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Abstract

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

Objective

For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis.

Methods

One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1–5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity.

Results

In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission.

Conclusion

In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in ≥48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.

Disease remission is the major goal for patients with rheumatoid arthritis (RA) (1). This should equate to the absence of signs and symptoms of inflammation and the stabilization of radiographic and functional states. Remission has traditionally been defined using the modified American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria (2) and the Disease Activity Score (DAS) or the DAS in 28 joints (DAS28) (3, 4), both of which represent composites of clinical criteria. Reported remission rates have considerable variation and are dependent on the criteria used to define remission, the study population (e.g., early RA versus established RA), and the type of therapy used to induce remission.

Treatment with disease-modifying antirheumatic drugs (DMARDs) has typically resulted in ACR remission rates of 7–20% (5–7), while the early use of combination therapy with tight control of inflammation using steroids has led to increased remission rates (8). Despite achieving sustained remission of their disease, a significant proportion of patients treated with DMARDs continue to have radiographic progression (9–11). This can be explained by the presence of persistent synovitis detected by imaging in patients fulfilling remission criteria (12), with the most powerful predictor of radiographic damage being an increased power Doppler signal in a joint on ultrasound (US) examination (odds ratio 12.21, P < 0.001) (11).

Remission rates are consistently higher in patients treated with the combination of tumor necrosis factor (TNF) blockade and methotrexate (MTX) than in patients treated with monotherapy (13–15) (ironically, patients with more severe disease have higher rates of remission because they require the more effective combination treatment). Furthermore, use of the combination of TNF blockade and MTX reduces the progression of joint damage to a minimum in some patients, even in the presence of continued active disease (16–18).

Thus, synovitis (detected clinically or with the use of imaging techniques, especially power Doppler US) is strongly correlated with damage in patients with early and established disease treated with DMARDs (11, 12, 19, 20). However, in patients treated with the combination of TNF blockade and MTX, the explanation for the reduced progression of joint damage is unknown. It has not been determined whether this is primarily due to a more complete suppression of synovitis or whether additional mechanisms are involved (e.g., the effect of TNF blockade on RANKL, resulting in reduced differentiation and activation of osteoclasts). To address the issue of synovitis suppression, the joints of matched patients with disease in remission induced either by the combination of TNF blockade and MTX or by DMARD therapy were imaged for synovitis.

PATIENTS AND METHODS

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

Patients.

Fifty patients with disease in remission (DAS28 <2.6) induced by the combination TNF blockade and MTX (combination treatment) and 50 patients with disease in remission (DAS28 <2.6) induced by DMARDs were analyzed in this cross-sectional case–control study. Patients were recruited from the Leeds Teaching Hospitals National Health Service (NHS) Trust remission clinic. Recruitment of patients into the DMARD group was initially more rapid. Ethical approval was obtained from the local ethics committee, and all patients gave written informed consent. Patients had to fulfill the following 6 criteria: 1) RA classified according to the 1987 revised criteria of the ACR (21), 2) age >18 years, 3) disease in remission (DAS28 <2.6), 4) no flares of disease in last 6 months, 5) stable treatment for 6 months, and 6) no indication for a change in treatment.

Definitions of remission.

All patients recruited were required to fulfill the DAS28 criteria for remission of disease (3–5). Remission according to imaging results was defined in this study as a grey scale synovitis score of 0 and a power Doppler activity score of 0.

Clinical assessments.

Clinical assessments included duration of morning stiffness (in minutes), physician's assessment of global disease activity on a 0–100-mm visual analog scale (VAS), patient's assessments of fatigue, joint pain, and global health and disease activity on a 0–100-mm VAS, and the number of tender and swollen joints as determined by an independent trained metrologist. Joints included in the 28-joint count were examined (bilateral shoulders, elbows, wrists, metacarpophalangeal [MCP] joints, proximal interphalangeal joints, and knees). Routine laboratory tests were performed for C-reactive protein (CRP) level, erythrocyte sedimentation rate, and rheumatoid factor (RF) positivity. The Health Assessment Questionnaire (HAQ) (22) and the Rheumatoid Arthritis Quality of Life (RAQoL) questionnaire (23) were used to assess function and quality of life, respectively.

US assessment.

US examination of MCP joints 1–5 and the wrist joints of the dominant hand was performed in the combination treatment group using an ATL HDI 5000 machine (Philips, Mahwah, NJ) and in the DMARD group using an ATL HDI 3000 machine (Philips) with 12–5 MHz and 15–8 MHz “hockey stick” transducers. Grey scale and power Doppler US were used to assess synovial hypertrophy and synovial vascularity according to Outcome Measures in Rheumatology Clinical Trials definitions and using standard methodology (24, 25). US was performed by experienced ultrasonographers (AKB, HK, JF, and ZK) who were blinded to all other study findings.

MCP joints 1–5 and the wrist joints (intercarpal, radiocarpal, and ulnar carpal) of the dominant hand were scanned, imaging both dorsal and palmar surfaces. Individual joints were scanned for grey scale synovitis and power Doppler activity using a validated semiquantitative scoring scale of 0–3 for each parameter (26, 27). For synovial hypertrophy (grey scale synovitis), results were scored as follows: 0 = no synovial hypertrophy, 1 = mild, 2 = moderate, and 3 = severe hypertrophy. For power Doppler activity, results were scored as follows: 0 = normal/minimal vascularity, 1 = mild hyperemia, 2 = moderate hyperemia, and 3 = marked hyperemia. The US scores were expressed per joint and as a total score for each patient (sum of the scores for all joints).

Each patient evaluation took ∼30 minutes, and representative images were archived. Intraobserver reliability data for the rheumatologist (ZK) who performed the US examinations on the patients in the DMARD group showed 90% exact agreement, with a weighted kappa score of 0.62 (12). HK performed 90% of the US scans in the combination treatment group, and JF performed the remainder. For HK and JF, the percentages of exact agreement were 55% and 69%, respectively, with weighted kappa scores of 0.40 and 0.59, respectively, although the percentage of close agreement was 94%, with a kappa score of 0.59.

Statistical analysis.

The SPSS 14.0 software package (SPSS, Chicago, IL) was used for the analysis. Fifty patients (from a cohort of 66 patients) with DMARD-induced clinical remission were matched for age and sex to 50 patients with clinical remission induced by combination treatment. The data were analyzed using remission according to imaging results as a grey scale synovitis score of 0 and a power Doppler activity score of 0. Non-normally distributed and ordinal data were analyzed using nonparametric tests (Mann-Whitney U test, Kruskal-Wallis test) and were summarized as the median and range. Categorical data were analyzed using chi-square tests.

RESULTS

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

Demographic and clinical findings.

Table 1 demonstrates baseline characteristics. There were no significant differences between groups in the DAS28, CRP level, or RF positivity, or in the patient's assessment of disease activity, fatigue, or pain. Patients with combination treatment–induced remission had longer disease duration with higher HAQ and RAQoL scores. The median duration of remission was 13 months and 18 months for the combination treatment group and the DMARD group, respectively (P = 0.004). All patients in the combination treatment group were receiving MTX at a median dosage of 15 mg/week along with a TNF blocking agent, 6% were receiving prednisolone at a median dosage of 2.5 mg/day, and 12% had previously received an alternative TNF antagonist agent that had failed. Fifty percent of patients in the DMARD group were receiving MTX, 20% were receiving leflunomide, 16% were receiving hydroxychloroquine, 14% were receiving sulfasalazine, and 10% were receiving prednisolone (median dosage of 2.5 mg/day). Sixteen percent of patients in the DMARD group were receiving dual combination therapy, and 8% were receiving triple combination therapy.

Table 1. Baseline clinical, laboratory, and imaging characteristics of the patients, by treatment group*
 Combination treatment group (n = 50)DMARD group (n = 50)P
  • *

    Except where indicated otherwise, values are the median (interquartile range). DMARD = disease-modifying antirheumatic drug; RF = rheumatoid factor; CRP = C-reactive protein; VAS = visual analog scale; DAS28 = Disease Activity Score in 28 joints; SDAI = Simplified Disease Activity Index; RAQoL = Rheumatoid Arthritis Quality of Life questionnaire; HAQ = Health Assessment Questionnaire.

  • Patients were treated with the combination of tumor necrosis factor blockade and methotrexate.

Age, years55 (42–60.25)59 (47.75–69)0.019
Women, no. (%)29 (58.0)32 (64.0)0.539
Disease duration, months120 (72–183)90 (72–129)0.030
Duration of remission, months13 (12–18)18 (12–32)0.004
RF positive, no. (%)34 (68.0)29 (58.0)0.300
Tender joints, range 0–280 (0–0)0 (0–0)0.486
Swollen joints, range 0–280 (0–0)0 (0–2)0.016
CRP, mg/dl0 (0–5)0 (0–7)0.685
Patient's assessment of global disease activity, 0–100-mm VAS10 (2.75–20)12 (3–16)0.730
Patient's assessment of pain, 0–100-mm VAS9 (2–21)11.5 (4–18.25)0.550
Patient's assessment of fatigue, 0–100-mm VAS19 (7–34)20 (7.5–33.25)0.831
Physician's assessment of global disease activity, 0–100-mm VAS4 (2–10)9 (4–11)0.034
DAS281.65 (1.11–2.08)1.78 (1.28–2.06)0.183
SDAI score2.50 (1.18–4.60)3.25 (1.88–6.60)0.014
RAQoL score, range 0–304 (1–10.5)1.5 (0–7.25)0.039
HAQ score, range 0–30.638 (0.000–1.500)0.250 (0.000–0.688)0.052

US findings.

As shown in Table 2, complete remission according to imaging results (using a grey scale synovitis score of 0 and a power Doppler activity score of 0) was seen in 10% of patients in the combination treatment group compared with 16% of patients in the DMARD group (P not significant [NS]). However, while more patients in the combination treatment group than in the DMARD group had a power Doppler activity score of 0 (52% versus 40%; P = 0.229), significantly more patients in the combination treatment group had a grey scale synovitis score ≥2 (P < 0.001).

Table 2. Synovitis detected by imaging*
 Combination treatment group (n = 50)DMARD group (n = 50)P
  • *

    Except where indicated otherwise, values are the median (interquartile range). DMARD = disease-modifying antirheumatic drug; GS = grey scale synovitis; PD = power Doppler activity.

  • Patients were treated with the combination of tumor necrosis factor blockade and methotrexate.

GS score 0, no. (%)5 (10.0)8 (16.0)0.372
GS score <2, no. (%)19 (38.0)37 (74.0)<0.001
PD score 0, no. (%)26 (52.0)20 (40.0)0.229
GS score 0, PD score 0, no. (%)5 (10.0)8 (16.0)0.372
Total GS score7 (2–12)3 (1–5)<0.001
Total PD score0 (0–3)1 (0–2)0.815

The median grey scale synovitis score was higher in joints in the combination treatment group than in joints in the DMARD group (1 [interquartile range (IQR) 0–2] versus 0 [IQR 0–1]; P < 0.001, by Mann-Whitney U test). The power Doppler activity score was also higher in the combination treatment group than in the DMARD group (P = 0.029, by Mann-Whitney U test).

To determine whether patients with longer disease duration and less time with disease in remission had more synovitis, patients were stratified according to disease duration and duration of remission. For duration of remission of <12 months, more joints in the combination treatment group than in the DMARD group had grey scale synovitis scores ≥1 (70% versus 42%; χ2 = 21.03, P ≤ 0.001) and power Doppler activity scores ≥1 (23% versus 10%; χ2 = 6.75, P = 0.009). For duration of remission of ≥12 months, similar proportions of joints in both groups had synovitis detected by imaging (for grey scale synovitis scores ≥1, 46% of joints in the combination treatment group versus 40% of joints in the DMARD group; for power Doppler activity scores ≥1, 14% of joints in both groups), although the combination treatment group still had higher grey scale synovitis scores than the DMARD group (for grey scale synovitis scores ≥2, 20% versus 6%).

Stratifying for disease duration produced similar results; for disease duration of ≤7 years, more joints in the combination treatment group than in the DMARD group had grey scale synovitis (62% versus 34%), while a similar proportion of joints in each group had power Doppler activity (21% versus 11%, respectively). For disease durations of 7–12 years and >12 years, similar percentages of joints in each group had grey scale synovitis (50%) and power Doppler activity (20%). Therefore, longer disease duration and less time with disease in remission did not explain the imaging findings when we compared patients in the combination treatment group with those in the DMARD group. However, a significant correlation was seen between grey scale synovitis scores and both disease duration (ρ = 0.3, P = 0.011) (Figure 1) and duration of remission (ρ = −0.3, P = 0.005) in the combination treatment group but not in the DMARD group (ρ = 0.1, P = 0.412 for disease duration; ρ = 0.1, P = 0.307 for duration of remission).

thumbnail image

Figure 1. Scatterplot demonstrating correlation between grey scale synovitis (GS) and disease duration (ρ = 0.3, P = 0.011) in patients with disease in remission after treatment with the combination of tumor necrosis factor blockade and methotrexate.

Download figure to PowerPoint

Signs and symptoms during disease remission.

The majority of patients with disease in remission had no tender joints and no swollen joints. Eighty-four percent of patients (42 of 50) in the combination treatment group had no tender joints and no swollen joints, compared with 66% of patients (33 of 50) in the DMARD group. Similar numbers of patients in the combination treatment group and DMARD group had tender joints (3 versus 2, respectively). However, fewer patients in the combination treatment group than in the DMARD group had swollen joints (7 versus 16; P = 0.016). In both groups, ∼40% of tender joints were swollen. In the combination treatment group, 17% of swollen joints were tender compared with 8% in the DMARD group.

In patients with combination treatment–induced remission of disease who had no tender joints and no swollen joints, 88% had grey scale synovitis scores >0 and 43% had power Doppler activity scores >0. In patients with DMARD-induced remission of disease who had no tender joints and no swollen joints, 82% had grey scale synovitis scores >0 and 58% had power Doppler activity scores >0 (P NS).

Patient-reported outcomes and remission.

There were no differences between the 2 groups in patient-determined assessment of disease activity, fatigue, or pain (see Table 1). Regardless of the therapy that induced remission, the presence of synovitis according to imaging (by grey scale synovitis score or power Doppler activity score) did not affect the patients' assessments of disease activity, fatigue, or pain (ρ = 0.1 for all comparisons). However, as expected, the presence of tender joints was associated with a higher score on patients' assessment of disease activity in those in the combination treatment group (ρ = 0.39, P = 0.004) but not those in the DMARD group (ρ = 0.1, P = 0.302). Both groups had low levels of functional impairment and disability as measured by the HAQ and the RAQoL. The combination treatment group had worse RAQoL and HAQ scores than the DMARD group (P = 0.052). However, these results were explained by the differences in disease duration between the 2 groups; a significant correlation was found between the RAQoL score and disease duration (ρ = 0.326, P = 0.001) and between the HAQ score and disease duration (ρ = 0.493, P = 0.001), although there were no correlations between the grey scale synovitis score or the power Doppler activity score and either the HAQ score or the RAQoL score (data not shown).

Table 3 demonstrates the relationship between remission according to the imaging results and the functional and quality-of-life measures. Patients with disease in remission according to the imaging results did not have better HAQ or RAQoL scores than did patients with disease not in remission according to the imaging results.

Table 3. Relationship between synovitis detected by imaging and patient-assessed quality-of-life measurements*
 Imaging results
Remission (GS score 0, PD score 0)No remission (GS score >0, PD score >0)P
  • *

    Values are the median (interquartile range). GS = grey scale synovitis; PD = power Doppler activity; RAQoL = Rheumatoid Arthritis Quality of Life questionnaire; HAQ = Health Assessment Questionnaire.

  • Fifty patients were treated with the combination of tumor necrosis factor blockade and methotrexate. According to the imaging results, 5 patients had remission of their disease and 45 did not.

  • Fifty patients were treated with disease-modifying antirheumatic drugs (DMARDs). According to the imaging results, 8 patients had remission of their disease and 42 did not.

Combination treatment group   
 RAQoL score, range 0–305 (1–10)4 (1–12)0.975
 HAQ score, range 0–30.37 (0.00–1.25)0.65 (0.00–1.50)0.550
DMARD group   
 RAQoL score, range 0–301 (0–13)2 (0–6)0.726
 HAQ score, range 0–30.13 (0.00–0.63)0.25 (0.00–0.88)0.687

DISCUSSION

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

For patients with early and established RA, treatment with the combination of TNF blockade and MTX has produced increased clinical remission rates associated with greater control of radiographic progression as compared with traditional DMARDs or MTX monotherapy. In patients with active early disease and those with disease in remission after treatment with DMARDs, radiographic progression is related to the level of disease activity (detected clinically or by imaging) (12). This is consistent with magnetic resonance imaging studies in DMARD-treated patients that have shown a direct relationship between the level of synovitis and the degree of bone damage (19). Therefore, it would be predicted that the combination of TNF blockade and MTX is likely to produce superior suppression of imaging-detected synovitis compared with DMARDs, resulting in superior control of radiographic progression.

However, recent evidence in patients treated with the combination of TNF blockade and MTX suggests that this relationship may be more complex (16–18). Therefore, the current study aimed to use clinical and imaging assessments to compare patients with an equivalent clinical state (those with disease in remission as a result of combination treatment versus DMARD treatment). The key finding of the current study was that with disease in remission, patients treated with the combination of TNF blockade and MTX and patients treated with DMARDs (although selected from different patient populations) have comparable rates of imaging-detected synovitis (power Doppler activity score) and comparable clinical measurements of disease activity (patient-determined assessments, tender and swollen joint counts, CRP levels, and DAS28).

Patients with disease in remission in the combination treatment group had significantly higher grey scale synovitis scores than those with disease in remission in the DMARD group (P < 0.001). Significant correlations between grey scale synovitis scores and both disease duration and duration of remission (patients in the combination treatment group had longer disease duration and shorter duration of remission) were demonstrated in patients treated with the combination of TNF blockade and MTX but not in patients treated with DMARDs. Also, 48% of patients in the combination treatment group and 60% of patients in the DMARD group had power Doppler activity, which represents a measure of vascularity (and angiogenesis) of the synovial membrane and is predictive of radiographic deterioration in DMARD-treated patients (11).

The comparable levels of imaging-detected synovitis and also the equivalent clinical measurements of disease activity (tender and swollen joint counts and CRP level) may explain the comparable patient-assessed outcomes (disease activity, pain, and fatigue) between the 2 groups. Also, patient-determined outcomes did not appear to be affected by disease duration, duration of remission, or the presence of remission according to imaging. However, the use of multiple item questionnaires revealed that patients treated with the combination of TNF blockade and MTX had worse quality of life and function. This difference is probably a consequence of the selection bias that resulted in differences in disease duration between the 2 groups and is consistent with existing evidence showing that reversibility of function is dependent on duration of disease (28, 29). However, a direct correlation between grey scale synovitis score and HAQ score or RAQoL score was not observed in our cohort. Despite the lack of association seen in this cross-sectional study between imaging-detected synovitis and function, the long-term implications of persistent synovitis need to be considered. Sensitive assessment of disease activity (US/imaging assessment) is required to determine remission accurately, especially since the presence of imaging-detected synovitis is not directly related to patient-assessed outcome measures.

Our results are particularly interesting in light of recent evidence that suggests a “dampening” between synovitis, inflammation, and radiographic progression in patients treated with TNF antagonists (16–18, 30). It has been postulated that the combination of TNF blockade and MTX reduces radiographic progression by a direct effect on synovitis and by an indirect effect via osteoclasts. The results of this study provide some evidence supporting the notion of an effect in addition to the suppression of synovitis (detected by imaging) that produces the structural benefits of the combination of TNF blockade and MTX.

Overall, the results suggest that in these patients with late disease, the combination of TNF blockade and MTX (as compared with DMARD therapy) does not produce a more complete remission as measured by imaging and clinical (tender and swollen joint counts, CRP level, patient-assessed disease activity, pain, and fatigue) outcomes. However, since this study population was not randomized, the patients were subject to selection bias, and despite matching, the patients in the combination treatment group had longer disease duration, shorter time with disease in remission, and worse quality-of-life measurements (mainly as a consequence of these patients awaiting eligibility for TNF-blocking therapy according to UK guidelines). They represent a cohort of patients with previous severe disease who have achieved remission. Also, since remission is less frequent in patients treated with DMARDs, these patients in this group may represent a selected subgroup of patients with less severe disease.

Another potential limitation may be the use of the DAS28 as the inclusion criterion. This scoring method allows for residual tender and/or swollen joints in disease remission and does not include the feet; it may thereby miss evidence of disease activity and misclassify patients as having disease in remission. However, in the UK, the DAS28 is the recommended score for assessing response to treatment in the NHS. Furthermore, the DAS28 is a recommended remission outcome measure as stated by the European League Against Rheumatism (EULAR)/ACR collaborative recommendations for reporting disease activity (31). It remains an important primary outcome measure for clinical studies (14). It should also be noted that in the majority of cases the synovitis was subclinical, and examination of more joints or use of more stringent remission criteria would not have been associated with less imaging-detected synovitis (data not shown). Furthermore, the findings were unchanged when patients with no tender or swollen joints were studied. Thus, our data provide important information on the relationship between clinical signs and levels of synovitis.

For pragmatic reasons, 2 US machines were used during the course of the study. This may be considered a limitation to the study, but a recent study by EULAR showed good reliability between different types and grades of US machines when examining the MCP joints (32). Also, although not reported, our group performed a crossover study showing no significant differences between machines for examination of the hand and wrist joints (Wakefield R, et al: unpublished observations).

In summary, this study demonstrates that despite satisfying criteria for remission of disease and with comparable clinical data, patients treated with the combination of TNF blockade and MTX not only have ongoing synovitis, but they also have levels of inflammation that are similar to those in patients in clinical remission treated with DMARDs. As such, allowing for differences that may have arisen from patient selection, suppression of inflammation is not necessarily superior using the combination of TNF blockade and MTX. Furthermore, the imaging findings in these patients imply potential for future joint damage.

AUTHOR CONTRIBUTIONS

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

Dr. Emery 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 design. Saleem, Brown, Keen, Karim, Quinn, Wakefield, Conaghan, Emery.

Acquisition of data. Saleem, Brown, Keen, Nizam, Freeston, Karim, Emery.

Analysis and interpretation of data. Saleem, Brown, Keen, Wakefield, Hensor, Conaghan, Emery.

Manuscript preparation. Saleem, Brown, Keen, Karim, Quinn, Wakefield, Conaghan, Emery.

Statistical analysis. Saleem, Hensor.

ROLE OF THE STUDY SPONSOR

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

Abbott Laboratories supplied an unrestricted research grant. Abbott Laboratories was not involved in the study design, data collection, data analysis, or writing of the manuscript. Publication of this article was not contingent on the approval of Abbott Laboratories.

REFERENCES

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