Department of Rheumatology, Moscow Medical Academy, Moscow, Russia,
1 Department of Internal Medicine, University of Graz, Graz and
2 Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Innsbruck, Austria
SIR, The expression of cell adhesion molecules is up-regulated (or induced) by pro-inflammatory cytokines, and may have a central role in the mechanism of immune-mediated inflammation [1]. In rheumatoid arthritis (RA), pro-inflammatory cytokines such as tumour necrosis factor- (TNF-
), interleukin-1 (IL-1), IL-6, and IL-8 are produced in excess [2], and they may induce the expression of cell adhesion molecules on endothelial cells and leucocytes [3]. More recently, soluble isoforms of several types of cellular adhesion molecules have been described [4], and previous reports have shown increased levels of serum soluble intercellular adhesion molecule-1 (sICAM-1), sICAM-3 and sP-selectin in RA [57]. However, in some cases the data are contradictory, especially regarding their association with disease activity.
We analysed 35 patients (28 females, age: 47.0 ± 15.2 yr; mean ± S.D.) with RA according to American Rheumatism Association (ARA) criteria [8]. Patients received anti-rheumatic medications including non-steroidal anti-inflammatory drugs (NSAIDs) (n = 35); remittive agents, gold, penicillamine, antimalarials, sulphasalazine (n = 25); methotrexate (n = 3), and prednisolone (<10 mg/day; n = 9). Clinical variables included: disease duration (43.2 ± 38.1 months), functional class, according to the criteria of the ARA, duration of morning stiffness (73.5 ± 100.9 min), number of tender joints (16.5 ± 14.6), number of swollen joints (10.5 ± 8.4), grip strength (right: 30.1 ± 19.5; left: 30.9 ± 23.0 mmHg), Lansburry index, number of extra-articular features, and laboratory findings including haemoglobin, platelet count, erythrocyte sedimentation rate (ESR: 32.4 ± 16.5 mm/h; Westergren), latex fixation test (by agglutination; 29 positive = 83%), and C-reactive protein [CRP: 109.1 ± 128.4 mg/l; enzyme-linked immunosorbent assay (ELISA)]. Disease activity (4.8 ± 2.1) and disease severity indices (7.6 ± 3.4) were determined according to Wilkey et al. [9].
sICAM-1, sICAM-3 and sP-selectin concentrations were determined by commercially available ELISAs (Bender, Vienna, Austria), together with neopterin (Brahms, Berlin, Germany) and soluble TNF receptor type I (55 kDa; sTNF-R55) and sIL2-R (T-Cell Sciences, Cambridge, MA, USA), according to the manufacturers' instructions.
For comparisons of grouped data Student's t-test and the MannWhitney U-test were performed. Correlations between variables were analysed employing Spearman's rank correlation coefficient. P-values less than 0.05 were considered significant after BonferroniHolm adjustment for multiple comparisons using standard statistical software SPSS for Windows (release 6.1.3., October 1995).
Compared with normal, a significant proportion of the patients with RA had increased serum concentrations of sICAMs (Table 1). Concentrations did not differ between patients with or without steroid therapy. Positive correlations were obtained between sP-selectin concentrations and effusion count (rs = 0.44; P = 0.01), disease activity (rs = 0.41; P < 0.05) and disease severity index (rs = 0.53; P < 0.01). sP-selectin was suggested to be a marker of platelet but not endothelial cell activation which has been implicated in the pathogenesis of RA as well. However, we failed to find any correlations between sP-selectin and von Willebrand factor concentrations or platelet counts.
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There were significant correlations of sICAM-3 with sTNF-R55 (rs = 0.46, P < 0.01) and neopterin (rs = 0.41, P < 0.05) and between sIL-2R and sTNF-R55 (rs = 0.49, P < 0.01). ESR correlated with sICAM-3, sIL-2R, sTNF-R55 and neopterin (all P < 0.01). Concentrations of sICAM-1, sICAM-3 and sP-selectin did not correlate with each other, which agrees well with the results of other investigators [6]. There were no other significant correlations between soluble adhesion molecules, cytokine receptors, neopterin and platelet counts.
In contrast to most other members of the immunoglobulin superfamily, ICAM-3 is primarily expressed on resting and activated lymphocytes. ICAM-3 has co-stimulatory functions and may be particularly involved in initiating an immune response. Increased sICAM-3 has been shown in several autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis, GuillainBarré syndrome [10]. The correlations found between sICAM-3 concentrations and RA activity, severity indices and ESR confirm and extend the results of other authors who revealed elevated levels of sICAM-3 in patients with RA [5, 6].
Our results also extend earlier data demonstrating increased serum concentrations of sIL-2R, sTNF-R55 and neopterin in patients with RA. It is interesting that serum neopterin concentrations were correlated much more strongly with disease activity and severity and especially ESR as compared with sIL-2R and sTNF-R55, which correlated only weakly (not significantly). This observation suggests that the determination of sP-selectin and neopterin might be superior for the evaluation of patients with RA compared with the other immune system parameters in this study. Prospective studies are still necessary to extend this point. Other important conclusions resulting from our studies are the significant correlations between sICAM-3, neopterin and sTNF-R55, which indicate that increased concentrations of sICAM-3 may be alternative markers of cell-mediated immune activation in RA.
This work was financially supported by the Austrian funds Zur Förderung der wissenschaftlichen Forschung, P10776Med.
Notes
Correspondence to: D. Fuchs, Fritz Pregl Strasse 3, A-6020 Innsbruck, Austria.
References