Rheumatoid factor autoantibody repertoire profiling reveals distinct binding epitopes in health and autoimmunity.

BACKGROUND: Rheumatoid factors (RF) are one of the hallmark autoantibodies characteristic of rheumatoid arthritis (RA), and are frequently observed in other diseases and in healthy individuals. RFs comprise multiple subtypes with different specificities towards the constant region of human IgG. Studies indicate that these patterns differ between naturally occurring RFs and RFs associated with disease. However, individual specificities characteristic of either have not been clearly defined. METHODS: In this study, we developed an extended set of engineered IgG-fragment crystallisable (Fc) targets with preferential RF binding to specific (conformational) epitopes, which was subsequently used for profiling of RF binding patterns in a compiled exploration cohort, consisting of sera from healthy donors with measurable RF and patients with RA, primary Sjögren's syndrome (pSS) and seropositive arthralgia. RESULTS: We identified an epitope that is strongly associated with RA, which was targeted by both IgM-RF and IgA-RF. We also identified an epitope that is preferentially targeted by healthy donor (IgM) RFs. IgM-RFs derived from healthy donors and patients with RA and pSS all target distinct regions on the IgG-Fc, whereas overall, the IgA-RF repertoire is largely restricted to pathology-associated specificities. Using monoclonal RFs with different specificities, we furthermore demonstrate that the capacity to activate complement or even inhibit IgG-mediated complement activation varies according to the epitopes to which RFs bind. CONCLUSIONS: Our results demonstrate both the need and feasibility to redefine 'RF' into pathological and physiological autoantibody subtypes.

Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis.

OBJECTIVES: The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis. METHODS: We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA). RESULTS: Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not. CONCLUSIONS: HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

Oral health-related quality of life in patients with early rheumatoid arthritis is associated with periodontal inflammation and painful temporomandibular disorders: a cross-sectional study.

OBJECTIVES: To evaluate oral health-related quality of life (OHRQoL) in early rheumatoid arthritis (ERA) patients and individuals at risk of rheumatoid arthritis (RA) compared to healthy controls, and to explore possible associated factors. MATERIALS AND METHODS: Fifty ERA patients, 50 at-risk individuals, and 50 age and gender matched healthy controls were recruited. OHRQoL (Oral Health Impact Profile-14 (OHIP-14)); number of decayed, missing, and filled teeth (DMFT); denture use; periodontal inflamed surface area (PISA); xerostomia (xerostomia inventory (XI)); and possible TMD (-pain) diagnoses were recorded. The groups were compared on these variables. Subsequently, backward multiple regression analyses were performed for the ERA and at-risk groups, with OHRQoL as the dependent variable and gender, age, DMFT, denture use, PISA, XI, non-painful TMD, and TMD pain as independent variables. RESULTS: At-risk individuals had higher XI scores (U = 789.5, z = -3.181, p = 0.001, r = -0.32) and higher prevalence of TMD pain (p = 0.046, OR = 4.57; 95% CI 0.92-22.73) than healthy controls and higher OHIP-14 scores than the ERA group (U = 894.5, z = -2.418, p = 0.016, r = -0.24), while no difference in OHIP-14 was found between the control group and both other groups. For ERA patients, OHRQoL was associated with PISA and TMD pain (R2 = 0.498, p < 0.001). For at-risk individuals, OHRQoL was associated with XI score (R2 = 0.410, p < 0.001). CONCLUSIONS: Alertness of health professionals to TMD pain and periodontal inflammation in ERA patients and to xerostomia and TMD pain in at-risk individuals is recommended. CLINICAL RELEVANCE: The results of this study address orofacial aspects that require attention of health professionals in the timeframe around RA onset. TRIAL REGISTRATION: Dutch National Trial Register (NTR, NTR6362).

Subclinical synovitis in arthralgia: how often does it result in clinical arthritis? Reflecting on starting points for disease-modifying anti-rheumatic drug treatment.

OBJECTIVES: According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. 'false positives'). METHODS: Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. RESULTS: Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. CONCLUSION: Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44-89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.

Lipid profile and NT-proBNP changes from pre-clinical to established rheumatoid arthritis: A 12 years follow-up explorative study.

OBJECTIVES: The aim of the current study was to explore the changes in lipid and NT-proBNP levels in rheumatoid arthritis (RA) patients through different phases of the disease: from the pre-clinical stage and RA onset up to the treatment phase with biological disease-modifying anti-rheumatic drugs (bDMARDS). METHODS: Thirty-eight consecutive patients, initially with arthralgia and rheumatoid factor and/or anti-citrullinated protein antibodies without arthritis, who later developed RA and eventually started treatment with bDMARDs, were included. Lipid spectrum and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured longitudinally from several months before diagnosis through treatment with bDMARDs. RESULTS: From baseline, C-reactive protein (CPR) initially increased sharply, decreasing with the start of biological treatment. Low-density lipoprotein-cholesterol (LDL-c) remained stable, high-density lipoprotein-cholesterol (HDL-c) increased, apolipoprotein A1 (ApoA1 and lipoprotein (a) (Lp(a)), and total cholesterol (TC)/HDL-c ratio and apolipoprotein B (ApoB) decreased during follow-up. NT-proBNP closely followed progression of CRP. TC, LDL-c, TC/HDL-c ratio, ApoA and ApoB inverse correlated with CRP, while Lp(a) positively correlated. HDL-c and triglycerides showed no correlation. CONCLUSION: Changes in the lipid profile and NT-proBNP in RA patients seem to be related to inflammation, with changes reflecting an increase in CVD risk occurring along with rises in CRP levels. These changes seem to already be present at diagnosis, indicating the need for timely control of inflammation.

Next-generation rheumatoid factor assay provides improved predictive power for the development of arthritis in patients at risk.

OBJECTIVE: Rheumatoid arthritis (RA) is characterised by the presence of autoantibodies, among which those targeting the constant region of immunoglobulin G (IgG), called rheumatoid factors (RF). Despite this link, RFs can also be found in other disorders and the healthy population, which hampers its use as a diagnostic tool. We recently showed that a subset of RA-derived RFs target a distinct epitope on the IgG-Fc, a feature that is currently not used in the clinic. METHODS: We determined immunoglobulin M (IgM)-RF levels specific against an RA-associated epitope (using our engineered next-generation RF antigen 'T3-17') in a prospective cohort of 475 patients with seropositive (for IgM-RF or aCCP) arthralgia that were followed for 5 years or until the development of arthritis. RESULTS: The presence of RFs targeting T3-17 was more strongly associated with progression to arthritis in comparison to traditional RF measurements. Within the group of patients positive for T3-17 RF the risk of arthritis development was increased as compared with wild-type RF, HR=3.2 (95% CI 2.4 to 4.3) vs HR=2.2 (95% CI 1.7 to 3.0). Predictive power of T3-17 RF was improved in combination with aCCP titres, HR=6.4 (4.7-8.7) vs HR=5.1 (3.9-6.8). This combination performed better than aCCP detection on its own. CONCLUSION: The detection of disease-specific RF is feasible and seems to improve the diagnostic power of RF and should be considered to be implemented in the clinic.

How to enhance recruitment of individuals at risk of rheumatoid arthritis into trials aimed at prevention: understanding the barriers and facilitators.

OBJECTIVES: Several trials to test the efficacy of a pharmacological intervention aimed at primary prevention of rheumatoid arthritis (RA) are ongoing or have recently been completed. A common issue in these trials is the severe difficulty with patient recruitment. In order to enhance recruitment, this qualitative study identified barriers and facilitators of individuals at risk of RA to participate in a prevention trial. METHODS: Individuals at risk of developing RA (ie, arthralgia with anticitrullinated protein antibodies and/or rheumatoid factor without arthritis), who had previously been asked to participate in a prevention trial, participated in focus group discussions (n=18) exploring their facilitators and barriers for trial participation. Thematic analysis identified factors that were important in at-risk individuals' decision about trial participation. RESULTS: The prospect of personal benefit, the acknowledgement of one's symptoms and the desire to contribute to society facilitated trial participation. In contrast, misconception about what it means to be at risk, or about the aim of the prevention trial, negative views on trial medication, and a low perceived urgency to act on the possibility of developing RA versus a high perceived burden of participating in a trial discouraged participation. CONCLUSIONS: To enhance inclusion in trials aimed to prevent RA, the results suggest to use strategies such as optimising education about RA, personal risk, trial aim and trial medication, explicitly addressing misconceptions and concerns, using tools to improve information provision, limiting study burden in trial design and encouraging physicians to mention trial participation.

Atorvastatin is unlikely to prevent rheumatoid arthritis in high risk individuals: results from the prematurely stopped STAtins to Prevent Rheumatoid Arthritis (STAPRA) trial.

OBJECTIVES: Persons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals. METHODS: Arthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development. RESULTS: Due to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6-35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95. CONCLUSIONS: In this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.

Differences in the Oral Microbiome in Patients With Early Rheumatoid Arthritis and Individuals at Risk of Rheumatoid Arthritis Compared to Healthy Individuals.

OBJECTIVE: It has been suggested that rheumatoid arthritis (RA) may originate at the oral mucosa. The aim of the present study was to assess the oral microbiome and periodontal condition in patients with early RA and individuals at risk of developing RA compared to healthy controls. METHODS: Three groups were recruited (n = 50 participants per group): 1) patients with early RA (meeting the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 classification criteria), 2) individuals at risk of developing RA (those with arthralgia who were positive for RA-associated autoantibodies), and 3) healthy controls. A periodontal examination was conducted to assess the presence of bleeding on probing (BOP), pocket probing depth (PPD), and periodontal inflamed surface area (PISA). The microbial composition of subgingival dental plaque, saliva, and tongue coating was assessed using 16S ribosomal DNA amplicon sequencing, and findings were compared between groups with permutational multivariate analysis of variance (PERMANOVA). RESULTS: There were no significant differences in any of the 3 periodontal variables between patients with early RA, at-risk individuals, and healthy controls (P = 0.70 for BOP, P = 0.30 for PPD, and P = 0.57 for PISA, by Kruskal-Wallis test). PERMANOVA analyses comparing microbial composition between the groups showed significant differences in the microbial composition of saliva (F = 2.08, P = 0.0002) and tongue coating (F = 2.04, P = 0.008), but not subgingival dental plaque (F = 0.948, P = 0.51). However, in post hoc tests, no significant differences in microbial composition of the saliva or tongue coating were observed between the early RA group and the at-risk group (F = 1.12, P = 0.28 for saliva; F = 0.834, P = 0.59 for tongue coating). In assessing microbial diversity based on the number of zero-radius operational taxonomic units per sample, Prevotella in the saliva and Veillonella in the saliva and tongue coating were each found at a higher relative abundance in samples from patients with early RA and at-risk individuals compared to healthy controls. CONCLUSION: The results show similarities in the oral microbiome between patients with early RA and at-risk individuals, since in both groups, the oral microbiome was characterized by an increased relative abundance of potentially proinflammatory species when compared to that in healthy controls. These findings suggest a possible association between the oral microbiome and the onset of RA.

The effect of a multidisciplinary lifestyle program for patients with rheumatoid arthritis, an increased risk for rheumatoid arthritis or with metabolic syndrome-associated osteoarthritis: the "Plants for Joints" randomized controlled trial protocol.

Low-grade inflammation and metabolic syndrome are seen in many chronic diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). Lifestyle interventions which combine different non-pharmacological therapies have shown synergizing effects in improving outcomes in patients with other chronic diseases or increased risk thereof, especially cardiovascular disease. For RA and metabolic syndrome-associated OA (MSOA), whole food plant-based diets (WFPDs) have shown promising results. A WFPD, however, had not yet been combined with other lifestyle interventions for RA and OA patients. In this protocol paper, we therefore present Plants for Joints, a multidisciplinary lifestyle program, based on a WFPD, exercise, and stress management. The objective is to study the effect of this program on disease activity in patients with RA (randomized controlled trial [RCT] 1), on a risk score for developing RA in patients with anti-citrullinated protein antibody (ACPA) positive arthralgia (RCT 2) and on pain, stiffness, and function in patients with MSOA (RCT 3), all in comparison with usual care.We designed three 16-week observer-blind RCTs with a waiting-list control group for patients with RA with low to moderate disease activity (2.6 ≤ Disease Activity Score [DAS28] ≤ 5.1, RCT 1, n = 80), for patients at risk for RA, defined by ACPA-positive arthralgia (RCT 2, n = 16) and for patients with metabolic syndrome and OA in the knee and/or hip (RCT 3, n = 80). After personal counseling on diet and exercise, participants join 10 group meetings with 6-12 other patients to receive theoretical and practical training on a WFPD, exercise, and stress management, while medication remains unchanged. The waiting-list control group receives usual care, while entering the program after the RCT. Primary outcomes are: difference in mean change between intervention and control groups within 16 weeks for the DAS28 in RA patients (RCT 1), the RA-risk score for ACPA positive arthralgia patients (RCT 2), and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score for MSOA patients (RCT 3). Continued adherence to the lifestyle program is measured in a two-year observational extension study.

Identification of Clinically and Pathophysiologically Relevant Rheumatoid Factor Epitopes by Engineered IgG Targets.

OBJECTIVE: Rheumatoid factors (RFs), which are anti-IgG autoantibodies strongly associated with rheumatoid arthritis (RA), are also found in other diseases and in healthy individuals. RFs bind to various epitopes in the constant (Fc-) domain of IgG. Therefore, disease-specific reactivity patterns may exist. This study was undertaken in order to develop a new approach to dissecting RF epitope binding patterns across different diseases. METHODS: We analyzed RF reactivity patterns in serum from patients with seropositive arthralgia, patients with RA, and patients with primary Sjögren's syndrome (SS) using bioengineered, natively folded IgG-Fc targets that demonstrated selective RF binding toward several distinct regions of the IgG-Fc domain. RESULTS: Rheumatoid factor responses primarily bound the Fc Elbow region, with a smaller number of RFs binding the Fc Tail region, while the Fc receptor binding region was hardly targeted. A restricted reactivity against the IgG-Fc Tail region was associated with less positivity for anti-citrullinated protein antibodies (ACPAs) and less arthritis development in arthralgia, whereas combined reactivity toward IgG-Fc Tail and Elbow regions was associated with more arthritis development. Reactivity toward the IgG-Fc Tail region was observed far more frequently in RA than in primary SS. CONCLUSION: Bioengineered IgG targets enable serologic characterization of RF reactivity patterns, and use of this approach appears to reveal patterns associated with ACPA detection and arthritis development in patients with arthralgia. These patterns are able to distinguish RA patients from primary SS patients. This new methodology improves the clinical value of RFs and our understanding of their pathophysiologic processes.

Cardiovascular risk in persons at risk of developing rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased cardiovascular disease (CVD) risk which may start even before diagnosis. To explore this CVD risk prior to RA, we determined multiple risk factors and two 10-year clinical risk scores in a cohort of individuals at-risk of RA. We also analyzed associations with arthritis development and autoantibody status and compared a subset of at-risk individuals to an age and sex matched seronegative control group. METHODS: In a cohort of 555 consecutive arthralgia patients positive for rheumatoid factor (RF) and / or anti-citrullinated protein antibody (ACPA) we retrospectively identified patients with preclinical arthritis (i.e. those who developed arthritis), and non-arthritis patients (those without arthritis development during maximum 5 years follow up). Demographics, CVD risk factors and the 10-year cardiovascular risk according to the SCORE and QRISK3 system were determined at baseline. RESULTS: Preclinical arthritis patients (n = 188) had a higher heart rate (68 vs 63 bpm, p = 0.048) and lower cholesterol (5.2 mmol/l vs 5.5, p = 0.006), HDL (1.0 mmol/l vs 1.1, p0.003) and ApoB (0.85 g/l vs 0.91, p = 0.011) compared to non-arthritis patients (n = 367). Lipid levels were associated with ACPA status in both the preclinical arthritis and non-arthritis group. Ten-year CVD risk scores did not differ between preclinical arthritis and non-arthritis patients, in total, 7% (SCORE) and 8% (QRISK3) of seropositive arthralgia patients were classified as high risk. Seropositive at-risk patients (n = 71) had higher total cholesterol (5.4 vs 4.9, p<0.001), TC/HDL ratio (4.0 vs 3.0, p<0.001), triglycerides (1.4 vs 1.0, p = 0.001), ApoB (1.0 vs 0.9, p = 0.019) and 10-year risk scores (median SCORE 1.0 vs 0.0, p = 0.030 and median QRISK3 4.4 vs 3.1, p<0.001) compared to seronegative controls. CONCLUSION: Our results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role.

Patients' and rheumatologists' perceptions on preventive intervention in rheumatoid arthritis and axial spondyloarthritis.

BACKGROUND: Individuals at risk of developing rheumatoid arthritis (RA) may benefit from lifestyle or pharmacological interventions aimed at primary prevention. The same may apply to individuals at risk of axial spondyloarthritis (axSpA). Our aim was to investigate and compare the willingness of individuals at risk of RA or axSpA and rheumatologists to initiate preventive intervention. METHODS: Individuals at risk of RA (arthralgia and anti-citrullinated protein antibodies and/or rheumatoid factor positivity without arthritis (RA-risk cohort; n = 100)), axSpA (first-degree relatives of HLA-B27-positive axSpA patients (SpA-risk cohort; n = 38)), and Dutch rheumatologists (n = 49) completed a survey on preventive intervention which included questions about disease perception, lifestyle intervention, and preventive medication. RESULTS: At-risk individuals reported willingness to change median 7 of 13 lifestyle components in the areas of smoking, diet, and exercise. In contrast, 35% of rheumatologists gave lifestyle advice to ≥ 50% of at-risk patients. The willingness to use 100% effective preventive medication without side effects was 53% (RA-risk), 55% (SpA-risk), and 74% (rheumatologists) at 30% disease risk which increased to 69% (RA-risk) and 92% (SpA-risk and rheumatologists) at 70% risk. With minor side effects, willingness was 26%, 29%, and 31% (at 30% risk) versus 40%, 66%, and 76% (at 70% risk), respectively. CONCLUSIONS: Risk perception and willingness to start preventive intervention were largely similar between individuals at risk of RA and axSpA. Although the willingness to change lifestyle is high among at-risk individuals, most rheumatologists do not advise them to change their lifestyle. In contrast, rheumatologists are more willing than at-risk patients to start preventive medication.

Predicting Rheumatoid Arthritis in At-risk Individuals.

The typical evolution of rheumatoid arthritis (RA) is that a person with genetic risk factors develops autoantibodies and subclinical inflammation under relevant environmental influences, culminating in symptoms and finally clinically detectable arthritis. Because several of these characteristics can be present before the outbreak of clinical arthritis, it is possible to study the at-risk phase (the presence of ≥1 risk factors for RA in an individual) with the aim of quantifying the risk for that individual. As a person progresses through the different phases of disease development, different markers can be used for prediction. In the early asymptomatic phase, genetics, environmental factors, and autoantibodies are relevant, whereas in later phases additional markers, such as symptoms and imaging, come into play, conveying the risk of not only RA but sometimes even of imminent RA. Prediction is of limited use when not coupled with the possibility to intervene and lower the risk of RA. There is a clear need for effective preventive strategies that take the phase of disease development into account. On the other hand, selecting the right persons for preventive treatment according to their stage of disease development requires the improvement of current prediction models and strategies. This commentary presents an overview of risk factors and their combination into prediction models for use in different stages of RA development. Although clear progress has been made and assuming a future with effective options to intervene, there are still several gaps in our knowledge that need to be filled before it is clear who should be tested and when.

Associations Between Statin Use and Physical Function in Older Adults from The Netherlands and Australia: Longitudinal Aging Study Amsterdam and Australian Longitudinal Study on Women's Health.

BACKGROUND: Statin therapy may cause myopathy, but long-term effects on physical function are unclear. OBJECTIVE: We investigated whether statin use is associated with poorer physical function in two population-based cohorts of older adults. METHODS: Data were from 691 men and women (aged 69-102 years in 2005/2006) in the LASA (Longitudinal Aging Study Amsterdam) and 5912 women (aged 79-84 years in 2005) in the ALSWH (Australian Longitudinal Study on Women's Health). Statin use and dose were sourced from containers (LASA) and administrative databases (ALSWH). Physical function was assessed using performance tests, questionnaires on functional limitations and the SF-12 (LASA) and SF-36 (ALSWH) questionnaires. Cross-sectional (both studies) and 3-year prospective associations (ALSWH) were analysed for different statin dosage using linear and logistic regression. RESULTS: In total, 25 % of participants in LASA and 61 % in ALSWH used statins. In the cross-sectional models in LASA, statin users were less likely to have functional limitations (percentage of subjects with at least 1 limitation 63.9 vs. 64.2; odds ratio [OR] 0.6; 95 % confidence interval [CI] 0.3-0.9) and had better SF-12 physical component scores (mean [adjusted] 47.3 vs. 44.5; beta [B] = 2.8; 95 % CI 1.1-4.5); in ALSWH, statin users had better SF-36 physical component scores (mean [adjusted] 37.4 vs. 36.5; B = 0.9; 95 % CI 0.3-1.5) and physical functioning subscale scores (mean [adjusted] 55.1 vs. 52.6; B = 2.4; 95 % CI 1.1-3.8) than non-users. Similar associations were found for low- and high-dose users and in the prospective models. In contrast, no significant associations were found with performance tests. CONCLUSIONS: Two databases from longitudinal population studies in older adults gave comparable results, even though different outcome measures were used. In these two large cohorts, statin use was associated with better self-perceived physical function.