{"paper_id":"c32fd9ca-4dc9-4f01-bb81-806473a4a912","body_text":"We identified 4472 hyperthyroid patients in the age- and sex-matched control cohorts.\nCompared with the control cohort ( Table 1 ), hyperthyroid patients\nare more likely to have comorbid autoimmune diseases ( P  < .001), diabetes mellitus\n( P  < .001), hypertension ( P  < .001), hyperlipidemia ( P  <\n.001), coronary heart disease ( P  < .001), and chronic liver disease ( P  <\n.001).  Figure 1  presents the hazard curves of hyperthyroid patients\ndiagnosed with adhesive capsulitis and the control cohort during the 7-year follow-up\nperiod, after adjusting for patient age, sex, diabetes mellitus, coronary heart disease,\nhypertension, hyperlipidemia, autoimmune diseases, chronic liver disease, cancer, and\nurbanization level (log-rank test,  P  < .001).\nTable 2  shows the incidence and hazard ratios (HRs) of adhesives\ncapsulitis in hyperthyroid patients and the control cohort. Of the 4472 hyperthyroid\npatients, 162 patients (671/100 000 person-years) exhibited adhesive capsulitis during the\n24 122 person-year follow-up period. The crude HR of stroke was 1.26 (95% confidence\ninterval [CI], 1.06 to 1.49), which was larger than that obtained for the control group.\nTable 3  presents the adjusted HRs of adhesive capsulitis in both\nthe hyperthyroid patients and control cohort. The adjusted HR obtained for hyperthyroid\npatients was 1.22 (95% CI, 1.03 to 1.45), which was statistically significant. In addition,\nother confounding factors of adhesive capsulitis were analyzed. The results showed that age\n(adjusted HR: 1.05, 95% CI, 1.04 to 1.05), the male sex (adjusted HR: 069, 95% CI, 0.58 to\n0.82), hyperlipidemia (adjusted HR: 1.49, 95% CI, 1.25 to 1.77), and chronic liver disease\n(adjusted HR: 1.37, 95% CI, 1.14 to 1.66) were all statistically significant regarding the\ndevelopment of frozen shoulder during the 7-year follow-up period.\n\nThis study showed that hyperthyroid patients have 1.22 times the risk of developing\nadhesive capsulitis compared to the general population. Until now, no relevant large-scale\nlongitudinal population-based study has been conducted on the risk of adhesive capsulitis in\nhyperthyroid patients. All previously conducted studies regarding the risk of adhesive\ncapsulitis in thyroid-disorder patients have been small-sample cross-sectional studies 12 . Limited information has been obtained regarding the temporal relationship\nbetween hyperthyroidism and adhesive capsulitis in previous studies. We adjusted for\nfactors, such as diabetes and dyslipidemia, and identified hyperthyroid patients who were\nsubsequently diagnosed with adhesive capsulitis. The results show that hyperthyroidism\npatients have a high comorbidity risk of adhesive capsulitis.\nThe definite pathogenesis of adhesive capsulitis remains under investigation. Shoulder pain\nonset that indicates adhesive capsulitis is considered to be mediated through nerve\nstimulation. Adhesive-capsulitis shoulder pain can be caused by alpha-adrenoreceptor\nhyperresponsiveness, in which both nociceptive and proprioceptive fibers are stimulated,\nresulting in pain 13 . The inflammatory process is considered another\npathogenesis of adhesive capsulitis. Rodeo et al found elevated levels of pro-inflammatory\ncytokines in adhesive capsulitis patients 14 . They proposed that the\nstimulation of inflammation caused by cytokines can engender shoulder synovitis, and this\ncan result in a fibrotic cascade that is associated with growth factors such as\nTGF-beta 14 . The chronic fibrosis process of capsulitis is confirmed by\nobserving the histologic presentation of fibroblast cell proliferation. Matrix\nmetalloproteinase and fibrogenic growth factors are also increased in adhesive capsulitis\npatients 15 .\nSimilar to the inflammatory and fibrosis process pathogenesis of adhesive capsulitis\npatients, hyperthyroid patients also present an inflammatory cytokine release and fibrosis\nphenomenon. Regarding thyroid disorder-associated ophthalmopathy patients, cell-mediated\n(Th1) and humoral-mediated immune responses infiltrate the orbital area. High levels of\nIL-2, IFN-γ, and TNF-α cytokines are secreted by Th1 cells in the retro-orbital area of\npatients who are diagnosed with Graves disease 16 17 . However, another study\nfound Th2 cell-secreted cytokines, such as IFN-γ, IL-4, and IL-10, in patients 18 . Moreover, a previous study described the cytokine profiles of patients\ndiagnosed with Graves disease and thyroid disorder-associated ophthalmopathy 17 . Cytokines have been proven as capable of inducing several proteins in orbital\nfibroblasts, and these cytokines have the ability to stimulate orbital fibroblast\nproliferation 19 . We propose that cytokine and fibroblast proliferation\ncontributes to not only the process of thyroid ophthalmopathy but also to adhesive\ncapsulitis. This can explain why hyperthyroid patients are vulnerable to adhesive\ncapsulitis.\nSLE and RA patients were analyzed in this study, but were not found to have a high risk of\nadhesive capsulitis. Regarding SLE patients, cytokines have been proposed to have a\npathogenic role in autoantibody production and immune complex deposition. These cytokines\nare interleukin-6, interleukin-17, interleukin-18, type I interferons, and TNF-alpha 20 . Cytokines have also been found in the pathogenesis of rheumatoid arthritis.\nOne review article provided a comprehensive list of related cytokines, such as TNF-alpha, IL\n1, 6, 15, 17, and 18, GM-CSF, VEGF, and TGF-beta 21 . However, this article\nstated that how these cytokines are organized within a hierarchical regulatory network\nremains unclear. In addition, the article stated that TNF-alpha plays a key role because\nTNF-alpha-blockage agents can are involved in successfully treating RA 21 . We\npropose that the pro-inflammatory cytokine and fibrosis process modulation is different in\nthese autoimmune diseases and adhesive capsulitis.\nWe controlled other possible hazard factors for developing adhesive capsulitis. In addition\nto hyperthyroidism, the results showed that hyperlipidemia patients have a high risk of\nadhesive capsulitis. These results support those of a previous case-controlled study that\nanalyzed the lipid profiles of patients diagnosed with frozen shoulders and found that\nfasting serum triglyceride and cholesterol levels were increased in these patients compared\nwith the levels of participants without frozen shoulders 22 . However, the\npathogenesis of adhesive capsulitis in hyperlipidemia patients remains unclear.\nIn contrast to a previous population-based longitudinal study, our results showed that\ndiabetes mellitus patients do not have an increased risk of adhesive capsulitis 23 . This could be because the controlled group selection was different from that\nof the previous study either because of differing circumstances or participant matching to\nthe hyperthyroid group. Our patients were predominantly women and were younger than those in\nthe previous study on diabetes mellitus and frozen shoulders. A different control group\nselection can result in the influence of confounding factors. Long longitudinal follow-up\ndata collection is the strength of our study. In addition, we attempted to control\nconfounding factors, such as diabetes, hyperlipidemia, and autoimmune diseases such as SLE\nand RA. The long follow-up period and large number of potential confounding factors that\nwere considered in this study enabled producing reliable results.\nThe LHID2005 data released by the Taiwan NHI Institutes were used in this study. However,\nthis study has several possible limitations. First, the diagnosis of adhesive capsulitis and\nhyperthyroidism was determined using the ICD codes listed in the NHI claim database;\nhowever, the diagnostic accuracy of the results obtained from the database were not\nconfirmed. To increase the accuracy of diagnoses, the NHI Bureau has formed various audit\ncommittees that randomly sample claim data regularly to verify diagnostic validity and care\nquality. In addition, we used only consecutively coded cases to avoid inaccurate codes in\nthe database records. These methods might improve the accuracy of registering rheumatic\ndiseases. Second, the NHIRD records do not contain the laboratory data of hyperthyroid\npatients, and information regarding disease stratification severity is also limited. Third,\nthe influences of thyroid medications, I131 radioiodine therapy, and thyroid surgery were\nnot analyzed. Finally, our results were based on a retrospective cohort study. Information\nregarding lifestyles, obesity, cigarette smoking, and alcohol consumption cannot be obtained\nfrom the administrative database.\n\nIn conclusion, our 7-year longitudinal population-based case-controlled cohort study\nresults showed that hyperthyroid patients have a 1.22-fold higher risk of adhesive\ncapsulitis than that of patients without this condition. In addition to hyperthyroidism, the\nresults showed that hyperlipidemia is another risk factor of adhesive capsulitis. Additional\nstudies regarding the influence of hyperthyroidism treatment on the risk of adhesive\ncapsulitis are recommended.\n\nWe analyzed records that were obtained from the Longitudinal Health Insurance Database 2005\n(LHID2005), which is maintained by the Taiwan National Health Insurance (NHI) Institutes.\nThe LHID contains data of all health insurance claims, including demographic, inpatient\ncare, ambulatory care, and prescription drug data, as well as International Classification\nof Diseases, Ninth Revision, Clinical Modification diagnostic codes. Overall, the records of\n1 000 000 beneficiaries, who were enrolled in 2005, were randomly sampled from the records\nof the 25.56 million people contained in this database (the NHI program insures\napproximately 99% of the population in Taiwan). To protect the privacy of personal data, the\nrecords obtained from the database were de-identified. In addition, informed consent was\nwaived in this secondary data analysis study.\nThe study cohort contained all patients who had been diagnosed with a hyperthyroid disease\n(ICD-9-CM codes 242.9) between January 1, 2004 and December 31, 2007 according to data on\nambulatory medical care visits. The hyperthyroid group consisted of patients who had\nreceived a principal diagnosis of hyperthyroidism (ICD-9-CM codes 242.9) during an\nambulatory medical care visit between January 1, 2004 and December 31, 2007. To improve the\ndiagnosis accuracy, only patients who had at least 2 consecutive ambulatory visits in which\nthe principal diagnosis was hyperthyroidism were recruited in this study (N = 4779).\nPatients who were diagnosed with adhesive capsulitis (ICD-9-CM codes 726.0) prior to a\nthyroid disorder diagnosis (N = 57, hyperthyroidism) or multiple diagnosed with other\nthyroid disease such as thyroid cancer or hypothyroidism (N = 85) or whose records were\nmissing variables, such as date of birth, sex, and age < 18 years (N = 165) were\nexcluded. A total of 4472 hyperthyroid patients met the inclusion and exclusion criteria and\nwere enrolled in this study. Patients in the control group were matched with those in the\nstudy cohort (5 control patients per case patient) according to age (< = 30, 31–40,\n41–50, 51–60, 61–70, and >70 y) and sex by using the remaining patient records obtained\nfrom the LHID. Patients were excluded if they had been diagnosed with a thyroid disorder\nbetween 2004 and 2010, or had been diagnosed with adhesive capsulitis before 2004.\nWe obtained baseline variables, including age, sex, urbanization level (stratified into 3\nlevels: urban, suburban and rural), and confounding factors, such as diabetes mellitus\n(DM; ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM\ncodes 272.0–272.4), autoimmune diseases (rheumatoid arthritis: ICD-9-CM code 714.0; SLE\nICD-9-CM code 710.0), chronic liver disease (ICD-9-CM code 571), cancer (ICD-9-CM codes\n140-208), and coronary heart disease (ICD-9-CM codes 410–414), for all patients.\nWe used the initial diagnosis of adhesive capsulitis (ICD-9-CM codes 726.0) as the study\nendpoint. All participants were followed from the index date until the occurrence of the\nendpoint or until December 31, 2010, whichever was first, and final-date observations were\ncensored observations.\nThe Pearson chi-squared test or the Fisher exact test was applied to compare demographic\ncharacteristics and comorbidities. The Cox proportional hazard model was used to evaluate\nthe hazard rates of adhesive capsulitis between the study and control cohorts, after\nadjusting for potential confounding factors, constituting patient age (as continuous),\nsex, diabetes mellitus, coronary heart disease, hypertension, hyperlipidemia, urbanization\nlevel, autoimmune disease, chronic liver disease, and cancer. To fulfill the\nproportional-hazard assumption, exploratory diagnostic log-log survival plots were applied\nto verify the proportionality of each dichotomous variable in the model and meet the\nproportional-hazard assumption. We plotted the stroke hazard curves based on the Cox model\nof the patient and control cohorts after adjusting for potential confounding factors. The\nSAS statistical package (SAS System for Windows, Version 9.1.3, SAS Institute Inc., Cary,\nNC, USA) and SPSS version 20 were used for analysis. A  P  value < .05 was\nconsidered statistically significant.\n\nConceived and designed the experiments: S.W.H., J.W.L. Performed the experiments: S.W.H.,\nH.W.L. Analyzed the data: H.W.L., W.T.W. Prepare Tables and Figure: T.H.L., C.W.W. Wrote the\npaper: S.W.H. All authors reviewed the manuscript.","source_license":"CC-BY-4.0","license_restricted":false}