Objective

We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder.

Methods

The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod.

Results

As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL).

Conclusions

The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039-0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75-5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML.

Importance:In 40 of 50 US states, scheduled dialysis is withheld from undocumented immigrants with end-stage renal disease (ESRD); instead, they receive intermittent emergency-only dialysis to treat life-threatening manifestations of ESRD. However, the comparative effectiveness of scheduled dialysis vs emergency-only dialysis and the influence of treatment on health outcomes, utilization, and costs is uncertain. Objective:To compare the effectiveness of scheduled vs emergency-only dialysis with regard to health outcomes, utilization, and costs in undocumented immigrants with ESRD. Design, Setting, and Participants:Observational cohort study of 181 eligible adults with ESRD receiving emergency-only dialysis in Dallas, Texas, who became newly eligible and applied for private commercial health insurance in February 2015; 105 received coverage and were enrolled in scheduled dialysis; 76 were not enrolled in insurance for nonclinical reasons (eg, lack of capacity at a participating outpatient dialysis center) and remained uninsured, receiving emergency-only dialysis. We examined data on eligible persons during a 6-month period prior to enrollment (baseline period, August 1, 2014-January 31, 2015) until 12 months after enrollment (follow-up period, March 1, 2015-February 29, 2016), with an intervening 1-month washout period (February 2015). All participants were undocumented immigrants; self-reported data on immigration status was collected from Parkland Hospital electronic health records. Exposures:Enrollment in private health insurance coverage and scheduled dialysis. Main Outcomes and Measures:We used enrollment in health insurance and scheduled dialysis to estimate the influence of scheduled dialysis on 1-year mortality, utilization, and health care costs, using a propensity score-adjusted, intention-to-treat approach, including time-to-event analyses for mortality, difference-in-differences (DiD) negative binomial regression analyses for utilization, and DiD gamma generalized linear regression for health care costs. Results:Of 181 eligible adults with ESRD, 105 (65 men, 40 women; mean age, 45 years) received scheduled dialysis and 76 (38 men, 38 women; mean age, 52 years) received emergency-only dialysis. Compared with emergency-only dialysis, scheduled dialysis was significantly associated with reduced mortality (3% vs 17%, P = .001; absolute risk reduction, 14%; number needed to treat, 7; adjusted hazard ratio, 4.6; 95% CI, 1.2-18.2; P = .03), adjusted emergency department visits (-5.2 vs +1.1 visits/mo; DiD, -6.2; P < .001), adjusted hospitalizations (-2.1 vs -0.5 hospitalizations/6 months; DiD, -1.6; P < .001), adjusted hospital days (-9.2 vs +0.8 days/6 months; DiD, -9.9; P = .007), and adjusted costs (-$4316 vs +$1452 per person per month; DiD, -$5768; P < .001). Conclusions and Relevance:In this study, scheduled dialysis was significantly associated with reduced 1-year mortality, health care utilization, and costs compared with emergency-only dialysis. Scheduled dialysis should be the universal standard of care for all individuals with ESRD in the United States.

Background and objectives

To describe the characteristics of patients with MS reporting cryptococcal meningitis (CM) while treated with fingolimod.

Methods

The Novartis safety database was searched for cases with CM between January 26, 2006, and February 28, 2020. The reporting rate of CM was estimated based on the case reports received and exposure to fingolimod in the postmarketing setting during the relevant period.

Results

A total of 60 case reports of CM were identified, mostly from the United States. The median age was 48 years, and 51.8% were women. Most of the patients had recovered or were recovering at the time of final report. A fatal outcome occurred in 13 cases. During the study period, the rate of CM in patients with MS receiving fingolimod was estimated to be 8 per 100,000 patient-years (95% CI: 6.0; 10.0). The incidence of CM seemed to increase with duration of treatment; however, this relationship remains uncertain due to wide CIs and missing data.

Discussion

The causal relationship between fingolimod treatment and CM is not yet fully understood. The CM mortality rate in fingolimod-treated patients is similar to that reported in HIV-negative patients. Vigilance for signs and symptoms of CM in patients receiving fingolimod, particularly the new onset of headaches and altered mental status, is essential. Early diagnosis and treatment are critical to reducing CM-associated mortality.