Multiple sclerosis in the year 2000: advances in the treatment with interferon beta-1b

The decline of millennium brings forward new challenges in therapeutic immunomodulation of relapsing-remittent multiple sclerosis (RR MS). Interferon beta-1b (Betaferon) belongs to expanding family of soluble cytokines which are capable to modify beneficially cellular immunity in RR MS. IFN beta-1b is indicated for young or middle-aged, ambulant patients with RR MS who have frequent relapses, "aggressive" brain lesions in magnetic resonance imaging and higher levels of pro-inflammatory cytokines. Betaferon reduced in people with RR MS mean annual rate and severity of relapses (34% and 49%) and lengthened median time to second relapse (to 295 days). IFN beta-1b also increased the number of relapse-free patients (31%). Although the drug diminishes weakly progression and activity (disability) it might improve slightly participation (handicap) and quality of life. The course of treatment, withdrawals from the trials, side-effects and the occurrence of neutralizing antibodies to IFN beta-1b are concisely described. Combination of IFN beta-1b with other immunotherapeutic drugs needs further clinical trials.     

Lessons from 10 years of interferon beta-1b (Betaferon/Betaseron) treatment

In 1993, interferon beta-1b (IFN beta-1b, Betaferon/Betaseron) was the first interferon approved in the USA for relapsing-remitting multiple sclerosis (RRMS). Since then, dose-dependent effects of IFN beta in MS have been extensively discussed. Such effects had already been observed in the pivotal trial and were followed by dose comparison trials with IFN beta-1a. Later, the therapeutic efficacy of IFN beta-1b could also be demonstrated in secondary progressive (SP) MS patients. We learnt from further studies that benefit from IFN beta in SPMS seems to be most pronounced in those patients still having active disease with superimposed relapses or clear progression. The most common IFN beta-related adverse events, especially in the early treatment phase, have been flu-like symptoms and injection-site reactions. The consequent management of those as well as of other, less frequent, side-effects turned out to be of tremendous importance to ensure patients' compliance. Based on the experience of 10 years, IFN beta-1b belongs to the firstline therapeutics in RR and SPMS.     

High-dose, frequently administered interferon beta therapy for relapsing-remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study

Long-term trials have demonstrated the continued efficacy of interferon (IFN) beta treatment in patients with relapsing-remitting (RR) multiple sclerosis (MS) during prolonged administration. The objective of the work was to evaluate the effects of reducing IFN beta administration frequency and total weekly dose in patients with RR MS who have achieved clinical and MRI disease activity stabilization during long-term IFN beta-1b treatment. Prospective 1-year follow-up of 27 RR MS patients on long-term 250 microg every other day (standard dose) IFN beta-1b treatment were randomized either to gradually reduce dose to 30 microg once-a-week IFN beta-1a (13 patients), or to continue on IFN beta-1b standard dose (14 patients). We found significant differences in the two group of patients. In the group of patients continuously treated with IFN beta-1b standard dose, 79% remained relapse free compared to 23% in the group receiving once-weekly IFN beta-1a (p=0.006). The number of patients without new PD/T2 lesions was higher in the group of patients continuously treated with IFN beta-1b standard dose (77%) compared to the once-weekly IFN beta-1a group (23%) (p=0.04). IFN beta is a long-term treatment for MS. The reduction of IFN beta-1b administration frequency and dose is not advisable even in patients free from clinical and MRI disease activity for many years.     

Urinary myelin basic protein-like material in patients with multiple sclerosis during interferon beta-1b treatment.

OBJECTIVES: To determine levels of urinary myelin basic protein-like material (MBPLM) in patients with multiple sclerosis (MS) openly treated with interferon beta-1b and to correlate these with clinical changes. BACKGROUND: Levels of urinary MBPLM correlate with the presence of the progressive phase of MS and with the disease burden detected on T2-weighted, cranial magnetic resonance imaging. Measurement of urinary MBPLM level may be a feasible test for monitoring or predicting response to therapeutic measures. DESIGN AND METHODS: In a prospective study at one site, 166 patients with MS (131 with relapsing-remitting [RR] and 35 with secondary progressive [SP] disease) were treated for a minimum of 1 year and up to 3 years with interferon beta-1b and underwent assessment for neurologic disability (Expanded Disability Status Scale and Scripps Neurological Rating Scale) and change in disease subtype. Urine samples were obtained at 1219 of 1378 clinic visits, and urinary MBPLM level was determined and related to creatinine level to adjust for renal function. RESULTS: Statistical analysis using the general linear models procedure confirmed previous findings that the level of urinary MBPLM related to urinary creatinine level (MBPLM/creatinine) was higher (P<.001) in patients with SP than RR MS. Of the 131 patients with RR MS, SP disease developed in 13 during the observation period. Compared with those in the RR group, the RR to SP group had a higher level (P<.001) of urinary MBPLM and did not differ from the SP group. CONCLUSIONS: The level of urinary MBPLM is higher in SP MS than RR MS but not in RR MS that converts to SP MS. Level of urinary MBPLM may permit the examination of treatment tested to prevent RR disease from becoming progressive.     

Effect of drugs in secondary disease progression in patients with multiple sclerosis

Secondary progressive multiple sclerosis (SPMS) is a form of MS characterized by continuously worsening disability with or without superimposed relapses that occurs after a variable period of relapsing remitting disease and results in limited ambulation for almost all patients. The use of interferon beta (IFN beta) for immunomodulation in patients with SPMS has been evaluated in four recent clinical trials: The European multicentre trial on IFN beta-1b in SPMS (EUSPMS), the Secondary Progressive Efficacy Trial of Rebif (IFN beta-1a) in MS (SPECTRIMS), the North American Study of IFN beta-1b in SPMS (NASPMS), and the International MS Secondary Progressive Avonex Clinical Trial (IMPACT). EUSPMS was the only trial to demonstrate a significant positive effect of therapy on disease progression as measured by the expanded disability status scale (EDSS). However, results from all studies demonstrated significant positive effects of treatment on relapse, T2 lesion load, and gadolinium enhancement. Immunomodulation with IFN beta has the potential to significantly slow disease progression and improve quality of life for patients with SPMS. While results with monthly i.v. Ig were disappointing, positive effects on disease progression have been reported with the application of immunosuppressants, especially Mitoxantrone. The risk-benefit ratio of these cytostatic agents remains controversial. New strategies addressing the important neurodegenerative aspects of the disease are urgently needed.     

Interferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy

BACKGROUND: Brain atrophy, as assessed by magnetic resonance imaging (MRI), has been correlated with disability in patients with multiple sclerosis (MS). Recent evidence indicates that both white matter (WM) and gray matter (GM) are subject to atrophy in patients with MS. Although neurological deficiencies in MS are primarily due to loss of WM, the clinical significance of GM atrophy has not been fully explored in MS. METHODS: We have undertaken a three-year, open-label study, comparing 26 patients who elected to receive intramuscular interferon beta-1a (IFN beta-1a) therapy, with 28 patients who elected not to receive therapy. Both groups had quantitative cranial MRI scans at study entry and after three years, and standardized clinical assessments every six months. Brain parenchymal fraction (BPF), GM fraction (GMF), and WM fraction (WMF) percent changes were calculated, and T2- and T1-lesion volumes (LVs) assessed. RESULTS: After three years, mean percent (%) change in BPF favored the IFN beta-1a treatment group (IFN beta-1a -1.3% versus the control group -2.5%, P=0.009), as did the mean percent change in GMF (+0.2 versus -1.4%, P=0.014), and the mean percent change in T1-LV (-9.3 versus +91.6%, P=0.011). At the end of the study, there was a significant within-patient decrease in BPF for both groups (P=0.02 for the IFN beta-1a treatment group, and P<0.001 for the control group), a significant within-patient decrease in WMF for the IFN beta-1a treatment group (P=0.01), and a significant decrease in GMF for the control group (P=0.013) when compared with baseline. CONCLUSION: Over a three-year period, treatment with IFN beta-1a significantly slowed the progression of whole-brain and GM atrophy, and of T1-hypointense LV accumulation, when compared with the control group.     

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis

OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.     

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.     

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.     

Cyclophosphamide-based combination therapies for autoimmunity

Immunomodulatory agent (IMA)-unresponsive multiple sclerosis (MS) can quickly evolve to a dramatic and irreversible disability. Treating these patients with appropriate immunosuppressive therapies can be a chance to arrest disease activity and progression. Cyclophosphamide (Cyc)-based intense immunosuppression has been successfully used to treat rapidly deteriorating, IMA-refractory MS patients. Therapeutic protocols combining Cyc and interferon beta (IFNβ) have also been successfully applied to treat IFNβ-unresponsive MS. The association of Cyc with other immunomodulatory drugs or monoclonal antibodies is currently being investigated in clinical trials aimed at treating severe forms of autoimmune diseases.     

Advancing treatment with interferon beta-1b (Betaferon/Betaseron) in the next decade--thinking beyond the standard dose

Early therapeutic intervention with disease modifying agents in multiple sclerosis (MS) is recommended in an attempt to minimise damage to the central nervous system and improve clinical outcome. Interferon betas (IFN betas) are the most widely used approved therapies for MS at the present time. While optimal dosage and frequency of IFN administration is not fully known, evidence is growing that high-dose, high-frequency IFN beta may be the most effective regimen for controlling clinical activity and minimizing MRI lesion development for at least 1-2 years. Past experience demonstrates that commonly observed side-effects associated with IFN beta injections, such as flu-like symptoms and injection-site reactions, can be markedly reduced through a number of measures. Moreover, the incidence of these side-effects decreases with time. Taking these observations into account, it seems reasonable to consider increasing the maximum approved therapeutic dose of IFN beta-1b (Betaferon/Betaseron) in MS. It has recently been demonstrated that dose escalation of IFN beta-1b combined with pre-medication with ibuprofen enables doses as high as 500 microg every other day to be well tolerated. Further administration of IFN beta-1b (500 microg) in patients with hepatitis C revealed no safety or tolerability concerns, no unexpected or unusual symptoms and no relevant laboratory abnormalities during the 24-week treatment period. It is also noteworthy that the 500 microg dose produced a more marked increase in biological response markers (Mx protein) than that induced by the standard dose of IFN beta-1b, and that other studies have demonstrated similar effects on other such markers. Taken together, the available evidence provides a rationale for using an increased dose of IFN beta-1b in the treatment of MS. This will be investigated further in a new Phase III clinical trial (BEYOND).     

Relationship of urinary myelin basic protein-like material with cranial magnetic resonance imaging in advanced multiple sclerosis

BACKGROUND: A significant correlation exists between disability and the volume of black holes (BHL VOL), defined as hypointense lesions on T1-weighted cranial magnetic resonance imaging. A consistent correlation has also been reported between urinary myelin basic protein-like material (MBPLM) and the transition toward secondary progression (SP) from relapsing-remitting (RR) multiple sclerosis (MS). OBJECTIVE: To improve the management of MS through a noninvasive and cost-effective test for monitoring disease activity or disease status. DESIGN AND METHODS: From 662 patients with MS (86 with RR MS, 259 with SP MS without continued attacks, and 317 with SP MS with continued attacks), 24-hour urine samples were obtained at enrollment in the phase 3 Linomide (roquinimex) drug study. The urine specimens were analyzed for MBPLM and correlated with clinical features and findings on cranial magnetic resonance imaging. RESULTS: Significant but weak correlations existed between urinary MBPLM and BHL VOL in all patients with MS (r = 0.114, P =.003; n = 662), patients with SP MS without attacks (r = 0.185, P =.003; n = 259), and all patients with SP MS (r = 0.122, P =.003; n = 576). No significant correlations were detected in the RR MS group or any of the disease groups or subgroups whose Expanded Disability Status Scale score was 5.0 or lower. In subgroup analysis, the most significant correlation was detected between urinary MBPLM after adjustment for creatinine and BHL VOL in patients with SP MS with an Expanded Disability Status Scale score of 5.5 or higher but without continued relapses (r = 0.417, P<.001; n = 138). CONCLUSIONS: In patients with advanced SP MS, urinary MBPLM may possibly serve as an indicator of failed remission and axonal damage. Urinary MBPLM correlates with disease status in MS, especially the transition of RR MS to SP MS with advancing disability.     

Intrathecal IgG synthesis: marker of progression in multiple sclerosis patients

OBJECTIVES: We study the power of IgG synthesis value as a marker of disease activity in multiple sclerosis (MS). MATERIAL AND METHODS: Link index was calculated in 202 MS patients. Time between first, second and third attack and progression index (PI) were compared in patient with normal (NLI) high (HL) or very high Link index (VHLI). RESULTS: Secondary progressive (SP) patients had a higher LI than relapsing-remitting (RR) and primary progressive (PP) courses (1.10 +/- 0.5 for SP vs 0.86 +/- 0.5 for RR and 0.81 +/- 0.5 for PP, P=0.01 and 0.03, respectively). Having a HLI in MS RR and SP patients has no time effect in the development of the second and third attack. PI was higher in patients with VHIL (0.67 +/- 0.7) vs patients with NLI (0.42 +/- 0.4, P=0.008) and with HLI (0.39 +/- 0.3, P=0.001). CONCLUSIONS: This study confirmed that LI is a good marker of subsequent progression of MS.     

Quality Assessment in Multiple Sclerosis Therapy (QUASIMS)

Interferon beta (IFN beta) preparations are the most frequently prescribed therapies for patients with relapsing multiple sclerosis (MS). Several open-label observational studies report similar efficacy among IFN beta preparations. The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFN beta preparations as disease-modifying therapies for relapsing MS across a wide range of clinical practice settings. This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland. Enrolled patients had received one of the four available IFN beta preparations/dosing regimens (intramuscular IFN beta-1a 30 microg 1x/week [Avonex], subcutaneous (SC) IFN beta-1a 22 or 44 microg 3 x/week [Rebif], or SC IFN beta-1b 250 microg 3.5x/week [Betaferon/Betaseron]) for >or= 2 years. Pre-planned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (< 1.0 EDSS point), annualised relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change. Of 4754 evaluable patients, 3991 (84%) received IFN beta as initial therapy. There were no significant differences among IFN betas when used as initial or follow-up therapy on almost all outcome variables. Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy. Results of QUASIMS showed similar effectiveness among IFN beta products. Benefits were consistently superior when IFN beta was used as initial rather than follow-up therapy. Our results suggest that patients do not benefit in terms of disease outcome from switching between IFN beta preparations/dosing regimens.     

Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS patients treated with IFN beta-1b

Few trials issued the effect of disease-modifying medications on cognitive functions in multiple sclerosis. We designed an open-label longitudinal study to evaluate, during 2 years, cognitive performance and its relationship with MRI data and ApoE polymorphism findings in a group of relapsing-remitting (RR) multiple sclerosis (MS) Interferon (IFN) beta-1b-treated patients (median age 30 years, median disease duration 3.4 years). Complete neuropsychological battery was grouped into attention, information learning/memory, language and visuo-spatial functions. Fifty-two patients (33 females) were enrolled in the study. Six patients (11.5%) dropped out, mainly due to side effects. At baseline neuropsychological evaluation, we found 54% normal, 42% mildly impaired and 4% moderately impaired patients. At 2 years follow-up, cognitive status was stable in 65%, improved in 33% and worsened in 2% of patients. No significant relations were found between global cognitive outcome vs. EDSS change, clinical disease activity, MRI data or ApoE gene polymorphisms over the 2 years follow-up. EDSS and MRI fractional volumes were found to correlate with the performance at single tests. Twenty-one patients (45.6%) showed active MRI scans throughout the study, without any worsening at the corresponding neuropsychological examination. This ongoing trial suggests a possible beneficial effect of IFN beta-1b treatment on cognitive functions in RRMS patients. Extension of follow-up and further data analyses are needed to confirm and clarify these findings.     

Dose and frequency of interferon treatment matter--INCOMIN and OPTIMS

Three different interferon beta (IFN beta) products are currently approved for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). However, the recommended method of administration, the dosage and the frequency of administration differ widely between each of the three products. Although controlled clinical trials have demonstrated the efficacy of both alternate-day IFN beta-1b (Betaferon/Betaseron) and once-weekly IFN beta-1a (Avonex) compared with placebo, it is likely that patient compliance, efficacy and tolerability are affected by the dosage regimen used. There are several issues to consider. Once-weekly administration may be associated with fewer adverse events and greater convenience, and it has been suggested that this may increase compliance. Conversely, frequent administration may be associated with increased overall efficacy. There is a convincing pharmacological rationale indicating that frequent dosing, with an interval of less than 72 h, is necessary to sustain the activity of intracellular molecular signalling pathways responsible for regulating IFN beta-induced gene expression. However, there was a need to explore the overall effectiveness of the two administration protocols in a comparative trial. The INCOMIN (Independent Comparison of Interferon) study compared clinical and magnetic resonance imaging (MRI) efficacy of IFN beta-1b 250 microg (8 MIU) subcutaneously (s.c.) on alternate days and IFN beta-1a 30 microg (6 MIU) intramuscularly (i.m.) once weekly in patients with RRMS. INCOMIN demonstrated convincingly that clinical and MRI outcome measures were significantly better in the IFN beta-1b-treated group. Blinded MRI evaluation confirmed the clinical results. Despite some limitations of the study design, imposed by the ethical and practical challenges of conducting comparative trials of injectable therapies, the concordance of the clinical and MRI findings indicate that frequently administered IFN beta-1b reduced evidence of disease activity more effectively than once-weekly administered IFN beta-1a, with the clinical benefits for patients becoming more pronounced over time. Given that the response to IFN beta appears to be dose dependent, the question that might be asked is whether greater efficacy can be obtained by increasing doses beyond those currently approved. OPTIMS (Optimization of Interferon dose for MS) is currently examining the safety and efficacy of a dose of IFN beta-1b that is higher than any currently marketed IFN beta. While OPTIMS is still underway, preliminary safety analyses indicate that higher doses are well tolerated.     

A sensitive radioimmunoprecipitation assay for assessing the clinical relevance of antibodies to IFN beta

BACKGROUND: Some multiple sclerosis (MS) patients treated with interferon beta (IFN beta) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN beta are expensive and the clinical relevance of the results has been debated. OBJECTIVE: To establish a cheap, sensitive, and reliable assay for antibodies to (125)I-IFN beta, and to correlate levels of antibodies with clinical response to IFN beta treatment. METHODS: We established a radioimmunoprecipitation assay (RIPA) using (125)I-IFN beta. We tested NAB positive sera, healthy control sera, and serial samples of 33 IFN beta-1b treated MS patients from the Vancouver cohort of the Berlex pivotal trial who had a high incidence of NABs. RESULTS: We found that the RIPA was highly sensitive for the detection of antibodies to IFN beta-1a and -1b, and that there was a strong correlation between reactivity of NAB positive sera for (125)I-IFN beta-1b and for (125)I-IFN beta-1a. The RIPA was more sensitive and consistent than the NAB. Moreover, there was a trend towards poorer MRI outcomes in RIPA positive patients, but not in NAB-positive patients. CONCLUSIONS: The RIPA assay is sensitive and easy to perform. It should be of value in assessing the clinical impact of IFN beta antibodies, and its use could help target expensive INF beta treatments to those who will respond best.     

The window of therapeutic opportunity in multiple sclerosis

From 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.     

Secondary progressive multiple sclerosis - clinical course and potential predictive factors

BACKGROUND AND PURPOSE: To characterize the course of secondary progressive multiple sclerosis (SPMS), with an attempt to assess the predictive value of early clinical variables. MATERIAL AND METHODS: Medical records of 100 patients with SPMS (40 men, 60 women, aged 34-73) were analyzed retrospectively. Age at onset of MS, first symptoms, annual exacerbation rate (AER), time to progressive phase (TTP), degree of disability at its beginning (Expanded Disability Status Scale; EDSS SP), and annual progression in disability in relapsing-remitting and progressive phases (APD RR and APD SP) were compared for the gender subgroups, and the relationships between them were analyzed. RESULTS: Time to progressive phase range was 2-29 years (mean 11.51) and EDSS SP 2-7.5 (mean 5.55). Time to progressive phase in women was longer and EDSS SP was lower than in men. Age at onset of MS, AER and ADP RR correlated positively with TTP. Optic neuritis was the most common first symptom (49%; motor deficit and cerebellar/brainstem involvement 26% and 21%, respectively). Time to progressive phase in the former subgroup was shorter than in the latter, but no differences in ADP SP were found. Annual progression in disability in relapsing-remitting was higher than APD SP. Degree of disability at its beginning (EDSS SP) correlated negatively with ADP SP. CONCLUSIONS: Older age at onset, male gender, frequent relapses and fast increase in disability in the relapsing-remitting phase are risk factors for conversion to SPMS. Increase in disability during the progressive phase is slower than in the relapsing-remitting phase and depends mainly on initial EDSS. Individual variability of the course of MS has to be considered.     

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