Consequences of multiple sclerosis for patients in Sweden

This study aimed to consider consequences of multiple sclerosis for patients in Sweden throughout various stages of the life course. The thesis was separated into four constituent papers, which dealt with different aspects of the disease, its symptoms, and implications at different life stages.

The first study considers life expectancy, one of the most crucial aspects concerning the implications of the consequences of a chronic disease. The paper found MS patients had a hazard ratio (HR) for mortality of 2.92 (95% confidence interval (CI) 2.86-2.99)) at any given age relative to a group of non-MS comparators when the entire study period from 1968 to 2012 was analysed. When trends were considered, however, it was shown that the improvement to survival for MS patients had been considerable, and dropped from an HR of 6.52 (95% CI 5.79–7.34) when considering the earliest time period (1968 to1980), down to an HR of 2.08 (95% CI 1.95–2.22) for the most recent time period (2001 to 2012). Cause specific mortality also improved over time for MS patients, with mortality beginning to more closely reflect mortality trends for the general population. The largest excess mortality for MS patients came from respiratory and infectious diseases. Cardiovascular disease was the leading cause of death for both the MS and non-MS cohorts.

Alongside issues pertaining to life expectancy, how patients are affected by their symptoms is an important consideration when answering questions about consequences of MS. Pain has been noted as a particularly distressing symptom by MS patients, and previous studies have indicated it is likely MS patients experience pain to a greater degree than the general population. As far as we are aware, however, there have been very few studies making direct comparisons of pain between MS patients and non-MS comparators with regard to pain, perhaps due to difficulties in drawing direct comparisons. In order to attempt objectivity and a fair comparison across MS and non-MS subjects, the second and third studies utilized the prescribed drugs register (PDR) of Sweden in order to ascertain when prescriptions for pain relief had been collected. An excess of pain relief prescriptions would imply an excess of pain among MS patients. Information on pain type can also be extracted using this method through the anatomical therapeutic code (ATC) entered into the PDR. Study two was able to provide evidence supporting the hypothesized increased risk of pain among MS patients, and demonstrated MS patients had an HR of 2.52 (95% CI 2.38-2.66) for overall pain prescription. It was additionally shown that this increased risk of pain was primarily driven by increased likelihood of neuropathic pain. The HR for MS patients being prescribed these treatments relative to their non-MS comparators was 5.73 (95% CI 5.07-6.47). MS patients were also at marginally increased risk of anti-migraine preparation prescriptions, however no increased risk of prescriptions for the treatment of musculoskeletal pain was detected.

Study three followed on from study two, which considered pain relief prescription, and included the same definition of the outcome. However, the study aimed primarily to consider the effect of genotype on MS and pain phenotype. Past murine studies have indicated that the major histocompatibility complex (MHC) is associated with pain-like behavior when considering peripheral nerve injury, however the same association was not observed when considering injury to the central nervous system (CNS), which more closely mimics the nervous system injuries seen in MS patients due to demyelination. Past research has identified that the DQB1*0302 class II HLA genes are associated with neuropathic pain presentation in individuals undergoing surgery for inguinal hernia, or for spinal disc herniation. As far as we are aware, the role of this allele in pain presentation, and whether it is differential by MS status has not been previously studied. A modest increased risk of pain for non-MS carriers of the DQB1*0302 allele was found, with an odds ratio (OR) of 1.18 (95% CI 1.03-1.35), however no increased risk was identified for MS patients (OR 1.02, (95% CI 0.85-1.24)), mimicking the results found in murine studies.

Given that the average age at diagnosis is childbearing age for women, and that the majority of patients are women, issues surrounding MS and pregnancy were important to consider when answering questions of consequences of MS. Paper four assessed whether exposure to interferon –beta during pregnancy influenced intrauterine growth, by considering its effect on birth weight, height, and head circumference. This was an international study comprised of data from both Sweden and Finland. The study, which used prescribed medication to identify pre-natal exposure, and additionally the MS register within Sweden, concluded that exposure to interferon-beta did not seem to be associated with intrauterine growth in either Sweden or Finland.

List of scientific papers

I. Burkill S, Montgomery S, Hajiebrahimi M, Hillert J, Olsson T, Bahmanyar S. (2017). Mortality trends for multiple sclerosis patients in Sweden between 1968 and 2012. Neurology. 89 (6): 555-562.
https://doi.org/10.1212/WNL.0000000000004216

II. Burkill S, Montgomery S, Kockum I, Piehl F, Stridh P, Hillert J, Alfredsson L, Olsson T, Bahmanyar S. (2019). The association between multiple sclerosis and pain medications. Pain. 160 (2): 424-432.
https://doi.org/10.1097/j.pain.0000000000001429

III. Burkill S, Smith KA, Stridh P, Kockum I, Lindahl H, Alfredsson L, Olsson T, Piehl F, Montgomery S, Bahmanyar S. The DQB1*0302 genotype and treatment for pain in people with and without Multiple Sclerosis. [Submitted]

IV. Burkill S, Vattulainen P, Geissbuehler Y, Sabido M, Popescu C, Suzart-Woischnik K, Hillert J, Artama M, Verkkoniemi-Ahola A, Myhr KM, Cnattingius S, Korhonen P, Montgomery S, Bahmanyar S. The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis. [Submitted]