Mike Boggild

Treatment of neuromyelitis optica with rituximab: Retrospective analysis of 25 patients

BACKGROUND Neuromyelitis optica (NMO) is an uncommon, life-threatening inflammatory demyelinating disorder. Recently, much has become known about its immunopathogenesis. However, optimal treatments, with expected outcomes, have not been established. OBJECTIVE To evaluate the use and efficacy of rituximab for treating NMO. DESIGN Retrospective multicenter case series of NMO patients treated with rituximab. SETTING Seven tertiary medical centers in the United States and England. PATIENTS Twenty-five patients (including 2 children), 23 of whom experienced relapses despite use of other drugs before rituximab. Extended follow-up of 7 previously reported patients is included. INTERVENTIONS Infusions of rituximab at median intervals of 8 months. MAIN OUTCOME MEASURES Annualized relapse rate and disability (expressed as Expanded Disability Status Scale score). RESULTS At a median follow-up of 19 months, the median annualized posttreatment relapse rate was lower than the pretreatment rate (0 [range 0-3.2] vs 1.7 [range, 0.5-5] relapses, P < .001). Disability improved or stabilized in 20 of 25 patients (80%, P = .02). Two patients died during the follow-up period, 1 owing to a brainstem relapse and 1 owing to suspected septicemia. Infections were reported in 20% of patients. CONCLUSIONS In NMO, treatment with rituximab appears to reduce the frequency of attacks, with subsequent stabilization or improvement in disability.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort

Objective: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). Methods: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7–107.3). Results: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12–18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02–17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50–6.19) were predictive of AID expression. Conclusions: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. Classification of evidence: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

A randomised controlled trial comparing rehabilitation against standard therapy in multiple sclerosis patients receiving intravenous steroid treatment

Background: There is evidence to support both the use of intravenous methylprednisolone (IVMP) in multiple sclerosis (MS) relapse and physiotherapy in the management of MS, but no studies have investigated the combination of steroids and rehabilitation together. Objectives: To evaluate the benefits of IVMP with planned, comprehensive multidisciplinary team (MDT) care compared to IVMP with standard care. Methods: In this randomised controlled trial, patients confirmed to have had a definite MS relapse severe enough to warrant IVMP (1 g daily for three days) were randomised to two groups. The control group was managed according to the standard ward routine; the treatment group received planned coordinated multidisciplinary team assessment and treatment. Baseline assessments, including demographics and Expanded Disability Status Scale (EDSS) were carried out on both groups. The primary outcome measures were Guy’s Neurological Disability Scale (GNDS), and Amended Motor Club Assessment (AMCA). The secondary measures were the Barthel Index (BI), Human Activity Profile (HAP), and Short Form Item 36 Health Survey (SF-36). All measures have published data on reliability and validity. Measures were administered at one and three months. Results: Forty subjects, including 27 females, completed data collection. There were no significant differences between the two groups at baseline. Results showed statistically significant differences in GNDS (p = 0.03), AMCA (p = 0.03), HAPM (p < 0.01), HAPA (p = 0.02), and BI (p = 0.02) at three months in favour of planned MDT care. Conclusion: This study indicates that combining steroids with planned MDT care is superior to administering them in a standard neurology or day ward setting. Further research is necessary in order to confirm this finding.

Multiple sclerosis risk sharing scheme: two year results of clinical cohort study with historical comparator

Objective To generate evidence on the longer term cost effectiveness of disease modifying treatments in patients with relapsing-remitting multiple sclerosis. Design Prospective cohort study with historical comparator. Setting Specialist multiple sclerosis clinics in 70 centres in the United Kingdom. Participants Patients with relapsing-remitting multiple sclerosis who started treatment from May 2002 to April 2005 under the UK risk sharing scheme. Interventions Treatment with interferon beta or glatiramer acetate in accordance with guidelines of the UK Association of British Neurologists. Main outcome measures Observed utility weighted progression in disability at two years’ follow-up assessed on the expanded disability status scale (EDSS) compared with that expected by applying the progression rates in a comparator dataset, modified for patients receiving treatment by multiplying by the hazard ratio derived separately for each disease modifying treatment from the randomised trials. Results In the primary per protocol analysis, progression in disability was worse than that predicted and worse than that in the untreated comparator dataset (“deviation score” of 113%; excess in mean disability status scale 0.28). In sensitivity analyses, however, the deviation score varied from −72% (using raw baseline disability status scale scores, rather than applying a “no improvement” algorithm) to 156% (imputing missing data for year two from progression rates for year one). Conclusions It is too early to reach any conclusion about the cost effectiveness of disease modifying treatments from this first interim analysis. Important methodological issues, including the need for additional comparator datasets, the potential bias from missing data, and the impact of the “no improvement” rule, will need to be addressed and long term follow-up of all patients is essential to secure meaningful results. Future analyses of the cohort are likely to be more informative, not least because they will be less sensitive to short term fluctuations in disability.

Susceptibility and outcome in MS Associations with polymorphisms in pigmentation-related genes

Multiple sclerosis (MS) risk is determined by environment and genes. The authors investigated in 419 cases and 422 controls if polymorphism in the vitamin D receptor (VDR), melanocortin-1 receptor (MC1R), and tyrosinase (TYR) genes is linked with MS risk and outcome. VDR ff was associated with reduced (odds ratio [OR] = 0.59) and MC1R His294-encoding alleles with increased (OR = 2.21) risk. MC1R Glu84/Glu84 was linked with disability (OR = 5.65). These preliminary data suggest a role for these genes in MS pathogenesis.

Therapy-related acute leukaemia with Mitoxantrone: what is the risk and can we minimise it?

Background Therapy-related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for multiple sclerosis (MS). The timing of this complication, risk, mortality and relationship to exposure remain uncertain. Methods We searched literature for publications relating to Mitoxantrone in MS, reviewed publication references and handsearched abstract lists to identify case-series reporting follow-up and complications of treatment with Mitoxantrone. We combined this with our local database of 250 cases treated since 1997. We also identified all reported individual cases of TRAL and extracted data reporting exposure (dose or mg/m2), timing and outcome of TRAL. Results Case-series including 5472 patients were identified; mean dose of Mitoxantrone was 74.2 mg/m2 (range:12–120 mg/m2). TRAL was diagnosed in 0.30% (1 in 333). In 34 TRAL cases, sufficient data was available to inform analysis of exposure. Onset was a median of 18.5 months following Mitoxantrone treatment (range:4–60). Acute Myelocytic Leukaemia and Acute Promyelocytic Leukaemia represented 46.4% each of the leukaemia subtypes. Six of 25 TRAL patients, where outcome was reported, died (24%). Over 80% of cases occurred in patients exposed to >60 mg/m2, with a relative risk of 1.44 (CI95%:1.18–1.70) when comparing total dose >60 mg/m2 against <60 mg/m2 strongly suggesting a relationship between risk of TRAL and total dose.

Glutathione S-transferase polymorphisms in MS Their relationship to disability

Background: Oxidative stress has been implicated in inflammatory demyelination. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1/GSTT1), encode low activity variants (GSTP1), or are associated with variable inducibility (GSTM3). Objectives: To investigate the association between clinical outcome in MS and allelic variants of GSTM1, GSTM3, GSTT1, and GSTP1. Methods: Four hundred patients with clinically definite MS were studied. Disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS). Disability was graded as mild (EDSS 0–4), moderate (4.5–5.5), or severe (EDSS 6–10). PCR-based genotyping was performed using DNA extracted from lymphocytes. Significant associations between GST genotypes and clinical outcome were corrected for gender, onset age, and disease duration using logistic regression. Results: We found that the GSTM3 AA genotype was associated with severe disability in patients with a disease duration of more than 10 years (p = 0.027, n = 177, OR = 2.4, 95% CI = 1.1–5.0). Homozygosity for both GSTM1*0 and GSTP1*Ile105 containing allele was associated with severe disability in patients with a disease duration greater than 10 years (p = 0.022, n = 179, OR = 5.0, 95% CI = 1.3–19.8). Conclusions: Our results suggest that long-term prognosis in MS is influenced by a genetically determined ability to remove the toxic products of oxidative stress.

The Multiple Sclerosis Risk Sharing Scheme Monitoring Study--early results and lessons for the future.

BackgroundRisk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS.MethodsThis case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis (MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments.ResultsCentres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies.ConclusionSuccessful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed.

Glatiramer acetate exposure in pregnancy: preliminary safety and birth outcomes

With the increasing incidence of multiple sclerosis (MS) in women and the earlier use of disease modifying therapy (DMT), issues surrounding DMT and pregnancy are a regular subject of discussion with regards to optimal management. Current recommendations are to withdraw DMT prior to conception, leaving patients exposed to an uncertain period of untreated disease. The objective of this study is to report preliminary experience on glatiramer acetate (GA) exposure through conception, pregnancy and the post-partum period in a series of 13 patients with previously highly active relapsing-remitting MS. This is a prospective observational case series. Fourteen pregnancies of 13 women resulted in 13 live births (one twin pregnancy), nine exposed to GA throughout pregnancy. There were no birth defects and treatment was well tolerated. No relapses occurred during pregnancy in those continuing on treatment. In conclusion, our early experience suggests that when considering the risks and benefits of treatment withdrawal prior to pregnancy, it may be reasonable to continue GA in those patients with previously highly active disease. Consideration should also be given to the initiation of a birth register, similar to such initiatives in epilepsy, to generate more robust safety data in this controversial area.

A randomized controlled trial of a health promotion education programme for people with multiple sclerosis

Objective: To evaluate the effectiveness of a health promotion education programme for people with multiple sclerosis (the OPTIMISE programme) in terms of increasing the level of health-promoting activity undertaken, improving self-efficacy and enhancing quality of life. Design: A randomized controlled single blinded trial. Non-parametric analysis was undertaken to test for significant differences between treatment and control groups change scores. Subjects and setting: Sixty-two adults (32 treatment and 30 control subjects) with multiple sclerosis of any type, Expanded Disability Status Scale (EDSS) 1-7. Intervention: An eight-week multidisciplinary outpatient health promotion education programme aimed at increasing knowledge, skills and confidence in undertaking health promotion activities. Outcome measures: Health Promoting Lifestyle Profile, Self-Rated Abilities for Health Practices Scale and the Short Form 36 Item Health Survey. Results: Following completion of the programme, treatment subjects had significantly higher levels of health promotion activity undertaken (P<0.01) and self-efficacy for health promotion activities (P<0.01). These benefits were sustained for at least three months after the programme ceased. Certain domains of quality of life also improved in treatment subjects more than controls (physical P=0.03, mental health and general health P=0.01), although only mental health and general health showed further improvement at three months. Participants provided positive feedback regarding the usefulness of the intervention and demonstrated observable changes to their health promotion behaviours. Conclusions: The OPTIMISE programme produced significant changes in health-promoting behaviours.