Cancer related mortality in multiple sclerosis. A population based cohort study.

BACKGROUND: Cancer is a major cause of death, but how cancer influences mortality risk in Multiple Sclerosis (MS) is unclear. OBJECTIVES: Determine all-cause mortality and mortality following a cancer diagnosis among MS patients compared with matched population controls. METHODS: Norwegian MS patients born 1930 - 1979 (n= 6950) followed-up 1953 - 2016, were matched with 37 922 controls. We compared incident cancer diagnosis from the Cancer Registry of Norway, date of death from the Cause of Death Registry, education from the National Education Database, by multivariate Cox proportional hazard regression. RESULTS: Hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality among MS patients was 4.97 (4.64 - 5.33), and 2.61 (2.29 - 2.98) for mortality following a cancer diagnosis. Mortality in MS was highest following urinary- (2.53: 1.55 - 4.14), colorectal- (2.14: 1.47 - 3.11), hematological- (1.76: 1.08 - 2.88), ovarian - 2.30 (1.73-3.06) and breast cancer diagnosis (2.61: 1.85 - 3.68), compared to controls. High education was inversely associated with mortality among MS patients. CONCLUSIONS: All-cause mortality was five- fold and mortality following a cancer diagnosis was two- fold increased among MS patients. Mortality following specific cancers raises the possibility of diagnostic neglect.

Incidence of cancer in multiple sclerosis before and after the treatment era- a registry- based cohort study.

BACKGROUND: Whether disease-modifying therapies (DMTs) influence cancer in multiple sclerosis (MS) is uncertain. OBJECTIVES: Assess incidence of cancer diagnosis among Norwegian MS patients compared to the general population in 1953 to 1995 and 1996 to 2017-reflecting era before and after introduction of DMTs. METHODS: We performed a nationwide cohort study comprising 6949 MS patients and 37,922 controls, matched on age, sex and county. The cohort was linked to Norwegian Cancer Registry, Cause of Death Registry and National Educational database. We used Poisson regression to calculate incidence rate ratio (IRR) of cancer. RESULTS: During 1953-1995 MS patients had similar cancer frequency compared to controls (IRR: 1.11 (95% Confidence Intervals (CI): 0.90-1.37)), although MS patients had increased frequency of cancer in endocrine glands (IRR: 2.51 (1.27-4.93). During 1996-2017 we identified significant increased frequency of cancer among MS patients compared to controls (IRR: 1.38 (95% CI: 1.28-1.52): in brain (IRR: 1.97 (1.41-2.78)), meninges (IRR: 2.44 (1.54-3.77)), respiratory organs (IRR: 1.96 (1.49-2.63)). The excess cancer diagnosis was most frequent among MS patients ≥ 60 years of age (HR 1.30 (1.15-1.47)). CONCLUSION: Incidence of cancer among MS patients compared to controls was higher in 1996 to 2017, corresponding in time to the introduction of DMT for MS. This was observed more frequently among MS patients older than 60 years of age.

Chronic fatigue and depression due to multiple sclerosis: Immune-inflammatory pathways, tryptophan catabolites and the gut-brain axis as possible shared pathways.

Chronic fatigue and major depression (MDD)-like symptoms are common manifestations of multiple sclerosis (MS), both with huge impact on quality of life. Depression can manifest itself as fatigue, and depressive symptoms are often mistaken for fatigue, and vice versa. The two conditions are sometimes difficult to differentiate, and their relationship is unclear. Whether chronic fatigue and depression occur primarily, secondarily or coincidentally with activated immune-inflammatory pathways in MS is still under debate. We have carried out a descriptive review aiming to gain a deeper understanding of the relationship between chronic fatigue and depression in MS, and the shared pathways that underpin both conditions. This review focuses on immune-inflammatory pathways, the kynurenine pathway and the gut-brain axis. It seems likely that proinflammatory cytokines, tryptophan catabolites (the KYN pathway) and the gut-brain axis are involved in the mechanisms causing chronic fatigue and MDD-like symptoms in MS. However, the evidence base is weak, and more research is needed. In order to advance our understanding of the underlying pathological mechanisms, MS-related fatigue and depression should be examined using a longitudinal design and both immune-inflammatory and KYN pathway biomarkers should be measured, relevant clinical characteristics judiciously registered, and self-report instruments for both fatigue and depression should be used.

Pregnancy outcomes and postpartum relapse rates in women with RRMS treated with alemtuzumab in the phase 2 and 3 clinical development program over 16 years.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is frequently diagnosed in women of reproductive age. Because the use of disease-modifying therapies (DMTs) early in the disease course is increasing, it is important to evaluate the safety of DMTs in pregnant women and their developing fetuses. Alemtuzumab, approved for the treatment of relapsing forms of MS, is administered as 2 courses of 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Alemtuzumab is eliminated from the body within approximately 30 days after administration; it is recommended that women of childbearing potential use effective contraception during and for 4 months after treatment. Here, we report pregnancy outcomes in alemtuzumab-treated women from the phase 2 and 3 clinical development program over 16 years. METHODS: We followed 972 women who had alemtuzumab in phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, and/or in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). In the extension studies, patients could receive additional alemtuzumab (12 mg/day on 3 days; ≥12 months apart) as needed for disease activity. All women who received alemtuzumab in the clinical development program were included. Pregnant or lactating patients were followed up for safety. RESULTS: As of November 26, 2018, 264 pregnancies occurred in 160 alemtuzumab-treated women, with a mean age at conception of 32.6 years, and mean time from last alemtuzumab dose to conception of 35.9 months. Of the 264 pregnancies, 233 (88%) were completed, 11 (4%) were ongoing, and 20 (8%) had unknown outcomes; 16 (6%) conceptions occurred within 4 months, and 5 conceptions within 1 month of the last alemtuzumab dose. Of the 233 completed pregnancies with known outcomes, there were 155 (67%) live births with no congenital abnormalities or birth defects, 52 (22%) spontaneous abortions, 25 (11%) elective abortions, and 1 (0.4%) stillbirth. Maternal age was associated with an increased risk of spontaneous abortion in alemtuzumab-treated patients (<35 years: 15%; ≥35 years: 37%; relative risk [RR], 2.46 [95% CI: 1.53-3.95], p=0.0002). Risk of spontaneous abortion was not increased in patients becoming pregnant ≤4 months versus >4 months since alemtuzumab exposure (19% vs 23%; RR, 1.08 [95% CI: 0.41-2.85], p=0.88). Autoimmune thyroid adverse events did not increase risk for spontaneous abortion (patients with vs without thyroid adverse events, 23.7% vs 21.3%; RR, 1.11 [95% CI: 0.69-1.80], p=0.75). Annualized relapse rate was 0.10 and 0.12 in the 2 years prior to pregnancy (post alemtuzumab), and was 0.22, 0.12, and 0.12 in each of the first 3 years postpartum, respectively. CONCLUSION: Normal live births were the most common outcome in women exposed to alemtuzumab 12 mg or 24 mg in clinical studies. Spontaneous abortion rate in alemtuzumab-treated patients was comparable with rates in the general population and treatment-naive MS patients, and was not increased in women with pregnancy onset within 4 months of alemtuzumab exposure. There was a minimal increase in postpartum relapses.

Risk of cancer among multiple sclerosis patients, siblings, and population controls: A prospective cohort study.

BACKGROUND: Risk of cancer in multiple sclerosis (MS) patients compared to their siblings is unknown. OBJECTIVE: The objective was to prospectively investigate the risk of cancer among MS patients compared to siblings without MS and to population controls. METHODS: We retrieved data on MS patients born between 1930 and 1979 from the Norwegian Multiple Sclerosis Registry and population studies and on cancer diagnosis from the Cancer Registry of Norway. We used adjusted Cox proportional hazard regression to estimate cancer risk among 6883 MS patients, 8918 siblings without MS, and 37,919 population controls. RESULTS: During 65 years of follow-up, cancer risk among MS patients was higher than that among population controls (hazard ratio (HR) = 1.14, 95% confidence interval (CI): 1.05-1.23) in respiratory organs (HR = 1.66, 95% CI: 1.26-2.19), urinary organs (HR = 1.51, 95% CI: 1.12-2.04), and the central nervous system (HR = 1.52, 95% CI: 1.11-2. 09). Siblings had higher risk of hematological cancers compared with MS patients (HR = 1.82, 95% CI: 1.21-2.73) and population controls (HR = 1.72, 95% CI: 1.36-2.18). CONCLUSION: MS patients were associated with increased risk of cancer compared to population controls. Siblings had increased risk of hematological cancer. This indicates that MS and hematological cancer could share a common etiology.

MYO9B polymorphisms in multiple sclerosis.

Single-nucleotide polymorphisms (SNPs) in the 3' region of myosin IXB (MYO9B) gene have recently been reported to associate with different inflammatory or autoimmune diseases. We monitored for the association of MYO9B variants to multiple sclerosis (MS) in four Northern European populations. First, 18 SNPs including 6 SNPs with previous evidence for association to immune disorders, were tested in 730 Finnish MS families, but no linkage or family-based association was observed. To ensure the power to detect variants with a modest effect size, we further analyzed 10 variants in 899 Finnish cases and 1325 controls, and in a total of 1521 cases and 1476 controls from Denmark, Norway and Sweden, but found no association. Our results thereby do not support a major function of the tested MYO9B variants in MS.

Lack of association with the CD28/CTLA4/ICOS gene region among Norwegian multiple sclerosis patients.

Chromosome region 2q33 encodes several regulators of the immune system, among these the CD28, CTLA4, and ICOS molecules. Involvement of these genes in multiple sclerosis (MS) is not yet clear. We investigated six microsatellites and three SNPs in a relatively large and clinically well characterised Norwegian MS cohort. No associations were observed for any of the markers analysed in 575 MS patients and 551 controls. Associations were neither found when stratifying the material for the HLA-DRB1*1501, DQB1*0602 haplotype, gender, age at onset, disease course nor familial aggregation. In conclusion, this study could not confirm association with the CD28/CTLA4/ICOS gene region.