Faculty Bibliography

BACKGROUND:Tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin-6 receptor, is approved for treatment of rheumatoid arthritis and several other immune-mediated disorders. Off-label use of the intravenous formulation of tocilizumab for Neuromyelitis Optica Spectrum Disorder (NMOSD) decreased relapse rates in two small case series. However, treatment protocol that requires frequent intravenous infusions may adversely affect adherence to therapy, especially in the more disabled patients, thereby reducing effectiveness. A subcutaneous formulation of tocilizumab was shown to be noninferior to the IV formulation for approved rheumatologic diseases. The effectiveness of subcutaneous TCZ for NMOSD is unknown. METHODS:We retrospectively reviewed clinical, radiological and serological data on all NMOSD patients who received subcutaneous TCZ in two tertiary referral centers between 2014-2019. RESULTS:Twelve NMOSD patients who received at least 6 months of subcutaneous TCZ were identified. Eleven were female; mean age was 46.9 ± 14.5 years and mean disease duration was 6.6 ± 4.6 years. Seven patients were seropositive for AQP-4 antibodies, two - for MOG-IgG antibodies, and three were doubly seronegative. During subcutaneous TCZ treatment, eight patients (66.6%) were relapse-free, one patient (8.3%) experienced 1 relapse, two patients (16.6%) - 2 relapses, and one patient (8.3%) - 3 relapses. The median relapse rate within 1 year after starting subcutaneous TCZ - 0 (interquartile range =1.75-0) - was significantly lower than in the year prior to treatment initiation (2, interquartile range = 4.0-0.25; p = 0.04). Overall, the annual relapse rate (ARR) decreased from a median of 2 (interquartile range = 5.75-1.29) prior to subcutaneous TCZ to 0 (interquartile range= = 1.0-0) on treatment (p = 0.0015). One TCZ-treated patient died following a severe myelitis attack. CONCLUSIONS:Effectiveness of subcutaneous TCZ in NMOSD appears to be similar to that reported for the IV formulation and has an advantage of at-home administration. Prospective, comparative studies of subcutaneous TCZ for NMOSD are warranted.

Rituximab is a chimeric anti-CD20 monoclonal antibody that is an effective therapy for multiple sclerosis. Rituximab has been associated with the development of serum sickness (type III hypersensitivity) characterized by arthralgia, fever, and rash during the treatment of other conditions, such as rheumatoid arthritis. Here we describe serum sickness associated with rituximab in multiple sclerosis patients and discuss both the management of serum sickness itself and implications for utilizing alternative anti-CD20 monoclonal antibodies for disease management in this patient population.

OBJECTIVE:To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS:This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS:< 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION/CONCLUSIONS:Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

Background/UNASSIGNED:Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS. Methods/UNASSIGNED:Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS. Results/UNASSIGNED:Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS. Conclusions/UNASSIGNED:We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Background: Natalizumab, a highly efficacious therapy for relapsing-remitting multiple sclerosis (RRMS), is also associated with progressive multifocal leukoencephalopathy (PML) risk. A recent analysis of the TOUCH dataset demonstrated that extended interval dosing (EID) is associated with significantly lower PML risk in anti-JC virus antibody positive patients. There have been no randomized studies to assess EID efficacy.
Objective(s): To describe the design of a phase 3b study to evaluate the efficacy of EID natalizumab initiated after a stable period of standard interval dosing (SID) compared with continuing SID.
Method(s): A prospective, interventional, controlled, randomized, open-label, rater-blinded, global study will be conducted. Eligibility requirements include age 18-60, Expanded Disability Status Scale <=5.5, RRMS, stable on SID natalizumab for >=1 year with no relapses in the prior year, no prior immunosuppressant use, and no gadolinium-enhancing (Gd+) lesions at screening. Patients will be randomized 1:1 to natalizumab SID (every 4 weeks) or EID (every 6 weeks). Study duration will be 88 weeks (4-week screening, 72 weeks randomized treatment, 12 weeks follow-up). The primary endpoint is number of new/newly enlarging T2 lesions at 48 weeks. Key secondary endpoints include time to relapse, relapse rate, number of new radiologic lesions, and incidence of serious adverse events. Exploratory endpoints include Timed 25-Foot Walk, Nine-Hole Peg Test, Symbol Digit Modality Test, and confirmed disability worsening or improvement. Data on natalizumab serum concentration, alpha-4 integrin saturation, lymphocyte counts, and body weight will be collected to explore relationships between pharmacokinetics/pharmacodynamics and efficacy.
Result(s): Approximately 480 patients will be enrolled. The rationale for study sample size, inclusion criteria, dosing intervals, and endpoints will be presented.
Conclusion(s): This study will provide the first randomized, controlled efficacy data for patients treated with EID natalizumab and will inform on the potential of EID as a future PML risk mitigation strategy