Abstract
Objectives
To assess the efficacy of tocilizumab (TCZ) in the treatment of persistent arthritis in patients with rheumatoid arthritis (RA).
Methods
The response to TCZ was evaluated in 304 patients with RA. TCZ treatment was completed after no fewer than 168 consecutive days between 28 May 2008 and 31 July 2019. Efficacy was evaluated using the DAS28-ESR and EULAR response criteria.
Results
The mean DAS28-ESR decreased from 4.5 at baseline to 2.0 and 1.5, at 2 months and 1 year after treatment initiation, respectively, and was below 1.5 at 10 years. The retention rate within 1 year was 92.3%. TCZ re-administration to 74 patients with relapsed RA after TCZ withdrawal was also effective. The mean DAS28-ESR decreased from 4.4 at baseline to 1.8 and 1.6 at 2 months and 1 year after retreatment initiation, respectively. The mean swollen joint count decreased from 4.1 in initial TCZ administration and 2.8 in re-administration at baseline to 0.8 and 0.4 at 2 months, respectively. In all patients, good or moderate responses were achieved at least once within 12 months in both initial TCZ administration and re-administration.
Conclusion
TCZ efficiently ameliorated persistent arthritis in RA, regardless of initial administration and re-administration.
Introduction
The characteristic pathophysiology in rheumatoid arthritis (RA) is the destruction of bone and cartilage due to persistent synovitis. This persistent inflammatory state is mediated by inflammatory cytokines which stimulate immunocytes and fibroblast-like synoviocytes (FLSs). Once stimulated, immunocytes and FLSs proliferate, increasing the production of inflammatory cytokines, resulting in the formation of a positive feedback loop in inflamed joints.
To date, it remains unclear how classical disease-modifying antirheumatic drugs (DMARDs) affect the pathological mechanism of RA at the molecular level. With the advent of cytokine-specific antibodies, we can investigate the involvement of particular cytokines in inflammation in actual patients with RA.
From 2001 to 2008, clinical trials of tocilizumab (TCZ), an anti-interleukin-6 (IL-6) receptor antibody, such as SAMURAI [Citation1], SATORI [Citation2], and STREAM [Citation3], were performed in Japan. Of these trials (more than 20), for patients with RA at Tohoku University Hospital, inefficacy of TCZ was not observed. This raised the question of whether TCZ can definitively stop the disease process; in other words, it is unclear as to whether IL-6 signaling is essential for sustaining the positive feedback loop of joint inflammation in RA. The main aim of this study was to answer to this question, not to comprehensively evaluate the efficacy of TCZ or to compare the relative merits of TCZ to those of other drugs. The author performed a retrospective review of the efficacy of TCZ for the treatment of RA in 304 patients, with a follow-up of 10 years.
Patients and methods
Patients
Eligible patients met the 1987 revised RA classification criteria from the American College of Rheumatology and were treated with TCZ in real clinical practice for not less than 168 consecutive days (24 weeks), between 28 May 2008, and 31 July 2019. Patients with overlap syndrome (RA with other concomitant autoimmune diseases) were not included, as the aim was to evaluate the efficacy of TCZ for RA. For safety, patients were screened according to the guidelines of the Japan College of Rheumatology. To the extent possible, all relevant comorbidities were treated or controlled for, before and during TCZ administration, to avoid unnecessary production of IL-6 and to decrease adverse events (AEs). For smokers, complete cessation of smoking was a pre-condition for TCZ therapy. Patients received TCZ either intravenously, at a dose of 8 mg/kg every 4 weeks, or subcutaneously, at a dose of 162 mg every 2 weeks, which is the dosage permitted by the health insurance in Japan. The posology of TCZ was not intentionally changed during the treatment.
Study protocol
The tender joint count (TJC), swollen joint count (SJC), patient global assessment-visual analog scale (PGA-VAS), erythrocyte sedimentation rate (ESR), and serum levels of C-reactive protein (CRP) and matrix metalloproteinase-3 (MMP-3) were assessed at the following points: the first TCZ dose (day 0); at 1 month (day 28 ± 10), 2 months (day 56 ± 10), 3 months (day 84 ± 15), and 6 months (day 168 ± 15) after treatment initiation; and subsequently, on a yearly basis at 1 year (365 ± 30 days), 2 years (730 ± 30 days), 3 years (1095 ± 30 days), 4 years (1460 ± 30 days), 5 years (1825 ± 30 days), 6 years (2190 ± 30 days), 7 years (2555 ± 30 days), 8 years (2920 ± 30 days), 9 years (3285 ± 30 days), and 10 years (3650 ± 30 days). Based on these outcome measures, the 28-joint disease activity score using ESR (DAS-28ESR) was calculated [Citation4]. In case of interruption of TCZ therapy, if the interval of TCZ dose exceeded 70 days, data within 60 days after TCZ re-administration were not included ( and ). In TCZ re-administration, the above-mentioned outcome measures were assessed at day 0, 1 month (day 28 ± 10), 2 months (day 56 ± 10), 3 months (day 84 ± 15), 6 months (day 168 ± 15), and 1 year (365 ± 30 days) (). Response to TCZ was assessed using the European League against Rheumatism (EULAR) response criteria at 1, 2, 3, 6, and 12 months, as usual [Citation5]. Besides, response values were calculated as the decrease from the initial DAS-28ESR to the best DAS28-ESR value among the measured values at 1, 2, 3, 6, and 12 months.
Figure 1. Changes in clinical parameters of disease activity among all patients, from the disease onset start to 1 year. (a) Tender joint count (TJC), (b) swollen joint count (SJC), (c) patient global assessment-visual analog scale (PGA-VAS), (d) erythrocyte sedimentation rate (ESR), (e) Disease Activity Score-28 (DAS28-ESR), (f) C-reactive protein (CRP), (g) matrix metalloproteinase-3 (MMP-3) in women, and (h) MMP-3 in men. The broken line indicates the value of MMP-3 in the patients using corticosteroids at baseline (g, h). The solid line indicates the value of MMP-3 in the patients not using corticosteroids at baseline (g, h). –n: the number of patients not using corticosteroids. +n: the number of patients using corticosteroids. psl: the mean daily average reduced dose of prednisolone (mg/day). Mean values are shown, with bars indicating the +1 standard deviation (SD). The dotted line indicates upper limit of normal value.
Figure 2. Changes in clinical parameters of disease activity in all patients from start to 10 year. (a) tender joint count (TJC), (b) swollen joint count (SJC), (c) patient global assessment-visual analog scale (PGA-VAS), (d) erythrocyte sedimentation rate (ESR), (e) Disease Activity Score-28 (DAS28-ESR), (f) C-reactive protein (CRP), (g) matrix metalloproteinase-3 (MMP-3) in women, and (h) MMP-3 in men. Mean values are shown, with bars indicating the +1 standard deviation (SD). The dotted line indicates upper limit of normal value.
Figure 3. Changes in clinical parameters of disease activity from retreatment initiation to 1 year in patients whose DAS28ESR was not less than 2.6 at TCZ re-administration. (a) Tender joint count (TJC), (b) swollen joint count (SJC), (c) patient global assessment-visual analog scale (PGA-VAS), (d) erythrocyte sedimentation rate (ESR), (e) Disease Activity Score-28 (DAS28-ESR), (f) C-reactive protein (CRP), and (g) matrix metalloproteinase-3 (MMP-3) in women. The broken line indicates the value of MMP-3 in women using corticosteroids at restarting TCZ (g). The solid line indicates the value of MMP-3 in women not using corticosteroids at restarting TCZ (g). –n: the number of patients not using corticosteroids. +n: the number of patients using corticosteroids. psl: the mean daily average reduced dose of prednisolone (mg/day). (h) Changes in DAS28ESR from the start of retreatment to 1 year in patients whose DAS28ESR was <2.60 at restart. Mean values are shown, with bars indicating the +1 SD. The dotted line indicates upper limit of the normal value.
The study was a retrospective observational nonintervention study that was approved by the Ethics Committee of Hikarigaoka Spellman Hospital (20181019) and carried out in compliance with the Helsinki Declaration. No formal consent was required, in accordance with the ‘Ethical guidelines for epidemiological study’ by Ministry of Health, Labour and Welfare, Japan.
Results
Efficacy of initial TCZ treatment
The demographics and clinical characteristics of 304 patients at baseline are summarized in . Concomitant corticosteroids and DMARDs at each evaluation point are shown in . At day 0, 192 (63%) patients were treated with corticosteroids at a mean dose of 4.4 mg/day as the average reduced dose of prednisolone. When the dose of corticosteroids was more than 5 mg/day, it was gradually tapered to 5 mg/day. Thereafter, it was decreased at the rate of about 1 mg per year to avoid adrenal insufficiency. Sometimes, corticosteroids was not tapered to less than around 3 mg/day in elderly patients more than 70 years old and in patients with allergic diseases. In such patients, corticosteroids withdrawal depends on a case-by-case basis. Small doses of corticosteroids were transiently combined within several months in a few patients when arthralgia/arthritis worsened during remission. The ratio of patients using corticosteroids and the dose of corticosteroids decreased with the lapse of time. At 1 year, the ratio and the dose decreased to 33% and 3.7 mg/day, respectively. After 1 year, the dose hovered around 3.3 mg/day while the ratio decreased little by little. At day 0, 34 (11%) and 4 (1%) patients were treated with MTX and tacrolimus at a mean dose of 5.9 mg/week and 1.4 mg/day, respectively. Both drugs were tapered off within 6 months. Other DMARDs were not used during TCZ treatment. After 6 months, most patients received TCZ monotherapy.
Table 1. Baseline characteristics of the patients.
Table 2. Concomitant corticosteroids and disease-modifying antirheumatic drugs at each evaluation point.
The results within one year from the beginning principally indicate the efficacy of TCZ in suppression of disease activity ( and ), while the results during 10 years principally indicate the efficacy of TCZ in preventing disease flares (). The mean (± standard deviation, SD) TJC decreased from 4.2 ± 4.9 at day 0, to 0.6 ± 1.9 at 3 months (mean ≤1). The TJC decreased further to 0.1 ± 0.7 (mean + SD ≤ 1) at 2 years, with the TJC being ≤1 in about 68% of patients in the study group. At 5 years, the TJC was 0.1 ± 0.2 (mean + 2 × SD ≤1), with about the TJC being ≤1 in about 95% of patients ( and ). The mean SJC decreased more rapidly than the TJC, from an initial score of 4.1 ± 3.8 (day 0) to 0.8 ± 1.5 (mean ≤1) at 2 months, 0.2 ± 0.6 (mean + SD ≤1) at 6 months, and 0.1 ± 0.4 (mean + 2 × SD is ≤1) at 2 years ( and ). The mean PGA-VAS decreased from 47.8 ± 25.3 at day 0 to 16.8 ± 18.7 at 6 months, and remaining stable around 15 mm, thereafter ( and ). The mean ESR decreased quickly from baseline levels of 38.6 ± 26.0 (day 0), remaining stable around 10 mm/1 h after 1 month ( and ). Consequentially, the mean DAS28-ESR score decreased from 4.5 ± 1.3 at day 0 to 2.58 ± 1.2 at 1 month, meeting the DAS28-ESR criteria for RA remission. The DAS28-ESR decreased further to 1.7 ± 0.9 (mean + SD <2.6) at 3 months, remaining stable around 1.4, thereafter ( and ). The mean CRP was decreased from 1.51 ± 2.08 mg/dl (day 0) to within normal range (<0.3 mg/dl) after 1 month, and thereafter ( and ).
Table 3. EULAR response rate, disease activity, and DAS28ESR variables at time points.
As serum levels of MMP-3 are affected by several factors, including sex and corticosteroids, serum levels of MMP-3 were stratified by sex and corticosteroids use. The mean MMP-3 in women using corticosteroids at baseline (abbreviated as w+) and in women not using corticosteroids (abbreviated as w–) were 189.3 ± 226.9 ng/ml and 189.4 ± 237.1 ng/ml, respectively, at day 0 (). The mean MMP-3 in w + and in w– decreased to 68.4 ± 49.0 ng/ml and 59.1 ± 80.1 ng/ml, respectively, after 1 year. Mean MMP-3 levels in men using corticosteroids at baseline (abbreviated as m+) and in men not using corticosteroids (abbreviated as m–) were 299.8 ± 218.4 ng/ml and 272.2 ± 246.4 ng/ml, respectively, at day 0 (). The mean MMP-3 in m + and in m– decreased to 180.0 ± 86.2 ng/ml and 86.2 ± 32.1 ng/ml, respectively, after 1 year.
Response to TCZ was assessed using the EULAR response criteria in 300 patients (). Of the 304 treated patients, four (one whose DAS28ESR at day 0 was not assessed, three who had no symptoms and a day 0 DAS28-ESR of <1.3) were excluded. Usually, EULAR response is calculated by comparing the DAS28 value at each evaluation point to the initial DAS28 value. However, when the DAS28 value is exacerbated by AEs, such patients were falsely classified as ‘no response’ though RA did not apparently worsen. Then, in addition to the usual method (the points at 1, 2, 3, 6, and 12 months in ), response values were calculated as decreases from the initial DAS28 to the best DAS28 value among the measured values at 1, 2, 3, 6, and 12 months (# in ). In this situation, among the 48 patients who had an initial DAS28-ESR ≤3.2, including the 21 patients who had an initial DAS28-ESR <2.6, a good response was achieved in 41 patients and a moderate response in 7. The maximum, median and minimum best response values were 2.9, 2.0, and 0.7, respectively. All 252 patients whose initial DAS28-ESR was >3.2 achieved a moderate response. The maximum, median and minimum best response value were 8.0, 3.4, and 0.7, respectively. In 298 of 300 patients, good or moderate responses were achieved at least once within 6 months.
In total, 304 patients were followed up, and the treatment period in six patients was less than 1 year. Among 298 patients, the 1-year retention rate was 92.3%. The reasons for discontinuation and number of patients were as follows: change of address or medical institution, 5; AEs, 7; senility, 1; wish to terminate due to remission, 6; pregnancy, 2; and not coming, 2. No patient withdrew due to inadequate response (IR), which corresponds to # in .
Efficacy of TCZ retreatment
TCZ was re-administered after more than 70 withdrawal days in 85 patients. These patients were considered as retreated cases in this study. The reasons for TCZ cessation were complete remission, AEs, or others. After cessation of TCZ, the patients were under antirheumatic drug-free condition during remission. Corticosteroids were not discontinued at cessation of TCZ if it was used. In 74 patients, the DAS28-ESR at TCZ re-administration was not <2.6. The mean TJC decreased from 2.7 ± 3.0 at day 0 to 0.2 ± 0.6 (mean + SD ≤1) at 2 months. At 3 months, the TJC was 0.1 ± 0.2 (mean + 2 × SD ≤1), with the TJC ≤1 in approximately 95% of patients (). The mean SJC decreased from an initial score of 2.8 ± 2.9 (day 0) to 0.4 ± 0.7 (mean ≤1) at 2 months, 0.2 ± 0.5 (mean + SD ≤1) at 3 months, and 0.1 ± 0.3 (mean + 2 × SD is ≤1) at 6 months (). The mean PGA-VAS decreased from 50.2 ± 31.9 at day 0 to 12.9 ± 20.4 at 12 months gradually (). The mean ESR decreased quickly from baseline levels of 47.5 ± 28.3 (day 0) and remained stable at <10 mm/1 h after 2 months (). Consequentially, the mean DAS28-ESR score decreased from 4.4 ± 1.2 at day 0 to 1.8 ± 0.9 at 2 months, meeting the DAS28-ESR criteria for RA remission. The DAS28-ESR decreased further to 1.6 ± 0.7 (mean + SD <2.6) at 3 months and 1.3 ± 0.7 at 12 months (). The DAS28ESR remission rate rapidly increased and reached 90% at 3 months. The rate in TCZ retreatment cases improved similarly to the rate in initial TCZ treatment cases (). The Boolean remission rate also well improved and reached 60% and 70% at 3 months and at 1 year, respectively. The rate in TCZ retreatment exceeded the rate in initial TCZ treatment cases ().
Figure 4. Comparison of changes in (a) DAS28ESR remission rate and (b) Boolean remission rate in initial TCZ treatment cases (solid line) and TCZ retreatment cases (dotted line).
The mean CRP decreased from 1.6 ± 2.1 mg/dl (day 0) to within the normal range (<0.3 mg/dl) after 1 month and thereafter (). The mean MMP-3 levels in women using corticosteroids at restarting TCZ (abbreviated as wr+) and in women not using steroid (abbreviated as wr–) were 148.7 ± 162.3 ng/ml and 197.4 ± 211.9 ng/ml, respectively, at day 0 (). The mean MMP-3 levels in wr + and in wr– decreased to 56.1 ± 55.5 ng/ml and 44.2 ± 38.9 ng/ml, respectively, after 1 year. MMP-3 levels of men are not shown because the total number of retreated male patients was only 10.
At TCZ re-administration, 11 patients had DAS28-ESR <2.6. The mean DAS28-ESR score improved from 1.8 ± 0.4 at day 0 to 1.1 ± 0.5 at 1 month, remaining stable around 1.1 thereafter (). RA flare was not observed.
The EULAR response was assessed in a total of 82 patients (). Three patients who had no symptoms and day 0 DAS28-ESRs of <1.5 at TCZ re-administration were excluded from the 85 retreated patients. Among the 22 patients who had an initial DAS28-ESR ≤3.2, including the eight patients who had an initial DAS28-ESR <2.6, good responses were achieved in 13 patients and moderate responses in 9 patients. All 60 patients whose initial DAS28-ESR was >3.2 achieved moderate responses. In all 82 patients, good or moderate responses were achieved at least once within 6 months. Overall, the efficacy of TCZ retreatment was equal to that of the initial TCZ treatment.
Discussion
The mechanism of the positive feedback loop for persistent synovitis of RA has been clarified [Citation6]. In this positive feedback loop, IL-6 stimulates FLS to produce IL-7. Subsequently, IL-6 and IL-7 collaboratively activate Th17 cells, resulting in IL-6 and IL-17 production. Moreover, IL-6 and IL-17 then collaboratively stimulate FLS further, thereby inducing the reproduction of IL-6. In addition, IL-17 induces resistance to endoplasmic reticulum stress-induced apoptosis in FLS, thereby contributing pannus formation [Citation7]. Platelets can be considered as an alternative pathway for IL-6 reproduction. IL-6 stimulates the production and activation of platelets [Citation8,Citation9]. Microparticles released from activated platelets, in turn, prominently induce the release of IL-6 and IL-8 from FLS [Citation10]. Either way, IL-6 is a key component of the positive feedback loop.
The contributing factors to this positive feedback loop can be grouped into three categories: (a) continuous stimulation of the loop – ‘accelerator’; (b) continuous maintenance of the loop – ‘frictional resistance’; and (c) breakdown of the intrinsic system, which halts the loop – ‘decelerator’. ‘Frictional resistance’ may correspond with regulation of IL-6 synthesis, shared epitope, etc. [Citation11, Citation12]. An example of a ‘decelerator’ is SOCS1 or SOCS3 [Citation13]. Factors contributing to frictional resistance (b) and deceleration (c) of the loop cannot be modified at present, although accelerator (a) factors can be modified in clinical practice [Citation14]. Minimizing an undesirable production of inflammatory cytokines is important for reducing accelerator factors. The following are essential considerations in achieving this therapeutic goal. First, all comorbidities should be treated or controlled to the extent possible. Common adult diseases (diabetes mellitus, hypertension, hyperlipidemia, hyperuricemia, etc.) were treated to normalize the disorder. All patients were recommended at least to participate in the municipal cancer screening program. Especially, chronic infections must be treated [Citation15]. For example, the patients who have not had regular dental examinations were strongly recommended to go to the dentist, and abnormalities of the oral cavity such as periodontal diseases or dental caries were treated. Patients with suspected sinusitis and hemorrhoid/anal fistula were referred to otolaryngologists and proctologists, respectively. Second, complete cessation of smoking must be maintained as smoking induces the production of inflammatory cytokines in the lungs, as well as reducing the efficacy of anti-rheumatic drugs [Citation16]. Third, maintaining an ideal body weight is important, as enlarged adipocytes produce IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1 [Citation17]. The body mass index (BMI) at baseline was 22.0 ± 3.6 in women and 22.8 ± 3.3 in men (). It was reported that the value of BMI associated with the lowest morbidity of 10 medical problems (lung disease, heart disease, upper gastrointestinal disease, hypertension, renal disease, liver disease, hyperlipidemia, hyperuricemia, diabetes mellitus, and anemia) was 21.9 kg/m2 in women and 22.2 kg/m2 in men in a Japanese cohort [Citation18]. Hence, the BMI at baseline were appropriate for reducing complications. During TCZ treatment, all patients were requested to keep or get ideal body weight as possible. In the case of TCZ, a minimum effective blood concentration of TCZ >1 µg/ml has previously been suggested [Citation19]. However, a dose of 8 mg/kg intravenously every 4 weeks or 162 mg subcutaneously every 2 weeks is not sufficient to elevate the blood concentration of TCZ to 1 µg/ml in some patients [Citation20]. Since TCZ inhibits the IL-6 signaling by competitive inhibition with IL-6 against IL-6 receptor, minimizing the production of IL-6 through the above-mentioned approaches is important to promote the therapeutic benefit of TCZ.
A previous study reported that SJC and ESR, but not TJC, PGA-VAS and CRP, are associated with radiographic progression of RA [Citation21]. This is reasonable because in principal joint swelling is caused by joint inflammation. The ESR is more sensitive to change of RA activity than the CRP [Citation22]. IL-6 is strongly correlated to SJC at baseline, with the time-integrated value of IL-6 being strongly correlated to SJC and joint destruction [Citation23]. Earlier achievement of SJC ≤1 resulted in better outcomes in actual clinical practice [Citation24]. These suggest that the most important items for assessment of joint inflammation are SJC and ESR. In the current study, SJC and ESR were maintained at a low level with initial TCZ treatment, with the mean ESR being <10 mm/1 h and mean SJC <1 after 2 months. In fact, the mean SJC + SD was <1 after 6 months. Achieving this SJC level at 6 months may be an appropriate goal to achieve long-term structural remission [Citation24]. In this study, the progression of bone destruction could not be examined by the Sharp score. Instead, the MMP-3 level was measured as a surrogate marker of bone destruction. The levels of MMP-3 within 1 year in women using corticosteroids at baseline or at restarting TCZ (w + and wr+) were slightly higher than levels in those not using corticosteroids (w– and wr–) ( and ). The levels of MMP-3 within 1 year in men using corticosteroids at baseline (m+) were higher than those in patients not using corticosteroids (m–) (); however, this result was uncertain because the number of male patients was small. On the other hand, in the patients not using corticosteroids (w–, wr–, and m–), the mean MMP-3 decreased rapidly to the upper limit of normal range within 2 months. After 1 year, the levels of MMP-3, not stratified by corticosteroids use, were maintained around the upper limit of normal range until 10 years after, for both men and women (). Normalization of the MMP-3 level is thought to reflect inhibition of pathologic bone destruction. In practice, joint deformity was not observed by physical examination during TCZ treatment in patients who received TCZ before the onset of joint deformity. Further imaging study of joints will be necessary to confirm the results.
Even if TCZ was re-administered to patients who had an RA flare, all outcome measures (TJC, SJC, PGA-VAS, ESR, CRP, and MMP-3) were rapidly improved. These results were compatible with those in a previous report [Citation25]. The efficacy of TCZ retreatment was comparable to that of initial TCZ treatment.
In previous reports, good + moderate EULAR response rates at 24 weeks (6 months) were 84% [Citation26], 77.9% [Citation27], and 86.1% [Citation28], while it was 98.2% in initial treatment and 100% in retreatment in this study. When response values were calculated as the decrease from the initial DAS28 to the best DAS28 value among the measured values at 1, 2, 3, 6, and 12 months (# in ), good or moderate responses were achieved in all patients at any of the assessment points in both initial TCZ administration and re-administration. This is consistent with the fact that no patient withdrew because of IR. BMI did not affect responses to TCZ, compatible with findings of a previous report [Citation29]. Possible reasons why the results in this study were better than those of previous reports [Citation26–28] include countermeasures for comorbidities and primary self-care including complete cessation of smoking and maintaining an ideal body weight. These must contribute to reduce AEs or unnecessary production of IL-6 which interfere with the efficacy of TCZ.
In conclusion, TCZ was effective regardless of the baseline characteristics of the patients, supporting the evidence that no predictive parameters for induction of RA remission have been identified among patients treated using TCZ [Citation30]. IL-6 may play a critical role in sustaining joint inflammation in RA. In other words, if the IL-6 signal transduction in inflamed joints is completely inhibited, arthritis may be certainly eradicated.
Acknowledgements
The author thanks Editage (www.editage.jp) for English language editing.
Conflict of interest
YH has received speaking fees from Chugai.
Additional information
Funding
References
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