Rheumatology

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Rheumatology 1999; 38: 1074-1080
© 1999 British Society for Rheumatology

Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis

M. C. Kraan, J. J. Haringman¹, W. J. Post², J. Versendaal¹, F. C. Breedveld¹ and P. P. Tak

Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Academic Medical Centre, Amsterdam,
¹ Department of Rheumatology, Leiden University Medical Centre and
² Department of Medical Statistics, Leiden University, Leiden, The Netherlands

Correspondence to: M. C. Kraan, Division of Clinical Immunology and Rheumatology FU, Dept of Internal Medicine, Academic Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands.

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective. An early diagnosis in patients presenting with arthritis is important to provide information about prognosis and to initiate treatment. The objective of this study was to determine which markers applied in immunohistological analysis of synovial tissue (ST) specimens could be used to differentiate rheumatoid arthritis (RA) from other forms of arthritis.

Methods. Synovial biopsies were obtained by blind needle techniques from 95 patients with early arthritis. After follow-up of at least 2 yr to verify the diagnosis, the patients could be classified as follows: RA (n=36), undifferentiated arthritis (UA; n=21), osteoarthritis (OA; n=17), reactive arthritis (ReA; n=10), ankylosing spondylitis (AS; n=3), psoriatic arthritis (PsA; n=2) and crystal-induced arthritis (CA; n=6). ST sections were analysed by immunohistochemistry using monoclonal antibodies against CD3, CD4, CD8, CD22 (B cells), CD38 (plasma cells), CD68 (macrophages) and CD55 (fibroblast-like synoviocytes).

Results. Logistic regression analysis revealed that the higher scores for the numbers of CD38+ plasma cells and CD22+ B cells in RA were the best discriminating markers comparing RA to non-RA patients (CD38: P=0.0001; CD22: P<0.05). Polychotomous regression analysis comparing three diagnostic categories (1: RA; 2: UA, ReA, AS and PsA; 3: OA and CA) also identified the score for the number of CD38+ plasma cells (P<0.0001) as well as the numbers of CD68+ macrophages in the synovial sublining (P=0.05) as discriminating markers.

Conclusion. The results suggest that immunohistochemical analysis of ST specimens from early arthritis patients can be used to differentiate RA from non-RA patients. The numbers of plasma cells, B cells and macrophages are especially increased in ST of patients with RA. Future studies in early arthritis patients with clinical features which do not allow an immediate confident diagnosis may clarify the role of this test system in differential diagnosis.

KEY WORDS: Rheumatoid arthritis, Arthritis, Synovial tissue, Plasma cells, Macrophages, Differential diagnosis

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Recent studies indicate that early intervention may alter disease outcome in rheumatoid arthritis (RA) when instituted before invasive pannus growth and proteinase production have led to the loss of cartilage [1]. Therefore, it has become increasingly important to differentiate RA from other forms of arthritis during the early phases of the disease. Although clinical characteristics may be strongly suggestive of RA early in the disease, the diagnosis is usually established by a constellation of clinical findings, detection of rheumatoid factors, and radiographic features over a period of time.

It is clear that analysis of synovial tissue (ST) may help to make a diagnosis in some relatively rare infectious, infiltrative and deposition diseases of joints. Moreover, it has been shown that it is possible to assess differences in the synovial cell infiltrate as well as in the expression of adhesion molecules, cytokines and metalloproteinases in biopsy specimens when ST from RA patients is compared to other arthritides [2–6]. The interpretation of ST characteristics has been complicated, however, by the large variability of synovial inflammation between individual patients in both early and long-standing RA [7–11], and by the fact that many of the pathological changes in the rheumatoid synovium, such as vascular congestion, synovial lining layer hyperplasia, mononuclear cell infiltration and fibrin depositions, commonly occur in disorders other than RA [3, 12–21]. Consequently, the place of routine histological examination of synovial biopsy specimens for diagnostic purposes has been limited so far.

It can be expected that immunohistochemical analysis performs better than routine histological examination of ST in distinguishing RA from other forms of arthritis. The aim of this study was to identify immunohistochemical features of synovium that could be used to discriminate between RA and other forms of arthritis in the early phases of the disease. This was done by regression analysis of ST characteristics of a large series of patients presenting with recent-onset arthritis and an established diagnosis after 2 yr follow-up.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Study population
Ninety-five patients presenting with a recent onset and at presentation unclassified active arthritis were investigated. All of these 95 patients had an actively inflamed knee joint and a disease duration of <1 yr, as measured from the first clinical signs of arthritis regardless of which joint was initially affected. After at least 2 yr follow-up after the biopsy procedure, the patients fulfilled the criteria for either RA [22], (inflammatory) osteoarthritis (OA) [23], ankylosing spondylitis (AS) [24], reactive arthritis (ReA) [25], psoriatic arthritis (PsA) [24], crystal-induced arthritis (CA) [26] or undifferentiated arthritis (UA), based on the exclusion of other rheumatic diseases [27]. Patients with both a rheumatoid factor-positive polyarthritis and psoriasis were excluded. Furthermore, five control patients with a torn meniscus without signs of joint inflammation were studied. The majority of the patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) (89 out of 95 subjects) and none of the patients included received corticosteroids or cytotoxic disease-modifying anti-rheumatic drugs (DMARDs), such as azathioprine, methotrexate or cyclophosphamide, at the time the biopsies were performed. However, DMARDs such as hydroxychloroquine, sulphasalazine and gold were allowed at inclusion. All patients gave their informed consent and the medical ethics committee of the Leiden University Medical Centre approved the study protocol.

Biopsies
An average of 15 biopsy specimens of ST were taken from the suprapatellar pouch with a Parker Pearson needle [28, 29]. All samples were snap frozen together en bloc in Tissue-Tek OCT (Miles Diagnostics, Elkhart, IN, USA) by immersion in methylbutane (-70°C). The frozen blocks were stored in liquid nitrogen until sectioned for staining. Five micrometre sections were cut in a cryostat and mounted on glass slides (Star Frost adhesive slides, Knittelgläser, Braunschweig, Germany). The glass slides were sealed and stored at -80°C until immunohistochemical analysis could be performed.

Immunohistochemical analysis
Serial sections were stained with the following monoclonal antibodies (mAb): anti-CD68 (EBM11, Dako, Glostrup, Denmark), anti-CD3 (Leu-4, Becton-Dickinson, San Jose, CA, USA), anti-CD4 (Becton-Dickinson), anti-CD8 (Dako), anti-CD22 (CLB-B-Ly/1, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands), anti-CD38 (leu-17, Becton-Dickinson), and Mab67, which recognizes CD55 [30, 31]. For control sections, the primary antibodies were omitted or irrelevant isotype-matched mouse antibodies were applied. Staining was performed according to a three-step immunoperoxidase method [32]. Before use, the slides were warmed to room temperature and air dried. The sections were washed between all steps with phosphate-buffered saline (PBS). All incubations were carried out at room temperature. The primary antibodies were diluted in PBS–1% bovine serum albumin (BSA). The horseradish peroxidase (HRP)-conjugated secondary antibodies were diluted in PBS–1% BSA with 10% normal human serum (NHS) as blocking serum. Endogenous peroxidase activity was inhibited using 0.1% sodium azide and 0.3% hydrogen peroxide in PBS. The primary antibodies were incubated for 60 min. HRP-conjugated goat anti-mouse antibody was added for 30 min, followed by incubation with HRP-conjugated swine anti-goat antibody for another 30 min. HRP activity was detected using hydrogen peroxide as substrate and amino ethylcarbazole (AEC) as dye.

Microscopic analysis
All sections were analysed semiquantitatively in a random order by two independent observers, who were unaware of the clinical data. The expression of CD3 (T cells), CD4, CD8, CD22 (B cells), CD38 (plasma cells) and CD68 (macrophages) in the sublining(s) was scored on a five-point scale (0–4) which has proven to be sensitive and reproducible [10, 32]. A score of 0 represented minimal infiltration, while a score of 4 represented infiltration by numerous inflammatory cells. For the evaluation of CD38+ plasma cells, only strongly positive cells with plasma cell morphology were taken into account, because CD38 can be present in low density on subsets of NK cells, T cells, B cells and macrophages. We confirmed these data with another plasma cell-specific monoclonal antibody (ID4, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands) which gave similar results. Similarly, for evaluation of CD4+ cells, only cells with lymphocyte morphology were included, since CD4 can be expressed by macrophages.

CD3-positive aggregates (CD3a) were scored on a three-point scale (0=absence of lymphocyte aggregates of >25 positive cells/section; 1=1–3 aggregates; 2=>3 aggregates). The expression of CD55 (fibroblast-like synoviocytes) and CD68 in the synovial lining layer (1) was also scored semiquantitatively on a five-point scale, representing the mean number of cells in the lining layer positive for these markers. Minor differences between observers were resolved by mutual agreement. Examples of the semiquantitative scores are shown in Fig. 1.

View larger version (124K): [in this window] [in a new window]   FIG. 1.  Examples of the semiquantitative scores for infiltration by CD22+ B cells, CD38+ plasma cells and CD68+ macrophages in synovial tissue.

 
Statistical analysis
To determine which markers are discriminating predictors for the various diagnostic groups, we used logistic regression analysis for the comparison of two groups (RA vs non-RA) and polychotomous regression analysis for the comparison of three categories of diagnostic groups (1: RA; 2: AS, PsA, ReA and UA; 3: OA and CA).

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Clinical features
The demographic data of the patients and controls studied are shown in Table 1. The sex and age distributions for the diagnostic groups were as expected; the mean disease duration of the various groups was similar.

View this table: [in this window] [in a new window]   TABLE 1.  Clinical and demographic data of the patients investigated

 
Immunohistological features
ST stainings were negative when the primary antibody was omitted or irrelevant antibodies were applied. The mean scores for cell markers investigated in this study were higher in the various forms of arthritis than in controls (Table 2). Considerable variation in scores of ST between patients was observed for most markers in each diagnostic group. Comparison of the RA patients (n=36) with the pooled non-RA patients (n=59) employing logistic regression analysis identified CD38 (P=0.0001) and CD22 (P<0.05) as the best discriminating markers. These same results were found comparing RA to the separate diagnostic groups by logistic regression analysis. In addition to the observations made for CD38 and CD22, CD68s expression was significantly higher in ST from RA compared to OA patients (P<0.0006). Polychotomous regression analysis for comparison of three categories of diagnostic groups (1: RA, n=36; 2: AS, PsA, ReA and UA, n=36; 3: OA and CA, n=23) also identified CD38 (P<0.0001) as well as CD68s (P=0.05) as the best discriminating markers. The percentages of correctly predicted diagnostic categories based on the use of CD38 and CD68s are shown in Table 3. It was possible to predict a diagnosis of RA solely on the basis of ST examination in 85% of the cases when maximal scores for CD68s and CD38 were present. Similarly, minimal expression of CD68s and CD38 indicated another diagnosis than RA in 96% of the cases. Representative sections of ST from patients with RA, UA, OA, ReA, AS and controls showing infiltration by CD38+ plasma cells, CD22+ B cells and CD68+ macrophages are depicted in Fig. 2.

View this table: [in this window] [in a new window]   TABLE 2.  Immunohistological features of synovial tissue from patients with various forms of arthritis in an early phase of the diseasea

 

View this table: [in this window] [in a new window]   TABLE 3.  Percentages of correctly predicted diagnoses for three diagnostic categories [category 1: rheumatoid arthritis (RA); category 2: ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA) and undifferentiated arthritis (UA); category 3: osteoarthritis (OA) and crystal-induced arthritis (CA)] based on polychotomous regression analysis using the markers CD38 and CD68s

 

View larger version (113K): [in this window] [in a new window]   FIG. 2.  Sections of synovial tissue from patients with rheumatoid arthritis (RA), undifferentiated arthritis (UA), osteoarthritis (OA), reactive arthritis (ReA), ankylosing spondylitis (AS) and controls (Con.) showing infiltration by CD38+ plasma cells, CD22+ B cells and CD68+ macrophages.

 

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
This study confirms that ST of early RA patients is characterized by an increase in the number of macrophages and fibroblast-like synoviocytes in the synovial lining layer, and by infiltration of the sublining by T cells, B cells, plasma cells and macrophages [10, 11]. The predominant cell types are T cells, macrophages and plasma cells. Other inflammatory cells, such as mast cells and neutrophils, are also present. These cells were not included here, since their numbers are relatively low in ST and because the number of variables involved in statistical significance testing should be restricted to decrease the chance of erroneously reporting statistically significant effects. The importance of restricting the number of variables, and the limited value of conventional histology for differential diagnosis as shown in previous studies, was also the reason why we did not include variables obtained by routine histopathology. In the present study, we chose to include the markers that are routinely available in most laboratories. The data suggest that immunohistochemical analysis of synovial biopsy specimens of early arthritis patients can be used to differentiate RA from non-RA patients. In particular, marked infiltration by plasma cells, B cells and macrophages in the synovial sublining differs between RA and other forms of arthritis.

The Parker Pearson blind needle biopsy technique was used in this study because this procedure is generally available, safe, well tolerated and technically easy to perform [33]. Most measures of inflammation in needle biopsies were found to be similar to those obtained at arthroscopy [29]. However, the intensity of macrophage infiltration may be underestimated in some RA patients when blind needle biopsies are used [29]. Thus, the difference in macrophage infiltration in ST between RA and non-RA patients described here may even be an underestimation of the findings if synovial biopsy specimens selected arthroscopically from the pannus–cartilage junction had been studied.

To quantify the number of inflammatory cells in ST, semiquantitative analysis was used. In contrast to a quantitative analysis and computer-assisted analysis, this grading system is easy to perform, takes relatively little time and, therefore, offers the opportunity to evaluate sections from many biopsy specimens and from many patients, as in the present study. Semiquantitative analysis is a sensitive and reproducible tool [34] to assess differences between patient groups and to evaluate the effects of therapeutic interventions [10, 35]. Moreover, there is a highly significant correlation between semiquantitative scores for immunohistochemical characteristics of ST and scores for local disease activity [10, 11].

The methods described above enabled us to study ST from a group of arthritis patients large enough to permit adequate statistical analysis in order to identify markers that could distinguish between RA and non-RA in the early phases of the disease. The patients were not selected on the basis of diagnosis, but merely on the presence of arthritis of <1 yr duration; the definite diagnosis was made after 2 yr follow-up. Furthermore, only patients were included who did not use corticosteroids or cytotoxic DMARDs at the time the biopsies were taken in order to reduce the chance of bias as a result of effects of treatment.

The results presented here indicate that ST analysis has diagnostic potential in distinguishing early RA from other forms of early arthritis. Multivariate models could predict a diagnosis of RA solely on the basis of ST examination with an accuracy of 85% when massive infiltration by plasma cells and macrophages in the synovial sublining was present and a diagnosis other than RA in even 96% of the cases when minimal infiltration by these cells was found. A limitation of this study is the low number of patients with PsA and AS included. We excluded patients with both a rheumatoid factor-positive polyarthritis and psoriasis in this study, aimed at identifying immunohistological markers with diagnostic potential, since it can be difficult to establish a definite diagnosis in these cases. In particular, in PsA and AS, high scores for both plasma cells and macrophages in the sublining were found, similar to the findings in RA. This is line with other recent reports [18, 21]. It seems that in these cases examination of synovial biopsy specimens has a limited role in differential diagnosis. Future research should focus on the sensitivity, specificity and the predictive value of scores for B cells, plasma cells and macrophages in synovial tissue of consecutive early arthritis patients with clinical features which do not allow an immediate confident diagnosis. Such studies may clarify the role of this test system in differential diagnosis.

In conclusion, the results suggest that quantification of the number of plasma cells, B cells and macrophages in ST specimens from early arthritis patients can be used to differentiate RA from non-RA patients.

	References

Top Abstract Introduction Patients and methods Results Discussion References

 

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Submitted 20 April 1999; revised version accepted 25 May 1999.
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