| 1. |
- Burkill, Sarah
(författare)
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Consequences of multiple sclerosis for patients in Sweden
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Burkill, Sarah M., et al.
(författare)
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Pain and Painkiller Use Among Multiple Sclerosis Patients in Sweden
- 2017
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Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 26:Suppl. 2, s. 634-634
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis is an autoimmune disease which leads to demyelination and subsequent damage of axons and neurons. Pain is known to commonly affect MS patients, however the clinical characteristics of this pain are not fully described. Prescribed pain medication identifies more severe and chronic pain and different drug types can be used to identify other pain characteristics.Objectives: To assess whether MS patients in Sweden are at increased risk of receiving medication for pain relative to non-MS comparators. We aim to study overall pain, neuropathic pain, musculoskeletal pain and migraine.Methods: This cohort study using data on 5,555 MS patients in Sweden individually matched to 5,555 non-MS Swedish residents on sex, year of birth and place of residence at the time of MS diagnosis. We used Cox PH models using date of entry or 1stJuly 2006 as the beginning of follow up, whichever occurred later, and end of study was date of death, date of prescription of a painkiller or December 31st 2014, whichever occurred first. Painkillers were identified through relevant ATC codes. For neuropathic pain, pregabalin, gabapentin, amitriptyline, capsaicin or nortriptyline were used for identification, and for migraine prescriptions of anti-migraine preparations were included in the outcome. Musculoskeletal pain was identified primarily through topical products for joint and muscular pain.Results: Cox PH models showed MS patients to be at a 2.43 (CI 2.31–2.55) times increased risk of being prescribed any painkiller. The risk increased to 5.63 (CI 5.03–6.31) for neuropathic painkillers, however there was no significant difference for musculoskeletal painkillers (RR = 0.92 (CI 0.79–1.07)). MS patients were at a 1.28 (CI 1.10-1.50) times increased risk of being prescribed anti-migraine preparations. Restricting the data to MS patients showed that exposure to neuropathic painkillers was present in 32.8% of MS patients, and is associated with lower educational attainment and female sex. Conclusions: MS patients are at significantly increased risk of pain overall, with a particularly elevated risk for neuropathic pain. It seems that lower educational attainment and female sex are risk factors of neuropathic pain. However, the reason for this is not fully understood.*We would like to acknowledge the funding from the Science for Life - Astra Zeneca collaborative grant that supported this research
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| 3. |
- Burkill, Sarah, et al.
(författare)
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Mortality trends for multiple sclerosis patients in Sweden from 1968 to 2012
- 2017
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 89:6, s. 555-562
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess trends in mortality and causes of death for patients with multiple sclerosis (MS) relative to those without MS in Sweden.Methods: Patients with an MS diagnosis in Sweden between 1964 and 2012 were identified with the Patient Register and the Multiple Sclerosis Register. For this cohort study, each patient with MS (n = 29,617) was matched with 10 individuals without MS (n = 296,164) on sex, year of birth, vital status, and region of residence at the time of MS diagnosis with the Total Population Register. The Causes of Death Register was used to identify causes of death. Cox proportional hazard models were constructed to assess whether risk of mortality was increased for patients with MS.Results: The hazard ratio (HR) for patients with MS was 2.92 (95% confidence interval [CI] 2.86-2.99) for all-cause mortality over the entire study period. The largest differences between the cohorts were death resulting from respiratory (HR 5.07, 95% CI 4.87-5.26) and infectious (HR 4.07, 95% CI 3.70-4.47) diseases. Overall and for each specific cause, there have been improvements for the MS group and a subsequent reduction in the HR. The HR decreased from 6.52 (95% CI 5.79-7.34) for the period of 1968 to 1980 to 2.08 (95% CI 1.95-2.22) for the time period of 2001 to 2012. An interaction between time period and MS exposure showed that the decrease in mortality over time was statistically significant, with a larger decrease for patients with MS than their matched comparators.Conclusions: There has been a substantial improvement in mortality overall and for each specified cause of death for patients with MS compared with individuals without MS; however, large differences still remain.
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| 4. |
- Burkill, Sarah, et al.
(författare)
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Pharmacological Treatments Preceding Diagnosis Of Progressive Multifocal Leukencephalopathy
- 2016
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Ingår i: Pharmacoepidemiology and Drug Safety. - : Wiley-Blackwell. - 1053-8569 .- 1099-1557. ; 25:Suppl. 3, s. 496-497
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, which is present in most people and is usually harm-less. For immunocompromised persons, such as those who are taking immunosuppressive treatments, the risk of JC virus causing PML is increased, although still rare. As PML diagnosis is not always accurate, epidemiology of PML, including the true incidence and patient characteristics, is incompletely described.Objectives: To identify pharmacological treatments preceding diagnosis of definitive, probable and possible PML, after excluding incorrect PML diagnoses by medical record review.Methods: Patients with a PML diagnosis in Sweden between 1988 and 2013 were identified through the Patient register using ICD 9 code 046D and ICD 10code A81.2 (n = 281). Medical records were reviewed and information on clinical characteristics and pharmacological treatments were collected. Each of the diagnoses was determined as definite PML, possible PML, probable PML or non-PML based on the consensus statement for the AAN neuroinfectious disease section published in 2013. (PMCID: 3662270).Results: Medical records for 251 patients (89%) were available and examined. In total, 84 (33%) of the 251 PML diagnoses were confirmed. For those with a record of being exposed to immunosuppressant drugs, 60 (65%) of the 92 records were confirmed as being definite PML. Among 12 patients exposed to rituximab 11 (92%) had definite and 1 (8%) had probable PML. For the 9 natalizumab users, 8 (89%) had definite PML and 1 (11%) was diagnosed incorrectly.Conclusions: A substantial proportion of PML diagnoses recorded in Sweden are incorrect, however amongst those exposed to immunosuppressants such as rituximab and natalizumab the majority of diagnoses are correct. Assessing immunosuppressive drug history could be an important part of the diagnostic processes for PML.
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| 5. |
- Burkill, Sarah, et al.
(författare)
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The association between exposure to interferon-beta during pregnancy and birth measurements in offspring of women with multiple sclerosis
- 2019
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 28:Suppl. 2, s. 371-372
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Interferon-beta (IFN-beta) is a commonly used treatment for multiple sclerosis (MS). Current guidelines recommend cessation of treatment during pregnancy, however the results of past studies on the safety of prenatal exposure to IFN-beta have been conflicting. A large scale study of a population of MS women is therefore warranted.OBJECTIVES: To assess whether, among those born to women with MS, infants prenatally exposed to IFN-beta show evidence of smaller size at birth relative to infants which were not prenatally exposed to any MS disease modifying drugs.METHODS: Swedish and Finnish register data was used. Births to women with MS in Sweden and Finland between 2005-2014 for which a birth measurement for weight, height, and head circumference was available were included. The exposure window was from 6 months prior to LMP to the end of pregnancy.RESULTS: In Sweden, 411 pregnancies were identified as exposed to IFN-beta during the exposure window, and 835 pregnancies were counted as unexposed to any MS DMD. The corresponding numbers for Finland were 232 and 331 respectively. Infants prenatally exposed to interferon-beta were on average 28 grams heavier (p = 0.17), 0.01 cm longer (p = 0.95), and had head circumferences 0.14 cm larger (p = 0.13) in Sweden. In Finland, infants were 50 grams lighter (p = 0.27), 0.02 cm shorter (p = 0.92) and had head circumferences 0.22 cm smaller (p = 0.15) relative to those unexposed.CONCLUSIONS: This study provides evidence that exposure to IFN-beta during pregnancy does not influence birth weight, length, or head circumference.
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| 6. |
- Burkill, Sarah, et al.
(författare)
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The association between multiple sclerosis and pain medications
- 2019
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Ingår i: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 160:2, s. 424-432
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Tidskriftsartikel (refereegranskat)abstract
- Patients with multiple sclerosis (MS) are at greater risk of pain than people without the disease; however, the occurrence and characteristics of pain among these patients are incompletely described. We aimed to assess characteristics of pain amongst MS patients using MS patients who were recruited to participate in 3 studies in Sweden (n = 3877) and were matched with individuals without MS (n = 4548) by sex, year of birth, and region of residence. The Prescribed Drugs Register identified prescribed pain medication, overall and restricted to those given 4 or more prescriptions in 1 year to assess chronic pain. Anatomical therapeutic chemical codes classified whether pain was neuropathic, musculoskeletal, or migraine. Cox-proportional hazard models were used to estimate associations. Our findings showed patients with MS were at increased risk of pain treatment, with a hazard ratio (HR) of 2.52 (95% confidence interval 2.38-2.66). The largest magnitude HR was for neuropathic pain (5.73, 5.07-6.47) for which 34.2% (n = 1326) of the MS and 7.15% (n = 325) of the non-MS cohort were prescribed a treatment. The HR for chronic pain treatment was 3.55 (3.27-3.84), indicating an increased effect size relative to any pain treatment. Chronic neuropathic pain showed the largest HR at 7.43 (6.21-8.89). Neuropathic pain was shown to be the primary mechanism leading to increased risk of pain in patients with MS.
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| 7. |
- Burkill, Sarah, et al.
(författare)
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The DQB1* 03:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis
- 2020
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Ingår i: Frontiers in Neurology. - : Frontiers. - 1664-2295. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.
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| 8. |
- Hajiebrahimi, Mohammadhossein, et al.
(författare)
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Risk of Premenopausal and Postmenopausal Breast Cancer among Multiple Sclerosis Patients
- 2016
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Ingår i: PLOS ONE. - San Francisco, USA : Public Library of Science. - 1932-6203. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate risk of premenopausal and postmenopausal breast cancer among Multiple Sclerosis (MS) patients, considering tumor stage.Methods: The Swedish Patient Register identified 19,330 women with MS between 1968 and 2012, matched individually with a cohort of 193,458 without MS. Matching variables were year of birth, sex, region of residence and vital status at the time of diagnosis. The cancer register identified 471 and 5,753 breast cancer cases among the MS and non-MS cohorts, respectively. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (CI) for premenopausal and postmenopausal breast cancer.Results: Overall risk of postmenopausal breast cancer was 13% higher among MS patients compared with women without MS (HR = 1.13, 95% CI 1.02-1.26). Stratified analyses showed that the risk was statistically significantly increased in women diagnosed between 1968 and 1980 and those who were diagnosed at age 65 or older age. We observed a non-statistically significant risk only for stage 0-1 postmenopausal breast cancer (HR = 1.17, 95% CI 0.93-1.48). MS was not associated with premenopausal breast cancer.Conclusion: The modest increased risk of postmenopausal breast cancer in women with MS may be due to surveillance bias, where contact with health services for one disease increases the risk of a second diagnosis being recorded.
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| 9. |
- Hakkarainen, Katja Marja, et al.
(författare)
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Pregnancy outcomes after exposure to interferon beta : a register-based cohort study among women with MS in Finland and Sweden
- 2020
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Ingår i: Therapeutic advances in neurological disorders. - : Sage Publications. - 1756-2856 .- 1756-2864. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Our aim was to estimate and compare the prevalence of adverse pregnancy outcomes among pregnant women with multiple sclerosis (MS) exposed to interferon beta (IFNB) and among women with MS unexposed to any MS disease-modifying drug (MSDMD).Methods: This cohort study used Finnish (1996-2014) and Swedish (2005-2014) national register data. Women with MS having IFNB dispensed 6 months before or during pregnancy as the only medication were considered as IFNB exposed (only IFNB-exposed), whereas women with MS unexposed to any MSDMD were considered unexposed (MSDMD-unexposed). Prevalence was described and compared using log-binomial or logistic regression and adjusted for potential confounders including maternal age and comorbidity.Results: Among 2831 pregnancies, 2.2% of the only IFNB-exposed and 4.0% of the MSDMD-unexposed women had serious adverse pregnancy outcomes [elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA) in live, or stillbirth]. After adjustments, the prevalence of serious adverse pregnancy outcomes was lower among the only IFNB-exposed compared with the MSDMD-unexposed [relative risk 0.55, 95% confidence interval (CI) 0.31-0.96]. The prevalence of individual outcomes, including MCA, spontaneous abortions, and stillbirths was not increased with IFNB exposure. Women with MS exposed to IFNB appeared more likely to terminate their pregnancy for reasons other than foetal anomaly, compared with MSDMD-unexposed pregnant MS patients (odds ratio 1.71, 95% CI 1.06-2.78).Conclusion: In this large cohort study, no increase in the prevalence of adverse pregnancy outcomes was observed in women with MS exposed to IFNB compared with MS patients unexposed to any MSDMDs. This study together with other evidence led to a change in the labels of the IFNB products in September 2019 in the European Union, and IFNB use today may be considered during pregnancy, if clinically needed.
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| 10. |
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