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
Recent findings have provided a molecular basis for the combined contributions of multifaceted risk factors for the onset of multiple sclerosis (MS). MS appears to start as a chronic dysregulation of ...immune homeostasis resulting from complex interactions between genetic predispositions, infectious exposures, and factors that lead to pro‐inflammatory states, including smoking, obesity, and low sun exposure. This is supported by the discovery of gene–environment (GxE) interactions and epigenetic alterations triggered by environmental exposures in individuals with particular genetic make‐ups. It is notable that several of these pro‐inflammatory factors have not emerged as strong prognostic indicators. Biological processes at play during the relapsing phase of the disease may result from initial inflammatory‐mediated injury, while risk factors for the later phase of MS, which is weighted toward neurodegeneration, are not yet well defined. This integrated review of current evidence guides recommendations for clinical practice and highlights research gaps.
This article provides practical guidance on successful management of women with multiple sclerosis (MS) through pregnancy and the postpartum period.
Recent studies indicate that most women diagnosed ...with MS today can have children, breast-feed, and resume beta interferons or glatiramer acetate per their preferences without incurring an increased risk of relapses during the postpartum period. More than 40% of women with mild MS do not require any treatment before conception or in the postpartum period. Women with highly active MS can now become well-controlled before, throughout, and after pregnancy via highly effective treatments. Unfortunately, pregnancy does not protect against relapses following the cessation of fingolimod or natalizumab, and some women experience severe rebound relapses during pregnancy. Accidental first-trimester exposure to teriflunomide or fingolimod increases the risk of fetal harm.
Most women with MS can have normal pregnancies and breast-feed without incurring harm. Clinicians should avoid prescribing medications with known teratogenic potential (teriflunomide, fingolimod), known risk of severe rebound relapses (fingolimod, natalizumab), or unclear but plausible risks (dimethyl fumarate, alemtuzumab) to women of childbearing age who desire pregnancy or are not on reliable birth control. If a treatment needs to be resumed during breast-feeding, clinicians should opt for glatiramer acetate, interferon beta, natalizumab, or rituximab/ocrelizumab, as biologically plausible risks to the infant are exceedingly low.
The incidence of multiple sclerosis (MS) is rising in women.
To determine whether the use of combined oral contraceptives (COCs) are associated with MS risk and whether this varies by progestin ...content.
We conducted a nested case-control study of females ages 14-48 years with incident MS or clinically isolated syndrome (CIS) 2008-2011 from the membership of Kaiser Permanente Southern California. Controls were matched on age, race/ethnicity and membership characteristics. COC use up to ten years prior to symptom onset was obtained from the complete electronic health record.
We identified 400 women with incident MS/CIS and 3904 matched controls. Forty- percent of cases and 32% of controls had used COCs prior to symptom onset. The use of COCs was associated with a slightly increased risk of MS/CIS (adjusted OR = 1.52, 95%CI = 1.21-1.91; p<0.001). This risk did not vary by duration of COC use. The association varied by progestin content being more pronounced for levenorgestrol (adjusted OR = 1.75, 95%CI = 1.29-2.37; p<0.001) than norethindrone (adjusted OR = 1.57, 95%CI = 1.16-2.12; p = 0.003) and absent for the newest progestin, drospirenone (p = 0.95).
Our findings should be interpreted cautiously. While the use of some combination oral contraceptives may contribute to the rising incidence of MS in women, an unmeasured confounder associated with the modern woman's lifestyle is a more likely explanation for this weak association.
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
Background
Although nearly 40% of older adults receive care in Medicare Advantage (MA) plans, there are limited information on whether the patterns of dementia diagnosis and health care utilization ...differ from traditional Medicare fee‐for‐service. We examined first ADRD diagnoses by provider type and clinical setting and compared patient socio‐demographic and clinical characteristics across a large integrated health care system in southern California.
Methods
Patients 65 years and older who were continuously enrolled in the health plan for at least one year prior to January 1, 2015 and had a first dementia diagnosis code during the study period (January 1, 2015‐ December 31, 2018) were included in the analysis. Providers classified as dementia specialists included neurologists, psychiatrists, and geriatricians; all other providers were considered nondementia specialists and mostly represented primary care. Data were derived from electronic health records.
Results
There were a total of 25,278 incident ADRD codes over the entire study period, slightly more than half assigned in ambulatory care and the remainder during a hospital‐based encounter. For the clinic‐diagnosed cohort (n=13,962), other than a slightly younger age for those diagnosed in neurology/psychiatry compared to geriatrics or primary care (79 vs. 82 years old), there were no other differences, including race/ethnicity or spoken language. Compared to the clinic cohort, the hospital‐diagnosed cohort (n=11,316) was slightly older (83 vs. 81 years old), more likely to be white (59% vs. 53%) and English speaking (90% vs. 85%); had more missed appointments (13% vs. 10%) and were more likely to have a non‐dementia cognitive impairment code in the two years prior (36% vs. 31%). They also had a higher burden of co‐morbidity (8.7 ± 3.8 vs. 7.0 ± 3.4) and higher rate of documented advance directive or POLST (49% vs. 41%) (all, p<.01).
Conclusions
Nearly half of the incident ADRD codes were associated with a hospital‐based encounter. Patients first diagnosed with ADRD in the hospital setting were generally older and sicker compared to patients diagnosed in the clinic. Given such differing socio‐demographic and clinical characteristics at diagnosis, claims based studies should distinguish patients first diagnosed in hospital vs. clinic‐based settings.
To determine whether childhood obesity is a risk factor for developing pediatric multiple sclerosis (MS) or clinically isolated syndrome (CIS).
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 Children's 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.
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).
Our findings suggest the childhood obesity epidemic is likely to lead to increased morbidity from MS/CIS, particularly in adolescent girls.
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
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