The impact of rehabilitation frequency on the risk of stroke in patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis are at higher risk of developing stroke due to augmented systemic inflammation. While regular exercise has been shown to reduce inflammation in human subjects, the purpose of our study is to determine whether increased frequency of rehabilitation is protective against stroke or not.
METHODS: A total of 16,224 rheumatoid arthritis patients with a catastrophic illness certificate were identified in our database from 2000 to 2006, and 663 of them developed stroke before the end of 2013. After statistically matching for age, sex, and the time interval between the diagnosis of rheumatoid arthritis and stroke, 642 patients without stroke were identified as the control group. Analyses with Student's t test and Chi-square test were done to compare the clinical characteristics of patients with and without stroke, and logistic regression analysis was then performed to evaluate the odds ratio of stroke.
RESULTS: Higher odds ratio of stroke was revealed in patients with hypertension, diabetes mellitus, and moderate degree of rheumatoid arthritis disease severity. Furthermore, more than 40 rehabilitation sessions per year reduced the risk of developing stroke in patients with moderate disease severity.
CONCLUSIONS: Physical activities brought by more rehabilitation sessions are beneficial and should be encouraged in patients with rheumatoid arthritis, particularly for those with higher disease activity but not taking biologic agents.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation.[1] Although the synovial joints are the main target of autoantibodies in patients with RA, many other organs or tissues may also be involved, such as skin, eyes, lungs, kidneys, blood vessels, and salivary glands.[2] Because of the involvement of systemic inflammation, many diseases closely related to inflammation may also be induced by RA. Patients with RA often suffer from decreased quality of life and disability due to destruction of joints in later life. It is thus vital to conduct thorough, ongoing evaluations in RA patients in order to identify and avoid comorbid diseases that may further exacerbate disability.

Stroke is caused by the interruption of blood supply to the brain. Both ischemic and hemorrhagic stroke can have a considerable negative impact on patients’ quality of life due to symptoms such as hemiplegia, hemianopia, aphasia, and dysphagia. Well-known risk factors of stroke include hypertension, type 2 diabetes mellitus (DM), dyslipidemia, physical inactivity, obesity, and cigarette smoking, etc..[3] In addition, risk of stroke has also been demonstrated to be higher in patients with RA.[4] As endothelial and systemic inflammation has long been considered to play a central role in the pathogenesis of stroke,[5] efforts should be directed toward reducing systemic inflammation in patients with RA to lower the incidence of stroke. The current mainstream treatment approach centers on medications, which range from corticosteroids and disease-modifying anti-rheumatic drugs to biological agents.[6] Additionally, exercise and physical activities also appear to play an important role in reducing systemic inflammation.[7] Exercise is proven to be beneficial for patients with RA in reducing fatigue,[8] lowering daily activity limitations, and improving both oxygen uptake and muscle strength.[9] However, to date, no studies have been conducted to clarify the relationship between the exercise frequency and risk of stroke development in patients with RA. Because rehabilitation programs for RA patients usually include strengthening exercises for the major muscles of the four limbs as well as cardiopulmonary endurance training, they constitute an important component of daily exercise in RA patients. We designed a retrospective nested case-control study to elucidate the association between rehabilitation frequency and stroke incidence in RA patients. We hypothesized that RA patients receiving more rehabilitation training sessions would have a lower incidence of stroke.

Materials and methods

The database

This study used data from Taiwan’s National Health Insurance Research Database (NHIRD), which was administered by the National Health Insurance (NHI) Administration, the single largest medical health insurance institution in Taiwan. More than 99% of Taiwan’s approximately 23 million residents, including foreign nationals, are enrolled in Taiwan’s NHI program.[10] Therefore, data from the NHIRD reflect the general medical health status of the entire population of Taiwan. The data that are made available to researchers include encrypted patients’ data such as date of birth, sex, medical diagnoses in the form of ICD-9-CM (International classification of diseases, ninth revision, clinical modification) codes, date of hospital admission and discharge, the procedures received, and the prescribed medications that are covered by the NHI. The database has been used extensively to conduct medical epidemiology studies in Taiwan.[11] Hence, it provides a valuable resource to investigate the relationship between the number of rehabilitation programs received and the incidence of stroke in patients with RA.

The study samples

The study employed a nested case-control design, which was approved by the Institutional Review Board of Taichung Veterans General Hospital in Taiwan. (No. CE13152) Patients with an unambiguous diagnosis of RA in Taiwan are certified with a catastrophic-illness card (CIC) by the NHI Administration, and it allows these patients to be exempted from most medical costs related to RA when they visit health facilities. In order to avoid mistaken diagnosis in the database, only patients with a CIC for RA were recruited in our study, and the period of recruitment was from January 1st, 2000 to December 31st, 2006. Moreover, the diagnosis of stroke was established only if an ICD-9 code from 430 to 438 was used for the major diagnosis at hospital admission after radiological confirmation. After excluding patients with a diagnosis of stroke before RA or age younger than 18 years old, a total of 16,244 patients with RA were enrolled as the study subjects. Among them, 663 patients (4.08%) developed stroke before December 31st, 2013.

After matching for age, sex, and the time interval between RA and stroke diagnosis, we identified an additional 642 RA patients without stroke occurrence before the end of 2013. An index date was assigned to each of these patients corresponding to the date of stroke attack in the study group. After excluding patients with a time interval between the date of RA diagnosis and stroke or index date less than one year, there were 591 cases of RA with subsequent stroke and 582 cases of RA without stroke. The flowchart of the study participants selection is summarized in Fig 1.

Fig 1

The flowchart of our study.

The enrollment of the study cases is illustrated in this figure.

The comorbidity definitions, groups setting, and study design

Medical comorbidities including hypertension, DM, and hyperlipidemia were taken into consideration in our study. Each patient was defined as having a particular medical comorbidity if it was registered as the major diagnosis at least three times in a patient’s outpatient records and at least one time within one year before the index or stroke date.

In order to study the effect of more rehabilitation sessions on patients with RA, we defined patients receiving 40 rehabilitation training sessions per year as the cutoff point. Rehabilitation programs for RA patients in Taiwan usually involve educating patients how to perform strengthening exercises for the four limbs to stabilize the vulnerable joints, cardiopulmonary endurance training, and splints fitting, as well as providing suggestions related to activities of daily living. As suggestions from American College of Sports Medicine, strengthening exercises are usually designed as 60–80% of 1 repetition maximum, 8–12 repetitions for 2–4 sets, 2–3 days per week, while cardiopulmonary endurance training emphasizes on exercises that maintaining the heart rate around 40–60% of heart rate reserve for an accumulation of 150 minutes per week.[12] Forty rehabilitation sessions per year roughly approximates to rehabilitation visits once per week under the instruction of professional physical therapists after subtracting national holidays and vacations.

In order to study the effect of rehabilitation in RA patients with different disease severity, we divided the RA patients into three groups. The advantage of our database is that the dosage of medications was available. Since medications prescriptions in Taiwan were regulated by the rules set by Taiwan’s NHI Administration, certain criteria of disease severity should be fulfilled in order to be eligible for treatment with biologic agents. Therefore, we can use the medication types and dosage to classify the severity of diseases in studies utilizing Taiwan’s NHIRD. We defined patients in the severe group as those who had ever received biologic agents, including etanercept, adalimumab, golimumab, abatacept, rituximab, and tocilizumab within one year before the stroke or index date. Patients in the moderate group were defined as those who had ever received methotrexate >420mg or prednisolone >280mg in one outpatient visit. The remaining patients were assigned to the mild group. The effects of different rehabilitation frequencies were determined in these three groups of RA disease severity.

Statistical analysis

We used SAS software, version 9.4 (SAS Institute, Cary, NC, USA) for all statistical analyses in this study. Student’s t test and Chi-square test were done to determine the statistical differences in age, sex, medical comorbidities, including hypertension, DM, and hyperlipidemia, number of rehabilitation sessions per year, and RA disease severity between the patients with stroke and without stroke. Next, multivariable logistic regression analysis was conducted to determine the odds ratio of stroke based on age, sex, medical comorbidities, number of rehabilitation sessions, and RA disease severity with statistical adjustment for all the variables mentioned above. In order to clarify the impact of different rehabilitation frequencies in the three groups of RA disease severity, a stratified analysis according to the disease severity was done with statistical adjustment of age, sex, hypertension, DM and hyperlipidemia. A p value less than 0.05 was considered significant in our study.

Results

The clinical characteristics of RA patients with and without stroke are shown in Table 1. Because the two groups of patients were matched for age, sex, and time interval between the diagnosis of RA and index date, no statistical differences in these three parameters were noted between patients with and without stroke. The average time interval between the diagnosis of RA and stroke attack was 6.0±3.0 years in our study. Significantly greater prevalence rates of hypertension, DM, and hyperlipidemia were noted in the stroke patients. However, the number of rehabilitation sessions per year and the disease severity of RA did not differ significantly between these two groups of patients, and the p values were 0.474 and 0.083, respectively. After grouping the patients according to the cutoff number of rehabilitation sessions, the Chi-square test still did not achieve statistical significance (p = 0.083).

Table 1

Clinical characteristics of RA patients with and without stroke.

Variables	Total (n = 1173)		Without Stroke (n = 582)		With Stroke (n = 591)		P-value
	n	(%)	n	(%)	n	(%)
Age, years (mean±SD)	62.1±10.7		62.0±10.6		62.1±10.7		0.938a
Gender							0.680
female	834	(71.1)	417	(71.6)	417	(70.6)
male	339	(28.9)	165	(28.4)	174	(29.4)
Hypertension							<0.001
No	632	(53.9)	369	(63.4)	263	(44.5)
Yes	541	(46.1)	213	(36.6)	328	(55.5)
DM							<0.001
No	958	(81.7)	510	(87.6)	448	(75.8)
Yes	215	(18.3)	72	(12.4)	143	(24.2)
Hyperlipidemia							0.002
No	993	(84.7)	512	(88.0)	481	(81.4)
Yes	180	(15.3)	70	(12.0)	110	(18.6)
Number of rehabilitation sessions per year	12.9±58.0		14.1±69.7		11.7±43.6		0.474a
0–39	1078	(91.9)	528	(90.7)	550	(93.1)	0.142
≧40	95	(8.1)	54	(9.3)	41	(6.9)
Severity of RA							0.083
Mild	794	(67.7)	402	(69.1)	392	(66.3)
Moderate	259	(22.1)	114	(19.6)	145	(24.5)
Severe	120	(10.2)	66	(11.3)	54	(9.1)
Time interval between RA and index date, years (mean±SD)	6.0±3.0		6.0±3.0		6.0±3.0		0.875a

a T test, Chi-squared test or Fisher's Exact Test for all other p-values.

To study the effect of the aforementioned parameters on stroke attack, logistic regression analysis was done with statistical adjustment for all the parameters including age, sex, disease comorbidities, number of rehabilitation sessions, and severity of RA. The odds ratios of stroke in RA patients with hypertension or DM were 2.10 and 1.92, respectively, with p values <0.001. However, RA patients with hyperlipidemia did not have a higher risk of developing stroke. (odds ratio = 1.29, p = 0.144) Regarding disease severity of RA, only patients with moderate severity had a higher risk of stroke compared to the group with mild severity (odds ratio = 1.37, p = 0.034). Furthermore, RA patients receiving more rehabilitation sessions did not have a significant reduction in risk of stroke attack (odds ratio = 0.66, p = 0.061). The results are shown in Table 2. Since physical activities brought by more frequent rehabilitation visits had been considered to be beneficial for stroke prevention, the result above seems to be unreasonable. Therefore, further stratified analysis on the effect of rehabilitation frequencies was done according to the disease severity. More rehabilitation sessions only resulted in a risk reduction effect in patients with moderate disease severity, (odds ratio = 0.32, p = 0.039) as shown in Table 3.

Table 2

Adjusted odds ratios of stroke for age, sex, hypertension, DM, hyperlipidemia, number of rehabilitation per year, and severity of RA in the multivariable logistic regression analysis.

Variable	Adjusted Odds ratio	95% CI	P-value
Age, years	0.99	(0.98–1.00)	0.213
Sex
female	1.00	─	─
male	1.14	(0.87–1.48)	0.339
Hypertension
No	1.00	─	─
Yes	2.10	(1.64–2.69)	<0.001*
DM
No	1.00	─	─
Yes	1.92	(1.38–2.66)	<0.001*
Hyperlipidemia
No	1.00	─	─
Yes	1.29	(0.92–1.83)	0.144
Number of rehabilitation sessions per year
0–39	1.00	─	─
≧40	0.66	(0.42–1.02)	0.061
Severity of RA
Mild	1.00	─	─
Moderate	1.37	(1.02–1.84)	0.034*
Severe	0.82	(0.55–1.23)	0.339

*p<0.05

Table 3

Adjusted odds ratio of stroke associated with number of rehabilitation sessions per year, stratified by disease severity of RA in the multivariable logistic regression analysis.

Variables	Adjusted Odds ratio	95% CI	P-value
Severity of RA:Mild
Number of rehabilitation sessions per year
0–39	1.00	─	─
≧40	0.75	(0.44–1.26)	0.272
Severity of RA:Moderate
Number of rehabilitation sessions per year
0–39	1.00	─	─
≧40	0.32	(0.11–0.95)	0.039*
Severity of RA:Severe
Number of rehabilitation sessions per year
0–39	1.00	─	─
≧40	0.97	(0.26–3.63)	0.961

*p<0.05

Discussion

This is the first study to analyze the relationship between rehabilitation frequencies and incidence of stroke in RA patients. We discovered that only patients with moderate RA severity had a higher incidence of stroke. Moreover, it was the only group in which a higher frequency of rehabilitation was shown to have protective effect against stroke.

The method of classifying RA disease severity in administrative databases has been investigated in several studies.[13,14] One such study that has been widely discussed in the literature proposes a claims-based index for RA severity (CIRAS),[15] which includes tests for rheumatoid factor, inflammatory markers, number of chemistry panels and platelet counts ordered, number of rehabilitation and rheumatology visits, and Felty's syndrome. Although this model was demonstrated to have a moderate correlation with a medical records-based index of RA severity,[16] many of the items in this index cannot be obtained in the database we used, such as blood tests including rheumatoid factor, inflammatory markers, chemistry panels and platelet counts. Another study attempted to determine disease severity by assessing lifetime exposure to various medications including corticosteroid, disease-modifying antirheumatic drugs (DMARD) and biologic agents.[17] However, this method could not distinguish between RA patients in the highest and lowest quartiles of disease severity. Nevertheless, the advantage of our database is that the dosage of medications was available, in contrast to the aforementioned study. Therefore, we were able to classify the patients’ disease severity by the dosage of medications they received. In addition, according to well-defined rules stipulated by Taiwan’s National Health Insurance program, patients are required to fulfill certain criteria of disease severity in order to be eligible for treatment with biologic agents, such as a Disease Activity Score (DAS 28)[18] higher than 5.1 and treatment failure for six months using at least two kinds of DMARDs confirmed by photographic evidence and X-ray study. Hence, we classified the patients that had ever received biologic agents as the most severe group, and the other groups were also defined according to the dosage of methotrexate and prednisolone the patients had ever received as shown on their outpatient records. This was found to be an objective way to classify RA disease severity in previous studies that used NHIRD [19,20].

Several epidemiological studies demonstrated a significantly higher risk of stroke in RA patients, and the odds ratio ranged from 1.18 (95% confidence interval 1.09–1.28)[21] to 2.98 (95% confidence interval 1.89–4.70).[22] Data from a meta-analysis revealed an odds ratio of 1.64 (95% confidence interval 1.32–2.05) for ischemic stroke and 1.68 (95% confidence interval 1.11–2.53) for hemorrhagic stroke in RA patients.[23] The risk of recurrent stroke was also higher in RA patients.[24] Because the relationship between RA and cerebrovascular diseases has been thoroughly evaluated in previous investigations, this topic was not the primary focus of the present study. Instead, we compared the stroke risk among different levels of RA disease severity. Our results showed a significantly higher odds ratio of stroke in the moderate severity group compared to the mild group, but not the severe group. By definition, biologic agents were only prescribed in the most severe group of RA patients in our study. Therefore, a possible reason is the anti-inflammatory effect of the biologic agents which would have reduced the likelihood of developing stroke in the most severe group in our study. For instance, etanercept was shown to protect the rat brain against ischemic stroke by inhibiting tumor necrosis factor (TNF) alpha and downregulating microglial activation.[25] Another biologic agent, adalimumab, could reduce endothelial dysfunction and arterial stiffness, and thus ameliorate carotid atherosclerosis.[26] Rituximab, another frequently prescribed biologic agent, was also revealed to have similar effects on endothelial function.[27] Hence, patients in the severe group, who were thought to have the highest risk of stroke, did not have a significantly higher risk compared to the mild group. On the contrary, without the potent anti-inflammatory effect of biologic agents, patients in the moderate group had a higher risk of developing stroke.

Exercise and physical activity can reduce inflammation and cardiovascular risk in RA patients.[28] In addition to inflammation, a sedentary lifestyle in RA patients also contributes to a significantly elevated cardiovascular risk, which can also be reverted by regular physical activity.[29] Our study revealed that a rehabilitation frequency of more than 40 sessions per year could reduce the risk of stroke in RA patients with moderate disease severity. This group of patients had a somewhat high degree of disease severity, but had never been protected by the potent biologic agents before their stroke attack. This is the circumstance in which exercise could exert its anti-inflammatory effect to protect these patients from stroke attack. Since rehabilitation doctors and physical therapists in Taiwan always design exercise programs for patients according to ACSM's Guidelines for Exercise Testing and Prescription,[12] the comprehensive rehabilitation programs in Taiwan regularly constitute of strengthening and aerobic parts of exercise training. The protective effect of exercise could also be observed in other groups in our study results. The odds ratio of stroke was 0.75 in the mild group, and 0.97 in the severe group. However, no statistical significance could be established, and the mechanism underlying these phenomena warrant further research.

This study is the first of its kind to evaluate the effect of rehabilitation frequency on the incidence of stroke among different levels of RA disease severity. The major strength of our study is the use of a population-based administrative database with a nested case-control design, which allowed us to track the results of a large sample of RA patients without the concern of immortal time bias.[30] However, there were at least five limitations in our study. First, the number of rehabilitation sessions might not have accurately reflected the amount of physical activity in the daily life of RA patients. Nevertheless, in this group of patients, a willingness to receive rehabilitation sessions almost every week for one year indicated a far greater motivation to exercise compared with those who did not attend weekly exercise sessions. These RA patients received instructions in a tailored exercise program from physical therapists every week, and thus it is reasonable to expect that they would maintain their exercise habits. Second, certain risk factors for stroke such as obesity, smoking, alcohol consumption, and dietary habits were not available in our database, and were therefore not possible to control or adjust for them in the analysis. However, these stroke risk factors are also risk factors for hypertension,[31] DM[32] and hyperlipidemia.[33] By statistically adjusting for these medical comorbidities, it was possible at least in part, to control for these risk factors simultaneously. Third, while medical comorbidities including hypertension, diabetes and hyperlipidemia are important contributing factors of stroke, only statistical adjustments were done instead of matching. The reason lies in that if these medical comorbidities in our study were all matched, the case number in the control group will be very few, rendering subsequent statistical analysis impossible and meaningless. Therefore, only age, sex, and the time interval between RA and stroke diagnosis were statistically matched between the two study groups. Fourth, the disease severity of RA patients was determined by the medications prescribed rather than the use of a validated disease severity index such as DAS28.[18] As certain items in the DAS28, such as the number of joints with tenderness or swelling, the erythrocyte sedimentation rate, and the patient global health status, are not available in NHIRD, it was not appropriate to define the disease severity groups using this index in our study. However, DAS28 is one of the criteria for initiation of biologic agent treatment in National Health Insurance regulations, and doctors always adjust the medication dosages according to the disease severity they observe in clinical practice. Thus, the use of medications prescribed as a surrogate to define disease severity in our study was reasonable. Finally, the type, intensity, frequency and duration of exercise incorporated in the rehabilitation sessions may influence the incidence of stroke. However, the information of detailed exercise programs mentioned above cannot be obtained in the database we used. Therefore, further prospective study to address this gap is needed in the future.

Conclusions

Our study revealed a higher risk of stroke in patients with hypertension, DM, and moderate disease severity in RA patients. Furthermore, more than 40 rehabilitation sessions per year reduced the risk of developing stroke in RA patients with moderate disease severity. Therefore, physical activities brought by more rehabilitation sessions were shown to be beneficial and should be encouraged in RA patients with high disease severity without the protection of biologic agents.

STROBE statement—Checklist of items that should be included in reports of case-control studies.

(DOC)

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3 Oct 2019

PONE-D-19-22440

The Impact of Rehabilitation Frequency on the Risk of Stroke in Patients with Rheumatoid Arthritis

PLOS ONE

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Reviewer #1: General comments:

In this case-control study, the authors use registry data aiming to investigate whether in people with rheumatoid arthritis, rehabilitation frequency is associated with lesser risk of stroke. People had higher odds of stroke if they had hypertension or diabetes and a greater number of rehabilitation sessions did not reduce the odds of stroke. Stratification by RA severity appears to reduce risk for people with moderate RA participating in more than 40 sessions of rehabilitation per year.

Exercise is an important modifiable risk factor for stroke, and as such the study investigates the effect of exercise on stroke risk in a population with an underlying chronic condition. While this knowledge is important for the RA population, the manuscript could be reviewed to make a more convincing argument for the importance of this study and the study findings. At present, the language overstates the findings and could be toned down.

Specific comments

Materials and methods:

1. An important addition would be greater detail about the rehabilitation sessions. While this may be difficult to ascertain from the registry, the rehabilitation sessions may or may not have included the type and intensity and frequency of exercise needed to plausibly influence the odds of stroke.

2. It would be helpful to include some further justification about the definition of RA severity used for stratification based on medication types.

3. The statistically adjustment information currently in the design section (lines 114-115) would be better placed in the statistical analysis paragraph.

Results:

1. In table 1, the groups are not matched for participant numbers (n=582 v n=591) can the reason for this be clarified in the text and any missing data explained.

2. Additionally, in table 1 – could the authors be more specific about the number of rehabilitation sessions. Is this the total number of sessions over the 6 years of data or a mean number of sessions with SDs? The numbers listed appear very low compared to the dose of exercise that would be required to significantly influence stroke via mechanisms such as modifying BP or diabetes status.

3. Table 2: It would be helpful for the results to reworded to clearly specify what variables are in the final adjusted model. This may be an English language issue, but it is difficult to interpret if the model includes all the variables listed from the table title and the text or if the table is presenting the variables listed. This is important for the reader to help interpret the results of the study and is not clear as written.

Discussion:

1. The discussion is quite long and would benefit from revision to more concisely discuss the study findings. It’s is difficult to read in its present form.

2. The section in the discussion that justifies the method of classifying RA severity appears contradictory. I appreciate that the registry has limited data available – However, previous literature does not fully support the method used in this study. Are there further justifications for the choice of methods used in this study?

3. The finding that the moderately severe RA group were at higher risk of stroke is interesting (lines 220-230) and perhaps a more robust finding than the effect of number of rehabilitation sessions. This could be discussed and highlighted further.

4. Paragraph commencing Line 237: the authors discuss the role of exercise and physical activity and a sedentary lifestyle. However, because of the limited detail about the rehabilitation sessions we do not know what the ‘active ingredient’ of the rehabilitation program is and this significantly reduces the strength of the findings. Perhaps the choice of words would be used consistently as to whether the rehabilitation is cardiovascular exercise, or more general physical activity (unplanned, not about fitness) or sedentary time. All confer different biological effects on cardiovascular and cardiometabolic health. The discussion here is mixed and therefore is less specific than it could be.

5. The authors consistently refer to >40 rehabilitation sessions as being ‘aggressive’. This language should be toned down through the manuscript as it is not in fact a high intensity of intervention.

Reviewer #2: This is an interesting paper looking at the association between rehabilitation frequency and incidence of stroke among people with rheumatoid arthritis.

Some comments for the authors are as below:

Major comments

Design

- I have a big concern regarding the study design since the control group was only matched with age, sex, time interval between RA diagnosis and stroke. The study aim was to investigate the association between rehab frequency and incidence of stroke among people with RA, it is assumed that the control group should ideally have similar age, gender, and health (e.g. comorbidities) as the case group. However, as shown in Table 2, those with stroke had higher rates of hypertension, diabetes and hyperlipidemia compared to those without stroke. Adjusting for these factors may not address the issue.

- It is unclear how investigators dealt with several disadvantages of the study design including retrospective nature, appropriateness of control group and possibility of recall bias.

- Please provide reference(s) for the cut-off point of 40 training sessions for intensive rehab.

Methods & findings

- In the legends of Table 2 and Table 3, Hazard ratios should be changed to Odds ratio since authors performed logistic regression.

- Please clarify the exact logistic regression models used for the findings shown in Table 2 and Table 3. Were they bivariable or multivariable models? It seems that after accounting for age, sex, comorbidities, and RA severity, there was no evidence of a statistically significant association between rehab frequency and stroke incidence.

- Please provide the reason for stratifying analyses by RA severity? Explain by checking interaction.

Discussion

- Some key discussions about the classification of RA severity could be moved up to the design section to support the reasons for using the dosage of medications to categorise the severity (instead of using other methods).

- In the earlier section, the authors stated that this study aim was to investigate the association between rehab frequency and incidence of stroke. However, in paragraph 3 of the discussion part, a different aim was mentioned “Instead, we compared the stroke risk among different levels of RA disease severity”. Please clarify.

- According to my concern above, the interpretation of findings shown in Tables 2 and 3 may need to be changed, and the relevant changes in the discussion part may be required.

- Is there any other potential factor that may influence the association between rehab frequency and incidence of stroke such as type of rehabilitation and the length of treatment? Please also discuss.

Minor comments

- The use of different terms such as aggressive rehabilitation and intensive rehabilitation throughout the paper may be unclear to non-specialists. Please provide definitions.

- STROBE Statement—Checklist of items that should be included in reports of case-control studies

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Reviewer #2: Yes: Hoang T Phan

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11 Oct 2019

Journal Requirements:

1. The database we analyzed in this study was authorized by Taiwan National Health Insurance Administration, and could only be assessed in the Research Laboratory of our hospital. After statistical analyzing this database, the tables and figure in our manuscript are the only data we’re able to take out from the Research Laboratory. Therefore, I’m afraid that the original whole authorized database owned by our hospital cannot be provided under this circumstance.

2. Due to the anonymous nature of the national database, informed consent cannot be signed by each study subject. However, our study was still approved by the Institutional Review Board of Taichung Veterans General Hospital in Taiwan. (No. CE13152), and the ethics approval statement was included in “The Study Samples” section of “Material and Methods” in our manuscript.

Response to Reviewer #1:

Thanks for the detailed evaluation and critical comments on our study. We agree with your opinion that exercise is an important component to prevent stroke attack, especially in those with higher risk of stroke, such RA patients. We will try to reinforce this important point of view in our manuscript without overstating the presented findings. Thank you very much!

Materials and Methods:

1. We agree that the detailed content of exercise programs designed for RA patients should be mentioned in our manuscript. Since rehabilitation doctors and physical therapists in Taiwan always design exercise programs for patients according to ACSM's Guidelines for Exercise Testing and Prescription by American College of Sports Medicine, we added the following sentences in the section of “The Comorbidity Definitions, Groups Setting, and Study Design”: “As suggestions from American College of Sports Medicine, strengthening exercises are usually designed as 60-80% of 1 repetition maximum, 8-12 repetitions for 2-4 sets, 2-3 days per week, while cardiopulmonary endurance training emphasizes on exercises that maintaining the heart rate around 40-60% of heart rate reserve for an accumulation of 150 minutes per week.” We understand the concern that the rehabilitation sessions shown in our study seemed not enough to influence the risk of stroke. However, it’s just the times of rehabilitation visits recorded in the registry. During each visits, rehabilitation doctors and physical therapists in Taiwan serve as roles of reminding patients to maintain exercise trainings in their daily lives according to the suggestions from ACSM guidelines in addition to just doing exercise trainings.

2. As mentioned in our discussion, medications prescriptions in Taiwan were regulated by the rules set by Taiwan’s National Health Insurance Administration. Doctors cannot prescribe medications at their own will because National Health Insurance Administration, the single largest health insurance institution in Taiwan, will not pay for the drugs if rules are not followed. Certain criteria of disease severity should be fulfilled in order to be eligible for treatment with biologic agents, such as a Disease Activity Score (DAS 28) higher than 5.1 and treatment failure for six months using at least two kinds of DMARDs confirmed by photographic evidence and X-ray study. Therefore, we can use the medication types and dosage to classify the severity of diseases in studies utilizing the Taiwan NHI research database. Furthermore, the methods were also adopted in the past to stratify RA severity.[1]

3. We agree that the statistical adjustment information should be placed in the statistical analysis section in our manuscript. Thank you very much for reminding us!

Results:

1. In our study, we identified 663 RA patients with stroke at first, and then we tried to find the control subjects exactly matching for age, sex, and the time interval between RA and stroke diagnosis from 15,581 RA patients without stroke. However, only 642 patients could be matched in our database. After excluding patients whose time interval between RA certification and stroke index date less than 1 year, we obtained 591 RA patients with stroke and 582 RA patients without stroke in our study. There was no missing data. The numbers are not matched just because of we could not find enough patients exactly matching for age, sex and the time interval in our database.

2. Thanks for your reminding that we should be more specific here. The number of rehabilitation sessions here means the mean number of rehabilitation visits per year from the diagnosis of RA to the onset of stroke or index date. As we mentioned before, it’s just the times of rehabilitation visits recorded in the registry. During each visits, rehabilitation doctors and physical therapists in Taiwan serve as roles of reminding patients to maintain exercise trainings in their daily lives according to the suggestions from ACSM guidelines in addition to just doing exercise trainings.

3. As described in the title of table 2, the variables included in our final adjusted model are age, sex, hypertension, DM, hyperlipidemia, number of rehabilitation per year, and severity of RA. The model is like an equation “y=ax1+bx2+cx3+dx4+ex5+fx6+gx7+h”. While y is stroke, x1 to x7 are age, sex, hypertension, DM, hyperlipidemia, number of rehabilitation per year, and severity of RA, respectively. In the “Statistical Analysis” section, we described “…logistic regression analysis was conducted to determine the odds ratio of stroke based on age, sex, medical comorbidities, number of rehabilitation sessions per year, and RA disease severity with statistical adjustment for all the variables mentioned above”, which specified the variables in our final adjusted model.

Discussion:

1. We agree that the paragraph of discussion is long in its current form. However, the first paragraph summarizes the study findings, the second one discussed the method stratifying RA disease severity, the third one focused on why patients in the moderate disease severity had a higher risk of stroke, the fourth one showed the relationship between hyperlipidemia and stroke in RA patients in a past study, the fifth one discussed why exercise has protective effect in the moderate disease severity against stroke in our study, and the last one discussed the limitations of our study. After deliberate consideration, we decided to delete the four section of our discussion because the relationship between hyperlipidemia and stroke in RA patients is not the main focus of our study.

2. One of the major limitations of NHI research database is lack of lab data. As we mentioned in the discussion, many components of claims-based index for RA severity (CIRAS) such as rheumatoid factor, inflammatory markers, chemistry panels and platelet counts are not available in our registry. Instead, the advantage of our database is that the dosage of medications was available. Since medications prescriptions in Taiwan were regulated by the rules set by Taiwan’s National Health Insurance Administration, certain criteria of disease severity should be fulfilled in order to be eligible for treatment with biologic agents, such as a Disease Activity Score (DAS 28) higher than 5.1 and treatment failure for six months using at least two kinds of DMARDs confirmed by photographic evidence and X-ray study. Therefore, we can use the medication types and dosage to classify the severity of diseases in studies utilizing the Taiwan NHI research database. Furthermore, the methods were also adopted in the past to stratify RA severity.[1]

3. Thanks for noticing the interesting finding in our study, and we’ve adjusted the sentences of discussion here as: “By definition, biologic agents were only prescribed in the most severe group of RA patients in our study. Therefore, a possible reason is the anti-inflammatory effect of the biologic agents which would have reduced the likelihood of developing stroke in the most severe group in our study.…Hence, patients in the severe group, who were thought to have the highest risk of stroke, did not have a significantly higher risk compared to the mild group. On the contrary, without the potent anti-inflammatory effect of biologic agents, patients in the moderate group had a higher risk of developing stroke.”

4. Thanks for the valuable suggestion, and we’ve added the sentences below to better describe the detail of rehabilitation programs in Taiwan: “Since rehabilitation doctors and physical therapists in Taiwan always design exercise programs for patients according to ACSM's Guidelines for Exercise Testing and Prescription, the comprehensive rehabilitation programs in Taiwan regularly constitute of strengthening and aerobic parts of exercise training.”

5. We agree that more than 40 rehabilitation sessions per year cannot be considered as aggressive. Therefore, the adjectives “aggressive” or “intensive” have been avoided throughout our manuscript, and descriptions with more rehabilitation sessions are used instead.

References:

1. Tang KT, Chen YH, Lin CH, Chen DY (2016) Methotrexate is not associated with increased liver cirrhosis in a population-based cohort of rheumatoid arthritis patients with chronic hepatitis C. Sci Rep 6: 33104.

Response to Reviewer #2:

Design:

1. Thanks for the critical comment, and we also agree that risk factors of stroke such as age, sex, and medical comorbidities should all be matched between the study and control groups. However, in real world it’s essentially not possible to match these risk factors between stroke patients and non-stroke patients. In our study, we identified 663 RA patients with stroke at first, and then we tried to find the control subjects exactly matching for age, sex, and the time interval between RA and stroke diagnosis from 15,581 RA patients without stroke. However, only 642 patients could be matched in our database. If medical comorbidities including hypertension, diabetes and hyperlipidemia were to be matched in our study, the case number in the control group will be very few, rendering subsequent statistical analysis impossible and meaningless.

2. One of the major limitations of a retrospective study is the immortal time bias. However, our study avoided this bias by the nested case-control design matching the time interval between the study and control group. Another important issue is recall bias, which is also not possible to exist in our study because of the medical record registry-based in nature. About the appropriateness of the control group, we tried to match the potential confounding factors of stroke including age, sex, and the time interval between RA diagnosis and stroke. Other risk factors such as medical comorbidities were then statistically adjusted in further logistic regression models. We tried to ameliorate the disadvantage of a retrospective study by efforts mentioned above.

3. After our meticulous searching on the internet, we can still not find the reference for the cut-off times of rehabilitation sessions to be referred as intensive rehabilitation. As mentioned in our manuscript, 40 times of rehabilitation sessions per year roughly approximates to rehabilitation visits once per week after subtracting national holidays and vacations. Thank you for the critical comment, and we admit that the adjectives “intensive” or “aggressive” in our manuscript are not appropriate. Therefore, the adjectives “aggressive” or “intensive” have been avoided throughout our manuscript, and descriptions with more rehabilitation sessions are used instead.

Methods and results:

1. We’ve changed the term “hazard ratio” to “odds ratio”. Thank you very much for reminding us the important naming error.

2. Our logistic regression model is multivariate in nature. The model is like an equation “y=ax1+bx2+cx3+dx4+ex5+fx6+gx7+h”. While y is stroke, x1 to x7 are age, sex, hypertension, DM, hyperlipidemia, number of rehabilitation per year, and severity of RA, respectively. Indeed, after statistical adjustment for age, sex, medical comorbidities, number of rehabilitation sessions and severity of RA, the odds ratio of rehabilitation sessions for stroke attack did not achieve statistical significance. Only in the stratified analysis did we find significant odds ratio in the moderate severity group of RA patients.

3. The reason for us to do stratified analysis by RA severity is because we cannot find significant association between rehabilitation frequency and stroke incidence in the entire cohort we located. Since more physical activities brought by more frequent rehabilitation visits had been considered to be beneficial for stroke prevention, our study result using the entire cohort seems to be unreasonable. Therefore, stratified analysis was needed to clarify the results in the subgroups patients with RA. We also examined the interaction between number of rehabilitation sessions and severity of RA by adding their product terms into the logistic regression model (set at two-tailed p ≤0.05), which showed no significant interaction effects (P = 0.703).

Discussion:

1. We agree that some key discussions about the stratification of RA severity should be moved to the design section for better delineating the reason why we used the dosage of medications to categorize the severity. Therefore, the following paragraphs have been added in the design section: “The advantage of our database is that the dosage of medications was available. Since medications prescriptions in Taiwan were regulated by the rules set by Taiwan’s NHI Administration, certain criteria of disease severity should be fulfilled in order to be eligible for treatment with biologic agents. Therefore, we can use the medication types and dosage to classify the severity of diseases in studies utilizing Taiwan’s NHIRD.”

2. The third section of discussion focused on why patients in the moderate disease severity had a higher risk of stroke. Because the relationship between RA and stroke has been thoroughly studied in the past, comparing the stroke risk among different level of RA disease severity serves as a minor aim of our study. The major aim of this study is still the association between times of rehabilitation sessions and stroke incidence. Relevant changes have been made in our discussions.

3. We agree that different types, intensity and durations of exercise incorporated in the rehabilitation sessions may influence the incidence of stroke. However, the information of detailed exercise programs mentioned above cannot be obtained in the database we used. Nevertheless, rehabilitation doctors and physical therapists in Taiwan always design exercise programs for patients according to ACSM's Guidelines for Exercise Testing and Prescription, and the comprehensive rehabilitation programs in Taiwan regularly constitute of strengthening and aerobic parts of exercise training. We’ve added the above sentences in the discussion paragraph, and relevant details from American College of Sports Medicine were added in the design section.

Minor comments:

1. We admit that the adjectives “intensive” or “aggressive” in our manuscript are not appropriate. Therefore, the adjectives “aggressive” or “intensive” have been avoided throughout our manuscript, and descriptions with more rehabilitation sessions are used instead.

2. We will provide the STROBE checklist as a supplemental file. Thank you very much for your valuable suggestions.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

11 Nov 2019

PONE-D-19-22440R1

The Impact of Rehabilitation Frequency on the Risk of Stroke in Patients with Rheumatoid Arthritis

PLOS ONE

Dear Mr. Lin,

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Reviewers' comments:

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Comments to the Author

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Reviewer #2: (No Response)

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Reviewer #2: Yes

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Reviewer #2: No

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Reviewer #2: Design:

1. The authors explained that “If medical comorbidities including hypertension, diabetes and hyperlipidemia were to be matched in our study, the case number in the control group will be very few, rendering subsequent statistical analysis impossible and meaningless.”

Response: Please acknowledge this study limitation in the discussion explaining why two groups were matched only for age, sex, and the time interval between RA and stroke diagnosis but not for comorbidities/other factors (e.g. lower statistical power).

Methods and results:

2. The authors explained that “Our logistic regression model is multivariate in nature. The model is like an equation “y=ax1+bx2+cx3+dx4+ex5+fx6+gx7+h”. While y is stroke, x1 to x7 are age, sex, hypertension, DM, hyperlipidemia, number of rehabilitation per year, and severity of RA, respectively.”

Response: Multivariable models should be mentioned in Tables 2 and 3 (in table legends or using footnotes)

3. “The reason for us to do stratified analysis by RA severity is because we cannot find significant association between rehabilitation frequency and stroke incidence in the entire cohort we located. Since more physical activities brought by more frequent rehabilitation visits had been considered to be beneficial for stroke prevention, our study result using the entire cohort seems to be unreasonable. Therefore, stratified analysis was needed to clarify the results in the subgroups patients with RA.”

Response: So the stratified analysis is more likely to be an ad-hoc analysis which you had not thought about upfront. This was because significant association between rehabilitation frequency and stroke incidence in the entire cohort was observed. To facilitate the readers, I would suggest acknowledge the main findings and clarify the reason for undertaking the ad-hoc analysis and its results in the results section

Discussion

3. “We agree that different types, intensity and durations of exercise incorporated in the rehabilitation sessions may influence the incidence of stroke. However, the information of detailed exercise programs mentioned above cannot be obtained in the database we used. Nevertheless, rehabilitation doctors and physical therapists in Taiwan always design exercise programs for patients according to ACSM's Guidelines for Exercise Testing and Prescription, and the comprehensive rehabilitation programs in Taiwan regularly constitute of strengthening and aerobic parts of exercise training”

Response: Please also acknowledge this limitation in the discussion section. Further research to address this gap may inform the current guidelines.

**********

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Reviewer #2: Yes: Hoang Phan

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17 Nov 2019

1. Thanks for the critical comment that it should be an important limitation in our study. We thus added the following sentences in our paragraph of study limitations in the discussion (Page 16 Line 284): “Third, while medical comorbidities including hypertension, diabetes and hyperlipidemia are important contributing factors of stroke, only statistical adjustments were done instead of matching. The reason lies in that if these medical comorbidities in our study were all matched, the case number in the control group will be very few, rendering subsequent statistical analysis impossible and meaningless. Therefore, only age, sex, and the time interval between RA and stroke diagnosis were statistically matched between the two study groups.”

2. We added “in the multivariate logistic regression analysis” in the table legends of Table 2 (Page 10 Line 189) and Table 3 (Page 11 Line 192). Thanks for your kindly reminding.

3. We revised our manuscript in the result section (Page 10 Line 178) as following: “…RA patients receiving more rehabilitation sessions did not have a significant reduction in risk of stroke attack (odds ratio=0.66, p=0.061). The results are shown in Table 2. Since physical activities brought by more frequent rehabilitation visits had been considered to be beneficial for stroke prevention, the result above seems to be unreasonable. Therefore, further stratified analysis on the effect of rehabilitation frequencies was done according to the disease severity.” Thanks for your valuable suggestion!

4. Thanks for your valuable advice, and we admit that it’s also one important limitation of our study. Therefore, the following sentences were added in our study limitations of discussion (Page 16 Line 299): “…Finally, the type, intensity, frequency and duration of exercise incorporated in the rehabilitation sessions may influence the incidence of stroke. However, the information of detailed exercise programs mentioned above cannot be obtained in the database we used. Therefore, further prospective study to address this gap is needed in the future.” Thanks again for your detailed review and critical comments on our study!

Submitted filename: Response to Reviewer2.docx

Click here for additional data file.

5 Dec 2019

PONE-D-19-22440R2

The Impact of Rehabilitation Frequency on the Risk of Stroke in Patients with Rheumatoid Arthritis

PLOS ONE

Dear Mr. Lin,

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PLOS ONE

Journal Requirements:

Additional Editor Comments:

Thank you for your revisions. Please amend the term 'multivariate' to 'multivariable'. The latter is the correct statistical term for this type of analysis.

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Reviewers' comments:

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13 Dec 2019

We’ve amended the term “multivariate” to “multivariable” in our manuscript. Thank you for the critical suggestion!

Submitted filename: Response to Reviewer3.docx

Click here for additional data file.

20 Dec 2019

The Impact of Rehabilitation Frequency on the Risk of Stroke in Patients with Rheumatoid Arthritis

PONE-D-19-22440R3

Dear Dr. Lin,

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Reviewers' comments:

30 Dec 2019

PONE-D-19-22440R3

The Impact of Rehabilitation Frequency on the Risk of Stroke in Patients with Rheumatoid Arthritis

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