Autoimmune and Atopic Disorders and Risk of Hodgkin Lymphoma
Autoimmune and Atopic Disorders and Risk of Hodgkin Lymphoma
In the present investigation, we found that HL risk was higher in patients with a self-reported history of RA and that the risk increase tended to correlate with proxy measures for severity of disease. Self-reported history of allergic rhinitis was associated with a lower risk of HL that was of borderline statistical significance, but this inverse association was not borne out by any other questionnaire-based measures of atopic disease or by serological analyses for IgE reactivity.
Our findings add further credence to the previously reported theory that the association between RA and HL is causal in nature thanks to a number of study strengths. Specifically, unlike the present investigation, several of the earlier studies on autoimmune diseases and HL exclusively included hospitalized patients. This subset of patients might constitute a biased subset of the autoimmune disease patient population who have a particularly higher risk of lymphoma either because they suffer from more aggressive autoimmune disease, in which high inflammatory activity promotes HL development, or because they receive lymphoma-inducing treatment for autoimmune disease. Indeed, a higher occurrence of HL in patients treated with disease-modifying antirheumatic drugs has been reported. Also, in contrast to the present study, the majority of previous studies have been register-based and therefore have not included control for risk factors common to both HL and autoimmune diseases, for example, smoking and socioeconomic status.
The observed association between HL and RA resembles those reported between a variety of autoimmune diseases, including RA and NHL. Therefore, in theory, misclassified cases of NHL could contribute to the observed relation between RA and HL. However, because tumor biopsies were reviewed by expert hematopathologists for more than 90% of the patients in our study, we consider this as an unlikely explanation for our observations.
Meanwhile, the use of self-reported rather than validated histories of autoimmune diseases is a potential source of bias. As described in a previous investigation of NHL in the same study population, the prevalence of RA among the controls was in the upper range of what has been reported for the general population elsewhere. This excess might reflect selection bias among the controls or, more likely, misclassification of RA. However, such misclassification of RA would only contribute to the observed association if it were more extreme among HL patients than among controls. Because the results of our analyses are congruent with those from register-based analyses in which an association between RA and HL was demonstrated, we find this an unlikely scenario, especially because all participants were unaware of the hypothesis under study.
Absent obvious methodological explanations, our analyses therefore indicate that patients with RA—particularly those with severe disease—truly have a higher risk of HL. This excess risk appeared higher for cases with EBV-positive HL than for cases with EBV-negative HL, although no formally significant heterogeneity was noted. Patients with autoimmune diseases have elevated anti-EBV antibody titers, but it is unclear whether EBV reactivation causes autoimmune disease or whether the elevated EBV antibodies are a consequence of the autoimmune disease. In prospective studies, however, autoimmune diseases appear to be associated with B-cell activation (e.g., leading to self-reactive antibodies) and with increased EBV replication in infected B cells. Thus, our findings are compatible with a model in which autoimmune disease activates EBV replication and thereby increases the risk of EBV-positive HL. A stronger correlation of RA with EBV-positive HL than with EBV-negative HL was suggested in 2 register-based studies in which the strongest association was observed for mixed-cellularity HL, which is typically more often EBV-positive than is nodular sclerosis, as was also the case in our study. In our analyses, we did not rule out the possibility that the risk of EBV-negative HL might also be higher in RA patients, which means that there are potentially other mechanisms that link autoimmune disease with HL risk, for example, treatment and shared genetic susceptibility.
Regarding atopic conditions, it has been speculated that atopy might be associated with a higher risk of HL, particularly among younger adults. In the present study, the prevalence of self-reported atopic diseases was lower among HL patients than among controls, albeit not statistically significantly so. Although the prevalence of overall serological evidence of atopy was also lower among HL patients than among controls, stratified analyses indicated that this could be explained to some extent by treatment. Indeed, self-reported hay fever and IgE reactivity in pretreatment samples also were not associated with HL risk. Atopic diseases and HL risks might both be related to correlates of socioeconomic affluence in childhood, such as number of siblings, housing density, and childhood infections, for which we controlled in our study. The findings with a lower prevalence of self-reported atopic diseases in HL patients are similar to observations in studies of NHL. However, for NHL, we previously found evidence of reverse causality, because analyses of prospectively sampled sera indicated that the inverse relationship with specific IgE reactivity arose only shortly before lymphoma diagnosis. On the whole, our observations are therefore entirely compatible with there being no association between atopic disease and HL risk.
Our investigation has a number of strengths and weaknesses. The strengths include the population-based setting, rapid case ascertainment, histopathologic review of more than 90% of the cases in connection with EBV typing, classification of all HL cases according to the World Health Organization system, a high participation rate among cases (90%), and relatively high participation rate among controls (70%).
Study weaknesses include potential participation bias and exposure misclassification. Accordingly, although we have no reason to assume this to be the case, we cannot fully exclude the possibility that participating controls differ from nonparticipants with respect to prevalence of the exposures under study that contributed to the observed associations. Autoimmune and atopic disease histories were self-reported and not validated. However, for most exposures, participants were asked specifically about medically confirmed diagnoses and, when relevant, about age at onset and treatment. Because autoimmune diseases are rare, the number of conditions that could be analyzed individually was limited.
In conclusion, we observed a statistically significantly higher prevalence of RA among patients who had been diagnosed with HL. Because the association was seemingly restricted to patients with EBV-positive tumors, we propose that chronic inflammation induces EBV replication, with an associated increased risk of EBV-positive HL.
Discussion
In the present investigation, we found that HL risk was higher in patients with a self-reported history of RA and that the risk increase tended to correlate with proxy measures for severity of disease. Self-reported history of allergic rhinitis was associated with a lower risk of HL that was of borderline statistical significance, but this inverse association was not borne out by any other questionnaire-based measures of atopic disease or by serological analyses for IgE reactivity.
Our findings add further credence to the previously reported theory that the association between RA and HL is causal in nature thanks to a number of study strengths. Specifically, unlike the present investigation, several of the earlier studies on autoimmune diseases and HL exclusively included hospitalized patients. This subset of patients might constitute a biased subset of the autoimmune disease patient population who have a particularly higher risk of lymphoma either because they suffer from more aggressive autoimmune disease, in which high inflammatory activity promotes HL development, or because they receive lymphoma-inducing treatment for autoimmune disease. Indeed, a higher occurrence of HL in patients treated with disease-modifying antirheumatic drugs has been reported. Also, in contrast to the present study, the majority of previous studies have been register-based and therefore have not included control for risk factors common to both HL and autoimmune diseases, for example, smoking and socioeconomic status.
The observed association between HL and RA resembles those reported between a variety of autoimmune diseases, including RA and NHL. Therefore, in theory, misclassified cases of NHL could contribute to the observed relation between RA and HL. However, because tumor biopsies were reviewed by expert hematopathologists for more than 90% of the patients in our study, we consider this as an unlikely explanation for our observations.
Meanwhile, the use of self-reported rather than validated histories of autoimmune diseases is a potential source of bias. As described in a previous investigation of NHL in the same study population, the prevalence of RA among the controls was in the upper range of what has been reported for the general population elsewhere. This excess might reflect selection bias among the controls or, more likely, misclassification of RA. However, such misclassification of RA would only contribute to the observed association if it were more extreme among HL patients than among controls. Because the results of our analyses are congruent with those from register-based analyses in which an association between RA and HL was demonstrated, we find this an unlikely scenario, especially because all participants were unaware of the hypothesis under study.
Absent obvious methodological explanations, our analyses therefore indicate that patients with RA—particularly those with severe disease—truly have a higher risk of HL. This excess risk appeared higher for cases with EBV-positive HL than for cases with EBV-negative HL, although no formally significant heterogeneity was noted. Patients with autoimmune diseases have elevated anti-EBV antibody titers, but it is unclear whether EBV reactivation causes autoimmune disease or whether the elevated EBV antibodies are a consequence of the autoimmune disease. In prospective studies, however, autoimmune diseases appear to be associated with B-cell activation (e.g., leading to self-reactive antibodies) and with increased EBV replication in infected B cells. Thus, our findings are compatible with a model in which autoimmune disease activates EBV replication and thereby increases the risk of EBV-positive HL. A stronger correlation of RA with EBV-positive HL than with EBV-negative HL was suggested in 2 register-based studies in which the strongest association was observed for mixed-cellularity HL, which is typically more often EBV-positive than is nodular sclerosis, as was also the case in our study. In our analyses, we did not rule out the possibility that the risk of EBV-negative HL might also be higher in RA patients, which means that there are potentially other mechanisms that link autoimmune disease with HL risk, for example, treatment and shared genetic susceptibility.
Regarding atopic conditions, it has been speculated that atopy might be associated with a higher risk of HL, particularly among younger adults. In the present study, the prevalence of self-reported atopic diseases was lower among HL patients than among controls, albeit not statistically significantly so. Although the prevalence of overall serological evidence of atopy was also lower among HL patients than among controls, stratified analyses indicated that this could be explained to some extent by treatment. Indeed, self-reported hay fever and IgE reactivity in pretreatment samples also were not associated with HL risk. Atopic diseases and HL risks might both be related to correlates of socioeconomic affluence in childhood, such as number of siblings, housing density, and childhood infections, for which we controlled in our study. The findings with a lower prevalence of self-reported atopic diseases in HL patients are similar to observations in studies of NHL. However, for NHL, we previously found evidence of reverse causality, because analyses of prospectively sampled sera indicated that the inverse relationship with specific IgE reactivity arose only shortly before lymphoma diagnosis. On the whole, our observations are therefore entirely compatible with there being no association between atopic disease and HL risk.
Our investigation has a number of strengths and weaknesses. The strengths include the population-based setting, rapid case ascertainment, histopathologic review of more than 90% of the cases in connection with EBV typing, classification of all HL cases according to the World Health Organization system, a high participation rate among cases (90%), and relatively high participation rate among controls (70%).
Study weaknesses include potential participation bias and exposure misclassification. Accordingly, although we have no reason to assume this to be the case, we cannot fully exclude the possibility that participating controls differ from nonparticipants with respect to prevalence of the exposures under study that contributed to the observed associations. Autoimmune and atopic disease histories were self-reported and not validated. However, for most exposures, participants were asked specifically about medically confirmed diagnoses and, when relevant, about age at onset and treatment. Because autoimmune diseases are rare, the number of conditions that could be analyzed individually was limited.
In conclusion, we observed a statistically significantly higher prevalence of RA among patients who had been diagnosed with HL. Because the association was seemingly restricted to patients with EBV-positive tumors, we propose that chronic inflammation induces EBV replication, with an associated increased risk of EBV-positive HL.
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