Decreased interleukin-10 and increased interleukin-12p40 mRNA are associated with disease activity and characterize different disease stages in multiple sclerosis.

It has been shown that proinflammatory and antiinflammatory cytokines correlate with disease activity in multiple sclerosis (MS). To establish whether such correlations depend on the disease stage, we assessed in a longitudinal fashion the expression of interleukin (IL)-12 (p40 and p35), tumor necrosis factor-alpha, interferon-gamma, and IL-10 mRNA by competitive polymerase chain reaction in unstimulated peripheral blood mononuclear cells of relapsing-remitting (RR) and secondary progressive (SP) MS patients, in relation to monthly clinical and magnetic resonance imaging monitoring. MS patients had increased levels of IL-12p40 and decreased levels of IL-10 mRNA compared with controls; this difference was most pronounced in SP patients. Both RR and SP patients had increased levels of IL-12p40 mRNA compared with controls during the development of active lesions. Moreover, in RR MS an increase was found before relapse. IL-12p35 mRNA was decreased in both groups, and in relation to disease activity it showed a pattern different from IL-12p40 mRNA. In RR MS, IL-10 mRNA was low 4 weeks before magnetic resonance imaging activity and 6 weeks before relapse; a significant increase to normal levels was noted when active lesions became apparent. In contrast, SP patients showed low IL-10 mRNA levels constitutively, suggesting that IL-10 plays an important role in the control of disease progression.     

Organizational strategy use in obsessive-compulsive disorder

It has been reported that the balance between T-helper type 1 (Th1) cytokines and T-helper type 2 (Th2) cytokines plays a role in psychiatric disorders such as bipolar disorder. The T-helper type 3 (Th3) cytokine, which transforming growth factor beta-1 (TGF-β1), has been shown to modulate the production of Th1 and Th2 cytokines. However, the role of TGF-β1 in bipolar disorder has not yet been explored. A total of 70 manic patients with bipolar disorder and 96 normal controls was recruited. The plasma levels of IFN-γ, IL-4, and TGF-β1 were studied at the time of admission and 8 weeks after mood stabilizer treatment. The detection rate and plasma concentrations of IFN-γ and IL-4 and the IFN-γ/TGF-β1 and IL-4/TGF-β1 ratios were significantly higher in patients than in controls, while the TGF-β1 level was significantly lower. The TGF-β1 level increased significantly after treatment and the IFN-γ/TGF-β1 and IL-4/TGF-β1 ratios returned to control values. TGF-β1 may play a role in the pathophysiology of bipolar disorder through the action of TGF-β1 in modulating the IL-4/TGF-β1 ratio.     

Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease

OBJECTIVE: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). BACKGROUND: MS is an immune-mediated disease and cytokines hove been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. METHODS: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T MS patients express significantly more CD4+ and CD8+ T cells were analyzed for IFN-gamma, IL-2, TNF-alpha, IL-4, IL-10 and IL-13 production. RESULTS: cells producing IFN-gamma compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-alpha and a significant increase in CD8+ T cells producing IL-4 and IL-10. CONCLUSIONS: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.     

Serial analysis of cytokine mRNA profiles in whole blood samples from patients with early multiple sclerosis

In this pilot study, we serially determined the cytokine messenger RNA (mRNA) expression pattern in whole blood samples from 12 patients with clinical isolated syndrome suggestive of early multiple sclerosis (MS) using a new sensitive quantitative polymerase chain reaction (PCR) method. Significantly higher levels of tumor necrosis factor- (TNF-; ×5.1), interferon-γ (IFN-γ; ×4.8) and interleukin-10 (IL-10; ×5.6) mRNA were detected in MS patients at the time of a relapse compared to healthy controls. Treatment with i.v. methylprednisolone (MP) led to an increase of IL-4 mRNA and a significant decrease of IFN-γ and TNF- mRNA expression. In this cohort of clinically stable patients, proinflammatory cytokines remained low during the 1-year follow-up period. As several indications point to a cytokine dysregulation in MS, quantitative analysis of cytokine mRNA profiles in whole blood samples by real time PCR may be a useful immunological marker to monitor disease activity in future therapeutic trials in MS.     

The role of osteopontin: A shared pathway in the pathogenesis of multiple sclerosis and osteoporosis?

Osteopontin (OPN) was suggested to have a role in the pathophysiology of MS and in bone metabolism. However, we formerly reported increased presence of osteoporosis in MS patients independent of corticosteroid treatment, there is only limited information about the mechanism of bone loss. In this study, we investigated the role of OPN on bone mineral density in MS patients. Thirty-three relapsing-remitting (RR), 12 secondary progressive (SP), and 5 primary progressive (PP) MS patients and 30 healthy controls were prospectively enrolled. Students' t test, chi-square test, and Pearson correlations were used. The mean OPN level was 155.4+/-81.8 ng/ml in controls, and 15.9+/-36.2 ng/ml in MS patients (p<0.001).No statistical difference was observed among RR, SP and PPMS patients (p=0.162). No relationship was found between OPN levels and age at onset of disease (p=0.830), gender (p=0.785), MS subtypes (p=0.330), disease duration (p=0.744), or EDSS scores (p=0.633).About 34% of MS patients versus 10.3% of controls had osteoporosis (p=0.017).Osteopontin levels showed no significant correlation with osteoporosis in controls, but were lower in MS patients with osteoporosis in femur neck (r=0.85, p=0.010).The cumulative dose of corticosteroid treatment did not correlate with OPN levels (p=0.285).In conclusion, our results suggest that OPN may have a role as a shared cytokine in pathogenesis of MS and osteoporosis.     

IFN-beta-regulated genes show abnormal expression in therapy-naïve relapsing-remitting MS mononuclear cells: gene expression analysis employing all reported protein-protein interactions

The molecular mechanism by which interferon beta (IFN-β) is effective in treating multiple sclerosis is not well understood. Mononuclear cells from therapy-naïve MS patients, IFN-β-1b-treated MS patients, and healthy controls were analyzed to examine mRNA changes that characterize both the disease and its treatment. The scientific literature was comprehensively searched for all protein–protein interactions. In MS patients who had never been treated with IFN-β, statistical analysis revealed coordinate changes in mRNA expression for proteins reported in the literature as “regulated by IFN-β.” As a positive control for this approach, samples from a separate MS patient cohort showed significant change of these same genes during in vivo treatment with IFN-β-1b.The strength of effect observed for regulation by IFN-β was greater than for IFN-, IFN-γ (Th1), or IL-4 (Th2). Of the sets we investigated, the most strongly affected by disease was the subset defined by regulation by both IFN-β and IFN-. Changes in cells from therapy-naïve MS patients thus anticipated the importance of IFN-β in therapy. These findings are a significant step towards marrying MS disease etiology and IFN-β mechanism of action at a molecular level.     

Mediators of apoptosis Fas and FasL predict disability progression in multiple sclerosis over a period of 10 years

TNF-alpha, IL-12p35, IL-12p40, IL-4, IL-10, TGF-beta1, CCR3, CXCR3, CCR5, Fas and FasL mRNA levels in PBMC of 25 multiple sclerosis (MS) patients were quantified at baseline by real-time PCR according to a post-hoc study design. The baseline values of the different markers were analysed with respect to their correlation with the increase in disability over a period of 10 years. High levels of Fas mRNA were associated with a favourable disease course in relapsing-remitting (RR) MS (R2 = 0.74, P = 0.0001, n = 13), as measured by the Expanded Disability Status Scale (EDSS); high levels of FasL mRNA were associated with relatively mild disease progression (R2 = 0.86, P = 0.0001, n =12) in secondary progressive (SP) MS. These findings suggest that Fas-mediated apoptosis plays a major role in the mechanism underlying long-term disease progression in MS.:     

Fatigue is not associated with raised inflammatory markers in multiple sclerosis

BACKGROUND: The pathogenesis of fatigue in patients with MS is poorly understood. OBJECTIVE: To test the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation. METHODS: Fatigue as assessed by the Fatigue Questionnaire Scale (FQS) and Krupp's Fatigue Severity Scale (KFSS) was correlated with several inflammatory markers in 38 patients with MS (16 relapsing-remitting [RR; 7 of whom had benign MS), 9 secondary progressive [SP], 13 primary progressive [PP]). The markers included daily urinary neopterin excretion, a marker of interferon-gamma-activated macrophage activity, and serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks. RESULTS: No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP levels (KFSS, 50 +/- 8 vs 41 +/- 14, p = 0.05; FQS, 13 +/- 4 vs 11 +/- 5, p = NS). When assessed using the FQS, patients with RR and SP MS were more fatigued than patients with PP MS (RR = 12.5 [4 to 23] vs SP = 13 [8 to 18] vs PP = 9 [7 to 14], p = 0.02). The patients with benign MS were as fatigued as patients with nonbenign disease. CONCLUSION: The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. Interestingly, patients with PP MS were less fatigued than patients with RR disease.     

Linomide suppresses chronic-relapsing experimental autoimmune encephalomyelitis in DA rats

Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that suppresses several experimental autoimmune diseases. Here we report the effects of Linomide on chronic progressive and/or relapsing experimental autoimmune encephalomyelitis (PR-EAE), a CD4⁺ T cell mediated animal model of multiple sclerosis (MS). PR-EAE induced in DA rats by inoculation with homogenized guinea pig spinal cord and Freund's complete adjuvant, was strongly suppressed by Linomide administered daily subcutaneously from the day of inoculation. Linomide dose-dependently delayed the interval between immunization and onset of clinical PR-EAE, reduced severity and relapse of clinical PR-EAE, and shortened clinical PR-EAE. These clinical effects were associated with the down-modulation of CNS antigen-induced T cell responses and production of proinflammatory cytokines (IFN-γ and TNF-) as well as with upregulation of IL-4 (except in spleen MNC), IL-10 and TGF-β in both spleen MNC and the spinal cord. These effects indicate that Linomide can suppress PR-EAE and may mediate its suppressive effects by regulation of cytokines.     

Cognitive impairment and decline in different MS subtypes

This paper presents results of two studies conducted to investigate cognition in different MS subtypes. First, the results of a study that has previously been published will be discussed. This was a cross-sectional study with 108 relapsing-remitting (RR), 71 secondary progressive (SP), 55 primary progressive (PP) MS patients, and 67 healthy controls [S.C.J. Huijbregts, N.F. Kalkers, L.M.J. de Sonneville, V. de Groot, I.E.W. Reuling, C.H. Polman, Differences in cognitive impairment of relapsing-remitting, secondary and primary progressive MS. Neurology 63 (2004) 335-339]. The second study involved a follow-up assessment after 2 years and included 30 SPMS patients, 25 PPMS patients, and 33 controls. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used for all cognitive assessments. All patient groups demonstrated cognitive deficits compared to healthy controls. RRMS patients were less affected compared to patients with progressive MS subtypes on the Paced Auditory Serial Addition Task (PASAT) and the Symbol Digit Modalities Test (SDMT). These differences were attenuated after control for physical disability level as measured by the Expanded Disability Status Scale. RRMS and SPMS patients were more severely impaired than PPMS patients on the 10/36 Spatial Recall Task and Word List Generation. Results of the follow-up study indicated that both progressive MS subtypes showed a lack of improvement compared to controls on the PASAT and the SDMT, but not on the other tasks of the BRB-N, indicating that performance on tasks requiring multiple abilities concurrently, i.e. visuo-spatial ability and processing speed (SDMT) or working memory and processing speed (PASAT), is most likely to decline across time.     

Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes

In multiple sclerosis (MS), matrix metalloproteinase (MMP) activity in tissues is the result of a balance between MMPs and their tissue inhibitors (TIMPs). MMP-9 predominates in acute MS lesions and is inhibited by TIMP-1, while MMP-2 may participate in the remodeling of the extracellular matrix (ECM) such as in chronic disease and is inhibited by TIMP-2. These differences may be reflected in serum and cerebrospinal fluid (CSF). We have tried to characterize MMP-2 and MMP-9 activities, in relation to their respective TIMPs, 2 and 1, as a factor of different types of the disease, as this information was not previously clearly stated. We found the MMP-2/TIMP-2 ratio in serum to show higher values in secondary progressive (SP, p=0.02) and primary progressive (PP, p=0.01) MS than short disease duration (SDD) relapsing-remitting (RR) MS, but not different from the healthy control (HC) group. Whereas the MMP-9/TIMP-1 ratio in serum showed higher (p=0.04) values in SDD RR MS than PP but also in active patients, evaluated either clinically (p=0.006) or from the magnetic resonance imaging (MRI, p<0.05), compared to inactive disease. CSF MMP to TIMP ratios did not differ between MS subtypes, suggesting systemic rather CNS-restricted changes. These results show that an increase in MMP-2/TIMP-2 ratio marks chronic progression in MS, but it is as high as in HC, and also confirm that high MMP-9 activity characterizes short duration relapsing and active forms of the disease.     

Elevated plasma homocysteine levels in patients with multiple sclerosis are associated with male gender

Elevated homocysteine (Hcy) levels exert several neurotoxic actions and vascular dysfunctions that may be involved in pathogenesis and progression of multiple sclerosis (MS). The effective role of Hcy in MS however remains to be determined. The aim of this work was to compare plasma Hcy levels in MS patients and neurological disease controls (NDC) and to evaluate their relationships with clinical and demographic variables. In this cross-sectional study, we examined plasma Hcy levels in 217 patients with MS [53 clinically isolated syndromes (CIS) suggestive of MS, 134 relapsing remitting (RR), 23 secondary progressive (SP) and seven primary progressive (PP) MS], recruited among patients attending a tertiary clinical center in southern Italy and in 219 age/sex-matched controls. Median Hcy levels were slightly higher in MS patients compared to NDC (9.1?μmol/l; range, 3.4-35.9 vs. 8.6, range 3.5-27.4; p?=?0.02). Median Hcy concentrations were increased in males more than in females in the MS population (10.4 vs. 8.4; p?相似文献   

Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated to a subset of multiple sclerosis patients with progressive forms

The purpose of this study was to provide further insight into the effective relevance of the association between Chlamydia pneumoniae and MS. We evaluated by ELISA technique cerebrospinal fluid (CSF) and serum levels of anti-C. pneumoniae IgG in 46 relapsing-remitting (RR), 14 secondary progressive (SP) and 11 primary progressive (PP) MS patients grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity. Fifty-one patients with other inflammatory neurological disorders (OIND) and 52 with non-inflammatory neurological disorders (NIND) were used as controls. A C. pneumoniae-specific intrathecal IgG synthesis as detected by the relative specific index was present in a small proportion of MS (17%), OIND (22%) and NIND (2%) patients and was significantly more frequent in MS and in OIND than in NIND (p<0.001) and in SP and PP MS than in RR MS patients (p<0.02). Among the patients with C. pneumoniae-specific intratecally produced antibodies, CSF high-affinity anti-C. pneumoniae IgG were found in the majority of SP or PP MS, occasionally in OIND, but not in RR MS and NIND patients. These findings confirm that the presence of a humoral immune response to C. pneumoniae within the central nervous system (CNS) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecal production of C. pneumoniae-specific high-affinity IgG can occur in a subset of patients with MS progressive forms in which a C. pneumoniae brain chronic persistent infection may play an important pathogenetic role.     

Metabolic differences between multiple sclerosis subtypes measured by quantitative MR spectroscopy

We used quantitative magnetic resonance (MR) spectroscopic imaging with T1-based image segmentation to evaluate the subtypes of multiple sclerosis (MS) (eight patients each group of relapsing-remitting [RR], secondary progressive [SP] and primary progressive [PP]). There was no significant difference in age between the PP group with the RP, SP or control group. We found that the metabolite ratio of choline/NA from the periventricular white matter region was not significantly different between the RR and SP groups. Using an ANOVA, the ratios of periventricular choline/NA or creatine/NA of these combined groups were significantly higher than the PP and control groups. Quantification of these data suggest that the major cause of the elevation of these parameters is due to an increase in choline and creatine in the RR group while NA is decreased in the SP group. Thus, early PP disease appears to be relatively intact with respect to neuronal loss.     

Cognitive impairment in different MS subtypes and clinically isolated syndromes

OBJECTIVE: To investigate the pattern of cognitive impairment in patients with relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) multiple sclerosis, and patients with clinically isolated syndrome (CIS) suggestive of MS, relative to control participants in the Greek population. METHODS: RR patients (N=75), SP patients (N=29), PP patients (N=23), CIS patients (N=33), and healthy control participants (N=43) were assessed by the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS: The overall prevalence of cognitive dysfunction in our patients was 52.8% with CIS patients excluded and 47.5% with CIS patients included. All MS patients differed significantly from controls in all BRBN measures. Similar was the pattern of cognitive dysfunction in patients with CIS suggestive of MS, although verbal learning/memory capacity (as measured by the Selective Reminding Test) remained relatively spared. The comparisons between patient groups revealed some differences in the performance mainly in favor of CIS and RRMS patients. These differences largely disappeared after controlling for physical disability (EDSS). CONCLUSION: All MS subtypes patients exhibit a pattern of cognitive impairment running across the studied cognitive domains. The pattern of cognitive dysfunction in patients with CIS is similar with relative sparing of verbal learning.     

Activity profile in multiple sclerosis: an integrative approach. A preliminary report

In order to define an activity profile in patients with multiple sclerosis (MS), T-cell subpopulations and proliferative responses to myelin basic protein (MBP) associated with anti-MBP antibodies, nitrotyrosine levels in serum and cerebrospinal fluid (CSF), and serum CD40L (sCD154) were simultaneously assessed in 29 consecutive and untreated MS patients. When compared to controls, patients in secondary progressive stable (SP/I), or in full remission (RR/I) stages, individuals with secondary progressive active disease (SPIA) or in acute relapse (RR/A) showed a significant decrease of CD4/CD45RA+ T cells associated with an increase of absolute numbers of CD4/45R0+ T cells (p < 0.001). In addition, in vitro-specific T-cell proliferative responses against MBP (SP/A, RR/A, SP/I: p < 0.001 versus controls) in association with augmented sCD154 serum levels (SP/A, RR/A, versus controls p < 0.001) and a significant increase of both CSF and serum levels of anti-MBP antibodies and nitrotyrosine levels (p < 0.001) were also found. Thus, the simultaneous evaluation of antibody and cell-mediated immunopathological parameters, along with the effector mediators of inflammation such as the nitric oxide products, offers a new integrative approach to characterize markers of clinical activity in MS patients, which may be used at the moment of the initial diagnosis and during an apparent recurrences of the disease to monitor therapeutic protocols and to determine whether immune-based nerve destruction mechanisms are still operating in patients with few clinical findings.     

Biological responsiveness to first injections of interferon-beta in patients with multiple sclerosis

MSRV is a retroviral element previously isolated in cell cultures from patients with multiple sclerosis. It is part of a new multi-copy endogenous retrovirus family named HERV-W and displays pro-inflammatory properties both in vitro in human PBMC cultures and in vivo in a humanized SCID mice model. In the present study, we have evaluated potential links between the pro-inflammatory properties of MSRV envelope protein and MS disease. Thus, cytokine productions mediated by the surface unit of MSRV envelope protein were evaluated in PBMC of MS patients and compared with healthy controls. Divergent reactivity to ENV-SU between MS and control PBMC was observed and was reflected by a significant increase of IFN-γ, IL-6 and IL-12p40 production by the tested MS population. Interestingly, the overproduction of IL-6 and IL-12p40 was found to correlate with disease severity (EDSS) in most patients. Altogether our data suggest that MSRV envelope protein may induce an abnormal cytokine secretion, thus contributing to the inflammatory process in MS.     

Insulin‐like growth factor (IGF)‐I and IGF‐binding protein‐3 serum levels in relapsing–remitting and secondary progressive multiple sclerosis patients

Background: Insulin‐like growth factor (IGF)‐I has a role in remyelination, and insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) might reduce its bioavailability. A role of IGFBP‐3 in multiple sclerosis (MS) progression was hypothesized in patients with primary progressive (PP) MS. Objective: To evaluate serum levels of IGF‐I and IGFBP‐3 in patients with relapsing–remitting (RR) and secondary progressive (SP) MS and their correlations with disease activity and progression. Methods: Sixty‐three (41 RR and 22 SP) ‘naive’ MS patients and 60 age‐matched healthy controls were enrolled. Patients were assessed through clinical [Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), number of relapses] and laboratory investigations. IGF‐I and IGFBP‐3 were measured by ELISA. Results: Levels of IGF‐I and IGFBP‐3 were similar in the two MS groups. IGFBP‐3 levels were higher in patients with MS than in controls (P < 0.001), with a reduction in IGF‐I/BP3 ratio (P < 0.001). Patients showing IGFBP‐3 levels higher than 2SD of the normal population had a higher EDSS (mean EDSS 3.7 vs. 2.8, P = 0.021). MSSS was not related to IGF‐I or IGFBP‐3 serum levels. Conclusions: Our patients showed high IGFBP‐3 serum levels respect to controls and higher serum levels were associated with a higher EDSS, despite of comparable disease duration. Therefore, MS and higher disability seem to be associated with a reduction in bioavailability of IGF‐I. MSSS score was not related to IGFBP‐3 levels, suggesting that IGFBP‐3 might not have the pathogenetic role previously suggested for PP MS, in the mechanism of progression in the SP form of disease.     

Treatment of progressive forms of multiple sclerosis by cyclophosphamide: a cohort study of 490 patients

There are no generally effective disease-modifying drugs for progressive forms of multiple sclerosis (MS). Some MS centres use cyclophosphamide (CYC) in secondary progressive (SP) forms of MS, especially after interferon beta-1b (INFbeta-1b) treatment failure. Moreover, there are currently no approved drugs for primary progressive (PP) MS. Using the collected data of patients with progressive MS, we studied clinical patterns that predicted a good response to CYC treatment. Secondly, we compared the therapeutic response of SPMS and PPMS patients to the treatment. Data from 490 MS patients were collected. All patients presented an SP (n = 362) or PP (n = 128) form of the disease and 476 had been treated for at least one year with a monthly pulse of CYC associated with methylprednisolone (MP). CYC treatment was justified because of at least a 1-point worsening on the Expanded Disability Status Scale (EDSS) during the previous year. The EDSS score was assessed at baseline and after 6 months (M6) and 12 months (M12) of treatment. After 12 months of CYC treatment, 78.6% of SPMS and 73.5% of PPMS patients had stabilised or had an improved EDSS score. Response to CYC was not significantly different in the two progressive forms of MS. Twenty-two patients presented noticeable drug side effects, one of whom withdrew from the treatment due to intolerance. Patients with an improved EDSS at M12 had a shorter mean progressive time course (5.1 years) than patients who stabilised or worsened (7.1 years) (p = 0.02). We also observed that poor responders at M6 were also poor responders at M12 (p < 0.001). This large cohort study showed that CYC treatment was well tolerated and suggested that a better response occurred in cases with a short progressive time course. We did not find any difference in treatment response between the two progressive forms of MS. To date, no treatment is approved for PPMS and we therefore propose a trial to test the use of CYC treatment early in the course of the disease in PPMS patients with disability progression.     

Contrasting responses to interferon beta-1b treatment in relapsing-remitting multiple sclerosis: does baseline interleukin-12p35 messenger RNA predict the efficacy of treatment?

Interferon (IFN)-beta treatment is effective in relapsing-remitting multiple sclerosis (RR-MS) via an as yet unidentified mechanism. In the present study, we investigated whether the expression of messenger RNA (mRNA) encoding the interleukin (IL)-12 subunits p40 and p35, IL-12 receptor chains, IL-18, tumor necrosis factor-alpha (TNFalpha), IFNgamma, IL-10, IL-4, or transforming growth factor-beta in unstimulated whole blood of 26 RR-MS patients changed during 6 months of IFNbeta-1b treatment. In these patients, a significant change was found in TNFalpha mRNA, whereas changes in IL-12 receptor-beta2 and IL-10 mRNA showed a trend. IFNbeta-1b-related changes in cytokine mRNA expression were next evaluated in clinical subgroups of RR-MS patients classified as either clinical responders or nonresponders on the basis of Expanded Disability Status Scale progression and the number of relapses and steroid interventions needed in the 2 years before initiation of treatment compared with the 2 years after initiation of treatment. These subgroups showed different response patterns to IFNbeta-1b treatment with respect to IL-10, TNFalpha, and IL-18 only. Surprisingly, clinical responders displayed no change in these cytokines, whereas nonresponders showed a decrease in TNFalpha and IL-18 mRNA as well as a transient increase in IL-10 mRNA. Baseline levels of IL-12p35 mRNA were lower in the responders compared with the nonresponders: this marker correctly predicted the clinical outcome in 81% of the 26 patients under investigation.