Risk and predictors of fractures in early rheumatoid arthritis - A long term follow up study of an inception cohort.

OBJECTIVES: To examine the risk of fractures in a cohort of patients with newly diagnosed rheumatoid arthritis (RA), compared to the background population, and predictors of fractures detectable early in RA. METHODS: An inception cohort of patients with RA (N = 233; 164 women/69 men, recruited 1995-2005) was evaluated according to a structured program, including repeated clinical assessments and measures of bone mineral density (BMD), from diagnosis to 10 years later. Matched population controls were identified using the national census register. Fractures through 2019 were identified based on ICD codes. Cox regression models were used to assess the risk of fractures in RA patients compared with controls, and for assessment of potential predictors for fractures in the RA population. RESULTS: RA patients had an increased risk of fractures (fully adjusted hazard ratio (HR) 1.52, 95 % CI 1.13; 2.06). In the RA cohort, high age, low body mass index, and low BMD were significant baseline predictors of future fractures in multivariate analyses, but baseline RA disease characteristics were not. Worse disability (i.e. higher Health Assessment Questionnaire (HAQ) scores) over time was significantly associated with increased risk of fractures (age-sex-adjusted HR 1.33 per SD, 95 % CI 1.09; 1.63) and there was an inverse association between BMD Z-scores over time and fractures. CONCLUSION: Patients with RA had higher risk of fractures than controls. Fracture risk was related to BMD at baseline and over time in patients with RA. In addition, worse disability (measured by HAQ) over time was associated with higher risk of fractures.

Osteoporosis-related fractures in men and women with established and early rheumatoid arthritis: predictors and risk compared with the general population.

OBJECTIVES: To study the risk of osteoporosis-related fractures in a community-based sample of men and women with rheumatoid arthritis (RA) overall, as well as early (< 1 year of disease duration, follow-up time maximum 10 years) and established (RA diagnosis since ≥ 5 years on July 1, 1997) RA, compared with the general population. To study potential risk factors for fractures in patients with RA from baseline questionnaire data. METHODS: A community-based cohort of patients with RA (n = 1928) was studied and compared to matched general population controls. Information on osteoporosis-related fractures (hip, proximal upper arm, distal forearm and vertebral fractures) during the period July 1, 1997 to December 31, 2017 was obtained by linkage to the Swedish National Inpatient Register and the Cause of Death Register. The incidence of fractures was estimated in patients and controls. Cox regression models were used to assess the relation between RA and the risk of fractures and to assess potential predictors of fractures in RA patients. Analyses were stratified by sex, and performed in all patients with RA, and in subsets with early and established RA. RESULTS: The overall incidence of osteoporosis-related fractures in the RA cohort was 10.6 per 1000 person-years (95% CI 9.31; 12.0). There was an increased risk of fractures overall in both men (hazard ratio (HR) 1.55, 95% CI 1.03; 2.34) and women (HR 1.52; 95% CI 1.27; 1.83) with RA compared to controls, with significantly increased risk also in the hip. No increased risk of osteoporosis-related fractures overall was seen in patients with early RA (HR 1.01, 95% CI 0.69; 1.49). Higher age, longer duration of RA, higher HAQ scores and higher scores in the visual analogue scale for global health were predictors of fractures. CONCLUSION: Both men and women with RA were at increased risk of osteoporosis-related fractures. Patients with early RA did not have significantly increased risk during the first 10 years of disease in this study.

Association Between Bone Mineral Density and Autoantibodies in Patients With Rheumatoid Arthritis.

OBJECTIVE: Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD). We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts. METHODS: Dual x-ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow-up and in 198 Swedish patients with early RA during 10 years of follow-up. The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations. RESULTS: In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA-positive patients compared to ACPA-negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm2 (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm2 (95% CI 0.93-0.97) (P = 0.01). In line with this, significantly lower Z scores at baseline were noted in the ACPA-positive group compared to the ACPA-negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01). However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time. Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies). In the Swedish cohort, ACPA-positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time. CONCLUSION: The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients. These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well-managed.

Changes in bone mineral density over 10 years in patients with early rheumatoid arthritis.

OBJECTIVES: To investigate changes in bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) over a 10-year period. METHODS: Consecutive patients with early RA (symptom duration <12 months) were followed according to a structured programme and examined with dual-energy X-ray absorptiometry (DXA) at inclusion and after 2, 5 and 10 years. Mean Z-scores over the study period were estimated using mixed linear effect models. Changes in Z-scores between follow-up visits were analysed using paired T-tests. RESULTS: At inclusion, 220 patients were examined with DXA. At the femoral neck, the mean Z-score over 10 years was -0.33 (95 % CI -0.57 to -0.08) in men and -0.07 (-0.22 to 0.08) in women. Men had significantly lower BMD at the femoral neck than expected by age at inclusion (intercept Z-score value -0.35; 95 % CI -0.61 to -0.09), whereas there was no such difference in women. At the lumbar spine, the mean Z-score over the study period for men was -0.05 (-0.29 to 0.19) and for women 0.06 (-0.10 to 0.21). In paired comparisons of BMD at different follow-up visits, femoral neck Z-scores for men decreased significantly from inclusion to the 5-year follow-up. After 5 years, no further reduction was seen. CONCLUSIONS: In this observational study of a limited sample, men with early RA had reduced femoral neck BMD at diagnosis, with a further significant but marginal decline during the first 5 years. Lumbar spine BMD Z-scores were not reduced in men or women with early RA. Data on 10-year follow-up were limited.

Severe Extraarticular Manifestations in a Community-based Cohort of Patients with Rheumatoid Arthritis: Risk Factors and Incidence in Relation to Treatment with Tumor Necrosis Factor Inhibitors.

OBJECTIVE: The aims of this study were to evaluate whether treatment with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) affects the risk of developing severe extraarticular rheumatoid arthritis (ExRA) manifestations and to investigate potential predictors for developing ExRA. METHODS: A dynamic community-based cohort of patients with RA was studied (n = 1977). Clinical records were reviewed and cases of severe ExRA were identified. Information on exposure to TNF inhibitors was obtained from a regional register. Exposure to TNF inhibitors was analyzed in a time-dependent fashion and the incidence of severe ExRA in exposed patients was compared with the incidence in unexposed patients. Cox regression models were used to assess potential predictors of severe ExRA. RESULTS: During treatment with TNF inhibitors, there were 17 patients with new onset of severe ExRA in 2400 person-years at risk (PY; 0.71/100 PY, 95% CI 0.41-1.13) compared with 104 in 15,599 PY (0.67/100 PY, 95% CI 0.54-0.81) in patients without TNF inhibitors. This corresponded to an incidence rate ratio of 1.06 (95% CI 0.60-1.78). The age- and sex-adjusted HR for ExRA in anti-TNF-treated patients was 1.21 (95% CI 1.02-1.43), with similar findings in models adjusted for time-dependent Health Assessment Questionnaire and propensity for anti-TNF treatment. Male sex, positive rheumatoid factor (RF), long disease duration, and greater disability were predictors for ExRA. CONCLUSION: This study suggests that patients treated with TNF inhibitors are at a slightly increased risk of developing severe ExRA. RF-positive patients with disabling disease of long duration were more likely to develop severe ExRA.

Regulatory T Cells from Colon Cancer Patients Inhibit Effector T-cell Migration through an Adenosine-Dependent Mechanism.

T cell-mediated immunity is a major component of antitumor immunity. In order to be efficient, effector T cells must leave the circulation and enter into the tumor tissue. Regulatory T cells (Treg) from gastric cancer patients, but not from healthy volunteers, potently inhibit migration of conventional T cells through activated endothelium. In this study, we compared T cells from colon cancer patients and healthy donors to determine the mechanisms used by Tregs from cancer patients to inhibit conventional T-cell migration. Our results showed that circulating Tregs from cancer patients expressed high levels of CD39, an ectoenzyme mediating hydrolysis of ATP to AMP, as a rate-determining first step in the generation of immunosuppressive adenosine. Tumor-associated Tregs expressed even more CD39, and we therefore examined the importance of adenosine in Treg-mediated inhibition of T-cell transendothelial migration in vitro. Exogenous adenosine significantly reduced migration of conventional T cells from healthy volunteers, and blocking either adenosine receptors or CD39 enzymatic activity during transmigration restored the ability of conventional T cells from cancer patients to migrate. Adenosine did not directly affect T cells or endothelial cells, but reduced the ability of monocytes to activate the endothelium. Taken together, our results indicate that Treg-derived adenosine acts on monocytes and contributes to reduced transendothelial migration of effector T cells into tumors. This effect of Tregs is specific for cancer patients, and our results indicate that Tregs may affect not only T-cell effector functions but also their migration into tumors.

Sleepiness or fatigue? Can we detect treatable causes of tiredness in primary Sjögren's syndrome?

OBJECTIVE: To study the prevalence of fatigue and daytime sleepiness in primary SS (pSS) and analyse predicting sleep disturbing factors and other potential determinants of fatigue and sleepiness. METHOD: Seventy-two consecutive pSS patients and 59 age-matched healthy controls were compared. Assessment instruments were profile of fatigue (ProF), visual analogue scale fatigue, Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale, restless legs syndrome (RLS) Diagnostic Criteria and Lund University Sleep Questionnaire. In addition, markers of immune disturbance, inflammation and disease activity using the European League Against Rheumatism SS Disease Activity Index were analysed in patients. RESULTS: Fatigue, especially somatic fatigue, is the main problem for pSS patients. Sleepiness is a minor problem. Patients had significantly more often anxiety, nocturia and woke up more frequently during the night than controls. The factors that predicted daytime fatigue in pSS patients were anxiety and nightly awakenings due to pain. Nocturia was frequent but was not associated with fatigue or sleepiness. RLS, depression and sicca symptoms contributed to fatigue in the univariate regression analysis only. CONCLUSIONS: This is the first study demonstrating not only the presence of disturbed sleep, but also that nightly musculoskeletal pain and other sleep disturbing factors and anxiety significantly influence fatigue. Management strategies aimed at these aspects should therefore be included in future trials for treatment of fatigue in pSS.