Grave’s disease and risk of incident SLE: A nationwide population-based cohort study
BACKGROUND
Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease that causes damage to multiple tissues and organs, including the thyroid gland. Several authors have linked Grave’s disease, an autoimmune disease characterized by an overactive thyroid gland, to incident SLE. However, divergences still exist regarding prevalence. Some studies reported the presence of anti-peroxidase and anti-thyroglobulin antibodies in SLE patients when compared to control groups, as well as in the general population. Furthermore, it has been reported that antithyroid medications for Grave’s disease can induce SLE. However, there are still questions about the association between Grave’s disease and the risk of SLE.
The objective of the study was to investigate the association between Grave’s disease and the risk of SLE.
STUDY DESIGN
Data
The National Health Insurance Program of Taiwan (NHIP), was used as the source to pool the patient databases. ICD-9-CM codes were given to all disease diagnoses and several subsets of patient data have been created within the NHIRD. The Longitudinal Health Insurance Database 2000 (LHID2000) was the subset used in this study; it includes all healthcare information of close to 100000 randomly chosen individuals from NHIRD between 1995 and 2013.
Inclusion criteria
The cohort included patients newly diagnosed with Grave’s disease (ICD-9-CM code: 242.0, toxic diffuse goiter) between 2000 to 2012. The study included only the ones treated with antithyroid drugs such as propylthiouracil, thiamazole, and carbimazole or undergone radioactive iodine ablation, or surgery (thyroidectomy) during the follow-up period.
Exclusion criteria
Patients diagnosed with Grave’s disease (ICD-9-CM: 242.9, thyrotoxicosis without mention of goiter or other cause), were excluded. Patients with SLE history (ICD-9-CM code: 710.0) between 1995 and the index date (the first diagnosis of Grave’s disease) were excluded from both case and control cohort.
The outcome of the study
In Taiwan, rheumatologists diagnose lupus and they request a catastrophic illness certificate from NHIP for patients who meet the diagnostic criteria for SLE. In this cohort study, patients newly diagnosed with SLE by board-certified rheumatologists were considered ‘incidents’. To ensure diagnostic validity, the authors used the catastrophic disease registry database. Each individual in the study was followed until diagnosed with SLE, death, removal from the NHIP, or the end of 2013 (whichever came first).
Covariates
Age (<40 and ≥40 years), gender, Charlson Comorbidity Index (CCI) score (0 and ≥1), index year were collected for each subject. The CCI was scored by summing the weight scores of 19 medical conditions and their mortality risk. Information and effect of antithyroid drugs (propylthiouracil, thiamazole, and carbimazole), radioactive iodine ablation, or surgery (thyroidectomy) in the case-cohort during the follow-up period were also evaluated.
Statistical Analysis
Demographic characteristics between the case-cohort and the control cohort were compared using Wilcoxon’s rank test (continuous variables) and the Chi-square test (nominal variables). The authors estimated the SLE incidence rate by dividing the number of incidents by person-years of follow-up.
The difference in SLE cumulative incidence for the two cohorts was determined using Kaplan-Meier analysis. The authors calculated the crude and adjusted hazard ratio (HR) using Cox regression analysis.
Sensitivity analyses were performed to minimize potential bias by excluding the first 0.5 and 1 year of the observation period. Data retrieval and analysis were performed using SAS version 9.4 (SAS Institute Inc., NC, USA), and the significance level was set as p < .05.
RESULTS
Demographic Status
- A total of 8779 patients with Grave’s disease met the inclusion criteria in this study. All of them were matched to 8779 controls by age, gender, index year, and CCI score.
- The age distribution in the case and control cohort was 52.7% and 47.3% for those <40 years and ≥40 years of age respectively.
- The percentage of females and males in the 2 cohorts was 76.6% and 23.4% respectively.
- The distribution of CCI scores in 2 cohorts was 91.8% for 0, and 8.2% for ≥1.
- During follow-up, 99.3% of the case-cohort had used antithyroid drugs, followed by surgery (10.2%), radioactive iodine ablation (1.9%).
- The mean age at diagnosis of incident SLE (43 – 44 years) and duration of follow-up (8.0 years) was found to be similar for both cohorts.
- At the end of the follow-up, the frequency of incident SLE was higher in the case-cohort (0.7%) than in the control cohort (0.2%).
SLE Risk
- The incidence rate of SLE per 10 000 person-years was higher in the case-cohort than in the control cohort (8.81 vs 2.83).
- Crude analysis showed a significantly higher risk of incident SLE in the case-cohort than the control cohort (HR: 3.06, 95% CI: 1.85-5.07).
- Kaplan-Meier analysis with a log-rank test revealed a significant association between Grave’s disease and the subsequent risk of incident SLE (P < .01).
- Even after adjusting the covariates, the case-cohort still had a significantly higher risk of SLE compared to the control cohort (HR: 5.45, 95% CI: 1.74-17.0).
Sensitivity analysis
- After excluding the first 0.5 years of observation, the authors reported a higher risk of SLE in the case-cohort in comparison to the control cohort (HR: 2.90, 95% CI: 1.70-4.95). After adjusting the variates, the ratio was HR: 4.30, 95% CI: 2.78-8.57.
- Similar results were obtained after adjusting the first 1 year of observation and significant risk associations between the case-cohort and SLE were noted in the crude analysis (HR: 2.89, 95% CI: 1.67-5.02) and after adjustment for the above-mentioned variables (HR: 4.63, 95% CI: 2.33-7.79).
DISCUSSION
Grave’s disease is an organ-specific autoimmune disease and SLE is a multisystemic autoimmune disorder. It is well known that many patients with SLE have a higher frequency of thyroid disorders. Searles et al., Amrhein et al., Sato-Matsumura et al., and Horton et al. independently suggested and discussed the existence of Propylthiouracil-induced lupus-like syndrome. Some other authors described the coexistence of thyrotoxicosis and SLE.
This population-based cohort study investigated the risk of SLE in patients with Grave’s disease. The authors used a cohort matching age, gender, index year, and CCI score with a 13-year follow-up period in a nationwide sample. The results obtained showed that patients with Grave’s disease had an increased risk of incident SLE compared with the unaffected control cohort. The possible explanations are as follows.
A shared genetic predisposition between Grave’s disease and SLE. According to some genetic association studies, polymorphisms in the PTPN22, IFIH1, and ITPR3 genes are associated with susceptibility to Grave’s disease and SLE. Some reports suggested that the amplified autoimmune reactions of Grave’s disease via shared genetic pathways could contribute to the onset of SLE.
Association of hyperthyroidism and oxidative stress. There have been reports describing increased oxidative stress in hyperthyroidism. It is well known that Grave’s disease causes hyperthyroidism and oxidative stress is linked to the onset and progression of SLE. Thus, some authors believe that Grave’s hyperthyroidism may increase the risk for developing SLE. Liu Y.-C et al. found that SLE patients had higher rates of hyperthyroidism than the non-SLE matched control cohort.
Possibility of antithyroid drug-induced SLE. This could be supported by the fact that SLE develops after a few months or years of exposure to antithyroid drugs. This study also reported an increased risk of incident SLE in patients who underwent antithyroid therapies. Although the actual pathophysiology of drug-induced lupus is unclear, one possible mechanism that may induce autoimmunity is the structural changes in the DNA-histone complex. The structural variations interfere with the normal hydrolysis of histones, causing them to retain immunogenicity or expose them to new epitopes. Many drugs are metabolized into active cytotoxic metabolites that lead to abnormal chromatin degradation and apoptosis. This, in turn, induces an autoimmune reaction against the DNA-histone complex in susceptible individuals.
Strengths & Limitations of the Study
This study’s biggest strengths include the large nationwide population-based cohort, adjustment for antithyroid therapies, and a long observation period. Also, the subjects of this study were confirmed by the certificate of catastrophic disease, which improved diagnostic validity.
There are several limitations to this study.
- First, it included only the patients who sought medical help for diagnosis and treatment of Grave’s disease or SLE. Also, it excluded patients with Grave’s disease code ICD-9-CM: 242.9. This indicates bias in patient data collection.
- The second limitation is the diagnostic bias. Although sensitivity analyses were performed to exclude the first 0.5 and 1 year of the observation period, diagnostic bias is still a concern.
- Third, the Taiwan NHIRD database doesn’t have the presentation of symptoms and laboratory data for Grave’s disease and incident SLE. Therefore, the authors couldn’t apply additional analyses, such as the association between thyroid hormone levels and autoantibodies of SLE.
- Fourth, this study didn’t consider the influence of individual medical comorbidities; only quantified the CCI score.
- Finally, lack of specific reasons for choosing a particular antithyroid therapy. This study treated all antithyroid therapies as time-dependent covariates. This reduces the possibility of demonstrating the effect of individual antithyroid treatment (ie, antithyroid drugs, radioactive iodine ablation, and surgery) on the risk of SLE.
Conclusion
In conclusion, in Taiwan, patients with Grave’s disease have a high risk of developing SLE. Further studies are needed to delineate the exact mechanisms of and factors affecting this association.
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