Is the relationship between deprivation and outcomes in rheumatoid arthritis mediated by body mass index? A longitudinal cohort study.

OBJECTIVES: To understand the relationships between deprivation and obesity with self-reported disability and disease activity in people with RA, and to determine whether BMI mediates the relationship between area-level deprivation and these outcomes. METHODS: Data came from the Rheumatoid Arthritis Medication Study (RAMS), a 1-year multicentre prospective observational cohort of people with RA recruited from rheumatology centres across England commencing MTX for the first time. A total of 1529 and 1626 people were included who had a baseline and at least one follow-up measurement at 6 or 12 months of HAQ-Disability Index (HAQ-DI) and DAS in 28 joints (DAS28), respectively. Linear mixed models estimated the associations of deprivation and obesity with repeated measures HAQ-DI and DAS28. Causal mediation analyses estimated the mediating effect of BMI on the relationship between deprivation and RA outcomes. RESULTS: Higher deprivation and obesity were associated with higher disability [adjusted regression coefficients highest vs lowest deprivation fifths 0.32 (95% CI 0.19, 0.45); obesity vs no obesity 0.13 (95% CI 0.06, 0.20)] and higher disease activity [adjusted regression coefficients highest vs lowest deprivation fifths 0.34 (95% CI 0.11, 0.58); obesity vs no obesity 0.17 (95% CI 0.04, 0.31)]. BMI mediated part of the association between higher deprivation and self-reported disability (14.24%) and DAS (17.26%). CONCLUSIONS: People with RA living in deprived areas have a higher burden of disease, which is partly mediated through obesity. Weight-loss strategies in RA could be better targeted towards those living in deprived areas.

The epidemiology of psoriatic arthritis in the UK: a health intelligence analysis of UK Primary Care Electronic Health Records 1991-2020.

OBJECTIVES: Epidemiological estimates of psoriatic arthritis (PsA) underpin the provision of healthcare, research, and the work of government, charities and patient organizations. Methodological problems impacting prior estimates include small sample sizes, incomplete case ascertainment, and representativeness. We developed a statistical modelling strategy to provide contemporary prevalence and incidence estimates of PsA from 1991 to 2020 in the UK. METHODS: Data from Clinical Practice Research Datalink (CPRD) were used to identify cases of PsA between 1st January 1991 and 31st December 2020. To optimize ascertainment, we identified cases of Definite PsA (≥1 Read code for PsA) and Probable PsA (satisfied a bespoke algorithm). Standardized annual rates were calculated using Bayesian multilevel regression with post-stratification to account for systematic differences between CPRD data and the UK population, based on age, sex, socioeconomic status and region of residence. RESULTS: A total of 26293 recorded PsA cases (all definitions) were identified within the study window (77.9% Definite PsA). Between 1991 and 2020 the standardized prevalence of PsA increased twelve-fold from 0.03 to 0.37. The standardized incidence of PsA per 100,000 person years increased from 8.97 in 1991 to 15.08 in 2020, an almost 2-fold increase. Over time, rates were similar between the sexes, and across socioeconomic status. Rates were strongly associated with age, and consistently highest in Northern Ireland. CONCLUSION: The prevalence and incidence of PsA recorded in primary care has increased over the last three decades. The modelling strategy presented can be used to provide contemporary prevalence estimates for musculoskeletal disease using routinely collected primary care data.

Association of anti-carbamylated protein antibodies with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register.

BACKGROUND: Anti-citrullinated protein antibodies (ACPA) predict increased disease activity and disability in patients with inflammatory arthritis such as rheumatoid arthritis. However, the absence of these antibodies does not confer universally good prognosis. Recently, a new set of antibodies, anti-carbamylated (anti-CarP) antibodies, have been identified in patients with rheumatoid arthritis. This study aimed to investigate the association between anti-CarP antibodies, disability, and disease activity in these patients. METHODS: Adults with two or more swollen joints for at least 4 weeks were recruited from the Norfolk Arthritis Register (NOAR). At baseline patients completed the health assessment questionnaire (HAQ). The Disease Activity Score in 28 joints (DAS28) was calculated and rheumatoid arthritis classification criteria applied. ACPA and anti-CarP antibodies were measured on stored serum samples obtained within the first year of the study. The HAQ was repeated after 1, 2, 3, 5, 7, 10, 12, 15, and 20 years, and DAS28 scores done every 5 years. Generalised estimating equations (GEE) tested the association between anti-CarP antibodies and longitudinal HAQ and DAS28 scores. FINDINGS: 1995 patients were included; 1310 (66%) were women and median age at onset was 55 years (IQR 43-66). Anti-CarP antibodies were positive in 460 patients (23%), and 1221 (61%) met rheumatoid arthritis classification criteria. Median follow-up was 7 years (IQR 5-11). Patients who were anti-CarP antibody positive had significantly more disability over time and higher levels of disease activity than those who were negative (multivariate GEE adjusted for age, sex, smoking status, ACPA, and year of recruitment to NOAR: ß coefficient for HAQ 0·13, 95% CI 0·03-0·23, and for DAS28 0·31, 0·12-0·49). Statistically significant associations were also seen in a subanalysis of 1092 ACPA-negative patients (HAQ 0·15, 0·02-0·29; DAS28 0·37, 0·11-0·63). In ACPA-positive and rheumatoid arthritis subgroups, anti-CarP antibodies were significantly associated with DAS28 (0·30 [0·02-0·57] and 0·21 [0·04-0·37], respectively), and positive associations were also seen with HAQ scores, but these did not meet statistical significance. INTERPRETATION: In this study the presence of anti-CarPA was associated with increased burden of disability as measured by the HAQ and higher disease activity in patients with inflammatory arthritis. Since GEE models include outcome data at all timepoints, these associations are long term. Our results suggest that anti-CarP antibodies might provide additional prognostic information to ACPA and in particular identify ACPA-negative patients with poor prognosis. FUNDING: Arthritis Research UK.

Anticarbamylated protein antibodies are associated with long-term disability and increased disease activity in patients with early inflammatory arthritis: results from the Norfolk Arthritis Register.

OBJECTIVES: Anticarbamylated protein (anti-CarP) antibodies are a novel family of autoantibodies recently identified in patients with inflammatory arthritis. The aim of this study was to investigate their association with long-term outcomes of disability and disease activity over 20 years' follow-up in a cohort of patients with inflammatory polyarthritis (IP). METHODS: Norfolk Arthritis Register recruited adults with recent-onset swelling of ≥2 joints for ≥4 weeks from 1990 to 2009. At baseline, Health Assessment Questionnaire (HAQ) and 28 joint disease activity scores (DAS28) were obtained, and C reactive protein, rheumatoid factor (RF), anticitrullinated protein antibodies (ACPA) and anti-CarP antibodies were measured. Further HAQ scores and DAS28 were obtained at regular intervals over 20 years. Generalised estimating equations were used to test the association between anti-CarP antibody status and longitudinal HAQ and DAS28 scores; adjusting for age, gender, smoking status, year of inclusion and ACPA status. Analyses were repeated in subgroups stratified by ACPA status. The relative association of RF, ACPA and anti-CarP antibodies with HAQ and DAS28 scores was investigated using a random effects model. RESULTS: 1995 patients were included; 1310 (66%) were female. Anti-CarP antibodies were significantly associated with more disability and higher disease activity, HAQ multivariate ß-coefficient (95% CI) 0.12 (0.02 to 0.21), and these associations remained significant in the ACPA-negative subgroups. The associations of RF, ACPA and anti-CarP antibodies were found to be additive in the random effects model. CONCLUSIONS: Anti-CarP antibodies are associated with increased disability and higher disease activity in patients with IP. Our results suggest that measurement of anti-CarP antibodies may be useful in identifying ACPA-negative patients with worse long-term outcomes. Further, anti-CarP antibody status provided additional information about RF and ACPA.

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord.

Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families-the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 µM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator.

Can the General Public Be a Proxy for an "At-Risk" Group in a Patient Preference Study? A Disease Prevention Example in Rheumatoid Arthritis.

BACKGROUND: When selecting samples for patient preference studies, it may be difficult or impractical to recruit participants who are eligible for a particular treatment decision. However, a general public sample may not be an appropriate proxy. OBJECTIVE: This study compares preferences for rheumatoid arthritis (RA) preventive treatments between members of the general public and first-degree relatives (FDRs) of confirmed RA patients to assess whether a sample of the general public can be used as a proxy for FDRs. METHODS: Participants were asked to imagine they were experiencing arthralgia and had screening tests indicating a 60% chance of developing RA within 2 yrs. Using a discrete choice experiment, participants were offered a series of choices between no treatment and 2 unlabeled hypothetical treatments to reduce the risk of RA. To assess data quality, time to complete survey sections and comprehension questions were assessed. A random parameter logit model was used to obtain attribute-level estimates, which were used to calculate relative importance, maximum acceptable risk (MAR), and market shares of hypothetical preventive treatments. RESULTS: The FDR sample (n = 298) spent more time completing the survey and performed better on comprehension questions compared with the general public sample (n = 982). The relative importance ranking was similar between the general public and FDR participant samples; however, other relative preference measures involving weights including MARs and market share differed between groups, with FDRs having numerically higher MARs. CONCLUSION: In the context of RA prevention, the general public (average risk) may be a reasonable proxy for a more at-risk sample (FDRs) for overall relative importance ranking but not weights. The rationale for a proxy sample should be clearly justified. HIGHLIGHTS: Participants from the general public were compared to first-degree relatives on their preferences for rheumatoid arthritis (RA) preventive treatments using a discrete choice experiment.Preferences were similar between groups in terms of the most important and least important attributes of preventive treatments, with effectiveness being the most important attribute. However, relative weights differed.Attention to the survey and predicted market shares of hypothetical RA preventive treatments differed between the general public and first-degree relatives.The general public may be a reasonable proxy for an at-risk group for patient preferences ranks but not weights in the disease prevention context; however, care should be taken in sample selection for patient preference studies when choosing nonpatients.

Postpublication validation of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: where do we stand?

PURPOSE OF REVIEW: To summarise the results of the validation studies testing the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) to date and highlight the areas for future research. RECENT FINDINGS: The 2010 ACR/EULAR classification criteria for RA were developed aiming to identify patients early in the natural history of the disease. Validation studies conducted since their publication have demonstrated that, compared with the 1987 ACR criteria for RA, the 2010 criteria identify more patients earlier in the disease course. Sensitivity for the initiation of disease-modifying antirheumatic drugs and persistent disease is increased, with decreased specificity. Patients who are seronegative may not satisfy the 2010 criteria despite meeting the 1987 criteria at presentation. The 2010 criteria may also incorrectly classify some patients with self-limiting disease as RA. SUMMARY: The 2010 criteria appear to be superior to the 1987 criteria in terms of identifying individuals with early RA. Their validity in established disease and their ability to predict worse prognosis in the long term have yet to be determined.

The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register.

OBJECTIVES: The development of new classification criteria for rheumatoid arthritis (RA) calls for a re-estimation of RA incidence rates. The objectives of this study were to estimate the age and sex-specific incidence rates (IR) of RA in Norfolk, England using the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism criteria, and to compare those with IRs estimated using the 1987 ACR criteria. SETTING: The Norfolk Arthritis Register (NOAR), a large primary care inception cohort of patients with inflammatory oligo- and polyarthritis (IP) aged ≥ 16. METHODS: All patients notified to NOAR from 1990-5 with symptom onset in 1990 were included. The former Norwich Health Authority population was the denominator. Age and sex specific IRs using 1987 and 2010 classification criteria were calculated at baseline visit, annually for the first 3 years and at 5 years. RESULTS: 260 patients were notified to NOAR with symptom onset in 1990 and without an alternative diagnosis. IRs applying the 2010 criteria at baseline were 54/100 000 for women and 25/100 000 for men. Age and sex-specific IRs using the 2010 classification criteria at baseline were similar to cumulative IRs applying the 1987 criteria up to 5 years. However, some patients only ever satisfied one set of criteria and a proportion of IA patients (20%) did not satisfy either criteria set over 5 years. CONCLUSIONS: The 2010 criteria classify similar numbers of patients as having RA at baseline, as the 1987 criteria would have taken up to 5 years to identify.

Dopamine exerts activation-dependent modulation of spinal locomotor circuits in the neonatal mouse.

Monoamines can modulate the output of a variety of invertebrate and vertebrate networks, including the spinal cord networks that control walking. Here we examined the multiple changes in the output of locomotor networks induced by dopamine (DA). We found that DA can depress the activation of locomotor networks in the neonatal mouse spinal cord following ventral root stimulation. By examining disinhibited rhythms, where the Renshaw cell pathway was blocked, we found that DA depresses a putative recurrent excitatory pathway that projects onto rhythm-generating circuitry of the spinal cord. This depression was D(2) but not D(1) receptor dependent and was not due exclusively to depression of excitatory drive to motoneurons. Furthermore, the depression in excitation was not dependent on network activity. We next compared the modulatory effects of DA on network function by focusing on a serotonin and a N-methyl-dl-aspartate-evoked rhythm. In contrast to the depressive effects on a ventral root-evoked rhythm, we found that DA stabilized a drug-evoked rhythm, reduced the frequency of bursting, and increased amplitude. Overall, these data demonstrate that DA can potentiate network activity while at the same time reducing the gain of recurrent excitatory feedback loops from motoneurons onto the network.

Does body mass index mediate the relationship between socioeconomic position and incident osteoarthritis?

OBJECTIVES: To investigate associations of socioeconomic position (SEP) and obesity with incident osteoarthritis (OA), and to examine whether body mass index (BMI) mediates the association between SEP and incident OA. METHODS: Data came from the English Longitudinal Study of Ageing, a population-based cohort study of adults aged ≥50 years. The sample population included 9,281 people. Cox regression analyses were performed to investigate the associations between SEP (measured by education, occupation, income, wealth and deprivation) and obesity (BMI ≥30 kg/m2) at baseline and self-reported incident OA. The mediating effect of BMI on the relationship between SEP and incident OA were estimated using Structural Equation Models. RESULTS: After a mean follow-up time of 7.8 years, 2369 participants developed OA. Number of person-years included in the analysis was 65,456. Lower SEP was associated with higher rates of OA (for example, hazard ratio (HR) lowest vs highest education category 1.52 (95% confidence interval (CI) 1.30, 1.79)). Obesity compared with non-obesity was associated with increased rates of incident OA (HR 1.37 (95% CI 1.23, 1.52)). BMI mediated the relationship between a lower SEP and OA (ß = 0.005, p < 0.001) and the direct effect was not significant (ß = 0.004, p = 0.212). CONCLUSIONS: Strategies to reduce social inequalities and obesity prevalence may help to reduce OA risk.

The association between lower socioeconomic position and functional limitations is partially mediated by obesity in older adults with symptomatic knee osteoarthritis: Findings from the English Longitudinal Study of Ageing.

Objective: To assess the longitudinal associations of socioeconomic position (SEP) with functional limitations and knee joint replacement surgery (JRS) in people with symptomatic knee osteoarthritis (OA), and whether body mass index (BMI) mediated these relationships. Methods: Data came from the English Longitudinal Study of Ageing, a national longitudinal panel study of adults aged ≥50 years. A total of 1,499 participants (62.3% female; mean age 66.5 (standard deviation (SD) 9.4) years; 47.4% obese) self-reporting an OA diagnosis and knee pain, with at least one BMI measurement were included. Mixed effect models estimated longitudinal associations of each SEP variable (education, occupation, income, wealth and deprivation index) and obesity (BMI ≥30.0 kg/m2) with repeated measures of functional limitations. Cox regression analyses estimated associations between SEP indicators and obesity at baseline and risk of knee JRS at follow-up. Structural equation modeling estimated any mediating effects of BMI on these relationships. Results: Lower SEP and obesity at baseline were associated with increased odds of functional limitations in people with knee OA [e.g., difficulty walking 100 yards: no qualification vs. degree adjOR 4.33 (95% CI 2.20, 8.55) and obesity vs. no obesity adjOR 3.06 (95% CI 2.14, 4.37); similar associations were found for the other SEP indicators]. A small proportion of the association between lower SEP and functional limitations could be explained by BMI (6.2-12.5%). Those with lower income, lower wealth and higher deprivation were less likely to have knee JRS [e.g., adjHR most vs. least deprived 0.37 (95% CI 0.19, 0.73)]; however, no clear association was found for education and occupation. Obesity was associated with increased hazards of having knee JRS [adjHR 1.87 (95% CI 1.32, 2.66)]. As the direction of the associations for SEP and obesity with knee JRS were in opposite directions, no mediation analyses were performed. Conclusions: Lower SEP was associated with increased odds of functional limitations but lower hazards of knee JRS among people with knee OA, potentially indicating underutilization of JRS in those with lower SEP. Obesity partially mediated the relationship between lower SEP and increased odds of functional limitations, suggesting adiposity as a potential interventional target.

Acceptable risks of treatments to prevent rheumatoid arthritis among first-degree relatives: demographic and psychological predictors of risk tolerance.

OBJECTIVES: To quantify tolerance to risks of preventive treatments among first-degree relatives (FDRs) of patients with rheumatoid arthritis (RA). METHODS: Preventive treatments for RA are under investigation. In a preference survey, adult FDRs assumed a 60% chance of developing RA within 2 years and made choices between no treatment and hypothetical preventive treatment options with a fixed level of benefit (reduction in chance of developing RA from 60% to 20%) and varying levels of risks. Using a probabilistic threshold technique, each risk was increased or decreased until participants switched their choice. Perceived risk of RA, health literacy, numeracy, Brief Illness Perception Questionnaire and Beliefs about Medicines Questionnaire-General were also assessed. Maximum acceptable risk (MAR) was summarised using descriptive statistics. Associations between MARs and participants' characteristics were assessed using interval regression with effects coding. RESULTS: 289 FDRs (80 male) responded. The mean MAR for a 40% reduction in chance of developing RA was 29.08% risk of mild side effects, 9.09% risk of serious infection and 0.85% risk of a serious side effect. Participants aged over 60 years were less tolerant of serious infection risk (mean MAR ±2.06%) than younger participants. Risk of mild side effects was less acceptable to participants who perceived higher likelihood of developing RA (mean MAR ±3.34%) and more acceptable to those believing that if they developed RA it would last for a long time (mean MAR ±4.44%). CONCLUSIONS: Age, perceived chance of developing RA and perceived duration of RA were associated with tolerance to some risks of preventive RA therapy.

Do associations between education and obesity vary depending on the measure of obesity used? A systematic literature review and meta-analysis.

BACKGROUND: Consistent evidence suggests a relationship between lower educational attainment and total obesity defined using body mass index (BMI); however, a comparison of the relationships between educational attainment and total obesity (BMI ≥30 kg/m2) and central obesity (waist circumference (WC) > 102 cm for men and WC > 88 cm for women) has yet to be carried out. This systematic literature review (SLR) and meta-analyses aimed to understand whether i) the associations between education and obesity are different depending on the measures of obesity used (BMI and WC), and ii) to explore whether these relationships differ by gender and region. METHODS: Medline, Embase and Web of Science were searched to identify studies investigating the associations between education and total and central obesity among adults in the general population of countries in the Organisation for Economic Co-operation and Development (OECD). Meta-analyses and meta-regression were performed in a subset of comparable studies (n=36 studies; 724,992 participants). RESULTS: 86 eligible studies (78 cross-sectional and eight longitudinal) were identified. Among women, most studies reported an association between a lower education and total and central obesity. Among men, there was a weaker association between lower education and central than total obesity (OR central vs total obesity in men 0.79 (95% CI 0.60, 1.03)). The association between lower education and obesity was stronger in women compared with men (OR women vs men 1.66 (95% CI 1.32, 2.08)). The relationship between lower education and obesity was less strong in women from Northern than Southern Europe (OR Northern vs Southern Europe in women 0.37 (95% CI 0.27, 0.51)), but not among men. CONCLUSIONS: Associations between education and obesity differ depending on whether total or central obesity is used among men, but not in women. These associations are stronger among women than men, particularly in Southern European countries.

Development of an extension of the OMERACT Summary of Measurement Properties table to capture equity considerations: SOMP-Equity.

OBJECTIVE: To develop an equity extension of the OMERACT Summary of Measurement Properties (SOMP) Table, SOMP Equity to describe whether a patient reported outcome measure (PROM) works well among patients of diverse languages and cultures, education levels, and other population characteristics. METHODS: We used the PROGRESS-Plus framework to categorize equity characteristics assessed in trials of PROM. PROGRESS refers to Place of residence, Race/ethnicity/culture/language, Occupation, Gender/sex, Religion, Education, Socioeconomic status, and Social Capital, while the 'plus' captures additional characteristics, such as age. We pilot tested our SOMP Equity Extension using the Health Assessment Questionnaire (HAQ) as a prototypical PROM. RESULTS: The SOMP Equity Extension retains the same columns as the original OMERACT SOMP (domain match, feasibility, construct validity, test-retest reliability, longitudinal construct validity, clinical trial discrimination, thresholds of meaning) but uses the PROGRESS-Plus characteristics as rows. We found several examples of studies of the HAQ which had assessed one or more PROGRESS-Plus characteristics. CONCLUSIONS: The most commonly reported equity considerations were related to language. OMERACT Equity virtual meeting participants were polled and they indicated that the SOMP Equity Extension is useful for highlighting and tracking equity considerations for OMERACT Core Outcome Measurement Instruments.