Multiple Sclerosis, Disease-Modifying Therapies, and Infections.

BACKGROUND AND OBJECTIVES: The use of highly effective multiple sclerosis (MS) disease-modifying therapies (DMTs) is rapidly increasing. Yet, little is known about their real-world risks of infections. The goals of this study were to assess the comparative risk of outpatient and serious infections across DMTs in a large, diverse, U.S. cohort and determine whether such risks are attributable to DMTs, having MS, or other factors. METHODS: We conducted a retrospective cohort study of Kaiser Permanente Southern California members from 2008 through 2020 with MS and non-MS controls matched on age, sex, race, and ethnicity. MS treatments, serious (those requiring hospitalization) and outpatient infections, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHR) and risk ratios (aRR) were estimated using the Cox and Poisson regression, respectively. RESULTS: Six thousand, six hundred and twenty-six patients with MS with 11,929 treatment episodes (2,487 rituximab, 546 natalizumab, 298 fingolimod, 4,629 interferon-beta/glatiramer acetate, IFN/GLAT, and 3,969 untreated) and 33,550 population controls were included in the analyses. The average age at treatment start ranged from 38.9 to 49.2 years, and 74% were women. Untreated (aRR = 1.39, [95% CI = 1.35-1.44]) and IFN/GLAT-treated patients with MS (aRR = 1.60, [95% CI = 1.56-1.65]) had a higher risk of outpatient infections and serious infections (aHR = 2.97, [95% CI = 2.65-3.32 and aHR = 2.31, [95% CI = 2.04-2.62], respectively) compared with controls. Rituximab (aRR = 1.19, [95% CI = 1.14-1.25]), fingolimod (aRR = 1.22, [95% CI = 1.09-1.37]), and to a lesser extent, natalizumab treatment (aRR = 1.08, [95% CI = 0.97-1.20]) were associated with an increased risk of outpatient infections compared with IFN/GLAT. Rituximab (aHR = 1.41, [95% CI = 1.09-1.84]) and natalizumab (aHR = 1.40, [95% CI = 0.96-2.04]) treatment were associated with a similar increased risk of serious infections compared with IFN/GLAT. The only treatment-specific association identified was fingolimod with outpatient herpetic infections. Higher comorbidity index, previous hospitalization for infections, and advanced disability significantly increased the risk of serious infections independent of DMTs. Hospitalization for UTI-related pseudorelapses accounted for 24%-48% of serious infections. DISCUSSION: Patients with MS have higher risks of outpatient and serious infections compared with patients without MS. The risk of outpatient infections was similarly increased by rituximab and fingolimod and serious infections by rituximab and natalizumab compared with IFN/GLAT. Steps to minimize risks include optimizing bladder care, comorbidity prevention, varicella vaccination, and considering discontinuing or avoiding DMT use in patients with advanced disability and/or previous hospitalizations for infections.

Analysis of Rituximab Use, Time Between Rituximab and SARS-CoV-2 Vaccination, and COVID-19 Hospitalization or Death in Patients With Multiple Sclerosis.

Importance: Rituximab and other B-cell-depleting therapies blunt humoral responses to SARS-CoV-2 vaccines, particularly when the vaccine is administered within 6 months of an infusion. Whether this translates into an increased risk of hospitalization or death from COVID-19 is unclear. Objectives: To examine whether rituximab treatment is associated with an increased risk of hospitalization for COVID-19 among SARS-CoV-2-vaccinated persons with multiple sclerosis (MS) and whether delaying vaccination more than 6 months after rituximab treatment is associated with decreased risk. Design, Setting, and Participants: This retrospective cohort study used Kaiser Permanente Southern California's electronic health record to identify individuals from January 1, 2020, to February 15, 2022, who had MS and who had been vaccinated against SARS-CoV-2. Exposures: Rituximab treatment compared with disease-modifying therapies (DMTs) that do not interfere with vaccine efficacy or being untreated (no or other DMT group). Among rituximab-treated patients, the exposure was receiving at least 1 vaccine dose more than 6 months after their last infusion compared with receiving all vaccine doses 6 months or less since their last infusion. Main Outcomes and Measures: The main outcome was hospitalization due to COVID-19 infection. The odds of infection resulting in hospitalization following SARS-CoV-2 vaccination were adjusted for race and ethnicity, advanced MS-related disability; vaccine type; booster dose; and, among rituximab-treated only analyses, cumulative rituximab dose and dose at last infusion. Exposures, outcomes, and covariates were collected from the electronic health record. Results: Among 3974 SARS-CoV-2-vaccinated people with MS (mean [SD] age, 55.3 [15] years; 2982 [75.0%] female; 103 [2.6%] Asian or Pacific Islander; 634 [16.0%] Black; 953 [24.0%] Hispanic; 2269 [57.1%] White; and 15 [0.3%] other race or ethnicity), rituximab-treated patients (n = 1516) were more likely to be hospitalized (n = 27) but not die (n = 0) compared with the 2458 individuals with MS receiving no or other DMTs (n = 7 and n = 0, respectively; adjusted odds ratio [aOR] for hospitalization, 7.33; 95% CI, 3.05-17.63). Receiving messenger RNA (mRNA) SARS-CoV-2 vaccine (aOR, 0.36; 95% CI, 0.15-0.90; P = .03) and receiving a booster vaccination (aOR, 0.31; 95% CI, 0.15-0.64; P = .002) were independently associated with a decreased risk of hospitalization for COVID-19. Among vaccinated rituximab-treated individuals with MS, receiving any vaccination dose more than 6 months after the last rituximab infusion was associated with a reduced risk of COVID-19 hospitalization (aOR, 0.22; 95% CI, 0.10-0.49). Conclusions and Relevance: This cohort study's findings suggest that rituximab-treated people with MS should be strongly encouraged to receive mRNA SARS-CoV-2 vaccines and boosters more than 6 months after their last rituximab infusion whenever possible. The low absolute risk of hospitalization for COVID-19 among mRNA-vaccinated individuals with MS should not preclude use of rituximab, which has marked efficacy, cost, and convenience advantages over other DMTs.

Validation of algorithms for identifying outpatient infections in MS patients using electronic medical records.

Background Our multiple sclerosis (MS) stakeholder groups expressed concerns about whether MS disease-modifying therapies (DMTs) increase the risk of specific outpatient infections. Validated methods for identifying the risk of these selected outpatient infections in the general population either do not exist, exclude the clinically important possibility of recurrent infections, or are inaccurate, largely because existing studies relied primarily on International Classification of Diseases (ICD) codes to identify infectious outcomes. Additionally, no studies have validated methods among the MS population, where some MS symptoms can be mistaken for infections (e.g., urinary tract infections (UTIs)). Objective To utilize multiple data elements in the electronic health record (EHR) to improve accurate identification of selected outpatient infections in an MS cohort and general population controls. Methods We searched Kaiser Permanente Southern California's EHR based on ICD-9/10 codes for specified outpatient infections from 1/1/2008-12/31/2018 among our MS cohort (n=6000) and 5:1 general population controls matched on age, sex, and race/ethnicity (n=30,010). Random sample chart abstractions from each group were used to identify common coding errors for outpatient pneumonia, upper and lower respiratory tract infection, UTIs, herpetic infections (herpes zoster (HZ), herpes simplex virus (HSV)), fungal infections, otitis media, cellulitis, and influenza. This information was used to define discrete infectious episodes and to identify the algorithm with the highest positive predictive value (PPV) after supplementing the ICD-coded episodes with radiology, laboratory and/or pharmacy data. Results PPVs relying on ICD codes alone were inaccurate, particularly for identifying recurrent herpetic infections (HZ (42%) and HSV (60%)), UTIs (42%) and outpatient pneumonia (20%) in MS patients. Defining and validating episodes improved the PPVs for all the selected infections. The final algorithms' PPVs were 80-100% in MS and 75-100% in the general population, after including dispensed treatments (UTI, herpetic infections and yeast vaginitis), timing of dispensed treatments (UTI, herpetic infections and yeast vaginitis), removal of prophylactic antiviral use (herpetic infections), and inclusion of selected laboratory (UTIs) and imaging results (pneumonia). The only exception was outpatient pneumonia, where PPVs improved but remained ≤70%. There were no significant differences in the PPVs for the final algorithms between the MS and general population. Conclusions Provided herein are accurate and validated algorithms that can be used to improve our understanding of how the risk of recurrent outpatient infections are influenced by MS treatments, MS-related disability, and co-morbidities. Findings from such studies will be important in helping patients and clinicians engage in shared decision-making and in developing strategies to mitigate risks of recurrent infections.

An exploratory study of diet in childhood and young adulthood and adult-onset multiple sclerosis.

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.

Seafood, fatty acid biosynthesis genes, and multiple sclerosis susceptibility.

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.

Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab.

OBJECTIVE: To examine outcomes among patients who were treated with the targeted anti-cytokine agents, anakinra or tocilizumab, for COVID-19 -related cytokine storm (COVID19-CS). METHODS: We conducted a retrospective cohort study of all SARS-coV2-RNA-positive patients treated with tocilizumab or anakinra in Kaiser Permanente Southern California. Local experts developed and implemented criteria to define COVID19-CS. All variables were extracted from electronic health records. RESULTS: At tocilizumab initiation (n = 52), 50 (96.2%) were intubated, and only seven (13.5%) received concomitant corticosteroids. At anakinra initiation (n = 41), 23 (56.1%) were intubated, and all received concomitant corticosteroids. Fewer anakinra-treated patients died (n = 9, 22%) and more were extubated/never intubated (n = 26, 63.4%) compared to tocilizumab-treated patients (n = 24, 46.2% dead, n = 22, 42.3% extubated/never intubated). Patients who died had more severe sepsis and respiratory failure and met COVID-CS laboratory criteria longer (median = 3 days) compared to those extubated/never intubated (median = 1 day). After accounting for differences in disease severity at treatment initiation, this apparent superiority of anakinra over tocilizumab was no longer statistically significant (propensity score-adjusted hazards ratio 0.46, 95% confidence interval 0.18-1.20). CONCLUSIONS: Prompt identification and treatment of COVID19-CS before intubation may be more important than the specific type of anti-inflammatory treatment. Randomized controlled trials of targeted anti-cytokine treatments and corticosteroids should report the duration of cytokine storm in addition to clinical severity at randomization.

Pregnancy-related relapses and breastfeeding in a contemporary multiple sclerosis cohort.

OBJECTIVE: To determine whether women with multiple sclerosis (MS) diagnosed according to current criteria are at an increased risk of postpartum relapses and to assess whether this risk is modified by breastfeeding or MS disease-modifying therapies (DMTs), we examined the electronic health records (EHRs) of 466 pregnancies among 375 women with MS and their infants. METHODS: We used prospectively collected information from the EHR at Kaiser Permanente Southern and Northern California between 2008 and 2016 of the mother and infant to identify treatment history, breastfeeding, and relapses. Multivariable models accounting for measures of disease severity were used. RESULTS: In the postpartum year, 26.4% relapsed, 87% breastfed, 36% breastfed exclusively for at least 2 months, and 58.8% did not use DMTs. At pregnancy onset, 67.2% had suboptimally controlled disease. Annualized relapse rates (ARRs) declined from 0.37 before pregnancy to 0.14-0.07 (p < 0.0001) during pregnancy, but in the postpartum period, we did not observe any rebound disease activity. The ARR was 0.27 in the first 3 months postpartum, returning to prepregnancy rates at 4-6 months (0.37). Exclusive breastfeeding reduced the risk of early postpartum relapses (adjusted hazard ratio = 0.37, p = 0.009), measures of disease severity increased the risk, and resuming modestly effective DMTs had no effect (time-dependent covariate, p = 0.62). CONCLUSION: Most women diagnosed with MS today can have children without incurring an increased risk of relapses. Women with suboptimal disease control before pregnancy may benefit from highly effective DMTs that are compatible with pregnancy and lactation. Women with MS should be encouraged to breastfeed exclusively.

Race, ethnicity, and cognition in persons newly diagnosed with multiple sclerosis.

OBJECTIVE: To determine whether black or Hispanic patients with newly diagnosed multiple sclerosis (MS) are more likely to have cognitive impairment than white patients when compared to controls matched on age, sex, and race/ethnicity. Whether black or Hispanic patients have a more aggressive MS disease course than white patients remains unclear. No prior studies have examined differences in early cognitive impairment. The oral Symbol Digit Modalities Test (SDMT) is sensitive to early cognitive impairment in MS but normative data in nonwhite patients are limited. METHODS: We studied 1,174 adults who enrolled in the MS Sunshine Study. SDMT and verbal fluency were measured in 554 incident cases of MS or clinically isolated syndrome (CIS) and 620 matched controls. Multivariable regression was used to examine correlates of abnormal SDMT in the entire cohort. RESULTS: The strongest independent predictors of lower oral SDMT scores in rank order were having MS/CIS, lower educational attainment, and being black or Hispanic. Black and Hispanic patients and controls had lower SDMT scores than white participants even after controlling for age, sex, and education. However, no interaction between race/ethnicity and MS case status on SDMT scores was detected. Easy-to-use reference scores stratified by age and educational attainment for black and Hispanic patients are provided. CONCLUSION: Persons with newly diagnosed MS/CIS are more likely to have subtly impaired cognitive function than controls regardless of race/ethnicity. Lower absolute SDMT scores among black and Hispanic patients compared to white patients highlight underlying US population differences rather than differences in MS disease severity.