Multimarker risk stratification approach at multiple sclerosis onset.

Delay in the diagnosis of multiple sclerosis (MS) stems from the lack of specific clinical and analytical markers to assist in the early diagnosis and prediction of progressive course. We propose a decision-tree model that better defines early at onset MS patients and those with the progressive form by analysing a 12-biomarkers panel in serum and CSF samples of patients with MS, other neurological diseases (OND) and healthy contols. Thus, patients at onset of neurological disease were first classified by serum IL-7 levels <141pg/ml (OR=6.51, p<0.001). Combination of IL-7 and CXCL10 indicated risk for a specific MS clinical form, where IL-7<141 and CXCL10<570pg/ml were associated with the highest risk for PP-MS (OR=22, p=0.01). Unexpectedly, both PP-MS and RR-MS patients shared significantly decreased prototypical biomarkers of inflammation and tissue regeneration in CSF than OND suggesting a defective intrinsic immune response playing a role at the beginning of the disease.

Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. METHODS: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. RESULTS: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2). INTERPRETATION: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.

Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.

Chitinase 3-like 1 (CHI3L1) has been proposed as a biomarker associated with the conversion to clinically definite multiple sclerosis in patients with clinically isolated syndromes, based on the finding of increased cerebrospinal fluid CHI3L1 levels in clinically isolated syndrome patients who later converted to multiple sclerosis compared to those who remained as clinically isolated syndrome. Here, we aimed to validate CHI3L1 as a prognostic biomarker in a large cohort of patients with clinically isolated syndrome. This is a longitudinal cohort study of clinically isolated syndrome patients with clinical, magnetic resonance imaging, and cerebrospinal fluid data prospectively acquired. A total of 813 cerebrospinal fluid samples from patients with clinically isolated syndrome were recruited from 15 European multiple sclerosis centres. Cerebrospinal fluid CHI3L1 levels were measured by enzyme-linked immunosorbent assay. Multivariable Cox regression models were used to investigate the association between cerebrospinal fluid CHI3L1 levels and time to conversion to multiple sclerosis and time to reach Expanded Disability Status Scale 3.0. CHI3L1 levels were higher in patients who converted to clinically definite multiple sclerosis compared to patients who continued as clinically isolated syndrome (P = 8.1 × 10(-11)). In the Cox regression analysis, CHI3L1 levels were a risk factor for conversion to multiple sclerosis (hazard ratio = 1.7; P = 1.1 × 10(-5) using Poser criteria; hazard ratio = 1.6; P = 3.7 × 10(-6) for McDonald criteria) independent of other covariates such as brain magnetic resonance imaging abnormalities and presence of cerebrospinal fluid oligoclonal bands, and were the only significant independent risk factor associated with the development of disability (hazard ratio = 3.8; P = 2.5 × 10(-8)). High CHI3L1 levels were associated with shorter time to multiple sclerosis (P = 3.2 × 10(-9) using Poser criteria; P = 5.6 × 10(-11) for McDonald criteria) and more rapid development of disability (P = 1.8 × 10(-10)). These findings validate cerebrospinal fluid CHI3L1 as a biomarker associated with the conversion to multiple sclerosis and development of disability and reinforce the prognostic role of CHI3L1 in patients with clinically isolated syndrome. We propose that determining cerebrospinal fluid chitinase 3-like 1 levels at the time of a clinically isolated syndrome event will help identify those patients with worse disease prognosis.

Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis.

OBJECTIVE: To identify a biomarker distinguishing patients who, despite a primary progressive multiple sclerosis (PPMS) clinical course, may nonetheless benefit from immune therapy. METHODS: The presence or absence of both immunoglobulin (Ig) G and IgM oligoclonal bands (OCB) was blindly examined in paired cerebrospinal fluid (CSF) and serum samples from a large PPMS patient cohort, and related to clinical and imaging evidence of focal inflammatory disease activity. RESULTS: Using both cross-sectional samples and serial sampling in a subgroup of patients followed prospectively as part of the placebo-controlled OLYMPUS study of rituximab in PPMS, we found that the presence of CSF-restricted IgM OCB (but not of IgG OCB) is associated with an active inflammatory disease phenotype in PPMS patients. This finding was confirmed in an independent, multicenter validation cohort. INTERPRETATION: The presence of CSF IgM OCB may be a biomarker for a subset of PPMS patients with more active inflammatory disease, who may benefit from immune-directed treatments.

Low DPP4 expression and activity in multiple sclerosis.

Multiple sclerosis (MS) is a prototypic Th1/Th17 chronic autoimmune disease of the central nervous system. Dipeptidyl peptidase 4 (DPP4 or CD26) is a multifunctional molecule involved in autoimmune diseases' pathophysiology. We sought to integrate disparate pieces of data and analyze the plasma levels of sDPP4, DPP activity and DPP4 surface expression on T-cells in 129 MS patients with different clinical forms and 53 healthy controls, across two independent cohorts. Herein, we provide new evidence that sDPP4 concentration and DPP activity are significantly lower in MS patients than controls (p < 0.0001 and p < 0.01, respectively). In contrast, the frequency of circulating CD8(+)DPP4(hi) T-cells (p = 0.02) was increased in MS patients. This is the first study that simultaneously analyzes DPP4 expression and function in a large cohort of MS patients. Our data indicate a putative role for DPP4 in MS pathophysiology and suggest that a deeper understanding of surface versus shed DPP4 biology is warranted.

A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score » 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Narcolepsy with cataplexy and comorbid immunopathological diseases.

Evidence suggests that autoimmune diseases tend to co-occur so that patients with an autoimmune disorder are at higher risk of a second autoimmune disease. The association between allergic and autoimmune diseases is also of considerable interest. There are no reports on the association between sporadic or familial narcolepsy with cataplexy and other non-neurological immune-mediated diseases. This study reported on the comorbid immunopathological diseases associated with narcolepsy. One-hundred and fifty six narcoleptic patients with a mean age at diagnosis of 39.1 ± 17.8 years (range, 6-70 years) were assessed using the clinical history, physical and neurological examinations, sleep questionnaires, neuroimaging and human leucocyte antigen typing. Diagnosis was confirmed by polysomnography followed by a multiple sleep latency test or by measuring hypocretin-1 levels. Patients with immunopathological diseases were matched for gender and age at the onset of narcoleptic symptoms with narcoleptic patients without immunopathological diseases. Twenty-six patients (16.6%; 50% women; one familial, 25 sporadic) had one or more immunopathological diseases associated: autoimmune diseases, such as idiopathic thrombocytopenic purpura, multiple sclerosis, systemic lupus erythematosus, psoriasis, Crohn's disease, ulcerative colitis, autoimmune thyroid disease, Peyronie's disease and idiopathic recurrent facial palsy; other immunopathological diseases, like atopic dermatitis, allergic asthma and allergic rhinitis. Although not significant, the age at diagnosis of narcolepsy was 9.3 years earlier in patients with narcolepsy + immunopathological diseases. The results demonstrate that the prevalence of comorbid immunopathological diseases is high in narcolepsy, and cataplexy is significantly more severe in patients with narcolepsy + immunopathological diseases.

Perforin expression by CD4+ regulatory T cells increases at multiple sclerosis relapse: sex differences.

Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ T(Reg) in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (T(Reg)) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ T(Reg) in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ T(Reg) playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ T(Reg) in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ T(Reg) in MS, and contributes to the understanding of MS pathophysiology.

Estradiol-dependent perforin expression by human regulatory T-cells.

BACKGROUND: CD4+CD25+FoxP3+ regulatory T-cells (nT(Reg)) have been shown to suppress immune responses to autoantigens and to other diverse antigens, this suppression is mainly mediated by a cell contact-dependent mechanism not yet fully defined. It has been reported that both human natural and induced T(Reg) exert cytotoxic activity against autologous target cells, which suggests that the perforin/granzyme pathway may be a relevant candidate mechanism for the suppressive function of T(Reg). Previous reports have shown that oestradiol (E2) modulates T(Reg) percentages and function. METHODS: We have evaluated in pregnant and non-pregnant subjects perforin intracellular expression in CD4+CD25+FoxP3+ regulatory T-cells by flow cytometry in whole blood, ex-vivo purified nT(Reg) and ex-vivo purified nT(Reg) after TCR and E2 stimulation. The expression of cellular degranulation markers was also phenotypically determined. RESULTS: We show that E2 expands T(Reg), enhances in vitro T(Reg) function and induces a T(Reg) phenotype in activated responder (CD4+CD25) T-cells, further increasing the expression of perforin on T(Reg) than in vitro T-cell receptor activation alone. We found surface lysosomal-associated membrane glycoproteins (LAMP)-1 and LAMP-2 expression by T(Reg), which is a sign of cell degranulation and therefore of cytotoxicity exerted by these cells. CONCLUSION: Our data demonstrates the presence of functional T(Reg) cytotoxic properties in biological systems and support the concept that E2 enhances the number and function of T(Reg) suggesting the potential interaction between E2 and immunoregulatory mechanisms.

IFNbeta-1a therapy for multiple sclerosis expands regulatory CD8+ T cells and decreases memory CD8+ subset: a longitudinal 1-year study.

The beneficial effects of interferon beta-1a (IFNbeta-1a) in multiple sclerosis (MS) remain only partially understood. CD8(+) T cells are key cells in MS pathogenesis that contribute to axonal damage in MS, whereas CD4(+) regulatory T cells (T(Reg)) and CD8(+) regulatory/suppressor T cells (Ts) play an important role in protecting against subsequent MS activity. We analysed ex vivo changes on T(Reg) and on the different subsets of CD4(+) and CD8(+) T lymphocytes, before IFNbeta-1a (Rebif) therapy and at 3, 6, and 12 months after treatment, in 23 MS patients and in 26 healthy controls. IFNbeta-1a significantly increased the proportions of CD4(+) T(Reg) and regulatory CD8(+) T cells (Tr). Memory CD8(+) T cells were significantly decreased after 1 year of treatment, maybe reflecting down-regulation of abnormally persistent systemic activation in MS patients. After 1 year of IFNbeta-1a, a direct correlation was observed between plasmacytoid dendritic cells and effector CD8(+) T cells.

Cytokine profile during pregnancy predicts relapses during pregnancy and postpartum in multiple sclerosis.

OBJECTIVE: To explore the serum cytokine profile associated with disease activity during pregnancy and postpartum in MS, and to assess any potential biomarkers predicting the occurrence of relapses during this period. METHODS: We included 53 MS pregnant women recruited between 2007 and 2018. Interferon-gamma, Tumor necrosis factor-alpha, interleukin-17, granulocyte/macrophage-colony stimulating factor, Activin-A, interleukin-10, and programmed-death-ligand-1 (PD-L1) were measured quarterly in serum by ELISA. RESULTS: Seventeen patients (32%) experienced relapses during pregnancy or puerperium and 37(68%) did not. We did not found differences in clinical characteristics or treatment status between the two groups. However, relapsing patients showed at the first trimester of pregnancy considerably lower levels of serum Activin-A (336.4 pg/dl [289.6-491.7], median [IQR] vs. 760.0 pg/dl [493.2-1108.0],p = .003), which correlated positively with serum PD-L1 (r = 0.53,p = .0005) and IL-10 (r = 0.43,p = .004) values. Activin-A levels lower than 515 pg/ml at the first trimester identified patients with high probability of relapsing during pregnancy and postpartum (OR = 13.75, CI: 2.5-76.8, p = .001). CONCLUSIONS: MS patients with no relapses during pregnancy and puerperium showed an early triggering of a tolerogenic innate immune response evidenced by high serum Activin-A concentrations during the first trimester of pregnancy. Thus, serum Activin-A can be a useful biomarker to predict clinical activity during this period.

Expansion of regulatory CD8+ T-lymphocytes and fall of activated CD8+ T-lymphocytes after i.v. methyl-prednisolone for multiple sclerosis relapse.

INTRODUCTION: Multiple sclerosis (MS) is a multifocal chronic inflammatory demyelinating disease of the central nervous system. Axonal damage correlates with the presence of macrophages and CD8+ T-lymphocytes at brain lesions. The gold standard of therapy at MS relapse are iv glucocorticoids (GC). The aim of the study was to assess the changes on the different subsets of circulating CD8+ T-lymphocytes at relapse and after iv GC therapy. PATIENTS AND METHODS: We consecutively studied 20 patients at MS relapse before and at day 5 after initiation of i.v. methyl-prednisolone (MP) therapy (1 g/day for 3-5 days). CD4+ and CD8+ T-lymphocytes subsets were studied by multiparametric flow-cytometry. As control group, 18 healthy subjects were studied. RESULTS: Treatment with i.v. MP suppressed activated (CD8+CD38+HLA-DR+, p=0.05) and effector memory (CD8+CD27-CD45RO+) T-lymphocytes (p=0.07). By contrast, an increase of naïve (CD8+CD27+CD45RO-) (p=0.07) and regulatory CD8+CD25+ T-lymphocytes was observed (p<0.002). At MS relapse, there was an inverse correlation between regulatory CD8+CD25+CD28- T-lymphocytes and activated CD4+ (r = -0.6; p=0.012) and CD8+ (r = -0.66; p=0.004) T-lymphocytes. After i.v. MP treatment, positive correlation between regulatory CD4+CD25+high T-lymphocytes and CD8+CD25+ T-lymphocytes was observed (r=0.74; p<0.0001). CONCLUSIONS: Our data suggest that i.v. MP may contribute to changes observed on the differentiation of CD8+ T-lymphocytes, namely blocking their complete maturation, and expansion of regulatory CD8+ T-lymphocytes. We hypothesize an additional effect of i.v. MP in inhibiting axonal damage which may add a neuroprotective effect on MS relapse.

Profiling of Canonical and Non-Traditional Cytokine Levels in Interferon-ß-Treated Relapsing-Remitting-Multiple Sclerosis Patients.

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease of the central nervous system in which inflammation plays a key role in the induction, development, and progression. Most of the MS patients present with relapsing-remitting (RR) form, characterized by flare-ups followed by periods of recovery. Many inflammatory and anti-inflammatory cytokines have been proposed as backers in MS pathogenesis, and the balance between these differing cytokines can regulate MS severity. Interferon (IFN)-ß, a current disease-modifying therapy for MS, has demonstrated beneficial effects in reducing disease severity in MS patients. However, its immunoregulatory and anti-inflammatory actions in MS are not wholly understood. The aim of the study was to define, in clinically stable patients with RR-MS, the serum concentration of several cytokines, canonical or not, and their modulation by IFN-ß therapy. Methods: Relapsing-remitting-MS patients were enrolled and diagnosed according to revised Mc Donald Diagnostic Criteria. A set of cytokines [including non-canonical neurotransmitter acetylcholine (ACh) and adipokines] and B-cell differentiation molecules, as potential biomarkers, were evaluated in 30 non-treated RR-MS patients compared to 30 IFN-ß-treated MS patients and 30 age, gender, and body mass index-matched healthy controls (HC). Results: Naïve MS patients showed significantly higher levels of interleukin (IL)-1ß, IL-12/IL-23p40, IL-18, high-mobility group box protein-1, and IL-18 binding protein (IL-18BP) than MS-treated patients (p < 0.001 for all) and HC (p < 0.01). IFN-ß therapy has significantly downmodulated IL-1ß, IL-12/IL-23p40, IL-18 to normal levels (p < 0.001), whereas it has decreased IL-18BP (p < 0.001). ACh was significantly higher in the IFN-ß-treated than HC and non-treated MS patients (p < 0.001). No significant differences were observed either in adipokines concentration or in B-cell-associated molecules among the three study groups. Conclusion: Although more experimental evidence are required, we speculate that the efficacy of treatment of MS with IFN-ß is mediated, at least in part, by its ability to work on several levels to slow down the disease progression. Proposed actions include the modulation of IL-1-inflammasome axis and modulation of ACh, B-cell activating factor/a proliferation-inducing ligand system, and several adipokines.

Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: an ex vivo and in vitro longitudinal study in relapsing-remitting multiple sclerosis.

Interferon beta-1a (IFNâ-1a) has demonstrated efficacy in multiple sclerosis (MS), although its mechanism of action remains only partly understood. We evaluated the ex vivo and in vitro effects of IFNâ-1a (Rebif) on regulatory T-cell (T(Reg)) function in 22 relapsing-remitting MS patients and 16 healthy controls. T(Reg) function was significantly enhanced after 3 and 6 months of IFNbeta-1a therapy. Furthermore, there was a trend towards increasing proportions of total CD4(+)CD25(+) and CD4(+)CD25(+)GITR(+) T(Reg) after 6 months of IFNbeta-1a therapy when compared with baseline. In conclusion, IFNbeta-1a therapy enhances T(Reg) function, and this may be relevant in the inflammatory environment of MS lesions.

Close Encounters of the First Kind: Innate Sensors and Multiple Sclerosis.

Although autoimmune diseases by definition imply adaptive immune system pathologies, growing evidence points to the relevance of innate receptors in modulating the initiation and progression of the autoreactive response. Multiple sclerosis (MS) is a chronic autoimmune disease characterised by central nervous system (CNS) demyelination, inflammation and axonal damage, in which the role of several pathogens such as herpes viruses have long been described as potential triggers. Encounters of these pathogens with altered innate receptors in susceptible individuals might drive pathological autoreactivity and inflammation, overcoming tolerance and causing subsequent CNS damage. In particular, functional and genetic studies reveal that Toll-like receptor (TLR) 2 and the Nod-like receptor (NLR) P3 could be involved in MS pathogenesis, whereas TLR3, the triggering receptor expressed on myeloid cells (TREM)-2 and the C-type lectin receptors (CLRs) MBL and MASP-3 would have a putative protective role. A better understanding of these interactions will provide important insights into the aetiopathogenesis of MS and could help design potential targets for novel therapies.

Activation of Blood CD3+CD56+CD8+ T Cells during Pregnancy and Multiple Sclerosis.

A striking common feature of most autoimmune diseases is their female predominance, with at least twice as common among women than men in relapsing-remitting multiple sclerosis (MS), the prevailing MS clinical form with onset at childbearing age. This fact, together with the protective effect on disease activity during pregnancy, when there are many biological changes including high levels of estrogens and progesterone, puts sex hormones under the spotlight. The role of natural killer (NK) and NKT cells in MS disease beginning and course is still to be elucidated. The uterine NK (uNK) cells are the most predominant immune population in early pregnancy, and the number and function of uNK cells infiltrating the endometrium are sex-hormones' dependent. However, there is controversy on the role of estrogen or progesterone on circulating NK (CD56dim and CD56bright) and NKT cells' subsets. Here, we show a significantly increased activation of CD3+CD56+CD8+ cells in pregnant MS women (MSP) compared with non-pregnant MS women (NPMS) (p < 0.001) and even with respect to healthy pregnant women (HP, p < 0.001), remaining increased even after delivery. The dynamics of expression of early activation marker CD69 on CD3+CD56+CD8+ cells showed a progressive statistically significant increase along the gestation trimesters (T) and at postpartum (PP) with respect to NPMS (1T: p = 0.018; 2T: p = 0.004; 3T: p < 0.001; PP: p = 0.001). In addition, early activation expression of CD69 on CD3+CD56+CD8+ cells was higher in MSP than HP in the first two trimesters of gestation (p = 0.004 and p = 0.015, respectively). NPMS showed significantly increased cytotoxic/regulatory NK ratio compared with healthy controls (p < 0.001). On the other hand, gender studies showed no differences between MS women and men in NK and CD3+CD56+CD8+ cells' subsets. Our findings may add on the understanding of the regulatory axis in MS during pregnancy. Further studies on specific CD8+ NKT cells function and their role in pregnancy beneficial effects on MS are warranted to move forward more effective MS treatments.

Circulating dendritic cells subsets and regulatory T-cells at multiple sclerosis relapse: differential short-term changes on corticosteroids therapy.

Glucocorticoids remain the treatment of choice for MS relapses. However, little is known on the effect of intravenous methylprednisolone (IVMP) on dendritic cells (DCs) and regulatory T-cells (TReg). Our main goal was to quantify circulating myeloid and plasmacytoid DCs (mDCs and pDCs), and TReg at MS relapse versus healthy controls; and to analyse the short-term changes after IVMP for MS relapse. MS patients at relapse compared to controls showed higher %CD4+CD25high+ TReg (p<0.01). After 5-days of IVMP, activated T-lymphocytes (p=0.001), pDCs (p<0.0001), and CD11c+ mDCs (p<0.0001) decreased. By contrast, CD4+CD25+ and CD4+CD25high+ TReg further increased (p<0.0001 both). Changes on these subsets may play a relevant role in the immunosuppressive activity of this drug.

Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study.

BACKGROUND: Several evidences suggest that autoimmune diseases (ADs) tend to co-occur in an individual and within the same family. Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a selective loss of hypocretin-producing neurons due to a mechanism of neural destruction that indicates an autoimmune pathogenesis, although no evidence is available. We report on the comorbidity of ADs and other immunopathological diseases (including allergy diseases) in narcolepsy. METHODS: We studied 158 Caucasian NT1 patients (60.7% male; mean age 49.4 ± 19.7 years), in whom the diagnosis was confirmed by polysomnography followed by a multiple sleep latency test, or by hypocretin-1 levels measurements. RESULTS: Thirty out of 158 patients (18.99%; 53.3% female; 29 sporadic and one familial cases) had one or more immunopathological diseases associated. A control group of 151 subjects were matched by gender and age with the narcolepsy patients. Results demonstrated that there was a higher frequency of ADs in our series of narcolepsy patients compared to the sample of general population (odds ratio: 3.17; 95% confidence interval: 1.01 - 10.07; P = 0.040). A temporal relationship with the age at onset of the diseases was found. CONCLUSIONS: Cataplexy was significantly more severe in NT1 patients with immunopathological diseases, and immunopathological diseases are a risk factor for severe forms of cataplexy in our series (odds ratio: 23.6; 95% confidence interval: 5.5 - 100.1).

Anti-JC virus seroprevalence in a Spanish multiple sclerosis cohort: JC virus seroprevalence in Spain.

OBJECTIVE: To estimate the seroprevalence of anti-JCV antibodies, seroconverting rates and evolution of antibody levels in a multiple sclerosis (MS) Spanish cohort. METHODS: Multicenter, retrospective cross-sectional and longitudinal study. The JCV seroprevalence was analyzed in 711 MS patients by using 1st (STRATIFY-1) and 2nd generation (STRATIFY-2) two-step ELISA over 2.65 (±0.97) years. Seroconversion rate was obtained over 2 samples from 314 patients, and index stability from 301 patients with 3 or more samples available. The effect of each ELISA generation, demographics, clinical characteristics and therapy on seroprevalence was assessed by logistic regression. RESULTS: The overall anti-JCV seroprevalence was 55.3% (51.6-58.9), similar across regions (p=0.073). It increased with age (p<0.000) and when STRATIFY-2 was used (60.5%, p=0.001). Neither sex nor immunosuppressive therapy had any influence. Yearly seroconversion rate was 7% (considering only STRATIFY-2). Serological changes were observed in 24/301 patients, 5.7% initially seropositive reverted to seronegative and 7% initially seronegative changed to seropositive and again to seronegative, all these cases had initial index values around the assay's cut-off. CONCLUSIONS: JCV seroprevalence in Spanish MS patients was similar to that reported in other European populations. Changes in serostatus are not infrequent and should be considered in clinical decisions.

Neuromyelitis optica spectrum disorders: Comparison according to the phenotype and serostatus.

OBJECTIVE: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO. METHODS: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays. RESULTS: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001). CONCLUSIONS: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.