Quinze-Vingts National Eye Hospital

OBJECTIVE:To evaluate the efficacy and safety of adalimumab, anakinra, and tocilizumab in patients with active and refractory noninfectious uveitis (NIU). DESIGN:Multicenter, Bayesian, randomized controlled trial. SUBJECTS:A total of 112 patients with active, noninfectious, nonanterior uveitis across 27 French centers were enrolled. METHODS:Participants were randomly assigned (1:1:1) to receive either subcutaneous adalimumab (n = 44; initial dose 80 mg, followed by 40 mg every other week), anakinra (n = 18; 100 mg daily), or tocilizumab (n = 50; 162 mg weekly) for a 16-week treatment period. MAIN OUTCOME MEASURES:The primary end point was a reduction of at least 2 steps on the Miami 9-step scale for vitreous haze with a corticosteroid dose of 0.1 mg/kg/d or less at week 16. RESULTS:During interim analyses, anakinra was shown to be ineffective, and this arm was stopped prematurely. By week 16, the primary outcome was achieved in 7 of 44 (16%) and 7 of 50 (14%) patients in the adalimumab and tocilizumab groups, respectively (mean difference -2.0%, 95% credible interval [CrI] -16.8% to +12.3%). Absence of macular edema and retinal vasculitis was seen in 54% and 56%, and in 59% and 57%, respectively (mean differences -2.0% [95% CrI, -14% to +26%] and 2.0% [95% CrI, -31% to +15%]). A prednisone taper to ≤0.1 mg/kg/d at week 16 was reached by 59% and 74% of patients, respectively (mean difference -15%, 95% CrI -4% to +32%). Mild to moderate adverse events occurred in 43% (adalimumab) and 54% (tocilizumab). CONCLUSIONS:Adalimumab and tocilizumab show comparable efficacy in active, refractory NIU, whereas anakinra was ineffective. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02929251.

BACKGROUND AND OBJECTIVES:The therapeutic strategy for late-onset multiple sclerosis (LOMS) with a relapsing-remitting onset remains unclear, potentially leading to underexposure to disease-modifying therapies (DMTs) compared with adult-onset multiple sclerosis (AOMS). We investigated the differences in DMT use between LOMS and AOMS within the French MS registry at comparable levels of disease severity. METHODS:This retrospective cohort study used data extracted in December 2024 from the French MS registry on patients with relapsing-remitting onset MS between 1997 and 2023. The primary outcome was the annual probability of receiving a DMT according to age at MS onset, adjusted for disease severity. Secondary outcomes included the annual probability of receiving a highly effective DMT (HEDMT), each DMT separately, having ≥1 EDSS measurement, having ≥1 brain MRI, and DMT initiations and discontinuations. We used a longitudinal logistic model with generalized estimating equations and an inverse-probability-of-censoring weighting. RESULTS:A total of 36,148 were included patients; 26,540 (73.4%) were female, mean age was 33.5 years (SD, 9.7), and 2,308 (6.4%) were aged ≥50 at disease onset. Median follow-up was 10.8 years (interquartile range, 5.6-17.0). Patients with LOMS had a lower annual probability of receiving a DMT compared with patients with AOMS (73.7% vs 83.1%; odds ratio [OR], 0.57 [95% CI 0.52-0.62]). The difference was greater for HEDMT (24.6% vs 44.4%; OR, 0.41 [95% CI 0.36-0.46]). Patients with LOMS were more likely to receive teriflunomide and less likely to receive fumarates, S1PR modulators, natalizumab, or anti-CD20. Clinical and radiologic follow-up did not differ significantly between patients with LOMS and AOMS. The rate of DMT initiation was lower in patients with LOMS (0.13 vs 0.17 initiation per patient-year). Although the proportions of DMT discontinuation were similar (59.7% vs 60.4%, excluding pregnancy-related discontinuations), these discontinuations were more often attributed to a complete discontinuation strategy (27.9% vs 22.3%) and less often to an escalation strategy (9.2% vs 13.8%) in patients with LOMS. DISCUSSION:At comparable levels of disease severity, patients with LOMS were less likely to be treated with DMTs, particularly HEDMT, than patients with AOMS. This gap was driven both by fewer DMT initiations and more frequent complete discontinuations.

Purpose: To describe the spectrum of optical coherence tomography (OCT) findings in acute posterior multifocal placoid pigment epitheliopathy (APMPPE), with a specific focus on the prevalence of pigment epithelium detachments (PEDs). Methods: Multicenter, retrospective, longitudinal study including patients diagnosed with APMPPE based on color fundus photography, OCT, and fluorescein angiography. Demographics, visual acuity, and the following OCT findings were assessed: outer retinal hyperreflectivity, serous retinal detachment (SRD), bacillary layer detachment (BALAD), and PED. Results: Forty-six eyes of 27 patients were included. The median age at presentation was 23 years (range: 18–36 years), and 17 patients (62.9%) were men. At baseline, outer retinal hyperreflectivity was found in all eyes, while BALAD, SRD, and PED were observed in 22 (47.8%), 14 (30.4%), and 26 eyes (56.5%), respectively. A univariate logistic regression showed a significant association between the presence of PED and a worse baseline visual acuity (odds ratio [OR]: 5.3; 95% confidence interval [CI]: 1.5–18.6; P = 0.01), the presence of BALAD (OR: 9.0; 95% CI: 2.3–35.6; P = 0.002), and the presence of SRD (OR: 7.3; 95% CI: 1.4–38.3; P = 0.02). Conclusion: PEDs were significantly associated with a poorer initial visual acuity, as well as with the presence of BALAD and SRD on presentation. These findings suggest that PEDs could be used as a biomarker of disease severity and choriocapillaris ischemia in APMPPE.

Rod-cone dystrophy, also known as retinitis pigmentosa (RP), is a genetically heterogeneous group of retinal disorders with progressive rod then cone photoreceptor loss, leading to severe visual impairment. Autosomal dominant RP has been associated with about thirty genes, while approximately 10% of our French autosomal dominantRP cohort remain genetically unsolved. Recently, several variants in small nuclear RNA (snRNA) genes have been identified in cases with autosomal recessive and autosomal recessive neurodevelopmental disorders as well as autosomal dominant RP. These snRNAs undergo post-transcriptional modifications and, in association with proteins and other snRNAs, assemble into small nuclear ribonucleoproteins that are components of the spliceosome. By performing genome and direct Sanger sequencing, combined with a candidate gene approach, we identified heterozygous variants in RNU4-2 and RNU6 paralogs in eight unrelated non-syndromic autosomal dominant RP families, which co-segregated with the phenotype in available family members. RNU4-2 and RNU6 encode U4 and U6, snRNA, respectively, forming with U5, the tri-sn ribonucleoprotein (RNP) complex, representing the core of the major spliceosome. Interestingly, variants in autosomal dominant RP cases cluster in distinct locations than variants implicated in neurodevelopmental disorders, affecting regions important for tri-snRNP complex assembly with PRPF3, PRPF8 and PRPF31, also implicated in RP. Together, our findings revealed that 2% of our genetically solved cases with autosomal dominant RP carry variants in RNU4-2 or RNU6 paralogs. This represents 6% of all cases having variants in genes coding for the multisubunit complex, highlighting the importance of screening snRNA genes in cases of RP.

BACKGROUND:Ofatumumab and ocrelizumab are widely used high-efficacy anti-CD20 therapies for relapsing-remitting multiple sclerosis (RRMS), but direct comparative evidence remains limited. We aimed to compare their effectiveness in routine clinical practice. METHODS:We conducted an observational cohort study emulating a target trial using data from the MSBase and Observatoire Français de la Sclérose en Plaques registries (January 2021 to December 2024). Adults with RRMS initiating ofatumumab or ocrelizumab were included. Patients were matched 1:1 using propensity scores. Primary outcomes were annualised relapse rate (ARR) and time to first relapse. Secondary outcomes included time to confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), MRI activity and treatment discontinuation. Negative binomial and Cox regression models were applied. RESULTS:A total of 5288 patients were matched with a median follow-up of 1.2 years for ofatumumab and 1.4 years for ocrelizumab. ARR was 0.07 (95% CI 0.05 to 0.08) with ofatumumab and 0.04 (0.03 to 0.05) with ocrelizumab, corresponding to an ARR ratio of 1.75 (1.43 to 2.13). Ofatumumab was associated with a lower risk of CDP (HR 0.66; 0.49 to 0.87) and PIRA (0.53; 0.39 to 0.73), but a lower probability of CDI (0.76; 0.60 to 0.96). No significant differences were observed in MRI activity or treatment discontinuation. CONCLUSIONS:Both therapies were highly effective in a large cohort of patients with RRMS, with very low relapse or CDP rates. Ofatumumab was associated with slightly greater disability control, while ocrelizumab more effectively suppressed relapses. These differences were modest, and their clinical relevance requires further evidence and should be interpreted with caution.