中南大学学报 ( 医学版 ) J Cent South Univ (Med Sci) 2017, 42(8) http://www.csumed.org 927 DOI:10.11817/j.issn.1672-7347.2017.08.009 www.csumed.org/xbwk/fileup/pdf/201708927.pdf Mortality trend of inpatients with connective tissue diseases: 2005 2014 LI Liya, ZUO Xiaoxia, LUO Hui, LI Yisha, YOU Yunhui, DUAN Liping, ZHANG Weiru, ZHAO Hongjun, LI Tong, NING Wangbin, XIE Yanli, LIU Sijia, XIE Xiaoyun, JIANG Ying, WU Shiyao, ZHU Honglin, ZHOU Ya ou ( Department of Rheumatology and Immunology, Xiangya Hospital, Central South University; Institute of Rheumatology and Immunology, Central South University, Changsha 410008, China ) ABSTRACT KEY WORDS Objective: To analyze the trend relevant factors leading to death and their patterns over a 10-year period in inpatients with connective tissue diseases (CTDs). Methods: All clinical data about death in inpatients with CTDs were retrospectively reviewed between 2005 and 2014 at the Department of Rheumatology and Immunology in Xiangya Hospital of Central South University. Results: In the 10-year time period, the overall hospital mortality was 15.68. The disease itself accounted for 44.71% of the total causes of death, infection accounted for 42.94%, and comorbidities accounted for 12.35%. Th e constituent ratio of deaths and the average hospital mortality caused by the disease itself declined gradually year by year, and the constituent ratio of deaths caused by infection and comorbidities increased gradually year by year (P<0.05). In 2013 2014, infection was the leading cause of death, which accounted for 51.06%. The survival time for CTDs inpatients with interstitial lung disease (ILD) was shorter than that of CTDs inpatients without ILD, and even the risk of death was 1.722 times of the latter. The proportion of deaths caused by the disease itself was the highest in systemic sclerosis and systemic lupus erythematosus, that by infection was the highest in idiopathic inflammatory myopathy (IIM), and that by comorbidities was the highest in rheumatoid arthritis. Conclusion: The proportion of deaths and the hospital mortality in CTDs inpatients caused by the disease itself show a declining trend, while the proportion of deaths caused by infection and comorbidities increase. CTDs patients with ILD have shorter survival time and an increase in risk of death. connective tissue diseases; hospital mortality; cause of death; trend Date of reception: 2016-10-21 First author: LI Liya, Email: liliyacsu@sina.com Corresponding author: ZHOU Ya ou, Email: zhouyaou@csu.edu.cn Foundation item: This work was supported by the National Natural Science Foundation (81373206, 81401357) and the National High Technology Research and Development Program (2012AA02A513), China.
928 中南大学学报 ( 医学版 ), 2017, 42(8) http://www.csumed.org 中南地区结缔组织病住院患者 10 年死亡趋势 :2005 2014 李丽雅, 左晓霞, 罗卉, 李懿莎, 游运辉, 段力平, 张卫茹, 赵洪军, 李通, 宁旺斌, 谢艳莉, 刘思佳, 谢晓韵, 蒋莹, 巫世瑶, 朱红林, 周亚欧 ( 中南大学湘雅医院风湿免疫科, 中南大学风湿免疫病研究所, 长沙 410008) [ 摘要 ] 目的 : 分析结缔组织病 (connective tissue diseases,ctds) 住院患者在 10 年期间死亡原因等的变化趋势 方法 : 采用回顾性分析的方法, 收集中南大学湘雅医院风湿免疫科在 2005 年 1 月 1 日至 2014 年 12 月 31 日期间, 确诊的 CTDs 住院患者中所有死亡病例的所有临床资料 结果 :10 年期间 CTDs 住院患者的总体住院病死率为 15.68 在 CTDs 患者的 3 大类死亡原因中, 疾病本身占 44.71%, 感染占 42.94%, 合并症占 12.35% 其中, 疾病本身的死因构成比和住院病死率呈逐年下降趋势, 感染和合并症的死因构成比呈逐年上升趋势 2013 2014 年, 感染成为最主要的死亡原因, 其死因构成比为 51.06% 合并肺间质病变的 CTDs 患者与没有合并肺间质病变的 CTDs 患者相比, 前者的生存时间明显缩短, 其死亡风险是后者的 1.722 倍 在各种 CTDs 中, 特发性炎性肌病患者的总住院病死率最高 (45.98 ), 系统性硬化症和系统性红斑狼疮患者的因疾病本身死亡比例最高, 特发性炎性肌病患者的因感染死亡比例最高, 类风湿关节炎的患者因合并症死亡比例最高 结论 : 在 CTDs 住院患者中, 因疾病本身导致死亡的死因构成比和住院病死率均呈逐年下降趋势 ; 因感染和合并症导致死亡的死因构成比呈逐年上升趋势, 且感染成为第一位死因 CTDs 合并肺间质病变患者生存时间缩短, 死亡风险增加 [ 关键词 ] 结缔组织病 ; 住院病死率 ; 死因 ; 趋势 Connective tissue diseases (CTDs) are autoimmune diseases characterized by chronic inflammation in the blood vessels, skin, bones, joints, and muscles. This group of diseases involves multiple systems; in addition, they are persistent and have high chances of recurrence. Patients who suffer from this condition are often positive for multiple autoantibodies. The common CTDs include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic inflammatory myopathy (IIM), systemic sclerosis (SSc), primary Sjogren s syndrome (pss), systemic vasculitis, undifferentiated connective tissue disease (UCTD), mixed connective tissue disease (MCTD), and adult-onset Still s disease (AOSD). With the improvements in clinical diagnosis and treatment, the mortality associated with CTDs has decreased significantly compared with last century. According to reports, the hospital mortality of SLE was 2.9% per year, both similarly in the 1990 1998 and 1993 2002 [1-2]. In the 1990 2012 period, the hospital mortality declined to 1.58% per year [3]. Some scholars have suggested that RA usually does not involve vital organs, and that the mortality in RA patients may be similar to that in the general population [4]. However, recently Metaanalysis on epidemiological surveys showed that the standardized mortality rates (SMR) of RA was 1.47/100 person-years [5]. Even though this datum is lower than SMR of SLE (3.02/100 person-years) and SSc (3.53/100 person-years) [6-7], it is still higher than that in the general population by 40% to 50% [8]. Currently, the related researches mainly focused on the mortality of each CTD, or causes of death in some specific CTD. There is a lack of comprehensive analysis on the overall mortality and causes of death in CTDs patients. Therefore, in order to gain a better understanding of the trend in hospital mortality and the changes in proportion of causes of death in CTDs inpatients, we retrospectively reviewed the data for mortality in CTDs inpatients at our hospital over a period of 10 years. The data will prove useful in improving the comprehension of the causes of death in CTDs patients and provide more information for the clinical management. 1 Patients and methods 1.1 Patients All the clinical data on inpatient deaths among patients diagnosed with CTDs were retrospectively reviewed from January 1st, 2005 to December 31st, 2014 at the Department of Rheumatology and Immunology in Xiangya Hospital of Central South University. There were 170 death cases during this period, and the patients were diagnosed and classified according to the standard criteria for each disease, organ involvement, complication and comorbidity.
Mortality trend of inpatients with connective tissue diseases: 2005 2014, LI Liya, et al 929 1.2 Study design Data on patients death were collected, including general information, clinical information, and causes of death. The cases were divided into 2-year period groups, and there were 5 groups in total. The causes of death were divided into 3 categories: 1) death caused by the progression of CTDs itself leading to dysfunction of vital organs or systems failure (disease itself); 2) death caused by severe infections resulting in multiple organ failure (infection); 3) including cardiovascular and cerebrovascular accidents, gastrointestinal bleeding or perforation, hepatic encephalopathy, hematological malignancies, adverse drug reactions and other unknown causes of death (comorbidities). 1.3 Statistical analysis All data analysis was conducted using SPSS Windows, release 18.0 (SPSS Inc., Chicago, IL., USA). Continuous distribution variables in each group were expressed as mean±standard deviation (x±s). Comparison between groups was performed with non-paired-sample t-test for continuous, normal distribution data. The chisquare, Fisher exact test or trend test was used to compare stratified categorical data (percentage). Cox regression analysis was carried out on the survival time for CTDs death risk factors. A value of P<0.05 was considered statistically significant. 2 Results 2.1 General information of the patients In the time period of 10 years, 10 842 CTDs patients were hospitalized, the most common dieases are SLE (25.22%), RA (13.37%), IIM (6.42%), pss (5.09%) and SSc (2.65%). The number of deaths was 170 and the overall hospital mortality was 15.68. In 170 death inpatients with CTDs, 35 were male and 135 were female. The age of onset of the CTDs deaths was 7 77 (40.37±15.27) years old. The age of death of the CTDs deaths was 16 78 (45.28±15.04) years old. The duration from onset to death was 0.04 33 (4.92 ± 5.85) years. 2.2 Variation trends in constituent ratio and hospital mortality of causes of death in CTDs In 170 death inpatients with CTDs, the main causes of death included 76 cases (44.71%) caused by disease itself, 73 cases (42.94%) caused by infections, and 21 cases (12.35%) caused by comorbidities. In the period of 10 years, the constituent ratio of death caused by disease itself declined while the proportion of the infection and comorbidities gradually increased, and there was a significance in variation trend (P=0.0197). In the period of 2013 2014, infection was the first death cause of CTDs (51.06%) (Figure 1). At the same time, the overall hospital mortality of CTDs deaths caused by disease itself was 7.01, infection and comorbidities were respectively 6.73 and 1.94. The 5 groups of average hospital mortality in CTDs inpatients caused by the disease itself showed a declining trend (P=0.0074, Figure 2 and Table 1). 2013 2014 2011 2012 2009 2010 2007 2008 2005 2006 0 50 100 Constituent ratio of causes of death in CTDs/% Disease itself Infection Comorbidities Figure 1 Variation trends in constituent ratio of causes of death in CTDs during the 10 years period The constituent ratio of death caused by disease itself declined with a significance in variation trend (P=0.0197). In the period of 2013 2014, infection was the first death cause of CTDs (51.06%) Figure 2 Average hospital mortality/ 15 10 5 0 2005 2006 2007 2008 2009 2010 Disease itself Infection Comorbidities 2011 2012 Variation trends in hospital mortality of causes of death in CTDs during the 10 years period 2013 2014 The 5 groups of average hospital mortality in CTDs inpatients caused by the disease itself showed a declining trend (P=0.0074) 2.3 CTDs survival time and interstitial lung disease Among the cases of CTDs death, 31.76% (54/170) of the patients were diagnosed with interstitial lung disease (ILD). The survival time (duration from onset to death) of the patients with ILD was significantly shorter than that of patients without ILD (P<0.05, Figure 3); moreover, the patients with ILD who died from pulmonary infections *
930 中南大学学报 ( 医学版 ), 2017, 42(8) http://www.csumed.org were much more than patients without ILD (P<0.05). In the cases whose death was caused by infection, 53.42% (39/73) of the patients had ILD as well, all of these 39 patients died of pneumonia, and the survival time of these patients was obviously shorter than CTDs cases which died from infection without ILD (P<0.01, Figure 3). The Cox proportional hazard model for CTDs death risk factors showed that the risk of death of CTDs inpatients with ILD was 1.722 times than that of CTDs inpatients without ILD. Table 1 Causes of death and hospital mortality for 170 CTDs deaths in the 10-year period Causes of death in CTDs patients Hospital mortality/[no.( )] 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Sum P Disease itself (injury to organs) 19(12.08) 12(7.30) 13(7.08) 18(6.71) 14(4.51) 76(7.01) 0.0074* Central nervous system 8(5.09) 2(1.22) 2(1.09) 2(0.75) 7(2.25) 21(1.94) Heart 4(2.54) 4(2.43) 2(1.09) 7(2.61) 0(0) 17(1.57) Kidney 3(1.91) 1(0.61) 4(2.18) 4(1.49) 2(0.64) 14(1.29) Lung 1(0.64) 3(1.82) 4(2.18) 2(0.75) 2(0.64) 12(1.11) Hematological system 2(1.27) 2(1.22) 1(0.54) 3(1.12) 1(0.32) 9(0.82) Digestive system 1(0.64) 0(0) 0(0) 0(0) 2(0.64) 3(0.28) Infection (lethal infection site) 11(6.99) 12(7.30) 9(4.90) 17(6.34) 24(7.73) 73(6.73) 0.7783 Lung 10(6.36) 11(6.69) 7(3.81) 15(5.59) 21(6.76) 64(5.90) Abdominal cavity (peritonitis) 1(0.64) 1(0.61) 0(0) 1(0.37) 1(0.32) 4(0.37) Central nervous system (meningitis) 0(0) 0(0) 2(1.09) 1(0.37) 0(0) 3(0.28) Skin and soft tissue 0(0) 0(0) 0(0) 0(0) 2(0.64) 2(0.18) Comorbidity 1(0.64) 6(3.65) 1(0.54) 4(1.49) 9(2.90) 21(1.94) 0.3476 Gastrointestinal perforation/bleeding 0(0) 1(0.61) 0(0) 1(0.37) 4(1.29) 6(0.55) Rheumatoid arthritis with methotrexate 1(0.64) 1(0.61) 1(0.54) 1(0.37) 1(0.32) 5(0.46) poisoning Cardiovascular and cerebrovascular accident 0(0) 2(1.22) 0(0) 1(0.37) 0(0) 3(0.28) Hematological malignancies 0(0) 0(0) 0(0) 1(0.37) 2(0.64) 3(0.28) Others 0(0) 2(1.22) 0(0) 0(0) 2(0.64) 4(0.37) Total 31(19.71) 30(18.25) 23(12.52) 39(14.54) 47(15.14) 170(15.68) 0.2001 Number of discharge patients with CTDs in 1 573 1 644 1 837 2 683 3 105 10 842 the same period (cases) * The hospital mortality caused by disease itself showed a decline with time (P<0.05, χ 2 test for trend). Including 1 case died of spread septicopyemia caused by abdominal skin cellulitis infection; another 1 case died of septicopyemia caused by herpes zoster and Pseudomonas aeruginosa mix-infection. The 2 cases were both in stable SLE, without specific infection at any other site. Including 2 SLE/UCTD patients combined with cirrhosis and hepatic encephalopathy, 1 SLE patient combined with acute pancreatitis, and 1 SLE patient s death cause unknown Survival time/year 8 6 4 2 0 P=0.0008 P<0.0001 ILD Without-ILD Infection-ILD Infection without ILD Figure 3 Comparison of survival time between CTDs with ILD and without ILD 2.4 Composition of deaths in CTDs In all CTDs death cases, the hospital mortality was the highest in patients with IIM, followed by SSc. The constituent ratio of the disease was the highest in patients with SLE, followed by IIM (Table 2). 2.5 Proportion of causes of death in CTDs The proportion of deaths caused by the disease itself was the highest in the SSc (61.54%, 8/13) and SLE (61.36%, 54/88) patients. Moreover, the proportion of deaths caused by infection was the highest in patients with IIM (81.25%, 26/32). The proportion of deaths caused by comorbidities was the highest in patients with RA
Mortality trend of inpatients with connective tissue diseases: 2005 2014, LI Liya, et al 931 (58.33%, 7/12). In the deaths caused by SSc itself, the specific death causes were renal crisis (50%), severe pulmonary arterial hypertension (PAH) (37.5%). In the deaths caused by SLE itself, the most common specific death cause was neuropsychiatric lupus (33.33%), followed by lupus nephritis (18.52%), diffuse alveolar hemorrhage and severe cardiac involvement (10.23%, Table 3). Among the 26 deaths caused by infection in IIM patients, 24 cases (92.31%) were died of pneumonia, which included 23 patients (95.83%) combined with ILD. Among the 7 deaths caused by comorbidities in RA, there were 5 cases for multiple organs/systems failure caused by methotrexate (MTX) poisoning. Table 2 Composition of deaths in CTDs Disease Total number of hospitalizations Total number of hospital-deaths Total hospital mortality/ Proportion of CTDs/% SLE 2 734 88 32.20 51.8 IIM 696 32 45.98 18.8 SSc 287 13 45.29 7.7 RA 1 450 12 8.29 7.1 Systemic vasculitis 182 6 32.97 3.5 pss 552 5 9.06 2.9 Others* 4 941 14 2.83 8.2 Sum 10 842 170 15.68 100.0 *Including UCTD, MCTD, antiphospholipid syndrome, autoimmune liver disease, overlap syndrome, osteoarthritis, ankylosing spondylitis, seronegative spondyloarthropathies, psoriatic arthritis, reactive arthritis, juvenile idiopathic arthritis, gout, relapsing polychondritis, IgG4 related diseases, AOSD, rheumatic fever, autoinflammatory diseases, fibromyalgia syndrome, polymyalgia rheumatica, fasciitis and so on. Including each two cases of granulomatous vasculitis/variability vasculitis, each one case of microscopic polyangitis/systemic vasculitis. Including 13 cases of UCTD, and 1 case of AOSD Table 3 Specific deaths caused by SLE itself Specific cause of death 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Total Neuropsychiatric lupus 7 2 2 2 5 18 Lupus nephritis 1 1 4 3 1 10 Diffuse alveolar hemorrhage 1 3 3 0 2 9 Severe cardiac involvement * 3 3 1 2 0 9 Thrombotic thrombocytopenic purpura 1 0 1 1 1 4 Others 2 0 0 1 1 4 Sum 15 9 11 9 10 54 *5 patients died of cardiopulmonary arrest, and 4 patients died of acute or chronic heart failure 3 Discussion CTDs are a group of diseases with a high rate of disability and mortality. The 5-year survival rate of SLE, IIM and SSc is lower than 90% [9-11]. This study retrospectively reviewed cases of death in CTDs patients who were hospitalized and analyzed the causes of death. The findings could help clinicians make a reasonable diagnosis, administer the appropriate treatment, and further improve the prognosis. In previous reports [1-3], the early hospital mortality of SLE, respectively 2.9% and 1.58% per year, was both much lower than the late hospital mortality of SLE in our study, approximately 3.8% per year. Probably it is differ from the case number, the national health conditions, the diagnosis and treatment level in different countries. Due to the applications of aggressive therapy with high-dose corticosteroids and immunosuppressants, blood purification and plasmapheresis in severe CTDs patients, the deaths caused by the disease itself had gradually
932 中南大学学报 ( 医学版 ), 2017, 42(8) http://www.csumed.org decreased. However, the incidences of various severe infections and comorbidities were increased, including mixed infection, drug adverse effects and so on [12-16]. During the time primary disease controlled by clinicians, it is required to pay more attention to the adverse effects of immunosuppression treatment and the managements of comorbidities and complications, in order to reduce the mortality of CTDs patients. This study showed that infection became the most common cause of death in CTDs patients with pneumonia forming the majority of the infections, and ILD was associated with a high risk of death in CTDs patients. In clinical practice, ILD and pneumonia can share similar symptoms, and the imaging abnormalities observed in the respiratory system can also be similar, so it is difficult to differentiate them. Therefore there is a clear need for biomarkers and imaging techniques that can detect infection in ILD patients with high sensitivity. ILD patients who have pneumonia can progress rapidly, and the treatment of this condition is more difficult in comparison to the patients without ILD [17-19], and alternative treatment with a ventilator was not found to be satisfactory. Currently, an individualized treatment protocol should be established according to the type and severity of ILD. In these patients, the use of immunosuppressants should be carefully determined after a detailed assessment of the risks and benefits involved. Once the signs of infection appear, physicians should pay more attention to the timing and intensity of anti-infection treatment, and broad-spectrum anti-fungal treatment should also be considered when necessary, because CTDs patients with ILD are especially vulnerable to mixed infections [20]. Another high risk lethal factor in CTDs is PAH [21-22]. Our data indicated that about 1/3 death cases in SLE were complicated with PAH. Associated with PAH (APAH) is the most common in CTDs patients, and the targeted treatment for PAH is less effective in CTDs-associated PAH compared to idiopathic PAH in terms of increasing 6-minute walk distance (6MWD) and preventing clinical worsening, and the success rate of rescue operations is very low [23]. So for clinicians, the risk of sudden death in CTDsassociated PAH should also be evaluated. Regarding to the cases of death caused by comorbidities, the ratio of deaths caused by gastrointestinal illness gradually increased. This may be related to the long-term usage of steroids or non-steroid antiinflammatory drugs [24]. In this study, five RA patients died of MTX overdose, which led to pancytopenia, multiple mucocutaneous ulcers and multiple organs failure. The usage of MTX in CTDs is special (once every week). The patients and their family members should be educated about the dosage and frequency of MTX emphatically before it is prescribed, and informed to monitor blood cell count and liver function. When side effects are detected, the drug dose should be reduced or the drug should be discontinued as soon as possible. SLE is the most common in the hospitalized patients with CTDs [25]. In four deaths of the SLE patients who were pregnant, three died of neuropsychiatric lupus, and one died of severe abdominal infection after cesarean section. It indicates that the pregnant SLE patients are in the high-risk category and are therefore easily prone to high active in SLE and serious comorbidities, increasing the emergency of maternal and fetal life-threatening outcomes [26]. In summary, with the improvements in the diagnosis and treatments, mortality caused by the CTDs itself has been showing a decreasing trend year by year. 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