Publications by authors named "Bernd C Kieseier"

244 Publications

Temporal profile of serum neurofilament light in multiple sclerosis: Implications for patient monitoring.

Mult Scler 2020 Dec 14:1352458520972573. Epub 2020 Dec 14.

Biogen, Cambridge, MA, USA.

Objective: To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage.

Methods: This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing-remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity.

Results: Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical ( = 0.02) and magnetic resonance imaging (MRI) ( < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (-9.5% vs. 6.8%;  < 0.01). sNfL was higher and more variable in patients with evidence of active MS.

Conclusion: These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.
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http://dx.doi.org/10.1177/1352458520972573DOI Listing
December 2020

Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode.

JAMA Netw Open 2020 11 2;3(11):e2016278. Epub 2020 Nov 2.

Biogen, Cambridge, Massachusetts.

Importance: Data are needed on the potential long-term prognostic association of serum neurofilament light in multiple sclerosis (MS).

Objective: To evaluate serum neurofilament light as a biomarker associated with long-term disease outcomes in clinically isolated syndrome.

Design, Setting, And Participants: This post hoc cohort study used data from the Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, a 36-month, multicenter, placebo-controlled interferon β-1a randomized clinical trial conducted from April 1996 to March 2000, and its long-term (5- and 10-year) extension study from February 2001 to March 2009. Participants included individuals with a symptomatic initial demyelinating event and brain magnetic resonance imaging (MRI) lesions suggestive of MS. Data were analyzed from April 2017 through 2019.

Exposure: The variable of interest was naturally occurring serum neurofilament light concentration.

Main Outcomes And Measures: Gadolinium-enhancing (Gd+) lesion number, T2 lesion volume, and brain parenchymal fraction, a measure of brain atrophy were measured at baseline and 5 and 10 years. Multivariate regression models evaluated whether age, sex, and baseline covariates, including serum neurofilament light, brain parenchymal fraction, Expanded Disability Status Scale, Gd+ lesion count, and T2 lesion volume, were associated with brain parenchymal fraction changes over 5 and 10 years.

Results: Among 308 included participants (mean [SD] age, 33.2 [7.6] years; 234 [76.0%] women), baseline serum neurofilament light concentrations were associated with Gd+ lesions (Spearman r = 0.41; P < .001) and T2 lesion volume (Spearman r = 0.42; P < .001). Among covariates for brain parenchymal fraction change, serum neurofilament light concentration had the greatest correlation with change in brain parenchymal fraction at 5 years (Spearman r = -0.38; P < .001) and was the only variable associated with brain parenchymal fraction at 10 years (Spearman r = -0.45; P < .001). Participants in the highest vs lowest baseline serum neurofilament light tertiles showed brain parenchymal fraction reduction at 5 years (-1.83% [95% CI, -1.49% to -2.18%] vs -0.95% [95% CI, -0.78% to -1.12%]; P < .001) and 10 years (-3.54% [95% CI, -2.90% to -4.17%] vs -1.90% [95% CI, -1.43% to -2.37%]; P < .001). At 5 years, 6 of 45 participants (13.3%) in the highest neurofilament tertile and 2 of 52 participants (3.8%) in the lowest neurofilament tertile achieved an Expanded Disability Status Scale score of 3.5 or greater.

Conclusions And Relevance: This cohort study found that higher baseline serum neurofilament light levels were associated with increased brain atrophy over 5 and 10 years. These findings suggest that serum neurofilament light could be a biomarker associated with disease severity stratification in early MS and may help to guide intervention.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.16278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645699PMC
November 2020

NK cell markers predict the efficacy of IV immunoglobulins in CIDP.

Neurol Neuroimmunol Neuroinflamm 2020 11 2;7(6). Epub 2020 Oct 2.

From the Department of Neurology (A.K.M., M.F., F.S., C.K., M.S.), Research Group for Clinical and Experimental Neuroimmunology, University Hospital Essen; Department of Neurology (M.K.H., H.-P.H., B.C.K.), Medical Faculty, Heinrich-Heine University Duesseldorf; Department of Neurology with Institute of Translational Neurology (G.M.Z.H.), University Hospital Münster; and Oncology and Tumor Immunology (S.C.), Charité University Medicine, Berlin, Germany.

Objective: To assess whether IV immunoglobulins (IVIgs) as a first-line treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) have a regulative effect on natural killer (NK) cells that is related to clinical responsiveness to IVIg.

Methods: In a prospective longitudinal study, we collected blood samples of 29 patients with CIDP before and after initiation of IVIg treatment for up to 6 months. We used semiquantitative PCR and flow cytometry in the peripheral blood to analyze the effects of IVIg on the NK cells. The results were correlated with clinical aspects encompassing responsiveness.

Results: We found a reduction in the expression of several typical NK cell genes 1 day after IVIg administration. Flow cytometry furthermore revealed a reduced cytotoxic CD56 NK cell population, whereas regulatory CD56 NK cells remained mostly unaffected or were even increased after IVIg treatment. Surprisingly, the observed effects on NK cells almost exclusively occurred in IVIg-responsive patients with CIDP.

Conclusions: The correlation between the altered NK cell population and treatment efficiency suggests a crucial role for NK cells in the still speculative mode of action of IVIg treatment. Analyzing NK cell subsets after 24 hours of treatment initiation appeared as a predictive marker for IVIg responsiveness. Further studies are warranted investigating the potential of NK cell status as a routine parameter in patients with CIDP before IVIg therapy.

Classification Of Evidence: This study provides Class I evidence that NK cell markers predict clinical response to IVIg in patients with CIDP.
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http://dx.doi.org/10.1212/NXI.0000000000000884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577535PMC
November 2020

Harnessing Real-World Data to Inform Decision-Making: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS).

Front Neurol 2020 7;11:632. Epub 2020 Aug 7.

Biogen, Cambridge, MA, United States.

Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is the first example of a learning health system in multiple sclerosis (MS). This paper describes the initial implementation of MS PATHS and initial patient characteristics. MS PATHS is an ongoing initiative conducted in 10 healthcare institutions in three countries, each contributing standardized information acquired during routine care. Institutional participation required the following: active MS patient census of ≥500, at least one Siemens 3T magnetic resonance imaging scanner, and willingness to standardize patient assessments, share standardized data for research, and offer universal enrolment to capture a representative sample. The eligible participants have diagnosis of MS, including clinically isolated syndrome, and consent for sharing pseudonymized data for research. MS PATHS incorporates a self-administered patient assessment tool, the Multiple Sclerosis Performance Test, to collect a structured history, patient-reported outcomes, and quantitative testing of cognition, vision, dexterity, and walking speed. Brain magnetic resonance imaging is acquired using standardized acquisition sequences on Siemens 3T scanners. Quantitative measures of brain volume and lesion load are obtained. Using a separate consent, the patients contribute DNA, RNA, and serum for future research. The clinicians retain complete autonomy in using MS PATHS data in patient care. A shared governance model ensures transparent data and sample access for research. As of August 5, 2019, MS PATHS enrolment included participants ( = 16,568) with broad ranges of disease subtypes, duration, and severity. Overall, 14,643 (88.4%) participants contributed data at one or more time points. The average patient contributed 15.6 person-months of follow-up (95% CI: 15.5-15.8); overall, 166,158 person-months of follow-up have been accumulated. Those with relapsing-remitting MS demonstrated more demographic heterogeneity than the participants in six randomized phase 3 MS treatment trials. Across sites, a significant variation was observed in the follow-up frequency and the patterns of disease-modifying therapy use. Through digital health technology, it is feasible to collect standardized, quantitative, and interpretable data from each patient in busy MS practices, facilitating the merger of research and patient care. This approach holds promise for data-driven clinical decisions and accelerated systematic learning.
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http://dx.doi.org/10.3389/fneur.2020.00632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426489PMC
August 2020

Corneal Confocal Microscopy Demonstrates Corneal Nerve Loss in Patients With Trigeminal Neuralgia.

Front Neurol 2020 24;11:661. Epub 2020 Jul 24.

Department of Neurology, University Medicine Essen, Essen, Germany.

The diagnosis of trigeminal neuralgia (TN) is challenging due to the lack of objective diagnostics. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging technique, which allows quantification of corneal nerve fibers arising from the trigeminal ganglion and may allow the assessment of neurodegeneration in TN. CCM was undertaken in 11 patients with TN and 11 age-matched healthy controls. Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length (CNFL), corneal nerve fiber width, corneal nerve fiber area, and dendritic cell and non-dendritic cell density with or without nerve fiber contact were quantified. Patients with TN had significantly lower CNFD and CNFL but no difference for any other corneal nerve or dendritic cell parameter in the ipsilateral and the contralateral cornea compared to the control group. There was no significant difference in corneal nerve and cell parameters between patients with TN with and without involvement of the ophthalmic nerve (V1) or with nerve vessel conflict. Corneal confocal microscopy is a rapid non-invasive imaging technique that identifies symmetrical corneal nerve loss in patients with TN.
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http://dx.doi.org/10.3389/fneur.2020.00661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393442PMC
July 2020

Blood neurofilament light levels segregate treatment effects in multiple sclerosis.

Neurology 2020 03 11;94(11):e1201-e1212. Epub 2020 Feb 11.

From the Department of Medicine Solna, Clinical Epidemiology Division (B.D.), The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Department of Clinical Neuroscience (A.M., I.K., T.O., F.P.), and Institute of Environmental Medicine (L.A.), Karolinska Institutet; Centre for Molecular Medicine (A.M., I.K., T.O., F.P.), Karolinska University Hospital, Stockholm, Sweden; Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine, and Clinical Research (C.B., Z.M., L.K., D.L., J.K.), and Clinical Trial Unit, Department of Clinical Research (P.B.), University Hospital Basel, University of Basel, Switzerland; Sanofi Genzyme (J.A.T.), Stockholm, Sweden; Biogen (T.P., B.C.K.), Cambridge, MA; Department of Neurology, Medical Faculty (B.C.K.), Heinrich-Heine University, Duesseldorf, Germany; and Institution of Neuroscience and Physiology (J.L.), Sahlgrenska Academy, University of Gothenburg, Sweden.

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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http://dx.doi.org/10.1212/WNL.0000000000009097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387108PMC
March 2020

Predicting disability progression in multiple sclerosis: Insights from advanced statistical modeling.

Mult Scler 2020 12 5;26(14):1828-1836. Epub 2019 Nov 5.

Biogen, Cambridge, MA, USA/Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Background: There is an unmet need for precise methods estimating disease prognosis in multiple sclerosis (MS).

Objective: Using advanced statistical modeling, we assessed the prognostic value of various clinical measures for disability progression.

Methods: Advanced models to assess baseline prognostic factors for disability progression over 2 years were applied to a pooled sample of patients from placebo arms in four different phase III clinical trials. least absolute shrinkage and selection operator (LASSO) and ridge regression, elastic nets, support vector machines, and unconditional and conditional random forests were applied to model time to clinical disability progression confirmed at 24 weeks. Sensitivity analyses for different definitions of a combined endpoint were carried out, and bootstrap was used to assess prediction model performance.

Results: A total of 1582 patients were included, of which 434 (27.4%) had disability progression in a combined endpoint over 2 years. Overall model discrimination performance was relatively poor (all -indices ⩽ 0.65) across all models and across different definitions of progression.

Conclusion: Inconsistency of prognostic factor importance ranking confirmed the relatively poor prediction ability of baseline factors in modeling disease progression in MS. Our findings underline the importance to explore alternative predictors as well as alternative definitions of commonly used endpoints.
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http://dx.doi.org/10.1177/1352458519887343DOI Listing
December 2020

Neurofilament light levels are associated with long-term outcomes in multiple sclerosis.

Mult Scler 2020 11 4;26(13):1691-1699. Epub 2019 Nov 4.

Biogen, Cambridge, MA, USA.

Background: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear.

Objective: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years.

Methods: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients ( = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon β-1a, and in serum ( = 164) from the extension study.

Results: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years ( < 0.0001,  = -0.46;  < 0.05.  = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9,  < 0.05; OR = 11.0, 95% CI = 2.0-114.6;  < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4;  < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes.

Conclusion: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.
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http://dx.doi.org/10.1177/1352458519885613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604552PMC
November 2020

A proof-of-concept application of a novel scoring approach for personalized medicine in multiple sclerosis.

Mult Scler 2020 08 30;26(9):1064-1073. Epub 2019 May 30.

Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Background: Stratified medicine methodologies based on subgroup analyses are often insufficiently powered. More powerful personalized medicine approaches are based on continuous scores.

Objective: We deployed a patient-specific continuous score predicting treatment response in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: Data from two independent randomized controlled trials (RCTs) were used to build and validate an individual treatment response (ITR) score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

Results: The ITR score for the combined treatment groups versus placebo detected differential clinical response in both RCTs. High responders in one RCT had a cross-validated ARR ratio of 0.29 (95% confidence interval (CI) = 0.13-0.55) versus 0.62 (95% CI = 0.47-0.83) for all other responders (heterogeneity  = 0.038) and were validated in the other RCT, with the corresponding ARR ratios of 0.31 (95% CI = 0.18-0.56) and 0.61 (95% CI = 0.47-0.79; heterogeneity  = 0.036). The strongest treatment effect modifiers were the Short Form-36 Physical Component Summary, age, Visual Function Test 2.5%, prior MS treatment and Expanded Disability Status Scale.

Conclusion: Our modelling strategy detects and validates an ITR score and opens up avenues for building treatment response calculators that are also applicable in routine clinical practice.
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http://dx.doi.org/10.1177/1352458519849513DOI Listing
August 2020

Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination.

Acta Neuropathol 2018 12 16;136(6):979-982. Epub 2018 Nov 16.

Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

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http://dx.doi.org/10.1007/s00401-018-1938-4DOI Listing
December 2018

Immune-mediated neuropathies.

Nat Rev Dis Primers 2018 10 11;4(1):31. Epub 2018 Oct 11.

Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.

Since the discovery of an acute monophasic paralysis, later coined Guillain-Barré syndrome, almost 100 years ago, and the discovery of chronic, steroid-responsive polyneuropathy 50 years ago, the spectrum of immune-mediated polyneuropathies has broadened, with various subtypes continuing to be identified, including chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). In general, these disorders are speculated to be caused by autoimmunity to proteins located at the node of Ranvier or components of myelin of peripheral nerves, although disease-associated autoantibodies have not been identified for all disorders. Owing to the numerous subtypes of the immune-mediated neuropathies, making the right diagnosis in daily clinical practice is complicated. Moreover, treating these disorders, particularly their chronic variants, such as CIDP and MMN, poses a challenge. In general, management of these disorders includes immunotherapies, such as corticosteroids, intravenous immunoglobulin or plasma exchange. Improvements in clinical criteria and the emergence of more disease-specific immunotherapies should broaden the therapeutic options for these disabling diseases.
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http://dx.doi.org/10.1038/s41572-018-0027-2DOI Listing
October 2018

Trapped in the epineurium: early entry into the endoneurium is restricted to neuritogenic T cells in experimental autoimmune neuritis.

J Neuroinflammation 2018 Aug 1;15(1):217. Epub 2018 Aug 1.

Department of Neurology, Medical Faculty, Heinrich Heine University Duesseldorf, 40225, Duesseldorf, Germany.

Background: Autoimmune polyneuropathies are acquired inflammatory disorders of the peripheral nervous system (PNS) characterized by inflammation, demyelination, and axonal degeneration. Although the pathogenesis has not been fully elucidated, T cells recognizing self-antigens are believed to initiate inflammation in a subgroup of patients. However, the route and time of T cell entry into the PNS have not yet been described in detail. In this study, we analyzed both kinetics as well as localization of retrovirally transfected green fluorescent protein (GFP)-expressing neuritogenic T lymphocytes in experimental autoimmune neuritis (EAN).

Methods: T lymphocytes obtained from rats following EAN induction by immunization with peripheral nerve protein peptide P2 were retrovirally engineered to express GFP. Non-specific T cells were negatively selected by in vitro restimulation, whereas GFP-expressing neuritogenic T cells (reactive to P2) were adoptively transferred into healthy rats (AT-EAN). Antigen-specific T cell tracking and localization was performed by flow cytometry and immunohistochemistry during the course of disease.

Results: After induction of autoimmune neuritis, P2-reactive T cells were detectable in the liver, spleen, lymph nodes, lung, peripheral blood, and the sciatic nerves with distinct kinetics. A significant number of GFP T cells appeared early in the lung with a peak at day four. In the peripheral nerves within the first days, GFP-negative T cells rapidly accumulated and exceeded the number of GFP-expressing cells, but did not enter the endoneurium. Very early after adoptive transfer, T cells are found in proximity to peripheral nerves and in the epineurium. However, only GFP-expressing neuritogenic T cells are able to enter the endoneurium from day five after transfer.

Conclusions: Our findings suggest that neuritogenic T cells invade the PNS early in the course of disease. However, neuritogenic T cells cross the blood-nerve barrier with a certain delay without preference to dorsal roots. Further understanding of the pathophysiological role of autoagressive T cells may help to improve therapeutic strategies in immune-mediated neuropathies.
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http://dx.doi.org/10.1186/s12974-018-1259-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090976PMC
August 2018

Progress in Recognizing and Treating Polyneuropathy.

Dtsch Arztebl Int 2018 02;115(6):81-82

Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany.

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http://dx.doi.org/10.3238/arztebl.2018.0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832889PMC
February 2018

Novel pathomechanisms in inflammatory neuropathies.

J Neuroinflammation 2017 Nov 28;14(1):232. Epub 2017 Nov 28.

Department of Neurology, Westfälische Wilhems-University, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Inflammatory neuropathies are rare autoimmune-mediated disorders affecting the peripheral nervous system. Considerable progress has recently been made in understanding pathomechanisms of these disorders which will be essential for developing novel diagnostic and therapeutic strategies in the future. Here, we summarize our current understanding of antigenic targets and the relevance of new immunological concepts for inflammatory neuropathies. In addition, we provide an overview of available animal models of acute and chronic variants and how new diagnostic tools such as magnetic resonance imaging and novel therapeutic candidates will benefit patients with inflammatory neuropathies in the future. This review thus illustrates the gap between pre-clinical and clinical findings and aims to outline future directions of development.
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http://dx.doi.org/10.1186/s12974-017-1001-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704548PMC
November 2017

Lysophosphatidic acid propagates post-injury Schwann cell dedifferentiation through LPA signaling.

Neurosci Lett 2018 Jan 16;662:136-141. Epub 2017 Oct 16.

Department of Neurology, Medical Faculty, University Duisburg-Essen, Essen, Germany.

Lysophosphatidic acid (LPA) is a pleiotropic signaling lipid that acts as ligand for at least six specific G-protein coupled receptors. Schwann cells (SC) are known to mainly express the LPA receptor subtype. An emerging body of evidence has linked LPA with injury-induced peripheral nerve demyelination as well as neuropathic pain. However, the molecular mechanisms underlying its demyelinating effect have not been conclusively elucidated. We aimed to decipher the demyelinating effect in vitro as well as in vivo by studying markers of SC differentiation and dedifferentiation: Myelinated dorsal root ganglia (DRG) cultures were treated either with LPA, LPA plus AM095 (LPA antagonist) or vehicle. Myelin content was subsequently investigated by Sudan Black staining and immunocytochemistry. In vivo, we performed sciatic nerve crush in C57BL/6 mice treated with AM095 at 10mg/kg. In DRG cultures, LPA caused a significant reduction of myelin as demonstrated by both Sudan Black staining and immunocytochemical analysis of myelin basic protein. Demyelination was paralleled by an upregulation of TNF-alpha as well as downregulation of Sox10, a marker for SC differentiation. LPA mediated effects were largely blocked by the addition of the LPA receptor antagonist AM095. In the in vivo model, AM095 treatment prior to crush injury increased Sox10 expression in SCs in the distal nerve stump while reducing the number of cells expressing the SC dedifferentiation marker Sox2. Additionally, TNF-alpha immunofluorescence was reduced in CD11b-positive cells. These data indicate that LPA may be a critical factor that shifts SCs towards a post-injury phenotype and contributes to the onset of Wallerian degeneration.
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http://dx.doi.org/10.1016/j.neulet.2017.10.023DOI Listing
January 2018

Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II.

Sci Rep 2017 10 2;7(1):12518. Epub 2017 Oct 2.

Department of Neurology, University Hospital Münster, Münster, Germany.

The activation of T helper cells requires antigens to be exposed on the surface of antigen presenting cells (APCs) via MHC class II (MHC-II) molecules. Expression of MHC-II is generally limited to professional APCs, but other cell types can express MHC-II under inflammatory conditions. However, the importance of these conditional APCs is unknown. We and others have previously shown that Schwann cells are potentially conditional APCs, but the functional relevance of MHC-II expression by Schwann cells has not been studied in vivo. Here, we conditionally deleted the MHC-II β-chain from myelinating Schwann cells in mice and investigated how this influenced post-traumatic intraneural inflammation and neuropathic pain using the chronic constriction injury (CCI) model. We demonstrate that deletion of MHC-II in myelinating Schwann cells reduces thermal hyperalgesia and, to a lesser extent, also diminishes mechanical allodynia in CCI in female mice. This was accompanied by a reduction of intraneural CD4+ T cells and greater preservation of preferentially large-caliber axons. Activation of T helper cells by MHC-II on Schwann cells thus promotes post-traumatic axonal loss and neuropathic pain. Hence, we provide experimental evidence that Schwann cells gain antigen-presenting function in vivo and modulate local immune responses and diseases in the peripheral nerves.
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http://dx.doi.org/10.1038/s41598-017-12744-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624882PMC
October 2017

CIDP and other inflammatory neuropathies in diabetes - diagnosis and management.

Nat Rev Neurol 2017 Oct 15;13(10):599-611. Epub 2017 Sep 15.

Weill Cornell Medicine-Qatar, Education City, PO Box 24144, Doha, Qatar.

Distal symmetric polyneuropathy (DSPN) is the most common neuropathy to occur in diabetes mellitus. However, patients with diabetes can also develop inflammatory neuropathies, the most common and most treatable of which is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Whether diabetes is a risk factor for CIDP remains under debate. Early studies suggested that patients with diabetes were at increased risk of CIDP, but epidemiological studies failed to confirm the association, and subsequent data have re-opened the debate. Inadequate interpretation of investigations and differentials between CIDP and other neuropathies that can occur in diabetes, such as DSPN, diabetic radiculoplexus neuropathies and vasculitic multiple mononeuropathy, might mean that CIDP is under-recognized. Despite a response rate of >80% to first-line therapies for CIDP in patients with or without diabetes, those with diabetes often present with greater disability owing to late referral and axonal pathology attributed to DSPN. The increasing worldwide prevalence of diabetes creates an urgent need to improve identification of potentially treatable neuropathies, such as CIDP. In this Review, we consider the features of CIDP in patients with diabetes, and discuss how these features can be used to differentiate the condition from other neuropathies. We also review the management options for CIDP and other inflammatory neuropathies in patients with diabetes.
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http://dx.doi.org/10.1038/nrneurol.2017.123DOI Listing
October 2017

Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta.

Front Neurol 2017 6;8:305. Epub 2017 Jul 6.

Medical Faculty, Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany.

Objective: To develop and validate a method for the detection of binding anti-drug antibodies (ADAs) against interferon beta (IFN-β) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk.

Method: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. : ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled Streptavidin and TMB substrate. : Screen "putative positive" samples are tested in the presence of excess drug (preincubation of sera with 0.3 µg/mL of soluble IFN-β) and percentage of inhibition is calculated.

Results: The assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control.

Conclusion: An ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium.
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http://dx.doi.org/10.3389/fneur.2017.00305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498465PMC
July 2017

Improvement in relapse recovery with peginterferon beta-1a in patients with multiple sclerosis.

Mult Scler J Exp Transl Clin 2016 Jan-Dec;2:2055217316676644. Epub 2016 Nov 15.

Department of Neurology, Allegheny General Hospital, Pittsburgh, PA, USA.

Background: Subcutaneous peginterferon beta-1a every 2 weeks significantly affects clinical outcomes in patients with relapsing-remitting multiple sclerosis (RRMS).

Objectives: To explore relationships between relapses and worsening of disability in patients with RRMS, and assess the treatment effect of peginterferon beta-1a on relapse recovery.

Methods: Post-hoc analysis of the 2-year, randomized, double-blind, parallel-group, Phase 3 ADVANCE study. The severity of relapses, proportion of patients with relapses associated with residual disability (onset of 24-week confirmed disability progression (CDP) within 90 days following a relapse), and persistence of changes in Functional Systems Scores, were compared between treatment groups.

Results: Subcutaneous peginterferon beta-1a every 2 weeks significantly reduced the proportion of patients experiencing relapse associated with CDP over 2 years (6.6%, compared with 15.1% of patients who received placebo in Year 1;  = 0.02). Reduction in relapses associated with residual disability was greater than the treatment effect on overall relapse rate, and occurred despite similar relapse severity across treatment groups.

Conclusions: The beneficial effect of peginterferon beta-1a on risk of CDP may be attributable to the combination of an overall reduction in the risk of relapses and improvement in recovery from relapses, thus limiting further disability progression.

Trial Registration: ClinicalTrials.gov identifier: NCT00906399.
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http://dx.doi.org/10.1177/2055217316676644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5433498PMC
November 2016

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

Ther Adv Neurol Disord 2017 Jan 16;10(1):41-50. Epub 2016 Nov 16.

Biogen, Cambridge, MA, USA.

Background: In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL).

Methods: In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset.

Results: Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% 10.5%, = 0.038; 24-week CDP: 4% 8.4%, = 0.0069, peginterferon beta-1a every 2 weeks placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks.

Conclusions: Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].
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http://dx.doi.org/10.1177/1756285616676065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400156PMC
January 2017

The Role of Peripheral Myelin Protein 2 in Remyelination.

Cell Mol Neurobiol 2018 Mar 26;38(2):487-496. Epub 2017 Apr 26.

Department of Neurology, Heinrich-Heine-University, Düsseldorf, Germany.

The protein component of the myelin layer is essential for all aspects of peripheral nerves, and its deficiency can lead to structural and functional impairment. The presence of peripheral myelin protein 2 (P2, PMP2, FABP8, M-FABP) in Schwann cells has been known for decades and shown recently to be involved in the lipid homeostasis in the peripheral neural system. However, its precise role during de- and remyelination has yet to be elucidated. To this end, we assessed remyelination after sciatic nerve crush injury in vivo, and in an experimental de/remyelination ex vivo myelinating culture model in P2-deficient (P2 ) and wild-type (WT) animals. In vivo, the nerve crush paradigm revealed temporal structural and functional changes in P2 mice as compared to WT animals. Concomitantly, P2 DRG cultures demonstrated the presence of shorter internodes and enlarged nodes after ex vivo de/remyelination. Together, these data indicate that P2 may play a role in remyelination of the injured peripheral nervous system, presumably by affecting the nodal and internodal configuration.
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http://dx.doi.org/10.1007/s10571-017-0494-0DOI Listing
March 2018

Peginterferon beta-1a improves MRI measures and increases the proportion of patients with no evidence of disease activity in relapsing-remitting multiple sclerosis: 2-year results from the ADVANCE randomized controlled trial.

BMC Neurol 2017 Feb 10;17(1):29. Epub 2017 Feb 10.

Biogen, 225 Binney St, Cambridge, MA, USA.

Background: Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years.

Methods: Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall.

Results: Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001).

Conclusion: Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period.

Trial Registration: ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009.
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http://dx.doi.org/10.1186/s12883-017-0799-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301356PMC
February 2017

Targeting lysophospholipid signaling as a therapeutic approach towards improved peripheral nerve regeneration.

Neural Regen Res 2016 Nov;11(11):1754-1755

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

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http://dx.doi.org/10.4103/1673-5374.194720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5204223PMC
November 2016

Dimethyl fumarate accelerates peripheral nerve regeneration via activation of the anti-inflammatory and cytoprotective Nrf2/HO-1 signaling pathway.

Acta Neuropathol 2017 03 20;133(3):489-491. Epub 2017 Jan 20.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

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http://dx.doi.org/10.1007/s00401-017-1676-zDOI Listing
March 2017

Predicting the Response to Intravenous Immunoglobulins in an Animal Model of Chronic Neuritis.

PLoS One 2016 6;11(10):e0164099. Epub 2016 Oct 6.

Department of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disabling autoimmune disorder of the peripheral nervous system (PNS). Intravenous immunoglobulins (IVIg) are effective in CIDP, but the treatment response varies greatly between individual patients. Understanding this interindividual variability and predicting the response to IVIg constitute major clinical challenges in CIDP. We previously established intercellular adhesion molecule (ICAM)-1 deficient non-obese diabetic (NOD) mice as a novel animal model of CIDP. Here, we demonstrate that similar to human CIDP patients, ICAM-1 deficient NOD mice respond to IVIg treatment by clinical and histological measures. Nerve magnetic resonance imaging and histology demonstrated that IVIg ameliorates abnormalities preferentially in distal parts of the sciatic nerve branches. The IVIg treatment response also featured great heterogeneity allowing us to identify IVIg responders and non-responders. An increased production of interleukin (IL)-17 positively predicted IVIg treatment responses. In human sural nerve biopsy sections, high numbers of IL-17 producing cells were associated with younger age and shorter disease duration. Thus, our novel animal model can be utilized to identify prognostic markers of treatment responses in chronic inflammatory neuropathies and we identify IL-17 production as one potential such prognostic marker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053527PMC
June 2017

Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial.

Lancet Neurol 2016 Oct 16;15(11):1148-59. Epub 2016 Aug 16.

Mitsubishi Tanabe Pharma Europe, London, UK.

Background: Patients with multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system with autoimmune pathogenesis, have shown partial response to a number of immunomodulating treatments, but the search for more effective, safe, and convenient therapeutic options continues. Amiselimod is an oral selective modulator of sphingosine 1-phosphate 1 (S1P1) receptor, which is being developed for the treatment of various autoimmune-mediated diseases. We assessed the safety and efficacy of amiselimod in patients with relapsing- remitting multiple sclerosis.

Methods: In this double-blind phase 2 trial, patients aged 18-60 years with active relapsing-remitting multiple sclerosis from 84 centres in Europe and Canada were randomly assigned (1:1:1:1) with an interactive web-response system to receive once daily oral amiselimod 0·1 mg, 0·2 mg, 0·4 mg, or placebo for 24 weeks. All study personnel, site personnel, investigators, and patients were masked to the treatment assignment during the study. The primary endpoint was the total number of gadolinium-enhanced T1-weighted lesions on monthly brain MRI scans from weeks 8 to 24. Analysis was done on the predefined evaluable population (all randomised patients who did not have any major protocol deviations, completed 24 weeks of treatment as planned, and had at least three valid post-dose MRI scans). This trial is registered with ClinicalTrials.gov, number NCT01742052.

Findings: Between Jan 31, 2013, and Dec 24, 2013, 536 patients were screened and 415 patients randomly assigned to amiselimod 0·1 mg (n=105), 0·2 mg (n=103), 0·4 mg (n=104), or placebo (n=103). The median total number of gadolinium-enhanced T1-weighted lesions from weeks 8 to 24 did not differ between the amiselimod 0·1 mg and placebo groups (median 1·6 lesions [range 0-132] in the placebo group vs 2·0 [0-105] in the 0·1 mg group [median difference 0·0, 95% CI -1·0 to 0·0, p=0·7517]), but was significantly lower in the two higher amiselimod dose groups than in the placebo group (0·0 lesions [range 0-35] in the 0·2 mg group [median difference vs placebo -1·0, 95% CI -1·0 to 0·0, p=0·0021] and 0·0 [range 0-30] in the 0·4 mg group [-1·0, -1·2 to 0·0, p=0·0003]). The estimated incident rate ratio compared with placebo was dose-dependently decreased with amiselimod (0·1 mg 0·53 [95% CI 0·33-0·85; p=0·0079], 0·2 mg 0·39 [95% CI 0·24-0·63; p=0·0001], and 0·4 mg 0·23 [95% CI 0·14-0·38; p<0·0001]). The incidence of treatment-emergent adverse events, including infections and cardiac disorders, were similar in the amiselimod treatment groups (59 [56%] of 105 patients in the 0·1 mg group, 69 [67%] of 103 in the 0·2 mg group, and 58 [56%] of 104 in the 0·4 mg group) to the incidence in the placebo group (66 [64%] of 103 patients); the most common treatment-emergent adverse events were headache (ten [10%], ten [10%], and ten [10%] vs four [4%]) and nasopharyngitis (nine [9%], seven [7%], ten [10%] vs eight [8%]). No serious treatment-emergent adverse event was reported for more than one patient in any group and no clinically significant heart rate reduction was observed at any amiselimod dose.

Interpretation: Amiselimod 0·2 mg and 0·4 mg significantly reduced the total number of gadolinium-enhanced T1-weighted lesions. The safety and efficacy profiles of amiselimod suggest that this S1P1 receptor modulator is a new potential treatment in multiple sclerosis and potentially other immune-mediated inflammatory diseases and deserves further investigation.

Funding: Mitsubishi Tanabe Pharma Corporation.
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http://dx.doi.org/10.1016/S1474-4422(16)30192-2DOI Listing
October 2016

Subcutaneous immunoglobulins in the treatment of chronic immune-mediated neuropathies.

Ther Adv Neurol Disord 2016 Jul 6;9(4):336-43. Epub 2016 Apr 6.

Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.

Intravenous immunoglobulins represent an established therapy for the treatment of chronic immune-mediated neuropathies, specifically chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) as well as multifocal motor neuropathies (MMNs). For the treatment of antibody deficiency syndromes, subcutaneous immunoglobulins (SCIgs) have represented a mainstay for decades. An emerging body of evidence suggests that SCIg might also exhibit clinical efficacy in CIDP and MMN. This article reviews the current evidence for clinical effectiveness, as well as safety of SCIg for the treatment of immune-mediated neuropathies, and addresses remaining open questions in this context. We conclude that despite the need for controlled long-term studies to demonstrate long-term efficacy of SCIg in immune-mediated neuropathies, SCIg may already represent a potential therapeutic alternative for selected patients.
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http://dx.doi.org/10.1177/1756285616641583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916522PMC
July 2016

Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial.

Ther Adv Neurol Disord 2016 Jul 10;9(4):239-49. Epub 2016 Mar 10.

14 Cambridge Center, Building 6A, Floor 6, Office K01, Cambridge, MA 02142, USA.

Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity.

Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS.

Methods: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated.

Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies.

Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.
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http://dx.doi.org/10.1177/1756285616633967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916515PMC
July 2016

Subgroup and sensitivity analyses of annualized relapse rate over 2 years in the ADVANCE trial of peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis.

J Neurol 2016 Sep 17;263(9):1778-87. Epub 2016 Jun 17.

Biogen, Cambridge, MA, USA.

ADVANCE was a 2-year, double-blind, placebo-controlled, Phase 3 study in 1512 patients aged 18-65 years with relapsing-remitting multiple sclerosis, which demonstrated that peginterferon beta-1a 125 mcg administered subcutaneously every 2 or 4 weeks led to significant reductions in annualized relapse rate (ARR) compared with placebo. This analysis examined ARR over 2 years in ADVANCE across subgroups. Patients were treated with peginterferon beta-1a every 2 weeks or every 4 weeks, or placebo during Year 1. Thereafter, patients on placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks (delayed treatment). Subgroup analyses were conducted by demographics and baseline disease characteristics. The following results compared ARR in these subgroups for patients in continuous 2-week treatment versus continuous 4-week treatment. ARR was similar in most demographic and baseline disease characteristic subgroups evaluated within the peginterferon beta-1a every-2-week arm or every-4-week arm over 2 years. Although for both doses some differences in the point estimates for ARR were noted among the subgroups, considerable overlap in the confidence intervals suggested that the efficacy of peginterferon beta-1a is similar in all patients irrespective of gender, age, body weight, geographical region, and disease activity at initiation of treatment. Within each peginterferon beta-1a dosing group, ARR was generally similar across most subgroups.
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http://dx.doi.org/10.1007/s00415-016-8182-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5010838PMC
September 2016

Fingolimod promotes peripheral nerve regeneration via modulation of lysophospholipid signaling.

J Neuroinflammation 2016 06 10;13(1):143. Epub 2016 Jun 10.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Background: The lysophospholipids sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are pleiotropic signaling molecules with a broad range of physiological functions. Targeting the S1P1 receptor on lymphocytes with the immunomodulatory drug fingolimod has proven effective in the treatment of multiple sclerosis. An emerging body of experimental evidence points to additional direct effects on cells of the central and peripheral nervous system. Furthermore, fingolimod has been reported to reduce LPA synthesis via inhibition of the lysophospholipase autotaxin. Here we investigated whether modulation of particular signaling aspects of S1P as well as LPA by fingolimod might propagate peripheral nerve regeneration in vivo and independent of its anti-inflammatory potency.

Methods: Sciatic nerve crush was performed in wildtype C57BL/6, in immunodeficient Rag1 (-/-) and Foxn1 (-/-) mice. Analyses were based on walking track analysis and electrophysiology, histology, and cAMP formation. Quantification of different LPA species was performed by liquid chromatography coupled to tandem mass spectrometry. Furthermore, functional consequences of autotaxin inhibition by the specific inhibitor PF-8380 and the impact of fingolimod on early cytokine release in the injured sciatic nerve were investigated.

Results: Clinical and electrophysiological measures indicated an improvement of nerve regeneration under fingolimod treatment that is partly independent of its anti-inflammatory properties. Fingolimod treatment correlated with a significant elevation of axonal cAMP, a crucial factor for axonal outgrowth. Additionally, fingolimod significantly reduced LPA levels in the injured nerve. PF-8380 treatment correlated with improved myelin thickness. Sciatic nerve cytokine levels were not found to be significantly altered by fingolimod treatment.

Conclusions: Our findings provide in vivo evidence for direct effects of fingolimod on cells of the peripheral nervous system that may propagate nerve regeneration via a dual mode of action, differentially affecting axonal outgrowth and myelination by modulating relevant aspects of S1P and LPA signaling.
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http://dx.doi.org/10.1186/s12974-016-0612-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901498PMC
June 2016