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This supplementary figure shows the gating strategy to analyze T cell transendothelial migration (A), and the migration of CD4+ (B) and CD8+ T cells (C) after endothelial activation.

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. Cancer Immunol Res; 4(3); 183–93. ©2016 AACR.

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/cm(2) (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm(2) (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.

ObjectivesTo investigate changes in bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) over a 10-year period.MethodsConsecutive patients with early RA (symptom duration ResultsAt 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.ConclusionsIn 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.

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. Cancer Immunol Res; 4(3); 183–93. ©2016 AACR.

Background Patients with Rheumatoid Arthritis (RA) have been shown to have an increased risk of osteoporosis and fractures. Most studies on RA and osteoporosis are cross-sectional. There are very few studies on changes in bone mineral density (BMD) over time. Objectives To study changes in BMD in men and women with early RA over a period of ten years. Methods An inception cohort of consecutive patients with early RA (n=233, symptom duration Results At inclusion, 219 patients were examined with DXA. The corresponding numbers at 2, 5 and 10 years were 196, 172 and 121. Among those with baseline DXA data, mean age was 60 years, mean symptom duration 7.4 months and 70% were women. Men were older (mean age 63 vs 59 years) and more often treated with corticosteroids (49% vs 35%) than women at inclusion. The majority of men and women were on disease modifying anti-rheumatic drugs (86% vs 81%). More women were treated for osteoporosis (bisphosphonates and/or calcium and vitamin D) and of the women, 16% were on oestrogen at inclusion. At the femoral neck, the mean Z-score over 10 years of time was −0.07 (-0.22; 0.08) in women and −0.33 (-0.57; −0.08) in men. Men had significantly lower BMD at the femoral neck than expected by age at inclusion (estimated by the intercept Z-score value −0.35; 95% CI −0.61; −0.09), whereas there was no significant overall change in Z-score over time in men or women. At the lumbar spine, the mean Z-score for women was 0.06 (-0.10; 0.21) and for men −0.05 (-0.29; 0.19). There was a significant increase in Z-scores at the lumbar spine over time in both groups (change/year 0.04 (0.03; 0.05) in women and 0.02 (0.00; 0.05) in men). The paired comparisons of BMD at different follow-up visits are shown in table 1. In the femoral neck, Z-scores for men decreased significantly from inclusion to the 5 year follow-up visit. After 5 years, no further reduction was seen. Lumbar spine BMD Z-scores increased in both men and women over the study period. Conclusions In this study of patients with early RA, men had low femoral neck BMD at study start and kept losing bone mass during the first 5 years of follow up. Lumbar spine BMD Z-scores in both women and men increased significantly over the study period. Potential explanations for the low femoral neck BMD in men include exposures that may predispose to both RA and low BMD, such as smoking and low androgen levels. The increasing lumbar spine BMD could be due to more extensive anti-osteoporotic treatment compared to the reference population, and possibly more artefacts, such as extensive aortic calcification or degenerative spinal changes, in patients with RA. Disclosure of Interest None declared

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.

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.

Background Extra-articular rheumatoid arthritis (ExRA) manifestations are associated with increased comorbidity and premature mortality. While tumour necrosis factor (TNF)-inhibitors efficiently reduce arthritis, their impact on the risk of ExRA is still uncertain. Objectives To evaluate whether treatment with TNF-inhibitors has any effect on the risk of developing severe ExRA, and to investigate potential predictors of ExRA in baseline questionnaire data obtained at the beginning of the study period. Methods A community based sample of patients with rheumatoid arthritis (RA) (n=1016), established in 1997, was studied. Clinical records were reviewed from 1 January 2005 to 31 December 2011 and cases with new onset of severe ExRA (i.e. pericarditis, pleuritis, vasculitis, interstitial lung disease, neuropathy, episcleritis/scleritis, Felty’s syndrome and glomerulonephritis), classified according to predefined criteria, were added to cases found in a previous survey [1][1]. Information on exposure to TNF-inhibitors during the study period was obtained from the South Swedish Arthritis Treatment Group (SSATG) register. Exposure to TNF-inhibitors was treated in a time dependent fashion, and person-years at risk (pyr) were appointed to the appropriate category of exposed or unexposed time. The incidence of ExRA in exposed patients was compared to incidence in unexposed patients. In addition, in 1997 all patients received a questionnaire including the Health Assessment Questionnaire (HAQ), visual analogue scales (VAS) for current pain and global health and questions on current and previous pharmacologic treatment. Cox regression analysis models were used to assess the impact of baseline characteristics and baseline disease severity measures on the risk of ExRA. Results During treatment with TNF-inhibitors there were 9 patients with new onset of ExRA in 1226 pyr [0.73/100 pyr, 95% confidence interval (CI) 0.34-1.4] compared to 72 in 8320 pyr [0.87/100 pyr, 95% CI 0.68-1.1] in patients without TNF-inhibitors. The relative risk comparing those treated to those not treated was 0.85 (95% CI 0.37-1.7). Male gender [age adjusted hazard ratio (HR) 1.88, 95% CI 1.20-2.93], long duration of disease [age and sex adjusted HR (per year) 1.03, 95% CI 1.01-1.05] and greater disability, measured by HAQ [age and sex adjusted HR (per unit) 1.38, 95% CI 1.00-1.90] at baseline were predictors for ExRA. Conclusions TNF-inhibitors did not have any major effect on the incidence of severe ExRA in this sample. However, the assessment of the impact of treatment on ExRA may be influenced by the association between ExRA and severe, longstanding disease. References 1. Nyhall-Wahlin BM, Petersson I, Jacobsson C, Geborek P, Nilsson JA, Nilsson K, Jacobsson L, Turesson C, Extra-articular manifestations in a community-based sample of patients with rheumatoid arthritis: incidence and relationship to treatment with TNF inhibitors . Scand J Rheumatol. 2012; 41: 434-7. Disclosure of Interest None Declared [1]: #p-6