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Plasma and serum levels of zinc (Zn) and copper (Cu) have been reported to be altered in patients with rheumatoid arthritis (RA).1,2 Few studies have measured these levels in tissues, particularly peripheral blood mononuclear cells (PBMCs), the site for a host of immunological aberrations.3 In a previous study we measured levels of Zn and Cu in plasma and PBMCs to see if they correlated with disease activity and reported reduced levels of Zn in the serum of patients with active RA.4
Patients attending the rheumatology clinic at our institute and satisfying the American College of Rheumatology (formerly American Rheumatism Association) criteria for the diagnosis of RA were studied.5 Patients were categorised as either active or inactive RA. All patients classified as active RA had at least three of the following: morning stiffness for more than 45 minutes, five swollen joints, five tender joints, and erythrocyte sedimentation rate (Westergren) more than 45 mm/1st h.6 Both plasma and lysed PBMC samples were read on atomic absorption spectrophotometer (Perkin Ellmer, Norwalk, CT) at a wavelength of 213.8 nm for Zn and 324.7 nm for Cu. The atomic absorption spectrophotometer was calibrated with reference standards obtained from Sigma Chemicals Company (St Louis, MA).
Thirty nine patients (31 women) with RA had a mean (SD) age of 36.2 (8.3) years (range 18–52) and mean disease duration of 55.8 (36.6) months (range 6–168). Twenty patients had inactive and 19 patients active disease, respectively. Twenty two healthy controls (14 women), well matched for age (mean age 34.2 (6.2) years, range 20–56) with the two patient groups, were studied at the same time. Both patients and controls were of middle socioeconomic status. Table 1 shows the plasma and PBMC levels of Zn and Cu.
Our results are in agreement with earlier studies which showed that plasma Zn levels are significantly lower and plasma Cu levels significantly higher in patients with active RA. 1,2 Additionally, it is shown here that PBMC levels of these elements have an inverse relation with plasma levels.
With acute inflammation, the acute phase response may move Zn into the liver and the reduced plasma concentration may not be indicative of overall deficiency.7 Possibly, also, PBMCs may be an additional site to which Zn is moved during inflammatory states. The average disease duration of patients with active disease was more than 54 months. In such a long process it is unclear whether chronic cytokine release, as is seen in RA, causes a shift of Zn from one compartment to another or if there is a true Zn depletion. Significantly, there was no correlation between age or duration of disease and plasma or PBMC levels of Zn.
The finding of raised Cu levels in the plasma is to be expected because of a concomitant rise of caeruloplasmin, which is an acute phase reactant.1,2 The reduced levels in PBMCs may signify a movement of Cu from PBMCs to the liver where it is absorbed and attached to caeruloplasmin. Thus the findings of plasma and PBMC Cu levels may merely be a reflection of an acute phase response, and the alterations may be due to increased hepatic synthesis of caeruloplasmin.
The effect of concomitant drugs also needs to be considered. The number of patients receiving non-steroidal anti-inflammatory and second line drugs was similar. None of the patients received corticosteroids in the preceding eight weeks.
It would be premature to speculate about a possible role for supplementation with Zn and Cu for patients with RA. From the results shown in this study, patients with inactive RA had similar levels of Cu and Zn as controls. If the diet of patients with active RA were deficient in Zn (as shown by plasma levels) it would be unlikely to contain an excess of Cu and vice versa for PBMC levels. The more plausible explanation would be that this represents a redistribution of trace elements between plasma and PBMCs, and a control of inflammation would lead to levels close to those seen in controls. Hence, further studies need to be carried out on paired samples in a cohort of patients, once when the disease is active and again when it becomes inactive. If plasma Zn levels increase and Cu levels decrease with the control of inflammation and attain the levels of controls then there would be no indication for dietary supplementation with these metals.
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