Mortality in coeliac disease: a population-based cohort study from a single centre in Southern Derbyshire, UK
Holmes GKT, Muirhead A. BMJ Open Gastro 2018;5:e000201. Doi:10.1136/bmjgast-2018-000201
Following the introduction of reliable serological tests and use of case-finding strategies for coeliac disease (CD), it has been hypothesised that milder cases of the condition might be coming to diagnosis and have a reduced risk of mortality. A previous study of deaths amongst a group of patients with CD in Southern Derbyshire, upto the end of 2006, stratified the results according to period of diagnosis, which corresponded to increasing use of serological testing in the diagnosis process.
Following the introduction of reliable serological tests and use of case-finding strategies for coeliac disease (CD), it has been hypothesised that milder cases of the condition might be coming to diagnosis and have a reduced risk of mortality. A previous study of deaths amongst a group of patients with CD in Southern Derbyshire, upto the end of 2006, stratified the results according to period of diagnosis, which corresponded to increasing use of serological testing in the diagnosis process.
The study found that the risk of mortality had not changed over the years of study. The aim of this current study was to re-examine this hypothesis using a larger number of patients, from the same area, followed for a further 8 years, up to the end of 2014.
2515 patients with a diagnosis of CD, in Southern Derbyshire, were available for the study and were followed prospectively from 1978-2014. Diagnosis was based on characteristic changes in small bowel biopsies (n=1765), or the presence of endomysial antibodies or a level of transglutaminase antibodies > 10x the upper limit of normal (ULN) for the test (n=750 for serological testing alone). Information on deaths was obtained from patient notes, hospital databases and the National Health Service Strategic Tracing Service. Population overall and cause-specific mortality rates were obtained from Office for National Statistics data. Interest was taken in deaths from any cause and those that could be attributed to one of the following ICD-10 disease headings including cardiovascular disease (CVD), neoplasms, accidents and suicide, respiratory disease and digestive disease. Two follow-up periods- ‘peridiagnosis’ (within two years of diagnosis) and ‘postdiagnosis’ (beginning two years from date of diagnosis) were considered for analysis. Patients were stratified according to when they were diagnosed: (i) before 1990; (ii) between 1990-1999 and (iii) from 2000 onwards.
By the end of 2014, 2174 patients with at least two years of follow-up were available contributing 23,955 person-years of follow up. The median duration of follow-up had risen from 6.2 to 9.3 years. The mean age at baseline had also increased to 46.1 years from 45.6 years in the previous study and in those with at least two years of follow up, to 45.5 years compared with 44.8 years previously. 284 deaths were noted in the post diagnosis group compared with 142 meaning considerably more data was available for analysis within this study.
In the postdiagnosis period, there were significant increases in deaths from all categories of diseases except for CVD, which fell just short of significant. Of note, is the SMR for deaths resulting from respiratory diseases and digestives diseases. The upper CIs suggest that the SMRs could be considerably higher for these two disease areas compared with overall mortality in the general population by as much as 4.5 times for digestives cases and 3 times greater for respiratory cases. In the peridiagnosis period, the SMR reduced in all instances apart from CVD. There is also now significant variation in the risk of deaths occurring in the post or peridiagnoisis period in each disease area compared with no significant differences previously, apart from accidents and suicide. For CVD and respiratory disease, SMRs in the postdiagnosis period is now significantly greater, whilst for malignancy, digestive diseases, accidents and suicide, it remains insignificant. The SMR for all deaths in the coeliac cohort was significantly higher in the postdiagnosis period.
Analysis of individual causes of death in the postdiagnosis period showed an increase for non-Hodgkin’s lymphoma. Breast cancers were non-significantly reduced whilst deaths from pneumonia were significantly increased as well as those from liver disease and oesophageal cancer. No changes for lung, uterine or ovarian cancers were observed.
In the previous study, there was no trend towards significant increased or decreased mortality in relation to serological testing. In the current dataset, analysis of all deaths suggests there has been a decline that falls just short of significant. An increase in mortality from respiratory diseases over the three periods is now more marked than in the previous study but still insignificant; this finding correlates with significance of death associated with respiratory disease overall. In other disease areas, risks were greatest during 1990-1999 but reduced post-2000, mirroring findings of the earlier study. Mortality from CVD has now demonstrated a significant reduction in SMR.
In the previous study, the overall mortality risk among people with CD was 14 per 1000 person-years compared with 10.2 in the general population. The findings from this study were 11.9 compared with 10.5, giving an absolute risk difference of 1.4 per 1000 person-years which has reduced by more than half. No difference in attributable risk between causes related to and not related to CD was observed. In the previous study, 34% of the overall difference in risk was attributable to CD deaths (66% was not), however, in the new study it was 50/50. Differences in risk attributed to CD (non-Hodgkin’s lymphoma, pneumonia, liver disease or CD) appears to be growing.
Survival rates from the diagnoses of CD to death have increased threefold over time from, on average, 3.53 years post diagnosis in the decade ending 1989 to 10.71 years postdiagnosis for the period 2010-2014. Since the introduction of serological tests, for those known to have died, survival postdiagnosis had increased from 5.9 to 10.7 years.
This new data affords opportunities to reduce the risk of death by improving medical interventions such as vaccinations for pneumococcus and more prompt treatment of chest infections in patients with CD. Earlier recognition and more aggressive treatment of hepatic problems may also help to reduce deaths in this patient group.
Read the full study
2515 patients with a diagnosis of CD, in Southern Derbyshire, were available for the study and were followed prospectively from 1978-2014. Diagnosis was based on characteristic changes in small bowel biopsies (n=1765), or the presence of endomysial antibodies or a level of transglutaminase antibodies > 10x the upper limit of normal (ULN) for the test (n=750 for serological testing alone). Information on deaths was obtained from patient notes, hospital databases and the National Health Service Strategic Tracing Service. Population overall and cause-specific mortality rates were obtained from Office for National Statistics data. Interest was taken in deaths from any cause and those that could be attributed to one of the following ICD-10 disease headings including cardiovascular disease (CVD), neoplasms, accidents and suicide, respiratory disease and digestive disease. Two follow-up periods- ‘peridiagnosis’ (within two years of diagnosis) and ‘postdiagnosis’ (beginning two years from date of diagnosis) were considered for analysis. Patients were stratified according to when they were diagnosed: (i) before 1990; (ii) between 1990-1999 and (iii) from 2000 onwards.
By the end of 2014, 2174 patients with at least two years of follow-up were available contributing 23,955 person-years of follow up. The median duration of follow-up had risen from 6.2 to 9.3 years. The mean age at baseline had also increased to 46.1 years from 45.6 years in the previous study and in those with at least two years of follow up, to 45.5 years compared with 44.8 years previously. 284 deaths were noted in the post diagnosis group compared with 142 meaning considerably more data was available for analysis within this study.
Overall mortality risk by diagnosis period
In the postdiagnosis period, there were significant increases in deaths from all categories of diseases except for CVD, which fell just short of significant. Of note, is the SMR for deaths resulting from respiratory diseases and digestives diseases. The upper CIs suggest that the SMRs could be considerably higher for these two disease areas compared with overall mortality in the general population by as much as 4.5 times for digestives cases and 3 times greater for respiratory cases. In the peridiagnosis period, the SMR reduced in all instances apart from CVD. There is also now significant variation in the risk of deaths occurring in the post or peridiagnoisis period in each disease area compared with no significant differences previously, apart from accidents and suicide. For CVD and respiratory disease, SMRs in the postdiagnosis period is now significantly greater, whilst for malignancy, digestive diseases, accidents and suicide, it remains insignificant. The SMR for all deaths in the coeliac cohort was significantly higher in the postdiagnosis period.
Risk of mortality by cause of death
Analysis of individual causes of death in the postdiagnosis period showed an increase for non-Hodgkin’s lymphoma. Breast cancers were non-significantly reduced whilst deaths from pneumonia were significantly increased as well as those from liver disease and oesophageal cancer. No changes for lung, uterine or ovarian cancers were observed.
Mortality stratified by period of diagnosis
In the previous study, there was no trend towards significant increased or decreased mortality in relation to serological testing. In the current dataset, analysis of all deaths suggests there has been a decline that falls just short of significant. An increase in mortality from respiratory diseases over the three periods is now more marked than in the previous study but still insignificant; this finding correlates with significance of death associated with respiratory disease overall. In other disease areas, risks were greatest during 1990-1999 but reduced post-2000, mirroring findings of the earlier study. Mortality from CVD has now demonstrated a significant reduction in SMR.
Mortality attributable to coeliac disease
In the previous study, the overall mortality risk among people with CD was 14 per 1000 person-years compared with 10.2 in the general population. The findings from this study were 11.9 compared with 10.5, giving an absolute risk difference of 1.4 per 1000 person-years which has reduced by more than half. No difference in attributable risk between causes related to and not related to CD was observed. In the previous study, 34% of the overall difference in risk was attributable to CD deaths (66% was not), however, in the new study it was 50/50. Differences in risk attributed to CD (non-Hodgkin’s lymphoma, pneumonia, liver disease or CD) appears to be growing.
Survival Rates
Survival rates from the diagnoses of CD to death have increased threefold over time from, on average, 3.53 years post diagnosis in the decade ending 1989 to 10.71 years postdiagnosis for the period 2010-2014. Since the introduction of serological tests, for those known to have died, survival postdiagnosis had increased from 5.9 to 10.7 years.
This new data affords opportunities to reduce the risk of death by improving medical interventions such as vaccinations for pneumococcus and more prompt treatment of chest infections in patients with CD. Earlier recognition and more aggressive treatment of hepatic problems may also help to reduce deaths in this patient group.
Read the full study
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