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Clinical and epidemiological research
Extended report
Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure
  1. U Møller Døhn1,
  2. A Boonen2,
  3. M L Hetland1,3,
  4. M S Hansen4,
  5. L S Knudsen4,
  6. A Hansen5,
  7. O R Madsen6,
  8. M Hasselquist7,
  9. J M Møller7,
  10. M Østergaard1,4
  1. 1
    Department of Rheumatology, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
  2. 2
    Department of Internal Medicine, Division of Rheumatology, Maastricht University Hospital, Maastricht, The Netherlands
  3. 3
    The DANBIO registry, Copenhagen University Hospital at Hvidovre, Hvidovre, Denmark
  4. 4
    Department of Rheumatology, Copenhagen University Hospital, Herlev, Denmark
  5. 5
    Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet, Denmark
  6. 6
    Department of Rheumatology, Copenhagen University Hospital at Gentofte, Gentofte, Denmark
  7. 7
    Department of Diagnostic Radiology, Copenhagen University Hospital at Herlev, Herlev, Denmark
  1. Correspondence to Dr U Møller Døhn, Department of Rheumatology, Copenhagen University Hospital at Hvidovre, Kettegaard Allé 30, 2650 Hvidovre, Denmark; umd{at}dadlnet.dk

Abstract

Objective: With computed tomography (CT) and radiography, to investigate if repair of bone erosions, defined as regression of erosion scores, occurs during adalimumab treatment of patients with rheumatoid arthritis (RA).

Methods: Fifty-two patients with RA, naïve to biological agents, with at least two low-grade radiographic erosions in the wrist or metacarpophalangeal (MCP) joints in the same (index) hand, initiated adalimumab 40 mg subcutaneously every other week. Thirty-five patients completed the study (median age 61 years (interquartile range 46–68), disease duration 8 years (3–15)). CT of the index wrist and MCP joints 2–5 and radiographs of hands and forefeet were obtained at baseline, 6 and 12 months. Images were evaluated by investigators blinded to chronology and clinical data, and assessed according to Sharp/van der Heijde (radiographs) and OMERACT RA MRI scoring (CT) methods.

Results: Disease activity score, C-reactive protein, tender and swollen joints count and Health Assessment Questionnaire score had all decreased at 6 and 12 months (wilcoxon signed-ranks test p<0.001). No significant change in any imaging parameters of joint destruction was observed at 6 and 12 months. High intrareader agreements were reached (mean intraobserver intraclass coefficients: 0.96 (CT) and 0.97 (radiography)). The number of patients with change scores exceeding the smallest detectable change (SDC) was comparable on CT and radiography, as were the proportions of patients progressing/regressing. Decreased erosion scores at 12 months were registered in 1.6% and 1.8% of sites assessed on CT and radiography, respectively.

Conclusion: Repair of erosions in adalimumab-treated patients with RA is rare, but erosive regression, exceeding the SDC, on CT and radiography occurred. The very limited overall erosive progression supports the view that joint destruction is minimal during adalimumab treatment of patients with RA.

https://doi.org/10.1136/ard.2008.097048

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    Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease with symmetric inflammation of peripheral joints, affecting approximately 1% of the population.1 2 RA is related to progressive disability with an increased risk of health-related retirement and an increased mortality rate compared with the general population.3 However, important improvements in patient outcome have been seen with earlier and aggressive use of combinations of conventional disease-modifying antirheumatic drugs,4 5 6 7 8 and the introduction of tumour necrosis factor α antagonists (anti-TNF).9 10 11 12 13 Based on scores of radiographic data from randomised placebo controlled studies, it appears that erosive progression is arrested and occasionally even reversed with a combination of methotrexate (MTX) and anti-TNF in patients with active RA.10 11 12 14 However, radiography is a two-dimensional visualisation of a three-dimensional anatomy, and is less sensitive for the detection of bone erosions15 16 17 and less sensitive to change than magnetic resonance imaging (MRI).18 19

    High-resolution multidetector computed tomography (CT) is a tomographic radiographic imaging method based on attenuation of x-rays. Because of a markedly higher x-ray attenuation by calcified tissue than by soft tissues, bones are depicted in detail with great contrast to the surrounding soft tissues. CT seems to be even more sensitive for the detection of bone erosions than radiography, MRI and ultrasonography and it can be considered a standard reference method for the detection of erosive bone destructions in patients with RA.20 21 For these reasons we expected that CT would prove to be a useful imaging technique for a detailed investigation of bone erosions and for determining whether erosion repair occurs. As far as we know, this study is the first longitudinal RA clinical trial in which CT findings are used as the primary outcome measure.

    The primary objective of this study was, by means of CT, to investigate frequency and extent of repair of erosions in patients with RA treated with the fully human TNFα antagonist adalimumab in combination with MTX.

    Patients and methods

    Fifty-two patients with RA, fulfilling the 1987 American College of Rheumatology criteria (ACR1987),22 were included in this investigator-initiated study. Inclusion criteria were active RA with a 28-joint count Disease Activity Score (DAS28 (V3)-C-reactive protein (CRP)) >3.2, indication for anti-TNF therapy according to the treating rheumatologist, treatment with MTX for at least 4 weeks before inclusion, no previous treatment with any biological agent and a minimum of two low-grade erosions (Larsen grade 2–3) in the wrist or metacarpophalangeal (MCP) joints in the same hand (index hand). Exclusion criteria were treatment with disease-modifying antirheumatic drugs other than MTX, oral glucocorticoids in a dose exceeding 10 mg/day, parenteral glucocorticoids or change in dose of oral glucocorticoids within 4 weeks before inclusion or any medical conditions contraindicating anti-TNF treatment.

    Patients were treated with adalimumab 40 mg subcutaneously every other week. Tapering of MTX or oral glucocorticoids during the study was allowed.

    Only patients completing the study protocol and had CT and radiography done at all time points were included in the per-protocol (PP) analysis. An intention-to-treat (ITT) analysis was also performed.

    The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee, the Danish Medicines Agency and the Danish Data Protection Agency. Written informed consent was obtained from all patients before any study-related procedures. Abbott Denmark provided financial support to the study, but had no influence on, or involvement in, the planning or design of the study, data collection, data analysis or preparation of the manuscript.

    Imaging

    Radiography and CT were performed on one day before inclusion and after 6 and 12 months. Before inclusion, radiographs of the hands were evaluated by a senior radiologist (MHa) to decide if the radiographic inclusion criterion was fulfilled and to choose the index hand. If patients dropped out from the study we attempted to obtain renewed imaging for the ITT analysis.

    Images were read blinded to chronology, with the assessors of CT (MØ) and radiographs (AB) unaware of clinical and other imaging data. For calculating intrareader intraclass correlation coefficients (ICCs) and the smallest detectable change (SDC) on radiographic and CT scores, a subset of 10 complete sets of representative images was re-evaluated by the same assessors at least 12 weeks after the initial reading.

    Radiography

    Radiography was performed on a Philips Digital Diagnost unit (Philips Medical Systems, Hamburg, Germany) (resolution 0.143 mm). Posterior–anterior and semisupine projections of both hands and posterior–anterior projection of both feet were obtained. Radiographs were evaluated according to the van der Heijde modified Sharp score.23 Overall, 16 and 6 sites in each hand and foot, respectively, were scored for erosions (score range 0–280), and 15 and 6 joints in each hand and foot, respectively, were scored for joint space narrowing (score range 0–168).

    Computed tomography

    A Philips Mx8000IDT multidetector unit (Philips Medical Systems, Cleveland, Ohio, USA) was used for obtaining CT images of index wrist and MCP joint 2–5 (parameters: voxel-size 0.4 mm×0.4 mm×0.4 mm, pitch 0.4 mm, slice spacing 0.4 mm, overlap 50%, 90 kV, 100 mAs). Images were reconstructed in the coronal and axial planes with a slice thickness of 0.4 mm. For better comparison of erosion size at the three time points, images were reconstructed in a standardised manner.

    Erosion score

    CT images were scored for erosions according to the definitions and principles of the OMERACT RA MRI scoring method. Briefly, erosions were defined as a sharply marginated bone lesion, with correct juxta-articular localisation, visible in two planes with a cortical break seen in at least one plane. Twenty-three bones of the hand were assigned a score by the percentage of bone volume involved (score 0–10, by 10% volume increments), leading to a total erosion score for one hand ranging from 0 to 230.24 25

    Erosion volume measurement

    To obtain an estimate of bone erosion volumes, erosions were measured with the OsiriX medical imaging software (DICOM viewer for Apple computers). All MCP joint erosions, identified on CT at the primary evaluation, were manually outlined on all coronal images where visible. Measurement of erosion volume was performed twice on all patients by one author (UMD) with at least a 1-week interval between measuring on the same sets of images. The mean of the two measurements was used for the analysis. ICC and the SDC for erosion volume were calculated based on all patients.

    Clinical assessment

    Patients were seen at baseline and at weeks 2, 6, 12, 26, 39 and 52 by the same senior rheumatologist. Assessment of physical function by the Health Assessment Questionnaire (HAQ) and assessment of 28 joints for tenderness and swelling was performed at all visits. Standard blood samples, including CRP, were obtained at all visits. Clinical data were entered into case report forms and into the Danish nationwide registry on rheumatological patients (DANBIO).26 Disease activity was assessed by the DAS28 (DAS28(3)-CRP) score.

    Statistics

    The primary analysis was done as a “per-protocol” analysis on patients adhering to the study protocol, and for whom all imaging at all time points was successful. The primary outcome was change in scores of joint destruction and bone erosion volume from baseline through 12 months. The main results are reported with descriptive statistics. The Wilcoxon signed-rank test was used for change within patients. For comparison between groups, the Mann–Whitney test was used for non-dichotomous variables and the Fisher exact test for dichotomous variables. p Values <0.05 were considered significant.

    Based on the images that were scored twice, the SDC was calculated for radiographic scores, CT erosion score and CT erosion volume, as suggested by Bruynesteyn et al27 using the formula:

    SDC = ±1.96×SDΔ(CHANGE-SCORES)/(√2×√k)

    where SDΔ(CHANGE-SCORES) is the standard deviation of change scores and k the number of readings. To compare reliability between different scores, the SDC expressed as percentage of the highest actually obtained score (SDC%) is reported. Single measure intraobserver ICCs for status and change scores on CT and radiography and for CT erosion volume were calculated.

    The ITT analysis was done using the last observation carried forward (LOCF) approach, and for the ACR’s improvement response criteria (ACR20/50/70) and the European League Against Rheumatism (EULAR) response rates, patients were considered non-responders if they were excluded from the study. When data were missing, imputation by linear interpolation/extrapolation was done. The Statistical Package for the Social Sciences (SPSS), version 15.0 was used.

    Results

    Fifty-two patients were included in the study, of whom 35 patients (20 women, 15 men) were included in the per-protocol analysis. Sixteen patients were excluded from the study and the primary analysis owing to lack of efficacy (n = 5), adverse events (n = 6) or violations to the study protocol (n = 5; two patients discontinued adalimumab treatment on their own, two patients paused adalimumab treatment for at least two consecutive injections and one patient had a baseline DAS28 <3.2), while one was omitted from the primary analysis owing to technical CT problems. All patients had baseline imaging and 48 had at least one follow-up imaging. No significant differences in the presented baseline values between the two groups were observed, except for more women in the PP group (table 1).

    View this table:
    Table 1

    Baseline disease characteristics and clinical response rates for the intention-to-treat and the per-protocol groups

    Clinical findings

    For the PP group, a significant decrease in the mean DAS28 compared with baseline was observed (4.9 vs 3.0 and 2.7 at 6 and 12 months, respectively, Wilcoxon signed rank test; p<0.001). The mean tender and swollen joints count, CRP and HAQ score were also significantly reduced at 6 and 12 months compared with baseline (p<0.001). For the ITT group, a significant decrease in the mean DAS28 compared with baseline was observed (4.8 vs 3.4 and 3.1 at 6 and 12 months, respectively, p<0.001). The mean tender and swollen joint count, CRP and HAQ score were also significantly reduced at 6 and 12 months (p<0.001). See table 1 for patients obtaining ACR20/50/70 response, EULAR good response and DAS remission in both groups.

    Imaging

    No significant mean difference in any of the investigated parameters of joint destruction was observed at 6 or 12 months compared with baseline. Values on change scores on radiography and CT are presented in table 2, including the number of patients with a definite change, defined as a change score exceeding the SDC at 6 and 12 months. It is noted that both by radiography and CT a minimal mean progression was observed at 6 and 12 months. The proportion of patients with an overall regression and progression above the SDC was similar, and comparable between imaging modalities. In the ITT analysis, with LOCF from a patient’s final visit while still receiving adalimumab treatment, similar results on change scores were found (table 2).

    View this table:
    Table 2

    Change in scores and number of patients with progression and regression exceeding the smallest detectable change

    The number of bones with a decreased erosion score ⩾1 point on CT at 12 months was 13 (1.6% of the total number of bones assessed), and the number of sites with a decreased erosion score on radiography was 27 (1.8% of the total number of sites assessed), while an increase in erosion score was seen in 18 (2.2%) bones on CT and in 30 (1.9%) sites on radiography. At baseline, 483 (60%) of the bones assessed on CT had erosions and 385 (25%) of the assessed sites on radiographs had erosions. Intraobserver ICCs on status scores were between 0.94 and 0.99 at all time points for all parameters on radiography, between 0.96 and 0.97 for CT erosion scores and 0.99 at all time points for CT erosion volume measurements. ICCs for change scores were between 0.15 and 0.76 on radiography, 0.89 and 0.95 for CT scores and 0.89 and 0.93 for CT erosion volume. ICCs and SDC are presented in table 3.

    View this table:
    Table 3

    Intraclass correlation coefficients and smallest detectable change for scorings of radiographs and CT and volume measurements on CT

    Discussion

    Earlier studies have shown that treatment with anti-TNF in combination with MTX is efficacious, safe and capable of slowing radiographic progression, and perhaps even to some extent reverting established destructions in patients with RA.10 11 12 The aim of this investigational study was to establish if true regression of erosions can occur during adalimumab treatment of patients with RA. In this first longitudinal CT study on patients with RA, we could not document an overall mean regression in erosion scores through 12 months on either CT or radiography even in the primary analysis on completers—that is, patients with persistent good clinical response to adalimumab and receiving treatment according to recommendations. A small minority of patients, however, had a decreased erosion score exceeding the SDC (6 (17% of patients) on CT and 3 (9%) on radiography). Furthermore, as a sign of erosive regression, decreased erosion scores were seen in a small proportion of the sites assessed on CT (1.6%) and radiography (1.8%) (fig 1). However, erosive progression was also observed (fig 2). The results from the ITT analysis were similar to those of the PP analysis. So even though this study confirmed that repair of erosions is a rare phenomenon, it provides strong support for the suggestion that erosive progression is minimal when patients with RA are treated with anti-TNFs in combination with MTX.

    Figure 1
    Figure 1

    The second metacarpophalangeal joint of a patient with rheumatoid arthritis with an erosion (arrows) illustrated on CT in the coronal (A, D, G) and axial (B, E, H) planes, and radiography in posterior–anterior projection (C, F, I). Regression in size of the bone erosion is seen on CT, and reflected by a decreased CT erosion score from 2 at baseline to 1 at 6 and 12 months, and an estimated erosion volume of 72, 34 and 27 mm3 at baseline, 6 and 12 months, respectively. The Sharp/van der Heijde erosion score of the joint was 1 at all time points. This patient was in 28-joint count Disease Activity Score (DAS28) remission (DAS28 <2.6) from week 2 to month 12.

    Figure 2
    Figure 2

    The third metacarpophalangeal joint of a patient with rheumatoid arthritis on CT in the coronal (A, D, G) and axial (B, E, H) planes, and radiography in posterior–anterior projection (C, F, I) illustrating erosive progression at 6 and 12 months. New erosions are seen on CT at the metacarpal head in two planes (white arrows) and the base of the proximal phalanx (open arrows). The CT erosion scores at baseline, 6 and 12 months were 0, 1 and 2 for the metacarpal head and 0, 1 and 1 for the proximal phalanx, respectively. The estimated volume of the erosion at the metacarpal head increased from 0 to 24 mm3 at 12 months. No erosion was identified on radiographs at baseline, 6 or 12 months. This patient had a 28-joint count Disease Activity Score (DAS28) of 5.9 at baseline, and was continuously above 4.0 through 9 months; thereafter the patient went into DAS28 remission (DAS28 <2.6).

    The reliability of the data was strongly supported by high levels of reproducibility in reading CT images and radiographs (table 3). The low to moderate ICCs observed for change scores on radiography can, at least partly, be explained by the very limited range in change scores in the material, where small differences have a profound effect on the ICC. Inter-reader reliability was not tested in this study; however, both readers of radiography and CT have vast experience from former RA imaging studies, including studies testing inter-reader reliability. The sensitivity to change of scores on both CT and radiography were documented, as both methods revealed a substantial proportion of patients with a change in scores above the SDC (table 2). The different imaging methods showed no marked difference in sensitivity to change per patient, and also at the single joint level the proportion of sites showing a changed erosion score from 0 to 12 months was similar (3.9% on CT vs 3.7% on radiography). Measuring erosion volumes did not improve the sensitivity to change in this study.

    The proportion of sites with change in erosion scores on radiography is in agreement with a study by van der Heijde et al, which also reported a low frequency of joints with decreased (4.5%) and increased (3.7%) erosion scores at a 1-year follow-up of patients receiving etanercept.12 28 The small, and not statistically significant, increase in the mean scores of joint destruction on radiography that was found in this study is in good agreement with earlier radiographic data on adalimumab-treated patients with RA.11 In the ITT analysis—that is, also including patients with an inadequate response to treatment, the progression of joint damage was comparable to that found in the PP analysis, supporting the view that erosive progression may be minimal even in patients without a clinical response.14 29

    In our study we defined repair as a negative change in scores in standardised scoring methods, which are based entirely on the number and size or erosions. Work is in progress under the banner of OMERACT to study whether features other than erosion number and size should be considered when evaluating radiographic repair.28 30 Trained readers agree well about which images show erosions that are better and worse when they are presented with concealed chronology; however, limited consensus on specific items such as cortication or filling-in of erosions has been found.31 Furthermore, a large degree of variability between expert readers in scoring different features of repair has been reported, except for assessment of the size of erosions32; for these reasons, scoring features other than erosion size do not yet seem justified.

    Experiences from comparative studies of radiography, MRI and CT have shown that CT is more sensitive for the detection of bone erosions,20 21 and therefore we considered that CT would be the optimal imaging technique to assess repair of erosions; subtle cortication and filling-in with calcified tissue, especially, were expected to be visualised with greater detail on CT than radiography. We applied the principles from the OMERACT RA MRI scoring system for scoring bone erosions on CT, and even though the scoring system was not developed for CT images we found it reasonable to use, owing to the similar tomographic visualisation of joints on CT and MRI. We have previously shown good inter-reader agreement in scoring CT images,20 and very good intrareader agreement was reached in this study, suggesting that RA bone erosions can also reliably be scored with CT.

    In order to obtain an accurate and quantitative assessment of erosion size, we estimated volumes of erosions in the MCP joints on CT. Measuring erosion volume had a very high level of reproducibility in this study, but also in previous studies,33 34 35 suggesting a potential role of erosion volume as an outcome measure of structural joint damage in longitudinal studies. The lack of significant overall progression in erosion volume also suggests that almost no erosive progression occurred in this study.

    A limited number of joints and joint regions can be examined by CT owing to the exposure to ionising radiation. Consequently, a smaller number of sites were assessed by CT than by radiography (23 vs 44), which potentially leads to a risk of missing signs of erosive progression by CT compared with radiography. However, an inclusion criterion in this study was the presence of moderate erosive changes on radiography in at least two sites of the index hand, thereby increasing the chance that CT covered a region in which a change in erosion size could be detected. We chose patients with not too severely damaged joints of the index hand, because we expected that small erosions had a greater chance of repair than large erosions.

    Although not a primary aim of the study, we noted that very good clinical response rates and a significant decrease in all investigated parameters of clinical disease activity was obtained, and this was also observed in the ITT analysis. The clinical results in this study are in good accordance with previous reports from other RA studies on adalimumab.11 36

    In conclusion, repair of erosions in patients with RA treated with adalimumab is rare. However, in a small proportion of patients, erosive regression on CT and radiography was found to exceed the SDC. Furthermore, definite examples of erosive regression at the single joint level were documented by CT in this 1-year follow-up study. The very limited mean overall progression of bone erosions on CT and radiography that was found at 1 year supports the view that erosive progression is minimal in patients with RA treated with adalimumab in combination with MTX.

    Acknowledgments

    We thank Professor Henrik S Thomsen who allowed all the imaging procedures to be carried out at the Department of Diagnostic Radiology, Copenhagen University Hospital. We also thank all patients who participated in the study.

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    Footnotes

    • Funding Abbott Denmark and the Danish Rheumatism Association provided financial support for the study.

    • Competing interests MO has received consulting fees, speaking fees and/or research grants from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Leo Pharma, Novartis, Novo, Pfizer, Roche, Schering-Plough and UCB-Nordic and Wyeth.

    • Ethics approval Approval from the local ethics committee, the Danish Medicines Agency and the Danish Data Protection Agency.