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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. Acknowledgements
  9. REFERENCES

Objective

To evaluate the prevalence and 8-year course of forefoot impairments and walking disability in patients with rheumatoid arthritis (RA).

Methods

A total of 848 patients with recent-onset RA from 1995 through the present were included. The patients were assessed annually. Pain and swelling of the metatarsophalangeal (MTP) joints, erosions and joint space narrowing of the MTP joints and first interphalangeal joints, and the Health Assessment Questionnaire walking subscale were analyzed using descriptive and correlational techniques.

Results

Pain and swelling of ≥1 MTP joint was present in 70% of patients at baseline, decreasing to ∼40–50% after 2 years. The forefoot erosion score was ≥1 in 19% of the patients at baseline, and the prevalence of forefoot erosion increased to ∼60% after 8 years, during which the mean forefoot erosion score increased from 1.3 to 7.9. At least mild walking disability was present in 57% of patients at baseline, stabilizing at ∼40% after 1 year.

Conclusion

The prevalence rates for pain and swelling of the MTP joints and walking disability are initially high and then stabilize, but the prevalence and severity of forefoot joint damage increase during an 8-year course of RA. The findings of this study quantitatively emphasize the importance of forefoot involvement in patients with RA.


INTRODUCTION

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

Rheumatoid arthritis (RA) is a systemic inflammatory disease with widespread synovial joint involvement. The manifestations of RA are frequently found in the metatarsophalangeal (MTP) joints of the forefoot. Synovitis of the MTP joints can have a destructive impact on the quality and structure of the joints and surrounding soft tissues. Synovitis, joint damage, and deformities of the forefoot can lead to pain and disability in weight-bearing activities, especially walking (1).

Foot pain in RA is reported to be very common. Studies have shown that 13–34% of patients with RA initially present solely with foot or ankle symptoms (2–4), and that ∼90% of patients report painful feet or ankles at some time during the course of their disease (4–6). However, these studies are cross-sectional and mostly outdated. The only recent study focusing on the prevalence of forefoot pain showed that 81% of 285 consecutive patients with a mean disease duration of 9.7 years reported mild to debilitating forefoot pain (7). Synovitis of the MTP joints is believed to be the main cause of foot pain in early RA and is usually accompanied by joint swelling. To our knowledge, there are no longitudinal studies to date that provide prevalence rates for pain and swelling of the MTP joints in early RA.

The small joints of the foot erode more quickly, and this erosion affects a greater number of joints compared with the joints of the hands (8–12). In a study by Hulsmans et al, both erosions and joint space narrowing in the MTP joints and first interphalangeal (IP) joints were found in 37% of patients with RA at disease onset (8). During the course of the disease, the number of involved forefoot joints increases and the severity of the lesions becomes more pronounced (8, 11). Although the prevalence and course of radiographic damage in patients with RA have been reported in cohort studies, no longitudinal studies have been published focusing specifically on the joints of the forefoot.

Walking disability is believed to be the most affected disability domain in patients with RA who experience foot problems. General disability during the course of RA has been described extensively (13). The most widely used instrument for measuring general disability in rheumatology research is the Health Assessment Questionnaire (HAQ) disability index (DI), which contains a subscale for walking disability. As of yet, the prevalence and course of walking disability in a cohort of patients with RA have not been reported.

The prevalence and course of different aspects of forefoot impairments and disability are of limited availability and are scattered throughout the literature. Knowledge of the prevalence of forefoot involvement during the disease process is important for further research and early diagnosis and treatment. Therefore, the aim of the present study was to investigate the prevalence of forefoot impairments (i.e., pain, joint swelling, and joint damage) and walking disability at initial presentation and during a maximum of 8 years of followup in newly diagnosed RA patients in The Netherlands.

PATIENTS AND METHODS

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

Study design.

Since 1995, patients age 18 years and older with recent-onset arthritis (symptom duration of less than 3 years) have been included in an Early Arthritis Cohort (EAC) (14). This cohort was established in 1995 to study a wide variety of arthritis research topics, including the presence and course of the signs and symptoms of the disease process. Exclusion criteria include having already been treated with disease-modifying antirheumatic drugs, as well as having crystal synovitis, osteoarthritis, psoriatic arthritis, and/or spondylarthropathy. By May 2007 a total of 1,622 patients had been evaluated. Among other measurements, the patients' disease activity, joint damage by scoring radiographs, and functional capacity have been assessed at different time points. For the present study, all patients fulfilling the 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) criteria for RA (15) at baseline and/or at 1 year after inclusion were selected. Data from annual assessments were used, with a maximum of 8 years of followup.

Patient selection.

In the present study, 848 (52%) patients fulfilled the ACR criteria for RA within the first year. Drug treatment decisions were made by the rheumatologists according to clinical practice standards. Because patients have been included from 1995 through the present, patients had a variable duration of followup. In the beginning of the disease course, data were present for all patients, whereas later data were only available for the patients with a longer followup period. The total number of patients assessed is presented in the first column of Table 1. The second column of Table 1 shows the number of patients who should potentially have had a followup measurement based on the number of years from the date of inclusion until the present. Patients who moved (n = 46) or died (n = 37) were extracted from the potential number of patients from the time point at which they were lost to followup. The percentage in the third column is the ratio of the number of patients assessed to the potential number of patients. The difference between the potential and the actual number of patients is due to various reasons of dropout during followup. The most common reasons for patients to drop out were no time (n = 81) and moving to another area (n = 46). Thirty-seven patients reported dropping out because their disease was in remission.

Table 1. Potential number of patients and number of patients assessed during followup in the present study
 Potential patients, nPatients assessed, n (%)
Baseline848848 (100)
Year 1779682 (88)
Year 2689558 (81)
Year 3584416 (71)
Year 4503341 (68)
Year 5441274 (62)
Year 6347200 (58)
Year 7294151 (51)
Year 8239121 (51)

Measures.

Pain and swelling of MTP joints. As part of the determination of disease activity, pain by palpation and the presence or absence of swelling of joints were assessed by a trained clinical research assistant (16). For this study, measurements of pain and swelling of the MTP joints were used. A score of ≥1 painful or ≥1 swollen MTP joint in either foot was regarded as the presence of forefoot pain or swelling, respectively.

Damage of MTP and IP joints.

For a subgroup of patients with a followup of ≥2 years (n = 539 at baseline), joint damage of the hands and feet was assessed by trained rheumatologists using the modified Sharp/van der Heijde (SHS) method (17). Two rheumatologists were involved in the scoring of the radiographs. The consensus between the 2 rheumatologists was high (calculated for a subgroup of 67 radiographs, Pearson's correlation coefficient r = 0.84; P < 0.01). The total score for the feet included a score for erosions (range 0–10 per joint) and a score for joint space narrowing (0–4 per joint) of the 10 MTP joints and the 2 IP joints of the big toes. The total score for joint damage in both feet (range 0–168), the total score for erosion in both feet (range 0–120), the total score for joint space narrowing in both feet (0–48), and the total overall score in both hands and feet (range 0–448) were used. The erosion score was regarded as the most obvious sign of joint damage in early disease. A joint was counted as eroded or narrowed if the score for either erosion or narrowing of the feet was ≥1, indicating that ≥1 erosion or joint space narrowing score in either foot was present (8, 18).

Walking disability.

For the assessment of walking disability, 1 category of the HAQ DI, i.e., walking (walking outside and stair climbing), was used. A Dutch version of the HAQ DI was used (19), and the total HAQ DI score was also calculated. The HAQ walking subscale and the total HAQ DI produce a score range of 0–3, where 0 = no disability and 3 = serious disability. The HAQ has been found to be valid, reproducible, and sensitive for change (20, 21). A score of ≥1 on the HAQ walking subscale was regarded as being disabled in walking.

Other measurements.

Baseline demographic data, the percentage of patients with a positive IgM rheumatoid factor (RF), and the Disease Activity Score in 28 joints (DAS28) (22) were also recorded.

Statistical analysis.

Means and medians were calculated for the characteristics of the patients at baseline. Additionally, t-tests were performed to compare the patients with full followup (n = 121) with the patients without full followup (n = 727). Two-sided testing was used, and P values less than 0.05 were considered significant.

For the prevalence of painful and swollen MTP joints, forefoot joint damage, and walking disability, percentages were calculated using a cutoff score of ≥1 for all variables. The prevalence estimates per time point were visualized in graphs. The prevalence estimates for the patients with full followup (n = 121) were calculated seperately.

Secondary analyses of the data included the calculation of the prevalence of pain, swelling, erosion, and joint space narrowing per forefoot joint. Relationships at baseline between 1) pain and swelling per MTP joint and 2) the erosion and joint space narrowing score per forefoot joint were calculated using Spearman's correlation coefficients (P values less than 0.05 were considered statistically significant). All analyses were performed using SPSS, version 15.0 (SPSS, Chicago, IL).

RESULTS

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

Patient characteristics.

The baseline characteristics of the patients are shown in Table 2. There were small differences between the patients with full followup (n = 121) and the patients without full followup (n = 727). However, these differences did not reach statistical significance. The percentages or mean scores for the baseline characteristics of the patients with full followup versus the patients without full followup were as follows: female sex 74% versus 68% (P = 0.16), age 52.9 years versus 55.5 years (P = 0.06), RF-positive 56% versus 50% (P = 0.24), DAS28 5.0 versus 5.2 (P = 0.15), SHS total 5.2 versus 3.7 (P = 0.26), and HAQ DI total score 1.5 versus 1.3 (P = 0.39).

Table 2. Patient (n = 848) baseline characteristics*
CharacteristicValue
  • *

    IQR = interquartile range; DAS28 = Disease Activity Score in 28 joints; SHS total = total Sharp/van der Heijde score for a subgroup of patients with a followup of at least 2 years; HAQ DI = Health Assessment Questionnaire disability index.

Female, %69
Age, mean ± SD years55.2 ± 14.2
Duration of symptoms, median (IQR)0.0 (0.0–1.0)
Rheumatoid factor positive, %51.3
DAS28, mean ± SD5.2 ± 1.2
SHS total, median (IQR)/mean ± SD0.0 (0.0–3.0)/4.1 ± 12.2
HAQ DI total score, median (IQR)1.1 (0.6–1.9)

Baseline prevalence of forefoot impairments and walking disability.

The prevalence of painful and swollen MTP joints, forefoot joint damage, and walking disability is shown in Table 3. The prevalence of painful and swollen MTP joints at baseline for the total cohort of 848 patients was 67.6% and 69.9%, respectively. The median number of painful and swollen MTP joints was 3. The prevalence of pain was the highest for MTP2, MTP3, and MTP4 (47.8%, 56.0%, and 50.2%, respectively) and the lowest for MTP1 and MTP5 (26.3% and 29.0%, respectively) (data not shown). The same trend was found for swollen MTP joints, with comparable percentages. Pain and swelling per MTP joint were moderately correlated (range r = 0.47–0.56, P < 0.01).

Table 3. Baseline prevalence of forefoot impairments and walking disability*
 ValueNo. patients evaluated
  • *

    MTP = metatarsophalangeal; IQR = interquartile range; SHS feet = Sharp/van der Heijde score of the feet for a subgroup of patients with a followup of at least 2 years; HAQ DI walking = Health Assessment Questionnaire disability index, walking disability subscale.

Painful MTP joints (≥1), %67.6848
Number of painful MTP joints, median (IQR)3.0 (0.0–6.0)848
Swollen MTP joints (≥1), %69.9848
Number of swollen MTP joints, median (IQR)3.0 (0.0–6.0)848
Erosions feet (≥1), %19.1539
Erosion score feet, median (IQR)/mean ± SD0.0 (0.0–0.0)/1.3 ± 4.9539
Joint space narrowing feet (≥1), %18.7539
Joint space narrowing score feet, median (IQR)/mean ± SD0.0 (0.0–0.0)/0.8 ± 2.6539
SHS feet, median (IQR)/mean ± SD0.0 (0.0–1.0)/2.1 ± 7.1539
HAQ DI walking (≥1), %56.7809
HAQ DI walking, median (IQR)1.0 (0.0–1.0)809

At baseline, the prevalence of forefoot erosion and joint space narrowing were 19.1% and 18.7%, respectively. In 8.9% of patients, both ≥1 forefoot erosion score and ≥1 forefoot joint space narrowing score were present. The mean erosion score of the feet was 1.3 (median 0). The mean joint space narrowing score of the feet was 0.8 (median 0). Analyses of the individual joints of the feet (MTPs and IP1) showed that erosions were the most frequent in MTP5 (9.5% of patients had ≥1 erosion score in at least 1 MTP5) and the least frequent in MTP2 (3.9%). Joint space narrowing was the most frequent in MTP1 and IP1 (7.4% and 10.0%, respectively) and the least frequent in MTP2 (2.0%) (data not shown). Erosions and joint space narrowing per forefoot joint were related (range r = 0.16–0.64, P < 0.01), with the lowest correlations for IP1 and MTP1.

The prevalence of disability in walking in the total cohort of 848 patients was 56.7%; 32% of patients reported mild walking disability, 20% reported moderate walking disability, and 4% reported severe walking disability. The median score of the HAQ walking disability subscale at baseline was 1.0.

No statistical differences were found between the clinical variables of the patients with full followup (n = 121) and the patients without full followup (n = 727). The mean scores of the clinical variables for the patients with full followup versus the patients without full followup were as follows: number of painful MTP joints 3.3 versus 3.4 (P = 0.98); number of swollen MTP joints 3.4 versus 3.5 (P = 0.74); erosion score feet 2.0 versus 1.2 (P = 0.22); and joint space narrowing score feet 0.8 versus 0.8 (P = 0.80). A tendency toward a difference was found for the HAQ DI walking subscale, for which the scores were 1.0 versus 0.7 (P = 0.06).

For the 121 patients with full followup, the prevalence of MTP pain and MTP swelling at baseline were 74.4% and 73.6%, respectively. The prevalence of forefoot erosions and joint space narrowing were 23.1% and 19.8%, respectively. Of these patients, 50.4% reported at least mild walking disability.

Prevalence of forefoot impairments and walking disability in the first 8 years of RA.

After an initial decrease in the first 2 years, the prevalence of pain and swelling of the MTP joints remained constant at ∼40–50% (Figure 1A). Except for at baseline, painful MTP joints were slightly more prevalent than swollen MTP joints. Sixty to 70% of the patients had an active disease during followup (DAS28 >2.6).

thumbnail image

Figure 1. Percentage of rheumatoid arthritis patients with A, active disease (Disease Activity Score in 28 joints [DAS28] >2.6), ≥1 painful metatarsophalangeal (MTP) joint, and ≥1 swollen MTP joint; B, total Sharp/van der Heijde score (SHS) of ≥1, a SHS of the feet of ≥1, an erosion score of the feet ≥1, and a joint space narrowing (jsn) score of the feet ≥1; and C, a Health Assessment Questionnaire (HAQ) walking disability subscale score of ≥1 and a total HAQ score of ≥1 during the first 8 years of the disease.

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In the first 2 years after initial presentation, the percentage of new patients with erosions in the forefoot increased rapidly (from 19.1% at baseline to 39.3% at 2 years' followup) (Figure 1B). From year 2 to year 8 the increase of new patients with forefoot erosions declined, resulting in 55.7% of patients having ≥1 erosion score of the forefoot at 8-year followup. When comparing the percentage of patients with a total SHS ≥1 with the percentage of patients with a SHS feet ≥1, ∼20% of patients had a score of only ≥1 on the radiographs of the hands, without damage to the feet, during the 8-year course of the disease. For the individual forefoot joints, the prevalence of erosion in MTP5 was still the highest at the eighth year of followup (T8) (40.2%). The prevalence of narrowing of IP and MTP1 at T8 were 18.6% and 26.8%, respectively.

The prevalence of patients experiencing mild to severe walking difficulty (a score of ≥1) stabilized at ∼40% after an initial decrease in the first year (Figure 1C). The same trend was found for the total HAQ DI score. The mean annual increase of the HAQ walking subscale score from T1 to T8 was 0.02 points.

The mean erosion score of the forefoot increased linearly (R2 = 0.99) (Figure 2). The mean rate of progression for forefoot erosion was 0.8 units per year with a mean erosion score of 7.9 at T8.

thumbnail image

Figure 2. Mean radiographic progression of the feet in rheumatoid arthritis patients with a followup of ≥2 years. Solid line indicates erosion and the dotted line indicates joint space narrowing.

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The mean forefoot erosion score of patients with full results (8 followup measurements) compared with the mean forefoot erosion score of the total number of patients (including dropouts and patients with a followup of <8 years) showed a similar course (Figure 3).

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Figure 3. Mean erosion score of the feet for patients with full results (dotted line) compared with the mean erosion score of the feet for the total of all patients included in the study (solid line).

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DISCUSSION

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

The present study investigated the prevalence of pain and swelling in the MTP joints, forefoot joint damage, and walking disability at initial presentation and during an 8-year followup in newly diagnosed RA patients.

At initial presentation, a high prevalence of painful and swollen MTP joints was found (67.6% and 69.9%, respectively), which decreased to ∼40–50% after 2 years. This is a rather high prevalence considering that medication is aimed at minimizing disease activity. To the best of our knowledge, no other recent data of MTP involvement at initial presentation and during the early course of RA have been reported; only total joint counts, as part of a disease activity score, have been reported. To confirm the high prevalence of MTP involvement observed in the present study, recent data from other centers are needed.

Pain and swelling per MTP joint were moderately correlated. We expected to find higher correlations because both pain and swelling are believed to be expressions of synovitis. However, pain without accompanying joint swelling can also be a symptom of mechanical overloading of joints. In an earlier study by our research group, a significant relationship between high forefoot pressure and pain was found in a population of RA patients with both early and established disease (23). Another explanation might be the large error term in assessing the pain and swelling of MTP joints that is generally assumed. However, to our knowledge no reliability studies have been performed to confirm this assumption.

In the present study, 19.1% of the patients' radiographs showed erosion and 18.7% showed joint space narrowing in ≥1 forefoot joint at initial presentation. Hulsmans et al reported a higher prevalence of erosion and joint space narrowing in the forefoot (37% for both) at baseline in their study (8). The differences in prevalence rates of erosions and joint space narrowing may be due to different study group selection criteria. Our study group consisted of an open cohort of early arthritis patients fulfilling the ACR criteria within the first year, whereas the study by Hulsmans et al included early RA patients who had participated in a randomized trial comparing different therapeutic strategies with second-line agents. Their study group may have been more homogeneous than ours.

Our results showed that during the first 2 years after initial presentation, a high percentage of patients with early RA developed erosions in the forefoot. In subsequent years, the increase in the percentage of patients with forefoot erosions declined, meaning that most patients with forefoot erosions already had erosions by 2 years. Consequently, the linear increase in the mean erosion score in these years was predominantly caused by the progression of erosions in patients who previously showed erosions in ≥1 forefoot joints. The study by Hulsmans et al provided additional information on the rate of progression per joint. It was concluded in that study that the rate of progression of newly damaged joints (in both hands and feet) declined and the rate of progression of already damaged joints increased during followup, leading to an equal contribution of progression of the SHS score at 5 years (8).

In our study, erosions were most frequent in MTP5 (9.5% of patients had MTP5 erosion in either foot) and least frequent in MTP2 (3.9%). The same trend was found by Hulsmans et al (8). We speculated that the frequent erosions in MTP5 might be due to the decreased loading of MTP5 compared with other MTP joints during walking at a self-selected speed (23, 24). As a consequence of this decreased loading, the cortex and subcortical bone of MTP5 might be weaker and therefore more vulnerable to the development of erosions. For MTP2 the same hypothesis can be generated, but in the opposite direction. In our study, MTP2 was one of the most painful and swollen MTP joints, but eroded less frequently. The cortex of MTP2 might be less vulnerable to erosions because it is the most heavily loaded MTP, resulting in a stronger cortex.

We reported both means and medians for forefoot joint damage in this study. The medians were found to be substantially lower than the means, which indicates that many patients had few or no radiographic abnormalities while patients who showed radiographic damage may have had many abnormalities (11).

The prevalence of walking disability at initial presentation was high (57%). After the first year, the prevalence of walking disability decreased and stabilized at ∼40%. However, the severity of the walking disability increased slowly at the rate of 0.02 points per year. This increase is equal to the results found in a study by Welsing et al in which the total HAQ DI score was used longitudinally (25). Walking disability can be influenced not only by forefoot involvement, but also by involvement of other lower extremity joints. Further investigation by our research group is aimed at the identification of predictors for walking disability during the course of RA.

There are some limitations of this study concerning the use of data from an open cohort. The main limitation is the dropout of patients, which may have resulted in selection bias. The rules of the EAC clinic were to follow up patients in strict intervals. Nevertheless, patients dropped out for various reasons during followup. The potential for selection bias was assessed in 3 different ways. First, a comparison between the demographics and clinical features at baseline for the patients with full followup (8 years; n = 121) and the patients without full followup (including dropouts; n = 727) revealed only small differences that did not reach statistical significance. Second, baseline prevalence estimates for forefoot pain and swelling, joint damage, and walking disability were computed separately using all data (n = 848) and using only data from patients with full followup (n = 121). These prevalence estimates differed only slightly, with a trend toward higher scores for the patients with full followup. Third, when comparing the mean erosion score of the patients with full followup with that of all patients, no substantial differences in the course were found. Based on these 3 findings, selection bias in patients with full followup is concluded to be minimal; however, the possibility of a slight overestimation of impairments and disability during the course is acknowledged.

Additionally, the selection of patients in this and other cohort studies was based on the definition of RA according to the ACR criteria within the first year. Although the diagnostic ability of these criteria in early arthritis was found to be nonoptimal (26), the ACR criteria are still being used as the gold standard for RA. Consequently, our data may contain patients with self-limiting arthritis and may miss patients who have undifferentiated arthritis but develop RA after the first year of followup. Even higher prevalence rates for foot symptoms can be expected when using more discriminative criteria.

Furthermore, the medical treatment history of patients with RA in this cohort, with a start in 1995, is heterogeneous. Around 2001 biologics were introduced, with possible effects on the frequency of foot impairments and walking disability. A recent study by Welsing et al (27) presented the differences on disease activity and functional ability in a recent cohort, in which the treatment strategy was more aggressive, compared with an older cohort. The authors concluded that the course of disease activity has become milder in more recent years. However, the results also showed that the HAQ DI did not show improvement, but instead a trend toward worsening in functional ability (27). Based on these findings, a possible improvement in foot impairments might not necessarily result in an improvement in self-reported walking ability.

An advantage of the current study is the use of foot variables that are routinely measured in early arthritis cohorts, making comparison with data from other cohorts possible in the future.

The results of the present study quantitatively emphasize the importance of forefoot involvement in patients with RA. The prevalence rates for pain and swelling of the MTP joints and walking disability are initially high and then stabilize, while the prevalence and severity of forefoot joint damage increase during an 8-year course of RA. The results indicate the need for further research concerning the early diagnosis and treatment of foot symptoms in RA.

AUTHOR CONTRIBUTIONS

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

Ms van der Leeden 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. Steultjens, van der Leeden, Ursum, Dahmen, Roorda, van Schaardenburg, Dekker.

Acquisition of data. Steultjens, van der Leeden, Ursum, van Schaardenburg.

Analysis and interpretation of data. Steultjens, van der Leeden, Dahmen, Roorda, van Schaardenburg, Dekker.

Manuscript preparation. Steultjens, van der Leeden, Dahmen, Roorda, van Schaardenburg, Dekker.

Statistical analysis. Steultjens, van der Leeden, Dekker.

Acknowledgements

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

We thank the clinical research assistants, E. de Wit-Taen and A. Abrahams, for collecting the data from the EAC. We also thank M. van der Esch for his contribution to the preparation of the manuscript.

REFERENCES

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