The Urine Proteome Profile Is Different in Neuromyelitis Optica Compared to Multiple Sclerosis: A Clinical Proteome Study.

Inflammatory demyelinating diseases of the CNS comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS). Despite clear classification criteria, differentiation can be difficult. We hypothesized that the urine proteome may differentiate NMO from MS.The proteins in urine samples from anti-aquaporin 4 (AQP4) seropositive NMO/NMO-SD patients (n = 32), patients with MS (n = 46) and healthy subjects (HS, n = 31) were examined by quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) after trypsin digestion and iTRAQ labelling. Immunoglobulins (Ig) in the urine were validated by nephelometry in an independent cohort (n = 9-10 pr. groups).The analysis identified a total of 1112 different proteins of which 333 were shared by all 109 subjects. Cluster analysis revealed differences in the urine proteome of NMO/NMO-SD compared to HS and MS. Principal component analysis also suggested that the NMO/NMO-SD proteome profile was useful for classification. Multivariate regression analysis revealed a 3-protein profile for the NMO/NMO-SD versus HS discrimination, a 6-protein profile for NMO/NMO-SD versus MS discrimination and an 11-protein profile for MS versus HS discrimination. All protein panels yielded highly significant ROC curves (AUC in all cases >0.85, p≤0.0002). Nephelometry confirmed the presence of increased Ig-light chains in the urine of patients with NMO/NMO-SD.The urine proteome profile of patients with NMO/NMO-SD is different from MS and HS. This may reflect differences in the pathogenesis of NMO/NMO-SD versus MS and suggests that urine may be a potential source of biomarkers differentiating NMO/NMO-SD from MS

Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus : A preliminary study

Background: Neuromyelitis optica (NMO)-systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. Objective: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. Methods: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. Results: AQP4-IgG1 was present 1-2-5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (

Switching to natalizumab or fingolimod in multiple sclerosis: Comparative effectiveness and effect of pre-switch disease activity

© 2022Background: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, “BRACETD”) often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. Methods: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. Results: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59–0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60–0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03–1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. Conclusions: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod

Cluster analysis of detected proteins in the urine comparing patients with NMO/NMO-SD, MS and healthy subjects.

<p>(A) Out of the 1112 proteins detected in the urine, 333 proteins were found in all samples. (B) PCA of all 333 proteins differentiated NMO/NMO-SD from HS samples. (C) MS samples could not be differentiated from HS by PCA. (D) NMO/NMO-SD samples could not be differentiated from MS samples by PCA. (E) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled differentiation of the NMO/NMO-SD samples from HS. (F) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled separation of the MS samples from HS. (G) PCA of proteins, which were differentially expressed (<i>p</i><0.05) compared to HS and present in at least 80% of the samples enabled separation of the NMO/NMO-SD samples from MS. <i>PCA</i>, <i>principal component analysis; NMO/NMO-SD</i>, <i>neuromyelitis optica/neuromyelitis optica spectrum disorder; MS</i>, <i>multiple sclerosis; HS</i>, <i>healthy subjects</i>.</p

False Discovery Rate Adjustment identifies 4 proteins significant for NMO/NMO-SD and MS discrimination in the urine.

<p>A) Heat maps comparing NMO/NMO-SD and MS samples by false discovery rate adjustment with <i>q</i>-values less than 0.05 are shown. The analysis identified 4 proteins that discriminated NMO/NMO-SD from MS. (B) Only the protein Ig-G3 chain were found to be upregulated in NMO/NMO-SD compared to MS. <i>Magenta</i>, <i>upregulated compared to HS; Green</i>, <i>downregulated compared to HS; NMO/NMO-SD</i>, <i>neuromyelitis optica/neuromyelitis optica spectrum disorder; MS</i>, <i>multiple sclerosis; HS</i>, <i>healthy subjects; Ig-G3</i>, <i>immunoglobulin 3 chain; ICAM–2</i>, <i>Intercellular adhesion molecule</i>.</p

Risk scores by logistic regression.

<p>Risk scores and ROC curves for the discriminating profiles are shown. (A) A 3- protein profile based on the 333 proteins detected in all 109 was the optimal model (ROC AUC = 0.93, <i>p</i><0.0001) for NMO/NMO-SD versus HS discrimination. (B) An 11-protein profile based on either proteins present in at least 80% of the samples in each group (520 proteins), or proteins present in at least 2 samples in each group (1021 proteins) was optimal for MS versus HS. (C) For NMO/NMO-SD versus MS discrimination, the best model was a 4-protein profile based on proteins present in at least 80% of the samples in each group (520 proteins).</p

Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD