PROGNOSTIC VALUE OF CONTRAST ...

British Journal of Rheumatology 1996;35(siippL 3)26-30

PROGNOSTIC VALUE OF CONTRAST ENHANCED Gd-DTPA MRI FOR DEVELOPMENT OF BONE EROSIVE CHANGES IN RHEUMATOID ARTHRITIS V. JEVTIQ* I. WATT.f B. ROZMAN4 M. PRESETNIX4 D. LOGAR, % S. PRAPROTNIK^ M. TOMSIC4 A. SIPEK4 M. KOS-GOLJA4 A. SEPE,§ O. JARH,§ F. DEMSAR,§ P. MUSIKIC^ and G. CAMPION^ *Radiology Institute, University Medical Centre Ljubljana, Slovenia, fDepartment ofClinical Radiology, Bristol Royal Infirmary, Bristol, f Department of Rheumatology, University Medical Centre Ljubljana, Slovenia, § Institute Jozef Stefan, Ljubljana, Slovenia and^Clinical Research Department, Amgen Synergen B V, The Hague, The Netherlands

SUMMARY Conventional radiograms have been used to quantitate the progression of rheumatoid arthritis, mainly through the assessment of bone erosions, but this approach has many limitations. It has been suggested that an advantage of contrast-enhanced Od-DTPA MRI over radiography may be its prognostic value due to its ability to show the natural history of active destructive to inactive fibrous pannus. The aim of this study was to evaluate the possible prognostic value of MRI for future development of bone erosive changes in small hand joints in patients with RA. The results of the study confirm that in joints in which inflammatory active pannus is shown by contrast-enhanced MRI, progression of bone-destructive changes can be expected. KEY WORDS: Magnetic resonance imaging,

Progression of bone erosions, Rheumatoid arthritis.

MATERIALS AND METHODS Fifteeen patients with RA (all females, mean age 52 yr) who had been enrolled in a double-blind, doseranging, placebo-controlled Anakinra (recombinant IL-lra, Amgen, USA) drug study were selected using the Larsen score [3]. The code has not been opened to date. Only the joints with early erosive changes demonstrated on plain films were included (grade II according to Larsen). Altogether 30 small hand joints (24 metacarpophalangeal and 6 proximal interphalangeal) examined by conventional radiography and MRI were analysed at the beginning of the study and again 6 months later. The clinical diagnosis of rheumatoid arthritis was made according to the revised American Rheumatism Association (ARA) criteria [4]. In all patients, standard postero-anterior hand and wrist radiographs were taken. MRI was performed on a Bruker Biospec System (Bruker, Germany). An Oxford Instruments, UKA 2.35 T magnet with a bore diameter of 22.5 cm was used; so that the probe filling factor was optimal and no surface coils were needed. Spin echo sequences with T\ weighted images (7*R 600 ms, 7E 18 ms, two averages) and T2 weighted images (!TR 2000 ms, TE 90 ms, two averages) were used, followed by T\ weighted postcontrast examination (using the same parameters) immediately after an i.v. injection of Gd-DTPA (0.1 mmol/kg body mass, Magnevist®, Schering), given as a bolus through a cannula. The field of view was 12 cm with a data acquisition matrix of 256 x 256. All the joints were imaged in the coronal plane using consecutive 3 mm thick slices. Plainfilmsand MRI were interpreted qualitatively by two radiologists blinded to clinical findings. In case of disagreement a consensus was reached. The entry criteria were early erosive changes (grade II according to Larsen). The marginal areas of bone erosions were

Correspondence to: V. Jevtic, Radiology Institute, University Medical Centre Ljubljana, Slovenia.

O 1996 British Society Tor Rheumatology

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INTRODUCTION THE MOST important event during the course of RA is the transition of synovitis to pannus, which usually represents the beginning of irreparable joint destruction. The evolution of erosions varies with the course of disease. It may be discontinuous, demonstrating phases of cessation followed by even remineralization of small erosions, but the progression of erosions leading to severe joint destruction is more typical. Moreover, progressive, destructive radiographic changes are frequently observed, despite a clinical improvement as a result of therapy. Consequently, the ability to predict the future development of bone erosive changes is of utmost clinical importance. Traditionally, conventional radiographs have been used to quantitate the progression of RA, mainly through the assessment of bone erosions, but this approach has many limitations [1]. The value of contrast-enhanced gadolinium chelate (Gd-DTPA) MRI for the non-invasive direct demonstration of synovial proliferation and bone erosions is now well established. Recently, it has been suggested that an important advantage of MRI over radiography may be its prognostic value due to its ability to show the natural history of active destructive to inactive fibrous pannus [2]. The aim of our prospective 6-month follow-up study was to evaluate the possible prognostic value of contrast-enhanced Gd-DTPA MRI for future development of bone erosive changes in small hand joints in patients with RA.

JEVTIC ETAL: PROGNOSTIC VALUE OF Gd-DTPA MRI

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TABLE I Comparison between MRI and conventional radiography at the beginning of the study and after a 6-month follow up (30 joints) 0 months MRI (pannus)

6 months Radiography*

Radiographyb

MRI (pannus) Inflammatory active

Moderately active

Non-active fibrous (71 = 6)

Jfiflnmmntnry aCtTVC (71 = 12)

distinct margins

1

2

distinct margins

3 indistinct margins (71=6)

indistinct margins distinct margms

2 1*

2

1

mdistmct margms (71 = 4)

Moderately active

distinc* margin* (/»= 12)

1

1

2

6

2

distinct margin* indistinct margin* (71 = 8)

1 indistinct margin*

Non-active fibrous

distinct margins

indistinct margin* 2

distinct margins (« = 2) indistinct margin* distinct margins

1

indistinct margins

indistinct margins

0 months: 30 joints; grade II according to Larsen's score. 6 months: 29 joints; grade n according to Larsen's score, one joint (*) grade III according to Larsen's score. 'Erosions: distinct margins n = 20; indistinct margins n = 10. b Erosions: distinct margins n = 12; indistinct margins (n = 18).

carefully analysed using a magnifying lens and those with indistinct margins were considered as having more aggressive local inflammation. MRI findings permitted the differentiation of subsets of disease [5] including findings compatible with inflammatory, active, destructive pannus; moderately active pannus (nodular masses within the erosions and homogeneous marked contrast enhancement or inhomogeneous moderate enhancement on the 7*i W post-contrast images) and inactive fibrous pannus (low signal intensity masses on all sequences). RESULTS The results of the study are summarized in Table I. At the beginning of the study, 30 joints were classified as grade II according to the Larsen score. Six months later only one joint showed larger erosions and progression from grade II to grade III. At the beginning of the study the margins of the erosions were indistinct on plain films in only 10 joints, suggesting more aggressive local inflammation. MRI findings compatible with inflammatory active pannus were revealed in 12 joints, and with moderately active pannus in 15. Quite a good correlation was found with the quality of synovial proliferation as demonstrated by MRI in nine out of 10 of these joints. In six joints the erosions were filled with inflammatory, active,

destructive pannus, while in three joints MRI findings were compatible with moderately active pannus. The discrepancy between plain film and MRI evaluation was shown in only one of these 10 joints in which MRI revealed inactive fibrous pannus and the bone erosion was indistinctly defined. At entry to the study the margins of bone erosions were distinct in 20 joints. Only in two of them did MRI findings show inactive fibrous pannus in which distinct margins could be expected. In the remaining 18 joints there was discrepancy between plain film and MRI evaluation. MRI suggested inflammatory active destructive pannus in six cases and moderately active pannus in 12. Follow-up conventional radiographic evaluation after 6 months demonstrated indistinctly defined erosions in 18 joints, suggesting active local inflammation and progression of RA. In 16 of the 18 joints with indistinct margins or bigger erosions on plain films, MRI findings were in accordance, demonstrating inflammatory active pannus in six (Figs 1A,B and 2A.B) and moderately active pannus in 10. The remaining two erosions were filled with fibrous inactive pannus. In one case at the beginning of the study, MRI showed inflammatory destructive pannus, which had changed to fibrous after 6 months. In the second case MRI findings of inactive fibrous pannus were revealed at the beginning of the study and after 6 months.


(71 = 3)

distinct margin* 2

MRI IN THE ASSESSMENT OF RA (A)

(A)

(B)

(B)

Fio. 2.—Plain film and MRI examination after 6 months. (A) Plain film. Progression of destructive changes with bigger bone erosions is shown (arrowheads). (B) MRI examination. Tiw spin echo post-contrast image. The persistence of marked contrast enhancement of inflammatory active pannus is revealed (arrowheads).

Of the 12 joints with distinct margins of erosions seen on plain films after 6 months, MRI was in accordance in four joints in which the erosions were filled with inactive fibrous pannus. In two of these four joints, MRI showed the persistence of fibrous pannus from the beginning of the study, while in the other two a transition of moderately active to inactive fibrous pannus has been demonstrated. In the remaining eight joints with distinct margins of erosions seen on plain films at 6 months, MRI was not in accordance, showing inflammatory active pannus in two joints and moderately active pannus in six joints. At the beginning of the study in the former two joints, MRI showed inflammatory active destructive pannus in one and moderately active pannus in the other, while plain films demonstrated distinctly marginal erosions. In the latter six joints with moderately active pannus on a follow-up examination, MRI revealed different qualities of synovial proliferation at the entry to the study. These ranged from inflammatory active destructive pannus (four joints, two with distinct and two with indistinct margins of erosions) to moderately active pannus (two joints, one each with distinct and indistinct margins of erosions).

DISCUSSION Plain film radiography is currently the most widely used imaging modality for the demonstration of bone erosions. Most existing scoring systems based on conventional radiography are designed to represent the progression of RA, mainly through the demonstration of enlargement of the present erosions and the appearance of new erosions [3, 6]. However, none of them score healing of erosions. Changes seen on conventional radiographs which reflect activity of RA are not reliable or easy to confirm particularly with regard to the destructive phase of the disease. It is widely accepted that 'active' erosions have poorly defined edges and that the bone looks as if it had been nibbled away, indicating the presence of active destructive pannus. On the other hand, the appearance of distinct margination and eventually a sclerotic border have been considered as signs of healing and 'non-active' erosions due to transition of active destructive to inactive fibrous pannus [1]. However, it is well known that the radiographic signs lag behind histopathological changes, especially remineralization, since RA characteristically does not stimulate the


Fio. 1.—Plain film and MRI examination at entry to the trial. (A) Plain film. Discrete bone erosions are shown on the radial aspect of the third proximal interphalangeal joint (arrowheads). (B) MRI examination. Tiw spin echo post-contrast image. Marked contrast enhancement of inflammatory active pannus is revealed (arrowheads).

JEVTIC ETAL: PROGNOSTIC VALUE OF Gd-DTPA MRI

and where the MRI findings were compatible with inflammatory active pannus. At entry to the study, the discrepancy possibly reflected too short a period from the onset of RA for the development of more pronounced bone destruction by inflammatory active synovial proliferation revealed using MRI. A further explanation for the lack of correlation on a follow-up examination may include possible local differencies in bone resistance to destructive pannus (especially over the short period of 6 months) and perhaps errors in the evaluation of plain films. Although the erosions of these joints were distinctly defined, due to the presence of inflammatory active pannus seen on MRI, future progression of bone erosive changes could be expected. However, altogether in 16 out of 18 joints with progression of bone-erosive changes as seen on plain films at the 6-month follow-up examination, MRI showed inflammatory active pannus at the beginning of the study. In two joints with inactive fibrous pannus revealed by MRI at entry to the study, no further development of bone destruction was seen on a follow-up evaluation by plain film. The results of this study confirm that in joints in which inflammatory active pannus is shown by contrast-enhanced MRI, progression of bone-destructive changes can be expected, even if erosions are not particularly impressive at the initial examination and the Larsen score does not significantly worsen on follow up. Although a six-month observation period is not long enough for a definite conclusion, and a long-term follow-up study is necessary, our preliminary results suggest that contrast-enhanced Gd-DPTA MRI of small hand joints in patients with early erosive RA may have possible prognostic value for the future development of bone-destructive changes. REFERENCES

1. Brower AC. Use of the radiograph to measure the course of rheumatoid arthritis. Arthritis Rheum 1990;33:316-24. 2. Jevtic V, Rozman B, Watt I, Presetnik M. Grand round— the use of contrast enhanced MR in the assessment of the therapeutic response to a disease modifying antirheumatic drug. Br J Rheumatol 1995^34:956-9. 3. Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard referencefilms.Acta RadiolDiag 1977;1&481-91. 4. Arnett FC, Edworthy SM, Block DA. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988^1:315-24. 5. Jevtic V, Watt I, Rozman B, Kos-Golja M, Rupenovic S, Logar D, Presetnik M, Jarh O, Demsar F, Musikic P, Campion G. Precontrast and postcontrast (Gd-DTPA) magnetic resonance imaging of hand joints in patients with rheumatoid arthritis. Clin Radiol 1993;4&176-81. 6. Sharp JT. Radiographic evaluation of the course of articular disease. Clin Rheum Dis 1983^:541-57. 7. Konig H, Sieper J, Wolf KJ. Rheumatoid arthritis: evaluation of hypervascular and fibrous pannus with dynamic MR imaging enhanced with Gd-DTPA. Radiology 1990;/76:473-7. 8. Scott DL, Houssien DA, Laasonen L. Proposed


production of bone. Therefore, the quality of pannus (active destructive or inactive fibrous) cannot be evaluated directly from plain films or by the margination of erosions. Consequently, prediction of future development of destructive changes is not possible. The results of Konig et al. [7] suggest that contrast enhancement, following i.v. injection of Gd-DTPA, can demonstrate hypervascular, pathologically permeable, inflammatory synovial proliferation and may be able to distinguish inflammatory from non-inflammatory fibrous pannus. MRI is capable of demonstrating directly different types of synovial proliferation within bone erosions, giving images consistent with active destructive and inactive fibrous pannus. Thus MRI has the potential to have prognostic value with regard to future development of bone destruction. Since radiographic signs lag behind histopathological changes MRI findings could be of special importance at an early erosive stage of RA when bone changes are discrete. This approach formed the rationale behind undertaking a short-term 6-month follow-up study to evaluate the eventual prognostic value of contrastenhanced MRI for the future development of bone-destructive changes in small hand joints in early erosive RA. One of the drawbacks to our study has been the lack of sensitive criteria for the evaluation of the progression of bone destructive changes during a short period of 6 months. It has been suggested that Larsen's score has arelativeweakness in the grading of early and mild disease [8]. This was confirmed in our study since in only one of the joints was the progression from grade II to grade III revealed on a follow-up examination. It was for this reason that the advancing loss of the distinctness of bone erosions was used as the criterion for the progression of bone destruction and that a magnifying lens was used. Athough it has been generally accepted that the margins of 'active' erosions are indistinctly defined, it is a finding that is not in practice easy to confirm. Thus evaluation can be quite subjective. Our results demonstrated congruence between MRI assessment of disease activity and plain film evaluation, but only in the joints in which the margins of bone erosions were indistinctly defined at the beginning of the study as well as at 6 months. In majority of these joints the quality of synovial proliferation within bone erosions seen on MRI was compatible with inflammatory active pannus. The discrepancy has been shown in three joints in which indistinctly marginalized erosions were filled with fibrous pannus. This could be explained by a time lag between reconstruction of the bone and actual histopathological change. There were no logical explanations for the case in which MRI findings of inactive pannus were revealed at the beginning and after 6 months, other than that the radiographic evaluation of the marginalization of erosions may not be valid. The lack of correlation between MRI and radiographic findings, which has been reported in other studies [9], was mainly demonstrated in those joints in which the margins of erosion were distinctly defined

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MRI IN THE ASSESSMENT OF RA

modification to Larscn's scoring methods for hand and wrist radiographs. Br J Rheumatol 1995;34:56. 9. Corvetta A, Giovagnoni A, Baldclli S, Ercoloni P, Pomponio G, Lenchetti MM, Rinoldi N, De Nigris E. MR

imaging of rheumatoid hand lesions: comparison with conventional radiography in 31 patients. Clin Exp Rheumatol 1992; I(h217-22.
