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.

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis - A cohort study.

BACKGROUND: Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation. OBJECTIVE: To investigate the safety and efficacy of off-label treatment with rituximab in an MS-cohort of predominantly de novo patients or as therapy escalation. METHODS: We retrieved safety and efficacy data from the Norwegian MS-registry and biobank for all MS-patients treated with rituximab at Haukeland University Hospital, Bergen, Norway, during a four year period. RESULTS: In the 365 MS-patients (320 relapsing-remitting MS (RRMS), 23 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS)), the overall annualized relapse rate (ARR) was 0.03 and annualized drug discontinuation rate (ADDR) was 0.05. NEDA-3 was achived in 79% of patients with available data (n=351). Sixty-one patients experienced infusion-related adverse events of which two were serious (CTCAE grade 3-4). Eighteen patients experienced serious non-infusion related adverse events, of which 16 were infections. Infections (n = 34; 9.3%, CTCAE grade 2-5), hypogammaglobulinemia (n = 19, 5.2%) and neutropenia (n = 16; 4.4%) were the most common non-infusion-related adverse events. CONCLUSION: Rituximab was a safe and highly efficient disease modifying therapy in this cohort of MS-patients; however, infections and neutropenia need to be monitored.

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.

Allelic imbalance of multiple sclerosis susceptibility genes IKZF3 and IQGAP1 in human peripheral blood.

BACKGROUND: Multiple sclerosis is a chronic inflammatory, demyelinating disease of the central nervous system. Recent genome-wide studies have revealed more than 110 single nucleotide polymorphisms as associated with susceptibility to multiple sclerosis, but their functional contribution to disease development is mostly unknown. RESULTS: Consistent allelic imbalance was observed for rs907091 in IKZF3 and rs11609 in IQGAP1, which are in strong linkage disequilibrium with the multiple sclerosis associated single nucleotide polymorphisms rs12946510 and rs8042861, respectively. Using multiple sclerosis patients and healthy controls heterozygous for rs907091 and rs11609, we showed that the multiple sclerosis risk alleles at IKZF3 and IQGAP1 are expressed at higher levels as compared to the protective allele. Furthermore, individuals homozygous for the multiple sclerosis risk allele at IQGAP1 had a significantly higher total expression of IQGAP1 compared to individuals homozygous for the protective allele. CONCLUSIONS: Our data indicate a possible regulatory role for the multiple sclerosis-associated IKZF3 and IQGAP1 variants. We suggest that such cis-acting mechanisms may contribute to the multiple sclerosis association of single nucleotide polymorphisms at IKZF3 and IQGAP1.

Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general.

Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.

Immunotherapies influence the influenza vaccination response in multiple sclerosis patients: an explorative study.

BACKGROUND: The immunogenicity of influenza vaccines in MS patients undergoing immunomodulatory treatment is not well studied. OBJECTIVES: This explorative study investigated the influence of immunomodulatory treatment on MS patients receiving pandemic H1N1 (swine flu) vaccination in 2009 and seasonal influenza vaccination in 2010. METHODS: We investigated the immune response to pandemic H1N1 vaccination among 113 MS patients and 216 controls during the pandemic of 2009. We also investigated the serological response to seasonal influenza vaccination (2010 - 2011 season) among 49 vaccinated and 62 non-vaccinated MS patients, versus 73 controls. We evaluated these vaccine responses by haemagglutination inhibition assay. RESULTS: MS patients receiving immunomodulatory treatment had reduced protection (27.4%), compared to controls (43.5%) (p = 0.006), after pandemic H1N1 vaccination (2009). The rates of protection were not influenced by interferon beta treatment (44.4% protected), but were reduced among patients receiving glatiramer acetate (21.6%), natalizumab (23.5%), and mitoxantrone (0.0%). A similar pattern emerged after MS patients received a seasonal influenza vaccination in 2010. CONCLUSIONS: These findings suggest that MS patients receiving immunomodulatory therapies other than interferon beta should be considered for a vaccine response analysis and perhaps be offered a second dose of the vaccine, in cases of insufficient protection.

Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles.

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Polymorphisms of the BDNF gene show neither association with multiple sclerosis susceptibility nor clinical course.

Brain-derived neurotrophic factor (BDNF) has been proposed a protective role in multiple sclerosis (MS) in several studies. The val(66)met polymorphism alters the function of the BDNF protein, and has along with rs56164415 previously been reported to be associated with MS. We genotyped BDNF SNPs val(66)met and rs56164415 in 2149 Norwegian MS patients and 2747 healthy controls. No association was found for any of the SNPs to disease susceptibility or any clinical or demographic parameters including sex, age at onset, disease course, disease severity and cognitive impairment.

Association to the Glypican-5 gene in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter including chromosome 13q31-32 and the Glypican-5 and Glypican-6 genes. In order to further explore the 13q31-32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (p(corr)=0.006). Thus, this study supports that MS susceptibility at 13q31-32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.

A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis.

A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.

Onconeural antibodies in sera from patients with various types of tumours.

PURPOSE: We assessed the frequency and levels of onconeural antibodies in 974 patients with various types of tumours, but without apparent paraneoplastic neurological syndromes (PNS). PATIENTS AND METHODS: We included patients with the following tumours: 200 small-cell lung cancer (SCLC) patients, 253 breast cancer patients, 182 ovarian cancer patients, 266 uterine cancer patients and 73 thymoma patients, as well as 52 patients with PNS and cancer and 300 healthy blood donors. Sera were screened for amphiphysin, CRMP5, Hu, Ma2, Ri and Yo antibodies using a multi-well immunoprecipitation technique. RESULTS: The most frequently detected antibodies were Hu followed by CRMP5. Ma2, Yo, amphiphysin and Ri antibodies were less common, but each was found at similar frequencies. Onconeural antibodies were present at similar levels in sera from the PNS control group and from cancer patients. Hu antibodies were rare in cancers other than SCLC. CRMP5 was the only antibody found in patients with thymoma and this antibody was more common among patients with thymoma than in other tumour patients. With one exception, coexisting antibodies were only found in patients with SCLC. The presence of onconeural antibodies in SCLC patients was not associated with prolonged survival. CONCLUSION: Onconeural antibodies are associated with various types of tumours suggesting that all antibodies should be included in the serological screening for possible PNS. The levels of onconeural antibody are not sufficiently sensitive to discriminate between cancer patients with PNS and those without.

CRMP5 antibodies in patients with small-cell lung cancer or thymoma.

The collapsin response mediator protein 5 (CRMP5) antibody is usually associated with paraneoplastic neurological syndrome (PNS) and small-cell lung cancer (SCLC) or thymoma. The objective of this study was to assess the frequency of CRMP5 antibodies in patients with such tumours and to see if the presence of antibodies was associated with prognosis in these cancers. A multi-well adapted immunoprecipitation assay using radiolabelled recombinant CRMP5 protein, produced by coupled in vitro transcription/translation, was used for the detection of CRMP5 antibodies. Sera from 200 patients with SCLC, 73 patients with thymoma and myasthenia gravis (MG) and from 300 healthy blood donors were examined for CRMP5 antibodies. Positive sera were also examined by immunofluorescence and immune blots. The serological results were compared with disease severity of the patients with thymoma or SCLC. CRMP5 antibodies were detected in 10/200 (5%) of the SCLC, 9/73 (12%) of the thymomas and in 2/300 (0.6%) of the healthy controls by immunoprecipitation. The antibodies were less frequently detected by immunofluorescence or immune blots. There was no significant correlation between CRMP5 antibodies and disease severity. CRMP5 antibodies are more than twice as frequent, and the antibody levels are higher in patients with thymoma and MG than in patients with SCLC. The antibodies are correlated to these tumours, but not to disease severity.

Increasing incidence and continued dismal outcome of primary central nervous system lymphoma in Norway 1989-2003 : time trends in a 15-year national survey.

BACKGROUND: The incidence of primary central nervous system lymphoma (PCNSL) appears to be increasing in some countries, whereas it is stable in others. Many reports the last decades have suggested that there have been improvements in the treatment of PCNSL. The objective of this study was to analyze time trends in the incidence, clinical features, histologic diagnosis, treatment, and outcome of nonacquired immunodeficiency syndrome (non-AIDS) PCNSL in Norway from 1989 to 2003. METHODS: Patients were identified by a chart review of all patients who had a recorded diagnosis of PCNSL from 1989 to 2003 in The Norwegian Cancer Registry. The histologic and cytologic material from each patient was re-examined by pathologists. Time trends were analyzed according to year of diagnosis grouped into 3 5-year periods: 1989-1993, 1994-1998, and 1999-2003. RESULTS: There were 98 patients who had confirmed, newly diagnosed non-AIDS PCNSL in Norway from 1989 to 2003. The incidence rate increased during the consecutive 5-year periods from 0.89 per million during 1989 to 1993, to 1.74 per million during 1994 to 1998, and to 1.82 per million during 1999 to 2003 (P = .013). Diagnostic delay and overall survival did not improve with time. Survival decreased from 1999 to 2003 compared with survival from 1994 to 1998, which was explained in part by reduced performance status and fewer patients receiving combined chemotherapy and radiotherapy during 1999 to 2003. In multivariate analysis, age

The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases.

We studied 26 patients belonging to 20 families with a disorder caused by mutations in the POLG gene. The patients were homozygous for 1399 G/A or 2243 G/C (giving the amino acid changes A467T and W748S, respectively) or compound heterozygotes for these two mutations. Irrespective of genotype, the patients exhibited a progressive neurological disorder usually starting in their teens and characterized by epilepsy, headache, ataxia, neuropathy, myoclonus and late onset ophthalmoplegia. However, major differences in survival were seen depending on genotype, with compound heterozygotes having a significantly shorter survival time than patients homozygous either for the A467T or W748S (P = 0.006). Epilepsy occurred in 22 of the 26 patients and in the majority of these there was an occipital EEG focus. Episodes of both generalized and focal motor status epilepticus were common and highly resistant to treatment, even with generalized anaesthesia. Status epilepticus was the recorded cause of death in 9 of 11 patients. Liver failure was the sole cause of death in two patients and evolved terminally in six others, all but one of whom were being treated with sodium valproate. Two patients underwent liver transplantation, but only one survived. Delayed psychomotor development and subsequent cognitive decline also occurs. This study demonstrates the clinical spectrum of a disorder that combines features of Alpers' syndrome and a later onset mitochondrial spinocerebellar ataxia with epilepsy and headache. Patients with this disorder are at high risk of death from status epilepticus and from liver failure, if exposed to sodium valproate. Each mutation appears capable of producing a disorder that is recessively inherited, although we also find evidence in one patient suggesting that heterozygotes may manifest. Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect.

Ri antibodies in patients with breast, ovarian or small cell lung cancer determined by a sensitive immunoprecipitation technique.

The presence of circulating antineuronal antibodies has been associated with paraneoplastic neurological syndromes (PNS). Ri antibodies are often associated with lung or breast cancer, but the prevalence of such antibodies in large cancer materials is largely unknown. We used a highly sensitive immunoprecipitation assay to study the level of Ri antibodies in blood samples from 200 patients with small cell lung cancer (SCLC), 253 patients with breast cancer and 557 patients with ovarian cancer. Two hundred blood donors and six Ri positive PNS patients served as controls. The recombinant antigen used in the immunoprecipitation assay was radiolabeled by a coupled in vitro transcription and translation (ITT) technique, enabling low levels of antibodies to be detected. None of the blood donors contained Ri antibodies, whereas all of the sera from the PNS patients were positive. Ri antibodies were present in 4.5% of the patients with SCLC, 0.8% of the patients with breast cancer and in 0.2% of the patients with ovarian cancer. Retesting of the Ri positive samples with immunofluorescense and immune blot showed that the immunoprecipitation technique was more sensitive than the other immune assays. Ri antibodies were not associated with PNS in the patients with breast or ovarian cancer. Neurological data were not available for the SCLC patients, but in these, Ri antibodies were not associated with survival.

Fcgamma receptor IIIA polymorphism as a risk-factor for coronary artery disease.

BACKGROUND: Inflammation is important in the pathogenesis of atherosclerosis. Polymorphisms of Fc receptors for IgG (FcgammaR) are associated with modifying effects of several infectious and autoimmune diseases. We have assessed the relationship between polymorphisms in three different FcgammaR genes and coronary artery disease (CAD). METHODS AND RESULTS: We genotyped for the FcgammaRIIA-R/H131, the FcgammaRIIIB-Na1/Na2, and the FcgammaRIIIA-F/V158 polymorphisms in 882 patients undergoing diagnostic coronary angiography. Significant CAD was defined as >/=50% lumen diameter stenosis in at least one coronary artery. In the analysis, no association was found between the FcgammaRIIA and FcgammaRIIIB genotypes and CAD, whereas the FcgammaRIIIA genotype was strongly related. Compared to those being heterozygous, or homozygous for the F allele, patients homozygous for the V allele had significantly reduced risk: OR, 0.53; (CI, 0.32-0.90). Additional adjustment for classical risk factors and sedimentation rate did not affect the results. The V/V genotype was also inversely related to the extent of CAD defined as no CAD, single, double or triple vessel disease (P trend=0.002). CONCLUSIONS: Our data provide evidence for an association between FcgammaRIIIA allelic variants and coronary atherosclerosis. Genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD.

Interleukin-10 promoter polymorphisms in patients with multiple sclerosis.

The expression level of interleukin-10 (IL-10) is related to polymorphisms -1082 (G/A), -819 (T/C) and -592 (A/C) in the promoter region of the IL-10 gene. The distribution of these polymorphisms was analyzed to determine whether they could influence disease susceptibility or clinical course in multiple sclerosis (MS). The -1082 (G/A), -819 (T/C) and -592 (A/C) genotypes were similarly distributed between MS patients and the controls. The primary progressive MS patients with the low IL-10 expression haplotype showed a trend towards a worse clinical outcome than did patients with medium- or high-expression haplotypes (P = 0.056). The polymorphisms did not influence the clinical course in patients with relapsing-remitting MS.