Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past two decades: results from a Japanese prospective observational cohort: IORRA

doi:10.21203/rs.3.rs-1838657/v1

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Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past two decades: results from a Japanese prospective observational cohort: IORRA

https://doi.org/10.21203/rs.3.rs-1838657/v1

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Background:

The mortality of patients with rheumatoid arthritis (RA) has been reported to have reduced due to the improved treatment of RA in the last two decades. However, it has not yet been clarified whether the progress of RA treatment improves the prognosis of patients with early RA. We aimed to investigate the mortality rate of patients with early RA over the past two decades.

Methods:

Patients with RA who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort within two years of disease onset between 2001– 2012 were enrolled and classified into Group A (2001–2006) and B (2007–2012). The standardized mortality ratio (SMR) versus the Japanese general population and five-year survival rate were calculated. A multiple imputation method was employed for the sensitivity analysis of SMR. The five-year survival rates were evaluated using the Kaplan–Meier method.

Results:

Groups A and B had 1,609 and 1,608 patients, respectively, of which 167 (10.4%) and 178 (11.0%) patients were lost during follow-up, respectively. Overall, 47 and 45 deaths of patients were confirmed in Groups A and B, respectively. The SMR (95% confidence interval) for Groups A and B were 0.81 (0.59–1.08) and 0.78 (0.57–1.04), respectively, with the condition that all untraceable patients were alive for 5 years. Assuming that the mortality rate of patients lost to follow-up was twice as high as that of the general population, the SMR was 0.90 (0.68–1.19) for Group A and 0.92 (0.68–1.23) for Group B. The 5-year survival rates were 96.9% and 97.0% for groups A and B, respectively (P=0.83).

Conclusions:

The 5-year mortality of patients with early RA has been comparable to that of the general Japanese population; the 5-year survival rate has been stable over the past two decades.

Early rheumatoid arthritis

Cohort study

Standardized mortality ratio

Mortality trends

Causes of death

Rheumatoid arthritis (RA) is a systemic inflammatory disease that may lead to life-threatening events, such as interstitial pneumonia, infection, malignancy, cardiovascular disease, and cerebrovascular disease (1–5). The mortality of patients with RA has been reported to be higher than that of the general population, with a higher risk of death of 1.4 to 1.7 times of that of the general population (6, 7). We reported that the standardized mortality ratio (SMR) of Japanese patients with RA registered in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort between 2000 and 2007 was 1.46–1.90, and that the risk factors for death in patients with RA were older age, higher physical impairment, and higher disease activity (8). These previous studies, including ours, enrolled patients with RA, irrespective of the disease duration.

In the last 20 years, remarkable progress has been observed in RA treatment (9). Notably, more efficacious treatments, such as biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors, have been approved and used to achieve remission (10–12). Improved treatment with targeted therapies along with a treat-to-target strategy leads to a better control of disease activity (11), which may contribute to a reduction in the mortality of patients with RA. Some studies suggest that a recent progress in treatment for RA have a positive effect on the vital prognosis of RA (13, 14). Changes in the life prognosis gap over time between patients with early RA and the general population have also been reported with controversial results by comparing the previous and later sub-cohorts in the same cohort (15–17). It has not yet been clarified whether the progress in RA treatment has improved the vital prognosis of patients with early RA in Japan, where different causes of death from Europe and the United States were reported in overall patients with RA (8).

The objective of our study was to investigate the changes in the vital prognosis of Japanese patients with early RA compared to that of the general population in the past two decades by comparing the 5-year SMRs and 5-year survival rates between patients with early RA enrolled in the IORRA cohort for the first time from 2001 to 2006 and from 2007 to 2012.

Patients

The subjects of this study were patients with RA who participated in the IORRA survey within two years of disease onset for the first time, from April 2001 to October 2012. These patients with early RA were divided into two groups: Group A, patients with early RA enrolled in the IORRA from 2001 to 2006; and Group B, patients with early RA enrolled from 2007 to 2012. The patients were observed for up to five years from the date of their first enrollment in the IORRA (Fig. 1).

The IORRA cohort

The details of the IORRA cohort have been described previously (18). Briefly, the IORRA cohort was established in October 2000 as a single, institute-based, large, observational cohort of Japanese patients with RA at the Institute of Rheumatology, Tokyo Women’s Medical University, the largest specialized treatment facility for RA located in the urban area of Tokyo, Japan, which treats approximately 3,000 patients with RA. All the Japanese patients diagnosed with RA at our institute were registered in the IORRA and asked to complete and submit a survey biannually. The IORRA study was conducted in accordance with the guidelines of the Declaration of Helsinki. This study was approved by the Ethics Committee of the Tokyo Women’s Medical University School of Medicine (No.2952-R, No. 2922-R16), and written informed consent was obtained from the patients at enrollment in the study and before the administration of each questionnaire survey. We created and managed the database in compliance with the guidelines for the protection of personal information established by the Tokyo Women’s Medical University School of Medicine. The data were managed only by authorized individuals using an offline device, considering the protection of personal information.

Follow-up survey and death reports

For patients who failed to participate in subsequent observations, a simple query was mailed biannually to confirm their survival. In addition, death reports were obtained using several methods. First, the physicians at affiliated hospitals directly reported patient deaths to our institute. Second, the bereaved family members reported a patient’s death voluntarily or in response to the simple mailed queries described above. Third, the police departments reported to us the deaths of our patients with RA when police officers found a sudden, unexplainable disease course and accidental death. The causes of death were classified according to the International Classification of Diseases − 10 (https://icd.who.int/browse10/2019/en).

Statistical analysis

Continuous and categorical variables are expressed as medians with interquartile range (IQR) and counts with proportions. The baseline characteristics of patients in Groups A and B were compared using the chi-square test and Wilcoxon test for categorical and continuous data, respectively. The primary endpoint, 5-year SMR, was calculated using the person-year method with the Japanese general population data as a reference, as reported by the Ministry of Health, Labour, and Welfare, Japan (19). The cases that were lost to follow-up were treated using two methods: first, assuming that all the lost to follow-up cases were alive for five years. Second, the effects of the lost to follow-up cases were evaluated using multiple imputation methods as a sensitivity analysis of SMR. The multiple imputation methods assumed that the mortality rate of patients who failed to follow-up was 1.0, 1.2, 1.4, 1.6, 1.8, or 2.0 times higher than that of the general population (Fig. 2). The secondary endpoint, the five-year survival rate, was analyzed using the Kaplan–Meier method, and the log-rank test was used to compare the two groups. The statistical significance was set at P < 0.05. All the statistical analyses were conducted using R version 4 and JMP statistical software (Japanese version 14; SAS Institute Inc., Cary, NC, USA).

Study Demographics

Of the 7,824 patients who participated in the IORRA between April 2001 and October 2012, we identified 3,217 patients with early RA with a disease duration ≤ 2 years. There were 1,609 patients in Group A and 1,608 in Group B. A total of 345 (10.7%) patients were lost during the 5-year follow-up: 167 (10.4%) patients in Group A and 178 (11.0%) patients in Group B. The median duration of follow-up for each group was 5.0 years [IQR: 5.0–5.0]. The total observational follow-up periods in Group A and Group B were 7,502 and 7,510 person-years, respectively. During the observational period, 47 and 45 patients died in Groups A and B, respectively. The baseline characteristics of Group A and Group B, which were collected at enrollment in the IORRA for the first time, are described in Table 1. The proportion of women was 79.4% in Group A and 81.8% in Group B. The median age at baseline was 55 years in both groups. The median disease duration until baseline was 1.0 year [IQR: 0.6–1.3] in Group A and 1.0 year [IQR: 0.7–1.3] in Group B. The Disease Activity Score in 28 joints (DAS28) and Japanese version of Health Assessment Questionnaire (J-HAQ) (20) at baseline in Group A were worse than those in Group B (P < 0.01 for both indices). The percentage of medication use for methotrexate (MTX) and bDMARDs in Group B was greater than that in Group A at baseline (P < 0.01 for both drugs).

Table 1

Patients’ characteristics at baseline
	Group A (2001–2006) (n = 1,609)	Group B (2007–2012) (n = 1,608)	P-value
Female, n (%)	1,279 (79.4)	1,315 (81.8)	0.10
Age (year), median (IQR)	54.7 (44.8–64.0)	55.4 (43.5–65.1)	0.27
Disease duration (year), median (IQR)	1.0 (0.6–1.3)	1.0 (0.7–1.3)	0.33
DAS28, median (IQR)	3.9 (3.0–4.9)	3.6 (2.6–4.5)	< 0.01
J-HAQ score, median (IQR)	0.5 (0.1–1.1)	0.5 (0–1.0)	< 0.01
Biological DMARDs, n (%)	4 (0.2%)	75 (4.7%)	< 0.01
Methotrexate, n (%)	468 (29.1%)	914 (56.8%)	< 0.01
*Follow-up period (year), median (IQR)	5.0 (5.0–5.0)	5.0 (5.0–5.0)	0.53
DAS28, Disease Activity Score in 28 joints; DMARDs, disease-modifying antirheumatic drugs; IORRA, Institute of Rheumatology Rheumatoid Arthritis; J-HAQ, Japanese version of Health Assessment Questionnaire. *Observation period in each group

Five-year survival

First, assuming that all 486 patients lost to follow-up were alive, the lowest possible SMR was calculated to be 0.81 [95% confidence interval (CI) 0.59–1.08] in Group A and 0.78 [0.57–1.04] in Group B (Table 2). Second, assuming that the mortality rate of the lost to follow-up patients was 1.0, 1.2, 1.4, 1.6, 1.8, 2.0 times higher than that of the general population, the SMRs ranged from 0.85 to 0.92 in the both groups (Table 2). The five-year survival rates of Groups A and B were 96.9% and 97.0%, respectively, and were not significantly different between the two groups (log-rank test; P = 0.83) (Fig. 3).

Table 2

The standardized mortality ratio in patients with early rheumatoid arthritis: Group A (2001–2006) vs. B (2007–2012)
		Group A (2001–2006)	Group B (2007–2012)
Patient-years		7,502.3	7,509.5
Death, n		47	45
SMR (95% CI)^a		0.81 (0.59–1.08)	0.78 (0.57–1.04)
Multiple^bimputation	1.0×	0.86 (0.65–1.15)	0.85 (0.63–1.14)
	1.2×	0.87 (0.65–1.15)	0.86 (0.65–1.15)
	1.4×	0.87 (0.66–1.16)	0.88 (0.66–1.18)
	1.6×	0.89 (0.67–1.18)	0.88 (0.66–1.18)
	1.8×	0.89 (0.67–1.18)	0.91 (0.68–1.21)
	2.0×	0.90 (0.68–1.19)	0.92 (0.68–1.23)
^aAssuming that all the lost to follow-up patients were alive for 5 years. ^bAssuming that the mortality rate the lost to follow-up patients was 1.0, 1.2, 1.4, 1.6, 1.8, or 2.0 times higher than that of the general population. CI, confidence intervals; SMR, standardized mortality ratio.

Causes of death

The deaths of 47 and 45 patients in Groups A and B were reported during the observation period, respectively. The causes of death in these patients are shown in Table 3. In both groups, malignancies and respiratory diseases were the most frequent causes of death: Group A, 13 patients (28%) with malignancy, 11 patients with respiratory disease (23%), 17 patients with malignancies (38%), and 18 patients with respiratory disease (40%). In Group A, death from both cardiovascular and cerebrovascular diseases was also reported in five patients (11%). In contrast, there were no deaths from cardiovascular disease (0%) and one death (2%) from cerebrovascular disease in Group B. The causes of death were unknown in eight patients (17%) in Group A and five patients (11%) in Group B.

Table 3

Causes of death in patients with early rheumatoid arthritis
Causes of death	Group A (2001–2006) (n = 47)	Group B (2007–2012) (n = 45)
Malignancy	13 (28)	17 (38)
Lung cancer	5	4
Gastric cancer	1	4
Others	7	9
Respiratory diseases	11 (23)	18 (40)
Interstitial lung disease	7	11
Pneumonia	4	3
Pneumocystis jirovecii pneumonia	0	1
Others	0	3
Cardiovascular diseases	5 (11)	0 (0)
Heart failure	3	0
Myocardial infarction	1	0
Aortic dissection	1	0
Cerebrovascular diseases	5 (11)	1 (2)
Infection	2 (4)	1 (2)
Gastrointestinal bleeding or perforation	2 (4)	0 (0)
Renal failure	1 (2)	0 (0)
Accidents	0 (0)	3 (7)
Others	2 (4)	0 (0)
Unknown	8 (17)	5 (11)
Number (%) was shown.

In this single institute-based large observational cohort from 2001 to 2017, we revealed that the 5-year all-cause mortality of patients with early RA was comparable to that of the Japanese general population in the periods from 2001 to 2006 and from 2007 to 2012. According to previous reports, the mortality rate of patients with early RA was reported to be consistently worse than that of the general population by observing a cohort starting in 1990 for 20 years in a UK study (16) and by analyzing a cohort starting in 1996 in a Canadian study (15). In contrast, Holmquvist et al.(14) analyzed the early RA cohort initiated in 1997 and reported that patients with early RA enrolled within one year of disease duration had a better prognosis than the general population; however, the prognosis of those patients was equivalent to that of the general population during the following four years and worsened after five years. In our study, the SMR of both Group A (2001–2006) and Group B (2007–2013) was 0.90 (95% CI 0.68–1.19) and 0.92 (95% CI 0.68–1.23) even after the most conservative assumption in sensitivity analyses and indicated comparable mortality to the general population. This preferable result for mortality in patients with early RA in our study could be explained by several factors. First, the patients with early RA were enrolled after 2000; MTX was approved for the treatment of RA in 1999 and five bDMARDs were approved between 2003 and 2010. Second, the patients started treatment at our institution specializing in rheumatology within two years after the onset of RA. The third reason was the moderate disease activity of RA at the baseline in this study. The median DAS28 at baseline was 3.9 in Group A and 3.6 in Group B, whereas the median DAS28 of the patients from the studies reporting the mortality in patients with early RA ranged from 4.31 to 4.61 in the UK study and the average DAS28 was 5.1 in a Dutch study (16, 17).

In our study, the mortality did not improve in Group B (2007–2012) compared to that in Group A (2001–2006). Changes in the prognosis of patients with early RA are controversial. One report divided the 1990–2007 cohort into four groups by era (17) and another divided the 1990–2004 cohort into three groups (16). There was no improvement in the vital prognosis over time in patients with early RA compared to the general population. On the other hand, shrinking of the mortality gaps over time between patients with early RA and the general population were reported; the 1999–2014 cohort was divided into two periods and the hazard ratios of mortality were 1.40 (95% CI 1.30–1.51) in the former and 0.97 (95%CI 0.89–1.05) in the latter (21). A similar trend was observed in a Canadian study in which the 1996–2006 cohort was divided into two periods and compared (15). In our study, there was no further improvement in the vital prognosis in Group B compared to that in Group A, probably because the SMR of patients with early RA in Group A was already comparable to that of the general population.

The main causes of death in this study were malignancy and respiratory disease. These causes were the same as those reported in our previous studies (8). Notably, no patient died of cardiovascular disease in Group B in five years, and the percentages of cause of death by cardiovascular disease and cerebrovascular disease decreased. Since atherosclerosis is a chronic inflammatory process, recent advances in the treatment of RA might also be effective in reducing the risk of cardiovascular disease (22) even in Japanese patients with RA who have a lower risk of cardiovascular disease than patients in Europe and the United States (23).

The strengths of this study were that we enrolled a large number of patients with early RA and followed them for five years prospectively in our hospital and that we had detailed characteristics of the patients related to RA, such as the disease activity and treatments. Our study had some limitations. First, the percentage of patients lost to follow-up was 15.1% in five years. As our hospital is located in the Tokyo metropolitan area, some patients do not settle for a long time in the same place. The patients can freely select and easily change their hospital in Japan. Second, Japanese physicians do not have access to death certificates or cancer registries to identify the cause of death. Therefore, we actively attempted to contact patients who failed to participate in subsequent observations by mail every six months to increase the reliability of this study. Nevertheless, it was difficult to completely compensate for the mortality data of each patient in this study. Since missing mortality data were considered as a potential cause of selection bias in this study, we estimated the SMR with multiple imputations. According to Kauppi et al., non-responders to a survey were 1.65 times more likely to die than responders (24). It has also been reported that non-responders to a survey have higher mortality and morbidity rates than responders, both in patients with RA and in the general population (25–28). As we had a substantial number of patients with missing mortality data in both groups in our study, we managed this limitation by estimating the SMRs with multiple imputations, which assumed that the mortality rate of patients who failed to follow-up was higher than that of the general population at fluctuating magnifications, as we reported previously (8). Third, our study was conducted at a single center in the Tokyo metropolitan area, which may cause some difficulty in generalizing our results. However, we showed the patients’ backgrounds in detail, which makes it easy for other investigators to compare their results with ours.

The mortality rates of patients with early RA were estimated to be comparable to those of the Japanese general population; additionally, the five-year survival rate of patients with early RA has not changed over the past two decades. Further studies are required to evaluate the long-term mortality of patients with early RA in the era of targeted therapies.

RA： Rheumatoid arthritis

IORRA： the Institute of Rheumatology, Rheumatoid Arthritis

SMR: Standardized mortality ratio

bDMARDs: Biological disease-modifying antirheumatic drugs

IQR: Interquartile range

DAS28: Disease Activity Score in 28 joints

J-HAQ: Japanese version of Health Assessment Questionnaire

MTX: Methotrexate

95%CI: 95% confidence interval

Ethics approval and consent to participate :

This study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments. This study was approved by the Ethics Committee of the Tokyo Women’s Medical University School of Medicine (No.2952-R, No. 2922-R16), and written informed consent was obtained from the patients at enrollment in the study and before the administration of each questionnaire survey.

Consent for publication :

Not applicable.

Availability of data and materials :

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests :

Naohiro Sugitani; NS has declared no competing interests, Eiichi Tanaka; ET has received lecture fees or consulting fees from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical Co., Ltd., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., Eisuke Inoue; EI has received leture fees or consulting fees from Bristol Myers Squibb Co., Ltd., Pfizer Japan Inc., and Nippontect systems Co., Ltd., Mai Abe; MA has declared no competing interests, Eri Sugano; ES has declared no competing interests, Kumiko Saka; KS has declared no competing interests, Moeko Ochiai; MO has declared no competing interests, Yoko Higuchi; YH has declared no competing interests, Rei Yamaguchi; RY has declared no competing interests; Naoki Sugimoto; NS has declared no competing interests, Katsunnori Ikari; KI hasreceived speaker fees from Asahi Kasei Corp., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd., and UCB Japan Co. Ltd. Ayako Nakajima; AN has received research grants from Asahi Kasei Pharma Co., Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Pfizer Japan Inc. AN has received speaker fees from AbbVie Japan GK, Actelion Pharmaceuticals Japan Ltd., Asahi Kasei Pharma Co., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Hisamitsu Pharmaceutical Co. Inc., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Teijin Pharma Ltd., Hisashi Yamanaka; HY has received speaker fees or consultant fee from Astellas Pharma Inc., Bristol Meyers Squibb Co., Ltd., CorEvitas LLC. , Eisai Co., Ltd., Pfizer Japan Inc., Mitsubishi Tanabe Pharma Co.,Teijin Pharma Ltd., and YL Biologics Ltd., Masayoshi Harigai; MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bayer Yakuhin Co. Ltd., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc., Eisai Co., Ltd., Eli Lilly Japan K.K., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Nippon Shinyaku Co., Ltd., Taisho Pharmaceutical Co., Ltd., Teijin Pharma Ltd., UCB Japan Co., Ltd., and Viatris Japan. MH has received speaker’s fee from AbbVie Japan GK, Asahi Kasei Corp., Astra Zeneca K. K., Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Gilead Sciences Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Nippn Shinyaku Co., Ltd., Novartis Japan, Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taisho Pharmaceutical Co., Ltd., Teijin Pharma Ltd and UCB Japan. MH is a consultant for AbbVie, Boehringer-ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co., Ltd. and Teijin Pharma.

The sponsors were not involved in the study design, collection, analysis, and interpretation of data, in the writing of this manuscript, or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations to which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

Funding :

This work was supported by a research grant from the Ministry of Health, Labour, and Welfare of Japan (H30-menneki-shitei-002). This work was supported by a UCB-Japan grant support 2020 from UCB Japan Co. Ltd. The IORRA cohort was organized by the support of Tokyo Women’s Medical University School of Medicine, and this study has been supported by an unrestricted grant from 20 pharmaceutical companies: Asahi Kasei Pharma Co., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Eisai Co., Ltd., Kaken Pharmaceutical Co., LTD., Kissei Pharmaceutical Co., LTD., Sekisui Medical Co., LTD., Taisho Pharma Co., Ltd., Daiichi Sankyo Co, Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., LTD., Teijin Pharma Ltd., Nippon Shinyaku Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Bristol-Myers Squibb Company, Mochida Pharmaceutical Co., Ltd., and UCB Japan Co. Ltd.

Authors’ contributions :

Ayako Nakajima and Hisashi Yamanaka designed this study. Material preparation and data collection were performed by Naohiro Sugitani, Eiichi Tanaka, Eisuke Inoue, Mai Abe, Eri Sugano, Kumiko Saka, Moeko Ochiai, Yoko Higuchi, Rei Yamaguchi, Naoki Sugimoto, Katsunori Ikari, Ayako Nakajima, Hisashi Yamanaka and Masayoshi Harigai. The analysis was performed by Naohiro Sugitani and Eisuke Inoue. The data were interpreted by Naohiro Sugitani, Eiichi Tanaka, Eisuke Inoue, Ayako Nakajima, and Masayoshi Harigai. The first draft of this manuscript was written by Naohiro Sugitani. Eiichi Tanaka, Eisuke Inoue, Ayako Nakajima, and Masayoshi Harigai commented on previous versions of the manuscript. All authors have read and approved the final manuscript.

Acknowledgements :

We thank all patients in the IORRA database and all members of the Institute of Rheumatology, Tokyo Women’s Medical University Hospital, for the successful management of the IORRA study cohort. We would also like to thank 23 pharmaceutical companies for providing unrestricted grants to support the IORRA database: Asahi Kasei Pharma Co., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Eisai Co., Ltd., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., LTD., Kyowa Pharma Chemical Co.,LTD., Sekisui Medical Co., LTD., Taisho Pharma Co., Ltd., Daiichi Sankyo Co, Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Torii Pharmaceutical Co., LTD., Nippon Shinyaku Co., Ltd., Nippon Kayaku Co., Ltd., Japan Tobacco Inc., Pfizer Japan Inc., Bristol-Myers Squibb Company, Mochida Pharmaceutical Co., Ltd., and UCB Japan Co. Ltd.

We would like to thank Editage (www.editage.com) for English language editing.

Authors’ information (Authors and Affiliations):

Institute of Rheumatology, Tokyo Women’s Medial University Hospital,
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Naohiro Sugitani, Eiichi Tanaka, Eisuke Inoue, Mai Abe, Eri Sugano, Kumiko Saka, Moeko Ochiai, Yoko Higuchi, Rei Yamaguchi, Naoki Sugimoto, Katsunori Ikari, Ayako Nakajima, Hisashi Yamanaka, Masayoshi Harigai
Division of Rheumatology, Department of Internal Medicine, Tokyo Women’s Medical University School of Medicine,
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Naohiro Sugitani, Eiichi Tanaka, Mai Abe, Eri Sugano, Kumiko Saka, Moeko Ochiai, Yoko Higuchi, Rei Yamaguchi, Naoki Sugimoto, Masayoshi Harigai
Research Administration Center, Showa University,
1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Eisuke Inoue
Department of Orthopedic Surgery, Tokyo Women’s Medial University School of Medicine,
8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
Katsunori Ikari
Center for Rheumatic Diseases, Mie University Hospital,
2-174 Edobashi, Tsu-city, Mie 514-8507, Japan
Ayako Nakajima
Rheumatology, Sanno Medical Center,
8-5-35 Akasaka, Minato-ku, Tokyo 107-0052, Japan
Hisashi Yamanaka
Department of Rheumatology, International University of Health and Welfare,
4-3, Kozunomori, Narita-city, Chiba 286-8686, Japan
Hisashi Yamanaka

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No competing interests reported.

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Unincreased mortality of patients with early rheumatoid arthritis compared to the general population in the past two decades: results from a Japanese prospective observational cohort: IORRA

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Abstract

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Background

Methods

Patients

The IORRA cohort

Follow-up survey and death reports

Statistical analysis

Results

Study Demographics

Five-year survival

Causes of death

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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