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N Koch-Henriksen

Publications and source records attributed to N Koch-Henriksen.

At least 19 recordsLinked to original sources
PubMed2006

A randomized study of two interferon-beta treatments in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate whether the efficacy of interferon-beta (IFNbeta) treatment of relapsing-remitting MS (RR-MS) was influenced by type, dose, and frequency of administration. METHODS: From June 1996 through October 1997, the authors offered participation to all Danish RR-MS patients who met the following criteria: definite MS, at least two relapses within 2 years, age 18 to 55, and an Expanded Disability Status Scale (EDSS) score of < or = 5.5. The study was multicenter, controlled, open-label, randomized, head-to-head comparing IFNbeta-1a 22 microg once a week (n = 143) with IFNbeta-1b 250 microg every other day (n = 158), both subcutaneously, for 24 months. Patients who declined randomization were offered treatment with IFNbeta-1b 250 microg every other day (n = 120). The primary end-points were the annualized relapse rate, the time to first relapse, and neutralizing antibody formation. The secondary endpoint was time to sustained progression. RESULTS: The annual relapse rates were virtually equal in the two arms of the randomized study (IFNbeta-1a: 0.70; IFNbeta-1b: 0.71); so were the time to first relapse and the time to sustained progression. In the nonrandomized patients (IFNbeta-1b), the annual relapse rate was not significantly different, but the time to progression was shorter. CONCLUSION: In this study, 250 microg interferon-beta-1b administered every other day did not prove clinically superior to once-a-week administration of 22 microg interferon-beta-1a.

Adjuvants, Immunologic↗
PubMed2006

Measuring and evaluating interferon beta-induced antibodies in patients with multiple sclerosis.

Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing-remitting multiple sclerosis (MS) were investigated for binding antibody (BAb) by protein-G affinity-chromatography radioimmunoassay and a commercially available enzyme immunoassay (EIA). Neutralizing antibody (NAb) was investigated by cytopathic effect assays (CEA) using both fixed amount and serially diluted sera. BAb correlated with log10-transformed titres obtained by EIA (r=0.70, P<0.0001); the latter, however, failed to demonstrate low-level BAb. Comparison of clinical significance of NAb-positivity measured by biological assays with different sensitivities demonstrated an optimal odds ratio for relapse rate using 10 laboratory units (LU)/mL. Purification of IgG prior to CEA removed toxicity from toxic sera. The neutralizing capacity data correlated linearly with logl0-transformed titres obtained by a Kawade 10-to-1 LU/mL CEA (r=0.77, P<0.0001). In conclusion, neutralizing capacity CEA utilizing a fixed amount of serum predicts differences in relapse rates in IFNbeta-treated MS patients and correlates with NAb titres of the 10-to-1 LU/mL CEA. Neutralizing capacity CEA is less laborious and more economical than titre-based NAb assays and suitable for large-scale screenings of MS patients.

Antibodies↗
PubMed2005

Appearance and disappearance of neutralizing antibodies during interferon-beta therapy.

BACKGROUND: Neutralizing antibodies (NABs) occur frequently in patients receiving interferon (IFN)-beta for multiple sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-beta therapy. METHODS: The authors used an antiviral neutralization bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-beta. Patients were classified into three groups: 1) persistently NAB-negative patients, defined as patients without any positive samples at any time; 2) definitely NAB-positive patients, defined as patients who had at least two consecutive positive samples; and 3) patients with fluctuating NAB-positive and NAB-negative samples. RESULTS: A total of 455 patients were included in the study. Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating. More patients treated with IFN-beta-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-beta-1b (Betaferon) and IFN-beta-1a (Rebif). Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive. CONCLUSIONS: NABs should be measured in all patients treated with IFN-beta. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued. Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.

Adjuvants, Immunologic↗
PubMed2005

Suicide among Danes with multiple sclerosis.

OBJECTIVE: To compare the suicide risk among Danish citizens with multiple sclerosis with that of the general population, and to evaluate changes over 45 years. METHODS: The study was based on linkage of the Danish Multiple Sclerosis Registry to the Cause of Death Registry. It comprised all 10,174 persons in whom multiple sclerosis was diagnosed in the period 1953 to 1996. The end of follow up was 1 January 1999. Standardised mortality ratios (SMRs) were calculated for various times after diagnosis and for age and calendar period of diagnosis. RESULTS: In all, 115 persons (63 men, 52 women) had taken their own lives, whereas the expected number of suicides was 54.2 (29.1 men, 25.1 women). Thus the suicide risk among persons with multiple sclerosis was more than twice that of the general population (SMR = 2.12). The increased risk was particularly high during the first year after diagnosis (SMR = 3.15). CONCLUSIONS: The risk of suicide in multiple sclerosis was almost twice as high as expected more than 20 years after diagnosis. The excess suicide risk has not declined since 1953.

Adult↗
PubMed2005

CD26 + CD4 + T cell counts and attack risk in interferon-treated multiple sclerosis.

Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta.

Adjuvants, Immunologic↗
PubMed2004

The risk of multiple sclerosis in bereaved parents: A nationwide cohort study in Denmark.

BACKGROUND: Previous studies have suggested that psychological stress may play a role in the risk of multiple sclerosis (MS), but the evidence is very limited. OBJECTIVE: To examine the association between MS and a well-defined major stressful life event: the death of a child. METHODS: In this follow-up study based on nationwide and population-based registers, all 21,062 parents who lost a child younger than 18 years from 1980 to 1996 in Denmark were included in the exposed cohort and 293,745 matched parents who did not lose a child in the unexposed cohort. The two cohorts were followed for incident MS from 1980 to 1997. Hazard ratios (HR) with 95% CI were calculated as the measure of association between the exposure and MS, using the Cox proportional hazards regression model. RESULTS: Two hundred fifty-eight MS patients were identified (28 in the exposed cohort and 230 in the unexposed cohort). The exposed parents had an increased risk of MS (HR 1.56, 95% CI 1.05 to 2.31), which is significant only when follow-up was at least 8 years. The HR for definite/probable MS was 1.42 (95% CI 0.90 to 2.24). Parents who lost a child unexpectedly had an HR of 2.13 (95% CI 1.13 to 4.03) for all MS, which is higher than that for other bereaved parents (HR 1.33; 95% CI 0.81 to 2.16). CONCLUSION: Psychological stress may play a role in the development of MS.

Adult↗
PubMed2001

Correlations of brain MRI parameters to disability in multiple sclerosis.

OBJECTIVES: The objective was to correlate magnetic resonance imaging (MRI) T2-weighted lesion load and measures of white matter atrophy in the brain to disability in a population-based sample of patients with multiple sclerosis (MS). MATERIAL AND METHODS: A well defined cohort of patients was drawn at random from the general MS population by using the Danish Multiple Sclerosis Registry. A semi-automated local thresholding technique was used to quantify T2-weighted lesions on MRI; whereas manual tracing was applied to measure the corpus callosum brain ratio (CCR) and the ventricle brain ratio (VBR). RESULTS: A sample of 86 patients with a mean age of 43.3 years (SD 4.3), mean disease duration of 13.6 years (SD 4.4) and a median Expanded Disability Status Score (EDSS) of 6.0 was identified. The correlation between total lesion area of the brain (TLA) and disability (EDSS) for the whole sample was moderate (Spearman rank correlation coefficient r=0.48, P<0.001). Also correlations of CCR and VBR to disability (r=0.32-0.46) were significant. CONCLUSIONS: Correlations of TLA and disability in this study were rather strong. Hence, T2-weighted MRI lesion load in the brain still plays an important role as a surrogate marker of disease and as a secondary outcome measure in phase III treatment trials.

Adult↗
PubMed2001

The Danish Multiple Sclerosis Registry. History, data collection and validity.

The Danish Multiple Sclerosis Registry was formally established in 1956 but started operating in 1949 with a nationwide prevalence survey. Since then, the Registry has continued collecting data on new and old cases of multiple sclerosis (MS) or suspected MS from multiple sources. The Registry reclassifies cases according to standardized diagnostic criteria (currently those of Poser et al). A total of 14,441 cases fulfilling the diagnostic criteria had been registered at the most recently completed follow-up by 1 January 1997; 10,851 had onset from 1948 to 1996 and 3560 before 1948. The completeness has formerly been estimated at about 90%, higher for cohorts with older onset and lower for cohorts with onset close to follow-up. The estimated validity of the diagnosis for autopsy cases classified as definite MS in the Registry is 94%. A long-term nationwide Registry has proved to be a valuable instrument for monitoring incidence and prevalence, analysing survival, performing genetic analysis, providing unselected patient samples for clinical analyses, performing case-control studies and prospective studies and estimating the need for treatment and care.

Age Distribution↗
PubMed2000

The Danish National Project of interferon-beta treatment in relapsing-remitting multiple sclerosis. The Danish Multiple Sclerosis Group.

After approval by the European Union in 1996 of interferon-beta for treatment of relapsing-remitting multiple sclerosis (RRMS), 862 patients in Denmark have received treatment (by April 1999), and 304 of those were enrolled into an open labelled randomised trial to compare the efficacy and tolerability of treatment with interferon-beta-1b (Betaferon) 8 MIU subcutaneous every other day and interferon-beta-1a (Rebif) 6 MIU subcutaneous once a week. Primary and secondary end-points included: (1) the relapse rate, (2) tolerability, (3) neutralizing antibody formation using the same specialised laboratory and validated assay, (4) time to first relapse, (5) time to sustained progression, and (6) number of gadolinium-enhancing lesions in T1-weighted MRI and the total lesion load in T2-weighted MRI. All the records are kept in a nationwide clinical database connected with the Danish Multiple Sclerosis Registry. The randomised trial will be completed by the end of 1999, and the results are not yet available. The annual relapse rate in all treated patients until April 1999 was 0.73, the annual rate of steroid treated relapses was 0.21. By 1 April 1999 8.8% of the patients had discontinued treatment and 10.4% had changed to another interferon-beta preparation. It has been planned to extend the follow-up of all patients treated according to the Danish National Protocol for a period of several years. The continuous and nation-wide registration of the course of the disease in interferon-beta treated RRMS patients may provide valuable knowledge of the treatment-modified long-term course of the disease in a cohort of patients, selected on the basis of well-defined criteria.

Adjuvants, Immunologic↗
PubMed2000

Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group.

A total of 754 consecutive patients with relapsing-remitting multiple sclerosis were investigated for interferon-beta (IFNbeta) antibodies by protein-G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 microg) of subcutaneous IFNbeta-1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 microg) of intramuscular IFNbeta-1a once weekly (n = 140), or 8 MIU every other day of IFNbeta-1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNbeta-1b compared with 6 MIU of IFNbeta-1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNbeta-1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNbeta-1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNbeta-1b group than in the IFNbeta-1a groups; these differences, however, were not significant after 12 months. The number of positive patients varied considerably and depended on the amount of IFN added to the bioassay; adding 10 LU/ml or more masked antibody detection. Antibodies induced by either preparation neutralized both IFNbeta species but not IFNalpha. In conclusion, IFNbeta-induced antibodies are frequently found in multiple sclerosis patients, and IFNbeta-1b is more immunogenic than IFNbeta-1a. The immunogenicity of IFNbeta-1a increases with the frequency of administration and if it is given subcutaneously.

Adolescent↗
PubMed1999

Reporting delay and corrected incidence of multiple sclerosis.

The incidence of multiple sclerosis can be adjusted for reporting delay in a way similar to that for AIDS incidence as described in this paper. Two models are applied to data from the Danish Multiple Sclerosis Registry. The first simply describes the delay distribution, the second is a regression model. For the latter it is shown how goodness-of-fit assessment for both time-dependent and time-independent covariates can be handled using ideas from the Cox proportional hazards model. The goodness-of-fit analysis shows that people with onset age below 40 years and people with onset age from 40 years and above should be analysed separately and this is done throughout the paper. The incidences are adjusted with the two estimated delays and an estimate of the variance for the adjusted incidence is given. Finally the crude incidences are compared with the adjusted ones. We find that the incidence has been increasing since 1965 but mostly for people with onset age below 40 years.

Adult↗
PubMed1999

Multiple sclerosis among utility workers.

The incidence of MS was assessed in a nationwide cohort study of 31,990 employees of Danish utility companies between 1900 and 1993. Overall, 32 cases of MS were diagnosed, as compared with 23.7 expected from national incidence rates, to yield a standardized incidence ratio of 1.35 (95% confidence interval, 0.92 to 1.91). We found no support for the hypothesis of an association between occupational exposure to electromagnetic fields and the risk of MS.

Adult↗
PubMed1999

The Danish Multiple Sclerosis Registry: a 50-year follow-up.

The Danish Multiple Sclerosis Registry was established in 1948 in continuation with a nationwide survey of the prevalence of Multiple Sclerosis (MS) in Denmark. The register has since collected information on MS patients from all Danish departments of neurology, practising neurologists, MS rehabilitation centres, the National Patient Registry, the Danish MS Society, and departments of neuropathology. The registry is linked with the Danish Central Population Registry. The completeness has been estimated at more than 90%. All cases are reclassified by two neurologists as to diagnosis and year of onset. 12 070 cases with a confirmed diagnosis of MS are kept in the databases. They were prevalent in 1949 or have had onset in the period 1948 - 1993. The registry is continuously updated with new information on registered cases and new cases. The crude average annual incidence rate 1980 - 89 was 4.99/105; the prevalence rate was 112/105 by 1 January 1990. Cross-linking with other registers have enabled analytical prospective epidemiological studies, and the registry has provided population based unbiased samples of patients for a number of clinical studies.

Adult↗
PubMed1999

Linkage and association analysis of susceptibility regions on chromosomes 5 and 6 in 106 Scandinavian sibling pair families with multiple sclerosis.

In the genetically homogeneous Scandinavian population, we have investigated chromosome 5 and the HLA (human leukocyte antigen) region on chromosome 6p21 by applying linkage and association analyses on 106 white sibling pair families with multiple sclerosis. The importance of genes within the HLA region for the susceptibility of multiple sclerosis has previously been reported. More recently, findings have suggested importance of regions on chromosome 5. Half of chromosome 5 was analyzed by using 14 microsatellite markers and a susceptibility region with a maximum LOD score of 1.1 was identified. Chromosome 6 was analyzed by HLA-DR typing and using the TNF alpha microsatellite marker. A peak maximum LOD score of 2.0 was found at the HLA-DR marker. Association studies were made for all the markers, comparing 106 probands from the sibling pairs with 100 unrelated controls. None of the markers on chromosome 5 showed significant association with multiple sclerosis, whereas strong association between multiple sclerosis and DR2 was found, with an odds ratio of 3.7 (p < 10(-5)). It is surprising that association was not seen for any of the TNF alpha alleles including the 121-bp allele, although this allele was in positive linkage disequilibrium with DR2 in both patients and controls. Our results support the existence of multiple sclerosis susceptibility loci on chromosomes 5p and 6p21.

Chromosome Mapping↗
PubMed1998

Underlying cause of death in Danish patients with multiple sclerosis: results from the Danish Multiple Sclerosis Registry.

OBJECTIVES: To determine the underlying causes of death in a large population based register series of patients with multiple sclerosis. METHODS: The Danish Multiple Sclerosis Registry, which contains virtually all diagnosed cases of multiple sclerosis in Denmark who were alive in 1949 plus cases with onset of multiple sclerosis in the period 1949-93, who have been diagnosed and notified by 1 January 1994, was linked with the Danish Registry of Causes of Death, in which ICD codes for causes of death from the death certificate are stored for all Danish citizens. RESULTS: 6068 register cases of multiple sclerosis, who had died in the period 1951-93, were included. Multiple sclerosis was noted on the death certificate as the underlying cause of death in 55.4%; cardiac or vascular diseases in 17.6%; cancers in 8.6%; respiratory or infectious diseases in 5.1%; other natural causes in 9.5%; accident or suicide in 3.8%. The distribution varied with age at death. Standardised mortality ratios (SMRs) were computed on the basis of the 8142 incident cases, who had onset of multiple sclerosis within the period 1951-93; the SMRs for causes of death other than multiple sclerosis were highest for infectious or pulmonary diseases: 2.46 (95% confidence interval (95% CI) 2.04-2.94); suicide: 1.62 (95% CI 1.29-2.01); cardiac or vascular diseases: 1.34 (95% CI 1.22-1.48); accidents 1.34 (95% CI 1.02-1.71); and significantly lower than unity for cancers: 0.79 (95% CI 0.70-0.90), lower for men than for women. CONCLUSIONS: More than half of the patients with multiple sclerosis die from multiple sclerosis or complications of the disease. Among other causes, patients with multiple sclerosis have an increased risk of dying from heart or vascular diseases but a reduced risk of dying from cancer. An increased risk of death from suicide and accidents can be indirectly attributed to multiple sclerosis. The diminished risk of dying from cancer may be a result of incomplete ascertainment of cancers in disabled patients with multiple sclerosis.

Accidents↗
PubMed1997

EBV-positive primary central nervous system lymphomas in monozygote twins with common variable immunodeficiency and suspected multiple sclerosis.

Common variable immunodeficiency represents the most frequently occurring primary immunodeficiency disorder and is usually detected sporadically in patients with no family history of immunodeficiency. We present the case stories of two monozygote twins, who following a period of decreasing serum immunoglobulins developed primary central nervous system lymphomas. One twin had clinical and paraclinical features mimicking multiple sclerosis. Immunohistochemical investigations on biopsy tissue showed expression of the bcl-2 and p53 gene products, and Epstein-Barr virus (EBV) encoded small RNA's (EBER) indicating latent infection were detected in lymphoma cells using in situ hybridisation techniques. The pathogenetic role of EBV in oncogenesis is discussed.

Adult↗
PubMed1995

Multiple sclerosis in Scandinavia and Finland.

Review of studies of incidence of MS over several decades in seven geographical areas scattered over Scandinavia and Finland have shown that incidence rates fluctuate significantly with time in most of the areas but in an inconsistent pattern. The incidence appeared to the lowest in the northernmost parts of Norway indicating that the well-known north-south gradient for risk of MS does not hold true for high latitudes.

Denmark↗