Search

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer's patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation in vitro and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10-producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.

Objectives: EULAR recently proposed to screen multimorbidities in chronic inflammatory rheumatic diseases. The aims of the study were to define the most common multimorbidities in chronic inflammatory rheumatic diseases, compare the screening approach performed in the clinic with the recent EULAR recommendations, validate the points to consider for the systematic standardized multimorbidity screening proposed by EULAR and assess feasibility of such a screening in a daily clinic., Methods: Data were collected prospectively during a 1-day multimorbidity clinic. Diabetes, hypertension, CVD damage, chronic respiratory diseases, osteoporosis and preventive measures were assessed. The comparison with EULAR points to consider was performed retrospectively., Results: We included 200 consecutive patients (157 with rheumatoid arthritis, 37 spondyloarthritis, and 6 connective tissue diseases or vasculitis). The most common multimorbidities already diagnosed in our patients were hypertension (26%) and diabetes (7.5%). Screening showed that 61.5% (CI95%: 54.6%-67.9%) patients presented at least one undiagnosed or uncontrolled diseases: diabetes (6%), hypertension (20.6%), dyslipidemia (16.1%) valvulopathies (16.8%), peripheral artery disease (4.5%); carotid stenosis (6.5%) and aortic aneurysm (5.5%). Overall, 39.9% patients had incomplete cancer screening and 52.8% incomplete vaccine schedule. Undiagnosed pulmonary obstruction and risk of sleep apnea were suspected in 15.5% and 40.1% patients, respectively., Conclusion: This study underlines the relevance of a systematic screening of multimorbidities in chronic inflammatory rheumatic diseases and its feasibility in a 1-day clinic. Spirometry and sleep apnea screening should be added to EULAR points to consider. The long-term impact of such screening needs to be evaluated., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Considering the implications of B, T, and natural killer (NK) cells in the pathophysiology of systemic autoimmune diseases, the assessment of their distribution in the blood could be helpful for physicians in the complex process of determining a precise diagnosis. In primary Sjögren's syndrome, transitional and active naive B cells are increased and memory B cells are decreased compared to healthy controls and other systemic diseases. However, their utility to improve the accuracy of classification criteria has not been proven. In early untreated rheumatoid arthritis, proportions of regulatory T cells are constantly reduced, but other patterns are difficult to determine given the heterogeneity of published studies. In systemic lupus erythematosus, the lack of studies using large cohorts of patients and the diversity of the possible pathological mechanisms involved are also important impediments. Nevertheless, transitional B cell and plasma cell proportions are increased in most of the studies, the CD4/CD8 ratio is decreased, and the number of NK cells is reduced. Despite the low number of studies, anomalies of lymphocyte subset distribution was also described in ANCA-associated vasculitis, systemic scleroderma, and myositis. For now, flow cytometric analysis of lymphocyte subsets has focused mainly on specific subpopulations and is more useful for basic and translational research than for diagnostics in clinical practice. However, new modern methods such as mass cytometry and bioinformatics analyses may offer the possibility to simultaneously account for the relative proportions of multiple lymphocyte subsets and define a global profile in homogeneous groups of patients. The years to come will certainly incorporate such global lymphocyte profiling in reclassification of systemic autoimmune diseases.

Many therapies are available for patients with rheumatoid arthritis (RA) while biological therapies have limited effects in patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS). In both cases, biomarkers predicting drug response would be very useful to guide clinicians in their choice. We performed a systematic review to evaluate the value of lymphocyte phenotyping as a marker of therapeutic response. Of the 1063 articles retrieved, 39 fulfilled inclusion criteria and were included in the present review (25 for RA, 10 for SLE, and 4 for pSS). Lymphocyte phenotyping was described as a biomarker of therapeutic response in many studies, but most results could not be confirmed by independent teams using multivariate analysis. The most consistent result might be the association between rituximab response and the levels of memory B cells before therapy, although some studies were controversial. Thus, lymphocyte phenotyping cannot yet be proposed as a biomarker of response in rheumatic autoimmune diseases. The lack of reproducibility between studies may be explained by technical issues influencing lymphocyte phenotyping so standardization procedures should be developed for future studies. The patients' characteristics vary between studies, and large population studies, including a wide range of patients' characteristics and biomarkers, are required to provide predictive models for clinical outcomes. The use of new flow cytometry techniques such as single-cell mass cytometry technology might also help finder reliable biomarkers in the future.

Dietary fibers are non-digestible polysaccharides functionally known as microbiota-accessible carbohydrates (MACs), present in inadequate amounts in the Western diet. MACs are a main source of energy for gut bacteria so the abundance and variety of MACs can modulate gut microbial composition and function. This, in turn, impacts host immunity and health. In preclinical studies, MAC-deprived diet and disruption of gut homeostasis aggravate the development of inflammatory diseases, such as allergies, infections, and autoimmune diseases. The present review provides a synopsis on the impact of a low-MAC diet on gut homeostasis or, more specifically, on gut microbiota, gut epithelium, and immune cells.

Objectives: To assess body composition of patients with inflammatory rheumatic disease and the effect of TNF inhibitors on it., Methods: This was systematic review with meta-analysis of studies consulted on PubMed, Cochrane Library and EMBASE and assessing body composition in patients with rheumatoid arthritis or spondyloarthritis. We compared i) patients with healthy controls and ii) body components before and after TNF inhibitors., Results: Among the 703 articles reviewed, 19 met the inclusion criteria. In patients with rheumatoid arthritis, a significant increase in fat mass (+1.85 kg, p=0.02), adiposity (+3.53%, p<0.00001) and android mass (+1.7 kg, p<0.00001) and a significant decrease in lean mass (-3.03 kg, p=0.01), were observed. In patients with spondyloarthritis, a significant but modest increase in fat mass (+0.69 kg, p=0.03) and a significant decrease in lean mass (-3.74 kg, p=0.03) were observed. Nine studies assessed impact of TNF inhibitors on body composition, with an increase of fat mass in the short and long term in all studies. Data on lean mass were controversial. Two studies found an increase in visceral or android mass under TNF inhibitors., Conclusions: Patients with inflammatory rheumatic disease have a significant decrease in lean mass and increase in fat mass. The use of TNF inhibitors is associated with a further increase in fat mass including android fat, which could potentially have cardiovascular consequences.

We report here the case of a 50-years-old man treated for mixed connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein (U1RNP) antibodies who secondarily developed a granulomatosis with polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of the association between anti-U1RNP and anti-PR3-ANCA antibodies by a systematic retrospective study in ten European hospitals. Overall, out of 11,921 samples analyzed for both auto-antibodies, 18 cases of anti-U1RNP and anti-PR3-ANCA double positivity were found and only one patient presented with both MCTD and GPA symptoms. Our retrospective analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double positivity is infrequent and very rarely associated with both MTCD and GPA. Our observation describes for the first time the coexistence of MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP and ANCA antibodies was rarely reported in the literature. Eleven cases of MCTD and ANCA vasculitis have been reported to date, with only two cases with anti-PR3-ANCA association, and only one vasculitis. The seven other cases reported in the literature presented with an association of MCTD and microscopic polyangiitis which appears to be a more frequent presentation than MTCD associated with GPA.

Overweight and obesity are increasing worldwide and now reach about one-third of the world's population. Obesity also involves patients with inflammatory arthritis. Knowing the impact of obesity on rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis) is thus an important issue. This article first reviews the epidemiological and clinical data available on obesity in inflammatory rheumatic diseases, that is, its impact on incident disease, disease characteristics and the therapeutic response. The second part of this review gives an overview of the factors potentially involved in the specifics of inflammatory arthritis in patients with obesity, such as limitations in the clinical assessment, diet, microbiota and adipokines.

Objectives: We aimed to assess the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, on B, T, NK and NKT cells in patients with RA and to study the cell type predictors of remission. We also compared NK cells in patients with RA and in controls., Methods: RA patients included in the study met the 2010 ACR/European League Against Rheumatism (EULAR) criteria, were receiving stable doses of steroids and had not received rituximab in the previous year. Different B and T cell subsets, NK cells and NKT cells were assessed by flow cytometry along with perforin A and granzyme B to estimate NK cell cytotoxicity., Results: We included 92 RA patients, including 20 requiring TCZ treatment and 15 requiring anti-TNF drugs, and 25 controls. At baseline, the proportion of CD56(dim)CD16(+)CD3(-) NK cells was inversely correlated with the 28-joint DAS (DAS28). In TCZ-treated patients, the baseline proportion of CD3(-)CD56(+) NK cells was inversely correlated with the change in DAS28 at 3 months and the proportion was 3-fold greater for patients with DAS28 remission at 3 months than other patients. Change in the proportion of CD56(bri)CD16(-) NK cells was linearly correlated with change in the DAS28 at 3 months. The baseline proportion of NK cells did not predict change in disease activity at 3 months with anti-TNF therapy. The perforin content in NK cells increased with TCZ treatment., Conclusion: This study supports NK cell involvement in RA and in the TCZ mechanism of action. NK cells at baseline could be a predictive factor of TCZ response if results are confirmed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Many therapies are now available for patients with rheumatoid arthritis (RA) who have an inadequate response to methotrexate including tumor necrosis factor inhibitors, abatacept, tocilizumab, and rituximab. Clinical response to drugs varies widely between individuals. A part of this variability is due to the characteristics of the patient such as age, gender, concomitant therapies, body mass index, or smoking status. Clinical response also depends on disease characteristics including disease activity and severity and presence of autoantibodies. Genetic background, cytokine levels, and immune cell phenotypes could also influence biological therapy response. This review summarizes the impact of all those parameters on response to biological therapies.

Background: Cardiovascular mortality is increased in patients with rheumatoid arthritis (RA). RA is associated with an increased left ventricular mass index (LVMI), a strong marker of cardiovascular mortality, and vessel abnormalities. Experimental studies have suggested that tumour necrosis factor α (TNFα) may induce LV hypertrophy., Objective: To study the effect of medium-term (3- and 6-months) treatment with the TNFα inhibitor etanercept (ETN) and synthetic disease-modifying antirheumatic drugs (sDMARDs) on LV morphological features and arterial stiffness in patients with RA., Methods: Consecutive female patients with active RA requiring treatment with ETN (n=28) or sDMARDs (n=20) were included. Clinical and biological monitoring, echocardiography and pulse wave velocity (PWV) assessment were performed at inclusion and at 3 and 6 months after the start of treatment. Paired t tests and multivariate linear regression analysis were used., Results: Mean LVMI tended to be higher at baseline in the ETN group than in the sDMARD group (96.5±19.8 vs 84.3±26.8 g/m2; p=0.11 for the ETN and sDMARD groups, respectively). In patients with ETN treatment, mean LVMI was significantly decreased at 3 and 6 months (-6.3±7.6 and -14.2±9.3 g/m2; p<0.001), with no change from baseline for patients with sDMARD treatment (-2.2±10.9 and -2.7±10.2 g/m2, respectively). Blood pressure (BP) and aortic PWV were not changed by either treatment., Conclusions: ETN induced a significant decrease in LVMI with medium-term treatment with no change in BP or PWV. TNFα may be an important factor of LV hypertrophy, which may explain the benefit of TNF inhibitors on cardiovascular morbidity and mortality in RA. These results need to be confirmed by larger studies and with other TNF inhibitors.

Objective: To evaluate the association between several candidate single-nucleotide polymorphisms (SNPs) and responsiveness to rituximab in patients with rheumatoid arthritis (RA)., Methods: Sixty-three RA patients were included. Nine genes (13 SNPs) were subsequently analyzed, including those coding for cytokines involved in synovitis (IL10, LTA, TGFβ1, TNF-α, TNF receptor II) and genes associated with RA susceptibility (-C5 TRAF1, STAT4, TNFAIP3 and PTPN22)., Results: Forty-four patients were defined as responders and 19 as nonresponders. TGFβ1 Codon 10 and TGFβ1 Codon 25 SNPs were both associated with clinical response (probability to respond to treatment with the Codon 10C/T genotype: OR = 1.6; P = 0.002, and with the Codon 25 G/C genotype: OR = 1.6; P = 0.025). The probability to be a responder when the TGFβ Codon10 C/T and TGFβ Codon 25 G/C genotypes were co-inherited, doubled (OR = 2.6; P = 0.008)., Conclusion: The TGFβ1 SNPs are associated with a good response to rituximab therapy and as such could be useful genetic biomarkers in predicting therapy outcome., (Copyright © 2011 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: For patients with rheumatoid arthritis (RA), recommendations are inconclusive about whether tumor necrosis factor-α (TNF-α)-blocker therapy should be evaluated at 3 or 6 months. Biomarkers are needed to predict at 3 months which patients would benefit from further treatment because of nonoptimal response. Our objective was to investigate whether serum etanercept (ETN) concentrations and anti-ETN antibodies at 3 months are predictors of clinical response to ETN at 6 months in patients with RA in terms of European League Against Rheumatism criteria and Disease Activity Score in 28 joints (DAS28)., Methods: Between 2009 and 2010, we included 19 women with active RA who were candidates for ETN therapy. Response criteria were evaluated at 3 and 6 months. Serum concentrations of ETN and anti-ETN antibodies were measured by ELISA at baseline and at 3 and 6 months., Results: Eighteen patients completed followup. Three-month ETN concentrations were lower for 6-month nonresponders than responders (p = 0.03). Three-month ETN levels correlated significantly with change in DAS28 between baseline and 6 months (r = -0.62, p = 0.006). The best predictor of response at 6 months was observed with an ETN threshold of 3.1 μg/ml at 3 months. No anti-ETN antibodies were found., Conclusion: ETN concentrations at 3 months predict response to ETN therapy at 6 months. Low ETN concentrations could explain the absence of response to ETN, suggesting that patients with low ETN levels could benefit from increased ETN dose or earlier interruption of treatment.

Background: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Lipid changes related to inflammation have been described in RA. Tumour necrosis factor α (TNFα) inhibitor (TNFi) treatment is effective in controlling inflammation and decreasing the number of cardiovascular events., Objective: To assess the change in lipid levels with TNFi treatment in patients with RA by systematic review and meta-analysis., Methods: A Medline search was performed for articles published up to March 2011. Reports describing values for total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), atherogenic index (AI) and apolipoprotein B/A (apoB/A) collected before and after TNFi initiation were included. Data were analysed according to short-, mid- and long-term treatment. Statistical analysis of pre-post data was performed by comprehensive meta-analysis. A random effects model was used when there was evidence of heterogeneity., Results: The search retrieved 32 articles, of which 13 prospective before/after studies were analysed. Long-term TNFi treatment was associated with increased levels of HDL (+0.27 mmol/l, p<0.0001) and TC (+0.27 mmol/l, p=0.03), whereas LDL levels and AI remained unchanged. After long-term treatment, TG levels increased (+0.28 mmol/l, p<0.001) and apoB/A decreased (-0.3, p<0.0001)., Conclusion: The presumed cardioprotective effects of TNFi in RA do not seem to be explained by quantitative lipid changes since long-term treatment has no effect on LDL levels or on AI. Increased HDL levels could have some beneficial effects, but this needs to be confirmed by prospective studies with long-term follow-up.

Mortality in rheumatoid arthritis (RA) is doubled when compared to the general population. This excess in mortality can be explained in half of cases by cardiovascular (CV) events. The risk of myocardial infarction is increased by about 60% in RA. Mortality secondary to cerebrovascular stroke is increased by 50% even if the incidence of stroke is not increased. Indeed, the risk of fatal CV events is increased in RA when compared to the general population. The increased CV risk cannot be explained only by traditional CV risk factors, even if smoking and changes in lipid profile may be implied. It is mainly related to the chronic inflammatory condition that causes many metabolic disturbances. Other parameters such as treatments used in RA also play a role. Thus, it is essential for proper management of RA patients to be aware of this risk and to treat any modifiable CV risk factors., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Objective: TNF blockers have been recently evaluated for treating refractory sarcoidosis and could be efficient. However, several cases of sarcoidosis have been diagnosed during anti-TNF therapy. Here, we report the largest series of sarcoid-like granulomatosis following TNF blocker treatment., Methods: A call for observations of sarcoid-like granulomatosis following TNF blocker treatment was sent to the members of the French 'Club Rhumatismes et Inflammation'. Histological evidence of granulomatosis was required., Results: Observations of 10 patients [seven females; median age 50.5 (range 27-72) years] with sarcoid-like granulomatosis while on anti-TNF treatment were collected: five were treated with etanercept and five with monoclonal antibodies; four patients received TNF blockers for RA and six for SpA. The median delay between anti-TNF agent introduction and granulomatosis diagnosis was 18 (range 1-51) months. Clinical symptoms were mainly pulmonary and cutaneous. Angiotensin-converting enzyme activity was increased in six cases. Lymph-node and/or lung involvement were observed by CT scan of the chest for eight patients. The median delay between drug discontinuation and remission was 6 (range 1-11) months for clinical signs and 6 (range 2-12) months for biological and radiographic findings. Improvement was observed in all patients after drug discontinuation with or without steroids., Conclusions: Sarcoid-like granulomatosis is rare but not exceptional in patients treated with TNF blockers (approximately 1/2800) and does not seem to be related to gender, rheumatic disease or in our series the type of anti-TNF drug used (monoclonal antibodies or soluble receptor). Discontinuation of anti-TNF usually leads to recovery.