Rheumatology

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Rheumatology 2001; 40: 367-374
© 2001 British Society for Rheumatology

Treatment-induced remission in rheumatoid arthritis patients is characterized by a reduction in macrophage content of synovial biopsies

M. D. Smith^1,5,, M. C. Kraan⁴, J. Slavotinek², V. Au², H. Weedon⁵, A. Parker⁵, M. Coleman⁶, P. J. Roberts-Thomson³ and M. J. Ahern¹

¹ Departments of Medicine and
² Radiology, Flinders Medical Centre,
³ Rheumatology Unit, Flinders Medical Centre, Adelaide, South Australia,
⁴ Department of Rheumatology, Amsterdam Medical Centre, Amsterdam, The Netherlands,
⁵ Rheumatology Unit and
⁶ Department of Pathology, Repatriation General Hospital, Daw Park, Adelaide, South Australia, Australia

	Abstract

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Objectives. To document the change in synovial membrane macrophage and T-lymphocyte content in rheumatoid arthritis (RA) patients who achieve remission induced by disease-modifying anti-rheumatic drugs (DMARDs).

Methods. Arthroscopic synovial biopsies were taken from four to seven sites around a knee joint in 13 patients with RA before and at regular intervals after commencing treatment with a DMARD. The cellular content of synovial membrane biopsies taken at regular intervals for a period of up to 3 yr after commencing treatment was quantitated by routine histopathology and immunohistochemical labelling with anti-macrophage (CD68) and anti-T lymphocyte (UCHL-1) antibodies. Synovial biopsies were quantitated with a validated semiquantitative scoring system and video image analysis.

Results. Nine patients obtained clinical remission, as defined by American College of Rheumatology (ACR) criteria. The changes that occurred in the synovial biopsies included a reduction in lining layer thickness, reduced vascularity and cellular infiltrate. The most significant reduction in cellular infiltrate was in the lining layer macrophages, with less dramatic change in the subintimal macrophage infiltrate. Although there was a reduction in CD45 Ro-positive T lymphocytes in the synovial membranes of patients who attained ACR-defined disease remission, it was less significant than the reduction in macrophage content of the synovial membranes and tended to plateau at a reduced level of T-cell infiltration.

Conclusions. Remission in RA patients is characterized by a predominant reduction in macrophage content of the synovial membrane, suggesting that current DMARDs may target this cell and its inflammatory mediators.

KEY WORDS: Rheumatoid arthritis, Synovial membrane, Macrophages, T lymphocytes.

	Introduction

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Rheumatoid arthritis (RA) is characterized by chronic inflammation of synovial membranes with increased thickness of the synovial lining and infiltration of the subintimal areas with macrophages and memory (CD45 Ro-positive) T lymphocytes. Infiltration is mainly due to trafficking from the blood, under the control of cytokines [1] and cell adhesion molecules [2], mediated either specifically by an antigen or non-specifically by lymphokines. Hyperplasia of the synovial lining layer in RA is a consequence of macrophage infiltration from the blood as well as limited synovial fibroblast proliferation [3].

Most of the second-line agents currently used in the treatment of RA have been discovered by chance, with little knowledge of their mechanisms of action. The response rate to these agents, with the possible exception of methotrexate, is low, and treatment-induced remission is an unusual event, estimated to occur in fewer than 15% of patients treated [5]. The long-term efficacy of specific T-cell-targeted therapies (anti-T cell and anti-interleukin 2-based therapies as well as cyclosporin) have been disappointing compared with the greater success of treatments aimed at macrophages, particularly therapies directed against tumour necrosis factor (TNF) [4].

Previous studies examining the effect of treatment with disease-modifying anti-rheumatic drugs (DMARDs) on the inflammatory cell infiltrate in RA synovial membranes have been limited [6–12], most studies having being of short duration and often measuring only one cell lineage in the inflammatory infiltrate, without any indication of the remission status of patients included in the study. It may be important to establish whether successful treatment with the DMARDs used in the treatment of RA is associated with changes in cellular content within the synovial membrane, so that future treatments can be targeted specifically and appropriately.

This study was undertaken with the specific aim of demonstrating what effect successful DMARD treatment, leading to remission according to American College of Rheumatology (ACR) criteria, had on the two major components of the inflammatory cell infiltrate in the RA synovial membrane, the memory T cell and the macrophage.

	Materials and methods

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Reagents
Ethanol, methanol, diaminobenzidine (DAB), methyl green, haematoxylin, xylene and sodium chloride were from BDH, Poole, UK. Hydrogen peroxide was from Univar, Auburn, Sydney, Australia. Normal donkey serum and biotinylated donkey anti-mouse secondary antibody were from Jackson ImmunoResearch, West Grove, PA, USA. Avidin–biotin–horseradish peroxidase complex (Vectastain kit) was from Vector Laboratories, Burlingame, CA, USA.

Monoclonal antibodies
Anti-human macrophage (CD68, clone PG-M1, IgG₃) and anti-human T cell (CD45 Ro, IgG_2a) were supplied by Dako (Glostrup, Denmark). Both antibodies were murine monoclonal antibodies. The isotype-specific negative control antibody X63 (IgG1; recognizes an irrelevant mouse myeloma protein) was a generous gift from Professor H. Zola.

Patients
The patients included in this study are described in Table 1 and were part of a larger cohort of 40 patients being studied with sequential synovial biopsies before and after treatment. All fulfilled the 1987 ACR criteria for RA [13]. Eligible patients had to have active RA [swollen and tender joint count >5, C-reactive protein (CRP) >20 mg/l] with involvement of at least one knee joint requiring DMARD treatment, and had to be willing to undergo sequential arthroscopic synovial biopsies before and after commencing DMARD treatment. All treatment-related decisions were made by the treating rheumatologist. Clinical assessment was performed using visual analogue scores (measured on a 10-cm horizontal scale anchored at both ends) for pain, generalized stiffness and well-being, as well as 28-joint tender and swollen joint scores and a Modified Health Assessment Questionnaire (HAQ). Serum CRP concentration, measured by rate nephelometry (normally <6 mg/l), was used as a laboratory measure of inflammation, and was obtained throughout the treatment period. Response to treatment was assigned on the basis of the clinical and laboratory parameters, using the ACR criteria for improvement [14] and remission [15] in response to drug treatment. Shared epitope (the common HLA DRB1 allele in RA patients) was measured by flow cytometry [16], using a commercial kit (Terra Nova Biotechnology, St John's, Nfld, Canada). X-rays of the hands and feet were taken before and at yearly intervals after treatment, using a standardized method. All films were read in chronological order by two radiologists (J.S. and V.A.), who were blinded to all treatment details and outcome measurements, using two well-defined radiological scoring systems, the Larsen and Sharp systems [17, 18]. The inter-observer correlation for both scoring systems was 0.9, while intra-observer scoring for both the Larsen and the Sharp system had a correlation of 0.95.

View this table: [in this window] [in a new window]   TABLE 1. Demographic details of patients

 

Arthroscopic biopsies
Sequential synovial membrane samples (five to seven biopsies) were obtained from the same knee joint from each patient under direct vision using a 2.7 mm mini-arthroscope (Dyonics, Andover, MA, USA) and standard approaches as described previously [19–21]. Synovial biopsies were obtained before and 3, 6, 12, 18, 24 and 36 months after commencing treatment with a DMARD in all patients except RA10, who had a total knee replacement in the target joint 2 yr into the study. This project was approved by the institutional ethics committee and informed consent was obtained from each patient.

Tissue processing and immunoperoxidase staining
Synovial tissue was processed immediately for paraffin sections as described previously [20–22]. Negative controls were performed using irrelevant isotype control antibody (X63) or normal donkey serum alone, or by leaving out the secondary antibody. A positive control (either lymph node or synovial tissue with known staining characteristics) was used in each run.

Colour video image analysis
The immunostained sections were examined using a computer-assisted colour video image analysis system (Video Pro 32, Leading Edge P/L, Adelaide, South Australia) as described previously [20–22]. At least two separate synovial biopsies, taken at each time point, were examined with a minimum of six randomly selected high-power fields measured. The measurements that were made included the mean optical density and the area of staining with the cell lineage-specific monoclonal antibody. The variability in measurements made by video image analysis has been shown to be less than 10%, mainly due to bias in field selection [22].

Statistical analysis
Results are given as mean±SD. Missing values (patient RA10) were managed by carrying the last measurement forwards. Changes within the group were analysed using the Wilcoxon signed rank test for data that were not normally distributed and Student's paired t-test for normally distributed continuous data. Differences were considered to be significant at P<0.05. For the statistical analysis, the treatment responses were recoded as follows: active disease was assigned a clinical score of 1, a 20% ACR response was assigned a clinical score of 2, a 50% or greater ACR response was assigned a clinical score of 3 and remission was assigned a clinical score of 4.

Additional analyses were performed using the statistical method of generalized estimating equations (GEE) to account for correlations between observations on the same individual [23]. Since the correlation between observations diminished over time, an autoregressive correlation structure was assumed. Three response variables (HAQ, CRP and treatment response) were analysed and GEE models were fitted to each variable. Preliminary analysis of CRP results showed that the residuals were unstable and did not follow a normal distribution, so the CRP values were log-transformed. HAQ scores were analysed assuming normally distributed errors.

	Results

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Nine of the 13 patients treated with DMARDs eventually attained clinical remission by ACR criteria that was maintained for the duration of the study, while one patient each achieved an ACR 80%, ACR 50% and ACR 20% response and one patient had no response to DMARD treatment. There was a significant reduction in the synovial lining layer thickness (P<0.01) at 3 yr (Table 2 and Fig. 2) in the patients attaining ACR remission. There was also a significant decrease in macrophage content of the lining layer in sequential synovial biopsies following treatment from 9209 pixels at initial biopsy to 3446 pixels at 36 months in all patients (P<0.05) (Table 2). This was particularly evident in those patients achieving ACR-defined clinical remission, the macrophage content of the lining layer decreasing from 10 158 to 240 pixels (P<0.02) (Figs 1 and 2A and Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Changes in synovial membrane pathology with DMARD treatment

 

View larger version (24K): [in this window] [in a new window]   FIG. 2. Changes in cell lining thickness and synovial lining and subintimal macrophage (CD68-positive) content (A) and CD45 Ro-positive T-cell content (B) for all patients in the study who achieved ACR remission as a result of treatment with DMARDs. *P<0.05 compared with baseline (Student's t-test).

 

View larger version (141K): [in this window] [in a new window]   FIG. 1. Changes in synovial membrane cellular infiltrate as a result of DMARD treatment (magnification x66) in patient RA7, who attained clinical remission with oral methotrexate. (A, C, E, G) Labelling for memory T cells using UCHL1 monoclonal antibody. (B, D, F, H) Labelling for macrophages using an anti-CD68 monoclonal antibody. (A, B) Baseline biopsy. (C, D) Three months after treatment. (E, F) Six months after treatment. (G, H) Twelve months after treatment.

 
There was also a significant decrease in the macrophage content of the sublining region, from 14 037 pixels at baseline to 6794 pixels at 36 months, which again was particularly pronounced in the remission patients, with a decrease from 15622 pixels at baseline to 447 pixels at 36 months (P<0.02). Changes in macrophage content of both the lining and sublining regions of the synovial membrane were significant for all three response variables used in separate analyses by GEE.

While there was also a significant decrease in memory T cells, this was significant when correlated to CRP (P<0.02) but not HAQ (P=0.34) or treatment response (P=0.2) using GEE analysis (Table 2 and Fig. 2B). Memory T cells could still clearly be found in the post-treatment synovial membranes, even in those patients who attained clinical remission (Table 2).

Quantitation of macrophage and T-cell areas using semiquantitative scores (data not shown) confirmed a significant decrease in the lining layer and sublining macrophage content. There was no significant difference between methotrexate-treated and gold-treated patients in the change in synovial membrane infiltrates with time, although the low numbers in each group make a type II error probable.

There was a significant amount of radiological damage (Fig. 3) at baseline, which only appeared to progress in those patients who failed to attain ACR clinical remission. A similar result was seen when the presence of joint erosions was graded on pre- and post-treatment X-rays, using the Sharp criteria (Fig. 3B). There was no statistically significant difference in Larsen or Sharp erosion scores between the initial and final X-rays, using Student's t-test.

View larger version (44K): [in this window] [in a new window]   FIG. 3. Changes in total joint damage (Larsen score for hands and feet) (A) and Sharp erosion score (B) in X-rays taken before (1) and after (2) commencing DMARD treatment. The mean period between X-rays was 3.8 yr (range 3–6). All patients achieved an ACR remission at the time of the second set of X-rays except RA5 (ACR 20% response), RA8 (ACR 80% response), RA10 (no response) and RA11 (ACR 50% response).

 

	Discussion

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The histopathological changes in the synovial membrane of patients with RA include a variable increase in lining layer thickness, variable infiltration with lymphocyte and macrophage lineage cells, increased vascularity and fibrosis [3]. The pathogenesis of RA remains unknown. The two major hypotheses propose either a lymphocyte-mediated or a macrophage-predominant central pathogenic mechanism of chronic inflammation. Several studies have examined a number of potential synovial membrane parameters as predictors of the clinical course in RA patients, including the progression of radiological damage [3, 24–26]. The major synovial membrane predictors of clinical course and radiological progression were lining layer thickness and macrophage infiltration. There were, however, some important differences between these studies and our study. Unlike this study, none of these studies examined sequential synovial membrane biopsies taken throughout the clinical course of treated patients. One study performed a single synovial membrane biopsy at entry into the study and performed clinical follow-up of the patients at 1 and 3 yr [3]. Another study performed a single synovial membrane biopsy 4–8 yr after entry into the study and correlated the synovial membrane pathology with radiological outcome [24]. The patient groups were unusual as well, with average disease durations of 2–2.5 yr in a group of patients who had never received any DMARD treatment, which contrasts with the current trend to early treatment of RA patients with DMARDs. Finally, although there was an overall improvement in disease activity with treatment, it is not clear that any of the patients studied achieved remission as defined by ACR criteria. In contrast, this study treated a small group of patients with a limited number of DMARDs, almost half the patients having a disease duration of less than 2 yr and over half achieving disease remission. This group of patients had poor prognostic factors for disease severity, all but one having at least one of the poor prognostic indicators (positive for rheumatoid factor, positive shared epitope status or the presence of erosions) at entry into the study. In addition, all patients had active disease with severe functional impairment at entry into the study.

Several studies have looked at the effect of treatment on synovial membrane pathology [6–12]. Two studies have looked at the changes in T lymphocytes only and demonstrated a modest reduction in the T-lymphocyte content of synovial membrane biopsies after 24 weeks [6] or 12 months [7] of treatment with various DMARDs. While the majority of patients improved with treatment, it is unclear whether any patients attained 50% improvement (ACR criteria) or remission in these studies. Three other studies (using the same group of patients) that examined changes in synovial membrane pathology resulting from treatment with gold injections showed little change in the T-lymphocyte content of sequential synovial membrane biopsies taken over a 12-week period of treatment, at a time when there was significant clinical improvement [8–10]. There was, however, a significant reduction in the number of cells of the macrophage lineage in the lining and subintimal regions of the synovial membranes of these patients, which correlated with clinical improvement. However, follow-up was limited to 12 weeks after commencing treatment and there was no attempt to assess the progression of radiological damage in these patients. In addition, it is again unclear how many of these patients attained a significant (50% improvement or remission) clinical response to drug treatment.

A recent paper examined the effect of treatment with antibodies against TNF- on synovial membrane pathology [11]. Follow-up was limited to 4 weeks, and there were variable changes in the T-lymphocyte content of the synovial membrane as a result of this treatment. This study did not evaluate any changes in macrophage lineage cells in the synovial membrane resulting from anti-TNF- therapy.

Finally, a recent paper has examined the effect of methotrexate on synovial membrane pathology in a group of patients with established disease (only one patient had a disease duration of less than 5 yr), over a 16-week treatment period [12]. They demonstrated modest reductions in T-lymphocyte and macrophage lineage cells in the synovial membranes with treatment, with a trend towards an association between clinical improvement and a decrease in macrophage scores. Even though there was clinical improvement in this group of patients as a result of methotrexate treatment, it is unclear whether any patients attained a significant clinical improvement or remission.

In contrast to all the above studies, this study examined a group of patients over a prolonged period (up to 3 yr) with sequential sampling of the synovial membrane from a single index knee joint and correlated the changes in synovial membrane pathology with clinical improvement and with progression of radiological changes. We have shown that the major change in synovial membrane pathology was a reduction in macrophage lineage cells in the lining and subintimal regions of the synovial membrane, which correlated significantly with clinical outcome, particularly in those patients who achieved disease remission. In contrast, changes in synovial membrane T lymphocytes were modest, often plateaued after an initial reduction and did not correlate with clinical improvement. There are, however, some unusual aspects of the patient population recruited into this study. There was a predominance of males, the mean age (72.3 yr) was significantly higher than the usual RA patient, the disease duration ranged from 0.2–25 yr (although almost half of the patients had a disease duration of less than 2 yr) and more than half the patients attained sustained remission status with treatment. In view of these limitations to our study, our findings cannot necessarily be extrapolated to the general RA patient population.

Despite these limitations, the results of this study suggest that the DMARDs used in this study (predominantly methotrexate and gold injections) target the macrophage rather than the T-lymphocyte inflammatory infiltrate in the patients included in this study. If the results from this study are applicable to the general population of RA patients, it raises the possibility that RA is predominantly a macrophage-mediated disorder and that a reduction in synovial membrane macrophage content should be a primary aim of successful treatment for RA patients.

	Acknowledgments

 
This study was supported by grants from the National Health and Medical Research Council, the Arthritis Foundation of Australia, the Clive and Vera Ramaciotti Foundation, the J.H. and J.D. Gunn Foundation and the Rebecca L. Cooper Medical Research Foundation. The authors would like to acknowledge the statistical advice contributed by Dr Lynne Giles, Flinders University of South Australia.

	Notes

 
Correspondence to: M. D. Smith, Rheumatology Research Unit, Repatriation General Hospital, Daws Road, Daw Park, South Australia 5041, Australia.

	References

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Submitted 19 May 2000; revised version accepted 9 October 2000.
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This Article Abstract FREE Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (21) Request Permissions Disclaimer Google Scholar Articles by Smith, M. D. Articles by Ahern, M. J. Search for Related Content PubMed PubMed Citation Articles by Smith, M. D. Articles by Ahern, M. J. Related Collections Rheumatoid Arthritis Social Bookmarking          What's this?

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