Annette Langer-Gould

B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis

BACKGROUNDnThere is increasing evidence that B lymphocytes are involved in the pathogenesis of multiple sclerosis, and they may be a therapeutic target. Rituximab, a monoclonal antibody, selectively targets and depletes CD20+ B lymphocytes.nnnMETHODSnIn a phase 2, double-blind, 48-week trial involving 104 patients with relapsing-remitting multiple sclerosis, we assigned 69 patients to receive 1000 mg of intravenous rituximab and 35 patients to receive placebo on days 1 and 15. The primary end point was the total count of gadolinium-enhancing lesions detected on magnetic resonance imaging scans of the brain at weeks 12, 16, 20, and 24. Clinical outcomes included safety, the proportion of patients who had relapses, and the annualized rate of relapse.nnnRESULTSnAs compared with patients who received placebo, patients who received rituximab had reduced counts of total gadolinium-enhancing lesions at weeks 12, 16, 20, and 24 (P<0.001) and of total new gadolinium-enhancing lesions over the same period (P<0.001); these results were sustained for 48 weeks (P<0.001). As compared with patients in the placebo group, the proportion of patients in the rituximab group with relapses was significantly reduced at week 24 (14.5% vs. 34.3%, P=0.02) and week 48 (20.3% vs. 40.0%, P=0.04). More patients in the rituximab group than in the placebo group had adverse events within 24 hours after the first infusion, most of which were mild-to-moderate events; after the second infusion, the numbers of events were similar in the two groups.nnnCONCLUSIONSnA single course of rituximab reduced inflammatory brain lesions and clinical relapses for 48 weeks. This trial was not designed to assess long-term safety or to detect uncommon adverse events. The data provide evidence of B-cell involvement in the pathophysiology of relapsing-remitting multiple sclerosis. (ClinicalTrials.gov number, NCT00097188 [ClinicalTrials.gov].).

Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis

Microarray analysis of multiple sclerosis (MS) lesions obtained at autopsy revealed increased transcripts of genes encoding inflammatory cytokines, particularly interleukin-6 and -17, interferon-γ and associated downstream pathways. Comparison of two poles of MS pathology—acute lesions with inflammation versus silent lesions without inflammation—revealed differentially transcribed genes. Some products of these genes were chosen as targets for therapy of experimental autoimmune encephalomyelitis (EAE) in mice. Granulocyte colony-stimulating factor is upregulated in acute, but not in chronic, MS lesions, and the effect on ameliorating EAE is more pronounced in the acute phase, in contrast to knocking out the immunoglobulin Fc receptor common γ chain where the effect is greatest on chronic disease. These results in EAE corroborate the microarray studies on MS lesions. Large-scale analysis of transcripts in MS lesions elucidates new aspects of pathology and opens possibilities for therapy.

Sociodemographic characteristics of members of a large, integrated health care system: comparison with US Census Bureau data.

BACKGROUNDnData from the memberships of large, integrated health care systems can be valuable for clinical, epidemiologic, and health services research, but a potential selection bias may threaten the inference to the population of interest.nnnMETHODSnWe reviewed administrative records of members of Kaiser Permanente Southern California (KPSC) in 2000 and 2010, and we compared their sociodemographic characteristics with those of the underlying population in the coverage area on the basis of US Census Bureau data.nnnRESULTSnWe identified 3,328,579 KPSC members in 2000 and 3,357,959 KPSC members in 2010, representing approximately 16% of the population in the coverage area. The distribution of sex and age of KPSC members appeared to be similar to the census reference population in 2000 and 2010 except with a slightly higher proportion of 40 to 64 year olds. The proportion of Hispanics/Latinos was comparable between KPSC and the census reference population (37.5% vs 38.2%, respectively, in 2000 and 45.2% vs 43.3% in 2010). However, KPSC members included more blacks (14.9% vs 7.0% in 2000 and 10.8% vs 6.5% in 2010). Neighborhood educational levels and neighborhood household incomes were generally similar between KPSC members and the census reference population, but with a marginal underrepresentation of individuals with extremely low income and high education.nnnCONCLUSIONSnThe membership of KPSC reflects the socioeconomic diversity of the Southern California census population, suggesting that findings from this setting may provide valid inference for clinical, epidemiologic, and health services research.

Exclusive Breastfeeding and the Risk of Postpartum Relapses in Women With Multiple Sclerosis

OBJECTIVEnTo determine if exclusive breastfeeding protects against postpartum relapses of multiple sclerosis (MS) and, if so, whether this protection is related to prolonged lactational amenorrhea.nnnDESIGNnWe conducted structured interviews to assess clinical, menstrual, and breastfeeding history during each trimester and 2, 4, 6, 9, and 12 months postpartum and collected neurological examination findings from the treating physicians of women with MS. Hazards ratios (HRs) were adjusted for measures of disease severity and age.nnnSETTINGnKaiser Permanente Northern California and Stanford University.nnnPARTICIPANTSnWe prospectively enrolled 32 pregnant women with MS and 29 age-matched, pregnant controls. Main Outcome Measure Postpartum relapse.nnnRESULTSnOf the 52% of women with MS who did not breastfeed or began regular supplemental feedings within 2 months postpartum, 87% had a postpartum relapse, compared with 36% of the women with MS who breastfed exclusively for at least 2 months postpartum (unadjusted HR, 5.0; 95% confidence interval, 1.7-14.2; P = .003; adjusted HR, 7.1; 95% confidence interval, 2.1-24.3; P = .002). Sixty percent reported that the primary reason for foregoing exclusive breastfeeding was to resume MS therapies. Women who breastfed exclusively had a later return of menses (P = .001) than women who did not, and lactational amenorrhea was associated with a reduced risk of postpartum relapses (P = .01).nnnCONCLUSIONSnOur findings suggest that exclusive breastfeeding and concomitant suppression of menses significantly reduce the risk of postpartum relapses in MS. Our findings call into question the benefit of foregoing breastfeeding to start MS therapies and should be confirmed in a larger study.

Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome.

Objective: To determine whether childhood obesity is a risk factor for developing pediatric multiple sclerosis (MS) or clinically isolated syndrome (CIS). Methods: Cases were identified through the Kaiser Permanente Southern California (KPSC) Pediatric Acquired Demyelinating Diseases Cohort between 2004 and 2010. For cases, body mass index (BMI) was obtained prior to symptom onset, for the underlying cohort BMI was obtained through the KPSC Childrens health study (n = 913,097). Weight classes of normal weight, overweight, moderate obesity, and extreme obesity were assigned based on BMI specific for age and sex. Results: We identified 75 newly diagnosed pediatric cases of MS or CIS, the majority of which were in girls (n = 41, 55%), age 11–18 (n = 54, 72%). Obesity was associated with a significantly increased risk of MS/CIS in girls (p = 0.005 for trend) but not in boys (p = 0.93). The adjusted odds ratio and 95% confidence intervals for CIS/MS among girls was 1.58 (0.71–3.50) for overweight compared to normal weight (reference category), 1.78 (0.70–4.49) for moderately obese, and 3.76 (1.54–9.16) for extremely obese. Moderately and extremely obese cases were more likely to present with transverse myelitis compared with normal/overweight children (p = 0.003). Conclusion: Our findings suggest the childhood obesity epidemic is likely to lead to increased morbidity from MS/CIS, particularly in adolescent girls.

Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children

Objective: To determine whether the incidence and clinical features of pediatric multiple sclerosis (MS) and other forms of pediatric acquired demyelinating syndromes (ADS) vary by race/ethnicity in a population-based cohort. Methods: We used a combination of electronic database searches followed by complete medical records review to identify all children diagnosed with MS and ADS in the multiethnic membership of Kaiser Permanente Southern California from January 1, 2004, to December 31, 2009. Incidence rates were standardized to the US census by age and gender. Results: We identified 81 incident cases of ADS from 4.87 million person-years of observation in children 0–18 years of age. The incidence rate of pediatric MS was 0.51 per 100,000 person-years (95% confidence interval [CI] 0.33–0.75) and incidence of other forms of ADS including optic neuritis, transverse myelitis, other forms of clinically isolated syndrome (CIS), and acute disseminated encephalomyelitis (ADEM) was 1.56 (95% CI 1.23–1.95) for an overall incidence of ADS of 1.66 per 100,000 person-years (95% CI 1.32–2.06). Incidence of ADS was higher in black (4.4 per 100,000 person-years, 95% CI 2.5–7.2, p < 0.001) and Asian/Pacific Islander (2.8, 95% CI 1.2–5.2, p = 0.02) than white (1.03, 95% CI 0.6–1.7) and Hispanic (1.5, 95% CI 1.1–2.1, per 100,000 person-years) children. Black children were also significantly more likely to have MS than white children (p = 0.001). Children who presented with ADEM were significantly younger than children with other types of ADS clinical presentations (mean age 5.6, range 0.7–17.6 years vs 14.6, range 2.7–18.5, respectively). Conclusions: The incidence of pediatric acquired demyelinating syndromes is 1.66 per 100,000 person-years in a population-based cohort of Southern Californian children. The incidence of ADS and MS is higher in black children compared with white and Hispanic children.

Autoimmune diseases prior to the diagnosis of multiple sclerosis: a population-based case-control study.

The objective of this study was to determine whether patients with multiple sclerosis (MS) are more likely to have other autoimmune disorders particularly prior to the diagnosis of MS. We conducted a population-based case—control study of patients enrolled in the Northern California Kaiser Permanente Medical Care Program. Electronic clinical records through 2005 were used to ascertain incident and prevalent MS cases and identify the presence and timing of 44 other diagnoses. Controls were matched 5:1 for gender, age, and Kaiser membership characteristics. We identified 5296 MS cases (including 924 diagnosed between 2001 and 2004) and 26,478 matched controls. Prior to MS diagnosis, cases were more likely than controls to have uveitis (OR = 3.2, 95%; CI 1.7—5.7), inflammatory bowel disease (IBD, OR = 1.7; 95%CI 1.2—2.5), and Bell’s palsy (OR = 3.2; 95%CI 1.2—8.3). Cases were also more likely to develop Guillain— Barré syndrome (GBS, OR = 5.0; 95%CI 1.6—15.4) and bullous pemphigoid (OR = 6.7; 95%CI 1.5—29.9). Cases were not more likely than controls to have or to develop rheumatoid arthritis, lupus or thyroiditis. MS may share environmental triggers, genetic susceptibilities and/or alterations in immune homeostasis with IBD and uveitis, but not with other autoimmune disorders.

Vaccines and the Risk of Multiple Sclerosis and Other Central Nervous System Demyelinating Diseases

IMPORTANCEnBecause vaccinations are common, even a small increased risk of multiple sclerosis (MS) or other acquired central nervous system demyelinating syndromes (CNS ADS) could have a significant effect on public health.nnnOBJECTIVEnTo determine whether vaccines, particularly those for hepatitis B (HepB) and human papillomavirus (HPV), increase the risk of MS or other CNS ADS.nnnDESIGN, SETTING, AND PARTICIPANTSnA nested case-control study was conducted using data obtained from the complete electronic health records of Kaiser Permanente Southern California (KPSC) members. Cases were identified through the KPSC CNS ADS cohort between 2008 and 2011, which included extensive review of medical records by an MS specialist. Five controls per case were matched on age, sex, and zip code.nnnEXPOSURESnVaccination of any type (particularly HepB and HPV) identified through the electronic vaccination records system.nnnMAIN OUTCOMES AND MEASURESnAll forms of CNS ADS were analyzed using conditional logistic regression adjusted for race/ethnicity, health care utilization, comorbid diseases, and infectious illnesses before symptom onset.nnnRESULTSnWe identified 780 incident cases of CNS ADS and 3885 controls; 92 cases and 459 controls were females aged 9 to 26 years, which is the indicated age range for HPV vaccination. There were no associations between HepB vaccination (odds ratio [OR], 1.12; 95% CI, 0.72-1.73), HPV vaccination (OR, 1.05; 95% CI, 0.62-1.78), or any vaccination (OR, 1.03; 95% CI, 0.86-1.22) and the risk of CNS ADS up to 3 years later. Vaccination of any type was associated with an increased risk of CNS ADS onset within the first 30 days after vaccination only in younger (<50 years) individuals (OR, 2.32; 95% CI, 1.18-4.57).nnnCONCLUSIONS AND RELEVANCEnWe found no longer-term association of vaccines with MS or any other CNS ADS, which argues against a causal association. The short-term increase in risk suggests that vaccines may accelerate the transition from subclinical to overt autoimmunity in patients with existing disease. Our findings support clinical anecdotes of CNS ADS symptom onset shortly after vaccination but do not suggest a need for a change in vaccine policy.

Incidence of multiple sclerosis in multiple racial and ethnic groups

Objective: To determine whether the incidence of multiple sclerosis (MS) varies by race/ethnicity in a multiethnic, population-based cohort. Methods: We conducted a retrospective cohort study of more than 9 million person-years of observation from the multiethnic, community-dwelling members of Kaiser Permanente Southern California health plan from January 1, 2008 to December 31, 2010. Incidence of MS and risk ratios comparing incidence rates between racial/ethnic groups were calculated using Poisson regression. Results: We identified 496 patients newly diagnosed with MS who met McDonald criteria. The average age at diagnosis was 41.6 years (range 8.6–78.3 years) and 70.2% were women. The female preponderance was more pronounced among black (79.3%) than white, Hispanic, and Asian individuals with MS (67.8%, 68.1%, and 69.2%, respectively; p = 0.03). The incidence of MS was higher in blacks (10.2, 95% confidence interval [CI] 8.4–12.4; p < 0.0001) and lower in Hispanics (2.9, 95% CI 2.4–3.5; p < 0.0001) and Asians (1.4, 95% CI 0.7–2.4; p < 0.0001) than whites (6.9, 95% CI 6.1–7.8). Black women had a higher risk of MS (risk ratio 1.59, 95% CI 1.27–1.99; p = 0.0005) whereas black men had a similar risk of MS (risk ratio 1.04, 95% CI = 0.67–1.57) compared with whites. Conclusions: Our findings do not support the widely accepted assertion that blacks have a lower risk of MS than whites. A possible explanation for our findings is that people with darker skin tones have lower vitamin D levels and thereby an increased risk of MS, but this would not explain why Hispanics and Asians have a lower risk of MS than whites or why the higher risk of MS among blacks was found only among women.

Natalizumab Use During the Third Trimester of Pregnancy

IMPORTANCEnNatalizumab reduces multiple sclerosis relapses very effectively; however, severe disease activity may return once natalizumab treatment is withdrawn, as recommended during pregnancy. Sometimes restarting natalizumab treatment may be the best option for the mother, but the consequences for the infant are unknown. Except for a few single case reports, to our knowledge, comprehensive data about third-trimester natalizumab exposure are scant.nnnOBSERVATIONSnIn a case series of 12 women with 13 pregnancies and highly active multiple sclerosis who were treated with natalizumab during their third trimester of pregnancy, we assessed the clinical and laboratory effects on the newborns. We observed mild to moderate hematologic alterations in 10 of 13 infants including thrombocytopenia and anemia. In a subsample of 5 mother-child pairs, we analyzed natalizumab levels in the umbilical cord blood. Natalizumab was detectable in all 5 newborns.nnnCONCLUSION AND RELEVANCEnNatalizumab can be a therapeutic option in patients with highly active multiple sclerosis during pregnancy. We recommend that a pediatrician be available at the time of delivery to evaluate for potential complications of anemia and thrombocytopenia in newborns exposed to natalizumab during the third trimester.