Objective To characterize the risk of injection-related reactions (IRRs: systemic and local-site) observed in relapsing multiple sclerosis (RMS) patients treated with ofatumumab in clinical trials and post-marketing surveillance. Methods Data from patients treated with ofatumumab in the core ASCLEPIOS I/II trials and ALITHIOS study (overall, N=1969; patients who received continuous ofatumumab, N=1292; patients newly switched from teriflunomide to ofatumumab, N=677) and post-marketing surveillance (cut-off: 29-Jan-2021) were included in the analysis. Incidence of both systemic and local-site IRRs, their severity and seriousness were reported. Results Systemic/local-site IRRs were observed in 24.6%/11.5% in overall; 25.6%/13.2% in continuous and 22.6%/8.3% in newly-switched groups. Upon first injection, incidence of systemic/local-site IRRs in overall, continuous, and newly-switched groups were 17.4%/2.9%, 17%/3.4%, and 18.2%/2.1%, respectively. Majority (99.5%) were mild-to-moderate (Grade 1/2) in severity. No life-threatening IRRs were observed during the study. In the overall population, systemic and local-site IRRs led to treatment discontinuation in 5 and 1 patient, respectively. The most common systemic IRR symptoms (≥5%) with all injections were fever, headache, chills, fatigue, and local site IRR symptoms (≥3%) were erythema/redness and pain. From the post-marketing, 6 serious cases were assessed as potential systemic IRRs (HCP/non-HCP: 2/4): 1 patient was hospitalized with weakness. In addition, 5 patients reported serious hypersensitivity reactions (HCP/non-HCP: 1/4) including 1 anaphylaxis. Conclusions Systemic and local-site IRRs reported upon first injection with ofatumumab in the ALITHIOS trial and post-marketing surveillance were mostly mild-to-moderate in severity. These results are consistent with the Phase 3 ASCLEPIOS I/II trials.

Objective: To determine the effect of long-term anti-CD20 B-cell-depleting treatment on regulatory T cell immune subsets that are subnormal in untreated MS patients. Methods: 30 clinically stable MS patients, before and over 38 months of ocrelizumab treatment, were compared to 13 healthy controls, 29 therapy-naïve MS, 9 interferon-β-treated MS, 3 rituximab-treated MS, and 3 rituximab-treated patients with other autoimmune inflammatory diseases. CD8, CD28, CD4, and FOXP3 expression in peripheral blood mononuclear cells was quantitated with flow cytometry. Results: CD8+ CD28− regulatory cells rose from one-third of healthy control levels before ocrelizumab treatment (2.68% vs 7.98%), normalized by 12 months (13.5%), and rose to 2.4-fold above healthy controls after 18 months of ocrelizumab therapy (19.0%). CD4+ FOXP3+ regulatory cells were lower in MS than in healthy controls (7.98%) and showed slight long-term decreases with ocrelizumab. CD8+ CD28− and CD4+ FOXP3+ regulatory T cell percentages in IFN-β-treated MS patients were between those of untreated MS and healthy controls. Interpretation: Long-term treatment with ocrelizumab markedly enriches CD8+ CD28− regulatory T cells and corrects the low levels seen in MS before treatment, while slightly decreasing CD4+ FOXP3+ regulatory T cells. Homeostatic enrichment of regulatory CD8 T cells provides a mechanism, in addition to B cell depletion, for the benefits of anti-CD20 treatment in MS.

Dimethyl fumarate (Tecfidera™) is an effective therapy for relapsing forms of multiple sclerosis (MS). Our study suggests that this drug may have immunosuppressive properties evidenced by significant sustained reduction in CD8 lymphocyte counts and, to a lesser extent, CD4 lymphocyte counts. This observation is relevant in light of the recent case of progressive multifocal leukoencephalopathy in a patient receiving this drug.

INTRODUCTION:Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy.METHODS:We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if ≥70% of respondents agreed on a particular strategy.RESULTS:Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies.CONCLUSION:These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis.FUNDING:Biogen.

April 21, 2015April 6, 2015Free AccessResults of a Delphi Panel to Address Management of Gastrointestinal Side Effects Observed with Use of Delayed-release Dimethyl Fumarate (P3.242)J. Theodore Phillips, April Erwin, Stephanie Agrella, Marcelo Kremenchutzky, John Kramer, Jonathan Kendter, Heather Abourjaily, Jitesh Rana, and Robert FoxAuthors Info & AffiliationsApril 6, 2015 issue84 (14_supplement)https://doi.org/10.1212/WNL.84.14_supplement.P3.242 Letters to the Editor

BACKGROUND:Bladder dysfunction is a common symptom of multiple sclerosis (MS). This study was designed to evaluate effects of natalizumab on bladder function in patients with relapsing-remitting MS.METHODS:The TRUST (EvaluaTion of Bladder Function in Relapsing-Remitting MUltiple Sclerosis Patients Treated with Natalizumab) study was an open-label, single-arm, two-center study. Natalizumab-naive MS patients with disabling bladder dysfunction and initiating natalizumab were enrolled and followed for 6 months. The primary endpoint was change in the Urogenital Distress Inventory short form (UDI-6) score from baseline. Change in Incontinence Impact Questionnaire short form (IIQ-7) score from baseline was a secondary endpoint.RESULTS:Thirty patients were enrolled. Mean baseline characteristics were age 49.9 years, Expanded Disability Status Scale score 4.6, number of relapses in previous year 2.4, UDI-6 score 10.4, and IIQ-7 score 12.3. Mean changes in UDI-6 and IIQ-7 scores were significantly improved from baseline beginning at week 4 and up to week 24; mean improvements at 24 weeks were 4.4 (P < .0001) and 4.9 (P = .0005) points, respectively. At week 24, 85.7% and 78.6% of patients demonstrated improvements from baseline in UDI-6 and IIQ-7 scores, respectively.CONCLUSIONS:Incontinence-related quality of life as measured by UDI-6 and IIQ-7 scores improved significantly during natalizumab treatment.

Muscle & NerveVolume 48, Issue 4 p. 624-624 Letters to the Editor Vascular access for therapeutic plasma exchange Bhupendra Khatri MD, Bhupendra Khatri MD Center for Neurological Disorders, Wheaton Franciscan Healthcare, St. Francis Hospital, Milwaukee, Wisconsin, USASearch for more papers by this authorJohn Kramer MD, John Kramer MD Center for Neurological Disorders, Wheaton Franciscan Healthcare, St. Francis Hospital, Milwaukee, Wisconsin, USASearch for more papers by this author Bhupendra Khatri MD, Bhupendra Khatri MD Center for Neurological Disorders, Wheaton Franciscan Healthcare, St. Francis Hospital, Milwaukee, Wisconsin, USASearch for more papers by this authorJohn Kramer MD, John Kramer MD Center for Neurological Disorders, Wheaton Franciscan Healthcare, St. Francis Hospital, Milwaukee, Wisconsin, USASearch for more papers by this author First published: 11 April 2013 https://doi.org/10.1002/mus.23873Citations: 1 Editor's Note: Guptil et al. declined to reply to this letter, because they have no experience with the vascular access technique described. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Guptill JT, Oakley D, Kuchibhatla M, Guidon AC, Hobson-Webb LD, Massey JM, et al. A retrospective study of complications of therapeutic plasma exchange in myasthenia. Muscle Nerve 2013; 47: 170–176. 2Khatri BO. Vascular access via temporary radial artery catheterization for therapeutic plasma exchange. J Clin Apheresis 2003; 18: 134. 3Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 2003; 17: 241–251. 4Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol 2006; 117: S525–S553. Citing Literature Volume48, Issue4October 2013Pages 624-624 ReferencesRelatedInformation

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system with exacerbations involving the optic nerves, spinal cord, or both. This study explores the utility of maintenance plasma exchange (mTPE) as a therapy in patients with relapsing, corticosteroid‐refractory, NMO. This retrospective case series presents data on patients who were diagnosed with NMO using currently accepted criteria. These patients were refractory to high‐dose corticosteroids and received mTPE. Seven patients met the criteria for NMO diagnosis and all were positive for antibodies against aquaporin‐4. Over a mean of 7.1 years (range, 2–16), these patients received between 21 and 154 TPE treatments (mean, 76). Although treated with mTPE, five out of the seven patients improved by more than one point on the Expanded Disability Status Scale. Interruption in mTPE in five patients resulted in clinical worsening. When mTPE was restarted in three out of the five patients who experienced a cessation of mTPE, these patients either stabilized or improved. The two patients who did not restart the mTPE protocol died. Patients treated with mTPE also experienced a reduction in the number of NMO exacerbations. Finally, stabilization of the retinal nerve fiber layer thickness was observed while on mTPE. In this preliminary study, mTPE appeared safe and may bring about improvement in disability and sustained stabilization of the clinical course in patients with steroid‐refractory relapsing forms of NMO. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

Fingolimod (Gilenya®) is the first oral immunomodulating drug approved for relapsing–remitting multiple sclerosis. Its novel mechanism of action inhibits the egress of autoreactive B and T cells from lymph nodes, thus preventing them from crossing into the CNS. Two recent large Phase III clinical trials both met their primary end points clearing the way for approval by the US FDA in September 2010. Despite robust clinical efficacy, safety concerns arose in both trials, including, but not limited to, increased risk of infection, cardiac issues and a higher incidence of cancer. Further long-term data will clarify these safety issues to enable clinicians to feel comfortable when prescribing fingolimod on a routine basis. This article will review the clinical trial data from the Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) and FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) studies.

For a disease whose cause remains elusive, there has been a paradoxical growth in multiple sclerosis (MS) therapeutics. During the past 17 years, six therapeutic drugs for MS were brought to market. All of these disease-modifying therapies (DMTs) have shown a beneficial effect in reducing the number of exacerbations in double-blind placebo-controlled trials, and three drugs (subcutaneous [SC]/IM interferon beta-1a, natalizumab) have been shown to reduce relapses, decrease MRI activity, and reduce the risk of sustained disability after 2 years of treatment. No controlled studies exist to show long-term benefit with any of the current DMTs. Immunosuppressive drug (ISD) therapies continue to play a role in the management of patients who fail to respond to immunomodulatory agents. These agents, however, have shown mixed data in terms of efficacy and put patients at higher risk for the development of secondary cancers. Plasma exchange for severe relapses not responsive to corticosteroid therapy has regained interest in the past few years. Furthermore, six new agents that will dramatically impact our ability to prevent disability in patients with MS are in late-stage or have completed phase 3 clinical development. Determining the risk-benefit calculations that we will need to employ toward these new drugs and the algorithms for switching therapies will be critical issues in the next 5 years. This article highlights the clinical efficacy of the current DMTs/ISDs and discusses the current treatment options for clinically isolated syndrome, relapsing-remitting MS (RRMS), and exacerbations of RRMS. It also addresses the management of a suboptimal response to the DMTs; discusses the challenge of primary progressive MS; and presents an overview of emerging therapeutic options.