P Rieckmann

King Faisal Specialist Hospital and Research Centre, Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia

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Publications (255)1273.09 Total impact

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    ABSTRACT: Recent large-scale association studies have identified over 100 MS risk loci. One of these MS risk variants is single-nucleotide polymorphism (SNP) rs17066096, located ~14 kb downstream of IL22RA2. IL22RA2 represents a compelling MS candidate gene due to the role of IL-22 in autoimmunity; however, rs17066096 does not map into any known functional element. We assessed whether rs17066096 or a nearby proxy SNP may exert pathogenic effects by affecting microRNA-to-mRNA binding and thus IL22RA2 expression using comprehensive in silico predictions, in vitro reporter assays, and genotyping experiments in 6,722 individuals. In silico screening identified two predicted microRNA binding sites in the 3'UTR of IL22RA2 (for hsa-miR-2278 and hsa-miR-411-5p) encompassing a SNP (rs28366) in moderate linkage disequilibrium with rs17066096 (r (2) = 0.4). The binding of both microRNAs to the IL22RA2 3'UTR was confirmed in vitro, but their binding affinities were not significantly affected by rs28366. Association analyses revealed significant association of rs17066096 and MS risk in our independent German dataset (odds ratio = 1.15, P = 3.48 × 10(-4)), but did not indicate rs28366 to be the cause of this signal. While our study provides independent validation of the association between rs17066096 and MS risk, this signal does not appear to be caused by sequence variants affecting microRNA function.
    Neurogenetics 03/2014; · 3.58 Impact Factor
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    ABSTRACT: The prevalence of multiple sclerosis (MS) is now considered to be medium-to-high in the Middle East and is rising, particularly among women. While the characteristics of the disease and the response of patients to disease-modifying therapies are generally comparable between the Middle East and other areas, significant barriers to achieving optimal care for MS exist in these developing nations. A group of physicians involved in the management of MS in ten Middle Eastern countries met to consider the future of MS care in the region, using a structured process to reach a consensus. Six key priorities were identified: early diagnosis and management of MS, the provision of multidisciplinary MS centres, patient engagement and better communication with stakeholders, regulatory body education and reimbursement, a commitment to research, and more therapy options with better benefit-to-risk ratios. The experts distilled these priorities into a single vision statement: "Optimization of patient-centred multidisciplinary strategies to improve the quality of life of people with MS." These core principles will contribute to the development of a broader consensus on the future of care for MS in the Middle East.
    Multiple sclerosis international. 01/2014; 2013:952321.
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    ABSTRACT: Late-onset myasthenia gravis (LOMG) has become the largest MG subgroup, but the underlying pathogenetic mechanisms remain mysterious. Among the few etiological clues are the almost unique serologic parallels between LOMG and thymoma-associated MG (TAMG), notably autoantibodies against acetylcholine receptors, titin, ryanodine receptor, type I interferons or IL-12. This is why we checked LOMG patients for two further peculiar features of TAMG - its associations with the CTLA4(high/gain-of-function) +49A/A genotype and with increased thymic export of naïve T cells into the blood, possibly after defective negative selection in AIRE-deficient thymomas. We analyzed genomic DNA from 116 Caucasian LOMG patients for CTLA4 alleles by PCR/restriction fragment length polymorphism, and blood mononuclear cells for recent thymic emigrants by quantitative PCR for T cell receptor excision circles. In sharp contrast with TAMG, we now find that: i) CTLA4(low) +49G(+) genotypes were more frequent (p = 0.0029) among the 69 LOMG patients with age at onset ≥60 years compared with 172 healthy controls; ii) thymic export of naïve T cells from the non-neoplastic thymuses of 36 LOMG patients was lower (p = 0.0058) at diagnosis than in 77 age-matched controls. These new findings are important because they suggest distinct initiating mechanisms in TAMG and LOMG and hint at aberrant immuno-regulation in the periphery in LOMG. We therefore propose alternate defects in central thymic or peripheral tolerance induction in TAMG and LOMG converging on similar final outcomes. In addition, our data support a 60-year-threshold for onset of 'true LOMG' and an LOMG/early-onset MG overlapping group of patients between 40 and 60.
    Journal of Autoimmunity 12/2013; · 8.15 Impact Factor
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    ABSTRACT: A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ∼20 000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta-analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 × 10(-6); rs630923: odds ratio = 0.89, P = 1.2 × 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 × 10(-6); rs180515: odds ratio = 1.12, P = 5.2 × 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 × 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 × 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology.
    Brain 06/2013; 136(6):1778-82. · 10.23 Impact Factor
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    ABSTRACT: BACKGROUND: Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis. METHODS: In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00879658. FINDINGS: Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17-57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29-69) for siponimod 0·5 mg (43 patients), 66% (48-80) for siponimod 1·25 mg (42 patients), 72% (57-84) for siponimod 2 mg (45 patients), and 82% (70-90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious). INTERPRETATION: Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial. FUNDING: Novartis Pharma AG.
    The Lancet Neurology 06/2013; · 23.92 Impact Factor
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    ABSTRACT: Objective To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 3× weekly (tiw) compared with placebo in patients with relapsing–remitting multiple sclerosis (RRMS). Methods This randomized, double-blind study was conducted in 142 sites in 17 countries. Patients with RRMS with at least 1 documented relapse in the 12 months before screening, or at least 2 documented relapses in the 24 months before screening, and an Expanded Disability Status Scale score ≤ 5.5, were randomized 2:1 to receive either subcutaneous (sc) GA 40mg tiw (1ml) or placebo for 12 months. ResultsOf 1,524 patients screened, 1,404 were randomized to receive GA 40mg sc tiw (n = 943) or placebo (n = 461). Ninety-three percent and 91% of patients in the placebo and GA groups, respectively, completed the 12-month study. GA 40mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with placebo (mean annualized relapse rate = 0.331 vs 0.505; p < 0.0001). Patients who received GA 40mg tiw experienced highly significant reduction (p < 0.0001) in the cumulative number of gadolinium-enhancing T1 (44.8%) and new or newly enlarging T2 lesions (34.7%) at months 6 and 12. GA 40mg tiw was safe and well tolerated. The most common adverse events in the GA group were injection site reactions (35.5% with GA vs 5.0% with placebo). InterpretationGA 40mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the convenience of fewer sc injections per week. ANN NEUROL 2013;73:705–713
    Annals of Neurology 06/2013; 73(6). · 11.19 Impact Factor
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    ABSTRACT: The epidemiology of multiple sclerosis (MS) is rapidly changing in many parts of the world. Based on the Kurtzke classification, the Arabian Gulf Region is located in a low-risk zone for MS; however, recent studies suggest a moderate-to-high prevalence nearby (31-55 MS per 10,0000 individuals), with an increase in incidence in recent years. The relapsing-remitting disease course ratio is 2.5:1 versus the primary progressive type. In a geographic area that was previously associated with low prevalence; the recent high prevalence and fast rising incidence of MS in the gulf countries, encouraged the neurologists of this region to meet in a consensus panel, in order to share our latest findings in terms of MS epidemiology and consent on MS management in the Arabian Gulf. Therefore 20 key opinion leader neurologists and MS experts representing various countries of the Arabian Gulf have met in Dubai on the 2 and 3 February 2012, they shared their latest epidemiological findings, discussed recent MS aspects in the region, and consented on MS management relevantly to this geographic area.
    Journal of Neurology 03/2013; · 3.58 Impact Factor
  • Journal of Medical Genetics 01/2013; · 5.70 Impact Factor
  • Multiple Sclerosis and Related Disorders. 01/2013; 2(1):29-35.
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    ABSTRACT: We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing-remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.
    Journal of Neurology 12/2012; · 3.58 Impact Factor
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    ABSTRACT: BACKGROUND: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. OBJECTIVE: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. METHODS: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. RESULTS: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44-0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (-28%, p=0.0209), fewer new T2 lesions/year (-42%, <0.0001) and lower T2 lesion volume (-22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. CONCLUSIONS: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.
    Multiple Sclerosis 12/2012; · 4.47 Impact Factor
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    ABSTRACT: BACKGROUND: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. METHODS: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. RESULTS: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 +/- 22 % of baseline amplitude, p < 0.001) and in MS patients (69 +/- 18 %, p < 0.001). In contrast, post-cTBS force production performance was only impaired in controls (2.2 +/- 2.8, p = 0.011), but not in MS patients (2.0 +/- 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. CONCLUSIONS: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.
    BMC Neurology 09/2012; 12(1):92. · 2.56 Impact Factor
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    ABSTRACT: The "MS in the 21st Century" initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm. The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada-consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers-participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centers of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The "MS in the 21st Century Steering Group" hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS.
    Journal of Neurology 08/2012; · 3.58 Impact Factor
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    ABSTRACT: BACKGROUND: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation. OBJECTIVE: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. METHODS: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. RESULTS: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. CONCLUSION: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
    Multiple Sclerosis 03/2012; · 4.47 Impact Factor
  • Neurology 03/2012; 78(11):841. · 8.30 Impact Factor
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    ABSTRACT: The objectives of this study were to identify and describe the demographic and clinical characteristics of multiple sclerosis (MS) in aboriginals in British Columbia (BC), Canada and compare these findings with non-aboriginal MS patients. This retrospective chart and database review accessed patient information from the linked BC-wide MS clinical and genetics databases. Data gathered included: demographics (age, sex and ethnicity); clinical characteristics (MS onset date, disease course and disability scores (Expanded Disability Status Scale [EDSS]). Aboriginals were identified via the database linkage augmented by physician and nurse recall. Two non-aboriginal comparator groups with definite MS were selected. Group one included all definite MS patients in the BC MS database, and group two comprised MS patients matched by sex, age at onset and initial disease course. Patient characteristics were compared using the Student's t-test, chi-squared test, and Kaplan-Meier survival analysis was used to examine disease progression (time to sustained and confirmed EDSS 6) We identified 26 aboriginals with MS, of which 19/26 (73%) were female, 23/26 (89%) had relapsing-onset MS and a mean onset age of 31.1 years. There were no significant differences between the MS aboriginals and the non-matched (n = 5708) comparator group with respect to age, sex or disease course (p > 0.1), However, aboriginals progressed more rapidly to EDSS 6 from disease onset (p < 0.001) when compared with the matched and unmatched comparator groups. We identified a small, but important cohort of aboriginals with MS; being the largest identified to date. There was evidence of more rapid MS progression in aboriginals compared with non-aboriginals.
    Multiple Sclerosis 03/2012; 18(9):1239-43. · 4.47 Impact Factor
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    ABSTRACT: Objective: The objective of this study was to assess the effect of treatment with interferon (IFN) β-1a, 44 µg subcutaneously (sc) three times weekly (tiw), on clinical and magnetic resonance imaging (MRI) outcomes in patients with relapsing multiple sclerosis (MS) following mitoxantrone therapy.Methods: This was an open-label, randomized, multicentre, rater-blinded, 96-week observational study conducted in Germany. Clinically stable patients with relapsing forms of MS, who had discontinued mitoxantrone treatment 1-6 months before study entry, were randomized to IFN β-1a sc 44 µg tiw, or no treatment. The primary endpoint was time to first relapse. Secondary endpoints included the number of relapse-free patients, disease activity assessed by MRI and time to 3-month confirmed Expanded Disability Status Scale (EDSS) progression, all at week 96.Results: A total of 30 patients were randomized (intent-to-treat population: 14 IFN β-1a, 15 untreated; one patient from the safety population discontinued the study after 25 days owing to an adverse event and without providing any postbaseline efficacy data, and was thus excluded from the intent-to-treat population). Overall, 71.4% (10/14) of patients in the IFN β-1a group remained relapse free over 96 weeks, versus 46.7% (7/15) in the untreated group (p = 0.26). IFN β-1a delayed the time to first relapse versus no treatment (p = 0.14); time to first relapse (25th percentile) was 95.4 (IFN β-1a) versus 46.0 weeks (no treatment). Confirmed EDSS progression was observed in five patients in each treatment group. Mean change in EDSS score was 0.3 in both groups (p = 0.79). Changes in the number or volume of T1 and T2 lesions at week 96 were not significantly different between treatment groups (p > 0.05). There were no new or unexpected adverse events related to IFN β-1a treatment.Conclusions: Several endpoints appeared to show a benefit of IFN β-1a treatment, but no significant differences could be detected owing to the small sample. Therefore, these data only permit, at best, tentative conclusions about the disease course in patients with MS after de-escalation from mitoxantrone and continuation with or without IFN β-1a. Larger confirmatory studies are required.
    Therapeutic Advances in Neurological Disorders 01/2012; 5(1):3-12.
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    ABSTRACT: Multiple sclerosis (MS) is a common, chronic, neurodegenerative condition associated with substantial healthcare and societal economic burden. Disease-modifying MS treatments have the potential to reduce health resource utilization (HRU), thereby reducing the attendant socioeconomic burden. This study aimed to compare health and societal resource use and productivity in patients with relapsing-remitting MS (RRMS) receiving cladribine tablets versus placebo over 96 weeks in the CLARITY study. The CLARITY study was a 96-week, randomized, double-blind, placebo-controlled study in patients with RRMS. HRU data, societal resource use and productivity data were collected at baseline and during scheduled patient visits, at 6-month intervals. The recall period for the HRU questionnaire was 3 months. The study was carried out at 155 sites across 32 countries worldwide. The intent-to-treat population comprised 1326 patients with RRMS randomized to cladribine 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) tablets or placebo (n = 437). Patient subgroups with high baseline disease activity were identified based on criteria of ≥2 relapses in the previous year (n = 392); ≥1 T1 gadolinium-enhancing (Gd+) lesion (n = 413); and ≥2 relapses in the previous year plus ≥1 T1 Gd+ lesion (n = 138). Cladribine tablets were administered in two (3.5 mg/kg group) or four (5.25 mg/kg group) short courses given at 4-week intervals at the start of a 48-week treatment period, followed by another two courses at the start of a subsequent 48-week re-treatment period. Interferon-β rescue therapy was permitted from week 24. Intravenous corticosteroids were available for the treatment of neurological relapses. HRU outcomes included mean number of hospital days and emergency room (ER), clinic and home visits during each study period. Societal resource use and productivity outcomes included mean number of hours and days of paid assistance, mean patient and carer work days missed, and self-reported productivity. The mean number of hospital days per patient over 96 weeks was lower in the cladribine tablets groups (3.5 mg/kg group: -3.19 days; 5.25 mg/kg group: -1.54 days [both p < 0.01]) versus placebo. Likewise the mean number of ER visits was lower in both cladribine tablet groups compared with placebo (3.5 mg/kg group: -0.09 visits; 5.25 mg/kg group: -0.11 visits [both p < 0.01]), and the mean number of clinic visits was also lower in both cladribine tablet groups (3.5 mg/kg group: -0.68 visits; 5.25 mg/kg group: -0.66 visits [both p = 0.01]). Furthermore, treatment with cladribine tablets was associated with reduced mean numbers of missed work days for patients (3.5 mg/kg group: -2.42 days [p < 0.01]; 5.25 mg/kg group: -0.60 days [p = 0.50]). Corticosteroid use was lower amongst patients in the cladribine tablet groups than in the placebo group. The reduction in hospital days following treatment with cladribine tablets was also observed in patients with high disease activity at study baseline. This study provides evidence that the efficacy of cladribine tablets observed during the CLARITY study was associated with a reduced consumption of healthcare resources and a decreased need for medical and societal support. TRIAL REGISTRATIon: ClinicalTrials.gov identifier: NCT00213135; EudraCT number: 2004-005148-28.
    Clinical Drug Investigation 01/2012; 32(1):15-27. · 1.70 Impact Factor
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    ABSTRACT: Background In the phase III CLARITY study, treatment with cladribine tablets at cumulative doses of 3.5 or 5.25 mg/kg over 96 weeks led to significant reductions in annualized relapse rates (ARR) versus placebo in patients with relapsing–remitting multiple sclerosis. Further post hoc analyses of CLARITY study data were conducted to determine the efficacy of cladribine tablets across patient subgroups stratified by baseline characteristics.Methods Relapse rates over the 96-week CLARITY study were analyzed in cohorts stratified by demographics; disease duration; treatment history and disease activity at baseline.ResultsIn the intent-to-treat population (n=437, 433 and 456 in the placebo, cladribine 3.5 and 5.25 mg/kg groups, respectively), treatment with cladribine tablets 3.5 and 5.25 mg/kg led to consistent improvements in ARR versus placebo in patients stratified by gender; age (≤40/>40 years); disease duration (<3/3–10/>10 years); prior disease-modifying drug treatment (treated/naïve); relapses in the prior year (≤1/2/≥3); Expanded Disability Status Scale score (<3.5/≥3.5); T1 gadolinium-enhancing lesions (presence, absence); and T2 lesion volume (≤median/>median) at baseline (all P≤0.05 for reduction in the relative risk of relapse [cladribine tablets versus placebo]). Significant effects were also observed in patients who had only one relapse in the year prior to study entry (n=306, 303 and 323 in the placebo, cladribine 3.5 and 5.25 mg/kg groups, respectively) and who were further stratified according to other measures of disease activity at baseline.Conclusions Treatment with cladribine tablets provides consistent reductions in ARR compared with placebo across the spectrum of baseline demographics and disease characteristics represented in the CLARITY study.
    Multiple Sclerosis and Related Disorders. 01/2012; 1(1):49–54.
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    ABSTRACT: Recent natural history studies suggest that multiple sclerosis (MS) is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach. We investigated whether MS disease progression has changed over time in British Columbia, Canada. The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration. Kaplan-Meier analysis was used to compare: the proportion of patients reaching EDSS 6 (primary analysis) and the time to EDSS 6 (secondary analysis) across the time-period groups. Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant temporal trend was found in the proportion of patients reaching EDSS 6 within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09) or in survival curves for time to reach the outcome (p = 0.14). Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.
    Multiple Sclerosis 09/2011; 18(4):442-50. · 4.47 Impact Factor

Publication Stats

6k Citations
1,273.09 Total Impact Points

Institutions

  • 2013
    • King Faisal Specialist Hospital and Research Centre
      Ar Riyāḑ, Ar Riyāḑ, Saudi Arabia
  • 2011–2013
    • Universitätsklinikum Erlangen
      • Department of Neurology
      Erlangen, Bavaria, Germany
  • 1996–2013
    • University of Wuerzburg
      • • Department of Neurology
      • • Institute for Pathology
      Würzburg, Bavaria, Germany
    • German Primate Center
      Göttingen, Lower Saxony, Germany
  • 2011–2012
    • Sozialstiftung Bamberg/Klinikum Bamberg
      Bamberg, Bavaria, Germany
  • 2008–2012
    • University of British Columbia - Vancouver
      • • Division of Neurology
      • • Department of Medicine
      Vancouver, British Columbia, Canada
    • Universität Heidelberg
      • Institute of Pathology (Mannheim)
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2009–2010
    • University of Groningen
      • Department of Neurology
      Groningen, Province of Groningen, Netherlands
  • 2007
    • Ruhr-Universität Bochum
      • Neurologische Klinik
      Bochum, North Rhine-Westphalia, Germany
    • Northwestern University
      • Feinberg School of Medicine
      Evanston, IL, United States
  • 2001
    • King College
      Guymon, Oklahoma, United States
  • 1988–2000
    • Universitätsmedizin Göttingen
      • Department of Neurology
      Göttingen, Lower Saxony, Germany
  • 1999
    • Karl-Franzens-Universität Graz
      Gratz, Styria, Austria
  • 1995–1997
    • Georg-August-Universität Göttingen
      • Division of Agroecology
      Göttingen, Lower Saxony, Germany
  • 1990–1992
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States