Is family history a predictor of response to tumour necrosis factor inhibitors in spondyloarthritis? A Swedish nationwide cohort study.

Objective: To determine whether a family history of spondyloarthritis (SpA) is associated with clinical presentation at the start of tumour necrosis factor inhibitor (TNFi) treatment, or predictive of TNFi drug survival and treatment response in patients with SpA.Method: Family history of SpA in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), and undifferentiated SpA (uSpA) from the Swedish Rheumatology Quality register starting a TNFi as their first biologic in 2006-2018 was assessed through national registers. Clinical characteristics at treatment start were compared by family history status. We used Cox regression to estimate hazard ratios for drug discontinuation, and analysed treatment response at 3 and 12 months with linear regression. Multiple imputation was used to address missing data.Results: We included 9608 patients. Patients with family history had an earlier age at onset and longer disease duration at TNFi treatment start, but did not differ regarding disease activity and presence of SpA manifestations. Hazard ratios for drug discontinuation were 1.08 [95% confidence interval (CI) 0.89-1.31] for AS patients with a family history of AS, 1.02 (95% CI 0.89-1.18) for PsA patients with a family history of PsA, and 1.11 (95% CI 0.85-1.45) for uSpA patients with a family history of uSpA, after adjusting for demographic, socioeconomic, and SpA-related factors. Treatment response at 3 and 12 months was similar between groups.Conclusion: Family history of SpA was not found to be associated with clinical presentation at the start of TNFi treatment, nor was it associated with drug survival or treatment response in SpA patients starting a first TNFi.

Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis.

BACKGROUND AND PURPOSE: Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS. METHODS: Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models. RESULTS: A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ. CONCLUSIONS: In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

Comparative analysis of first-year fingolimod and natalizumab drug discontinuation among Swedish patients with multiple sclerosis.

BACKGROUND: Natalizumab (NTZ) and fingolimod (FGL) are mainly used second line in relapsing-remitting multiple sclerosis (MS), although pivotal trials included mainly treatment-naïve patients. OBJECTIVE: This study aims to provide real-world data on safety and discontinuation rates. METHODS: Using IMSE, a drug monitoring registry for all newer MS drugs in Sweden, we analysed differences in baseline characteristics and 1-year drug survival for patients registered 2011-2013, initiating treatment with NTZ (n=640) or FGL (n=876). Among FGL initiators, n=383 (44%) had previously used NTZ (FGL(afterNTZ)). RESULTS: Compared with NTZ, the FGL cohort was older and more often male (36/38 years, 24%/33% males). Baseline Expanded Disability Status Scale was similar across groups, but MS Severity Score was higher in NTZ patients, and Symbol Digit Modalities Test and MS Impact Scale (MSIS-29) was higher in FGL(afterNTZ) versus FGL(NTZ-naïve) patients. Proportion on drug after 1 year was high, NTZ=87%, FGL(NTZ-naïve)=83% and FGL(afterNTZ)=76%. Adverse events was the most frequent reason for discontinuing FGL (FGL(NTZ-naïve)=9%, FGL(afterNTZ)=12%), and was significantly higher than on NTZ (3%). In contrast, the proportion of patients stopping treatment due to lack of effect was more similar: NTZ=4%, FGL(NTZ-naïve)=3%, FGL(afterNTZ)=8%. CONCLUSION: FGL and NTZ were both well tolerated, but FGL less so than NTZ, especially in patients switching to FGL from NTZ. Group differences were not explained by differences in recorded baseline characteristics.

Familial clustering of suicide risk: a total population study of 11.4 million individuals.

BACKGROUND: Research suggests that suicidal behaviour is aggregated in families. However, due to methodological limitations, including small sample sizes, the strength and pattern of this aggregation remains uncertain. METHOD: We examined the familial clustering of completed suicide in a Swedish total population sample. We linked the Cause of Death and Multi-Generation Registers and compared suicide rates among relatives of all 83 951 suicide decedents from 1952-2003 with those among relatives of population controls. RESULTS: Patterns of familial aggregation of suicide among relatives to suicide decedents suggested genetic influences on suicide risk; the risk among full siblings (odds ratio 3.1, 95% confidence interval 2.8-3.5, 50% genetic similarity) was higher than that for maternal half-siblings (1.7, 1.1-2.7, 25% genetic similarity), despite similar environmental exposure. Further, monozygotic twins (100% genetic similarity) had a higher risk than dizygotic twins (50% genetic similarity) and cousins (12.5% genetic similarity) had higher suicide risk than controls. Shared (familial) environmental influences were also indicated; siblings to suicide decedents had a higher risk than offspring (both 50% genetically identical but siblings having a more shared environment, 3.1, 2.8-3.5 v. 2.0, 1.9-2.2), and maternal half-siblings had a higher risk than paternal half-siblings (both 50% genetically identical but the former with a more shared environment). Although comparisons of twins and half-siblings had overlapping confidence intervals, they were supported by sensitivity analyses, also including suicide attempts. CONCLUSIONS: Familial clustering of suicide is primarily influenced by genetic and also shared environmental factors. The family history of suicide should be considered when assessing suicide risk in clinical settings or designing and administering preventive interventions.

Violent crime runs in families: a total population study of 12.5 million individuals.

BACKGROUND: Etiological theory and prior research with small or selected samples suggest that interpersonal violence clusters in families. However, the strength and pattern of this aggregation remains mostly unknown. METHOD: We investigated all convictions for violent crime in Sweden 1973-2004 among more than 12.5 million individuals in the nationwide Multi-Generation Register, and compared rates of violent convictions among relatives of violent individuals with relatives of matched, non-violent controls, using a nested case-control design. RESULTS: We found strong familial aggregation of interpersonal violence among first-degree relatives [e.g. odds ratio (OR)sibling 4.3, 95% confidence interval (CI) 4.2-4.3], lower for more distant relatives (e.g. OR cousin 1.9, 95% CI 1.9-1.9). Risk patterns across biological and adoptive relations provided evidence for both genetic and environmental influences on the development of violent behavior. Familial risks were stronger among women, in higher socio-economic strata, and for early onset interpersonal violence. There were crime-specific effects (e.g. OR sibling for arson 22.4, 95% CI 12.2-41.2), suggesting both general and subtype-specific familial risk factors for violent behavior. CONCLUSIONS: The observed familiality should be accounted for in criminological research, applied violence risk assessment, and prevention efforts.

Psychiatric morbidity associated with same-sex sexual behaviour: influence of minority stress and familial factors.

BACKGROUND: Increased psychiatric morbidity has been widely reported among non-heterosexual individuals (defined as reporting a homosexual/bisexual identity and/or same-sex sexual partners). However, the causes of this psychiatric ill-health are mostly unknown. METHOD: We attempted to estimate the influence of minority stress and familial factors on psychiatric disorder among adults with same-sex sexual partners. Self-report data from a 2005 survey of adults (age 20-47 years, n=17,379) in the population-based Swedish Twin Registry were analysed with regression modelling and co-twin control methodology. RESULTS: Rates of depression, generalized anxiety disorder (GAD), eating disorders, alcohol dependence and attention deficit hyperactivity disorder (ADHD) were increased among men and women with same-sex sexual experiences. Adjusting for perceived discrimination and hate crime victimization lowered this risk whereas controlling for familial (genetic or environmental) factors in within-twin pair comparisons further reduced or eliminated it. CONCLUSIONS: Components of minority stress influence the risk of psychiatric ill-health among individuals with any same-sex sexual partner. However, substantial confounding by familial factors suggests a common genetic and/or environmental liability for same-sex sexual behaviour and psychiatric morbidity.