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Editorial comment in the form of a Letter to the Editor is invited; however, it should not exceed 800 words, with a maximum of 10 references and no more than 2 figures (submitted as camera ready hard copy per Journal Guidelines) or tables and no subdivision for an Abstract, Methods, or Results. Letters should have no more than 3 authors. Full name(s) and addresses of the author(s) should accompany the letter as well as the telephone number, fax number, or E-mail address.

Contact. The Managing Editor, The Journal of Rheumatology, 920 Yonge Street, Suite 115, Toronto, Ontario M4W 3C7, CANADA. Tel: 416-967-5155; Fax: 416-967-7556; E-mail: Financial associations or other possible conflicts of interest should always be disclosed.


Deflazacort in Giant Cell Arteritis

To the Editor:

We read with interest the report by Cacoub, et al1, who found no significant difference between the bone loss for deflazacort versus prednisone in patients with giant cell arteritis. These results are in contrast to results we obtained with low doses2 and to results obtained with higher doses3-5. This apparent lack of effect in their study could be at least partly explained by a randomization leading accidentally to differences in both groups (compare the mean age and presence of symptoms of polymyalgia rheumatica). Even if not statistically significant, potentially clinically relevant differences in erythrocyte sedimentation rate, C-reactive protein, visual loss, and number of positive temporal artery biopsies tend to undermine the blinding of the study and lead to a longer duration of therapy in the group with a more severe condition. Furthermore, the choice of calcidiol as vitamin D supplementation was at least unfortunate, because this drug has been shown several times to interfere with bone metabolism and bone mass in patients treated with glucocorticoids6-8. For all these reasons we believe that the conclusions of the authors should be considered as premature, as far as the effects of prednisone and deflazacort on bone mass are concerned.

JEAN-PIERRE DEVOGELAER, MD, Department of Rheumatology, St-Luc University Hospital, B-1200 Brussels, Belgium; CARLO GENNARI, MD, Institute of Internal Medicine and Medical Pathology, University of Siena, 53100 Siena, Italy.


1. Cacoub P, Chemlal K, Khalifa P, et al. Deflazacort versus prednisone in patients with giant cell arteritis: effects on bone mass loss. J Rheumatol 2001;28:2474-9.

2. Devogelaer JP, Huaux JP, Dufour JP, Esselinckx W, Stasse P, Nagant de Deuxchaisnes C. Bone-sparing action of deflazacort versus equipotent doses of prednisone: a double-blind study in males with rheumatoid arthritis. In: Christiansen C, Johansen JS, Riis BJ, editors. Osteoporosis. Viborg: Norhaven A/S; 1987:1014-5.

3. Gennari C, Imbimbo B. Effects of prednisone and deflazacort on vertebral bone mass. Calcif Tissue Int 1985;37:592-3.

4. Olgaard K, Storm T, van Wovern N, et al. Glucocorticoid-induced osteoporosis in the lumbar spine, forearm, and mandible of nephrotic patients: a double-blind study on the high-dose, long-term effects of prednisone versus deflazacort. Calcif Tissue Int 1992;50:490-7.

5. Lippuner K, Casez J, Horber F, Jaeger P. Effects of deflazacort versus prednisone on bone mass, body composition and lipid profile. A randomized double blind study in kidney transplant patients. J Clin Endocrinol Metab 1998;83:3795-802.

6. Hahn TJ, Halstead LR, Teitelbaum SL, Hahn BH. Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration. J Clin Invest 1979;64:655-65.

7. Devogelaer JP, Esselinckx W, Nagant de Deuxchaisnes C. Calcidiol protects bone mass in rheumatoid arthritis treated by low dose glucocorticoids. In: Norman AW, Bouillon R, Thomasset M, editors. Vitamin D. A pluripotent steroid hormone: Structural studies, molecular endocrinology and clinical applications. Berlin: Walter de Gruyter; 1994:855-6.

8. Di Munno O, Beghe F, Favini P, et al. Prevention of glucocorticoid-induced osteoporosis effect on oral 25-hydroxyvitamin D and calcium. Clin Rheumatol 1989;8:202-7.

Manganese Superoxide Dismutase, Glutathione Peroxidase, and Total Radical Trapping Antioxidant Capacity in Active Rheumatoid Arthritis

To the Editor:

Rheumatoid arthritis (RA) is a chronic inflammatory disease that predominantly occurs in the joints by infiltration of T lymphocytes, macrophages, and plasma cells into the synovium1. Inflammation and tissue destruction are initiated by the influx of lymphocytes into the synovium, stimulating plasma cells and macrophages to produce inflammatory mediators such as tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1). Moreover, mononuclear phagocytes and neutrophils produce large amounts of reactive oxygen species (ROS)2. Antioxidant defence of eukaryotic cells is provided by a variety of enzymatic and nonenzymatic systems: copper-zinc (CuZnSOD) and manganese superoxide dismutase (MnSOD) enzymes act in tandem with glutathione peroxidase (GSH-Px), providing the primary enzymatic antioxidant defences. The MnSOD enzyme is inducible under conditions of stress or inflammation3.

We have described an upregulation of the MnSOD mRNA transcript in lymphocytes of patients with Alzheimer's disease and a significant increase in the enzymatic activity of the cytosolic CuZnSOD enzyme, while the total trapping antioxidant capacity (TRAP) was reduced4. Our aim here was to evaluate factors involved in antioxidant protection in the blood of patients with rheumatoid arthritis (RA), such as the concentrations of MnSOD in lymphocytes, cells playing a crucial role in RA, GSH-Px in erythrocytes, and TRAP in plasma, to investigate if active rheumatoid disease may lead to compensatory changes in the level of antioxidant.

We studied 20 consecutive hospitalized female patients, ranging in age from 20 to 73 years (mean 51.2 yrs), with RA according to the 1987 American Rheumatism Association criteria5. Mean disease duration was 4.5 years (range 2-10 yrs). All patients had active disease. Criteria for active disease were erythrocyte sedimentation rate > 30 mm/h and/or C-reactive protein > 10 mg/l, duration of morning stiffness > 60 min, > 6 swollen and tender joints, Ritchie index > 16. No patient had been treated with disease modifying antirheumatic drugs in the 3 months before the study. Therapy consisted of nonsteroidal antinflammatory drugs (NSAID). Twelve healthy age matched women made up the control group. All patients and controls provided informed consent to take part in the study.

Venous blood samples were drawn from each patient and control. Mononuclear cells (> 95% lymphocytes) were isolated from heparinized blood by centrifugation on a Ficoll-Hypaque gradient. MnSOD activity was assayed by the method of inhibition of hematoxylin autoxidation to hematein, in the presence of 5 mM cyanide6. GSH-Px enzyme assay was based on that of Paglia and Valentine7, monitored at 340 nm. The TRAP assay, described by Miller, et al8, was based on the quenching of the 2,2'-azinobis(3 thiolbenzothiazoline-6-sulfonic acid) radical cation (ABTS ) by the antioxidants.

Data were expressed as the mean ± SD of the indicated number of patients studied. We estimated differences between patients with RA and controls using one way analysis of variance (ANOVA) using Minitab software (Minitab, State College, PA, USA). When a significant effect was found, post-hoc comparison of means was by Fisher's test. Differences were considered significant at p < 0.05.

MnSOD levels were significantly higher in patients with RA than in controls (4.20 ± 2.28 vs 2.5 ± 0.73 µg/mg, respectively; p < 0.05) (Figure 1). We observed that GSH-Px activity appeared significantly lower in blood of patients compared with controls (115.2 ± 13.6 vs 198.2 ± 23.4 U/l, respectively; p < 0.01) (Figure 2). TRAP was significantly reduced compared with controls (723.0 ± 40.5 vs 1100.0 ± 85.0 mmol/l, respectively; p < 0.002) (Figure 3).

Figure 1. MnSOD activity (µg/mg protein) in lymphocytes of patients with RA and controls. Values are means ± SD.

Figure 2. GSH-Px activity (U/l) in erythrocytes of patients with RA and controls. Values are means ± SD.

Figure 3. TRAP (µM/l) in plasma of patients with RA and controls. Values are means ± SD.

The presence of T lymphocytes, macrophages, and neutrophils in inflamed joints raises the possibility of a role of ROS in the pathogenesis of RA9. Modification of the intracellular redox balance leads to important cellular changes derived from a modification of gene expression. Nuclear factor-kB and the transcription factor activator protein-1, which together mediate activation of genes involved in host defence, can be activated by oxidants in many cell types10. Mitochondrial concentrations of MnSOD enzyme are elevated in response to stimulation with IL-1ß and IL-6, and TNF-a regulates MnSOD mRNA expression11. TNF-a plays a central role in regulating lymphokine, chemokine, and growth factor expression in RA joints12. ROS are important regulator molecules implicated in the signaling cascade triggered by TNF-a12. It has been suggested that enzymatic or nonenzymatic antioxidant systems are impaired in RA13,14, thus patients with RA are exposed to oxidant. Higher SOD and xanthine oxidase levels and decreased or unchanged GSH-Px levels have been found in RA15,16.

Our patients were taking NSAID. Recent reports have indicated that NSAID diminished or had no significant effect on serum SOD and TRAP concentrations17, whereas we found MnSOD enzyme induced by the inflammatory process and TRAP capacity was decreased in patients with RA.

Our findings of elevated lymphocyte MnSOD and reduced erythrocyte GSH-Px concentrations in patients with RA suggest that the intracellular antioxidative system is compromised and peroxidation "reactions" are accelerated in active RA disease. As a result of the excess of H2O2 and hydroperoxides formed in these reactions, secondary antioxidant systems measured by TRAP are deficient.

MARIA EMILIA De LEO, MD, Istituto di Patologia Generale; ADELAIDE TRANGHESE, MD, Istituto di Medicina Interna e Geriatria, Divisione di Reumatologia; MASSIMO PASSANTINO, MD, Istituto di Patologia Generale; ALVARO MORDENTE, MD, Associate Professor, Istituto di Chimica Clinica; MARCO M. LIZZIO, MD, Istituto di Medicina Interna e Geriatria, Divisione di Reumatologia; TOMMASO GALEOTTI, Professor, Istituto di Patologia Generale; ANGELO ZOLI, MD, Assistant Professor, Istituto di Medicina Interna e Geriatria, Divisione di Reumatologia, Università Cattolica del Sacro cuore, Largo A. Gemelli 8, 00168 Roma, Italia.


1. Smeets TJ, Dolhain EM, Breedveld FC, Tak PP. Analysis of the cellular infiltrates and expression of cytokines in synovial tissue from patients with rheumatoid arthritis and reactive arthritis. J Pathol 1998;186:75-81.

2. Dularay B, Elson CJ, Dieppe PA. Enhanced oxidative response of polymorphonuclear leukocytes from synovial fluids of patients with rheumatoid arthritis. Autoimmunity 1988;1:159-69.

3. Sun Y. Free radicals, antioxidant enzymes and carcinogenesis. Free Radic Biol Med 1990;5:583-99.

4. De Leo ME, Borrello S, Passantino M, et al. Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer's disease. Neurosci Lett 1998;250:173-6.

5. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-24.

6. Martin JP, Dailey M, Sugarman E. Negative and positive assays of superoxide dismutase based on hematoxylin autoxidation. Arch Biochem Biophys 1987;255:329-36.

7. Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967;70:158-69.

8. Miller NJ, Rice-Evans C, Davies MJ. A new method for measuring antioxidant activity. Biochem Soc Trans 1993;21:95S.

9. Dewar CL, Marth M. Superoxide production from cytokine-treated adherent rheumatoid neutrophils. Clin Invest Med 1994;17:52-60.

10. Pepperl S, Dorger M, Ringel F, Kupatt C, Krombach F. Hyperoxia upregulates the NO pathway in alveolar macrophages in vitro: role of AP-1 and NF-kappa B. Am J Physiol Lung Cell Mol Physiol 2001;280:L905-13.

11. Rogers RJ, Monnier JM, Nick HS. TNF-alpha selectively induces MnSOD expression via mitochondria-to-nucleus signaling, whereas IL-1 beta utilizes an alternative pathway. J Biol Chem 2001;276:20419-27.

12. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001; 19:163-96.

13. Arthur JR. The glutathione peroxidases. Cell Mol Life Sci 2000;57:1825-35.

14. Heliovaara M, Knekt P, Amo K, Aaran RK, Alfthan G, Aromaa A. Serum antioxidant and risk of rheumatoid arthritis. Ann Rheum Dis 1994;53:51-3.

15. Ozturk HS, Cimen MYB, Cimen OB, Kackaz M, Durak I. Oxidant/antioxidant status of plasma samples from patients with rheumatoid arthritis. Rheumatol Int 1999;19:35-7.

16. Tarp U, Stengaard-Pedersen K, Hansen JC, Thorling EB. Glutathione redox cycle enzymes and selenium in severe rheumatoid arthritis: lack of antioxidative response to selenium supplementation in polymorphonuclear leukocytes. Ann Rheum Dis 1992;51:1044-9.

17. Pohle T, Brzozowski T, Becker JC, et al. Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C. Aliment Pharmacol Ther 2001;15:677-87.

Influence of Work Related Psychosocial Factors and Psychological Distress on Regional Musculoskeletal Pain

To the Editor:

In a recent interesting research report, Nahit, et al1 attempted to ascertain if there was an association between work related psychosocial factors, such as job demand and control, and reporting of perceived musculoskeletal pain. They demonstrated that those who perceived their work as stressful most of the time were most likely to report pain1.

As the above study was performed with newly employed workers, I would like to familiarize the readership with a series of studies performed with chronic pain patients (CPP) in a pain facility that also point to the importance of perceived job stress and its importance to pain.

In a series of 4 articles, Fishbain and colleagues have attempted to determine if preinjury job satisfaction influences "intent" to return to work to the preinjury job after pain facility treatment. In the first report, Fishbain, et al2 demonstrated that CPP not intending to return to work after pain facility treatment were more likely to complain of job dissatisfaction. In the second report from this group, Rosomoff, et al3 demonstrated that an association between non-intent to return to work after pain facility treatment and preinjury job dissatisfaction was similarly found across Workers' Compensation and non-Workers' Compensation CPP. In the third report, Fishbain, et al4 looked at actual return to work after pain facility treatment in relation to these variables. They found that actual return to work was predicted at one month "by intent," perceived job stress, and job like (job dissatisfaction) plus other variables. At 36 months, return to work was predicted by "intent" and by perceived job stress plus other variables. In the final study, Fishbain, et al5 attempted to predict "intent" to return to work after pain facility treatment in relation to actual return to work. "Intent" was predicted by perceived preinjury job stress plus other variables. In addition, those CPP who intended to return and did not were predicted by whether there was a job to go back to. Also, CPP not intending to go back to work to the preinjury job initially, but doing so later, were predicted by having a job to go back to. Overall, this series of studies points to a strong relation between preinjury work variables such as job dissatisfaction and "intent" to return to that job after treatment. In addition, these studies indirectly support the findings of Nahit, et al1. It seems that in trying to understand the low back pain injury and recovery process, it is important to take into account work related perceptions such as those of perceived job dissatisfaction and job stress.

DAVID A. FISHBAIN, MD, FAPA, University of Miami Comprehensive Pain and Rehabilitation Center, Miami Beach, FL, USA.


1. Nahit ES, Pritchard CM, Cherry MN, et al. The influence of work related psychosocial factors and psychological distress on regional musculoskeletal pain: a study of newly employed workers. J Rheumatol 2001;28:1378-84.

2. Fishbain DA, Rosomoff HL, Cutler R, et al. Do chronic pain patients' perceptions about their preinjury jobs determine their intent to return to the same type of job post-pain facility treatment? Clin J Pain 1995;11;267-78.

3. Rosomoff HL, Fishbain DA, Cutler R, et al. Do chronic pain patients' perceptions about their preinjury jobs differ as a function of worker compensation and non-worker compensation status? Clin J Pain 1997;12:297-306.

4. Fishbain DA, Cutler RB, Rosomoff HL, Khalil T, Steele-Rosomoff R. Impact of chronic pain patients' job perception variables on actual return to work. Clin J Pain 1997;13:197-206.

5. Fishbain DA, Cutler B, Rosomoff HL, et al. The prediction of chronic pain patient "intent," and "discrepancy with non-intent" for return to work post-pain facility treatment, in print. Clin J Pain 1999;15:141-50.

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