Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis.

OBJECTIVE: To identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype. METHODS: A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems. RESULTS: rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619. CONCLUSIONS: Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Complications after proton radiotherapy in children, focusing on severe late complications. A complete Swedish cohort 2008-2019.

BACKGROUND: Proton radiotherapy (RT) is an attractive tool to deliver local therapy with minimal dose to uninvolved tissue, however, not suitable for all patients. The aim was to explore complications, especially severe late complications (grades 3-4), following proton RT delivered to a complete Swedish cohort of paediatric patients aged <18 years treated 2008-2019. MATERIAL AND METHODS: Data was downloaded from a national registry. Complications with a possible causation with RT are reported. Proton treatments until July 2015 was performed with a fixed horizontal 172 MeV beam (The Svedberg Laboratory (TSL), Uppsala) in a sitting position and thereafter with gantry-based pencil-beam scanning technique (Skandion Clinic, Uppsala) in a supine position. RESULTS: 219 courses of proton RT (77 at TSL and 142 at Skandion) were delivered to 212 patients (mean age 9.2 years) with various tumour types (CNS tumours 58%, sarcomas 26%, germ cell tumours 7%). Twenty-five patients had severe acute complications (skin, mucous membrane, pharynx/oesophagus, larynx, upper gastrointestinal canal, lower gastrointestinal canal, eyes, ears). Fifteen patients had severe late complications; with increased proportion over time: 4% at 1-year follow-up (FU), 5% at 3-year, 11% at 5-year. Organs affected were skin (1 patient), subcutaneous tissue (4), salivary glands (1), upper GI (1), bone (7), joints (2), CNS (2), PNS (1), eyes (1) and ears (5). Twenty-one of the 28 patients with 10-year FU had at least one late complication grades 1-4 and fourteen of them had more than one (2-5 each). CONCLUSION: The most important result of our study is the relatively low proportion of severe late complications, comparable with other proton studies on various tumours. Furthermore, the numbers of late complications are lower than our own data set on a mixed population of photon and proton treated paediatric patients, assuring the safety of using proton therapy also in the clinical practice.

Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA.

OBJECTIVE: To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). METHODS: Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. RESULTS: PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. CONCLUSION: We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Elastin levels are higher in healing tendons than in intact tendons and influence tissue compliance.

Elastic fibers containing elastin play an important role in tendon functionality, but the knowledge on presence and function of elastin during tendon healing is limited. The aim of this study was to investigate elastin content and distribution in intact and healing Achilles tendons and to understand how elastin influence the viscoelastic properties of tendons. The right Achilles tendon was completely transected in 81 Sprague-Dawley rats. Elastin content was quantified in intact and healing tendons (7, 14, and 28 days post-surgery) and elastin distribution was visualized by immunohistochemistry at 14 days post-surgery. Degradation of elastin by elastase incubation was used to study the role of elastin on viscoelastic properties. Mechanical testing was either performed as a cyclic test (20× 10 N) or as a creep test. We found significantly higher levels of elastin in healing tendons at all time-points compared to intact tendons (4% in healing tendons 28 days post-surgery vs 2% in intact tendons). The elastin was more widely distributed throughout the extracellular matrix in the healing tendons in contrast to the intact tendon where the distribution was not so pronounced. Elastase incubation reduced the elastin levels by approximately 30% and led to a 40%-50% reduction in creep. This reduction was seen in both intact and healing tendons. Our results show that healing tendons contain more elastin and is more compliable than intact tendons. The role of elastin in tendon healing and tissue compliance indicates a protective role of elastic fibers to prevent re-injuries during early tendon healing. PLAIN LANGUAGE SUMMARY: Tendons transfer high loads from muscles to bones during locomotion. They are primarily made by the protein collagen, a protein that provide strength to the tissues. Besides collagen, tendons also contain other building blocks such as, for example, elastic fibers. Elastic fibers contain elastin and elastin is important for the extensibility of the tendon. When a tendon is injured and ruptured the tissue heals through scar formation. This scar tissue is different from a normal intact tendon and it is important to understand how the tendons heal. Little is known about the presence and function of elastin during healing of tendon injuries. We have shown, in animal experiments, that healing tendons have higher amounts of elastin compared to intact tendons. The elastin is also spread throughout the tissue. When we reduced the levels of this protein, we discovered altered mechanical properties of the tendon. The healing tendon can normally extend quite a lot, but after elastin removal this extensibility was less obvious. The ability of the healing tissue to extend is probably important to protect the tendon from re-injuries during the first months after rupture. We therefore propose that the tendons heal with a large amount of elastin to prevent re-ruptures during early locomotion.

Secretory anti-citrullinated protein antibodies in serum associate with lung involvement in early rheumatoid arthritis.

OBJECTIVE: A 'mucosal connection' in RA presently attracts increasing attention. We recently described the occurrence of secretory antibodies to citrullinated protein (SC-ACPA) in sera from patients with recent-onset RA. The current study was performed to evaluate possible associations between serum levels of secretory ACPA and signs of lung involvement in patients with early, untreated RA. METHODS: One hundred and forty-two RA patients were included as part of the 'LUng Investigation in newly diagnosed RA' study. One hundred and six patients were examined with high-resolution CT (HRCT) and 20 patients underwent bronchoscopy, where bronchial biopsies and bronchoalveolar lavage fluid (BALF) samples were obtained. SC-ACPA in serum and BALF were detected by an enzyme-linked immunoassay. Antibody levels were related to smoking history, pulmonary function, HRCT, BALF cell counts and findings in bronchial biopsies. RESULTS: SC-ACPA occurred in 16% of the serum samples and in 35% of the BALF samples. SC-ACPA levels in serum correlated with SC-ACPA levels in BALF (σ = 0.50, P = 0.027) and were higher among patients with HRCT parenchymal lung abnormalities (P = 0.022) or bronchiectasis (P = 0.042). Also, ever smoking was more frequent among serum SC-ACPA-positive patients (91% vs 67%, P = 0.023), and the SC-ACPA levels correlated with the number of pack-years (σ=0.20, P = 0.020). CONCLUSION: In early, untreated RA, serum levels of SC-ACPA reflect lung involvement in terms of local ACPA levels, smoking and lung abnormalities on HRCT. These findings strengthen the link between mucosal ACPA responses and the lungs in RA.

Antibodies to citrullinated peptides in serum and saliva in patients with rheumatoid arthritis and their association to periodontitis.

OBJECTIVES: A connection between prevalence of rheumatoid arthritis (RA) and periodontitis has been reported. The hypothesis for this association involves increased citrullination in the oral mucosa in patients with periodontitis. Whether ongoing periodontitis has an effect on IgA antibodies to citrullinated peptides (ACPA) in saliva is unknown. We studied IgA ACPA in saliva and serum and their relation to periodontitis and smoking in a population-based elderly RA cohort. METHODS: A population-based cohort of patients with RA ≥61 years of age (n=132) was examined by rheumatologists and a dental hygienist. Analyses of IgG ACPA in serum and IgA ACPA in serum and saliva were performed. The presence of ACPA was compared in patients with RA with and without periodontitis. RESULTS: IgA ACPA in serum occurred in 35% of RA patients with periodontitis and in 43% of RA patients without periodontitis (p=0.740). IgG ACPA in serum was found in 66% of RA patients with periodontitis, and in 69% without periodontitis (p=0.740). IgA ACPA in saliva occurred in 20% with periodontitis and 55% without periodontitis (p=0.062). A logistic regression analysis adjusting for age, gender and smoking gave an odds ratio (OR) of 0.456 (95% CI=0.183-1.137, p=0.092) for saliva IgA ACPA positive individuals to have periodontitis. CONCLUSIONS: IgA ACPA in serum or saliva was not more common in RA patients with periodontitis. This implies that local production of ACPA by the oral mucosa is not enhanced by periodontal inflammation, in patients with established RA.

Weight change among normal weight, overweight and obese employees and subsequent diagnosis-specific sickness absence: A register-linked follow-up study.

Aims: Obesity and weight change are associated with sickness absence; however, less is known about the diagnoses for sickness absence. We examined the association between stable and changing weight by body mass index groups with sickness absence due to any, musculoskeletal and mental diagnoses among midlife female and male employees. Methods: The Finnish Helsinki Health Study phase 1 survey took place in 2000-2002 (response rate 67%) and phase 2 in 2007 (response rate 83%). Based on self-reported body mass index, we calculated the weight change between phases 1 and 2 (body mass index change ⩾5%). The data were linked with registers of the Social Insurance Institution of Finland, including information on diagnoses (ICD-10) for sickness absence >9 days. We used a negative binom ial model to examine the association with sickness absence among 3140 women and 755 men during the follow-up (2007-2013). Results are presented as rate ratios. Covariates were age, sociodemographic factors, workload, health behaviors and prior sickness absence. Results: Weight-gain (rate ratio range=1.27-2.29), overweight (rate ratio range=1.77-2.02) and obesity (rate ratio range=2.16-2.29) among women were associated with a higher rate of sickness absence due to musculoskeletal diseases, compared to weight-maintaining normal-weight women. Similarly, obesity among men was associated with sickness absence due to musculoskeletal diseases (rate ratio range=1.55-3.45). Obesity among women (rate ratio range=1.54-1.72) and weight gain among overweight men (rate ratio=3.67; confidence interval=1.72-7.87) were associated with sickness absence due to mental disorders. Conclusions: Obesity and weight gain were associated with a higher rate of sickness absence, especially due to musculoskeletal diseases among women. Preventing obesity and weight gain likely helps prevent sickness absence.

Work disability in gout: a population-based case-control study.

OBJECTIVES: To examine the extent and cost of work disability among patients with gout compared with matched population controls and to analyse predictors of work disability. METHODS: A regional cohort study using data from Swedish national and regional registries from January 2000 through December 2012, including 4571 patients with gout of working age, with a first recorded diagnosis of gout in the years 2003-2009 and 22 482 population controls, matched by age, sex and place of residence. Differences in baseline characteristics (educational level, income, previous employment and comorbidities) and the number of work-loss days (absenteeism) due to sick leave and disability pension for 3 years after identification were calculated. Predictors for new-onset work absenteeism (>90 days/year) in a subset were determined by conditional logistic regression. RESULTS: Patients with gout (median age 53 years) had significantly more comorbidities, lower income and lower level of education than matched controls. The average work absentee rate during the 3-year follow-up period was higher among patients with gout than controls, 22% and 14%, respectively (P<0.0001). New-onset absenteeism was in multivariate analyses significantly predicted by gout (OR 1.47; 95% CI 1.23 to 1.75). Other variables independently related to new-onset absenteeism were education ≤12 years, previous unemployment and history of sick leave, in addition to several comorbidities (renal disease, cardiovascular disease, alcohol abuse and obesity). CONCLUSIONS: Gout is associated with substantially higher work absenteeism and costs for society due to productivity loss, after adjusting for associated comorbidities and socioeconomic differences. Whether more intensive treatment of gout is cost-effective needs to be addressed in future studies.

Obesity, change of body mass index and subsequent physical and mental health functioning: a 12-year follow-up study among ageing employees.

BACKGROUND: Studies suggest an association between weight change and subsequent poor physical health functioning, whereas the association with mental health functioning is inconsistent. We aimed to examine whether obesity and change of body mass index among normal weight, overweight and obese women and men associate with changes in physical and mental health functioning. METHODS: The Helsinki Health Study cohort includes Finnish municipal employees aged 40 to 60 in 2000-02 (phase 1, response rate 67%). Phase 2 mail survey (response rate 82%) took place in 2007 and phase 3 in 2012 (response rate 76%). This study included 5668 participants (82% women). Seven weight change categories were formed based on body mass index (BMI) (phase 1) and weight change (BMI change ≥5%) (phase 1-2). The Short Form 36 Health Survey (SF-36) measured physical and mental health functioning. The change in health functioning (phase 1-3) score was examined with repeated measures analyses. Covariates were age, sociodemographic factors, health behaviours, and somatic ill-health. RESULTS: Weight gain was common among women (34%) and men (25%). Weight-gaining normal weight (-1.3 points), overweight (-1.3 points) and obese (-3.6 points) women showed a greater decline in physical component summary scores than weight-maintaining normal weight women. Among weight-maintainers, only obese (-1.8 points) women showed a greater decline than weight-maintaining normal weight women. The associations were similar, but statistically non-significant for obese men. No statistically significant differences in the change in mental health functioning occurred. CONCLUSION: Preventing weight gain likely helps maintaining good physical health functioning and work ability.

Antibacterial effects of Lactobacillus and bacteriocin PLNC8 αß on the periodontal pathogen Porphyromonas gingivalis.

BACKGROUND: The complications in healthcare systems associated with antibiotic-resistant microorganisms have resulted in an intense search for new effective antimicrobials. Attractive substances from which novel antibiotics may be developed are the bacteriocins. These naturally occurring peptides are generally considered to be safe and efficient at eliminating pathogenic bacteria. Among specific keystone pathogens in periodontitis, Porphyromonas gingivalis is considered to be the most important pathogen in the development and progression of chronic inflammatory disease. The aim of the present study was to investigate the antimicrobial effects of different Lactobacillus species and the two-peptide bacteriocin PLNC8 αß on P. gingivalis. RESULTS: Growth inhibition of P. gingivalis was obtained by viable Lactobacillus and culture media from L. plantarum NC8 and 44048, but not L. brevis 30670. The two-peptide bacteriocin from L. plantarum NC8 (PLNC8 αß) was found to be efficient against P. gingivalis through binding followed by permeabilization of the membranes, using Surface plasmon resonance analysis and DNA staining with Sytox Green. Liposomal systems were acquired to verify membrane permeabilization by PLNC8 αß. The antimicrobial activity of PLNC8 αß was found to be rapid (1 min) and visualized by TEM to cause cellular distortion through detachment of the outer membrane and bacterial lysis. CONCLUSION: Soluble or immobilized PLNC8 αß bacteriocins may be used to prevent P. gingivalis colonization and subsequent pathogenicity, and thus supplement the host immune system against invading pathogens associated with periodontitis.

Obesity and psychotropic medication: a prospective register linkage study among midlife women and men.

BACKGROUND: Both obesity and mental health are major public health issues. This study aimed to examine whether overweight and obesity among midlife employees are associated with subsequent psychotropic medication. A further aim was to examine the potential effect of key covariates on the association. METHODS: The Helsinki Health Study baseline survey was conducted in 2000-2002 among 40-60-year-old employees of the City of Helsinki, Finland (n = 8960). The participants were classified as of normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), obese (30-34.9 kg/m(2)) or severely obese (≥35 kg/m(2)) based on self-reported body mass index. Data on psychotropic medication purchases from baseline to 2009 were derived from registers of the Social Insurance Institution of Finland. The final analysis included 4760 women and 1338 men. Antidepressants and sedatives were examined separately. Covariates included socio-demographic factors, workload, health behaviours, physical functioning, somatic ill-health and psychotropic medication prior to baseline. Hazard ratios (HR) for the first psychotropic medication purchase were calculated using Cox regression analysis. RESULTS: Third of women and quarter of men made at least one psychotropic medication purchase during the follow-up. Adjusting for age, obese (HR = 1.57; 95 % CI = 1.10-2.24) and severely obese (HR = 2.15; 95 % CI = 1.29-3.56) men were at risk of having psychotropic medication compared to men of normal weight. These associations disappeared after further adjustment. Severe obesity remained associated with subsequent sedative medication among the men even after full adjustment (HR = 2.12; 95 % CI = 1.17-3.84). No associations were found among the women. CONCLUSIONS: Obese and severely obese men, but not women, were at risk of psychotropic medication. Further studies are needed to deepen understanding of the relationship between obesity and mental ill-health, and the possible protecting effects of age, employment, and living environment.

Total Nitrite and Nitrate Concentration in Human Milk and Saliva during the First 60 Days Postpartum-A Pilot Study.

Nitric oxide (NO) in human milk may have important functions in lactation and infant health. This longitudinal pilot cohort study investigated the total nitrite and nitrate (NOx) concentration in human milk and maternal saliva during the first 60 days postpartum. Additionally, we explored the association between selected breastfeeding variables and milk and saliva NOx concentration. Human milk and maternal saliva samples were collected on days 2, 5, 14, 30, and 60 postpartum and analyzed for NOx concentration. Breastfeeding data were collected through self-assessed questions. Data analyses were performed using mixed models. The concentration of NOx in milk was significantly higher during the first 30 days compared to day 60, and there was a positive association between milk and saliva NOx concentrations throughout the entire study period. In absolute numbers, partially breastfeeding mothers had a lower concentration of NOx in milk on day 2 compared to exclusively breastfeeding mothers (8 vs. 15.1 µM, respectively). Partially breastfeeding mothers reported a later start of secretory activation and fewer mothers in this group started breastfeeding within the first hour after birth. Due to the small numbers, these differences could not be statistically evaluated. Further research is warranted to elucidate the role of NO in lactation success and breastfeeding outcomes.

The Joint Contributions of Overweight/Obesity and Physical and Mental Working Conditions to Short and Long Sickness Absence among Young and Midlife Finnish Employees: A Register-Linked Follow-Up Study.

INTRODUCTION: Overweight/obesity and strenuous working conditions are associated with work disability, but their joint contributions to sickness absence (SA) are unknown. We aimed to examine their joint contributions to SA periods of 1-7 and ≥8 days. METHODS: Self-reported data on body mass index and working conditions, including perceived physically and mentally strenuous work and hours per day spent in heavy physical work, were linked to the employer's SA register for the City of Helsinki, Finland, employees (n = 4,323, women 78%) who were 19-39 years old at baseline. We calculated rate ratios (RRs) and 95% confidence intervals (CIs) for SA periods using negative binomial regression models among participants with healthy weight and overweight/obesity, with and without exposure to strenuous working conditions. The mean follow-up time was 2.1 years. RESULTS: Participants with overweight/obesity and exposure to physically strenuous working conditions had the highest age- and gender-adjusted RRs for SA periods of both 1-7 and ≥8 days (physically strenuous work: RR: 1.38, CI: 1.25-1.52, and RR: 1.87, CI: 1.60-2.18, respectively; ≥3 h per day spent in physical work: RR: 1.40, CI: 1.26-1.55 and 2.04, CI: 1.73-2.40, respectively). The interaction between overweight/obesity and physically strenuous working conditions was additive for SA periods of 1-7 days and weakly synergistic for SA periods of ≥8 days. For mentally strenuous work, participants with overweight/obesity and exposure to mentally strenuous work had the highest age-adjusted RRs for SA periods of ≥8 days, and the interaction was additive. CONCLUSION: The joint contributions of overweight/obesity and exposure to strenuous working conditions to SA should be considered when aiming to reduce employees' SA. Employers might benefit from providing employees adequate support for weight management and adherence to healthy lifestyles while improving employees' working conditions.

Presence and Immunoreactivity of Aggregatibacter actinomycetemcomitans in Rheumatoid Arthritis.

The presence of periodontal pathogens is associated with an increased prevalence of rheumatoid arthritis (RA). The systemic antibody response to epitopes of these bacteria is often used as a proxy to study correlations between bacteria and RA. The primary aim of the present study is to examine the correlation between the presence of Aggregatibacter actinomycetemcomitans (Aa) in the oral cavity and serum antibodies against the leukotoxin (LtxA) produced by this bacterium. The salivary presence of Aa was analyzed with quantitative PCR and serum LtxA ab in a cell culture-based neutralization assay. The analyses were performed on samples from a well-characterized RA cohort (n = 189) and a reference population of blood donors (n = 101). Salivary Aa was present in 15% of the RA patients and 6% of the blood donors. LtxA ab were detected in 19% of RA-sera and in 16% of sera from blood donors. The correlation between salivary Aa and serum LtxA ab was surprisingly low (rho = 0.55 [95% CI: 0.40, 0.68]). The presence of salivary Aa showed no significant association with any of the RA-associated parameters documented in the cohort. A limitation of the present study is the relatively low number of individuals with detectable concentrations of Aa in saliva. Moreover, in the comparison of detectable Aa prevalence between RA patients and blood donors, we assumed that the two groups were equivalent in other Aa prognostic factors. These limitations must be taken into consideration when the result from the study is interpreted. We conclude that a systemic immune response to Aa LtxA does not fully reflect the prevalence of Aa in saliva. In addition, the association between RA-associated parameters and the presence of Aa was negligible in the present RA cohort.

Antibodies to leukotoxin A from the periodontal pathogen Aggregatibacter actinomycetemcomitans in patients at an increased risk of rheumatoid arthritis.

Objectives: Periodontitis and underlying bacteria have been linked to the development of rheumatoid arthritis (RA). One suggested pathogen is Aggregatibacter actinomycetemcomitans (A.a.), which expresses leukotoxin A (LtxA) that can citrullinate human proteins, providing a possible trigger for the production of anti-citrullinated protein antibodies (ACPA). In this study, we seek to determine the presence of antibodies toward LtxA in patients at risk of developing RA. Methods: Two prospective observational patient cohorts (one Swedish and one British) with symptomatic at-risk patients were studied. Anti-LtxA antibodies were analyzed by a cell-based neutralization assay in baseline serum and compared to 100 Swedish blood donors that served as controls. Results: Serum anti-LtxA levels or positivity did not differ between patients and blood donors. In the British cohort, anti-LtxA was more prevalent among ACPA-positive arthralgia patients compared with ACPA-negative arthralgia cases (24% vs. 13%, p < 0.0001). In the Swedish at-risk cohort, anti-LtxA positive patients were at increased risk of progression to arthritis (hazard ratio (HR) 2.10, 95% CI 1.04-4.20), but this was not confirmed in the UK at-risk cohort (HR 0.99, CI 0.60-1.65). Conclusion: Serum anti-LtxA is not elevated before RA diagnosis, and associations with disease progression and ACPA levels differ between populations. Other features of the oral microbiome should be explored in upcoming periodontitis-related RA research.

Antibodies against Porphyromonas gingivalis in serum and saliva and their association with rheumatoid arthritis and periodontitis. Data from two rheumatoid arthritis cohorts in Sweden.

Background: Periodontitis and oral pathogenic bacteria can contribute to the development of rheumatoid arthritis (RA). A connection between serum antibodies to Porphyromonas gingivalis (P. gingivalis) and RA has been established, but data on saliva antibodies to P. gingivalis in RA are lacking. We evaluated antibodies to P. gingivalis in serum and saliva in two Swedish RA studies as well as their association with RA, periodontitis, antibodies to citrullinated proteins (ACPA), and RA disease activity. Methods: The SARA (secretory antibodies in RA) study includes 196 patients with RA and 101 healthy controls. The Karlskrona RA study includes 132 patients with RA ≥ 61 years of age, who underwent dental examination. Serum Immunoglobulin G (IgG) and Immunoglobulin A (IgA) antibodies and saliva IgA antibodies to the P. gingivalis-specific Arg-specific gingipain B (RgpB) were measured in patients with RA and controls. Results: The level of saliva IgA anti-RgpB antibodies was significantly higher among patients with RA than among healthy controls in multivariate analysis adjusted for age, gender, smoking, and IgG ACPA (p = 0.022). Saliva IgA anti-RgpB antibodies were associated with RA disease activity in multivariate analysis (p = 0.036). Anti-RgpB antibodies were not associated with periodontitis or serum IgG ACPA. Conclusion: Patients with RA had higher levels of saliva IgA anti-RgpB antibodies than healthy controls. Saliva IgA anti-RgpB antibodies may be associated with RA disease activity but were not associated with periodontitis or serum IgG ACPA. Our results indicate a local production of IgA anti-RgpB in the salivary glands that is not accompanied by systemic antibody production.

Professionals' perspectives on existing practice and conditions for nurse-led gout care based on treatment recommendations: a qualitative study in primary healthcare.

BACKGROUND: Gout affects nearly 2 % of the population and is associated with repeated painful flares of arthritis. Preventive urate-lowering therapy is widely available, but only one third of patients receive adequate treatment. Lack of knowledge among healthcare professionals and patients within primary healthcare are implicated as partial explanations for this undertreatment. Nurse-led care has proved to be an effective model when treating patients with gout, but there is a need for more knowledge about factors that can be expected to influence the future implementation of such care. The aim of this study was to describe factors influencing existing gout care in primary healthcare and the conditions for a future implementation of nurse-led gout care based on national treatment recommendations. METHODS: In this qualitative study, focus group discussions with 56 nurses and physicians and individual interviews with eight managers were conducted at nine primary healthcare units in central Sweden. A deductive qualitative content analysis based on the main constructs of the framework Integrated Promoting Action on Research Implementation in Health Services was followed by an inductive analysis within the frames of the main constructs: innovation, recipients and context. RESULTS: Gout-related contacts with primary healthcare was described as being patient initiated, diagnostics was in some respects complex and nurse-led care was experienced as a favourable primary healthcare model in general (innovation). Gout was seen as a low-priority condition with acute flares and there was inadequate knowledge of gout, including preventive treatment (recipients). Primary healthcare was perceived as having a holistic but fragmented responsibility for gout care, recommendations against keeping waiting lists complicated follow-up appointments and a need for motivation and support when introducing new practices was emphasised (context). CONCLUSION: In this study, investigating the perspective of professionals, several factors were found to influence existing gout care. It will be crucial to target these factors in the development of a future implementation strategy.

A Comprehensive Evaluation of the Relationship Between Different IgG and IgA Anti-Modified Protein Autoantibodies in Rheumatoid Arthritis.

Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the "Cit-umbrella" similar to ACPA fine-specificities, while MAA reactivity is distinctly different.

Occupational exposure to inorganic dust and risk of gout: a population-based study.

BACKGROUND: Risk factors operating independently of hyperuricemia could be of importance in determining why only a minority of people with hyperuricemia develop gout. Exposure to inorganic dust has been linked to other inflammatory diseases and could influence the development of gout. OBJECTIVES: To evaluate if occupational exposure to inorganic dust increases the risk of gout. METHODS: Individuals aged 30-65 years with a first gout diagnosis in 2006-2012 in the population-based healthcare database of the Western Swedish Healthcare Region (VEGA) and population controls matched by age and sex were included. Data on occupation was collected from the Swedish occupational register. Exposure status was assigned by means of a job exposure matrix. Data on gout-related comorbidities was collected from VEGA. Alcohol use disorder and obesity were related both to gout and exposure to inorganic dust and were adjusted for in multivariate analyses. ORs were calculated using conditional logistic regression. RESULTS: 5042 gout cases and 20 682 controls were included. Exposure to inorganic dust was associated with gout in both unadjusted (OR 1.12, 95% CI 1.04 to 1.20) and multivariate (OR 1.08, 95% CI 1.00 to 1.16) analyses of the whole population. In sex-stratified multivariate analyses, dust exposure was significantly associated with gout in women (adjusted OR 1.26, 95% CI 1.05 to 1.51), but not in men (adjusted OR 1.05, 95% CI 0.97 to 1.13). CONCLUSIONS: We describe for the first time an association between exposure to inorganic dust and gout. After adjusting for confounders, the findings were statistically significant for women but not for men.