The ORLS1 (1963 to 1998) and ORLS2 (1999 to 2008) cover broadly the same population but at different times. The English linked dataset is completely independent of ORLS1 and it covers a far larger population in the same timeframe as ORLS2. The results of the analyses in the three datasets corroborate each other. Previous studies have found elevated risks of VTE in people with rheumatoid arthritis [6], type 1 diabetes mellitus [7], SLE[8] and inflammatory bowel disease [5]. We have not reported on inflammatory bowel diseases here as they are included in a different epidemiological study that we hope to publish separately. These previous findings, combined with our own, suggest that there may be a general association between immune-mediated diseases and the risk of subsequent VTE. This risk is not solely associated with the short term after hospital admission: for the diseases with large enough numbers to study, it was sustained over time.
The increased risks of VTE may have different underlying causes in each disease. The elevated risks may be a reflection of patients with more extreme cases of the immune-mediated diseases, in that the populations in our study are those admitted to hospital. Immobility [14], effects of treatment (corticosteroids promote haemostasis) [15] or a true effect of inflammation on coagulation [16] could all be implicated in the associations shown.
In 1856, Virchow proposed three precipitants for venous thrombosis: venous stasis, increased coagulability of the blood, and damage to the vessel wall [17]. Inflammation is a key determinant of endothelial function in both arteries and veins and results in changes in expression of selectins and cellular adhesion molecules [16]. Studies have shown that patients with VTE were more likely to have elevated plasma IL-8, IL-6, MCP-1 and TNF-α levels [18], that inflammation influences clotting factor levels [19], that an inflammatory gene is associated with VTE [20] and acute inflammation does contribute to VTE [21]. Taken together, inflammation is likely to contribute to some extent to the initiation of venous thrombus formation.
Methodological issues: datasets, population, and multiple comparisons
Strengths of the datasets include their size, with large numbers of fairly uncommon diseases. The ORLS1 data provide long duration of follow-up; the English data provide a much larger and more recent population but with shorter follow-up. The risk of VTE was therefore studied for a large number of immune-mediated diseases, all within a single population and using the same methodology. Accordingly, levels of risk associated with different immune-mediated diseases can be directly compared within the same study populations.
Our study should be regarded as exploratory rather than definitive. We studied a wide range of immune-mediated diseases with differing aetiologies. We did so because, as an exploratory study, with very large linked datasets in which many diseases can be studied, we saw no reason to be restrictive in our selection of diseases.
The datasets have limitations. The cohorts are based on prevalent cases, the first recorded hospital admission or episode of day case care for each person with each condition, rather than being cohorts with follow-up from the date of first diagnosis. Data are not recorded on patients who move out of the area covered by data collection or who are treated in hospitals outside the area (mainly affecting ORLS). The datasets are limited to people who were admitted to hospital, or who received day case specialist care. This would not capture all people with each immune-mediated disease, although it should identify the great majority with subsequent diagnosed VTE. These factors are part of our reasoning for including a comparison cohort of patients admitted to hospital, or in receipt of day case care, from the same database and for 'matching', through stratified analysis, for area of treatment and for year of first recorded diagnosis as well as for age and sex. The two Oxford datasets are not linked to each other due to changes in the data items available for linkage between 1998 and 1999. Consequently, it is likely that some people have been recorded as having a 'first admission' for each immune-mediated disease in each of the time periods studied.
We lack clinical and laboratory data. We lack treatment data for the immune-mediated diseases; and elements of their treatment could themselves influence VTE risk. There is very limited information on potential confounding factors such as socioeconomic status, and none on smoking or ethnicity. As we comment above, our results should be regarded as speculative rather than definitive: they represent results from what can be done using very large-scale, routinely collected administrative data. They need further work, in different study designs, to confirm or refute the findings, although epidemiological studies involving direct patient contact may be quite formidable logistical undertakings on the scale required.
Our rate ratio for VTE in people admitted to hospital with rheumatoid arthritis in the English dataset was 1.75, which is comparable with a previous study that reported a relative risk of 1.99 [6]. Our rate ratio for VTE in people aged under 30 with diabetes was 2.58 in the English dataset, which compares with a reported figure of 1.73 in hospitalised patients with diabetes aged 20 to 29 in the USA [7]. Although the literature is sparse on VTE in people with immune-mediated diseases, our findings seem broadly comparable with findings of others.
We used age at admission under 30 as a proxy for type 1 diabetes mellitus, as the type of diabetes is not routinely recorded on hospital admission records. Although this will mostly consist of people with type 1 diabetes, there may be a few people with type 2 diabetes in the cohort as well.
We studied a large number of associations between diseases. The effect of making multiple comparisons needs to be considered. For this reason, we have given exact P-values, as well as confidence intervals, so that the reader can judge the degree of significance of each immune-mediated disease and subsequent VTE. It is possible that some of the associations that are significant at a level of P < 0.05 or P < 0.01 may result from making multiple comparisons and the play of chance. This may particularly be so where there is no prior hypothesis to support the finding. On the other hand, even in a study with the number of comparisons that we have made, findings where the significance level is <0.001 or less, are unlikely to be attributable to chance alone. There were differences in levels of risk between the diseases studied: for example, the rate ratios for SLE were significantly and substantially higher than those for myxoedema. Even if the fairly low levels of elevation of risk, such as those associated with myxoedema and thyrotoxicosis, are considered unimportant, the high levels of risks associated with SLE, polyarteritis nodosa and diabetes mellitus are striking. The large numbers of findings with highly significant results in the England cohort needs comment. They no doubt in part reflect the very large numbers of patients in the cohort, such that many differences are significant, even if fairly small (for example, coeliac disease, thyroiditis, myxoedema, thyrotoxicosis), as a result of high statistical power.
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