Michael J. Olek

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study.

Background: A potential link between the recombinant hepatitis B vaccine and an increased risk of multiple sclerosis (MS) has been evaluated in several studies, but some of them have substantial methodologic limitations. Methods: The authors conducted a nested case-control study within the General Practice Research Database (GPRD) in the United Kingdom. The authors identified patients who had a first MS diagnosis recorded in the GPRD between January 1993 and December 2000. Cases were patients with a diagnosis of MS confirmed through examination of medical records, and with at least 3 years of continuous recording in the GPRD before their date of first symptoms (index date). Up to 10 controls per case were randomly selected, matched on age, sex, practice, and date of joining the practice. Information on receipt of immunizations was obtained from the computer records. Results: The analyses include 163 cases of MS and 1,604 controls. The OR of MS for vaccination within 3 years before the index date compared to no vaccination was 3.1 (95% CI 1.5, 6.3). No increased risk of MS was associated with tetanus and influenza vaccinations. Conclusions: These findings are consistent with the hypothesis that immunization with the recombinant hepatitis B vaccine is associated with an increased risk of MS, and challenge the idea that the relation between hepatitis B vaccination and risk of MS is well understood.

Geographic variation of MS incidence in two prospective studies of US women

Objective: To estimate the incidence of MS and its relation to latitude in two ongoing prospective studies of US women. Background: A higher incidence of MS has been found in northern areas compared with southern areas of the United States and other countries, but the attenuation of this gradient in Europe in the last few decades and the consideration of ethnic factors have led some authors to question the existence of a strong association between MS and latitude. Methods: The authors identified new cases of MS among participants in the Nurses’ Health Study (NHS), which took place between 1976 and 1994, and in the Nurses’ Health Study II (NHS II), which took place between 1989 and 1995. The NHS included women born between 1920 and 1946, and the NHS II included women born between 1947 and 1964. Results: The incidence of MS among NHS participants (181 definite/probable patients) increased significantly with latitude (p = 0.03, trend). Adjusted rate ratios were 3.5 (95% CI, 1.1, 11.3) for the north and 2.7 (95% CI, 0.8, 8.9) for the middle tiers relative to the southern tier. Among NHS II women (131 definite/probable patients), no association between latitude and MS was found (p = 0.89, trend). Adjusted rate ratios were 0.8 (95% CI, 0.4, 1.6) for the northern areas and 0.9 (95%, 0.4, 1.8) for the middle areas, relative to the southern areas. Conclusions: The association between latitude and risk of MS in the United States was corroborated, but there was an attenuation of the north–south gradient over time. If confirmed, this finding could provide new clues to identifying environmental causes of the disease.

Oral contraceptives and the incidence of multiple sclerosis

Background: Experimental and clinical data suggest a protective effect of estrogens on the development and progression of MS. Methods: We assessed whether MS incidence was associated with oral contraceptive use or parity in two cohort studies of U.S. women, the Nurses’ Health Study (NHS; 121,700 women aged 30 to 55 years at baseline in 1976) and the Nurses’ Health Study II (NHS II; 116,671 women aged 25 to 42 years at baseline in 1989). Participants with a diagnosis of MS before baseline were excluded. Oral contraceptive history and parity were assessed at baseline and updated biennially. During follow-ups of 18 years (NHS) and 8 years (NHS II) we documented a total of 315 definite or probable cases of MS. Results: Neither use of oral contraceptives nor parity were significantly associated with the risk of MS. As compared with women who never used oral contraceptives, the age-adjusted relative risk (95% CI) was 1.2 (0.9, 1.5) for past users, and 1.0 (0.6, 1.7) for current users. Similar results were obtained after adjustment for latitude, ancestry, and other potential confounding factors. There was no clear trend of MS risk with either increasing duration of use or time elapsed since last use. Age at first birth was also not associated with the risk of MS. Conclusions: These prospective results do not support a lasting protective effect of oral contraceptive use or pregnancy on the risk of MS. The decision to use hormonal contraception should not be affected by its effects on the risk of MS.

Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to the duration of progressive disease.

Objective: To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Scerosis (MS). Background: MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patient with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4-8 week intervals similar to lupus nephritis protocols. Design/Methods: We investigated a series of 95 consecutive progressive MS patient treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint associations were examined between outcome and patient characteristics including gender age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS. Result: Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patient that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients. Conclusions: Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patient enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agent for progressive MS, duration of progression should be considered as a randomization and analysis variable.

Intakes of carotenoids, vitamin C, and vitamin E and MS risk among two large cohorts of women

Background: Antioxidant nutrients may reduce the risk of MS. In a recent case-control study, vitamin C intake was significantly inversely associated with MS risk among women. However, no prospective data are available. Objective: To examine prospectively the associations of intakes of carotenoids, vitamin C, and vitamin E with the risk of MS among women. Methods: The authors documented the occurrence of definite and probable MS within two large cohorts of women who completed detailed and validated semiquantitative food frequency questionnaires. One cohort (Nurses’ Health Study) comprised 81,683 women aged 38 to 63 years in 1984, who were followed for 12 years; the other (Nurses’ Health Study II) comprised 95,056 women aged 27 to 44 years in 1991, who were followed for 6 years. Results: The authors documented a total of 214 cases of MS. After adjustments for age, latitude of birthplace, pack-years of smoking, and total energy intake, the pooled multivariate relative risks (95% CIs) comparing women in the highest quintile with those in the lowest quintile were 1.1 (0.7 to 1.7) for α-carotene, 1.1 (0.7 to 1.6) for β-carotene, 1.4 (0.8 to 2.2) for β-cryptoxanthin, 1.0 (0.6 to 1.5) for lycopene, 1.0 (0.7 to 1.6) for lutein/zeaxanthin, 1.4 (0.9 to 2.1) for total vitamin C, 1.3 (0.9 to 2.0) for dietary vitamin C, 0.8 (0.6 to 1.3) for total vitamin E, and 0.9 (0.6 to 1.4) for dietary vitamin E. The authors found no associations between intakes of fruits and vegetables and risk of MS. Use of vitamin C, vitamin E, and multivitamin supplements was also unrelated to risk of MS. Conclusions: These findings do not support hypotheses relating higher intakes of dietary carotenoids, vitamin C, and vitamin E to reduced risk of MS in women.

Incidence of multiple sclerosis in the United Kingdom : findings from a population-based cohort.

Existing data on the incidence of multiple sclerosis (MS) in the UK have some limitations. Few studies have reported age- and sex-specific incidence rates of MS, and none of those is based on a large sample of the general population. Further, no published reports have provided age- and sex-specific incidence rates of MS by clinical course from onset. To estimate the age- and sex-specific incidence rate and lifetime risk of multiple sclerosis, we identified all new cases of MS during the period 1993–2000 in the General Practice Research Database, which includes health information on over three million Britons. Based on 642 incident cases, incidence rates of MS adjusted to the world population were 7.2 (95 % CI 6.5, 7.8) in women and 3.1 (95 % CI 2.6, 3.5) in men. The incidence of MS with relapsing-remitting onset was higher in women than in men (incidence rate ratio 2.5, 95% CI 2.1, 3.1), but there were no sex differences for primary-progressive MS (incidence rate ratio 1.1, 95% CI 0.7, 1.8). The estimated lifetime risk from birth of receiving an MS diagnosis was 5.3 per 1,000 in women and 2.3 per 1,000 in men. These results confirm the relatively high incidence of MS in the UK and show marked differences in the sex-specific pattern of MS incidence by clinical course from onset.

Infection with Chlamydia pneumoniae and risk of multiple sclerosis

Background. Chlamydia pneumoniae (Cpn) has been proposed as a possible etiologic agent for multiple sclerosis (MS), but results of previous studies are conflicting. Methods. Using a nested case-control design, we examined the association between Cpn infection and MS in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II) cohorts. Among 32,826 women in the NHS and 29,722 women in the NHS II with blood samples, 141 incident cases of definite or probable MS were documented. Each case was matched to two healthy controls on year of birth and NHS cohort. Serum samples were tested for the presence of Cpn-specific immunoglobin G antibodies using microimmunofluorescence. Results. Cpn immunoglobin G seropositivity was positively associated with risk of MS (odds ratio [OR] = 1.7; 95% confidence interval [CI] = 1.1–2.7). This association did not change after adjusting for age at blood collection, ancestry, latitude of residence at birth, and smoking (OR = 1.9; CI = 1.1–3.1). Seropositivity for Cpn was only moderately associated with risk of relapsing-remitting MS (OR = 1.7; CI = 0.9–3.2), but it was strongly associated with risk of progressive MS (OR = 7.3; CI = 1.4–37.2). Geometric mean titers of Cpn-specific immunoglobin G antibody were similar in women with relapsing-remitting MS as compared with matched controls (44 vs 39), but they were elevated in women with progressive MS (99 vs 40). Conclusions. These results support a positive association between Cpn infection and progressive MS.

54 – Multiple Sclerosis

Autoimmune diseases in general and multiple sclerosis (MS) in particular affect more females than males. There are several candidate genes for MS, including human leukocyte antigen, T-cell receptor, myelin basic protein, immunoglobulin, complement, tumor necrosis factor, and mitochondrial genes. In terms of genetic heritage, MS is very rare in Japan, China, and Africa blacks. It has never been reported in ethnically pure Eskimos, Inuits, North and South Amerindians, Australian aborigines, New Zealand Maoris, Pacific Islanders, or Lapps. Worldwide, the most common thread for the development of MS is in women of Scandinavian and northern European ancestry. In one study, the highest risks for developing MS were found in daughters of either female or male patients with MS. For a female patient, a daughter had an age-adjusted lifetime risk of 4.96% of developing MS. The combined cumulative incidence for first, second, and third-degree relatives of MS index cases in this cohort, as well as in another study, approached 20%. These risks must be understood in the context of the incidence of MS in the general population, which is estimated at 3.2/100,000 people.