RESUMO
OBJECTIVE: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS). METHODS: A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics. RESULTS: We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy. INTERPRETATION: This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024.
RESUMO
BACKGROUND: Relapse risk after delivery is increased in women with active multiple sclerosis (MS), the best strategy to reduce it is unknown. We aimed to assess the association of four different postpartum strategies with relapses during the first 6 months post partum. METHODS: This cohort study includes data prospectively collected through structured telephone interviews from the German Multiple Sclerosis and Pregnancy Registry. Pregnancies with active MS (fingolimod or natalizumab treatment OR relapse within 1 year before pregnancy) and postpartum follow-up of ≥6 months were included. We compared four strategies: (1) intention to breastfeed exclusively without disease-modifying therapy (DMT) (exclusive breast feeding ≥2 months or switching to non-exclusive/weaning within 2 weeks after a relapse during the first 2 months), (2) early treatment with natalizumab/fingolimod and (3) other DMT initiated within 6 weeks post partum before a relapse. If women did not or only partially breastfed, or started DMT≤6 weeks after delivery after a relapse or later, we assumed (4) no-DMT-no-exclusive- breastfeeding-strategy. Main outcome was time to postpartum MS relapses. RESULTS: In 867 women with 911 pregnancies, most (n=416) intended to breastfeed exclusively or had no-DMT-no-exclusive-breastfeeding-strategy (n=290); fewer started fingolimod (n=38), natalizumab (n=74) or another DMT (n=93) early. Recurrent time-to-event analysis showed a statistically significant reduction in relapse hazard only with the natalizumab/fingolimod-strategy as of months 3-4 post partum compared with intention-to-breastfeed-exclusively-strategy. The very early relapse risk was highest in no-DMT-no-exclusive-breastfeeding-strategy. CONCLUSION: In active MS, an early postpartum treatment strategy should be determined well before delivery. Natalizumab/fingolimod-strategy reduced postpartum relapse hazard from month 3, but none diminished the early postpartum relapse hazard.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Gravidez , Feminino , Humanos , Esclerose Múltipla/tratamento farmacológico , Natalizumab/uso terapêutico , Estudos de Coortes , Cloridrato de Fingolimode/uso terapêutico , Período Pós-Parto , Recidiva , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , ImunossupressoresRESUMO
BACKGROUND: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start. METHODS: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. RESULTS: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories. CONCLUSIONS: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Velocidade de Processamento , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Cognição , RituximabRESUMO
OBJECTIVE: This study was undertaken to evaluate a multicomponent health system intervention designed to reduce escalating disease-modifying treatment (DMT) expenditures and improve multiple sclerosis (MS) outcomes by increasing use of preferred formulary and highly effective DMTs (HETs). METHODS: We conducted a trend study of treatment utilization and expenditure outcomes prior to (2009-2011) and during (2012-2018) MS Treatment Optimization Program (MSTOP) implementation in Kaiser Permanente Southern California (KPSC) compared to a Kaiser Permanente region of similar size. Annual relapse rates (ARRs) were obtained from KPSC's electronic health records. RESULTS: Adherence to preferred formulary DMTs increased from 25.4% in 2011 to 72.2% in 2017 following MSTOP implementation in KPSC and 22.1% to 43.8%, respectively, in the comparator. KPSC's annual DMT expenditures in 2018 were less than in 2011 despite an 11.3% increase in DMT-treated members. The decline in average per patient per year of treatment expenditures from a peak of $43.1 K in 2014 to $26.3 K in 2018 in KPSC was greater than the comparator, which peaked at $52.1 K and declined to $40.0 K in 2018. Over the 7 years following initiation of MSTOP, cumulative MS DMT expenditures were $161.6 million less than the comparator. HET use increased to 62.5% of per patient treatment-years versus 32.4% in the comparator. This corresponded to a 69% decline in adjusted ARR (95% confidence interval = 64.1-73.2%; p < 0.0001) among DMT-treated patients in KPSC. INTERPRETATION: A novel, expert-led health system intervention reduced MS DMT expenditures despite rising prices while simultaneously reducing MS relapse rates. Our focus on health system progress toward meaningful, measurable targets could serve as a model to improve quality and affordability of MS care in other settings. ANN NEUROL 2022;92:164-172.
Assuntos
Esclerose Múltipla , Gastos em Saúde , Humanos , Esclerose Múltipla/tratamento farmacológico , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: There is a paucity of information on maternal multiple sclerosis (MS) and risk of adverse pregnancy and perinatal outcomes. OBJECTIVE: The aim of this study was to determine the association between MS and risks of adverse pregnancy and perinatal outcomes in women with MS. In women with MS, the influence of exposure to disease-modifying therapy (DMT) was also investigated. METHODS: Population-based retrospective cohort study on singleton births to mothers with MS and matched MS-free mothers from the general population in Sweden between 2006 and 2020. Women with MS were identified through Swedish health care registries, with MS onset before child's birth. RESULTS: Of 29,568 births included, 3418 births were to 2310 mothers with MS. Compared with MS-free controls, maternal MS was associated with increased risks of elective caesarean sections, instrumental delivery, maternal infection and antepartum haemorrhage/ placental abruption. Compared with offspring of MS-free women, neonates of mothers with MS were at increased risks of medically indicated preterm birth and being born small for gestational age. DMT exposure was not associated with increased risks of malformations. CONCLUSIONS: While maternal MS was associated with a small increased risk of few adverse pregnancy and neonatal outcomes, DMT exposure close to pregnancy was not associated with major adverse outcomes.
Assuntos
Esclerose Múltipla , Nascimento Prematuro , Gravidez , Criança , Recém-Nascido , Feminino , Humanos , Estudos Retrospectivos , Nascimento Prematuro/epidemiologia , Estudos de Coortes , Preparações Farmacêuticas , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Placenta , Resultado da Gravidez/epidemiologiaRESUMO
Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.
Assuntos
Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Esclerose Múltipla/genética , Fatores de Transcrição/genética , Negro ou Afro-Americano , Alelos , Asiático , Feminino , Estudo de Associação Genômica Ampla , Antígeno HLA-A3/genética , Antígeno HLA-B7/genética , Haplótipos , Hispânico ou Latino , Humanos , Masculino , Esclerose Múltipla/patologia , Polimorfismo de Nucleotídeo Único , População BrancaRESUMO
OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84). INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699.
Assuntos
Cloridrato de Fingolimode/efeitos adversos , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Natalizumab/efeitos adversos , Neoplasias/epidemiologia , Rituximab/efeitos adversos , Adulto , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Suécia/epidemiologiaRESUMO
There is little evidence on the role of diet in childhood/adolescence and multiple sclerosis (MS) in adulthood. The MS Sunshine Study recruited adults with recent-onset MS (n = 602) and matched controls (n = 653). Of these, 84% provided dietary recall for specific ages between childhood and young adulthood (6-10, 11-15 and 16-20 years). We used logistic regression to test associations between age-specific diet and case-control status. Consumption of fruit (all ages), yoghurt (all ages) and legumes (11-15 years) was associated with lower probability of adult-onset MS (all p < 0.05). These results suggest that healthy dietary habits between childhood and young adulthood may reduce MS risk.
Assuntos
Esclerose Múltipla , Adolescente , Adulto , Criança , Dieta , Inquéritos sobre Dietas , Comportamento Alimentar , Frutas , Humanos , Esclerose Múltipla/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The role of omega-3 fatty acid in multiple sclerosis (MS) susceptibility is unclear. OBJECTIVE: To determine whether fish/seafood intake or genetic factors that regulate omega-3 fatty acids levels are associated with MS risk. METHODS: We examined the association of fish and shrimp consumption and 13 tag single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2 with risk of MS in 1153 individuals from the MS Sunshine Study, a case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California. RESULTS: Consuming fish/seafood at least once a week or at least once a month with regular fish oil use was associated with 44% reduced odds of MS/CIS (adjusted OR = 0.56; 95% CI = 0.41-0.76; p = 0.0002) compared with consuming fish/seafood less than once a month and no fish oil supplementation. Two FADS2 SNPs (rs174611 and rs174618) were independently associated with a lower risk of MS (adjusted ORs = 0.74, 0.79, p = 0.0056, 0.0090, respectively). Association of FADS2 SNPs with MS risk was confirmed in an independent dataset. CONCLUSION: These findings suggest that omega-3 fatty acid intake may be an important modifiable risk factor for MS. This is consistent with the other known health benefits of fish consumption and complementary genetic studies supporting a key role for omega-3 regulation.
Assuntos
Ácidos Graxos Ômega-3 , Esclerose Múltipla , Estudos de Casos e Controles , Dessaturase de Ácido Graxo Delta-5 , Dieta , Humanos , Esclerose Múltipla/genética , Fatores de Risco , Alimentos MarinhosRESUMO
The Swedish Multiple Sclerosis Register is a national register monitoring treatment and clinical course for all Swedish multiple sclerosis (MS) patients, with high coverage and close integration with the clinic. Despite its great value for epidemiologic research, it has not previously been validated. In this brief report, we summarize a large validation of >3,000 patients in the register using clinical chart review in the context of the COMBAT-MS study. While further improving the data quality for a central cohort of patients available for future epidemiologic research, this study also allowed us to estimate the accuracy and completeness of the register data.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Farmacoepidemiologia/normas , Sistema de Registros/normas , Antirreumáticos/uso terapêutico , Estudos de Coortes , Humanos , Imunoterapia/estatística & dados numéricos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Prontuários Médicos/estatística & dados numéricos , Esclerose Múltipla/fisiopatologia , Recidiva , Análise de Regressão , Suécia/epidemiologiaRESUMO
BACKGROUND: Only limited data are available on whether glatiramer acetate exposure during pregnancy has an effect on perinatal outcome. OBJECTIVE: To determine the effect of glatiramer acetate exposure during pregnancy on pregnancy outcomes in women with multiple sclerosis. METHODS: We compared the outcome of pregnancies of women with multiple sclerosis exposed to glatiramer acetate with pregnancies unexposed to disease-modifying therapies. Women were enrolled into the German Multiple Sclerosis and Pregnancy registry. A standardized questionnaire was administered during pregnancy and postpartum. Detailed information on course of multiple sclerosis and pregnancy, concomitant medications, labor, delivery, and outcome of pregnancy was obtained. RESULTS: We collected data on 246 multiple sclerosis pregnancies, 151 exposed to glatiramer acetate and 95 unexposed to disease-modifying therapies during pregnancy. Three (2.2%) congenital anomalies occurred in the exposed and 6 (6.7%) in the control group. We did not observe an increase in other adverse pregnancy or delivery outcomes including spontaneous abortions, preterm birth, Cesarean sections, or reduced birth weight in the exposed group. CONCLUSION: Our data provide further evidence that glatiramer acetate exposure during the first trimester of pregnancy appears safe and without teratogenic effect. These findings provide important additive knowledge to better counsel women with multiple sclerosis in planning a pregnancy.
Assuntos
Anormalidades Induzidas por Medicamentos , Aborto Espontâneo/induzido quimicamente , Peso ao Nascer/efeitos dos fármacos , Cesárea , Acetato de Glatiramer/efeitos adversos , Imunossupressores/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Nascimento Prematuro/induzido quimicamente , Sistema de Registros/estatística & dados numéricos , Anormalidades Induzidas por Medicamentos/epidemiologia , Aborto Espontâneo/epidemiologia , Adulto , Cesárea/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Recém-Nascido , Esclerose Múltipla/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Estudos ProspectivosRESUMO
BACKGROUND: Available data suggest that pregnancy exposure to interferon-beta might result in lower mean birth weight and preterm birth. OBJECTIVE: To determine the effect of interferon-beta exposure during pregnancy on pregnancy outcomes in multiple sclerosis patients. METHODS: We compared the pregnancy outcomes of women exposed to interferon-beta with pregnancies unexposed to disease-modifying therapies. Women were enrolled into the German Multiple Sclerosis and Pregnancy Registry. A standardized questionnaire was administered during pregnancy and postpartum. Detailed information on course of multiple sclerosis and pregnancy, concomitant medications, delivery, and outcome of pregnancy was obtained. RESULTS: We collected data on 251 pregnancies exposed to interferon-beta and 194 unexposed to disease-modifying therapies. In all, 246 (98.01%) women discontinued interferon-beta treatment during first trimester. No differences regarding mean birth weight (exposed: 3272.28 ± 563.61 g; unexposed: 3267.46 ± 609.81 g), mean birth length (exposed: 50.73 ± 3.30 cm; unexposed: 50.88 ± 3.45 cm), preterm birth (p = 0.187), spontaneous abortion (p = 0.304), and congenital anomalies (p = 0.197) were observed between the two groups. CONCLUSIONS: Interferon-beta exposure during early pregnancy does not influence the mean birth weight, risk of preterm birth, or other adverse pregnancy outcomes. Our study provides further reassurance that interferon-beta treatment can be safely continued up until women become pregnant.
Assuntos
Anormalidades Induzidas por Medicamentos , Aborto Espontâneo/induzido quimicamente , Peso ao Nascer/efeitos dos fármacos , Estatura/efeitos dos fármacos , Fatores Imunológicos/efeitos adversos , Interferon beta/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Nascimento Prematuro/induzido quimicamente , Sistema de Registros/estatística & dados numéricos , Anormalidades Induzidas por Medicamentos/epidemiologia , Aborto Espontâneo/epidemiologia , Adulto , Feminino , Alemanha/epidemiologia , Humanos , Recém-Nascido , Esclerose Múltipla/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Estudos ProspectivosRESUMO
We sought to determine whether a history of traumatic brain injury (TBI) could explain the lower symbol digit modalities test (SDMT) scores observed among newly diagnosed multiple sclerosis (MS) and control participants identifying as Black or Hispanic versus white in the MS Sunshine Study (n = 1172). 330 (29.2 %) participants reported a history of ≥1 TBI. Accounting for TBI did not explain the significant independent associations between having MS, being Black or Hispanic and lower SDMT. The pervasive effects of systemic racism in the United States remain the best explanation for the lower SDMT scores observed in Black and Hispanic participants.
Assuntos
Negro ou Afro-Americano , Lesões Encefálicas Traumáticas , Hispânico ou Latino , Esclerose Múltipla , População Branca , Humanos , Esclerose Múltipla/etnologia , Esclerose Múltipla/diagnóstico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Lesões Encefálicas Traumáticas/etnologia , Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/complicações , Hispânico ou Latino/estatística & dados numéricos , Negro ou Afro-Americano/etnologia , População Branca/etnologia , Estados Unidos/etnologia , Disfunção Cognitiva/etnologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico , Testes Neuropsicológicos , Racismo/etnologiaRESUMO
In February 2023, following extensive discussions with stakeholders and data review, the Institute for Clinical and Economic Review issued final policy recommendations for treatment of relapsing multiple sclerosis (RMS)1: "All stakeholders have a responsibility and an important role to play in ensuring that all effective treatment options for patients with RMS, including off-label use of rituximab, are utilized in ways to help improve affordability and access and reduce health inequities." The report calls on payers to remove barriers to rituximab coverage, the American Academy of Neurology and the National MS Society to publicly endorse rituximab for RMS, and clinicians to advocate for coverage of rituximab and its biosimilars. In July 2023, the World Health Organization listed rituximab as an essential medicine for MS.2 Yet not much has changed. Food and Drug Administration (FDA)-approved MS disease-modifying therapies continue to generate enormous profits for pharma, and rituximab remains hidden in plain sight.
Assuntos
Medicamentos Biossimilares , Medicamentos Essenciais , Esclerose Múltipla , Estados Unidos , Humanos , Medicamentos Biossimilares/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Rituximab/uso terapêutico , Academias e InstitutosRESUMO
BACKGROUND AND OBJECTIVES: B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS). METHODS: We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted. RESULTS: We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, p < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections. DISCUSSION: Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.
Assuntos
Agamaglobulinemia , Infecções , Esclerose Múltipla , Humanos , Feminino , Masculino , Rituximab/efeitos adversos , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/epidemiologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Estudos Retrospectivos , Estudos Transversais , Imunoglobulina G , Infecções/induzido quimicamente , Infecções/epidemiologiaRESUMO
OBJECTIVES: To estimate the incidence of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. METHODS: We conducted a retrospective cohort study of >10 million person-years of observation from members of Kaiser Permanente Southern California, 2011-2022. The electronic health record of individuals with text-string mention of NMDA and encephalitis were reviewed to identify persons who met diagnostic criteria for anti-NMDAR encephalitis. Age-standardized and sex-standardized incidences stratified by race and ethnicity were estimated according to the 2020 US Census population. RESULTS: We identified 70 patients who met diagnostic criteria for anti-NMDAR encephalitis. The median age at onset was 23.7 years (IQR = 14.2-31.0 years), and 45 (64%) were female patients. The age-standardized and sex-standardized incidence of anti-NMDAR encephalitis per 1 million person-years was significantly higher in Black (2.94, 95% CI 1.27-4.61), Hispanic (2.17, 95% CI 1.51-2.83), and Asian/Pacific Island persons (2.02, 95% CI 0.77-3.28) compared with White persons (0.40, 95% CI 0.08-0.72). Ovarian teratomas were found in 58.3% of Black female individuals and 10%-28.6% in other groups. DISCUSSION: Anti-NMDA receptor encephalitis disproportionately affected Black, Hispanic, or Asian/Pacific Island persons. Ovarian teratomas were a particularly common trigger in Black female individuals. Future research should seek to identify environmental and biological risk factors that disproportionately affect minoritized individuals residing in the United States.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Humanos , Encefalite Antirreceptor de N-Metil-D-Aspartato/etnologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/epidemiologia , Feminino , Adulto , Masculino , Incidência , Adulto Jovem , Estudos Retrospectivos , Adolescente , California/epidemiologia , Hispânico ou Latino/estatística & dados numéricos , Disparidades nos Níveis de Saúde , População Branca/etnologia , Negro ou Afro-Americano/etnologia , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/epidemiologia , Teratoma/epidemiologia , Teratoma/etnologia , Pessoa de Meia-Idade , EtnicidadeRESUMO
BACKGROUND: Cognitive impairment and dementia are frequently under-recognized. Health system strategies anchored in primary care are essential to address gaps in timely, comprehensive diagnosis. The goal of this paper is to describe the adaptation of a tablet-based brain health assessment (TabCAT-BHA) intervention and the study protocol to test its effectiveness in improving the detection of cognitive impairment, including dementia. METHODS: This mixed-methods, pragmatic, cluster randomized, hybrid effectiveness-implementation trial is being conducted in two 18-month waves with 26 Kaiser Permanente Southern California primary care clinics, with 13 serving as intervention clinics and 13 as usual care clinics. Patients 65 years and older with memory concerns (n ~ 180,000) receiving care at the 26 clinics will be included in the analyses. Primary care clinics are provided the following practice supports as part of the TabCAT-BHA intervention: brief education and training on neurocognitive disorders and study workflows; digital tools to assess cognitive function and support clinician decision making and documentation; and registered nurse support during the work-up and post-diagnosis periods for primary care providers, patients, and families. The intervention was adapted based on engagement with multiple levels of clinical and operational leaders in the healthcare system. Effectiveness outcomes include rates of cognitive impairment diagnosis in primary care and rates of completed standardized cognitive assessments and specialist referrals with incident diagnoses. Implementation outcomes include acceptability-appropriateness-feasibility, adoption, and fidelity. RESULTS: We identified seven themes organized by system-, provider-, and patient-level domains that were used to adapt the TabCAT-BHA intervention. Accordingly, changes were made to the provider education, diagnostic work-up, and post-diagnostic support. Results will be reported in fall of 2027. CONCLUSIONS: Our engagement with multiple primary and specialty care clinical and operational leaders to adapt the TabCAT-BHA intervention to these primary care clinics has informed the protocol to evaluate the intervention's effectiveness for improving the detection of cognitive impairment, including dementia, in an integrated healthcare system. TRIAL REGISTATION: Clinicaltrials.gov: NCT06090578 (registered 10/24/23).
Assuntos
Disfunção Cognitiva , Atenção Primária à Saúde , Humanos , Disfunção Cognitiva/diagnóstico , Idoso , Demência/diagnóstico , Participação dos Interessados , Computadores de Mão , Ensaios Clínicos Pragmáticos como Assunto , California , FemininoRESUMO
Multiple sclerosis (MS) commonly affects young women of childbearing age. Thus, the challenges of the disease are often faced simultaneously with the challenges of early adult life and family planning. This has led to great interest in the effects of pregnancy and breastfeeding on MS. It is now well known that the risk of MS relapse declines during pregnancy but increases in the first 3-4 months postpartum. However, important gaps in knowledge remain and are the focus of this review. What factors predict postpartum relapses? Are there modifiable factors, such as breastfeeding, particularly exclusive breastfeeding, that could reduce the risk of postpartum relapses? Does pregnancy or breastfeeding have any long-term effects on MS disease course? What immunological mechanisms underlie the effects of pregnancy and breastfeeding? Answering these questions will improve our ability to care for women with MS and may provide a greater understanding of the pathophysiology of the disease.