Insights from comorbidity into multiple sclerosis aetiology and outcomes

Aim: The overall aim of this research was to investigate the nature of the comorbidities in multiple sclerosis (MS) in four large population-based studies. The first study assessed whether the diagnosis underlying appendicectomy is a useful marker of MS risk. The second study identified whether an inherited risk of other immune-mediated diseases (IMD) contributes to the likelihood of developing MS. In the third study, we investigated if MS is associated with a raised risk of cardiovascular disease (CVD) and whether this varies by MS disease course, while in the final study we determined if cancer is under-diagnosed in MS patients by assessing mortality following cancer as a marker of delayed cancer diagnosis.

Methods: This thesis uses Swedish register data to identify patterns of comorbid disease among subjects with a diagnosis of MS compared with subjects without MS. We have identified subjects with MS through the Patient Register (PR) and the MS Register (SMSreg) and subjects without MS through the Total Population Register (TPR). By using personal identity numbers and ICD codes, comorbidities among MS patients and diseases in those without MS were identified. These included appendicectomy, other immune-mediated disease, cardiovascular disease and all-cause mortality following cancer diagnosis. The study designs included in this thesis are a nested case-control study and three cohort studies.

Results: There was a lower risk of MS in the group with perforated appendicitis but it was not statistically significant. Patients with MS had an elevated higher risk of other immune-mediated diseases while their parents had no increased risk. MS patients were more at risk of CVD and in particular, more likely to suffer from deep venous thrombosis than subjects without MS. This finding was observed in all MS courses. There was a lower magnitude raised risk of all-cause mortality after a cancer diagnosis in MS patients compared with the risk following cancer in the general population cohort.

Conclusions: We found equivocal evidence that association of acute appendicitis with MS risk may vary depending on the diagnosis underlying the appendicectomy. We found no convincing evidence of a raised risk of other immune-mediated diseases in the parents of patients with MS. MS sufferers themselves appear to have an increased risk of a diagnosis of several immune-mediated diseases. There appears to be a statistically significant increased relative risk of CVD in MS patients and it is of a notably high magnitude for venous thromboembolic disorders in progressive MS. We found a lower magnitude raised risk of all-cause mortality following a cancer diagnosis in MS compared with the mortality risk following a cancer diagnosis in a general population sample.

List of scientific papers

I. Roshanisefat H, Bahmanyar S, Hillert J, Olsson T and Montgomery SM. "Appendicectomy and multiple sclerosis risk." Eur J Neurol. 2011; 18(4): 667-669.
https://doi.org/10.1111/j.1468-1331.2010.03147.x

II. Roshanisefat H, Bahmanyar S, Hillert J, Olsson T and Montgomery S. "Shared genetic factors may not explain the raised risk of comorbid inflammatory diseases in multiple sclerosis." Mult Scler. 2012; 18(10): 1430-1436.
https://doi.org/10.1177/1352458512438240

III. Roshanisefat H, Bahmanyar S, Hillert J, Olsson T and Montgomery S. "Multiple sclerosis clinical course and cardiovascular disease risk-Swedish cohort ". Eur J Neurol. 2014 Jul 17. [Epub ahead of print]
https://doi.org/10.1111/ene.12518

IV. Roshanisefat H, Bahmanyar S, Hillert J, Olsson T and Montgomery S. "All-cause mortality following a cancer diagnosis amongst multiple sclerosis patients". [Submitted]