Anti-CD20 antibody therapy and risk of infection in patients with demyelinating diseases.

BACKGROUND: Anti-CD20 antibody therapy may be associated with an increased risk of infections. We therefore investigated risk factors for infection in patients with demyelinating diseases treated with anti-CD20 antibody therapy. METHODS: In this retrospective uncontrolled study, patients ever treated with anti-CD20 antibodies at an academic clinic were identified through the Danish Multiple Sclerosis Registry (DMSR). Data were collected from medical charts and the DMSR. We assessed occurrence of severe infections (requiring hospitalization), varicella zoster virus (VZV), major comorbidities and routine laboratory values for lymphocytes, IgG and IgM. RESULTS: A total of 447 patients ever treated with anti-CD20 antibody therapy were identified; of these 416 with 649 patient years of follow-up were still under therapy. In this group, seven patients had VZV infections, and 16 patients had been hospitalized with infections during up to three years of follow-up on anti-CD20 therapy. Comorbidity was recorded in 80 patients. The risk of severe infection was associated with comorbidities, higher age, longer duration of treatment, and higher Expanded Disability Status Scale (EDSS) scores. In multivariable analyses treatment duration, EDSS scores and presence of comorbidity were independently associated with risk of severe infections. Serum concentrations of IgG and IgM decreased with increasing duration of therapy but were not associated with risk of severe infections. Patients with VZV infection had lower lymphocyte counts and lower serum concentrations of IgM. In multivariable analyses only lymphocyte counts were independently associated with risk of VZV infection. CONCLUSIONS: In this retrospective study of patients treated with anti-CD20 antibodies, the risk of infections requiring hospitalization was independently associated with comorbidities, duration of treatment, and higher EDSS scores. Risk of VZV infection was independently associated with lymphopenia. Future studies investigating strategies for mitigating risk of infection in patients treated with anti-CD20 antibodies are warranted, especially for older patients, patients with higher levels of disability and for patients with a longer duration of treatment.

Expression of melanoma cell adhesion molecule-1 (MCAM-1) in natalizumab-treated multiple sclerosis.

The objectives were to study the expression of very late antigen (VLA)-4, melanoma cell adhesion molecule-1 (MCAM-1) and activated leukocyte cell adhesion molecule (ALCAM) on CD4+ T cells during natalizumab treatment and to investigate the association with disease activity. We find that subgroups of autoreactive T cells are retained in peripheral blood, in particular MOG-reactive CD4+ T cells expressing MCAM-1. The expression of MCAM-1 or ALCAM on CD4+ T cells was, however, not clearly associated with disease activity (clinical or MRI) during natalizumab treatment. We confirm upregulation of MCAM-1 on CD4+ T cells during natalizumab treatment while VLA-4 is downregulated.

Illegal cannabis use is common among Danes with multiple sclerosis.

BACKGROUND: Use of cannabis to alleviate multiple sclerosis (MS)-related symptoms is increasing. Due to strict regulations, only a minority of MS patients receive cannabis-based prescription drugs. The extent of recreational and medical cannabis use among Danes with MS is unknown. Our aim was to evaluate the prevalence of illegal and legal use of cannabis in MS patients, as well as reasons for use and perceived adverse effects. METHODS: An anonymous questionnaire was sent to all 3606 patients at the Danish Multiple Sclerosis Center, Rigshospitalet, University of Copenhagen. The questionnaire included questions about sociodemographic factors, clinical characteristics and medical or recreational cannabis use. RESULTS: Questionnaires were completed by 2244/3606 (62%), of which 2009 questionnaires from patients with MS or clinical isolated syndrome (CIS) were valid for analysis. Forty-nine percent (980/2009) had used cannabis at least once. Cannabis was used within the past year (current user) by 21%, and only 21% of those received prescribed cannabis-based medicine. Recreational use was reported by 17%. The primary reasons for use were to alleviate pain (61%), spasticity (52%) and sleep disturbances (46%). The most common adverse effects were drowsiness (30%), feeling quiet/subdued (23%) and dizziness (13%). Almost half (44%) of the non-cannabis users would consider use of cannabis to alleviate MS symptoms if the drug was legalized. CONCLUSION: This study shows that illegal cannabis use is common among Danes with MS as only 21% of the current cannabis users received prescribed cannabis-based medicine. Current cannabis users reported high efficacy in relieving pain, spasticity and sleep disturbances. In addition, only mild to moderate severity of adverse effects were reported. To the best of our knowledge, this is the most comprehensive survey of cannabis use among MS patients.

Bone microarchitecture and bone mineral density in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients are at increased risk of reduced bone mineral density (BMD) and fractures. The aetiology of bone loss in MS is unclear. Trabecular bone score (TBS) is a novel analytical tool that provides a measurement of the bone microarchitecture. Decreased TBS predicts increased fracture risk independently of BMD. To date, no studies have investigated TBS in MS patients. OBJECTIVES: To assess bone quality in MS patients by TBS and to evaluate potential risk factors that may affect BMD and TBS in patients with MS. METHODS: Two hundred sixty MS patients were included. TBS was calculated using TBS iNsight software (MediMaps® ). Multivariable regression analyses were performed with information on smoking, alcohol, glucocorticoid (GC) treatment, sun exposure, physical activity, vitamin D and BMI. RESULTS: Trabecular bone score was not significantly different from an age-matched reference population. Low TBS was associated with high age (P = .014) and smoking (P = .03). Smoking and physical inactivity were associated with low BMD in spine (P = .034, P = .032). GC treatment was not associated with TBS. CONCLUSION: We could not find altered TBS values among MS patients, suggesting that BMD alone, and not the bone microarchitecture, is affected in MS. However, larger studies are needed to verify these findings and to establish the role of TBS in MS. As in the background population, physical activity and non-smoking habits are associated with better bone health in MS.

CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases.

Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.

Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development.

BACKGROUND: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy. OBJECTIVES: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. METHODS: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2. RESULTS: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples. CONCLUSIONS: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.

Dendritic cell, monocyte and T cell activation and response to glatiramer acetate in multiple sclerosis.

BACKGROUND: Treatment with glatiramer acetate (GA) modestly decreases disease activity in multiple sclerosis (MS). The mechanism of action is incompletely understood and differences in the response to treatment between individuals may exist. OBJECTIVE: To study the activation of CD4+ T cells, monocytes and dendritic cells (DC) in relation to disease activity in MS patients treated with GA. METHODS: Flow cytometry was used to study the activation of CD4+ T cells and T cell subsets (CD25(high) and CD26(high) cells), monocytes and DCs in a cross-sectional study of 39 untreated and 29 GA-treated MS patients, the latter followed prospectively for one year. Gd-enhanced magnetic resonance imaging (MRI) studies were conducted in all patients. Disease activity was assessed as relapses. RESULTS: The median percentage of DCs expressing CD40 was 10% in untreated MS patients and 5.9% in GA-treated patients (Bonferroni-corrected p=0.0005). The hazard ratio of relapse was 1.32 (95% confidence interval 1.05-1.64) per 1% increase in CD40+ DCs. Patients treated with GA had fewer CD4+ T cells expressing surface markers associated with T helper type 1 effector responses and more CD4+ T cells expressing surface markers associated with regulatory, naïve or central memory T cell populations, but CD4+ T cell activation was not related with relapse risk. CONCLUSIONS: MS patients treated with GA show prominent changes in circulating antigen-presenting cells and CD4+ T cells. Expression of CD40 on DCs is significantly lower and associated with relapse risk in MS patients treated with GA.

FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis.

Expression of the forkhead box protein 3 (FoxP3) transcription factor is regulated by the E3 ubiquitin ligases Itch and Cbl-b and induces regulatory activity CD4(+) CD25(high) T cells. Treatment with interferon (IFN)-ß enhances regulatory T cell activity in multiple sclerosis (MS). We studied the phenotype of CD4(+) CD25(high) T cells in MS by flow cytometry and its relationship with expression of the FOXP3, ITCH and CBLB genes. We found that untreated MS patients had lower cell surface expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) on CD4(+) CD25(high) T cells and higher intracellular CTLA-4 expression than healthy controls. Cell surface expression of CTLA-4 on CD4(+) CD25(high) T cells correlated with expression of FOXP3 mRNA in untreated patients and increased significantly with time from most recent injection in patients treated with IFN-ß. FOXP3 mRNA expression correlated with CBLB and ITCH and T helper type 2 cytokine mRNA expression in MS patients. These data link expression of FOXP3, CBLB and ITCH mRNA and CTLA-4 expression on the surface of CD4(+) CD25(high) T cell in MS. We hypothesize that this may reflect alterations in the inhibitory effect of CTLA-4 or in regulatory T cell function.

Progression and CSF Inflammation after Eradication of Oligoclonal Bands in an MS Patient Treated with Allogeneic Hematopoietic Cell Transplantation for Follicular Lymphoma.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases. AIMS: To describe the effects of allo-HCT on the course of MS in a 49-year-old woman with longstanding progressive MS who was treated with allo-HCT for follicular lymphoma. METHODS: Non-myeloablative conditioning allo-HCT, examination for IgG oligoclonal bands and measurement of CXCL13 and matrix metalloproteinase-9 (MMP-9) concentration in the cerebrospinal fluid (CSF). RESULTS: Despite the disappearance of oligoclonal bands in CSF, disease progression and CSF inflammation was observed. CONCLUSIONS: We hypothesize that CXCL13 and MMP-9 detected in CSF may reflect ongoing, pathogenic immune activation even after the eradication of intrathecal IgG synthesis. This suggests that progressive MS may depend more on innate than on adaptive immune activation.

Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis.

BACKGROUND: Glatiramer acetate (GA) treatment suppresses disease activity in multiple sclerosis (MS). The immunological response to treatment may differ in patients who are stable on GA therapy and patients with breakthrough disease activity, but the results of previous studies are inconsistent. OBJECTIVES: We studied the immunological response to GA and its relationship with disease activity. METHODS: Anti-GA antibodies in plasma and the expression of genes encoding cytokines and T-cell-polarizing transcription factors in blood cells were analysed by flow cytometric bead array and polymerase chain reaction (PCR) analysis in 39 untreated and 29 GA-treated relapsing-remitting MS patients. Definition of breakthrough disease was based on the occurrence of relapses, disability progression, or gadolinium (Gd)-enhanced MRI. RESULTS: The expression of T helper type 1 (Th1) and Th17 cytokines and transcription factors was reduced during long-term treatment, but there was no relationship between the expression of cytokines and transcription factors and anti-GA antibodies. High expression of mRNA encoding GATA3 and lymphotoxin-ß (LT-ß) was associated with low disease activity in Gd-enhanced MRI studies. None of the variables studied were associated with clinical disease activity. GA treatment resulted in the development of IgG and IgG4 anti-GA antibodies during the first months of treatment, persisting during long-term treatment. CONCLUSIONS: The observed relationship between the expression of mRNA encoding GATA3 and LT-ß expression and MRI disease activity deserves further analysis in future studies. The development of anti-GA antibodies was observed in all patients treated with GA, but this was not related with measures of cellular immunity, clinical or MRI disease activity.

RGMA and IL21R show association with experimental inflammation and multiple sclerosis.

Rat chromosome 1 harbors overlapping quantitative trait loci (QTL) for cytokine production and experimental models of inflammatory diseases. We fine-dissected this region that regulated cytokine production, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), anti-MOG antibodies and pristane-induced arthritis (PIA) in advanced intercross lines (AILs). Analysis in the tenth and twelfth generation of AILs resolved the region in two narrow QTL, Eae30 and Eae31. Eae30 showed linkage to MOG-EAE, anti-MOG antibodies and levels of interleukin-6 (IL-6). Eae31 showed linkage to EAE, PIA, anti-MOG antibodies and levels of tumor necrosis factor (TNF) and IL-6. Confidence intervals defined a limited set of potential candidate genes, with the most interesting being RGMA, IL21R and IL4R. We tested the association with multiple sclerosis (MS) in a Nordic case-control material. A single nucleotide polymorphism in RGMA associated with MS in males (odds ratio (OR)=1.33). Polymorphisms of RGMA also correlated with changes in the expression of interferon-gamma (IFN-gamma) and TNF in cerebrospinal fluid of MS patients. In IL21R, there was one positively associated (OR=1.14) and two protective (OR=0.87 and 0.68) haplotypes. One of the protective haplotypes correlated to lower IFN-gamma expression in peripheral blood mononuclear cells of MS patients. We conclude that RGMA and IL21R and their pathways are crucial in MS pathogenesis and warrant further studies as potential biomarkers and therapeutic targets.

Increased cerebrospinal fluid concentrations of the chemokine CXCL13 in active MS.

BACKGROUND: Accumulating evidence supports a major role of B cells in multiple sclerosis (MS) pathogenesis. How B cells are recruited to the CNS is incompletely understood. Our objective was to study B-cell chemokine concentrations in MS, their relationship with disease activity, and how treatment with methylprednisolone and natalizumab affected the concentration in CSF. METHODS: Using a cross-sectional design, CSF and blood samples were obtained from cohorts of patients with clinically isolated syndromes (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), or secondary progressive MS (SPMS), and noninflammatory neurologic disease control subjects. Some patients with RRMS were studied before and after treatment with methylprednisolone or natalizumab. RESULTS: In CSF, concentrations of CXCL13, but not CXCL12, were higher in patients with CIS, RRMS, SPMS, and PPMS than in controls. CSF concentrations of CXCL13 correlated with the CSF B-cell count, with markers of immune activation, and with disease activity in patients with CIS and RRMS. CSF concentrations of CXCL13 decreased after treatment with high-dose methylprednisolone and natalizumab. High CSF concentrations of CXCL13 correlated with low expression of messenger RNA encoding the immunoregulatory cytokines interleukin 10 and transforming growth factor beta1, but not with the expression of T-helper type 1 (Th1) and Th17 factors. CONCLUSION: The chemokine CXCL13 may play a major role in recruitment of B cells and T-cell subsets expressing the chemokine receptor CXCR5 to the CNS in multiple sclerosis (MS), and may be a useful biomarker for treatment effects in MS. Furthermore, CXCL13 or its receptor CXCR5 should be considered as therapeutic targets in MS.

EFNS guidelines on disease-specific CSF investigations.

We reviewed the literature for disease-specific markers in cerebrospinal fluid (CSF) and evaluated their diagnostic and prognostic relevance in neurological diseases. High tau protein in combination with low amyloid beta levels has a high sensitivity (80%) and specificity (90%) for Alzheimer's disease (AD) against normal aging and can predict conversion of mild cognitive impairment to AD. The detection of 14-3-3 has a high sensitivity (80-90%) and specificity (90%) for the diagnosis of CJD. Low or undetectable CSF hypocretin-1 (orexin-1) levels constitute a diagnostic biomarker for narcolepsy with cataplexy. Detection of beta-2-transferrin indicates CSF contamination in oto- and rhinorrhoe with a sensitivity of > 79% at a specificity of 95% similar to the beta-trace protein (sensitivity > 90%, specificity 100%). However, beta-trace protein is faster and cheaper to perform. Possible future biomarkers are: elevated levels of vascular endothelial growth factor are relatively sensitive (51-100%) and specific (73-100%) for leptomeningeal metastases from solid tumors and are associated with a poor prognosis in this condition. Elevated CSF neurofilament (Nf) levels probably reflect acute neuronal degeneration. The prognostic value of CSF Nf levels is highest in acute conditions such as subarachnoid hemorrhage, acute optic neuritis and neuromyelitis optica.

The effects of natalizumab on inflammatory mediators in multiple sclerosis: prospects for treatment-sensitive biomarkers.

BACKGROUND: Natalizumab affects systemic cytokine expressions and clinical course in relapsing-remitting multiple sclerosis (RRMS). We analyzed levels of inflammatory cytokines in cerebrospinal fluid (CSF) cells and peripheral blood mononuclear cells (PBMCs), levels of matrix metalloproteinase (MMP)-9 and osteopontin (OPN) in CSF, and clinical outcome measures in 22 natalizumab-treated RRMS patients. METHODS: mRNA levels of cytokines in cells were detected with real-time RT-PCR. Protein levels of OPN and MMP-9 were measured by ELISA. RESULTS: Natalizumab reduced CSF cell counts (P < 0.0001). Tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) mRNAs were significantly increased in PBMCs. In contrast, expressions of IFN-gamma and interleukin (IL)-23 were decreased but IL-10 increased in the CSF cells. OPN and MMP-9 were reduced in the CSF. Patients being in remission at baseline showed the same deviations of mediators as those in relapse after natalizumab treatment. The open label clinical outcome measures were either stable or improved during therapy. CONCLUSIONS: Natalizumab attenuates pro-inflammatory mediators intrathecally and the reduced pro-inflammatory milieu may allow increased production of the anti-inflammatory mediator IL-10. The increased systemic cytokines may impede the improvement of certain clinical measures like fatigue. The affected mediators seem to be sensitive to an immune-modifying treatment which could be used as biomarkers for this therapy.

CD4(+) memory T cells with high CD26 surface expression are enriched for Th1 markers and correlate with clinical severity of multiple sclerosis.

An aberrant immune activation is believed to be important in the pathogenesis of multiple sclerosis (MS). Expression of CD4(+) T lymphocyte surface molecules indicative of immune activation and effector functions has been correlated with disease severity and activity. CD4(+) CD45R0(+) CD26(high) memory T lymphocytes contained the high levels of markers of Th1, activation, and effector functions and cell counts of this subset correlated with MS disease severity. This subset had lower expression of PD-1, CCR4, and L-selectin in MS than in controls. These changes were only partially normalised by treatment with interferon-beta. We point to this subset as a putative target for immunological monitoring of MS disease activity and of treatment efficacy.

Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force.

A great variety of neurological diseases require investigation of cerebrospinal fluid (CSF) to prove the diagnosis or to rule out relevant differential diagnoses. The objectives were to evaluate the theoretical background and provide guidelines for clinical use in routine CSF analysis including total protein, albumin, immunoglobulins, glucose, lactate, cell count, cytological staining, and investigation of infectious CSF. The methods included a Systematic Medline search for the above-mentioned variables and review of appropriate publications by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. It is recommended that CSF should be analysed immediately after collection. If storage is needed 12 ml of CSF should be partitioned into three to four sterile tubes. Albumin CSF/serum ratio (Qalb) should be preferred to total protein measurement and normal upper limits should be related to patients' age. Elevated Qalb is a non-specific finding but occurs mainly in bacterial, cryptococcal, and tuberculous meningitis, leptomingeal metastases as well as acute and chronic demyelinating polyneuropathies. Pathological decrease of the CSF/serum glucose ratio or increased lactate concentration indicates bacterial or fungal meningitis or leptomeningeal metastases. Intrathecal immunoglobulin G synthesis is best demonstrated by isoelectric focusing followed by specific staining. Cellular morphology (cytological staining) should be evaluated whenever pleocytosis is found or leptomeningeal metastases or pathological bleeding is suspected. Computed tomography-negative intrathecal bleeding should be investigated by bilirubin detection.

CD8+ T cell activation correlates with disease activity in clinically isolated syndromes and is regulated by interferon-beta treatment.

An increased percentage of blood CD8+ T cells from patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) was found to express CD26 and CD69. The percentage of CD26 or CD69 positive CD8+ T cells was higher in patients with MRI evidence of disease dissemination in space or with active MRI lesions than in the remaining patients. Treatment of MS with interferon (IFN)-beta resulted in a decrease in the percentage of CD26 and CD71 positive CD8+ T cells and an increase in the percentage of CD8+ T cells that expressed interleukin (IL)-10 and IL-13. CD8+ T cell activation in MS may be linked to disease activity already at disease onset, and is regulated by treatment with IFN-beta.

CD26 + CD4 + T cell counts and attack risk in interferon-treated multiple sclerosis.

Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta.

CD4 T cell activation and disease activity at onset of multiple sclerosis.

We studied CD4 T cell activation in patients with clinically isolated syndromes (CIS) suggesting an initial attack of multiple sclerosis. The percentage of blood CD26+ CD4 T cells was increased in these patients, and correlated with magnetic resonance imaging disease activity and clinical disease severity. In contrast, the percentage of CD25+ CD4 T cells in cerebrospinal fluid correlated negatively with the cerebrospinal fluid concentration of myelin basic protein and the presence of IgG oligoclonal bands. These results suggest that distinct systemic and intrathecal T cell activation states correlate with disease activity and risk of subsequently developing MS in CIS patients.