Enrique Alvarez

Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis.

OBJECTIVE To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab. DESIGN Case study. SETTING Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver. PATIENTS Four patients developing PML in the setting of rituximab therapy for RA. INTERVENTION Rituximab therapy. MAIN OUTCOME MEASURES Clinical and pathological observations. RESULTS Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease. CONCLUSION These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.

NMO-IgG DETECTED IN CSF IN SERONEGATIVE NEUROMYELITIS OPTICA

Neuromyelitis optica (NMO) is an inflammatory and demyelinating disease characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM).1 NMO is associated with antibodies against the aquaporin-4 (AQP4) water channel.2 NMO–immunoglobulin G (IgG) predicts a relapsing course and is a supportive criterion for NMO.3–5 The high risk of relapse, sometimes with devastating effects, makes early diagnosis important. Early identification permits counseling and consideration for immunosuppressive therapy. The serum NMO-IgG assay, using indirect immunofluorescence, is 73% sensitive and 91% specific for clinically defined NMO.6 While helpful when positive, the sensitivity is insufficient to exclude the diagnosis. We describe 3 of 26 patients with NMO at our institution with NMO-IgG positivity restricted to CSF. ### Case reports. #### Case 1. A 25-year-old African American woman presented with leg numbness and mild tetraparesis that resolved over 1 month. Two months later, she developed a midthoracic sensory level, again with recovery. The next month, bilateral leg weakness impaired her ability to ambulate. MRI (figure, A–C) demonstrated T2 hyperintensities (T2H) and patchy enhancement spanning the medulla through C7 and T2–T11. Brain MRI revealed a single nonspecific T2H. Visual evoked potentials (VEPs) were normal. Serum NMO-IgG was negative but CSF NMO-IgG was positive. IgG index was elevated to 0.79, CSF leukocytes were 24/μL, but albumin index, IgG synthesis, and oligoclonal bands (OCBs) were normal. Serum antinuclear antibodies (ANA) were negative. Treatment included IV glucocorticoids and rituximab with no further exacerbations. After 8 months of disease, Expanded Disability Status Scale (EDSS) was 6.0. Figure Neuroimaging of CSF antibody-positive neuromyelitis optica Case 1: Sagittal T2-weighted STIR …

Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis

Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients (p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS (p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers.

CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions.

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

Role of Magnetic Resonance Imaging, Cerebrospinal Fluid, and Electroencephalogram in Diagnosis of Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive dementia (RPD) that can be difficult to identify antemortem, with definitive diagnosis requiring tissue confirmation. We describe the clinical, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and electroencephalogram (EEG) measures of a small cohort of 30 patients evaluated for RPD. Clinical and diagnostic measures were cross-sectionally obtained from 17 sCJD patients (15 definite, two probable), 13 non-prion rapidly progressive dementia patients (npRPD), and 18 unimpaired controls. In a subset of patients (nine sCJD and nine npRPD) diffusion tensor imaging (DTI) measures [fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD)] were also obtained for the caudate, corpus callosum, posterior limb of the internal capsule, pulvinar, precuneus, and frontal lobe. Differences among groups were assessed by an analysis of variance. Compared to npRPD individuals, sCJD patients had cerebellar dysfunction, significantly higher CSF tau, “positive” CSF 14-3-3, and hyperintensities on diffusion-weighted imaging (DWI) that met previously established imaging criteria for sCJD. EEG changes were similar for the two groups. In addition, sCJD patients had significant decreases in DTI measures (MD, AD, RD but not FA) within the caudate and pulvinar compared to either npRPD patients or unimpaired controls. Our results confirm that CSF abnormalities and MRI (especially DWI) can assist in distinguishing sCJD patients from npRPD patients. Future longitudinal studies using multiple measures (including CSF and MRI) are needed for evaluating pathological changes seen in sCJD patients.

Female hormonal exposures and neuromyelitis optica symptom onset in a multicenter study

Objective: To study the association between hormonal exposures and disease onset in a cohort of women with neuromyelitis optica spectrum disorder (NMOSD). Methods: Reproductive history and hormone use were assessed using a standardized reproductive survey administered to women with NMOSD (82% aquaporin-4 antibody positive) at 8 clinical centers. Using multivariable regression, we examined the association between reproductive exposures and age at first symptom onset (FS). Results: Among 217 respondents, the mean age at menarche was 12.8 years (SD 1.7). The mean number of pregnancies was 2.1 (SD 1.6), including 0.3 (SD 0.7) occurring after onset of NMOSD symptoms. In the 117 participants who were postmenopausal at the time of the questionnaire, 70% reported natural menopause (mean age: 48.9 years [SD 3.9]); fewer than 30% reported systemic hormone therapy (HT) use. Mean FS age was 40.1 years (SD 14.2). Ever-use of systemic hormonal contraceptives (HC) was marginally associated with earlier FS (39 vs 43 years, p = 0.05). Because HC use may decrease parity, when we included both variables in the model, the association between HC use and FS age became more significant (estimate = 2.7, p = 0.007). Among postmenopausal participants, 24% reported NMOSD onset within 2 years of (before or after) menopause. Among these participants, there was no association between age at menopause or HT use and age at NMOSD onset. Conclusions: Overall, age at NMOSD onset did not show a strong relationship with endogenous hormonal exposures. An earlier onset age did appear to be marginally associated with systemic HC exposure, an association that requires confirmation in future studies.

High risk of postpartum relapses in neuromyelitis optica spectrum disorder

Objective: To study the effect of pregnancy on the frequency of neuromyelitis optica spectrum disorder (NMOSD) relapse and evaluate rates of pregnancy-related complications in an international multicenter setting. Methods: We administered a standardized survey to 217 women with NMOSD from 7 medical centers and reviewed their medical records. We compared the annualized relapse rate (ARR) during a baseline period 2 years prior to a participants first pregnancy to that during pregnancy and to the 9 months postpartum. We also assessed pregnancy-related complications. Results: There were 46 informative pregnancies following symptom onset in 31 women with NMOSD. Compared to baseline (0.17), ARR was increased both during pregnancy (0.44; p = 0.035) and during the postpartum period (0.69; p = 0.009). The highest ARR occurred during the first 3 months postpartum (ARR 1.33). A total of 8 of 76 (10.5%) with onset of NMOSD prior to age 40 experienced their initial symptom during the 3 months postpartum, 2.9 times higher than expected. Conclusions: The postpartum period is a particularly high-risk time for initial presentation of NMOSD. In contrast to published observations in multiple sclerosis, in neuromyelitis optica, relapse rate during pregnancy was also increased, although to a lesser extent than after delivery.

Comparison of fingolimod and dimethyl fumarate in the treatment of multiple sclerosis: Two-year experience:

Background Fingolimod (FTY) and dimethyl fumarate (DMF) are multiple sclerosis (MS) oral therapies that became available in 2010 and 2013, respectively. Objective The objective of this article is to compare discontinuation rates, efficacy, and adverse events (AEs) of FTY and DMF over two years. Methods Patients prescribed FTY or DMF at the Rocky Mountain MS Center at University of Colorado prior to October 2013 were identified. Clinician-reported data were retrospectively collected. Primary outcome was discontinuation of drug by the end of year two. Reasons for discontinuation were evaluated. Results A total of 271 FTY and 342 DMF patients were evaluated. Patients had a mean age of 42.5 (FTY) and 45.8 (DMF) years and were predominantly female (72.0% FTY; 69.6% DMF) and white (86.3% FTY; 82.2% DMF). At ≤24 months, 93 (34.3%) and 161 (47.1%) discontinued FTY and DMF, respectively, with an unadjusted odds ratio (OR) of 1.70 (1.23–2.37, p = 0.002), or 1.69 (1.16–2.46, p = 0.006) for the doubly robust propensity score weighted estimator. Primary reason for discontinuation was AEs, which were less likely for FTY 46 (17.0%) compared to DMF 82 (24.0%) (OR 1.54, 1.03–2.31, p = 0.035). Discontinuation due to disease activity (FTY (10%) DMF (11.1%); OR 1.13, 0.67–1.90, p = 0.647) and breakthrough disease activity, regardless of discontinuation (FTY (34.7%) DMF (33.6%); OR 0.95, 0.68–1.34, p = 0.783), were similar. Conclusions The odds of discontinuation were less for FTY than DMF, and were driven by AEs for both drugs.

Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures

Background B-cell depleting drugs show promise for treating multiple sclerosis. Objective We sought predictors of optimal response to rituximab, a B-cell depleting antibody, to help guide therapy selection. Methods We performed a post hoc study of 30 relapsing multiple sclerosis patients with breakthrough disease while on beta-interferon or glatiramer acetate who were treated with add-on rituximab. Standardized neurologic examinations, brain magnetic resonance imaging, and cerebrospinal fluid were obtained before and after rituximab. Tissue biomarkers were measured. Optimal responders were defined as having no evidence of disease activity. Results At baseline, optimal responders with no evidence of disease activity had higher IgG indices (P = 0.041), and higher CXCL13 indices ((cerebrospinal fluid CXCL13/serum CXCL13)/albumin index; P = 0.024), more contrast enhancing lesions (P = 0.002), better 25 foot timed walk (P = 0.001), and Expanded Disability Status Scale (P = 0.002). Rituximab treatment led to reduced cerebrospinal fluid biomarkers of tissue destruction: myelin basic protein (P = 0.046), neurofilament light chain (P < 0.001), and of inflammation (CXCL13 index; P = 0.042). Conclusions Multiple sclerosis patients with optimal response to rituximab had higher cerebrospinal fluid IgG and CXCL13 indices, more gadolinium-enhancing lesions, and less disability at baseline. Rituximab treatment led to decreased markers of inflammation and tissue damage. If validated, these results will help identify multiple sclerosis patients who will respond optimally to B-cell depletion.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll‐like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal‐appearing brain tissue, the thickness of the retinal nerve‐fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was ‐0.0010 per year with ibudilast and ‐0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain‐tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT‐MS ClinicalTrials.gov number, NCT01982942.)