The association between comorbidities and disease activity in patients with rheumatoid arthritis: a multicenter, cross-sectional cohort study in Japan with the highest proportion of elderly individuals

This study aimed to assess the association of disease activity with the presence of comorbidities in patients with rheumatoid arthritis, using the Akita Orthopedic Group on Rheumatoid Arthritis (AORA) registry, a multicenter, cross-sectional registry in Japan with the highest proportion of elderly people. We included 1838 patients (mean age: 66.4 years old) who visited our affiliated institutions between April 2018 and March 2019. The patients were divided into two groups based on the disease activity in 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR) into the remission or low disease activity group (L group) and the moderate or high disease activity group (H group). Patient demographics and comorbidities in the two groups were compared. The most common comorbidity was hypertension (33.7%), followed by renal disease (25.2%), respiratory disease (12.2%), diabetes mellitus (8.1%), cardiovascular disease (8.0%), malignancies (5.7%), and cerebrovascular disease (4.7%). The H group was older (p<0.0001); had a higher prevalence of hypertension (p<0.0001), diabetes (p=0.0011), respiratory disease (p<0.0001), cerebrovascular disease (p<0.0001), and cardiovascular disease (p=0.0030); and was less likely to use anti-rheumatic drugs. The prevalence of comorbidities other than renal disease and malignant tumor was higher in the H group. Multivariate logistic regression analysis showed that female sex (p=0.0054), advanced Steinbrocker class (p<0.0001), high anti-citrullinated protein antibody levels (p=0.0211), high prednisolone dose (p<0.0001), and absence of biologics’ or JAK inhibitors’ use (p<0.0001) were risk factors for high disease activity, and shorter treatment period was a low-risk factor for high disease activity (p=0.0041). Among comorbidities, the presence of cerebrovascular disease (p=0.0334) was the only independent risk factor for high disease activity. In our registry study with a high proportion of elderly RA patients, cerebrovascular disease was associated with high disease activity in patients with RA. Therefore, when treating elderly patients with RA, we need to pay careful attention to cerebrovascular disease, and treatment should be aimed at achieving adequate control of RA.

Page 2 of 7 Miura et al. Egyptian Rheumatology and Rehabilitation (2022) 49:7 Background Rheumatoid arthritis (RA) is a chronic inflammatory disease that can lead to joint destruction and dysfunction due to synovitis and bone erosion. However, in the last decade, the introduction of disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), biologics (Bio), and Janus kinase inhibitors (JAK) has dramatically improved the long-term prognosis of patients with RA [1]. The concept of "treatto-target" (T2T) in RA, which involves monitoring the disease activity in order to achieve remission or low disease activity, has been shown to be effective in improving pain and dysfunction [2,3]. RA is more common in middle-aged people between the ages of 40 and 60 years [3], and treatment response to MTX and biologics has been reported to be similar among younger and older patients with RA [4]. However, the increased incidence of comorbidities, such as cardiovascular and respiratory diseases, with aging, often makes it difficult to introduce and continue these effective drugs [3,4]. As a result, older patients with RA are more difficult to treat and have a higher disease activity [5][6][7][8]. Previous reports have also shown that patients with comorbidities have higher disease activity and poorer outcomes than those without comorbidities [5,6,9]. However, only few reports have examined the relationship between specific comorbidities and disease activity in RA [10]. Furthermore, there are no reports of studies that focus on elderly individuals with several comorbidities.
This study aimed to investigate which comorbidities affect disease activity in patients with RA using the Akita Orthopedic Group on Rheumatoid Arthritis (AORA) registry [11], a multicenter, cross-sectional RA cohort study in Japan with the highest proportion of elderly people.

The AORA registry
The AORA registry was established in 2010 as a multicenter cohort of Japanese patients with RA in Akita Prefecture, Japan. The AORA registry is maintained by the Department of Orthopedic Surgery at Akita University Graduate School of Medicine and covers 28 affiliated institutions. The data is collected once a year from the responsible physician at each institution. Japan is one of the world's most rapidly aging countries, and the Akita Prefecture has the highest rate of aging, with 33.8% of the population aged ≥65 years [12]. Therefore, compared to other cohort registries [13,14], the AORA registry is novel, owing to its high proportion of elderly patients.

Study design
We included 2175 patients with RA aged ≥18 years who visited our affiliated institutions between April 2018 and March 2019. Patients not assessed for comorbidities and those with insufficient clinical findings and laboratory data for assessment of disease activity were excluded; finally, 1838 patients (365 males and 1473 females) were included in this study. Patient information, including age, sex, medication, dosing period, disease stage and class as per the Steinbrocker classification system [15], serum levels of anti-citrullinated protein antibody (ACPA), the disease activity score in 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR), simplified disease activity index (SDAI), the health assessment questionnaire disability index (HAQ), and comorbidities, were collected. We investigated the use of the following drugs for RA: DMARDs, MTX, glucocorticoids (prednisolone, PSL), Bio, and JAK inhibitors (Bio/JAK). Regarding comorbidities, we evaluated the presence of hypertension; diabetes mellitus (DM); respiratory disease (chronic obstructive pulmonary disease (COPD), interstitial pneumonia (IP), asthma, and pulmonary infection); cerebrovascular disease (cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage); cardiovascular disease (myocardial infarction, heart failure, and cardiomyopathy); renal disease; and malignancy. We defined renal disease as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m 2 [16]. On the DAS28-ESR, remission was defined as <2.6, low disease activity as 2.6-3.2, moderate activity as 3.2-5.1, and high disease activity as >5.1 [17]. Therefore, we divided patients into two groups: the remission or low disease activity group (L group) and the moderate or high disease activity group (H group). We compared the measures between the two groups. Furthermore, factors that affected high disease activity were examined.
The study's retrospective protocol was approved by the Institutional Review Board for Clinical Research at Kakunodate General Hospital (approval number, 00409), and informed consent was obtained from all patients.

Statistical analysis
Values are expressed as means and standard deviations (SD) for continuous variables and as percentages for categorical variables. Comparisons between groups were made using independent sample t tests in the case of continuous variables, and Pearson's chi-square tests for categorical variables. To investigate the association between RA disease activity and comorbidities, a multivariate logistic regression analysis was performed. All statistical analyses were completed using R version 3.5.1 software (R Foundation for Statistical Computing, Vienna,
On comparing the two groups, the H group was older (p<0.0001); had a higher proportion of women (p=0.0017); and had a longer disease duration (p=0.0055), more advanced stage (p<0.0001) and Steinbrocker class (p<0.0001), and higher ACPA levels (p=0.0034) than the L group. The usage rate of DMARDs (p=0.0017), MTX (p=0.0387), and Bio/JAK (p<0.0001) was lower in the H group; however, the usage rate and dose of PSL were higher in the H group (p<0.0001) than in the L group. Moreover, the H group had a higher prevalence of hypertension (p<0.0001), diabetes (p=0.0011), respiratory disease (p<0.0001), cerebrovascular disease (p<0.0001), and cardiovascular disease (p=0.0030) ( Table 2). Multivariate logistic regression analysis revealed that female sex (p=0.0054), advanced Steinbrocker class (p<0.0001), high ACPA levels (p=0.0211), high PSL dose (p<0.0001), and absence of Bio/JAK use (p<0.0001) were risk factors for high disease activity; shorter treatment period was a low-risk factor for high disease activity (p=0.0041). Among comorbidities, the presence of cerebrovascular disease (p=0.0334) was associated with high disease activity (Table 3).

Discussion
Using our patient registry with a high proportion of elderly patients, we found that cerebrovascular disease was associated with high disease activity in patients with RA, among the comorbidities studied. Since patients from the registry had a higher average age of 66.4 years, and a higher prevalence of cardiovascular disease (8.0%) and cerebrovascular disease (4.7%) than those in other reports [4,8,18], this finding has important implications for the treatment of rheumatoid arthritis in the elderly.
In the comparison between the two groups, the H group was older, had more comorbidities, used MTX and Bio less often, and used a higher dose of PSL. This result is consistent with that of a previous study [14] which suggested that the presence of comorbidities influenced the choice of treatment. In addition, it has been reported that female RA patients who have a longer disease duration and belong to a higher disease functional class as per the Steinbrocker criteria do not respond to treatment as well as those with a shorter disease duration [19]. The results of our multivariate logistic regression analysis support these previous findings, indicating that early and adequate therapeutic intervention is necessary in the treatment of RA.
Conversely, it has been reported that RA is an independent risk factor for cardiovascular and cerebrovascular disease due to the progression of arteriosclerosis caused by chronic inflammation and decreased physical activity [20][21][22][23][24]. Previously, Crepaldi et al. reported that ischemic heart disease was related to RA disease . However, in our study, cardiovascular disease, including ischemic heart disease, was not a risk factor for high disease activity. This may have been due to several reasons. First, Asians have a lower risk of developing ischemic heart disease than Westerners [25], and therefore, there may have been fewer patients with ischemic heart disease in our study. Second, in our registry, the category of "cardiovascular disease" included not only ischemic heart disease, but also heart failure and cardiomyopathy. Heart failure and cardiomyopathy do not directly correlate with RA disease activity, and this may have influenced our results. The association between cerebrovascular disease and disease activity of RA has been previously reported, and proper treatment and maintenance of low disease activity in RA can suppress the progression of atherosclerosis [26], thereby reducing the risk of cerebrovascular events [27]. Our results suggest that cerebrovascular events may be more frequent in RA patients with high disease activity, and provide evidence for the effectiveness of appropriate treatment, including Bio, based on recent T2T strategies. Another possible interpretation is that patients with a history of cerebrovascular disease are not being treated appropriately. In fact, the physical limitations of patients have been reported to be barriers to achieving optimal disease activity [18], and the usage rate of biologics has been reported to be lower in patients with cerebrovascular disease because this comorbidity is attributed to increased fragility [28]. In this study as well, a high Steinbrocker class was a risk factor for high disease activity in the multivariate logistic regression analysis; impaired physical function was associated with high disease activity. Although the definition of patient fragility is unclear and the association between cerebrovascular disease and the patient's physical function and usage rate of biologics has not been investigated in this study, we hypothesized that the general health condition of patients with a history of stroke influenced the treatment choice of their physicians and resulted in high disease activity. The presence of respiratory disease is the most important comorbidity to consider when treating patients with both MTX and biologics, as it increases the risk of drugrelated risks, such as the development and exacerbation of IP and respiratory infections [28][29][30]. Therefore, respiratory disease could also be a risk factor for high disease activity in terms of drug selection. However, in this study, there was no statistically significant association between disease activity and respiratory disease in patients with RA. A previous study reported that respiratory comorbidity affected patient-reported outcomes [10]. However, to our knowledge, there are no studies that have revealed an association between RA disease activity and the presence of respiratory comorbidities. A variety of treatment options, including the careful use of MTX and biologics with close monitoring of symptoms [28,31] and the use of some biologic agents with a low risk of infection but good efficacy in improving activity, could contribute to achieving low disease activity in patients with comorbid conditions [32,33].
This study had several limitations. First, this was a cross-sectional observational study; hence, it was difficult to evaluate the influence of comorbidities on therapeutic response and selection of drugs, and to clearly establish a causal relationship between comorbidities, disease characteristics, and treatment. Second, we did not investigate other painful diseases, such as osteoarthritis and spondylosis, which may influence the assessment of disease activity. Although comorbidities generally increase in the elderly, we did not compare comorbidities in the non-RA group. Finally, our study was not limited to the elderly, as it included all RA patients older than 18 years. Finally, although our data is from the region with the highest rate of aging, our study is not limited to the elderly because we analyzed all registered cases, including all patients with RA aged 18 years and older. Further research is needed to confirm these findings by refining the registration methods, collecting more detailed data, and conducting longitudinal studies.

Conclusions
In our registry study with a high proportion of elderly RA patients, we revealed that in patients with moderate-to-high disease activity as classified by DAS28-ESR, the prevalence of hypertension, diabetes mellitus, respiratory disease, and cardio-cerebrovascular disease, but not renal disease and malignant tumor, was significantly higher. Furthermore, multivariate logistic regression analysis showed that among the comorbidities, only cerebrovascular disease was associated with high disease activity in patients with RA. Therefore, when treating elderly patients with RA, we need to pay careful attention to cerebrovascular disease, and treatment should be aimed at achieving adequate control of RA.