Effect of dietary and respiratory environmental factors on rheumatoid arthritis : epidemiological and metabolomic studies

Introduction. La polyarthrite rhumatoïde (PR) est un excellent champ d’application du concept de l’exposome. L’objectif de cette thèse est d’étudier l’association entre certaines expositions environnementales alimentaires et respiratoires et les caractéristiques et l’évolution de la PR. Méthode. Ce travail est composé de 3 études. Nous avons étudié l’association entre profils d’acides gras poly-insaturés (PUFA) et caractéristiques cliniques, biologiques et radiologiques de la PR, à l’inclusion et à 6 mois au sein de la cohorte française ESPOIR. Pour la partie respiratoire, nous avons utilisé un questionnaire qui permet de quantifier l’exposition professionnelle et non-professionnelle à la silice (Si02) afin de comparer le niveau d’exposition entre PR et témoins (Te), identifier les sources d’exposition à la SiO2 discriminantes entre PR et Te, et explorer une association entre niveau d’exposition à la SiO2 et caractéristiques de la PR. Enfin, nous avons comparé le métabolome des globules rouges des PR vs Te et des répondeurs au méthotrexate (MTX) vs non-répondeurs, en utilisant la chromatographie en phase liquide couplée à la spectrométrie de masse. Résultats. Nous avons identifié 3 profils de PUFA prédictifs de l’activité et sévérité de la PR, les activités ménagères comme source discriminante d’exposition à la Si02 entre femmes PR et Te et l’ergothionéine, polyamine issue de l’alimentation, comme métabolite discriminant de la  PR vs Te et prédicteur de la réponse  au MTX. Conclusion. Ce travail multidisciplinaire souligne la variété des expositions impliquées dans la PR et incite au couplage des différents outils dans une perspective de recherche de l’exposome dans la PR.Introduction. Rheumatoid arthritis (RA) is the epitome of multifactorial disease to which the exposome concept ideally applies. The aim of this thesis was to explore the association between different exposures (nutritional and respiratory) and disease variables in RA.Method. This work included 3 studies. First, we studied the association between polyunsaturated fatty acids (PUFA) profiles and clinical, biological and radiological characteristics of RA, at baseline and 6 months within the ESPOIR French national cohort of early RA. Then, we used a questionnaire derived from social sciences to quantify occupational and non-occupational silica (Si02) exposure in order to compare the level of exposure between RA patients and controls (C), to identify the sources of Si02 exposure, which may differentiate RA patients and C and to examine the association between the level of Si02 exposure and RA characteristics. Finally, we compared the red blood cells metabolome of RA patients to that of healthy C and that of methotrexate (MTX) responders (R) vs non-responders (NR), using liquid chromatography-mass spectrometry.Results. We identified 3 PUFA profiles predictive of RA activity and severity, we identified household activity as a major discriminating source of Si02 exposure between RA and C women and ergothioneine, a polyamine exclusively derived from food, as a discriminating metabolite both between RA and C and between R and NR to MTX.Conclusion. This multidisciplinary work highlights the multitude of exposures potentially involved in RA. These results encourage the integration of different tools, in the perspective of exposome research in RA

Implication des facteurs environnementaux alimentaires et respiratoires sur la polyarthrite rhumatoïde : études épidémiologiques et métabolomiques

Introduction. Rheumatoid arthritis (RA) is the epitome of multifactorial disease to which the exposome concept ideally applies. The aim of this thesis was to explore the association between different exposures (nutritional and respiratory) and disease variables in RA.Method. This work included 3 studies. First, we studied the association between polyunsaturated fatty acids (PUFA) profiles and clinical, biological and radiological characteristics of RA, at baseline and 6 months within the ESPOIR French national cohort of early RA. Then, we used a questionnaire derived from social sciences to quantify occupational and non-occupational silica (Si02) exposure in order to compare the level of exposure between RA patients and controls (C), to identify the sources of Si02 exposure, which may differentiate RA patients and C and to examine the association between the level of Si02 exposure and RA characteristics. Finally, we compared the red blood cells metabolome of RA patients to that of healthy C and that of methotrexate (MTX) responders (R) vs non-responders (NR), using liquid chromatography-mass spectrometry.Results. We identified 3 PUFA profiles predictive of RA activity and severity, we identified household activity as a major discriminating source of Si02 exposure between RA and C women and ergothioneine, a polyamine exclusively derived from food, as a discriminating metabolite both between RA and C and between R and NR to MTX.Conclusion. This multidisciplinary work highlights the multitude of exposures potentially involved in RA. These results encourage the integration of different tools, in the perspective of exposome research in RA.Introduction. La polyarthrite rhumatoïde (PR) est un excellent champ d’application du concept de l’exposome. L’objectif de cette thèse est d’étudier l’association entre certaines expositions environnementales alimentaires et respiratoires et les caractéristiques et l’évolution de la PR. Méthode. Ce travail est composé de 3 études. Nous avons étudié l’association entre profils d’acides gras poly-insaturés (PUFA) et caractéristiques cliniques, biologiques et radiologiques de la PR, à l’inclusion et à 6 mois au sein de la cohorte française ESPOIR. Pour la partie respiratoire, nous avons utilisé un questionnaire qui permet de quantifier l’exposition professionnelle et non-professionnelle à la silice (Si02) afin de comparer le niveau d’exposition entre PR et témoins (Te), identifier les sources d’exposition à la SiO2 discriminantes entre PR et Te, et explorer une association entre niveau d’exposition à la SiO2 et caractéristiques de la PR. Enfin, nous avons comparé le métabolome des globules rouges des PR vs Te et des répondeurs au méthotrexate (MTX) vs non-répondeurs, en utilisant la chromatographie en phase liquide couplée à la spectrométrie de masse. Résultats. Nous avons identifié 3 profils de PUFA prédictifs de l’activité et sévérité de la PR, les activités ménagères comme source discriminante d’exposition à la Si02 entre femmes PR et Te et l’ergothionéine, polyamine issue de l’alimentation, comme métabolite discriminant de la  PR vs Te et prédicteur de la réponse  au MTX. Conclusion. Ce travail multidisciplinaire souligne la variété des expositions impliquées dans la PR et incite au couplage des différents outils dans une perspective de recherche de l’exposome dans la PR

L’épaississement tendineux de l’arthropathie liée à la dialyse correspond à des dépôts amyloïdes

International audiencel’amylose à la bêta2-microglobuline (β2 M) liée à la dialyse (ALD) est une arthropathie invalidante initialement observée chez des patients traités par dialyse au long cours. Son incidence et sa prévalence ont fortement diminué parallèlement à l’amélioration des techniques de dialyse. Nous tentons ici de définir les caractéristiques cliniques et de l’IRM de cette affection pour en améliorer le diagnostic.MéthodesNous avons examiné de manière rétrospective les dossiers de 19 patients dialysés chez lesquels une ALD à β2 M était suspectée. Le diagnostic reposait sur les critères d’IRM (Hyposignal dans les séquences pondérées en T1 et T2). Lors de l’analyse IRM, des scores ont été attribués aux différentes lésions articulaires selon leur sévérité (de 0 à 3).RésultatsL’âge moyen des patients était de 66,0 ± 10,5 ans et la durée moyenne de la dialyse de 23,7 ± 10,5 ans. L’ALD touchait essentiellement les grosses articulations (épaule 73,7 % des cas, hanche 47,3 %) et le rachis (36,8 %). Les images IRM de huit épaules, huit hanches et trois rachis ont été analysées. Toutes ont révélé une synovite amyloïde avec un score moyen élevé sur les trois sites. Les lésions les plus fréquentes dans toutes les articulations étaient un épaississement tendineux (68,4 %) et des érosions osseuses (68,4 %). Le score moyen de l’épaississement des tendons était particulièrement élevé dans les épaules, mais également au rachis. Les érosions osseuses étaient plus fréquentes aux épaules et au bassin.ConclusionChez les patients traités par dialyse au long cours, l’ALD à β2M touche les grosses articulations et le rachis. L’épaississement tendineux doit faire l’objet d’une attention particulière. Le recours à l’IRM est nécessaire pour caractériser le profil des lésions et établir le diagnostic

Efficacy of Spice Supplementation in Rheumatoid Arthritis: A Systematic Literature Review

International audienceBackground: Spices, i.e., curcumin, ginger, saffron, and cinnamon, have a thousand-year history of medicinal use in Asia. Modern medicine has begun to explore their therapeutic properties during the last few decades. We aimed to perform a systematic literature review (SLR) of randomized controlled trials (RCTs) assessing the effect of spice supplementation on symptoms and disease activity in patients with chronic inflammatory rheumatic diseases (rheumatoid arthritis (RA), spondylarthritis, or psoriatic arthritis).Methods: An SLR of RCTs, reviews, and meta-analyses was performed, searching for articles in MEDLINE/PubMed. Abstracts from international rheumatology and nutrition congresses (2017-2020) were also scrutinized. The risk of bias of the selected studies was evaluated using the Cochrane Collaboration's tool and the Jadad scale.Results: Altogether, six studies, assessing the use of spice supplementation only in RA patients, were included: one on garlic supplementation, two on curcumin, one on ginger, one on cinnamon, and one on saffron supplementation. Garlic, ginger, cinnamon, or saffron supplementation was associated with a decrease in RA clinical activity. However, several points limit the external validity of these studies. No conclusion on the impact of curcumin supplementation on RA activity could be drawn due to low-quality studies.Conclusions: Garlic, ginger, cinnamon, and saffron supplementation could have a beneficial effect on RA activity, but the risk of bias of these studies is difficult to assess and data are too limited to recommend them in daily practice

Efficacy of Probiotics in Rheumatoid Arthritis and Spondyloarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

International audienceBackground: We aimed to provide a systematic review and meta-analysis of randomized controlled trials assessing the effect of probiotics supplementation on symptoms and disease activity in patients with chronic inflammatory rheumatic diseases (rheumatoid arthritis (RA), spondylarthritis (SpA), or psoriatic arthritis). Methods: A systematic literature review and meta-analysis from RA and SpA randomized controlled trials were conducted searching for articles in MEDLINE/PubMed and abstracts from recent international rheumatology meetings. The control group was a placebo or another dietary intervention. The risk of bias of the selected studies was evaluated using the Cochrane Collaboration tool and the Jadad scale. Results: The initial search yielded 173 articles. Of these, 13 studies were included in the qualitative synthesis, 8 concerning a total of 344 RA patients and 2 concerning a total of 197 SpA patients. Three meta-analyses were also analyzed. Probiotic strains and quantities used were different among trials (5 studies using Lactobacillus sp., 1 trial Bacillus coagulans and the others a mix of different probiotic strains). Time to assess response ranged from 8 weeks to one year. Two studies associated probiotic supplementation with a dietary intervention. Meta-analysis showed a statistically significant decrease of C-reactive protein (CRP) concentration (mean difference (MD)) −3.04 (95% CI −4.47, −1.62) mg/L, p < 0.001; I2 = 20%, n patients = 209) with probiotics in RA. However, after excluding high-risk-of-bias trials of meta-analysis, there was no difference between probiotics and placebo on DAS28 (standard MD −0.54; 95% CI −1.94 to 0.85, p = 0.45, I2 93%, n patients = 143). The two studies on SpA patients showed no efficacy of probiotics. Conclusions: Probiotic supplementation might decrease RA activity with a moderate decrease effect on CRP, but lack of evidence and studies’ heterogeneity do not allow us to propose them to patients with inflammatory arthritis to control their disease. Further RCTs are required in the future to determinate the efficacy of probiotics and the optimal administration design

HIGH SERUM LONG-CHAIN OMEGA-3 FATTY ACIDS ARE ASSOCIATED WITH 6-MONTHLOWER DISEASE ACTIVITY IN EARLY RA: RESULTS FROM THE ESPOIR COHORT

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Sustainability of TNF-blocker tapering in rheumatoid arthritis over 3 years: long-term follow-up of the STRASS (Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study) randomised controlled trial

International audienceINTRODUCTION: We have limited data on the sustainability of tumour necrosis factor (TNF)-blocker tapering in rheumatoid arthritis (RA) in remission over the long term in real-life settings. This study aimed to assess the probability of sustained dose reduction of TNF-blockers in an observational 3-year extended follow-up of the Spacing of TNF-blocker injections in Rheumatoid ArthritiS Study (STRASS), a randomised controlled trial comparing progressive TNF-blocker injections (spacing arm (S-arm) to maintenance arm (M-arm)) in patients with RA in stable remission.METHODS: In 2015, clinical data for the completer population were retrospectively collected at 1, 2 and 3 years after the end of the trial. The endpoints were the proportion of patients free of a biological disease-modifying antirheumatic drug (bDMARD) treatment, a sustainably spaced injection of TNF-blockers and a full-dose regimen as well as the mean dose of bDMARD intake and treatment switch rate.RESULTS: Overall, 96 patients (76.8% of the completers) had data available up to 3 years; 11.5% discontinued TNF-blockers (5.8% vs 18.2% in the M-arm and S-arm, p=0.06), 30.2% had a tapered regimen (28.8% vs 31.8%, p=0.76) and 37.5% retained a full dose (44.2% vs 29.5%, p=0.14). The mean TNF-blocker dose quotient was 66% of the full dose (74% vs 58% in the M-arm and S-arm, p=0.06); 20.8% switched to another bDMARD (21.2% vs 20.5%, p=0.94).CONCLUSION: Sustained TNF-blocker de-escalation or withdrawal is achievable in 41% of patients over 3 years with limited dose reduction. Optimal strategies remain to be determined to maintain remission after TNF-blocker tapering or discontinuation

Serum Fatty Acid Profiles Are Associated with Disease Activity in Early Rheumatoid Arthritis: Results from the ESPOIR Cohort

Background: Long-chain omega-3 and omega-6 fatty acids (n-3, n-6 FAs) may modulate inflammation and affect the risk of developing rheumatoid arthritis (RA). However, whether n-3/n-6 FA status affects RA after disease onset is unknown. This study aimed to assess whether FA profiles are independently associated with disease activity in a large prospective cohort of patients with early RA. Methods: Baseline serum FAs were quantified in 669 patients in the ESPOIR cohort. Principal component analysis identified three serum FA patterns that were rich in n-7–9, n-3 and n-6 FAs (patterns ω7–9, ω3 and ω6), respectively. The association of pattern tertiles with baseline variables and 6-month disease activity was tested using multivariable logistic regression. Results: Pattern ω3 was associated with low baseline and pattern ω6 with high baseline C-reactive protein level and disease activity. Both patterns ω3 and ω6 were associated with reduced odds of active disease after 6 months of follow-up (pattern ω3: odds ratio, tertile three vs. one, 0.49 [95% CI 0.25 to 0.97] and pattern ω6: 0.51 [0.28 to 0.95]; p = 0.04 and 0.03, respectively). Conclusions: In a cohort of early RA patients, a serum lipid profile rich in n-3 FAs was independently associated with persistently reduced disease activity between baseline and 6-month follow-up. An n-6 FA profile was also associated with lower 6-month disease activity