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Discussion and Conclusion
Previous reports, combined with the results we present here, suggest that there may be an association between some immune-mediated diseases and the risk of subsequent SAH. Of note, both our study and the Swedish study of haemorrhagic stroke found increased risks for ankylosing spondylitis, autoimmune haemolytic anaemia, Crohn's disease, hyperthyroid conditions, idiopathic thrombocytopenia purpura, pernicious anaemia, psoriasis, rheumatoid arthritis and SLE. However, the Swedish study did not investigate the SAH subtype of haemorrhage, and indeed the mechanisms linking immune-mediated disease to SAH and other haemorrhage types may differ. Even if the fairly low levels of significant elevation of risk found in our study, such as those associated with myxoedema (at 1.15), are considered unimportant clinically, the high levels of risks associated with some diseases, for example SLE (at 3.76), are striking. This risk does not appear to be confined to recent hospital admission as the elevated risk for SAH remained for more than a year after being admitted for SLE.
Little is known about the cause of intracranial aneurysms or the process by which they form, grow, and rupture. The most common histological finding following an aneurysm is a decrease in the tunica media of the involved vessel causing defects of the normal arterial structure. These defects, combined with haemodynamic factors, lead to aneurysmal outpouchings at arterial branch points in the subarachnoid space at the base of the brain. Spontaneous SAH is typically due to arterial bleeding and has been linked to hypertension, smoking and alcohol. More rarely SAH is associated with vasculitis. We tested a wide variety of immune-mediated diseases with differing aetiologies in this exploratory study. The elevated risks may be a reflection of vasculitis and/or immune or inflammatory influences upon circulation. Most of the systemic autoimmune disorders linked to SAH in this study have been associated with vasculitis. These data therefore raise the possibility that the SAH is sometimes a manifestation of an associated focal vasculitis of the intra-cranial arteries. Without confirmation from pathology, this remains a hypothesis. Another more intriguing hypothesis is that berry aneurysms, or a proportion of them, are autoimmune and due to an inflammatory disease of blood vessels. This is partially supported by finding inflammatory infiltrates in the walls of cerebral aneurysms. Only a few studies have investigated the possibility of some immunosuppressive medications commonly used in the treatment of immune-mediated diseases potentially contributing to an increased SAH risk. The use of non-steroidal anti-inflammatory drugs (NSAIDs) does not appear to be associated with an increased SAH risk. More recently in a Taiwanese study, the use of a relatively high mean daily dose of steroid has however been proposed as an independent risk factor of increased SAH risk in SLE patients, but this needs to be confirmed or refuted in further work and in other immune-mediated diseases. Further, the increased risks of SAH may have different causes in each disease. For example, type 1 diabetes (T1D) has recently been associated with a significantly increased risk of specifically non-aneurysmal SAH. This is thought to be due to microvascular rather than macrovascular damage, which is known to occur in T1D through non-immune mediated mechanisms. The mechanism behind the association between SAH and diabetes mellitus may therefore, at least in part, differ from that of another immune-mediated disease.
A key strength of the dataset is its size with large numbers of fairly uncommon diseases. The risk of SAH was studied within a single population, using the same methodology, which means that direct comparisons of risk between different immune-mediated diseases can be made. The dataset has limitations. The data is based on prevalent cases of immune disease – the first recorded hospital admission or episode of day case care for each person with each condition – rather than being a cohort with follow-up from the date of first diagnosis. The dataset is 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 SAH. We lack treatment and disability data for the immune-mediated diseases; and we lack data on potential confounding factors such as detailed socioeconomic characteristics, ethnicity, smoking, alcohol intake and blood pressure. The effect of making multiple comparisons needs to be considered. It is possible that some of the associations that are significant at levels close to p < 0.05 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. We studied 27 different immune-mediated diseases. At a significance level of p = 0.05, by chance alone one might expect one or two significant results. We have reported significant results for 15 of the 27: these associations with SAH are not the play of chance but a rather general characteristic of immune-mediated diseases.
Our findings and their interpretation should be regarded as speculative rather than definitive. The results represent what can be done using very large, linked, routinely collected administrative datasets; but such datasets lack detail. Alternative designs like epidemiological field studies - e.g. interviewing patients with SAH and controls about uncommon prior immune-mediated diseases, or following up cohorts of people with and without (say) SLE to identify later risk of SAH - would be substantial undertakings. Nonetheless, further work is needed, in different study designs, to confirm or refute the findings. Further studies should look at individual immune-mediated diseases in greater depth to aid understanding of mechanisms behind any association. This may be particularly warranted in people with diseases at relatively high risk of SAH, such as SLE.
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