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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. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

Osteoclast-mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer-based technique, digital x-ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA.

Methods

Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer-assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands.

Results

At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: −0.0034, denosumab 180 mg: 0.0001 gain, placebo: −0.0108; P ≤ 0.01 for both denosumab doses). Twelve-month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio.

Conclusion

Twice-yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Rheumatoid arthritis (RA) is a disabling inflammatory disease associated with significant periarticular and systemic bone loss that typically predates erosion of the bone (1–4). In spite of recent advances in the treatment of RA, many patients continue to experience progressive joint damage and functional impairment. Assessment tools that clinicians could use for early identification of patients at greatest risk might facilitate interventions that would prevent joint damage and disability (4).

Bone loss affecting the hands and feet is one of the earliest signs of radiographic changes in RA leading to bone erosions, and has been shown to be predictive of long-term RA damage (2, 4–9). Because the hand is a primary site of inflammation in RA, measurement of hand bone mineral density (BMD) and cortical bone thickness can provide quantification of the cumulative effects of overall disease progression (5, 10–12). Whole-hand bone density measurements using dual x-ray absorptiometry (DXA) have demonstrated increasingly severe osteoporosis in the metacarpal bone shaft, which occurs with increasing radiographic scores (13).

In the 1990s, a few investigators began to measure cortical thickness in the metacarpal bones and relate the results to the severity of disease and prognosis. Kalla et al reported in 1991 that cortical thickness measured in digitized images declined significantly in a period when RA patients were not receiving disease-modifying antirheumatic drugs and then stabilized with treatment (14). Subsequently, multiple studies demonstrated that loss of metacarpal shaft cortical thickness occurs in parallel with increasing radiographic scores (6, 15). In other studies, cortical thinning has been reported to parallel progression of erosion scores; one longitudinal study reported by Hoff and colleagues in 2009 showed that cortical thinning of the hand detected early in the disease predicts progression of erosive disease 5 and 10 years later (9). The measurement of metacarpal shaft cortical shaft thickness has been demonstrated to be a potentially useful tool for predicting disease progression in RA (4). To date, this measurement has been performed using a commercial system (16). The study reported here employs a novel computer-based method of measuring cortical thickness. The analysis was performed using an ImageJ plug-in to the public domain National Institutes of Health (NIH) ImageJ program (developed at the US NIH and available online at http://rsb.info.nih.gov/nih-image/). The plug-in, developed by the first author (JTS), will be made available in the public domain for download at http://rsb.info.nih.gov/ij/plugins/.

We consider it important to determine the discriminating ability of cortical measurements as the lone outcome measure to identify differences between treatment effects in a therapeutic trial setting. For that purpose, we have measured cortical thickness in a trial testing the effectiveness of denosumab, an investigational fully human monoclonal antibody that specifically binds to and neutralizes RANKL (an essential factor in activating osteoclasts) in preventing the development or worsening of erosions. Preclinical studies demonstrated that the inhibition of RANKL increases trabecular and cortical bone mass and strength (17–20). Earlier publications of the results of this trial reported inhibition of erosions detected by magnetic resonance imaging (MRI) and radiography, and improvement in spinal and hip BMD with denosumab in patients with RA (21, 22). Here we report correlations between these measures and cortical thickness, illustrating the use of a novel technique for measuring cortical thickness. We also report the effects of denosumab on cortical thickness.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Patients.

Full details of the study methods were previously described (21). Eligible patients from the US and Canada were enrolled if they had RA (American College of Rheumatology [formerly the American Rheumatism Association] criteria [23]) for at least 24 weeks, were receiving a stable dosage of methotrexate (MTX; 7.5–25 mg/week for ≥8 weeks), had at least 6 swollen joints on a 66-joint count (excluding distal interphalangeal joints), and evidence of erosive disease (either ≥3 erosions of the hands or feet, or both C-reactive protein level ≥2.0 mg/dl and anti–cyclic citrullinated peptide antibodies). Key exclusion criteria included glucocorticoid use >15 mg/day (prednisone or equivalent); scheduled surgery or joint replacement in the hands, wrists, or feet; or use of either a biologic agent for RA or leflunomide within the prior 8 weeks.

The institutional review boards and independent ethics committees of the participating medical centers approved the protocol and amendments. Each patient gave written informed consent before initiating any study-related procedures. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Study design.

In this randomized, double-blind, placebo-controlled, phase II study, patients were randomly allocated in a 1:1:1 ratio to receive denosumab 60 mg, denosumab 180 mg, or matching placebo, administered once subcutaneously at baseline and again at 6 months. All of the patients were to take daily supplements of 0.5–1.0 gm of elemental calcium and 400–800 IU of vitamin D. Patients were allowed to change doses of MTX or add hydroxychloroquine or sulfasalazine (individually or in combination), and add or change doses of steroids or nonsteroidal antiinflammatory drugs any time throughout the study, except within 2 weeks of a study visit. Patients were allowed to use bisphosphonates. Rescue with an anti–tumor necrosis factor therapy was allowed after 6 months.

Imaging.

The primary end point was the change in MRI erosion score from baseline to 6 months. MRI methodologies were previously described (21). Briefly, MRI of both hands (metacarpophalangeal joints) and wrists was obtained as 2 images with a standardized procedure at baseline and 6 months. All images were acquired using 1.5T whole-body MRI scanners. All images were scored for bone erosion using a variation (24) of the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring method originally developed by the Outcome Measures in Rheumatology Clinical Trials group (25). Two radiologists experienced in MRI and dedicated to clinical trials imaging independently read the images. Readers were blinded to each other's results, examination visit order, treatment allocation, and patient identity. Results were based on the average of the scoring from the blinded readers.

Plain radiographs of the hands/wrists and feet were obtained at baseline and at 6 and 12 months with a standardized procedure, and were sent to a central facility for analysis. Digitized radiograph images were captured at 100 microns per pixel (10 pixels per mm) at 3 time points: baseline, 6 months, and 12 months. BMD was assessed by DXA scans (Lunar; GE Healthcare, Madison, WI, and Hologic, Bedford, MA) of the lumbar spine (L1–L4), total hip, femoral neck, and trochanter; these assessments were performed at baseline and at 1, 6, and 12 months. All randomized patients who received ≥1 dose of the study treatment and had a baseline and ≥1 post-baseline radiographic evaluation were eligible for this analysis. Digitized images were scored by the modified Sharp/van der Heijde method to calculate the erosion scores, joint space narrowing scores, and total Sharp scores (26, 27).

Measurement of metacarpal cortical thickness.

In this post hoc analysis, we investigated the effect of denosumab on metacarpal shaft cortical bone thickness based on the digitized radiographs described above. Images were marked at the head and base of the second, third, and fourth metacarpal bones of each hand (Figure 1A) by an operator (CH-B or WT) who was unaware of patient treatment assignments. These top XY and bottom XY points were located so that a line from the top to the base of the metacarpal would pass through the bone within the medullary cavity without touching either the medial or the lateral cortex (Figure 1B). From the midpoint of the top XY to the bottom XY line, 21 measurements of cortical thickness were made, 10 above and 10 below the midpoint, each measurement separated by an empty interval of 1 pixel. Each measurement was made by computer-based edge detection of the outer and inner cortical margins of the ulnar and radial cortices. The location of the outer cortical margin was determined by measuring density at each X point, beginning from well outside the bone along a line perpendicular to the line from top XY to bottom XY. The slope between every 10 pixels on the x axis on the line of search was determined and the middle of the 10 pixels with the steepest slope was taken as the X point for the outer cortical margin. The Y for that point was determined by triangulation. This was repeated 21 times at every other Y to find the 21 XY points on the outer cortical margin centered at the eleventh XY point. The inner cortical margin was located by calculating the sum of densities for 10 consecutive XY points on the same line perpendicular to the top XY to bottom XY line used for detecting the outer cortical margin. The midpoint of the greatest sum was taken as the medial cortical margin.

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Figure 1. To determine cortical thickness and shaft width, the proximal and distal ends of the second, third, and fourth metacarpal bones were identified by an operator (A). The ImageJ plug-in program scans and detects both cortical margins for 21 points around the metacarpal midshaft (B). The shaft width and combined cortical thickness (CCT) are measured for 21 levels around the midshaft (C). Mean and median ratios of CCT to shaft thickness are computed.

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Statistical analysis.

We calculated the mean and median changes from baseline in the cortical thickness ratio (the average ratios of all 6 combined cortical thicknesses [CCTs] to shaft width) at 6 and 12 months between each denosumab dose group and placebo, and used Wilcoxon's rank sum test to compare the ranks of the changes.

Spearman's rank correlation coefficients were used to assess the relationship between the cortical thickness ratios and the erosion scores (as measured by MRI and radiography) by each treatment group and by visit (at baseline and 6 and 12 months). Spearman's rank correlation coefficients were also used to explore the relationship between the cortical thickness ratios and the BMD values at the lumbar spine and total hip, including both static values and changes from baseline, by treatment group and by visit.

The smallest detectable difference in median changes from baseline, or smallest detectable change (SDC) in the cortical thickness ratio (the average ratios of all 6 CCTs to shaft width), was calculated as SDC = 2.0 × SD, where SD = the SD for the change scores of (operator 1 − operator 2) (28). The SDC was calculated at months 6 and 12.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Characteristics of the measurement instrument.

The intraclass correlation coefficients between the 2 operators (CH-B and WT) for metacarpal cortical thickness (analyzed in a subset of patients) were >0.98 at baseline, 6 months, and 12 months for the second, third, and fourth metacarpal bones of both hands and for the average of all 6 metacarpal bones. The SDCs for average metacarpal thickness ratios (analyzed in a subset of patients) for the 2 operators (CH-B and WT) were determined to be 0.0283 at 6 months and 0.0207 at 12 months.

Patient demographics and baseline disease characteristics.

Baseline characteristics for the 227 enrolled patients were previously described (21). Of the 227 enrolled patients, 218 (75 placebo, 71 denosumab 60 mg, and 72 denosumab 180 mg) received treatment and were evaluated in this analysis. The baseline median values in cortical thickness for each of the metacarpal bones were similar across treatment arms (Table 1).

Table 1. Baseline values of metacarpal cortical thickness ratios, erosion scores, and bone mineral density*
 Placebo (n = 75)Denosumab 60 mg (n = 71)Denosumab 180 mg (n = 72)
  • *

    Values are the median (Q1, Q3) unless otherwise indicated. MRI = magnetic resonance imaging.

Metacarpal cortical thickness ratios   
 Second metacarpal bone0.55 (0.49, 0.60)0.52 (0.43, 0.59)0.53 (0.42, 0.61)
 Third metacarpal bone0.53 (0.46, 0.60)0.51 (0.43, 0.59)0.51 (0.41, 0.57)
 Fourth metacarpal bone0.59 (0.53, 0.64)0.57 (0.51, 0.64)0.57 (0.50, 0.65)
Erosion scores, mean ± SD   
 MRI erosion score32.1 ± 26.541.2 ± 37.446.7 ± 42.5
 Modified Sharp erosion score, plain radiograph16.6 ± 17.222.2 ± 22.030.0 ± 35.2
Bone mineral density T score, gm/cm2   
 Lumbar spine−0.60 (−1.30, 0.30)−0.60 (−1.40, 0.50)−0.80 (−1.90, 0.10)
 Total hip−0.70 (−1.40, 0.00)−0.80 (−1.60, 0.20)−0.90 (−1.50, 0.00)

Changes in metacarpal cortical thickness.

At 6 months, patients in the denosumab 60 mg group had significantly less (P = 0.032) metacarpal bone loss than patients in the placebo group, as measured by the mean change from baseline in the median cortical thickness ratio (average of the medians of all 6 metacarpal bones) (Figure 2). The mean change in median cortical thickness ratio was −0.0066 in the placebo group and −0.0023 in the each of the 2 denosumab arms (P < 0.05 for the denosumab 60 mg group, P = 0.09 for the denosumab 180 mg group). At 12 months, patients in both denosumab cohorts had significantly less decrease in cortical thickness ratios from baseline (−0.0034; P < 0.01 for denosumab 60 mg and 0.0001; P = 0.0001 for denosumab 180 mg) than those receiving placebo (−0.0108). Change from baseline in the mean cortical thickness scores at 6 and 12 months showed similar results.

thumbnail image

Figure 2. Mean ± SD change from baseline in the median cortical thickness ratio (average of the medians for 3 metacarpal bones per hand) shows denosumab-induced prevention of metacarpal shaft cortical bone loss.

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Twelve-month decreases from baseline greater than the SDC occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. A probability plot shows a clear difference between the treatment groups in the change in cortical thickness (Figure 3).

thumbnail image

Figure 3. A probability plot shows clear differences between the denosumab and placebo groups in the probability of change from baseline in the average cortical thickness ratio of all 6 metacarpal bones at 12 months. Horizontal lines show the smallest detectable change (SDC) from baseline at 12 months. The red box (A) identifies patients with decreases in combined cortical thickness (CCT) greater than the SDC. The blue box (B) identifies patients with any decrease in CCT. N = number of patients who had measurements at baseline and at ≥1 additional time point.

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Correlation with erosion scores.

A significant negative correlation was observed between static cortical thickness ratio and static erosion scores at baseline and at months 6 and 12 (Table 2). In the placebo group, changes in erosion scores and changes in cortical thickness ratio were negatively correlated, but this correlation was not evident in the denosumab treatment groups.

Table 2. Spearman's correlation coefficients between metacarpal cortical thickness ratio and erosion scores as assessed by magnetic resonance imaging (MRI) and by plain radiographs (modified Sharp erosion score)
 Baseline MRI erosion scoreBaseline modified Sharp erosion score6 months MRI erosion score6 months modified Sharp erosion score12 months modified Sharp erosion score
Hands and feetHands aloneHands and feetHands aloneHands and feetHands alone
  • *

    P ≤ 0.05.

  • Not significant.

  • P ≤ 0.0001.

  • §

    P ≤ 0.01.

Metacarpal cortical thickness ratio to actual erosion scores        
 Placebo (n = 75)−0.243*−0.147−0.241*−0.125−0.058−0.164−0.034−0.206
 Denosumab 60 mg (n = 71)−0.551−0.461−0.503−0.529−0.489−0.483−0.457−0.504
 Denosumab 180 mg (n = 72)−0.442§−0.433§−0.478−0.373§−0.440§−0.419§−0.415§−0.405§
 Overall−0.418−0.365−0.418−0.353−0.347−0.369−0.324−0.386
Metacarpal cortical thickness ratio to changes in erosion scores from baseline        
 Placebo (n = 75)0.006−0.397§−0.327§−0.320*−0.249*
 Denosumab 60 mg (n = 71)0.126−0.006−0.087−0.032−0.123
 Denosumab 180 mg (n = 72)0.009−0.071−0.075−0.2070.131
 Overall0.014−0.173*−0.167*−0.109−0.121

Erosion scores for the hands and feet (both MRI and the modified Sharp method) at 6 and 12 months also showed a decreased progression rate in the patients receiving denosumab compared with placebo, as described previously by Cohen et al (21).

Correlation with BMD.

Metacarpal cortical thickness values were significantly correlated with actual BMD values of the denosumab (but not placebo) treatment groups for lumbar spine and total hip (Table 3). The correlations between changes from baseline in lumbar spine or total hip BMD and metacarpal cortical thickness values were not significant for either the denosumab or placebo treatment groups.

Table 3. Spearman's correlation coefficients between metacarpal cortical thickness ratio and bone mineral density (BMD) at the lumbar spine and total hip: actual scores and changes from baseline
 Lumbar spineTotal hip
Baseline6 months12 monthsBaseline6 months12 months
  • *

    Not significant.

  • P ≤ 0.01.

  • P ≤ 0.05

  • §

    P ≤ 0.0001.

Metacarpal cortical thickness ratio to actual BMD scores      
 Placebo (n = 75)0.125*0.156*0.242*0.3140.3080.273
 Denosumab 60 mg (n = 71)0.3350.3200.2940.3850.3290.254
 Denosumab 180 mg (n = 72)0.4380.4070.4310.455§0.4200.486§
 Overall0.313§0.307§0.333§0.389§0.345§0.333§
Changes in metacarpal cortical thickness ratio to changes in BMD scores from baseline      
 Placebo (n = 75)−0.136*−0.093*0.055*0.038*
 Denosumab 60 mg (n = 71)0.152*−0.205*−0.089*−0.121*
 Denosumab 180 mg (n = 72)0.060*−0.083*0.087*0.080*
 Overall0.063*0.001*0.037*0.064*

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Accelerated bone loss in RA can be attributed to increased activity of osteoclasts (29), which are dependent on RANKL for their formation, function, and survival (30). RANKL-driven osteoclast activity is inhibited by denosumab, a fully human monoclonal antibody against RANKL, which was evaluated in this double-blind, randomized controlled trial comparing 2 doses of denosumab plus MTX with MTX alone. Primary data from this study demonstrated that denosumab substantially inhibited structural damage (as measured by MRI and radiography) compared with placebo in patients with RA (21). These results are consistent with those observed in postmenopausal women with low BMD (8, 31–34) and patients with bone metastases associated with solid tumors or multiple myeloma (35–37).

Various imaging modalities, such as DXA and quantitative computed tomography (QCT), are available for assessing osteoporosis and measuring BMD (10, 29, 38). DXA uses 2 different radiograph beams to provide a real bone density of the spine and hip, whereas QCT is a more recent innovation that provides not only high-precision measurement of bone density, but also a 3-dimensional output on bone geometry. However, these tools are relatively expensive and are not commonly used by rheumatologists. Conventional radiography is more cost effective and is the gold standard for detecting structural damage in RA (39), but has limited sensitivity in measuring periarticular bone loss, especially in the metacarpal bones (15). To overcome this limitation, digital techniques have greatly improved the precision and accuracy of bone density measurements using existing radiographs. Digital x-ray radiogrammetry (DXR) converts plain radiographs into high-resolution, digital images that are then analyzed for geometric dimensions by computer software. This method measures the total width of a bone and the medullary width at the midpoint of the metacarpal bone, and is typically used to calculate changes in the cortical bone (40). Various indices are then derived from this calculation, including the metacarpal index, the Garn index (defined as the cortical area), the Exton-Smith index (related to the cortical area and the surface area), and the Barnett and Nordin index (defined as the percentage of cortical thickness) (40–42). DXR has been shown to correlate highly with BMD measurements from DXA (43).

In this study, the inhibitory effect of denosumab was measured by 3 different methods: the scoring of erosions, the measurement of BMD using DXA, and the measurement of metacarpal shaft cortical thickness. Although it has been known that loss of cortical shaft thickness progressed with RA and could be inhibited by drug therapy, little evidence exists regarding the effectiveness of measuring cortical thickness as an outcome measure in controlled trials of patients with RA. In this study, statistically significant correlations were observed between cortical thickness measurements and both erosion scoring and BMD.

Significant negative correlations were observed between static erosion scores and static cortical thickness measurements. Significant negative correlation was also observed between change in erosion scores and change in cortical thickness in the placebo group, but negative correlation was not detected in the denosumab treatment groups. In the placebo group, erosive disease and cortical bone loss progressed. Because little change occurred in the active treatment groups, we were unable to detect a correlation in these groups. Significant positive correlations were observed between static BMD in the spine and hips and cortical thickness in the metacarpal bones. Active RA is associated with focal erosive periarticular bone and systemic bone loss measured as a reduction in BMD in the spine and hips and a reduction in CCT. Increase in erosion scores is associated with loss of BMD and a decrease in CCT, consistent with a negative correlation between these measures observed in the placebo-treated group. These changes were minimized with denosumab treatment.

Methods for measuring cortical thickness have evolved. Early studies employed digitizers, reticules, calipers, and other measures. In more recent years, computer-based methods have been used to define cortical thickness on each side of the metacarpal shaft, after which cortical thickness was related to the width of the metacarpal shaft as a ratio. Most studies appear to have measured 3 metacarpal bones (6, 38, 40). DXR, which has been extensively employed in studies of osteoporosis and in RA, may combine a measure of cortical thickness with a measure of cortical porosity (44). The benefit of combining the two has not been demonstrated, nor has the method of determining porosity in the cortex of the metacarpal shaft been described in the detail required to reproduce such measurements. Since we were unable to find a description of the method for measuring cortical porosity sufficiently detailed to allow us to develop a tool to measure porosity, and because we believed that determining the effect of each component in the measurement was important, we confined our measurement to cortical thickness alone in the metacarpal shaft.

Loss of cortical thickness has been recognized as a predictor of subsequent progression of structural damage for the last several years and also has been reported as an appropriate outcome measure. In this study of patients with an average duration of disease greater than 8 years, cortical thinning continued to progress in patients who received MTX treatment alone.

Measurement of cortical thickness in the metacarpal shaft clearly needs to be further explored in therapeutic trials, to clarify how much additional information it adds to the Sharp scoring system that has been traditionally used. It is not certain if the additional data about cortical thickness merely reinforces the results of Sharp scoring or whether it adds new information not revealed by scoring. Nevertheless, the simplicity of the method and the fact that it yields a metric value suggests that it could be a potentially useful outcome measure. This analysis suggests that CCT in the hands correlates with Sharp erosion scores in the hands and may be feasible for use in practice for monitoring progression in individual subjects. Earlier identification of changes in hand BMD may potentially improve the long-term prognosis and treatment strategies in patients with RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. 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 submitted for publication. Dr. Ory 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. Sharp, Tsuji, Ory, Newmark.

Acquisition of data. Sharp, Tsuji, Ory, Newmark.

Analysis and interpretation of data. Sharp, Tsuji, Ory, Harper-Barek, Wang, Newmark.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

This research was funded by Amgen Inc., which developed the protocol and statistical analysis plan, provided the study drug, coordinated the activities of study sites, performed the statistical analysis, and reviewed the manuscript. All authors approved the content of the submitted manuscript.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Ting Chang, PhD, and Sue Hudson provided medical writing assistance on behalf of Amgen Inc. Their contributions included the integration of author inputs to the manuscript, coordination of reviews, quality assurance, and editing the draft for compliance with journal requirements.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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