Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1-phase 2a study.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc. OBJECTIVE: We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc. METHODS: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6. RESULTS: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period. CONCLUSION: IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc.

Accuracy of self-reported diagnoses of polymyalgia rheumatica and giant cell arteritis in the French prospective E3N- EPIC cohort: A validation study.

OBJECTIVES: To assess the accuracy of self-reported giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) diagnoses in a large French population-based prospective cohort, and to devise algorithms to improve their accuracy. METHODS: The E3N-EPIC cohort study (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale) includes 98,995 French women born between 1925 and 1950, recruited in 1990 to study risk factors of cancer and chronic diseases. They completed biennially mailed questionnaires to update their health-related information and lifestyle characteristics. In three questionnaires, women could self-report a diagnosis of GCA/PMR. Those women were additionally sent a specific questionnaire, designed to ascertain self-reported diagnoses of GCA/PMR. Four algorithms were then devised to improve their identification. Accuracies of self-reported diagnoses and of each algorithm were calculated by comparing the diagnoses with a blinded medical chart review. RESULTS: Among 98,995 participants, 1,392 women self-reported GCA/PMR. 830 women sent back the specific questionnaire, and 202 women provided medical charts. After independent review of the 202 medical charts, 87.6 % of the self-reported diagnoses of GCA/PMR were accurate. Using additional data from a specific questionnaire (diagnosis confirmation by a physician, and self-report of >3-month of glucocorticoids), and from a reimbursement database (at least two deliveries of glucocorticoids in less than 3 consecutive months) improved their accuracy (91.8 % to 92.8 %). CONCLUSION: The accuracy of self-reported diagnosis of GCA/PMR was high in the E3N-cohort but using additional data as a specific GCA/PMR questionnaire and/or corticosteroid reimbursement database further improved this accuracy. With nearly 600 detected cases of GCA/PMR, we will be able to investigate risk factors for GCA/PMR in women.

Association between infection and the onset of giant cell arteritis and polymyalgia rheumatica: a systematic review and meta-analysis.

OBJECTIVE: We aimed to analyse the association between infections and the subsequent risk of giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR) by a systematic review and a meta-analysis of observational studies. METHODS: Two databases (Medline and Embase) were systematically reviewed. Epidemiological studies studying the association between any prior infection and the onset of GCA/PMR were eligible. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. Outcomes and pooled statistics were reported as OR and their 95% CI. RESULTS: Eleven studies (10 case-control studies and one cohort study) were analysed, seven of them were included in the meta-analysis. Eight were at low risk of bias. A positive and significant association was found between prior overall infections and prior Herpes Zoster (HZ) infections with pooled OR (95% CI) of 1.27 (1.18 to 1.37) and 1.20 (1.08 to 1.21), respectively. When analysed separately, hospital-treated and community-treated infections, were still significantly associated with the risk of GCA, but only when infections occurring within the year prior to diagnosis were considered (pooled OR (95% CI) 1.92 (1.67 to 2.21); 1.67 (1.54 to 1.82), respectively). This association was no longer found when infections occurring within the year prior to diagnosis were excluded. CONCLUSION: Our study showed a positive association between the risk of GCA and prior overall infections (occurring in the year before), and prior HZ infections. Infections might be the reflect of an altered immunity of GCA patients or trigger the disease. However, reverse causation cannot be excluded.CRD42023404089.

Association between beverage consumption and risk of rheumatoid arthritis: a prospective study from the French E3N Cohort.

OBJECTIVES: To assess the relationship between consumption of largely consumed beverages (coffee, tea, alcohol and soft drinks) and the risk of RA. MATERIAL AND METHODS: The E3N Study (Étude Épidémiologique auprès des femmes de la Mutuelle Générale de l'Éducation Nationale) is a French prospective cohort including 98 995 women since 1990. Food and beverage consumption was assessed using a validated food-frequency questionnaire. Hazard ratios (HR) and their 95% CI for incident RA were estimated by Cox proportional hazards model. RESULTS: Among 62 631 women, 481 incident RA cases were identified. Consumptions of tea, alcohol and sugar-sweetened soft drinks were not associated with RA risk. We observed a linear association between coffee consumption and RA risk [≥4 cups/day vs ≤1cup/day, HR = 1.24; 95% CI (0.94, 1.64), Ptrend = 0.04], and a higher risk of RA with artificially sweetened soft drinks consumption [consumers vs not, HR = 1.66; 95% CI (1.12, 2.45)], particularly in never-smokers. Among ever-smokers, moderate liquor intake was associated with a reduced risk of RA [1-3 glasses/week vs non-consumers, HR = 0.63; 95% CI (0.43, 0.91)] and moderate wine consumption with a reduced risk of seropositive RA. CONCLUSIONS: In a large cohort of women, tea, alcohol and sugar-sweetened soft drinks consumption was not associated with RA risk, whereas consumption of coffee (especially caffeinated coffee), and artificially sweetened soft drinks was associated with higher RA risk, particularly among never-smokers. If further confirmed, these results could lead to novel mechanistic hypotheses and to simple prevention measures.

Low Central Nervous System Posaconazole Concentrations during Cerebral Phaeohyphomycosis.

Posaconazole diffusion has been documented in various organs, which contrasts with the scarce data available for the human central nervous system (CNS). We analyzed posaconazole concentrations in plasma and multiple CNS specimens taken from a patient who received posaconazole because of cerebral phaeohyphomycosis. Low posaconazole concentrations were obtained in CNS specimens, with sample-to-plasma ratios between 5% and 22%. This case highlights the role of neurosurgery during cerebral phaeohyphomycoses, even those caused by posaconazole-susceptible black fungi.