Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study.

BACKGROUND: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. METHODS: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis. RESULTS: In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015). CONCLUSIONS: In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Can objective parameters in optical coherence tomography be useful markers in the treatment and follow-up of type 1 and type 2 macular neovascularizations related to neovascular age-related macular degeneration?

PURPOSE: The aim of this study was to compare the responses of type 1 and type 2 macular neovascularizations (MNV) caused by neovascular type age-related macular degeneration (n-AMD) to intravitreal anti-vascular endothelial growth factor (VEGF) treatments using quantitative parameters determined by optical coherence tomography (OCT). Additionally, it was also intended to assess the connections between these quantitative parameters and changes in best-corrected visual acuity (BCVA) and the number of intravitreal anti-VEGF injections required within a year. MATERIALS AND METHODS: In our retrospective and observational study, the data of 90 eyes of 90 patients diagnosed with n-AMD and treated with intravitreal anti-VEGF with the "Pro re nata" method were evaluated. Subtypes of existing MNVs were distinguished with previously taken optical coherence tomography angiography (OCTA) images. In spectral domain OCT examinations, central macular thickness (CMT) and central macular volume (CMV) values were recorded at baseline and 12th month. The number of intravitreal anti-VEGF injections during the 12 month follow-up period was also recorded for each patient. Obtained data were compared between MNV types. RESULTS: Of the n-AMD cases examined in the study, 56.66% had type 1 MNV and 43.34% had type 2 MNV. The mean baseline BCVA logMAR values in eyes with type 2 MNV (1.15 ± 0.43) were higher than those observed in eyes with type 1 MNV (0.76 ± 0.42) (p = 0.001). Similarly, mean baseline CMT and CMV values in eyes with type 2 MNV were higher than those observed in eyes with type 1 MNV (respectively 424.89 ± 49.46 µm vs. 341.39 ± 37.06 µm; 9.17 ± 0.89 µm3 vs. 8.49 ± 0.53 µm3; p < 0.05). After 12 months of treatment, logMAR values of BCVA (0.86 ± 0.42) in subjects with type 2 MNV were higher than those in subjects with type 1 MNV (0.57 ± 0.37) (p = 0.001). Mean CMT and CMV values at 12th month in subjects with type 2 MNV (379.11 ± 46.36 µm and 8.66 ± 0.79 µm3, respectively) were observed to be higher than those with type 1 MNV (296.95 ± 33.96 µm and 8.01 ± 0.52 mm3, respectively) (p < 0.05). In type 2 MNVs, positive correlations were observed between both baseline and 12th month BCVA logMAR values and baseline CMV (p < 0.05). Similarly, in type 2 MNVs, a positive correlation was observed between 12th month BCVA logMAR values and 12th month CMV (p < 0.05). The total number of intravitreal anti-VEGF injections at 12 months was similar in both groups (p = 0.851). CONCLUSION: In this study, in which we performed a subtype analysis of MNV cases, we observed that the visual function was worse at the beginning and the end of the 12th month, and the CMT and CMV values were higher in the type 2 MNV group compared to the type 1 MNV cases. In addition, we found significant correlations between BCVA logMAR values and CMV values in type 2 MNV cases. In the follow-up of these cases, CMT, which is a more widely used quantitative method, and CMV, which is a newer OCT measurement parameter, may be more useful in patient follow-up and evaluation of treatment efficacy, especially for type 2 MNV cases.

Using the Amsler Grid Test for Age-Related Macular Degeneration Screening.

Objectives: To evaluate the use of the Amsler grid test (AGT) in screening for age-related macular degeneration (AMD), one of the most common causes of blindness, in primary healthcare settings. Materials and Methods: The AGT was applied to 700 eyes of 355 people aged 50 and over who applied to a family health center in Ankara and had no eye complaints. The test was considered positive if the lines on the AGT card were seen as broken or curved, there was a difference in shape or size between the squares, or a color change or blurring was described in any area. An ophthalmologist was consulted if the AGT was positive in one or both eyes. Patients considered suitable by ophthalmologists were evaluated with optical coherence tomography. AGT results were compared with ophthalmologist examination and tomography findings in terms of AMD detection. Results: The AGT was positive in 97 (13.9%) and negative in 603 (86.1%) out of 700 eyes included in the study. A total of 184 eyes, 79 with a positive AGT and 105 eyes with a negative test, were evaluated by an ophthalmologist. As a result of examinations and tests performed by ophthalmologists, AMD was detected in a total of 67 eyes: 42 of 79 eyes with positive AGT and 25 of 105 eyes with negative AGT but referred to an ophthalmologist for different reasons. In our study, the AGT had 62.7% sensitivity and 68.4% specificity. Conclusion: The AGT is an inexpensive and easily applicable test. Although moderate sensitivity and specificity were found in our study; further studies are needed to evaluate the suitability of its use for AMD screening in primary care with limited facilities.

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial.

BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.

A plain language summary on the effectiveness of cladribine tablets compared with other oral treatments for multiple sclerosis: results from the MSBase registry.

WHAT IS THIS SUMMARY ABOUT?: Patient registries contain anonymous data from people who share the same medical condition. The MSBase registry contains information from over 80,000 people living with multiple sclerosis (MS) across 41 countries. Using information from the MSBase registry, the GLIMPSE (Generating Learnings In MultiPle SclErosis) study looked at real-life outcomes in 3475 people living with MS who were treated with cladribine tablets (Mavenclad®) compared with other oral treatments. WHAT WERE THE RESULTS?: Results showed that people treated with cladribine tablets stayed on treatment for longer than other treatments given by mouth. They also had fewer relapses (also called flare ups of symptoms) than people who received a different oral treatment for their MS. WHAT DO THE RESULTS MEAN?: The results provide evidence that, compared with other oral treatments for MS, cladribine tablets are an effective medicine for people living with MS.

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

Real Life Multicenter Comparison of 24-Month Outcomes of Anti-VEGF Therapy in Diabetic Macular Edema in Turkey: Ranibizumab vs. Aflibercept vs. Ranibizumab-Aflibercept Switch.

The aim of this study was to compare the outcomes of diabetic macular edema (DME) treated with aflibercept (AFB) or ranibizumab (RNB) only, and after switching from RNB to AFB. This was a retrospective, real-world, multicenter (7 cities) 24 month study. Overall, 212 eyes in the AFB group, 461 in the RNB group, and 141 in the RNB to AFB group were included. The primary endpoints were differences in visual acuity (VA) and central macular thickness (CMT) from baseline to the final visit. The secondary outcomes were the percentage of eyes that achieved ≥10 letters gain and ≥10 letters loss in vision at month 12 and 24, and the percentage of eyes that achieved a thinning of ≥20% in CMT at month 3 and month 6. The results showed that VA did not significantly differ at baseline (AFB: 0.62 ± 0.38, RNB: 0.61 ± 0.36, RNB to AFB: 0.61 ± 0.38), at checkpoints, or at the final visit (AFB: 0.46 ± 0.38, RNB: 0.5 ± 0.37, RNB to AFB: 0.53 ± 0.36) (p > 0.05). Though the mean CMT at baseline was significantly thicker in the RNB to AFB group (479 ± 129.6 µm) when compared to the AFB (450.5 ± 122.6 µm) and RNB (442 ± 116 µm) groups (p < 0.01), similar measurements were obtained after 12 months. The percentages of eyes that gained or lost ≥10 letters in the AFB, RNB, and RNB to AFB groups at year 1 and 2 were similar, as was the percentages of eyes that demonstrated ≥20% CMT thinning at month 3 and 6. Our study showed similar visual improvements in non-switchers (AFB and RNB groups) and switchers (RNB to AFB group) through 2 years follow-up, however, AFB patients required fewer injections, visits, or need for additional treatments.

Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis.

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Comparative effectiveness in multiple sclerosis: A methodological comparison.

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Effects of the epiretinal membrane on the outcomes of intravitreal dexamethasone implantation for macular edema secondary to branch retinal vein occlusion / Os efeitos de uma membrana epirretiniana nos resultados da implantação de dexametasona intravítrea para edema macular secundário à oclusão de ramo da veia retiniana

ABSTRACT Purpose: To investigate the effects of epiretinal membrane formation on the clinical outcomes of intravitreal dexamethasone implantation for macular edema secondary to branch retinal vein occlusion. Methods: This retrospective interventional case series includes the treatment of naive patients with macular edema secondary to non-ischemic branch retinal vein occlusion who underwent intravitreal dexamethasone implantation. The patients were divided into two groups as follows: Group 1 (n=25), comprised of patients with macular edema secondary to branch retinal vein occlusion without epiretinal membrane, and Group 2 (n=16), comprised of patients with macular edema secondary to branch retinal vein occlusion with an epiretinal membrane. Corrected visual acuity, central macular thickness, and central macular volume values were measured before and after treatment. The clinical outcomes of the groups were compared. Results: Mean age and male-to-female ratio were similar between the two groups (p>0.05, for both). The baseline and final corrected visual acuity values, central macular thickness, and central macular volumes of the groups were similar (p>0.05, for all). All the parameters were significantly improved after intravitreal dexamethasone implantation treatment (p<0.001, for all). The changes in central macular thickness and volume were also similar (p>0.05, for both). The mean number of intravitreal dexamethasone implantations was 2.1 ± 1.0 (range, 1-4) in Group 1 and 3.0 ± 1.2 (range, 1-5) in Group 2 (p=0.043). Conclusion: Epiretinal membrane formation had no effects on the baseline and final clinical parameters, including corrected visual acuity and central macular thickness and volume. The only parameter affected by the presence of epiretinal membrane formation is the number of intravitreal dexamethasone implantations, a greater number of which is needed for macular edema secondary to branch retinal vein occlusion with an epiretinal membrane.

RESUMO Objetivo: Investigar os efeitos da formação de uma membrana epirretiniana nos resultados clínicos da implantação intravítrea de dexametasona para edema macular secundário à oclusão de um ramo da veia retiniana. Métodos: Esta série retrospectiva de casos intervencionais inclui o tratamento de indivíduos com edema macular secundário à oclusão não isquêmica de um ramo da veia retiniana, sem tratamento prévio e que foram submetidos a implantação intravítrea de dexametasona. Os indivíduos foram divididos em dois grupos: Grupo 1 (n=25), composto por indivíduos com edema macular secundário à oclusão de um ramo da veia retiniana sem a presença de uma membrana epirretiniana, e Grupo 2 (n=16), composto por indivíduos com edema macular secundário à oclusão de um ramo da veia retiniana com a presença de uma membrana epirretiniana. Os valores da acuidade visual corrigida, espessura macular central e volume macular central foram obtidos antes e após o tratamento. Os resultados clínicos dos grupos foram comparados. Resultados: A média de idade e a proporção entre homens e mulheres foram semelhantes nos dois grupos (p>0,05 para ambos os valores). Os valores iniciais e finais da acuidade visual corrigida, espessura macular central e volume macular central foram semelhantes nos dois grupos (p>0,05 para todos os valores). Todos os parâmetros melhoraram significativamente após o tratamento com implante de dexametasona intravítrea (p<0,001 para todos os parâmetros) e as alterações na espessura macular central e no volume macular central também foram semelhantes (p>0,05 para ambos os valores). O número médio de implantações intravítreas de dexametasona foi 2,1 ± 1,0 (faixa de 1-4) no Grupo 1 e 3,0 ± 1,2 (faixa de 1-5) no Grupo 2 (p=0,043). Conclusão: A formação de uma membrana epirretiniana não tem efeitos sobre os parâmetros clínicos iniciais e finais, incluindo a acuidade visual corrigida, a espessura macular central e o volume macular central. O único parâmetro afetado pela formação de uma membrana epirretiniana é o número de implantações intravítreas de dexametasona, sendo necessário um número maior de implantações em casos de edema macular secundário à oclusão de um ramo da veia retiniana com a presença de uma membrana epirretiniana.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry.

BACKGROUND: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. OBJECTIVES: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. METHODS: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). RESULTS: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. CONCLUSION: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

External validation of a clinical prediction model in multiple sclerosis.

BACKGROUND: Timely initiation of disease modifying therapy is crucial for managing multiple sclerosis (MS). OBJECTIVE: We aimed to validate a previously published predictive model of individual treatment response using a non-overlapping cohort from the Middle East. METHODS: We interrogated the MSBase registry for patients who were not included in the initial model development. These patients had relapsing MS or clinically isolated syndrome, a recorded date of disease onset, disability and dates of disease modifying therapy, with sufficient follow-up pre- and post-baseline. Baseline was the visit at which a new disease modifying therapy was initiated, and which served as the start of the predicted period. The original models were used to translate clinical information into three principal components and to predict probability of relapses, disability worsening or improvement, conversion to secondary progressive MS and treatment discontinuation as well as changes in the area under disability-time curve (ΔAUC). Prediction accuracy was assessed using the criteria published previously. RESULTS: The models performed well for predicting the risk of disability worsening and improvement (accuracy: 81%-96%) and performed moderately well for predicting the risk of relapses (accuracy: 73%-91%). The predictions for ΔAUC and risk of treatment discontinuation were suboptimal (accuracy < 44%). Accuracy for predicting the risk of conversion to secondary progressive MS ranged from 50% to 98%. CONCLUSION: The previously published models are generalisable to patients with a broad range of baseline characteristics in different geographic regions.

Effects of the epiretinal membrane on the outcomes of intravitreal dexamethasone implantation for macular edema secondary to branch retinal vein occlusion.

PURPOSE: To investigate the effects of epiretinal membrane formation on the clinical outcomes of intravitreal dexamethasone implantation for macular edema secondary to branch retinal vein occlusion. METHODS: This retrospective interventional case series includes the treatment of naive patients with macular edema secondary to non-ischemic branch retinal vein occlusion who underwent intravitreal dexamethasone implantation. The patients were divided into two groups as follows: Group 1 (n=25), comprised of patients with macular edema secondary to branch retinal vein occlusion without epiretinal membrane, and Group 2 (n=16), comprised of patients with macular edema secondary to branch retinal vein occlusion with an epiretinal membrane. Corrected visual acuity, central macular thickness, and central macular volume values were measured before and after treatment. The clinical outcomes of the groups were compared. RESULTS: Mean age and male-to-female ratio were similar between the two groups (p>0.05, for both). The baseline and final corrected visual acuity values, central macular thickness, and central macular volumes of the groups were similar (p>0.05, for all). All the parameters were significantly improved after intravitreal dexamethasone implantation treatment (p<0.001, for all). The changes in central macular thickness and volume were also similar (p>0.05, for both). The mean number of intravitreal dexamethasone implantations was 2.1 ± 1.0 (range, 1-4) in Group 1 and 3.0 ± 1.2 (range, 1-5) in Group 2 (p=0.043). CONCLUSION: Epiretinal membrane formation had no effects on the baseline and final clinical parameters, including corrected visual acuity and central macular thickness and volume. The only parameter affected by the presence of epiretinal membrane formation is the number of intravitreal dexamethasone implantations, a greater number of which is needed for macular edema secondary to branch retinal vein occlusion with an epiretinal membrane.

Predictors of treatment switching in the Big Multiple Sclerosis Data Network.

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods. Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry. Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect. Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006). Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

Cumulative dissipated energy in eyes with and without corneal opacity.

Objective: To compare ultrasonic energy delivered into the eye [cumulative dissipated energy, (CDE)] and frequencies of required auxiliary surgical methods during phacoemulsification surgery in eyes with and without corneal opacity. Methods: The study was designed as a retrospective comparative observational study. The study group [Corneal Opacity Group, (COG)] was comprised of 31 eyes of 31 cataract patients with corneal opacity. Only nebular and macular corneal opacities (according to slit-lamp based classification of Agrawal) were included in the study. The control group (CG) was comprised of 40 eyes of 40 cataract patients without corneal opacity. The CDE values were obtained using the Centurion system (Alcon, Fort Worth, TX) and the patients were followed-up postoperatively for a period of one month. Results: The mean age of the subjects was 71.46 ± 8.86 years (52-89) in COG and 66.12 ± 5.96 years (55-80) in CG (p >0.05). In COG, the most common etiologic factors were trauma, keratitis, and degenerative diseases. The mean CDE value was 15.16 ± 8.71 (2.20-42.65) in COG and 10.04 ± 6.28 (3.77-31.80) in CG and it was found as significantly higher in COG (p=0.003). Some auxiliary surgical methods including posterior synechiolysis and anterior capsule staining were more commonly performed in COG (p=0.044 and p=0.040, respectively). No intraoperative or postoperative complication was observed. Conclusion: More ultrasonic energy is delivered into the eye and more auxiliary surgical methods are needed in cataract patients with corneal opacity who underwent phacoemulsification. Abbreviations: CDE = Cumulative dissipated energy, COG = Corneal Opacity Group, CG = Control group, IOL = Intraocular lens, LOCS = Lens Opacities Classification System, BCVA = best-corrected visual acuity, SRK/T = Sanders, Retzlaff, and Kraff theoretical, OVD = ophthalmic viscosurgical device, SPSS = Statistical Package for the Social Sciences.

Early predictors of disability in paediatric multiple sclerosis: evidence from a multi-national registry.

BACKGROUND: Early recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time. OBJECTIVE: To identify early predictors of rapid disability accrual in patients with paediatric-onset MS. METHODS: Using the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data. RESULTS: 672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15-17) years. Older age at symptom onset (exp(ß)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)). CONCLUSIONS: A relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.