Pediatric transverse myelitis (TM) is an acquired, immune-mediated disorder that leads to injury of the spinal cord and often manifests as weakness, numbness, bowel dysfunction, and/or bladder dysfunction. Multiple etiologies for myelitis can result in a similar clinical presentation, including idiopathic transverse myelitis (TM), multiple sclerosis (MS), neuromyeltis optica spectrum disorder (NMOSD) associated with anti-aquaporin 4 antibodies, MOG antibody-associated disease, and acute flaccid myelitis (AFM). Diagnosis relies on clinical recognition of the syndrome and confirming inflammation through imaging and/or laboratory studies. Acute treatment is targeted at decreasing immune-mediated injury, and chronic preventative therapy may be indicated if TM is determined to be a manifestation of a relapsing disorder (i.e., NMOSD). Timely recognition and treatment of acute transverse myelitis is essential, as it can be associated with significant morbidity and long-term disability.

Background

We sought to review safety and efficacy of therapeutic plasma exchange (TPE) in a cohort of pediatric patients with transverse myelitis.

Methods

Billing data of all plasma exchanges performed at our tertiary care pediatric hospital between August 2010 and August 2016 were compared to electronic medical records to find all patients whose indication for apheresis was transverse myelitis. Patient outcomes were quantified on the modified Rankin Scale.

Results

Fifteen of 19 patients (79%) had major improvement in symptoms after a course of 4-7 therapeutic plasma exchanges. The majority required further inpatient (6, 32%) or outpatient (8, 42%) physical therapy. Four (21%) patients returned to baseline and over 75% regained their ability to ambulate as of last follow-up. Four adverse events were noted over 114 treatments.

Conclusions

TPE can be a useful treatment for pediatric transverse myelitis. The retrospective nature of this study without a comparator group limits conclusions about efficacy. However, controlled trials would help to validate our results.

Classification of evidence

This study provides Class IV evidence that plasma exchange is safe and effective in pediatric transverse myelitis.

Background

The current landscape and treatment patterns of disease-modifying therapy (DMT) use in pediatric patients with multiple sclerosis (MS) are not yet well understood. This study examined DMT utilization and treatment patterns in pediatric patients newly diagnosed as having MS.

Methods

Pediatric patients (<18 years old) with two MS diagnosis claims from January 1, 2010, to December 31, 2016, were identified from the MarketScan Commercial Database. The index date was defined as the date of first MS diagnosis, and patients were followed up for 1 year post-index date. Outcomes evaluated included percentage of patients who initiated treatment after MS diagnosis, different DMTs initiated, treatment discontinuation, and switching treatment during follow-up.

Results

Of 182,057 patients newly diagnosed as having MS, 288 pediatric patients (mean age, 14 years; 61% female) were identified. Within the first year of diagnosis, 188 patients (65.3%) did not receive any DMT. The most common first-initiated treatments were interferons and glatiramer acetate (83%), but 28% of patients switched or discontinued from first-initiated treatment within 6 months of treatment initiation.

Conclusions

This study suggests that a considerable proportion of pediatric patients with MS remain untreated within 1 year of diagnosis. Patients most commonly initiated injectables as their first DMT. Overall, therapy failed early in approximately one in three patients. Thus, the study warrants urgency in treating these patients with currently approved treatment options.

Objective

The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).

Methods

Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months.

Results

rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of C_max and AUC_0-Last. The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort.

Conclusions

Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

A 51-year-old woman with relapsing-remitting multiple sclerosis (RRMS) and 3-year history of natalizumab use developed expressive aphasia. A brain magnetic resonance image (MRI) showed left frontotemporal and right parietal lesion with mild contrast enhancement and cerebrospinal fluid (CSF) was positive for John Cunningham virus (JCV) by polymerase chain reaction (PCR). The patient received five cycles of plasmapheresis followed by intravenous immunoglobulin. Despite this intervention, her speech deteriorated and she developed right hemiparesis. Upon referral to our institution, CSF quantitative JCV PCR was notable for 834 copies/ml. The patient was given an initial dose of 50,000 units of interleukin-2 (IL-2) subcutaneously (SQ) followed by 1 million units IL-2 SQ daily. Due to concern for immune reconstitution inflammatory syndrome (IRIS), the patient also received intravenous methylprednisone weekly. The regimen was tolerated well by the patient with no severe adverse effects. Clinically, the patient showed some improvement, and became more responsive and regained right lower extremity antigravity strength. After 12 weeks of IL-2 therapy, JCV quantitative PCR was notable for 31 copies/ml and the patient was more responsive. Due to persistence of JCV, IL-2 therapy was changed to mefloquine. At follow up after 6 months, the patient showed no clinical deterioration.

Current treatments for antibody-mediated autoimmunity are associated with lack of specificity, leading to immunosuppressive effects. To overcome this limitation, we have developed a class of antibody-based therapeutics for the treatment of autoimmunity involving antibodies that recognize the autoantigen, myelin oligodendrocyte glycoprotein (MOG). These agents ("Seldegs," for selective degradation) selectively eliminate antigen (MOG)-specific antibodies without affecting the levels of antibodies of other specificities. Seldeg treatment of mice during antibody-mediated exacerbation of experimental autoimmune encephalomyelitis by patient-derived MOG-specific antibodies results in disease amelioration. Consistent with their therapeutic effects, Seldegs deliver their targeted antibodies to Kupffer and liver sinusoidal endothelial cells that are known to have tolerogenic effects. Our results show that Seldegs can ameliorate disease mediated by MOG-specific antibodies and indicate that this approach also has the potential to treat other autoimmune diseases where the specific clearance of antibodies is required.

BACKGROUND:The acute effects of aerobic exercise on improved mood and anxiety reduction have been demonstrated across clinical and nonclinical populations. Limited work has evaluated the acute effects of aerobic exercise on negative affect, obsessions, and compulsions in patients with Obsessive Compulsive Disorder (OCD). METHOD:Fifty-five patients (64% female) with treatment-resistant OCD were randomized to either 12 weeks of aerobic exercise (AE) or health education contact (HEC) control. Participants rated negative affect (i.e., mood and anxiety), obsessions and compulsions before and after each weekly AE or HEC session. Multilevel models were constructed to evaluate the effect of intervention condition, treatment week (time), and their interaction in terms of acute change in affect, obsession, and compulsions. RESULTS:Results reflected a main effect of condition, such that AE resulted in significantly larger increases in positive mood, and reductions in anxiety and compulsions, as compared to HEC. There was also a main effect of time in predicting acute anxiety reduction, such that linear reductions in anxiety over the course of treatment were observed. No significant effects were observed for acute changes in obsessions. LIMITATIONS:The sample was small and was limited in demographic heterogeneity. Bouts of aerobic exercise were not standardized in terms of duration and mode, which could impact affective response to exercise, and acute affective OCD effects were exclusively self-reported. DISCUSSION:The current findings may help elucidate potential mechanisms of action of exercise on OCD outcomes. In addition, these results point toward the potential of designing exercise interventions that can teach patients to utilize individual bouts of physical activity, "in-the-moment" to improve mood and reduce anxiety and compulsions.

Adeno-associated viruses (AAVs) are being increasingly used as gene therapy vectors in clinical studies especially targeting central nervous system (CNS) disorders. Correspondingly, host immune responses to the AAV capsid or the transgene-encoded protein have been observed in various clinical and preclinical studies. Such immune responses may adversely impact patients' health, prevent viral transduction, prevent repeated dosing strategies, eliminate transduced cells, and pose a significant barrier to the potential effectiveness of AAV gene therapy. Consequently, multiple immunomodulatory strategies have been used in attempts to limit immune-mediated responses to the vector, enable readministration of AAV gene therapy, prevent end-organ toxicity, and increase the duration of transgene-encoded protein expression. Herein we review the innate and adaptive immune responses that may occur during CNS-targeted AAV gene therapy as well as host- and treatment-specific factors that could impact the immune response. We also summarize the available preclinical and clinical data on immune responses specifically to CNS-targeted AAV gene therapy and discuss potential strategies for incorporating prophylactic immunosuppression regimens to circumvent adverse immune responses.

Background Duchenne muscular dystrophy (DMD) is a neuromuscular disorder caused by mutations within the dystrophin gene. DMD is characterized by progressive skeletal muscle degeneration and atrophy and progressive cardiomyopathy. It has been observed the severity of cardiomyopathy varies in patients with DMD. Methods and Results A cohort of male patients with DMD and female DMD carriers underwent whole exome sequencing. Potential risk factor variants were identified according to their functional annotations and frequencies. Cardiac function of 15 male patients with DMD was assessed by cardiac magnetic resonance imaging, and various cardiac magnetic resonance imaging parameters and circulating biomarkers were compared between genotype groups. Five subjects carrying potential risk factor variants in the cystic fibrosis transmembrane regulator gene demonstrated lower left ventricular ejection fraction, larger left ventricular end-diastolic volume, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels compared with 10 subjects who did not carry the potential risk factor variants (P=0.023, 0.019 and 0.028, respectively). Conclusions This study revealed heterozygous cystic fibrosis transmembrane regulator gene missense variants were associated with worse cardiac function in patients with DMD. The cystic fibrosis transmembrane regulator gene may serve as a genetic modifier that accounts for more severe cardiomyopathy in patients with DMD, who would require more aggressive management of the cardiomyopathy.

Background

Recombinant human immunoglobulin M22 (rHIgM22) has promoted remyelination in animal models and was well tolerated in people with clinically stable multiple sclerosis.

Objective

Safety/tolerability of a single rHIgM22 dose was investigated following an acute relapse and to determine whether this enhanced CNS/CSF concentrations.

Methods

Adults (N = 27) with acute relapse were assigned to rHIgM22 (0.5 or 2.0 mg/kg) or placebo. Study included screening/steroid administration periods and 10 study visits over 6 months. rHIgM22 CSF concentrations were assessed on days 2 and 29. Pharmacokinetic and safety samples were taken for up to 60 days. Assessments included adverse events and other clinical measures. Brain magnetic resonance imaging was performed with/without gadolinium.

Results

rHIgM22 CSF levels were consistent with dose-dependent concentration on both days 2 and 29. Infusion was generally well tolerated during an acute relapse. Immunogenicity was mild. Most adverse events did not appear to be dose dependent, were mild/moderate, and were events often associated with multiple sclerosis.

Conclusion

Although limited by high variability and small sample size, the data suggest enhanced CNS uptake associated with a drop in CSF levels. This study demonstrated safety of an antibody directed to myelin and oligodendrocytes in the course of active demyelinating disease. Further research into rHIgM22 is warranted.ClinicalTrials.gov: NCT02398461 https://clinicaltrials.gov/ct2/show/study/NCT02398461?term=M22&draw=2&rank=8.