Prognostic factors for worsening and improvement in multiple sclerosis using a multistate model.

BACKGROUND: The long-term disease trajectory of people living with multiple sclerosis (MS) can be improved by initiating efficacious treatment early. More quantitative evidence is needed on factors that affect a patient's risk of disability worsening or possibility of improvement to inform timely treatment decisions. METHODS: We developed a multistate model to quantify the influence of demographic, clinical, and imaging factors on disability worsening and disability improvement simultaneously across the disability spectrum as measured by the Expanded Disability Status Scale (EDSS). We used clinical trial data from the Novartis-Oxford MS database including ~130,000 EDSS assessments from ~8000 patients, spanning all MS phenotypes. RESULTS: Higher brain volume was positively associated with disability improvement at all disability levels (hazard ratio (HR) = 1.09-1.19; 95% credible interval (CI) = 1.02-1.27). Higher T2 lesion volume was negatively associated with disability improvement up to EDSS 6 (HR = 0.80-0.89; 95% CI = 0.75-0.94). Older age, time since first symptoms, and the number of relapses in the past year were confirmed as predictors of future disability worsening. CONCLUSIONS: Brain damage was identified as the most consistent factor limiting the patient's probability for improvements from the earliest stages and across the whole course of MS. Protecting brain integrity early in MS should have greater weight in clinical decision-making.

Fatigue, depression, and product tolerability during long-term treatment with intravenous immunoglobulin (Gamunex® 10%) in patients with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterized by progressive weakness and sensory loss, often affecting patient's ability to walk and perform activities of daily living independently. Furthermore, patients often report fatigue and depression which can affect their quality of life. These symptoms were assessed in CIDP patients receiving long-term intravenous immunoglobulin (IVIG) treatment. METHODS: GAMEDIS was a multi-center, prospective, non-interventional study in adult CIDP patients treated with IVIG (10%) and followed for two years. Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, Hughes Disability Scale (HDS), Fatigue Severity Scale (FSS), Beck Depression Inventory II (BDI), Short Form-36 health survey (SF-36) and Work Productivity and Activity Impairment Score Attributable to General Health (WPAI-GH) were assessed at baseline and quarterly. Dosing and treatment intervals, changes in outcome parameters, and adverse events (AEs) were analyzed. RESULTS: 148 evaluable patients were followed for a mean of 83.3 weeks. The mean maintenance IVIG dose was 0.9 g/kg/cycle (mean cycle interval 38 days). Disability and fatigue remained stable throughout the study. Mean INCAT score: 2.4 ± 1.8 at baseline and 2.5 ± 1.9 at study end. HDS: 74.3% healthy/minor symptoms at baseline and 71.6% at study end. Mean FSS: 4.2 ± 1.6 at baseline and 4.1 ± 1.7 at study end. All patients reported minimal/no depression at baseline and throughout. SF-36 and WPAI-GH scores remained stable. Fifteen patients (9.5%) experienced potentially treatment-related AEs. There were no AEs in 99.3% of infusions. DISCUSSION: Long-term treatment of CIDP patients with IVIG 10% in real-world conditions maintained clinical stability on fatigue and depression over 96 weeks. This treatment was well-tolerated and safe.

How patients with multiple sclerosis acquire disability.

Patients with multiple sclerosis acquire disability either through relapse-associated worsening (RAW) or progression independent of relapse activity (PIRA). This study addresses the relative contribution of relapses to disability worsening over the course of the disease, how early progression begins and the extent to which multiple sclerosis therapies delay disability accumulation. Using the Novartis-Oxford multiple sclerosis (NO.MS) data pool spanning all multiple sclerosis phenotypes and paediatric multiple sclerosis, we evaluated ∼200 000 Expanded Disability Status Scale (EDSS) transitions from >27 000 patients with ≤15 years follow-up. We analysed three datasets: (i) A full analysis dataset containing all observational and randomized controlled clinical trials in which disability and relapses were assessed (n = 27 328); (ii) all phase 3 clinical trials (n = 8346); and (iii) all placebo-controlled phase 3 clinical trials (n = 4970). We determined the relative importance of RAW and PIRA, investigated the role of relapses on all-cause disability worsening using Andersen-Gill models and observed the impact of the mechanism of worsening and disease-modifying therapies on the time to reach milestone disability levels using time continuous Markov models. PIRA started early in the disease process, occurred in all phenotypes and became the principal driver of disability accumulation in the progressive phase of the disease. Relapses significantly increased the hazard of all-cause disability worsening events; following a year in which relapses occurred (versus a year without relapses), the hazard increased by 31-48% (all P < 0.001). Pre-existing disability and older age were the principal risk factors for incomplete relapse recovery. For placebo-treated patients with minimal disability (EDSS 1), it took 8.95 years until increased limitation in walking ability (EDSS 4) and 18.48 years to require walking assistance (EDSS 6). Treating patients with disease-modifying therapies delayed these times significantly by 3.51 years (95% confidence limit: 3.19, 3.96) and 3.09 years (2.60, 3.72), respectively. In patients with relapsing-remitting multiple sclerosis, those who worsened exclusively due to RAW events took a similar length of time to reach milestone EDSS values compared with those with PIRA events; the fastest transitions were observed in patients with PIRA and superimposed relapses. Our data confirm that relapses contribute to the accumulation of disability, primarily early in multiple sclerosis. PIRA begins in relapsing-remitting multiple sclerosis and becomes the dominant driver of disability accumulation as the disease evolves. Pre-existing disability and older age are the principal risk factors for further disability accumulation. The use of disease-modifying therapies delays disability accrual by years, with the potential to gain time being highest in the earliest stages of multiple sclerosis.

Immunomodulatory potential of anti-IFN-beta antibodies on monocyte-derived macrophages.

Introduction: Multiple sclerosis (MS) is a disabling neurological disease with an unknown etiology, where the recombinant interferon beta (rIFNß) is the most established treatment. However, the development of anti-IFNß antibodies has posed a significant therapeutic drawback. In this study, the interaction between anti-IFNß antibodies and macrophages was investigated to assess the effects on the immune system. Methodology: Using magnetic beads, anti-IFNß antibodies were extracted from MS patients' sera positive for anti-IFNß antibodies. A negative control (antibody-negative situation) and a baseline control were obtained in parallel. Bead or extracted beadantibody complexes were then incubated vitro with monocyte-derived human macrophages. After incubation, macrophage cultures were tested for 91 immunologically relevant gene expressions by RT-PCR. Results and Discussions: A Gene expression difference between antibody positive and negative situations was hypothesized to reflect the direct effects between antibodies and macrophages. Thus, 37-39 genes were either up-regulated or downregulated due to this direct interaction. Of these, only 2-4 genes were up-regulated, and the rest were down-regulated. These observations suggest that anti-IFNß antibodies have an overall suppressive effect on immunologically relevant gene activity when antibodies interact with macrophages. Conclusion: The fate and effects of circulating anti-IFNß antibodies are mainly unknown. With the observations obtained at in vitro level, such effects, especially from an immunological point of view, are suppressive on immunocompetent cells such as macrophages. However, in vivo verification is necessary.

Effect of ofatumumab versus placebo in relapsing multiple sclerosis patients from Japan and Russia: Phase 2 APOLITOS study.

BACKGROUND: Ofatumumab, the first fully human anti-CD20 monoclonal antibody, has been developed as a treatment for relapsing multiple sclerosis (RMS) which can be self-administered at home. OBJECTIVE: To investigate the efficacy and safety of ofatumumab in RMS patients from Japan and Russia. METHODS: APOLITOS included a 24-week, double-blind, placebo-controlled core-part followed by an open-label extension-part. Patients were randomized (2:1) to subcutaneous ofatumumab 20 mg or placebo. Primary outcome was the number of gadolinium-enhancing (Gd+) T1 lesions per scan over 24 weeks. RESULTS: Sixty-four patients were randomized (ofatumumab, n = 43; placebo, n = 21). Primary endpoint was met; ofatumumab reduced Gd + T1 lesions versus placebo by 93.6% (p < 0.001) and the results were consistent across regions (Japan/Russia). Ofatumumab reduced annualized T2 lesion and relapse rate versus placebo by week 24. Both groups showed benefit from ofatumumab in the extension-part. Incidence of adverse events was lower with ofatumumab versus placebo (69.8% vs 81.0%); injection-related reactions were most common. No deaths, opportunistic infections, or malignancies were reported. CONCLUSION: Ofatumumab demonstrated superior efficacy versus placebo, with sustained effect through 48 weeks in RMS patients from Japan/Russia. Switching to ofatumumab after 24 weeks led to rapid radiological and clinical benefits. Safety findings were consistent with pivotal trials.

Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years.

BACKGROUND: Ofatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile. OBJECTIVE: Report the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years. METHODS: Patients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide. RESULTS: The safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections. CONCLUSION: In patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II.

BACKGROUND: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. OBJECTIVES: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. METHODS: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. RESULTS: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. CONCLUSION: The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).

Corneal confocal microscopy differentiates inflammatory from diabetic neuropathy.

BACKGROUND: Immune-mediated neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) are treatable neuropathies. Among individuals with diabetic neuropathy, it remains a challenge to identify those individuals who develop CIDP. Corneal confocal microscopy (CCM) has been shown to detect corneal nerve fiber loss and cellular infiltrates in the sub-basal layer of the cornea. The objective of the study was to determine whether CCM can distinguish diabetic neuropathy from CIDP and whether CCM can detect CIDP in persons with coexisting diabetes. METHODS: In this multicenter, case-control study, participants with CIDP (n = 55) with (n = 10) and without (n = 45) diabetes; participants with diabetes (n = 58) with (n = 28) and without (n = 30) diabetic neuropathy, and healthy controls (n = 58) underwent CCM. Corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and dendritic and non-dendritic cell density, with or without nerve fiber contact were quantified. RESULTS: Dendritic cell density in proximity to corneal nerve fibers was significantly higher in participants with CIDP with and without diabetes compared to participants with diabetic neuropathy and controls. CNFD, CNFL, and CNBD were equally reduced in participants with CIDP, diabetic neuropathy, and CIDP with diabetes. CONCLUSIONS: An increase in dendritic cell density identifies persons with CIDP. CCM may, therefore, be useful to differentiate inflammatory from non-inflammatory diabetic neuropathy.

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

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 (p = 0.02) and magnetic resonance imaging (MRI) (p < 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%; p < 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.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

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

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 p = 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 p = 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.

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

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 C-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.

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

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 (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon ß-1a, and in serum (n = 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 (p < 0.0001, r = -0.46; p < 0.05. r = -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, p < 0.05; OR = 11.0, 95% CI = 2.0-114.6; p < 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; p < 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.

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

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 P255-78 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 P255-78) 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.

The Role of Peripheral Myelin Protein 2 in Remyelination.

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.

Novel pathomechanisms in inflammatory neuropathies.

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.

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.

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.

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.

Pseudomonas aeruginosa and Its Bacterial Components Influence the Cytokine Response in Thymocytes and Splenocytes.

Infections with Pseudomonas aeruginosa may cause many different diseases. The spectrum of such infections in general includes inflammation and bacterial sepsis. Hospital-acquired pneumonia, naturally resistant to a wide range of antibiotics, is associated with a particularly high mortality rate in mechanically ventilated patients. The pathogenesis of P. aeruginosa is complex and mediated by several virulence factors, as well as cell-associated factors. We have previously demonstrated that stimulation with different bacteria triggers the cytokine response of thymocytes. In this study, we investigated the effect of P. aeruginosa and its different components on the cytokine production of immature and mature immune cells. We found that the induced cytokine pattern in the thymus and the spleen after infections with P. aeruginosa is primarily mediated by lipopolysaccharide (LPS) of the outer cell membrane, but other components of the bacterium can influence the cytokine secretion as well. Stimulation with heat-killed P. aeruginosa and LPS does not influence the amount of cytokine-producing CD4(+) T cells but instead suppresses the emergence of Th17 cells. However, stimulation with P. aeruginosa or its components triggers the interleukin-17 (IL-17) response both in thymocytes and in splenocytes. We conclude that infections with P. aeruginosa affect the cytokine secretion of immature and mature cells and that IL-17 and Th17 cells play only a minor role in the development of pathological systemic inflammatory disease conditions during P. aeruginosa infections. Therefore, other inflammatory immune responses must be responsible for septic reactions of the host.

Alteration of the cytokine signature by various TLR ligands in different T cell populations in MOG37-50 and MOG35-55-induced EAE in C57BL/6 mice.

Interleukin 17 (IL-17), produced by T cells, plays an important role in Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). In contrast to IL-17-producing CD4+ T cells, the contribution of IL-17-producing CD8+ T cells (Tc17) in CNS autoimmunity has been investigated less intensively. Here we investigate the role of TC17 in EAE. We compare different T cell populations and their cytokine pattern in the MOG35-55- and MOG37-50-induced EAE. We detected a similar cytokine phenotype for both EAE models in the autoimmune process assessed at different stages. Regarding the migratory activity, an involvement of IL-17 and IFN-γ in disease onset was suggested. Furthermore, we show that PAMPs have the ability to drive autoimmune process. To modify the cytokine pattern of different T cell populations, a combination of distinct factors is required (the activation of MyD88 or Syk, the genetic background, the presence of APCs and CD4+ T cells).