Treatment optimization in multiple sclerosis: report of an international consensus meeting

Multiple sclerosis (MS) is a chronic disease for which there is currently no proven cure. Nevertheless, desperate views have changed to substantial optimism over recent years, as several lines of evidence have indicated that disease-modifying drugs (DMDs) have beneficial effects on neurological deterioration in MS. However, assessing the success of DMD therapy in an individual patient may not always be clear-cut for the doctor . In order to address this issue, an International Working Group of doctors experienced in treating patients with MS convened to discuss the optimization of DMD therapy, and the outcome of this consensus meeting is reported here. Participants developed statements that classify changes in relapses, disease progression and brain magnetic resonance imaging in a patient with MS who is taking DMD therapy, according to whether they are worthy of note, of some concern, or of serious concern and requiring a reassessment of current therapy. Based on these statements, the performance of standardized examinations to document changes in the disease enables a visual measure of the progress of an individual patient to be built up on an analogue model. This model provides a useful framework to help the neurologist to identify those patients for whom the therapeutic options should be reconsidered.     

Disease-modifying agents in multiple sclerosis

Since 1993, six disease-modifying therapies for multiple sclerosis (MS) have been proven to be of benefit in rigorous phase III clinical trials. Other agents are also available and are used to treat MS, but definitive data on their efficacy is lacking. Currently, disease-modifying therapy is used for relapsing forms of MS. This includes clinically isolated syndrome/first-attack high-risk patients, relapsing patients, secondary progressive patients who are still experiencing relapses, and progressive relapsing patients. The choice of agent depends upon drug factors (including affordability, availability, convenience, efficacy, and side effects), disease factors (including clinical and neuroimaging prognostic indicators), and patient factors (including comorbidities, lifestyle, and personal preference). This review will discuss the disease-modifying agents used currently in MS, as well as available alternative agents.     

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis

Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased. No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone. A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16–66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent. Received in revised form: 19 September 2005     

Natalizumab is effective as second line therapy in the treatment of relapsing remitting multiple sclerosis

Background:  Natalizumab has been recommended for the treatment of patients with relapsing remitting multiple sclerosis with insufficient response to interferon-beta (IFN-beta) or glatiramer acetate (GA).
Method:  Prospective, observational study.
Results:  We found a reduction of the annualized relapse rate from 2.1 under IFN-beta or GA to 0.2 one year after switching to natalizumab. There were 94% fewer gadolinium enhancing lesions with natalizumab.
Conclusion:  Natalizumab reduced short term clinical and MRI activity in second line therapy and efficacy is comparable to first line therapy as demonstrated in the pivotal trials.     

A prospective, open-label treatment trial to compare the effect of IFN β-1a (Avonex), IFNβ-1b (Betaseron), and glatiramer acetate (Copaxone) on the relapse rate in relapsing-remitting multiple sclerosis

A prospective, non‐randomized, open‐label treatment trial was performed in patients with relapsing‐remitting multiple sclerosis (RRMS), with follow up for 12 months. Our primary objective was to prospectively compare the effect of IFNβ‐1a (Avonex), IFNβ‐1b (Betaseron), and glatiramer acetate (GA, Copaxone) on the relapse rate in patients with RRMS. Between August 1996 and September 1999, 156 consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 12 months, from the time of initiating therapy or electing to remain untreated. Prior 2‐year relapse history and available chart information was carefully reviewed at the time of enrolment. Thirty‐three of 156 elected no treatment (mean age 32.5 years; mean EDSS 2.64) at enrolment; 40 elected IFNβ‐1a (mean age 32.4 years; mean EDSS 2.69), 41 IFNβ‐1b (mean age 32.1 years; mean EDSS 2.56), and 42 chose GA (mean age 31.5 years; mean EDSS 2.57). Annual relapse rate based upon the 2 years prior to enrolment was 1.08 in the untreated group, 1.20 in the AV group, 1.21 in the BE group, and 1.10 in the GA group. There were no statistically significant differences among the four groups at enrolment. After 12 months of treatment, patients in the untreated groups had a relapse rate of 0.97, whereas patients in the IFNβ‐1a, IFNβ‐1b, and GA groups had relapse rate of 0.85, 0.61, and 0.62, respectively. Compared to the untreated group, reduction in the relapse rate was statistically significant only in the GA (P=0.003) and IFNβ‐1b (P=0.002) groups, in contrast to the IFNβ‐1a treated patients, who did not show a significant reduction (P=0.309). Compared to the untreated patients, mean EDSS was significantly reduced only in the GA (P=0.001) and IFNβ‐1b (P=0.01), in contrast to IFNβ‐1a treated patients (P=0.51). In this prospective, controlled, open‐label, non‐randomized 12‐month study, treatment with only GA and IFNβ‐1b significantly reduced the relapse rate compared to untreated patients, supporting early treatment in RRMS. Our results are similar to the observations made after 12 months of therapy in phase III studies of IFNβ‐1a, IFNβ‐1b, and GA. Despite some limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment‐naïve RRMS patients.     

Therapeutic outcome 3 years after switching of immunomodulatory therapies in patients with relapsing–remitting multiple sclerosis in Argentina

Switching treatment may be beneficial in patients with relapsing–remitting multiple sclerosis (RRMS) who respond inadequately to first-line immunomodulatory therapy. The objective of this study was to evaluate clinical outcomes after switching treatment in such patients. This prospective longitudinal observational study included 114 patients with RRMS who failed first-line monotherapy and were switched treatments after 3 years. Every 3 months, patients underwent a full neurological examination. Outcome was compared between the 3-year Before Switch and After Switch treatment periods. The primary outcome measure was the annualized relapse rate; secondary outcome measures were the proportion of relapse-free patients and the median change in Expanded Disability Status Scale (EDSS). Patients were switched either from low-dose to high-dose interferon-β (IFNβ; n  = 31), from IFNβ to glatiramer acetate (GA; n  = 52) or mitoxantrone ( n  = 13), or from GA to IFNβ ( n  = 16). In 3 years after switching, annualized relapse rates fell by 57–78% according to the group. The proportion of relapse-free patients varied from 56% to 81%. Least improved was observed in patients switching between INFβ preparations. Median EDSS scores remained stable in all groups except the GA to IFNβ switchers. In conclusion, patients who fail first-line immunomodulatory therapy generally benefit from switching to another class of immunomodulatory therapy.     

Significance of neutralizing antibodies to interferon beta during treatment of multiple sclerosis: expert opinions based on the Proceedings of an International Consensus Conference

On August 30, 2002, an international panel of neurologists who specialize in the treatment of multiple sclerosis (MS) was convened in Paris (France) to discuss the issue of neutralizing antibodies (NAb) to interferon beta (IFN-beta) therapy in patients with MS. The goals of this meeting were to: (i) review the most recent clinical information on NAb, (ii) come to a consensus on the clinical relevance of NAb in the management of patients with MS receiving IFN-beta therapy, and (iii) establish a framework for the development of patient management guidelines based on scientific consensus. The meeting was chaired by Hans-Peter Hartung (Heinrich-Heine University, Düsseldorf, Germany) and Huub Schellekens (Utrecht University, Utrecht, the Netherlands). This article summarizes the opinions of the expert panel on a number of key issues raised at the meeting.     

Long-term clinical experience with weekly interferon beta-1a in relapsing multiple sclerosis

Post-marketing surveillance studies are needed to assess the long-term safety, compliance and clinical efficacy of interferon beta-1a (IFN β -1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long-term intramuscular (i.m.) IFN β -1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 ± 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with ≤2 relapses in the previous 2 years and with baseline EDSS scores of ≤2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFN β -1a, extending the reported follow-up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.     

Immunological assay for assessing the efficacy of glatiramer acetate (Copaxone) in multiple sclerosis

Recently we described an enzyme-linked immunoadsorbent spot (ELISPOT) assay allowing us to define an immunological response profile observed in multiple sclerosis patients treated with Copaxone (glatiramer acetate; GA) but not untreated subjects [4]. The profile encompasses three criteria, a) reduced proliferative response to GA (as observed with a standard primary proliferation assay); b) strong in vitro activation of interferon-γ-producing T cells at high concentrations of GA (as detected by interferon-γ ELISPOT); and c) activation of interleukin–4-producing T cells over a wider range of concentrations of GA (as detected by interleukin–4 ELISPOT). It is at present unknown whether the immunological response to GA correlates with the clinical response. To address this question we performed the pilot study reported here. We asked the major German multiple sclerosis centres to send us blood samples from all GA-treated patients who were going to discontinue treatment because of treatment failure. The clinical nonresponders either had an unchanged or increased exacerbation rate, or developed a secondary progressive course during GA treatment. Over more than one year, we prospectively collected 9 samples from clinical non-responders. We compared the immune response to GA of peripheral blood mononuclear cells from the 9 clinical nonresponders with 15 clinical responders, using a standard proliferation assay combined with ELISPOT assays for detection of interferon-γ and interleukin–4 secreting cells. Thirteen (86 %) of the 15 clinical responders met at least 2 of the immunological response criteria mentioned above. In contrast, only 2 (22 %) of the 9 clinical nonresponders met two of the immunological criteria (p = 0.0006). We conclude that the ELISPOT assay may provide a promising additional tool for monitoring the treatment response in multiple sclerosis patients treated with GA. Received: 31 January 2002, Received in revised form: 27 June 2002, Accepted: 8 July 2002 Correspondence to R. Hohlfeld     

Clinical and immune responses correlate in glatiramer acetate therapy of multiple sclerosis

Glatiramer acetate (GA) treatment for relapsing remitting multiple sclerosis (RRMS) leads to decreased GA-specific proliferative responses and a Th2 cytokine shift. To study a possible correlation between immunological and clinical responses to GA therapy, we prospectively followed RRMS patients clinically, by magnetic resonance imaging and by primary immunological assays. Fluctuation of GA-specific proliferative responses was significantly lower in treatment responders than in untreated patients, and GA-specific proliferative responses were increased during relapses. These associations suggest a possible causal relationship between immunological and clinical responses to GA therapy. Primary proliferation assays may thus be a useful marker for treatment response.     

Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate

OBJECTIVES: We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes. MATERIAL AND METHODS: Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone. RESULTS: T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro. CONCLUSION: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.     

Interferon beta in secondary progressive multiple sclerosis

Abstract Background and objective Observational studies may provide additional information about the behaviour of different drugs in the post-marketing period. We present the data from a cohort of secondary progressive multiple sclerosis (SPMS) patients treated with interferon beta (IFNβ-1b) at our MS clinic. Methods This was an independent, open-label, non-randomised, observational study. Within the period 1998 to 2005, all patients with SPMS who started therapy with IFNβ-1b at our centre were studied. Each patient was included in a follow-up protocol collecting demographic and baseline clinical data. Results We studied 146 SPMS patients with a median follow-up of 60 months. Over the total study period, 62.2% of patients had confirmed progression. The analysis of the time to con- firmed progression showed that patients with two or more relapses in the 2 years before IFNβ initiation, had a higher risk of disability increase than those patients with less than two relapses (p = 0.002). Multiple regression analysis showed disease activity in terms of relapses as the only factor to predict increase of disability during the follow-up period. A significant proportion of patients (36%) stopped treatment during the follow-up period. IFNβ was safe, although some unexpected adverse events were observed. Conclusions A higher disease activity before the beginning of treatment with IFNβ in SPMS patients with a given EDSS rank could identify those with faster disability progression after treatment initiation.     

Clinical features of Sjogren’s syndrome in patients with multiple sclerosis

Annunziata P, De Santi L, Di Rezze S, Millefiorini E, Capello E, Mancardi G, De Riz M, Scarpini E, Vecchio R, Patti F. Clinical features of Sjogren’s syndrome in patients with multiple sclerosis.
Acta Neurol Scand: 2011: 124: 109–114.
© 2010 John Wiley & Sons A/S. Objectives – To assess the frequency of clinical features of Sjogren’s syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease‐modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. Methods – A multicentre cross‐sectional observational study was designed, based on a structured neurologist‐administered questionnaire to 440 patients. Results – Twenty‐eight of 230 (12%) patients receiving treatment with DMDs (DMDs⁺) and 14 of 210 (6.6%) treatment‐naïve patients (DMDs⁻) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs⁺ and two were DMDs⁻. Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium‐enhanced MRI‐positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). Conclusions – Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.     

Comparison of interferon beta products and azathioprine in the treatment of relapsing-remitting multiple sclerosis

We compared the relative efficacy of interferon beta (IFNβ) products and azathioprine (AZA) in the treatment of relapsing- remitting multiple sclerosis (RRMS). Ninety-four previously untreated patients of short duration with RRMS were randomly allocated to the two treatment groups. The first group received IFNβ products (Betaferon,Avonex or Rebif); the second group received AZA for 12 months. Response to treatment was assessed at 3, 6, and 12 months after starting therapy. The mean number of relapse during one year of the study was lower in the AZA group than in the IFNβ products group (0.28 vs. 0.64, P < 0.05).After 12 months, 57.4% of patients receiving IFNβ products remained relapse free compared with 76.6% of those given AZA. The Expanded Disability Status Scale (EDSS) decreased by 0.30 units in IFNβ-treated patients (P < 0.05) and 0.46 in AZAtreated patients (P < 0.001). Treatment with IFNβ products and AZA significantly reduces the relapse rate and EDSS score in patients with RRMS, while AZA is more effective than the IFNβ formulations.     

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease‐modifying therapies in patients with relapsing‐remitting multiple sclerosis

Background: Most disease‐modifying therapies (DMTs) for multiple sclerosis (MS) are self‐injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing‐remitting MS. Methods: This was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta‐1a (IFNβ‐1a), subcutaneous IFNβ‐1a, IFNβ‐1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long‐term DMTs. Results: Two thousand six hundred and forty‐eight patients were studied, revealing an average treatment duration of 31 months. Seventy‐five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non‐adherence were forgetting to administer the injection (50.2%) and other injection‐related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non‐adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non‐adherent patients. Women were more likely than men to adhere to treatment. Conclusion: Identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long‐term DMTs.     

Neurologic consequence of delaying glatiramer acetate therapy for multiple sclerosis: 8-year data

OBJECTIVE: To assess the long-term effectiveness of continuous glatiramer acetate (GA) therapy in relapsing-remitting multiple sclerosis (RRMS). METHODS: This open-label extension followed a randomized, placebo-controlled, double-blind study of GA of approximately 30 months duration. Patients originally randomized to GA continued on it (group A) and those randomized to placebo switched to GA (group B). RESULTS: Of 251 original patients, 142 (56.6%) remained in the study after 8 years. Annual relapse rate for both groups declined to approximately 0.2 (approximately one relapse every 5 years). However, a significantly larger proportion of patients in group A had stable or improved Expanded Disability Status Scale scores compared with group B (65.3% vs 50.4%, respectively; P = 0.0263), possibly attributable to the delay of GA treatment for approximately 30 months in group B. GA was well tolerated and no drug-related laboratory changes were observed. CONCLUSIONS: These data support early initiation of GA therapy as an efficacious and well-tolerated long-term treatment for RRMS patients.     

Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS

BACKGROUND : Glatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients. OBJECTIVE : To determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy. DESIGN/METHODS : 40 RRMS patients, aged 18 to 55 years, with 1-15 Gd-enhancing lesions on screening MRI and EDSS score 0-6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15. RESULTS : At baseline, mean (+/- SD) age was 37.2 +/- 9.7 years; disease duration, 3.5 +/- 4.8 years; EDSS score, 2.3 +/- 1.1; and number of Gd-enhancing lesions, 3.75 +/- 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11-0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone. CONCLUSIONS : Longterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.