rheumatoid Arthritis Disease Activity and Periodontitis Defined by Tooth Loss: Longitudinal and Cross-Sectional Data From Two Observational Studies.

OBJECTIVE: To analyze the effect of tooth loss/periodontitis on disease activity in early and established rheumatoid arthritis (RA). METHODS: Participants of the Course And Prognosis of Early Arthritis (CAPEA) early arthritis cohort reported their number of teeth at baseline. The number of teeth had been validated as a predictor of periodontitis. Clinical end points, including disease activity score (Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ESR]), swollen joint count (SJC), ESR, and C-reactive protein level were collected at baseline, 3, 6, 12, 18, and 24 months. We used linear mixed regression models to estimate the association between tooth loss and clinical end points over time in early arthritis. For established RA, we analyzed cross-sectional data from the German National Database (NDB). All models accounted for age, sex, smoking, seropositivity, education level, and disease duration (only NDB). RESULTS: Among 1,124 CAPEA participants with early arthritis, those with higher tooth loss were older, more often male, smokers, and seropositive, and they had higher disease activity and inflammation markers at baseline. Tooth loss was associated with higher disease activity and ESR values over time. Inflammatory markers decreased comparably across tooth loss categories. Glucocorticoid use was higher among those with more tooth loss, whereas dose reduction was similar across tooth loss categories. Among 7,179 NDB participants with longstanding RA, disease activity and inflammation markers but not SJC were significantly higher in patients with more tooth loss. CONCLUSION: Although we observed an association between tooth loss and disease activity scores and inflammation markers in early and established RA, longitudinal results suggest that tooth loss does not hamper treatment response.

Mediterranean diet and risk of Sjögren's syndrome.

OBJECTIVES: Non-genetic risk factors for Sjögren's syndrome (SS) are poorly understood. Adherence to a Mediterranean diet has been associated with reduction in other autoimmune diseases. We examined the association of Mediterranean diet with SS. METHODS: New patients attending a single centre warranting investigation for primary SS (pSS) were recruited into the Optimising Assessment in Sjögren's Syndrome cohort established in Birmingham, UK (2014-2018). Participants were classified into pSS and non-SS sicca, considered as cases and non-cases, respectively, and asked to complete an optional food frequency questionnaire on their diet before onset of symptoms. A semi-quantitative Mediterranean diet score (MDS) was calculated (possible range=0 to 18). Using multivariate logistic regression, corrected for energy intake, body-mass index, sex, age, symptom duration, and smoking status, we examined the association of MDS with SS. RESULTS: Dietary data were available for 133/243 (55%) eligible patients (n=82 pSS and n=51 sicca). In the adjusted model, a higher total MDS (mean ± SD, 9.41±2.31 points) was associated with lower odds of pSS (OR 0.81, 95% CI 0.66-0.99; p=0.038) per one unit of MDS. Among MDS components, the strongest association was seen with fish with OR 0.44 (95% CI 0.24-0.83; p=0.01) in the comparison between <1 portion/week and 1 to 2.5 portions/week. Higher galactose, vitamin A-retinol-equivalents and vitamin C showed associations with lower odds of pSS in multivariate analysis, where the association of vitamin C was attenuated when adjusted for MDS. CONCLUSIONS: When adjusted for potential confounders, adherence to the Mediterranean diet was associated with lower likelihood of having pSS.

Gums and joints: is there a connection? Part two: the biological link.

Rheumatoid arthritis (RA) and periodontitis (PD) are inflammatory diseases characterised by an exacerbated immune-inflammatory reaction that leads to the destruction of bone and other connective tissues that share numerous similarities. Although a significant and independent association between these two conditions has been described, the pathophysiological processes that may explain this relationship remain unknown and multiple theories have been proposed. This review presents the most important theories currently proposed to explain the biological link between RA and PD.

Gums and joints: is there a connection? Part one: epidemiological and clinical links.

Rheumatoid arthritis (RA) and chronic periodontitis are common chronic inflammatory diseases that share numerous clinical and pathobiological characteristics. Due to their similarities, despite manifesting at anatomically distinct sites, the relationship between these two diseases has been investigated for many years. This review attempts to summarise the state of the field based on evidence published in the last ten years.

The role of ultrasound-defined tenosynovitis and synovitis in the prediction of rheumatoid arthritis development.

OBJECTIVES: Tenosynovitis (TS) is common in early arthritis. However, the value of US-defined TS in predicting RA development is unclear. We assessed the predictive utility of US-defined TS alongside US-defined synovitis and clinical and serological variables in a prospective cohort of early arthritis patients. METHODS: One hundred and seven patients with clinically apparent synovitis of one or more joint and symptom duration ⩽3 months underwent baseline clinical, laboratory and US assessment of 19 bilateral joint sites and 16 bilateral tendon compartments. Diagnostic outcome was determined after 18 months, applying the 2010 ACR/EULAR classification criteria for RA. The predictive values of US-defined TS for persistent RA were compared with those of US-defined synovitis, clinical and serological variables. RESULTS: A total of 4066 US joint sites and 3424 US tendon compartments were included in the analysis. Forty-six patients developed persistent RA, 17 patients developed non-RA persistent disease and 44 patients had resolving disease at follow-up. US-defined TS in at least one tendon compartment at baseline was common in all groups (RA 85%, non-RA persistent disease 71% and resolving 70%). On multi-variate analysis, US-defined digit flexor TS provided independent predictive data over and above the presence of ACPA and US-defined joint synovitis. CONCLUSION: US-defined digit flexor TS provided independent predictive data for persistent RA development in patients with early arthritis. The predictive utility of this tendon site should be further assessed in a larger cohort; investigators designing imaging-based predictive algorithms for RA development should include this tendon component as a candidate variable.

Dysbiotic Subgingival Microbial Communities in Periodontally Healthy Patients With Rheumatoid Arthritis.

OBJECTIVE: Studies that demonstrate an association between rheumatoid arthritis (RA) and dysbiotic oral microbiomes are often confounded by the presence of extensive periodontitis in these individuals. This study was undertaken to investigate the role of RA in modulating the periodontal microbiome by comparing periodontally healthy individuals with RA to those without RA. METHODS: Subgingival plaque was collected from periodontally healthy individuals (22 with RA and 19 without RA), and the 16S gene was sequenced on an Illumina MiSeq platform. Bacterial biodiversity and co-occurrence patterns were examined using the QIIME and PhyloToAST pipelines. RESULTS: The subgingival microbiomes differed significantly between patients with RA and controls based on both community membership and the abundance of lineages, with 41.9% of the community differing in abundance and 19% in membership. In contrast to the sparse and predominantly congeneric co-occurrence networks seen in controls, RA patients revealed a highly connected grid containing a large intergeneric hub anchored by known periodontal pathogens. Predictive metagenomic analysis (PICRUSt) demonstrated that arachidonic acid and ester lipid metabolism pathways might partly explain the robustness of this clustering. As expected from a periodontally healthy cohort, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were not significantly different between groups; however, Cryptobacterium curtum, another organism capable of producing large amounts of citrulline, emerged as a robust discriminant of the microbiome in individuals with RA. CONCLUSION: Our data demonstrate that the oral microbiome in RA is enriched for inflammophilic and citrulline-producing organisms, which may play a role in the production of autoantigenic citrullinated peptides in RA.

High erythrocyte levels of the n-6 polyunsaturated fatty acid linoleic acid are associated with lower risk of subsequent rheumatoid arthritis in a southern European nested case-control study.

OBJECTIVES: Findings relating to dietary intake of n-3 polyunsaturated fatty acids (PUFA) and risk of rheumatoid arthritis (RA) are mixed. Erythrocyte membrane PUFA is an accurate objective biomarker of PUFA status; however, there are little data on erythrocyte membrane PUFA and risk of RA. The objective was therefore to compare erythrocyte membrane PUFA between pre-RA individuals and matched controls from a population-based sample, and specifically to test the hypothesis that higher levels of longer chain n-3 PUFA are associated with lower risk of RA. METHODS: The European Prospective Investigation into Cancer and Nutrition (EPIC) is a large European prospective cohort study of apparently healthy populations. We undertook a nested case-control study by identifying RA cases with onset after enrolment (pre-RA) in four EPIC cohorts in Italy and Spain. Confirmed pre-RA cases were matched with controls by age, sex, centre, and date, time and fasting status at blood collection. Conditional logistic regression analysis was used to estimate associations of PUFA with the development of RA, adjusting for potential confounders including body mass index, waist circumference, education level, physical activity, smoking status and alcohol intake. RESULTS: The study analysed samples from 96 pre-RA subjects and 258 matched controls. In this analysis, the median time to diagnosis (defined as time between date of blood sample and date of diagnosis) was 6.71 years (range 0.8-15). A significant inverse association was observed with n-6 PUFA linoleic acid (LA) levels and pre-RA in the fully adjusted model (highest tertile: OR 0.29; 95% CI 0.12 to 0.75; P for trend 0.01). No association was observed with any individual n-3 PUFA, total n-3 PUFA or total n-3:n-6 ratio. CONCLUSIONS: Erythrocyte levels of the n-6 PUFA LA were inversely associated with risk of RA, whereas no associations were observed for other n-6 or n-3 PUFA. Further work is warranted to replicate these findings and to investigate if lower LA levels are a bystander or contributor to the process of RA development.

Periodontitis prevalence and serum antibody reactivity to periodontal bacteria in primary Sjögren's syndrome: a pilot study.

AIMS: The aims of this study were as follows: (i) To assess the prevalence of periodontitis among patients with primary Sjögren's syndrome (pSS) and comparator groups of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). (ii) To perform a pilot study to compare serum antibody responses to 10 oral/periodontal bacteria in these patient groups and a historical comparator group of patients with periodontitis. MATERIALS AND METHODS: Standard clinical periodontal assessments were performed on 39 pSS, 36 RA and 23 OA patients and "In-house" antibody ELISAs for serum antibodies against 10 oral/periodontal bacteria were performed in these groups. RESULTS: Forty-six percent of the pSS group, 64% of the RA group and 48% of the OA group had moderate/severe periodontitis. These frequencies did not reach statistical significance between groups. Raised antibody levels to Prevotella denticola were found in the pSS, RA and periodontitis groups compared to the OA group. Significant between group differences were seen for Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Campylobacter showae. None of these differences were specifically associated with pSS. CONCLUSION: This study showed no increase in periodontitis in pSS patients. Although the P. denticola data are of interest, identifying bacterial triggering factors for pSS will likely require alternative strategies including modern techniques such as microbiome analysis.

Smoking, Porphyromonas gingivalis and the immune response to citrullinated autoantigens before the clinical onset of rheumatoid arthritis in a Southern European nested case-control study.

BACKGROUND: Antibodies to citrullinated proteins (ACPA) occur years before RA diagnosis. Porphyromonas gingivalis expresses its own peptidylarginine deiminase (PPAD), and is a proposed aetiological factor for the ACPA response. Smoking is a risk factor for both ACPA-positive RA and periodontitis. We aimed to study the relation of these factors to the risk of RA in a prospective cohort. METHODS: We performed a nested case-control study by identifying pre-RA cases in four populations from the European Prospective Investigation into Cancer and nutrition, matched with three controls. Data on smoking and other covariates were obtained from baseline questionnaires. Antibodies to CCP2 and citrullinated peptides from α-enolase, fibrinogen, vimentin and PPAD were measured. Antibodies to arginine gingipain (RgpB) were used as a marker for P.gingivalis infection and validated in a separate cohort of healthy controls and subjects with periodontitis. RESULTS: We studied 103 pre-RA cases. RA development was associated with several ACPA specificities, but not with antibodies to citrullinated PPAD peptides. Antibody levels to RgpB and PPAD peptides were higher in smokers but were not associated with risk of RA or with pre-RA autoimmunity. Former but not current smoking was associated with antibodies to α-enolase (OR 4.06; 95 % CI 1.02, 16.2 versus 0.54; 0.09-3.73) and fibrinogen peptides (OR 4.24; 95 % CI 1.2-14.96 versus 0.58; 0.13-2.70), and later development of RA (OR 2.48; 95 % CI 1.27-4.84 versus 1.57; 0.85-2.93), independent of smoking intensity. CONCLUSIONS: Smoking remains a risk factor for RA well before the clinical onset of disease. In this cohort, P.gingivalis is not associated with pre-RA autoimmunity or risk of RA in an early phase before disease-onset. Antibodies to PPAD peptides are not an early feature of ACPA ontogeny.

Diagnostic outcomes associated with ankle synovitis in early inflammatory arthritis: a cohort study.

OBJECTIVES: To examine the diagnostic outcomes associated with clinical ankle synovitis in an early inflammatory arthritis cohort. METHODS: Data from the Birmingham early inflammatory arthritis cohort (BEACON) were used to obtain information about baseline disease and demographic variables and diagnostic outcomes at 18 month follow-up. The prevalence of clinical ankle synovitis (defined as joint swelling on examination) was calculated. Relative risk (RR) and 95% confidence interval (95% CI) were used to estimate whether clinical ankle synovitis at baseline predicts diagnostic outcomes independent of age, sex, baseline 66-joint swollen joint count, and presence of either rheumatoid factor (RF) or anti-CCP antibody. RESULTS: 324 patients (52% women) were included. 103 had clinical ankle synovitis at the first clinic visit. Patients with bilateral ankle synovitis were more likely to be classified as having acute sarcoid arthritis (aRR (95%CI) 10.15 (1.13-90.89)). Among patients presenting with oligoarthritis and seronegative for RF and anti-CCP antibodies those with ankle synovitis were significantly more likely to be classified as having seronegative spondyloarthritis (RR (95%CI) 6.15 (1.58-23.88) and unclassified arthritis (RR (95%CI) 4.07 (1.05-15.81)) than RA. CONCLUSIONS: Current predictive algorithms for patients with early arthritis focus on the prediction of RA or persistent arthritis. This alternative approach focused on a specific joint shows that baseline ankle synovitis predicts specific diagnostic outcomes besides RA. Future work should address the development of models to predict the totality of potential outcomes based on clinical phenotype and the results of routinely available investigations and clinical data.

Vitamin B12 deficiency is associated with geographical latitude and solar radiation in the older population.

BACKGROUND: Vitamin B12 and folic acid deficiency are common in the older and are associated with several conditions including anaemia, cardiovascular disease, cognitive impairment and cancer. Evidence from in vitro studies suggests that solar radiation can degrade both vitamins in the skin. Chile is the longest country in the world running perfectly North-South making it an ideal place to study potential associations of latitude and solar radiation on vitamin B12 and folic acid deficiency. OBJECTIVES: The objective was to examine the association between vitamin B12 and folic acid deficiencies and latitude. METHODS: Plasma samples were collected from Chileans aged 65+ years (n=1013) living across the whole country and assayed for vitamin B12 and folic acid concentrations as part of the Chilean Health Survey 2009-2010, which is a national representative sample study. RESULTS: Overall, the prevalence of vitamin B12 deficiency was 11.3%, with the prevalence in the North of the country being significantly greater than in the Central and South zones (19.1%,10.5%, and 5.7%, respectively; P<0.001). The prevalence of folic acid deficiency in the whole cohort was 0.7% with no difference between the 3 geographical zones. Using logistic regression analyses, vitamin B12 deficiency was significantly associated with geographical latitude (OR 0.910 [95% confidence intervals 0.890-0.940], P<0.001) and solar radiation (OR 1.203 [95% confidence intervals 1.119-1.294], P<<0.001). These associations persisted after adjustments for confounders (OR 0.930, P<0.001 and 1.198, P=0.002, respectively). CONCLUSIONS: In the Chilean population of 65+, the prevalence of vitamin B12 deficiency is associated with living closer to the Equator and solar radiation. Although degradation by solar radiation might explain this observation, further work is required to establish the potential mechanisms. In countries that routinely fortify food with folic acid, efforts to identify vitamin B12 deficiency might be more cost-efficiently targeted in areas closest to the Equator.

The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis?

BACKGROUND: Studies suggest that periodontitis may be a risk factor for rheumatoid arthritis (RA). The purpose of this study was to determine whether periodontitis is associated with autoantibodies characteristic of RA. METHODS: Serum samples were tested for anti-cyclic citrullinated peptide (CCP), anti-mutated citrullinated vimentin (MCV), anti-citrullinated α-enolase peptide-1 (CEP-1), anti-citrullinated vimentin (cit-vim), anti-citrullinated fibrinogen (cit-fib) and their uncitrullinated forms anti-CParg (negative control for anti-CCP), anti-arginine-containing α-enolase peptide-1 (REP-1), anti-vimentin and anti-fibrinogen antibodies in patients with and without periodontitis, none of whom had RA. RESULTS: Periodontitis, compared with non-periodontitis, was associated with a normal frequency of anti-CCP and anti-MCV (∼1%) but a higher frequency of positive anti-CEP-1 (12% vs 3%; p=0.02) and its uncitrullinated form anti-REP-1 (16% vs 2%; p<0.001). Positive antibodies against uncitrullinated fibrinogen and CParg were also more common among those with periodontitis compared to non-periodontitis patients (26% vs 3%; p<0.001, and 9% vs 3%; p=0.06). After adjusting for confounders, patients with periodontitis had 43% (p=0.03), 71% (p=0.002) and 114% (p<0.001) higher anti-CEP-1, anti-REP-1 and anti-fibrinogen titres, compared with non-periodontitis. Non-smokers with periodontitis, compared with non-periodontitis, had significantly higher titres of anti-CEP-1 (103%, p<0.001), anti-REP-1 (91%, p=0.001), anti-vimentin (87%, p=0.002), and anti-fibrinogen (124%, p<0.001), independent of confounders, confirming that the autoantibody response in periodontitis was not due to smoking. CONCLUSIONS: We have shown that the antibody response in periodontitis is predominantly directed to the uncitrullinated peptides of the RA autoantigens examined in this study. We propose that this loss of tolerance could then lead to epitope spreading to citrullinated epitopes as the autoimmune response in periodontitis evolves into that of presymptomatic RA.