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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To investigate the relationship between synovial vascularity and progression of structural bone damage in each finger joint in patients with rheumatoid arthritis (RA) and to demonstrate synovial vascularity as a potential therapeutic marker.

Methods

We studied 250 metacarpophalangeal (MCP) and 250 proximal interphalangeal (PIP) joints of 25 patients with active RA who were administered adalimumab or tocilizumab. Patients were examined with clinical and laboratory assessments. Power Doppler sonography was performed at baseline and at the fourth and eighth weeks. Synovial vascularity was evaluated according to quantitative measurement. Hand and foot radiography was performed at baseline and the twentieth week.

Results

Clinical indices such as the 28-joint Disease Activity Score, the Clinical Disease Activity Index, and the Simplified Disease Activity Index were significantly decreased by biologic agents. The MCP and PIP joints with no response in synovial vascularity between baseline and the eighth week (vascularity improvement of ≤70% at the eighth week) showed a higher risk of radiographic progression compared with responsive joints (vascularity improvement of >70% at the eighth week; relative risk 2.33–9). Radiographic progression at the twentieth week was significantly lower in responsive joints than in nonresponsive joints.

Conclusion

The improvement of synovial vascularity following treatment with biologic agents led to suppression of radiographic progression of RA in each finger joint. The alteration in synovial vascularity numerically reflected therapeutic efficacy. Using vascularity as a marker to determine the most suitable therapeutic approach would be beneficial for patients with active RA.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Several biologic agents against rheumatoid arthritis (RA) have been developed for clinical application in the last decade. For clinical trials and/or clinical practice, clinical indices such as the American College of Rheumatology (ACR) core data set or the European League Against Rheumatism (EULAR) 28-joint Disease Activity Score (DAS28) (1, 2) have been utilized as markers of disease activity. Although those general comprehensive markers have been well established, neither the ACR core data set nor the DAS28 predict precisely the destruction of each individual joint. Brown et al reported that some joints with poor prognosis were detected in an individual patient, even if systemic improvement had been obtained (3). Considering that one of the current goals of treatment for RA is to prevent joint destruction (radiologic remission), establishing new markers to reflect local inflammation precisely and predict bone destruction in each joint have been the subjects of enthusiastic research.

Appearance and increase of synovial vascularity related to vasodilation and angiogenesis indicate active joint inflammation (4). Power Doppler sonography (PDS) enables the visualization of synovial vascularity and has the ability to represent local inflammation numerically (5). PDS has been reported as a useful tool to detect arthritis in the early stages and monitor disease activity (6, 7). PDS has been studied as a clinical device having the potential to provide supplemented joint information in clinical practice (8, 9). While 4-graded semiquantitative scoring has been widely used to evaluate synovial vascularity, we previously established quantitative measurement of joint PDS that enables the detection of detailed changes in local finger joints (10). In this study, we used quantitative PDS to investigate the relationship between synovial vascularity and bone destruction for patients treated with disease-modifying antirheumatic drug (DMARD) therapy. The results showed that improvement in synovial vascularity in response to DMARDs leads to suppression of radiographic progression in each local finger joint. To extend our previous findings, we focused on biologic agent therapies that were more drastic in their control of joint inflammation than DMARDs. In this study, we investigated a potential relationship between synovial vascularity and bone destruction during therapy with 2 different biologic agents, adalimumab (ADA) or tocilizumab (TCZ).

Significance & Innovations

  • In clinical practice recommendations for treatment of rheumatoid arthritis, tight control of disease activity would lead to better joint prognosis.

  • Accurate and direct markers of the joint inflammation are essential for tight control of disease activity in place of traditional composite clinical indices.

  • Synovial vascularity reflects local joint inflammation. The early alteration in synovial vascularity by antirheumatic therapy has potential to be a therapeutic marker of joint destruction. Using synovial vascularity as a guide to make therapeutic decisions could be possible in the near future.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Patients.

Twenty-five patients with RA who had ADA or TCZ therapies were enrolled. All patients satisfied the ACR 1987 revised criteria for the classification of RA (11). The patients had been pretreated with DMARDs (ADA group: 6 patients with methotrexate [MTX], 1 patient with tacrolimus [TAC], 1 patient with bucillamine [BUC] + TAC, and 1 patient with MTX + TAC; TCZ group: 8 patients with MTX, 1 patient with BUC, and 1 patient with TAC) or pretreated with biologic agents (ADA group: 1 patient with MTX + infliximab [IFX]; TCZ group: 3 patients with MTX + IFX, 1 patient with MTX + etanercept, and 1 patient with MTX + ADA). Despite these pretreatments, all patients had at least 1 swollen joint of the metacarpophalangeal (MCP)/proximal interphalangeal (PIP) joints and showed a DAS28–erythrocyte sedimentation rate (ESR) of >2.7 mm/hour. Demographic, clinical, and laboratory characteristics of the patients are shown in Table 1. After baseline examinations, ADA was given to 10 patients and TCZ to 15 patients. The biologic agents were given according to the standard protocols (ADA 40 mg subcutaneous injection biweekly, TCZ 8 mg/kg intravenous infusion every 4 weeks). Biologic agent therapies were continued throughout the study. None of the patients received an additional or escalating dose of DMARDs or steroid after the eighth week in the study. We performed clinical and imaging examinations as described in each section.

Table 1. Clinical and laboratory characteristics of patients at baseline*
 AdalimumabTocilizumabAll
  • *

    Values are the median (interquartile range) unless otherwise indicated. ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; VAS = visual analog scale; DAS28 = 28-joint Disease Activity Score; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index.

Age, mean (range) years52 (30–69)57 (34–75)55 (30–75)
Sex, no. female/male10/014/124/1
Duration of symptoms, months78 (42–225)96 (51–144)78 (48–150)
ESR, mm/hour39 (23–52)55 (35–69)48 (33–64)
CRP level, mg/dl0.29 (0.08–0.69)1.77 (0.53–2.9)0.66 (0.22–2.48)
Swollen joint count3 (2–5)5 (3–6)4 (2–6)
Tender joint count4 (2–9)7 (4–10)6 (3–9)
Patient's global assessment by VAS57 (41–76)65 (40–74)64 (40–75)
Examiner's global assessment by VAS45 (40–75)50 (33–70)50 (35–70)
DAS28-ESR, mean ± SD5.27 ± 1.215.34 ± 1.135.31 ± 1.14
CDAI, mean ± SD22.6 ± 10.423 ± 11.822.8 ± 11.1
SDAI, mean ± SD23.3 ± 10.724.9 ± 12.124.3 ± 11.4

The study was conducted in accordance with the Helsinki Declaration. Informed consent to the protocol approved by the local ethics committee was obtained from all patients.

Clinical examination.

Swollen, tender joints and global assessment on a visual analog scale were assessed at baseline and at the fourth, eighth, and twentieth weeks by rheumatologists (JF, MS, MM, KT) who were blinded to ultrasonographic results. Blood tests for ESR and C-reactive protein were performed at each visit.

Ultrasonography and assessment.

Ultrasonography was performed at baseline and at the fourth, eighth, and twentieth weeks by 1 of the 3 ultrasonographers (MH, FS, AN) specialized in musculoskeletal ultrasonography who were blinded to other clinical information. A 13 MHz linear array transducer was used (Hitachi EUP-L34P). Pulse Doppler settings were standardized for the detection of synovial blood flow by adjusting color gain, pulse repetition, and flow optimization parameters according to a previous study (12). Power Doppler settings (75 dB dynamic range, medium persistence, medium frame rate, low wall filter, 1,300 Hz pulse repetition frequency, flow optimization: medium vein, 1,300 Hz speed velocity) were identical throughout the examinations. Room temperature was kept at 25°C. The patients were positioned comfortably, and examinations were then started after 10 minutes of stabilization of pulse rate. The scanning technique on each finger joint was standardized and fixed as follows: first through fifth MCP and first through fifth PIP joint scanning was performed in the longitudinal plane over the dorsal surface of the joint with light skin pressure. The basic scanning technique followed the EULAR guidelines (13). The synovial vascular area with the most pronounced power Doppler activity was identified from the cine-loop and stored. The PDS images were recorded in the hard disk of the ultrasonographic machine. All examinations were completed within 15 minutes. The quantitative PDS method was established in a previous report (10). A synovial vascularity value was determined by counting the number of vascular flow pixels in the region of interest (ROI). The ROI was a standardized box type (5 mm × 10 mm) that was located to contain as many of the vascular flow pixels as possible. Vascular flow pixels in the ROI were measured automatically using the program's vascularity mode in the ultrasonographic machine (Hitachi EUB-7500).

Radiography and assessment.

Plain radiographs of the hands, wrists, and feet were obtained at baseline and the twentieth week. Radiologic assessments were examined according to the Genant-modified Sharp score by a rheumatologist (MS) who was blinded to other clinical information (14).

Statistical analysis.

Statistical analyses were calculated with the use of the Excel program (Microsoft) and MedCalc program 11.5.0.0. Differences between the 2 groups were examined using either the Student's t-test or a nonparametric test (Wilcoxon's signed rank test, Mann-Whitney U test), as applicable. Categorical data of clinical improvements were analyzed by the chi-square test or by Fisher's exact test. Intra- and interobserver reliability of quantitative PDS was estimated using calculations of intraclass correlation coefficients (ICCs). The smallest detectable change (SDC) for the radiographic score change was calculated according to a previous study (15).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Clinical disease activity.

The disease activity of the patients at baseline is described in Table 1. In both the ADA and TCZ groups, the DAS28-ESR, Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI) were significantly decreased from baseline (Figure 1). There were no significant differences in any disease activity markers between the ADA and TCZ groups for the change from baseline to the fourth week (DAS28: P = 0.879, CDAI: P = 0.319, SDAI: P = 0.580) and for the change from baseline to the eighth week (DAS28: P = 0.853, CDAI: P = 0.907, SDAI: P = 0.90).

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Figure 1. The change in clinical indices and radiographic progression for adalimumab (ADA) and tocilizumab (TCZ). The graphs of the 28-joint Disease Activity Score (DAS28) (A), Clinical Disease Activity Index (CDAI) (B), and Simplified Disease Activity Index (SDAI) (C) are shown. The left side of each graph is the course of ADA and right side of each graph is the course of TCZ. The cumulative probability plots for change in total Genant-modified Sharp score (ΔTGSS) for ADA and TCZ (D) are also shown.

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Radiographic evaluation of joint damage.

The radiographic images of the hands, wrists, and feet at baseline and the twentieth week in 25 patients were evaluated. The medians of the total Genant-modified Sharp score (TGSS) for the ADA and TCZ groups at baseline were 95.8 (interquartile range [IQR] 48.4–-154.5) and 60 (IQR 47.8–128), respectively. In both the ADA and TCZ groups, the TGSS did not progress significantly from baseline to the twentieth week (P = 0.636 and P = 0.843, respectively). The cumulative probability plots of the change in TGSS (ΔTGSS) from baseline to the twentieth week are shown in Figure 1. At the twentieth week, 60% of patients treated with ADA and 27% of patients treated with TCZ had no radiographic progression (ΔTGSS ≤0). There was no significant difference in the rate of number of patients with no progression of TGSS (ΔTGSS ≤0) between the ADA and TCZ groups (P = 0.122).

We next focused on local finger joints. Two hundred fifty MCP joints and 250 PIP joints of 25 patients were evaluated for changes in synovial vascularity and the local Genant-modified Sharp score (LGSS). The medians of the LGSS in ADA therapy at baseline for the MCP and PIP joints were 2 (IQR 1–4.25) and 1.5 (IQR 0.5–4), respectively. The medians of LGSS in TCZ therapy at baseline for the MCP and PIP joints were 2 (IQR 1–4) and 1.5 (IQR 1–6), respectively. The SDC values were calculated for the LGSS for single MCP and PIP joints (0.35 and 0.28, respectively). None of the calculated SDCs exceeded the smallest unit of the scoring (0.5).

Relationship between change of synovial vascularity and radiographic progression in local finger joints.

Finger joints with positive synovial vascularity at baseline were selected (ADA: MCP n = 28, PIP n = 22; TCZ: MCP n = 60, PIP n = 47). The medians of the MCP joint synovial vascularity were 355 (range 71–3,053) for the ADA group and 1,207 (range 80–4,686) for the TCZ group, showing no significant difference between the 2 groups (P = 0.0547). The medians of PIP joint synovial vascularity were 497 (range 65–2,414) for the ADA group and 781 (range 74–4,260) for the TCZ group, showing no significant difference between the 2 groups (P = 0.994). At the eighth week, the medians of MCP joint synovial vascularity were 0 (range 0–1,917) for the ADA group and 142 (range 0–3,621) for the TCZ group, showing a significant decrease from baseline (P = 0.0001 and P < 0.0001, respectively). The medians of PIP joint synovial vascularity were 0 (range 0–213) for the ADA group and 0 (range 0–2,201) for the TCZ group, showing a significant decrease from baseline (P < 0.0001 in both cases).

We arbitrarily categorized these finger joints into 2 groups: the response group (R-group), with vascularity improvement of >70% at the eighth week (ADA: MCP n = 21, PIP n = 18; TCZ: MCP n = 36, PIP n = 36), and the no response group (NR-group), with vascularity improvement of ≤70% at the eighth week (ADA: MCP n = 7, PIP n = 4; TCZ: MCP n = 24, PIP n = 11). Representative pictures for change in Doppler sonographic images and corresponding radiographic images are shown in Figure 2. In the ADA group, 95% (20 of 21) of the MCP joints and 89% (16 of 18) of the PIP joints in the R-group had no significant radiographic progression (change in LGSS [ΔLGSS] ≤0) compared with 57% (4 of 7) and 25% (1 of 4), respectively, in the NR-group (P = 0.0376 and P = 0.0209, respectively). In the TCZ group, 75% (27 of 36) of the MCP joints and 83% (30 of 36) of the PIP joints in the R-group had no significant radiographic progression compared with 42% (10 of 24) and 45% (5 of 11), respectively, of the NR-group (P = 0.0145 and P = 0.0198, respectively). Assuming no response in synovial vascularity (NR-group) as a risk factor for radiographic progression, the NR-group had a significantly higher risk compared with the R-group in both the ADA and TCZ groups (Table 2). In the period from baseline to the twentieth week, the ΔLGSS in the R-group was significantly lower compared with the NR-group for both the ADA and TCZ groups (Figure 3).

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Figure 2. The change in synovial vascularity and bone destruction. In the left second proximal interphalangeal joint, images for synovial vascularity improvement (baseline to eighth week) (A) and halting radiographic progression (baseline to twentieth week) (B) are shown. In the right second metacarpophalangeal joint, images for synovial vascularity persistence (baseline to eighth week) (C) and radiographic progression (baseline to twentieth week) (D) are shown. White arrows show the time course. The red arrow indicates the occurrence of bone erosion.

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Table 2. Change in synovial vascularity and radiographic progression in local finger joints*
 Joints with progression (ΔLGSS >0)/total numberRR (95% CI)P
R-groupNR-group
  • *

    ΔLGSS = change in local Genant-modified Sharp score; R-group = synovial vascularity response group; NR-group = synovial vascularity no response group; RR = relative risk; 95% CI = 95% confidence interval; MCP = metacarpophalangeal; PIP = proximal interphalangeal.

Adalimumab    
 MCP joints1/213/79 (1.11–73.2)0.0398
 PIP joints2/183/46.75 (1.63–28.0)0.0086
Tocilizumab    
 MCP joints9/3614/242.33 (1.21–4.51)0.0118
 PIP joints6/366/113.27 (1.32–8.11)0.0105
All    
 MCP joints10/5717/313.13 (1.64–5.97)0.0006
 PIP joints8/549/154.05 (1.89–8.67)0.0003
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Figure 3. The change in the local Genant-modified Sharp score (ΔLGSS). Metacarpophalangeal (MCP) joints and proximal interphalangeal (PIP) joints that were positive for synovial vascularity at baseline were categorized into the synovial vascularity response group (R-group) and no response group (NR-group; see Results). For the adalimumab treatment, the ΔLGSS of MCP joints (A) and PIP joints (B) are shown. For the tocilizumab treatment, the ΔLGSS of MCP joints (C) and PIP joints (D) are shown.

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Intra- and interobserver reliability for power Doppler PDS.

Representative PDS images for 20 MCP joints and 20 PIP joints were randomly chosen, and synovial vascularity was measured 3 times each by the 3 ultrasonographers (MH, FS, AN). The obtained intraobserver ICC values were 0.997–0.998 for MCP joints and 0.995–0.999 for PIP joints. The interobserver ICC values were 0.991–0.995 for MCP joints and 0.992–0.999 for PIP joints.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

In this pilot study, we found that synovial vascularity was a direct marker of local joint inflammation and the early alteration in synovial vascularity by antirheumatic therapy was a potential therapeutic marker of joint destruction.

Recent biologic agents exert strong antiinflammatory effects in the short term; therefore, accurate and sensitive measurement of their therapeutic efficacy is essential for their appropriate usage (16, 17). Although composite scores such as the DAS28, CDAI, SDAI, and ACR core data set had been widely used for RA assessment, such markers do not directly reflect local joint inflammation. To closely control disease activity, direct and sensitive evaluation for local joint abnormality would be useful as well as those general disease activity markers. For this purpose, we focused on synovial vascularity as an index of local joint inflammation.

In this study, we selected ADA and TCZ for the investigation so as not to limit the clinical significance of synovial vascularity to a single drug. While ADA is a representative biologic agent inhibiting tumor necrosis factor α, TCZ has a different mechanism and reduces inflammation by neutralizing the interleukin-6 receptor (18, 19). There was no difference between ADA and TCZ therapies in clinical indices such as the DAS28, CDAI, and SDAI at baseline. These clinical indices were decreased significantly by treatment in both the ADA and TCZ groups and suppressed bone destruction, as reported previously (20–23). Comparing these 2 therapies, the cumulative probability plots of the ΔTGSS showed that there was a space between each of the curves (Figure 1). There was no significant difference in the rate of number of patients with no progression of TGSS (ΔTGSS ≤ 0) between the ADA and TCZ groups. We next explored a relationship between synovial vascularity and bone radiographic progression in local MCP and PIP joints. We observed synovial vascularity at baseline and the fourth and eighth weeks. Previously we had established a quantitative PDS method (10). All of the ICCs calculated for intra- and interobserver reliability during the PDS measurements were acceptable in the study.

Focusing on each finger joint with positive synovial vascularity at baseline, there was no significant difference between ADA and TCZ for synovial vascularity. We found that the synovial vascularity that did not respond to biologic agents in the local finger joints (NR-group) showed a higher risk for progression of joint destruction compared to the responsive joints (R-group) (Table 2). Additionally, the R-group showed suppression of joint destruction (Figure 3). The 2 biologic agents with different therapeutic mechanisms shared similar outcomes. The clinical implications of our results include an observed improvement of synovial vascularity, suggesting that this physiologic parameter is a potential therapeutic marker of bone destruction in each local finger joint.

In a previous study, we showed that improvement of vascularity by DMARDs was correlated with suppression of radiographic progression (10). In this study, we have shown a correlation between the change in synovial vascularity by biologic agents and radiographic progression. It is noteworthy that the synovial vascularity improvement by the therapies is a sign of therapeutic response. Brown et al (3, 24) reported that joints with persistent vascularity positively showed being a risk factor of joint destruction. We further investigated the link between the change in synovial vascularity and that of bone destruction in each finger joint level, confirming a clear correlation between them.

In conclusion, change in synovial vascularity should be a direct marker of therapeutic efficacy. According to the EULAR recommendations for the treatment of RA, tight control of disease activity in the early stage would be necessary to obtain long-term improvement of the disease (25).

In RA, an improvement of synovitis in the short term is a first step toward the better outcome. It is interesting as well whether synovial vascularity is a predictive marker for bone destruction in the long term. We further pursue research on the relationship between synovial vascularity and bone destruction. Although our pilot study was limited to a small number of patients and short-term observation, using synovial vascularity as a guide to make therapeutic decisions could control disease activity and promise better prognosis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Fukae had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Fukae, Isobe, Kitano, Ito, Shimizu, Tanimura, Matsuhashi, Kamishima, Atsumi, Koike.

Acquisition of data. Fukae, Isobe, Kitano, Henmi, Sakamoto, Narita, Ito, Mitsuzaki, Shimizu, Tanimura, Matsuhashi, Kamishima, Atsumi, Koike.

Analysis and interpretation of data. Fukae, Kitano, Henmi, Sakamoto, Narita, Ito, Mitsuzaki, Shimizu, Tanimura, Matsuhashi, Kamishima, Atsumi, Koike.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
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