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Rheumatology 2001; 40: 62-69
© 2001 British Society for Rheumatology
The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis
Department of Rheumatology, St Vincent's University Hospital, Dublin 4, Ireland
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Abstract |
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Objective. To evaluate the effects of treatment with interleukin-1 receptor antagonist (IL-1Ra) on synovial tissue in rheumatoid arthritis (RA).
Methods. Twelve patients with RA entering a randomized clinical trial of human recombinant IL-1Ra underwent synovial biopsies before and after treatment. Cellular infiltration and adhesion molecule expression were evaluated after immunohistochemical staining.
Results. There was a notable reduction in intimal layer macrophages and subintimal macrophages and lymphocytes after treatment with IL-1Ra at 150 mg/day (n=3). Increased cellular infiltration was observed in all patients receiving placebo (n=3); variable changes were observed after IL-1Ra 30 mg/day (n=6). In a limited study of adhesion molecule expression, down-regulation of E-selectin and vascular cell adhesion molecule-1 was observed after treatment with IL-1Ra 150 mg/day, but not after IL-1Ra 30 mg/day or placebo. The apparent arrest of progressive joint damage seen in four patients after treatment with IL-1Ra was associated with reduced intimal layer macrophage accumulation in all patients.
Conclusion. Treatment of RA with IL-1Ra resulted in reduced mononuclear cell infiltration of synovial membrane, which may represent the in vivo inhibition of biologically relevant IL-1ß-mediated pathogenic effects.
KEY WORDS: Rheumatoid arthritis, Inflammation, Synovial membrane, Interleukin-1 receptor antagonist, Macrophages.
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Introduction |
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Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation and progressive erosion of cartilage and bone [1]. A variety of cell populations infiltrate the synovium and produce mediators capable of maintaining the inflammatory process and stimulating the production of destructive enzymes. Cytokine networks influence events at both the local and the systemic level. It has been suggested that interleukin-1ß (IL-1ß) and tumour necrosis factor
(TNF-) are pivotal proinflammatory cytokines [1, 2]. In experimental models, IL-1 increases cell migration into the inflamed synovium by the up-regulation of adhesion molecules, stimulates the production of prostaglandins and metalloproteinases, inhibits collagen and proteoglycan synthesis and stimulates osteoclastic bone resorption [2, 3]. The physiological regulation of IL-1 is due to the presence of its naturally occurring inhibitor, interleukin-1 receptor antagonist (IL-1Ra) [2]. IL-1Ra is a specific competitive inhibitor of IL-1 and binds avidly to IL-1 receptors without activating the target cell. IL-1Ra is also produced mainly by synovial macrophages [4]. It is thought that dysregulation of IL-1Ra may be responsible for the predominance of IL-1 in RA [5].
The therapeutic potential of IL-1Ra in inflammatory arthritis has been investigated in in vitro studies, animal models and in human RA. IL-1Ra inhibited both IL-1 and TNF--induced prostaglandin E2 and collagenase production by human synoviocytes [6]. It inhibited neutrophil infiltration and cartilage proteoglycan loss after intra-articular injection of IL-1 into rabbit knee joints [7]. A recent randomized controlled trial of IL-1Ra in patients with severe, active RA demonstrated significant clinical improvements compared with placebo [8]. In addition, IL-1Ra caused a 41% reduction in the rate of progressive joint damage. In this study, we examined the in vivo effects of IL-1Ra on inflamed synovial tissue. The reduction in mononuclear cell infiltration, possibly mediated by the down-regulation of adhesion molecule expression, was striking after treatment with IL-1Ra at 150 mg/day.
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Methods |
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Patients
The patients included in this study had been recruited into one of two randomized clinical trials of recombinant human IL-1Ra in RA. In the first trial, 472 patients entered one of four treatment groups: placebo and IL-1Ra at 30, 75 and 150 mg/day by self-administered subcutaneous injection for 24 weeks [8]. In brief, patients aged 18–75 yr were eligible for inclusion in this study if they met the American College of Rheumatology criteria for the diagnosis of RA [9], had symptoms of RA for more than 6 months and less than 8 yr, had clinical features of active disease and a C-reactive protein (CRP) concentration greater than 1.5 mg/dl. In all, 11 patients were recruited to the multicentre study at St Vincent's University Hospital, Dublin, and 10 agreed to a needle biopsy of an affected knee joint immediately before starting treatment. Written consent was obtained from all who participated in this small substudy. A follow-up needle biopsy was undertaken in seven patients after 24 weeks and evaluable pretreatment and post-treatment synovial tissue was available in six patients. In a 24-week extension study, patients who had received placebo were randomized to one of the three IL-1Ra treatment groups for a further 24 weeks. One patient who had initially received placebo agreed to a third biopsy after 24 weeks in the extension study. In addition, pretreatment and post-treatment tissue samples obtained by arthroscopic biopsy of an affected knee were obtained at the same time-points from one patient attending the Karolinska Hospital, Stockholm, Sweden, and one patient attending Leiden University Hospital, Leiden, The Netherlands. All tissue samples were evaluated by the same investigator (GC), who had no knowledge of the treatment, clinical course or radiological outcome. Radiographs of hands and wrist of each of these nine patients were obtained at weeks 0 and 24. They were reviewed and scored according to Larsen et al. [10] by two radiologists who were blinded both to the treatment group and the time of radiography. Approval of the study was obtained from the ethics committee of each participating institution.
In a second multicentre, dose-finding, randomized clinical trial with similar entry criteria, 10 patients were recruited at St Vincent's University Hospital and received placebo, IL-1Ra 2.5, 10 or 30 mg/day for 12 weeks. After the code had been broken, three patients were identified from the two treatment groups relevant to the biopsy substudy (placebo and IL-1Ra 30 mg/day) with evaluable pretreatment and post-treatment tissue samples. The tissues were evaluated by the same investigator (GC). In view of the shorter study duration, radiographic analysis was not included as an outcome measure.
Synovial biopsy and analysis of tissue
Needle biopsy of one clinically inflamed knee was performed under sterile conditions as described previously [11]. The same location was chosen for the second biopsy. Multiple samples of synovial tissue were obtained from as wide an area as possible within reach of the needle. Arthroscopic biopsy was performed on two patients. The biopsy procedure was similar to needle biopsy, using a Stors 2.7 mm needle arthroscope.
The primary monoclonal antibody (mAb) clones used, their antigen and predominant cell specificities and the dilutions used are shown in Table 1
. A standard three-stage immunoperoxidase technique using serial sections was applied [11]. Only synovial sections in which the lining layer was clearly evident were included in the study. All sections were examined under 400x magnification with a 1-mm graticule by a blinded observer (GC). For each analysis, all samples of tissue from each patient were examined. A cell was considered to exhibit positive staining only if a nucleus was identified in association with appropriate staining. In the intimal layer, the number of positive cells was expressed as the percentage of the total number of lining cells counted, up to a maximum of 300 cells. In the subintimal layer, analysis of CD3+ and CD68+ cells was carried out by counting the mean number of positive cells per high-power field over the entire area of all the sections available from each patient. The mean count per mm2 was calculated using a conversion factor (x0.0625-1). Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) expression in the subintima was measured in five representative high-power fields and calculated as the percentage of the total number of cells present. Vessels staining positively for E-selectin and P-selectin were expressed as the percentage of the total number of vessels counted. The coefficient of variation was 2.1% for the measurement of the percentage of CD68+ cells in the intimal layer, and 6.4 and 3.7% for CD68+ and CD3+ cells in the subintimal layer respectively.
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Results |
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Changes in mononuclear cell infiltration
Twelve paired synovial tissue samples, obtained before and after treatment, were available from 11 patients. One patient underwent needle biopsy before and after 24 weeks of treatment with placebo (Patient 1a; Table 2
) and again after 24 weeks of treatment with IL-1Ra 150 mg/day (Patient 1b; Table 2). In all, three patients had received placebo, six IL-1Ra 30 mg/day and three IL-1Ra 150 mg/day.
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All tissue samples demonstrated a high degree of intimal and subintimal mononuclear cell infiltration before treatment (Table 2
). After treatment, patients receiving placebo demonstrated an 8–11% increase in the percentage of macrophages in the synovial intimal layer (Table 2 and Fig 1). Patients receiving IL-1Ra 30 mg/day demonstrated little change in intimal macrophages (+3 to -5%). More notably, the three patients receiving IL-1Ra 150 mg/day demonstrated a consistent decrease in intimal layer macrophages (5, 24 and 51%). Patients receiving placebo also demonstrated a 5–25% increase in subintimal macrophage infiltration (Table 2). Treatment with IL-1Ra 30 mg/day had a variable effect on subintimal macrophage infiltration (+19 to -19% change). However, the three patients receiving IL-1Ra 150 mg/day demonstrated a consistent and striking reduction in subintimal macrophage infiltration (41–75%). Patients receiving placebo demonstrated a variable effect on subintimal lymphocyte infiltration (+47 to -53%) (Table 2). A variable effect was also observed after IL-1Ra 30 mg/day (+97 to -25%). IL-1Ra 150 mg/day resulted in a consistent decrease in subintimal lymphocyte infiltration, ranging from -26 to -97%. Figures 2 and 3 illustrate the changes in mononuclear cell infiltration before and after placebo and after IL-1Ra 150 mg/day (patient 1; Table 2). A variable effect on blood vessels was observed in all three groups (data not shown).
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Changes in adhesion molecule expression
Sufficient tissue samples for the analysis of adhesion molecule expression were available from only six patients: one receiving placebo, four receiving IL-1Ra 30 mg/day and one receiving IL-1Ra 150 mg/day (Table 3). The patient who had received IL-1Ra 150 mg/day demonstrated a reduction (74%) in the expression of synovial membrane E-selectin, but not P-selectin, on vascular endothelial cells (Table 3 and Fig 4). In the five patients receiving IL-1Ra 30 mg/day or placebo, no convincing changes in E-selectin or P-selectin expression were observed. The patient receiving IL-1Ra 150 mg/day also demonstrated a striking reduction in VCAM-1 expression on infiltrating mononuclear cells in both the intimal (64%) and subintimal layers (26%) (Table 3 and Fig 5). A reduction (20 and 24%) in ICAM-1 expression on infiltrating cells in the intimal and subintimal layers was also observed. Among the four patients receiving IL-1Ra 30 mg/day, a modest reduction of 10–20% in VCAM-1 expression was observed on the intimal layer cells in only one (Patient 9) and on the subintimal layer cells in two (Patients 4 and 8; Table 3). Minimal or no changes were observed in the remainder. A reduction in ICAM-1 expression of greater than 10% was observed in the subintimal layer in only one patient (Patient 4; Table 3).
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Changes in the clinical course and radiological outcome
The clinical course, represented by CRP values, and the radiological outcome are documented in Table 4. It is noteworthy that an inconsistent clinical response and considerable radiological progression was observed in patients receiving placebo. By comparison, a fall in CRP concentration was observed in eight of nine patients receiving IL-1Ra 30 or 150 mg/day and an apparent arrest of radiological progression was observed in four of nine with serial radiological analysis. There was no correlation between the radiological outcome and changes in the CRP values. Correlations were sought between radiological outcome and changes in intimal macrophages and subintimal macrophages and T lymphocytes. The data highlighting the relationships between joint damage and changes in intimal layer macrophage infiltration are shown in Fig 6. Thus, in the four patients demonstrating apparent arrest of joint damage (Patients 5, 7, 10 and 1b; Fig 6) a consistent reduction in the percentage of intimal macrophages was observed, and all had received IL-1Ra. This contrasted with patients who demonstrated progressive joint damage (Patients 1a, 2, 4, 6 and 11; Fig 6), which was associated with an increase in intimal macrophages in three. No statistical differences were observed between the two groups when changes in the subintimal populations of macrophages and T lymphocytes were examined.
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Discussion |
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In this study, treatment of RA with IL-1Ra 150 mg/day resulted in reduced numbers of intimal macrophages and subintimal macrophages and lymphocytes. Synovial biopsy and immunohistochemical evaluation have been employed previously in the study of the therapeutic response to conventional and biological agents [12–18]. In this and other multicentre studies of biological agents, the numbers recruited for immunohistological analysis have been unavoidably small [15, 16], as relatively few participating centres have facilities for serial synovial biopsy. The small numbers precluded meaningful statistical analysis. Nevertheless, many of the immunohistological changes observed in therapeutic studies could be attributed directly or indirectly to phar-macological effects [15–18]. The method of histological analysis used in this study can identify small changes of biological relevance [19]. The validity of the method was augmented by the demonstration that quantification of limited areas of synovial tissue (equivalent to only 1 mm2) provided results which were similar to those obtained from the analysis of areas up to 6.7 mm2 from the same joint [20]. The very low coefficients of variation observed in this study (see Methods) further suggest that the small immunohistological changes observed in some patients represented biologically significant in vivo effects.
The proliferating synovial intimal layer is composed of two distinct cell populations [21, 22]. In health the majority are fibroblast-like synoviocytes. In RA the majority are macrophages derived from monocyte precursors in the bone marrow. Circulating monocytes infiltrate inflamed synovial tissue after adhesion to molecules such as E-selectin and VCAM-1 expressed on the surface of vascular endothelial cells. Synovial tissue macrophages accumulate in both the subintimal and the intimal layer. The intimal layer macrophages are typically CD68+ and they may also express both VCAM-1 and ICAM-1. Intimal macrophages are a major source of IL-1. Macrophages produce a number of other proinflammatory cytokines which have a central role in RA, including TNF- and GM-CSF [20]. We have previously demonstrated significant correlations between the numbers of both intimal and subintimal layer macrophages and the degree of articular damage in RA [11]. The present study provided an opportunity to further explore these relationships. The reduced intimal layer macrophage accumulation observed after IL-1Ra treatment may explain the apparent arrest of joint damage observed in four of nine patients treated for 24 weeks. Reduced macrophage accumulation may also be accompanied by inhibition of the IL-1-mediated production of tissue-degrading enzymes by macrophages and synoviocytes. Synoviocytes activated by IL-1 and other cytokines are the major source of tissue-degrading enzymes, including matrix metalloproteinases, serine proteases and cathepsins, which are believed to be the direct cause of cartilage damage. This study did not evaluate synovial fibroblasts and other cell populations, such as NK cells, dendritic cells and mast cells, which may also contribute to the pathogenesis of joint damage.
IL-1 up-regulates the expression of E-selectin, but not P-selectin, on vascular endothelium [23]. The effect of IL-1Ra 150 mg/day on synovial tissue adhesion molecule expression could be evaluated in only one patient, but the selective down-regulation of E-selectin and not P-selectin that was observed suggests an in-vivo biological effect. The selectin family of adhesion molecules are responsible for the tethering of leukocytes to the vessel surface, permitting the rolling of the cell in the direction of flow. This phase occurs before the integrin-mediated arrest of leukocyte motion, firm adhesion and transmigration. E-selectin and P-selectin are both expressed in RA synovial tissue, but only E-selectin expression is increased compared with non-inflamed synovium [24]. Both E-selectin and P-selectin are involved in macrophage adhesion [23]. The reduction in macrophage infiltration, despite the persistent expression of P-selectin, supports the suggestion that E-selectin is more important than P-selectin in mediating macrophage migration in inflamed RA joints, as previously described in studies of neutrophil migration [17]. E-selectin is also involved in lymphocyte migration but P-selectin is not. VCAM-1 and ICAM-1 are more widely distributed in RA synovium and both are also up-regulated by IL-1 [23]. These are important molecules in cell-to-cell interactions, including macrophage–fibroblast and macrophage–lymphocyte interactions, and in regulating the migration of cells through synovial tissue into the synovial fluid.
Studies of IL-1Ra treatment in experimental models of arthritis have consistently demonstrated relatively modest effects on clinical measures of joint inflammation [25–28]. However, the effects on inhibiting IL-1-mediated metalloproteinase release, proteoglycan breakdown and cartilage damage observed in the same animal models have been striking. Moreover, when the human IL-1Ra gene was transferred into the knee joints of rabbits with antigen-induced arthritis, a marked chondroprotective effect was observed in association with a limited anti-inflammatory effect [29]. Similarly, when the IL-1Ra gene was transferred into human synoviocytes using a SCID mouse model, chondrocyte-mediated chondrolysis of human cartilage was inhibited [30]. The apparent arrest of joint damage associated with a variable and incomplete clinical response, observed in the present study, is entirely consistent with the experimental models.
Cytokine blockade reduces joint inflammation in RA [8, 31, 32]. However, IL-1Ra is the first biological agent targeting a cytokine that has demonstrated an effect on progressive joint damage [8]. This study provides some preliminary evidence which may help explain the mechanisms that are critical in this effect.
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Acknowledgments |
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We are grateful to Dr Staffan Lindblad, Stockholm, Sweden, and Dr Paul Peter Tak, Leiden, The Netherlands, for providing synovial tissue samples from two patients. Dr Iain Watt and Dr Mark Cobby, Bristol, performed the radiological analyses. Ms Nicola Cassidy provided technological expertise in preparing the immunohistological sections. We also acknowledge the helpful discussions with Dr Jean-Michel Dayer, Geneva, Switzerland, and Dr Charles Dinarello, Denver, USA, during the preparation of this manuscript. This study was supported by a grant from Amgen. GC was supported by a grant from the Health Research Board of Ireland. EM is the Rohan Newman Scholar, National University of Ireland, Dublin.
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Notes |
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Correspondence to: B. Bresnihan
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