Previous reports [4, 5, 10, 21], combined with the results we present here, suggest that there is an association between some immune-mediated diseases and the risk of subsequent TB. Rates of subsequent TB were significantly high in both the all-England and the ORLS datasets for Addison’s disease, ankylosing spondylitis, chronic active hepatitis, Crohn’s disease, pernicious anemia, rheumatoid arthritis, and systemic lupus erythematosus. In addition, in the England dataset alone there were significantly high risks of TB following admission for autoimmune hemolytic anemia, coeliac disease, dermatomyositis, Goodpasture's syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia purpura, myasthenia gravis, myxedema, pemphigoid, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, scleroderma, Sjögren's syndrome, thyrotoxicosis and ulcerative colitis. A lack of significance in the ORLS dataset does not necessarily imply that the English data are uncorroborated findings; the ORLS dataset may merely be underpowered to detect these effects. Though small numbers of patients with the immune-mediated diseases, and with TB, may appear both in the ORLS and later in the Oxford element of HES, the ORLS and the much larger and later English national dataset are largely independent of each other.
There was also evidence of an increased risk for some immune-mediated diseases after TB, but the question of which disorder came first is difficult to disentangle. Information to determine the direction of the association between these diseases and TB would need incidence dates of development of each disease; and these are not available. We looked at the risks for TB first recorded after a year and after 5 years of first admission for each immune-mediated disease (and vice versa) in order to minimize the risk of detection bias or any misdiagnosis between immune-mediated diseases and subsequent recognition that they were, instead, manifestations of TB. We also did this to help interpretation of the causal direction of the associations. Of interest in this respect are Addison’s, Sjögren’s and SLE showing associations in both directions in the 5-year analysis. It is likely that the great majority of cases of Addison’s are caused by TB. There is also evidence to suggest that TB may be an infective trigger for immune-mediated disease, mechanistically by molecular mimicry, bystander activation or acting as an adjuvant [22, 23].
The associations between other immune-mediated diseases, and their mechanisms, warrant further attention. One possible mechanism could be immune dysfunction predisposing to both immune-mediated disease and TB. Whether this dysfunction leads to an increased susceptibility to infection with TB or a greater risk of TB activation will be important to tease out. Another possible mechanism is the effect of treatment of autoimmune diseases on TB risk. Immunosuppressive drugs such as corticosteroids have long been associated with the risk of TB, and more recently, TNF antagonists have also been shown to increase risk . In addition, patients who are on these therapies are more likely to be intensively investigated for infections, including TB, if complications arise during treatment. These are perhaps the most likely explanation for some of the associations observed. However, even when excluding individuals treated with TNF antagonists, studies have observed an increased risk for TB in patients with rheumatoid arthritis . Vitamin D deficiency as a result of immune-mediated disease increasing TB risk has also been hypothesized .
Based on our data, screening for latent TB at immune-mediated disease diagnosis and regular timely screening thereafter may be beneficial. This will be especially true where we have identified particularly high levels of risk and/or where pre-existing data corroborate our findings. Although we have grouped these disorders together as immune mediated, these diseases are looked after by a diverse range of specialists (hematologists, rheumatologists, dermatologists, endocrinologists, hepatologists, respiratory physicians). Raising awareness of the importance of screening for TB in this context is more difficult but needs to be put in place.
A key strength of the dataset is its size with large numbers of fairly uncommon diseases. The risk of TB was studied within a single population, using the same methodology, which means that direct comparisons of risk between immune-mediated diseases can be made. The dataset has limitations. The data is based on prevalent cases of immune-mediated diseases and of TB (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. 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. The dataset is limited to people who were admitted to hospital, or who received day case specialist care and thus there exists the potential for selection bias. This would not capture all people with each immune-mediated disease, although it should identify the great majority with subsequent diagnosed TB. We lack treatment data for immune-mediated diseases. There is very limited information on potential confounding factors such as detailed socioeconomic characteristics, other co-infections (for example, HIV with idiopathic thrombocytopenia purpura), ethnicity and smoking. The majority of individuals in the ORLS were born in Britain, and thus associations seen in the ORLS are in a reasonably homogeneous population in respect of ethnicity. 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 for each immune-mediated disease and subsequent TB. It is possible that some of the associations that are significant at a level of 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. However, many of the associations are very strong, and levels of significance high, and it is unlikely that most of these are attributable to chance alone. The ORLS data is also helpful in this regard: associations between several diseases and increased risks of TB were seen consistently in this smaller dataset suggesting that, taking the findings from both datasets together, these are not chance findings. The fact that we see the classic association between Addison’s and TB, and confirm previous findings of association between coeliac disease and rheumatoid arthritis and TB [4, 5] adds further weight to the validity of our datasets and analyses.