Raph Goldacre

Autoimmune disease preceding amyotrophic lateral sclerosis: An epidemiologic study

Objective: To study whether the risk of amyotrophic lateral sclerosis (ALS) is increased in people with prior autoimmune disease. Methods: An all-England hospital record-linkage dataset spanning 1999–2011 was used. Cohorts were constructed of people with each of a range of autoimmune diseases; the incidence of ALS in each disease cohort was compared with the incidence of ALS in a cohort of individuals without prior admission for the autoimmune disease. Results: There were significantly more cases than expected of ALS associated with a prior diagnosis of asthma, celiac disease, younger-onset diabetes (younger than 30 years), multiple sclerosis, myasthenia gravis, myxedema, polymyositis, Sjögren syndrome, systemic lupus erythematosus, and ulcerative colitis. Conclusions: Autoimmune disease associations with ALS raise the possibility of shared genetic or environmental risk factors.

HIV and lower risk of multiple sclerosis: beginning to unravel a mystery using a record-linked database study

Objectives Even though multiple sclerosis (MS) and HIV infection are well-documented conditions in clinical medicine, there is only a single case report of a patient with MS and HIV treated with HIV antiretroviral therapies. In this report, the patients MS symptoms resolved completely after starting combination antiretroviral therapy and remain subsided for more than 12 years. Authors hypothesised that because the pathogenesis of MS has been linked to human endogenous retroviruses, antiretroviral therapy for HIV may be coincidentally treating or preventing progression of MS. This led researchers from Denmark to conduct an epidemiological study on the incidence of MS in a newly diagnosed HIV population (5018 HIV cases compared with 50 149 controls followed for 31 875 and 393 871 person-years, respectively). The incidence rate ratio for an HIV patient acquiring MS was low at 0.3 (95% CI 0.04 to 2.20) but did not reach statistical significance possibly due to the relatively small numbers in both groups. Our study was designed to further investigate the possible association between HIV and MS. Methods We conducted a comparative cohort study accessing one of the world’s largest linked medical data sets with a cohort of 21 207 HIV-positive patients and 5 298 496 controls stratified by age, sex, year of first hospital admission, region of residence and socioeconomic status and ‘followed up’ by record linkage. Results Overall, the rate ratio of developing MS in people with HIV, relative to those without HIV, was 0.38 (95% CI 0.15 to 0.79). Conclusions HIV infection is associated with a significantly decreased risk of developing MS. Mechanisms of this observed possibly protective association may include immunosuppression induced by chronic HIV infection and antiretroviral medications.

Associations between age-related macular degeneration, Alzheimer disease, and dementia - record linkage study of hospital admissions

IMPORTANCE The potential association between age-related macular degeneration (AMD) and Alzheimer disease (AD) is uncertain and has implications for understanding disease pathogenesis, referral, and treatments. OBJECTIVES To determine whether individuals admitted to the hospital with AMD were significantly more or less likely to develop AD or dementia in the following years, as well as to assess whether people with AD or dementia were significantly more or less likely to be admitted to the hospital for AMD treatment in the years following diagnosis of dementia. DESIGN, SETTING, AND PARTICIPANTS An AMD cohort of 65,894 people was constructed from English National Health Service, linked hospital episode statistics from January 1, 1999, through February 28, 2011, by identifying computerized record abstracts for all people with an admission or day case care for AMD. A dementia cohort (168,092 people) and a reference cohort (>7.7 million people) were constructed in similar ways. MAIN OUTCOMES AND MEASURES Risk of AD or dementia following AMD and risk of AMD following AD or dementia. Rate ratios were calculated based on standardized rates of AD and dementia in the AMD cohort, as well as standardized rates of AMD in the AD and dementia cohort, relative to those in the reference cohort. RESULTS The risk of AD or dementia following AMD was not elevated. The rate ratio was 0.86 (95% CI, 0.67-1.08) for AD and 0.91 (0.79-1.04) for dementia. The likelihood of being admitted for AMD following AD or dementia was very low: the rate ratio was 0.04 (0.01-0.10) for people with AD and 0.07 (0.04-0.11) for those with dementia. CONCLUSIONS AND RELEVANCE These neurodegenerative conditions may share environmental risk factors and histopathologic features. However, considering AD and other dementia after AMD, their coexistence at the individual level is no different from that expected by chance. Our data also suggest that patients in England with dementia may be substantially less likely to receive AMD treatment. Further research is required to determine whether people with dementia receive appropriate investigation and treatment for AMD, as well as identify and address potential barriers.

Associations between selected immune-mediated diseases and tuberculosis: record-linkage studies

BackgroundPrevious studies have suggested that there may be an association between some immune-mediated diseases and risk of tuberculosis (TB).MethodsWe analyzed a database of linked statistical records of hospital admissions and death certificates for the whole of England (1999 to 2011), and a similar database (the Oxford Record Linkage Study (ORLS)) for a region of southern England in an earlier period. Rate ratios for TB were determined, comparing immune-mediated disease cohorts with comparison cohorts.ResultsIn the all-England dataset, there were significantly elevated risks of TB after hospital admission for the following individual immune-mediated diseases: Addisons disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, coeliac disease, Crohns disease, dermatomyositis, Goodpastures syndrome, Hashimotos thyroiditis, idiopathic thrombocytopenia purpura (ITP), myasthenia gravis, myxedema, pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma, Sjögrens syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis and ulcerative colitis. Particularly high levels of risk were found for Addison’s disease (rate ratio (RR) = 11.9 (95% CI 9.5 to 14.7)), Goodpasture’s syndrome (RR = 10.8 (95% CI 4.0 to 23.5)), SLE (RR = 9.4 (95% CI 7.9 to 11.1)), polymyositis (RR = 8.0 (95% CI 4.9 to 12.2)), polyarteritis nodosa (RR = 6.7 (95% CI 3.2 to 12.4)), dermatomyositis (RR = 6.6 (95% CI 3.0 to 12.5)), scleroderma (RR = 6.1 (95% CI 4.4 to 8.2)) and autoimmune hemolytic anemia (RR = 5.1 (95% CI 3.4 to 7.4)).ConclusionsThese two databases show that patients with some immune-mediated diseases have an increased risk of TB, although we cannot explicitly state the direction of risk or exclude confounding. Further study of these associations is warranted, and these findings may aid TB screening, control and treatment policies.

Testicular hypofunction and multiple sclerosis risk: A record‐linkage study

The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3–8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. Ann Neurol 2014;76:625–628The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3–8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. Ann Neurol 2014;76:625–628

Subsequent Primary Malignancies in Patients with Nonmelanoma Skin Cancer in England: A National Record-Linkage Study

Background: Conflicting evidence exists about whether people with a history of nonmelanoma skin cancer (NMSC) are at higher risk of subsequent primary malignant cancers than those without. Methods: An all England record-linked hospital and mortality dataset spanning from 1999 to 2011 was used. We constructed two cohorts: one that comprised people with a history of NMSC (502,490 people), and a control cohort that comprised people without. We “followed up” these two cohorts electronically to determine observed and expected numbers of people with subsequent primary cancers in each, based on person-years at risk, and calculated standardized risk ratios (RR). Results: Comparing the NMSC cohort with the non-NMSC cohort, the RR for all subsequent malignant cancers combined was 1.36 [95% confidence interval (CI), 1.35–1.37]. Significantly increased RRs (P < 0.05) were found for 26 of the 29 cancer types studied, in particular for salivary gland, melanoma, bone, and upper gastrointestinal tract cancers. The RRs were also particularly high when comparing younger people with and without NMSC. Conclusions: NMSC is strongly associated with a broad spectrum of other primary cancers, particularly in younger age groups. The pattern suggests a genetic or early-acquired etiologic association. Impact: These results represent what can be done using very large, linked, routinely collected administrative datasets; but such datasets lack detail. Further work to establish the mechanisms behind these associations is warranted. Cancer Epidemiol Biomarkers Prev; 23(3); 490–8. ©2014 AACR.

Hospital admissions for vitamin D related conditions and subsequent immune-mediated disease: record-linkage studies

BackgroundPrevious studies have suggested that there may be an association between vitamin D deficiency and the risk of developing immune-mediated diseases.MethodsWe analyzed a database of linked statistical records of hospital admissions and death registrations for the whole of England (from 1999 to 2011). Rate ratios for immune-mediated disease were determined, comparing vitamin D deficient cohorts (individuals admitted for vitamin D deficiency or markers of vitamin D deficiency) with comparison cohorts.ResultsAfter hospital admission for either vitamin D deficiency, osteomalacia or rickets, there were significantly elevated rates of Addison’s disease, ankylosing spondylitis, autoimmune hemolytic anemia, chronic active hepatitis, celiac disease, Crohn’s disease, diabetes mellitus, pemphigoid, pernicious anemia, primary biliary cirrhosis, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus erythematosus, thyrotoxicosis, and significantly reduced risks for asthma and myxoedema.ConclusionsThis study shows that patients with vitamin D deficiency may have an increased risk of developing some immune-mediated diseases, although we cannot rule out reverse causality or confounding. Further study of these associations is warranted and these data may aid further public health studies.

Career plans and views of trainees in the Academic Clinical Fellowship Programme in England

Background: The Academic Clinical Fellowship (ACF) programme in England was introduced in 2007 to support the training of clinical academics. Aim: To report on career plans and views of ACF trainees. Method: Questionnaire survey of trainees appointed in 2008. Results: Of 102 responders, 63% expected to work eventually wholly in clinical academic posts, 34% in clinical service posts with some teaching and research, and none in clinical service posts with no teaching or research. Of factors that had influenced the choice of an academic career ‘a great deal’, 83% of responders cited having a ‘varied and stimulating career’, 79% the ‘intellectual environment’ of academic departments, 78% the ‘challenge of research’ and 62% the ‘stimulation of teaching’. The most important factors that might dissuade them from eventually pursuing an academic career were ‘difficulty obtaining research grants’ (specified by 42%), followed by ‘competing pressures in the three areas of research, clinical work and teaching’, lack of ‘pay parity with NHS colleagues’, and concerns about adequate availability of academic posts at senior levels. Conclusions: The responders were highly motivated by the challenges of academic work. However, policymakers need to consider what, if anything, might realistically be done about potentially demotivating factors.

Associations between primary open angle glaucoma, Alzheimer’s disease and vascular dementia: record linkage study

Aims The potential association between primary open angle glaucoma (POAG) and Alzheimers disease (AD) is uncertain and has implications for understanding disease pathogenesis, referral and treatments. The aim was to determine whether individuals diagnosed with POAG are at higher risk of subsequently developing AD or vascular dementia. Methods A POAG cohort of 87 658 people was constructed from English National Health Service linked hospital episode statistics from 1999 to 2011. An AD cohort (251 703 people), vascular dementia cohort (217 302 people) and reference cohort (>2.5 million people) were constructed in similar ways. Risk of dementia following POAG was determined: rate ratios were calculated based on standardised rates of dementia in the POAG cohort. Results The risk of AD following a diagnosis of POAG was not elevated: the rate ratio was 1.01 (95% CI 0.96 to 1.06). The risk of vascular dementia after POAG was modestly elevated, with rate ratio 1.10 (1.05 to 1.16). The likelihood of a hospital record of POAG following AD or vascular dementia was very low, with rate ratios 0.28 (0.24 to 0.31) and 0.32 (0.28 to 0.37), respectively. Conclusions POAG and AD are neurodegenerative conditions that share some pathological features. However, considering AD after POAG, their coexistence at the individual level is no different from that expected by chance. By contrast, a diagnosis of POAG is modestly associated with later development of vascular dementia, presumably owing to shared vascular risk factors. People with dementia in England are much less likely to be admitted subsequently with POAG, perhaps through poor access to hospital eye services and diagnostic challenges.

Viral hepatitis and Parkinson disease: A national record-linkage study.

Objective: To study associations between viral hepatitis and Parkinson disease (PD). Methods: A retrospective cohort study was done by analyzing linked English National Hospital Episode Statistics and mortality data (1999–2011). Cohorts of individuals with hepatitis B, hepatitis C, autoimmune hepatitis, chronic active hepatitis, and HIV were constructed, and compared to a reference cohort for subsequent rates of PD. Results: The standardized rate ratio (RR) of PD following hepatitis B was 1.76 (95% confidence interval [CI] 1.28–2.37) (p < 0.001), based on 44 observed compared with 25 expected cases. The RR of PD following hepatitis C was 1.51 (95% CI, 1.18–1.9) (p < 0.001), based on 48.5 expected and 73 observed cases. There was no significant association between autoimmune hepatitis, chronic active hepatitis or HIV, and subsequent PD. When including only those episodes of care for PD that occurred first at least 1 year following each exposure condition, the RR for hepatitis B and hepatitis C were 1.82 (1.29–2.5) and 1.43 (1.09–1.84), respectively. Conclusions: We report strong evidence in favor of an elevation of rates of subsequent PD in patients with hepatitis B and hepatitis C. These findings may be explained by factors peculiar to viral hepatitis, but whether it reflects consequences of infection, shared disease mechanisms, or the result of antiviral treatment remains to be elucidated. Further work is needed to confirm this association and to investigate pathophysiologic pathways, potentially advancing etiologic understanding of PD more broadly.