The role of serum lipid profile and comorbidities in the onset and progression of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, autoimmune disorder of the central nervous system (CNS) with considerable heterogeneity in clinical outcome and a leading cause of disability in young adults. The disease is caused by interplay of genetic and environmental factors and recent evidence suggests a role for an adverse lipid profile (low HDL, increased LDL and triglycerides) and comorbidity in MS clinical course. This thesis therefore investigates the etiological role of the serum lipid profile and comorbidity in the onset and progression of the disease. A literature review on the role of vascular comorbidities in the onset and progression of MS showed a potential association of vascular comorbidities with MS risk and disability progression. However, the number of prospective studies was sparse, thus precluding ascription of causality. It was therefore recommended that future studies of the frequency and effects of vascular comorbidities on MS risk and disability should be prospective and objective where relevant. A literature review on the frequency of commonly reported autoimmune comorbidities in MS and the contribution of interferon-beta (IFN-˜í‚â§) to the frequency of thyroid autoimmunity and dysfunction in MS patients identified a consistent increase in the risk of clinical thyroid disorder, inflammatory bowel disease and psoriasis among people with MS compared to a comparator population. It also appears that IFN-˜í‚⧠therapy is associated with higher occurrence of thyroid autoimmunity and dysfunction compared to IFN-˜í‚⧠naive MS patients. It was recommended that future studies should have a population-based design with large sample size and a concurrent control to minimize heterogeneity due to differences in study design. The Tasmanian MS Longitudinal Study was used to examine the association between serum lipid profile and disability, progression in disability and time to relapse in a cohort with established disease. A cohort of 178 MS patients was followed for a total of 2.5 years and serum samples and other data were obtained at each biannual review. Among 141 relapsing‚Äö-remitting MS patients, neither body mass index (BMI) nor any of the lipid-related measures were associated with the hazard of relapse. In relation to disability, higher levels of total cholesterol (TC), apolipoprotein B (ApoB) and apolipoprotein B to apolipoprotein A-I ratio (ApoB/ApoA-I ratio) were associated with a greater disability. In addition, a significant independent effect of BMI on disability was observed. This suggests that clinicians should monitor and treat adverse lipid profiles and BMI. Importantly, a higher TC/HDL ratio was associated with faster accrual of disability, suggesting that lipid lowering interventions may be of benefit for people with MS. The Tasmanian MS Longitudinal Study was also used to examine whether the frequency of comorbidities was higher in MS patients compared to the Australian population and whether comorbidities were associated with clinical disability and relapse. It was found that age-standardised prevalence of hypertension, dyslipidaemia, psoriasis, eczema, asthma and anaemia was significantly higher in the MS cohort compared to the general Australian population and that reporting overweight/obesity and dyslipidaemia was associated with significantly higher disability. However, there was no significant association with annual change in disability. In the relapse analysis, rheumatoid arthritis and anaemia were associated with increased risk of relapse. The final set of analyses was conducted using the Ausimmune Longitudinal Study (AusLong), an internationally unique cohort with a first clinical diagnosis of demyelination, which has been followed annually up to five year review. The association between serum lipids and conversion to clinically definite MS (CDMS), time to relapse and annualised change in disability was investigated. It was found that higher BMI and triglycerides were associated with increased risk of relapse while none of the serum lipid-related variables were significantly associated with conversion to CDMS. In addition, higher BMI and TC/HDL ratio was associated with a higher annualised change in clinical disability. In summary, this thesis presents a number of epidemiological studies suggesting that improving the lipid profile, decreasing BMI into the healthy range and increasing physical activity may reduce the risk of comorbidity and modulate the accumulation of disability. Further, long-term monitoring and treatment of lipid profile and comorbidities in MS is recommended in order to prevent increased morbidity as people age with their MS. We examined reverse causality, and this cannot be completely ruled out in these observational studies. Regardless of the direction of some associations, the findings of this thesis are important from a clinical perspective, and the increased awareness of this issue may assist in an improved management of the disease.