Nils Koch-Henriksen

The changing demographic pattern of multiple sclerosis epidemiology.

The uneven distribution of multiple sclerosis (MS) across populations can be attributed to differences in genes and the environment and their interaction. Prevalence and incidence surveys could be affected by inaccuracy of diagnosis and ascertainment, and prevalence also depends on survival. These sources of error might play a part in the geographical and temporal variations. Our literature search and meta-regression analyses indicated an almost universal increase in prevalence and incidence of MS over time; they challenge the well accepted theory of a latitudinal gradient of incidence of MS in Europe and North America, while this gradient is still apparent for Australia and New Zealand; and suggest a general, although not ubiquitous, increase in incidence of MS in females. The latter observation should prompt epidemiological studies to focus on changes in lifestyle in females. New insights into gene-environment and gene-gene interactions complicate interpretations of demographic epidemiology and have made obsolete the idea of simple causative associations between genes or the environment and MS.

Clinical importance of neutralising antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis.

BACKGROUND Interferon beta is the first-line treatment for relapsing-remitting multiple sclerosis, but the drug can induce neutralising antibodies against itself, which might reduce effectiveness. We aimed to assess the clinical effect of neutralising antibodies. METHODS We measured neutralising antibodies every 12 months for up to 60 months in 541 patients with multiple sclerosis, randomly selected from all patients who started treatment with interferon beta between 1996 and 1999. Patients left the study if they changed or discontinued therapy. Antibodies were measured blindly, using antiviral neutralisation bioassays with high, medium, and low sensitivity, and with different neutralising capacities as cutoff value for definition of a neutralising-antibody-positive result. FINDINGS Patients developed neutralising antibodies independent of age, sex, disease duration, and progression index at start of treatment. Relapse rates were significantly higher during antibody-positive periods (0.64-0.70) than they were during antibody-negative periods (0.43-0.46; p<0.03). When comparing the number of relapses in the neutralising-antibody-positive and neutralising-antibody-negative periods we found odds ratios in the range 1.51 to 1.58 (p<0.03). Time to first relapse was significantly increased by 244 days in patients who were antibody-negative at 12 months (log rank test 6.83, p=0.009). During this short-term study, presence of neutralising antibodies did not affect disease progression measured with the expanded disability status scale. INTERPRETATION Our findings suggest that the presence of neutralising antibodies against interferon beta reduces the clinical effect of the drug. In patients who are not doing well on interferon beta, the presence of such antibodies should prompt consideration about change of treatment.

Immunogenicity of interferon-β in multiple sclerosis patients: Influence of preparation, dosage, dose frequency, and route of administration

A total of 754 consecutive patients with relapsing‐remitting multiple sclerosis were investigated for interferon‐β (IFNβ) antibodies by protein‐G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 μg) of subcutaneous IFNβ‐1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 μg) of intramuscular IFNβ‐1a once weekly (n = 140), or 8 MIU every other day of IFNβ‐1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNβ‐1b compared with 6 MIU of IFNβ‐1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNβ‐1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNβ‐1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNβ‐1b group than in the IFNβ‐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 IFNβ species but not IFNα. In conclusion, IFNβ‐induced antibodies are frequently found in multiple sclerosis patients, and IFNβ‐1b is more immunogenic than IFNβ‐1a. The immunogenicity of IFNβ‐1a increases with the frequency of administration and if it is given subcutaneously. Ann Neurol 2000;48:706–712

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.

Childhood body mass index and multiple sclerosis risk: a long-term cohort study.

Background: Obesity in late adolescence has been associated with an increased risk of multiple sclerosis (MS); however, it is not known if body size in childhood is associated with MS risk. Methods: Using a prospective design we examined whether body mass index (BMI) at ages 7–13 years was associated with MS risk among 302,043 individuals in the Copenhagen School Health Records Register (CSHRR). Linking the CSHRR with the Danish MS registry yielded 774 MS cases (501 girls, 273 boys). We used Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Among girls, at each age 7–13 years, a one-unit increase in BMI z-score was associated with an increased risk of MS (HRage 7=1.20, 95% CI: 1.10–1.30; HRage 13=1.18, 95% CI: 1.08–1.28). Girls who were ≥95th percentile for BMI had a 1.61–1.95-fold increased risk of MS as compared to girls <85th percentile. The associations were attenuated in boys. The pooled HR for a one-unit increase in BMI z-score at age 7 years was 1.17 (95% CI: 1.09–1.26) and at age 13 years was 1.15 (95% CI: 1.07–1.24). Conclusion: Having a high BMI in early life is a risk factor for MS, but the mechanisms underlying the association remain to be elucidated.

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 unbiassed samples of patients for a number of clinical studies.

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.

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.

Cancer risk among patients with multiple sclerosis: A population-based register study

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population‐based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population‐based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live‐born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person‐years of follow‐up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89–1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94–1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05–1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Autoimmune disease in patients with multiple sclerosis and their first-degree relatives: a nationwide cohort study in Denmark.

Background Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. Methods Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. Results Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4–2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7–27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4–0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3–0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn’s disease (RR = 1.4 (CI: 1.04–1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99–1.7), n = 51), Addison’s disease (RR = 3.4 (CI: 1.3–9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4–10.0), n = 4). Conclusion Patients with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.