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TRACE ELEMENTS IN THE TREATMENT OF RHEUMATIC CONDITIONS
COMPLEMENTARY AND ALTERNATIVE THERAPIES FOR RHEUMATIC DISEASES I
0889-857X/99 $8.00
+ .OO
TRACE ELEMENTS IN THE TREATMENT OF RHEUMATIC CONDITIONS Elliot D. Rosenstein, MD, and Jacques R. Caldwell, MD
The oft-quoted Ebers papyrus, a therapeutic compendium from the eighteenth Dynasty of ancient Egypt (about 1500 BC), is one of the first known citations of the use of trace elements, particularly various metallic compounds, for relief of musculoskeletal disorders. Verdigris (basic copper acetate), blue vitriol (copper(I1) sulfate), and pulverized metallic copper were recommended as topical therapies for rheumatic pains.3o The role of these trace elements in chronic inflammatory conditions such as rheumatoid arthritis (RA) is of great interest because many of them are co-factors in metabolic processes involving collagen and bone or immune system function.*,7, 13, 32 Studies of the nutritional status of patients with active RA frequently demonstrate deficiencies in these "micronutrients," in Earticular various metallic elements, including copper, zinc, selenium, and magnesium.', l3 The increase in levels of proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factora (TNF-a) and IL-6 seen in the setting of active RA may affect the availability of these elements by inducing the production of metalbinding proteins, metallothioneins, in the liver or intestine.32The increased metallothionein production may result in sequestration of these
From the Arthritis and Rheumatic Disease Center and Division of Rheumatology, Saint Bamabas Medical Center, Livingston, New Jersey (EDR); Department of Medicine, Mount Sinai School of Medicine, New York, New York (EDR); Halifax Clinical Research Institute, Daytona Beach (JRC), Gainesville Clinical Research Center; and the Department of Medicine, University of Florida (JRC), Gainesville, Florida
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 25 NUMBER 4 * NOVEMBER 1999
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ROSENSTEIN & CALDWELL
metal ions so that they are unavailable to peripheral tiss~es.~, 13, 32 In peripheral tissues, including within inflammatory cells, many of these trace metallic elements are incorporated into antioxidant enzymes. Antioxidant metalloenzymes interfere with the production of free radicals by inactivating reactive oxygen molecules in tissues and immune cells. Although the physiologic role for these trace elements may be reasonably well substantiated, their therapeutic usefulness is less compelling.
COPPER
Arthritis patients have worn copper amulets, anklets, and bracelets for thousands of years, and their use continues today as a folk remedy, despite the skepticism of most Most serum copper is bound to ceruloplasmin, the levels of which increase as part of the acute phase response. Ceruloplasmin has been shown to have antioxidant properties, including binding superoxide. The levels of both copper and ceruloplasmin have been shown to positively correlate with levels of IL-lP and TNF-a.32 Despite this, the role of copper in inflammatory processes remains quite obscure. Both pro- and anti-inflammatory effects of copper have been documented. Because all soluble copper is bound in physiologic environments, the oxidation state of copper, monovalent copper(I), or divalent copper(II), may determine differing phlogistic effects. It may, in fact, be their respective ligands rather than the metallic portions of the molecules that mediate the inflammatory response to copper Along with zinc and manganese, copper has been shown to be an essential cofactor for antioxidant metalloenzymes such as cytoplasmic superoxide dismutase, which plays an essential role in inhibiting free radical damage. Other copper-dependent enzymes have been identified in lymphocytes, including cytochrome C oxidase and sulfhydryl oxidase.16Despite the importance of these enzymes, dietary intake of copper and other heavy metals does not enhance their antioxidant activity once saturated, leaving the mechanism of action of copper un~1ear.l~ The therapeutic benefit of penicillamine had been attributed in part to the chelation of copper salts.5 The complex of D-penicillamine-copper(1) has been shown to suppress arthritis in animal models, however, in addition to suppressing mediators of inflammation such as lysosomal enzymes, prostaglandins, and the oxidative metabolites of the respiratory b ~ r s t . ~ Whitehouse and Walker30 detected modest anti-inflammatory and antiarthritic effects of a variety of copper salts in rats. Of interest, copper complexes of nonsteroidal anti-inflammatory drugs have been demonstrated to be more active than the nonsteroidal anti-inflammatory
TRACE ELEMENTS
931
drugs themselves, although the clinical significance of this observation remains unclear. Copper salicylate has been shown to have analgesic and anti-inflammatory effects when administered either systemically or topically in experimental animal models of arthritis. In the rat, copper salicylate and copper phenylbutazone were superior anti-inflammatory agents compared with either salicylate or phenylbutazone, respectively.2 In humans, when copper salicylate is topically applied, higher plasma salicylate levels are established than when the equivalent amount of salicylic acid is applied.29 Copper has been documented to dissolve in human sweat, and soluble copper can permeate through skin. Copper jewelry worn in contact with the skin has been documented to lose weight (up to 13 mg/mo)?O The potential therapeutic value of copper bracelets was examined in a poorly controlled trial, using questionnaires and psychological parameters as outcome measures. Walker et alZ9performed a comparison of patients with self-diagnosed "arthritis" or "rheumatism" who wore copper bracelets, anodized aluminum bracelets resembling copper, or no bracelets at all. Of 77 evaluable subjects, a significant number of patients noted symptomatic improvement with the copper bracelets (copper vs aluminum, P < 0.01). They obtained a 93% response rate from 323 patients and noted that those who wore copper bracelets felt worse without them (P < 0.02). Although these results do not inspire one to suggest purchasing copper bracelets, this is the only existing attempt to evaluate this common alternative i~eatrnent.2~ SELENIUM
Selenium is an' essential component of the enzymes glutathione peroxidase and phospholipid hydroperoxidase, which catalyze the reduction of organic and inorganic peroxides as well as hydroperoxides derived from arachidonic acid metabolism and modulate superoxide and hydrogen peroxide generati~n.'~ Selenium has been suggested to have antimutagenic, antiproliferative, anti-inflammatory, antiviral, and zo Abnormalities in the serum, blood, and immunomodulatory effects.1z* red blood cell concentration of selenium have been noted in studies of RA patients. When compared with those of healthy controls, selenium concentrations have been noted to be relatively low, with a mean reduc20, 27 It has been observed that selenium tion of approximately levels drop in response to inflammation, including acute bacterial infections in people and adjuvant arthritis in rats, as well as in comparisons 27 Low activity of of RA patients with active versus quiescent disease.20* glutathione peroxidase has been found in serum, red blood cells, and neutrophils of patients with active RA. Interestingly, despite long-term
932
ROSENSTEIN & CALDWELL
supplementation with selenium, the activity of neutrophil glutathione peroxidase remained suppressed, although that of other isozymes imAfter an open trial of 10 RA patients suggested clinical improvement with sodium selenite supplementation, a double-blind study of 40 patients with active RA h-eated for 6 months with 256 rJ.gof yeast selenium revealed no clinical or laboratory improvement, although, as expected, serum and red blood cell levels of selenium had The results of two subsequent studies (published in abstract form) that examined selenium supplementation compared with vitamin A, vitamin E, or n-3 fatty acid supplementation did not demonstrate beneficial effects of selenium therapy.s,22 Peretz et al?' however, treated 8 patients with recent onset RA using 200 bg of yeast selenium for 3 months and found a significant reduction in articular pain and joint score. Aaseth et all treated 25 patients with 600 bg of selenium for 8 months in a double-blind study compared with 22 placebo-treated patients who were switched to selenium after 4 months. After the initial 4-month controlled portion of the study, no clinical differences were seen between the two groups. After the full 8 months of supplementation, however, significant improvements in articular pain index, grip strength (left hand only), and morning stiffness were noted in the long-term-treated population.' The therapeutic benefits of oral selenium supplementation appear to be quite limited. The unresponsiveness of neutrophil glutathione peroxidase to selenium supplementation may play some role in the continued inflammation seen in these patients.
ZINC
Low serum zinc levels have been reported in patients with RA, although correlation with disease activity has been incon~istent.'~, 25 A recent report of RA patients has demonstrated a negative correlation between proinflammatory cytokine levels (IL-lp, TNF-a) and serum zinc Reports of defective absorption of zinc in RA have recently appeared, but there remains significant controversy over whether these findings are a reflection of true zinc deficiency or instead indicate changes in zinc-protein binding.I9 Zinc deficiency has been demonstrated to blunt lymphocyte proliferation, inhibit delayed cutaneous hypersensitivity, reduce natural killer cell activity, and slow neutrophil chemotaxis. The importance of zinc to normal immune function, the anti-inflammatory effects of zinc preparations in chronic models of inflammation, and the role of zinc as a cofactor in collagen ~ynthesis'~ have prompted many investigations of the therapeutic role of zinc supplementation in RA. Simkin25treated 24 refractory chronic RA patients with 220 mg of zinc sulfate administered
TRACE ELEMENTS
933
three times daily, observing improvement in walking time, patient global assessment of disease activity, duration of morning stiffness, and joint 17, 24 swelling.25Subsequent investigators could not repeat these res~lts.~, Although there is no consensus about the potential role of zinc supplementation at this time, Simkinz6has suggested that zinc supplementation may only be beneficial is those patients who are deficient in zinc.
Gold has been used for the treatment of rheumatic diseases since the late 1800s. Although complex gold compounds are used therapeutically, their mechanism of action is poorly understood. Although not incorporated into antioxidant enzymes like other trace metals, gold compounds have been demonstrated to inhibit growth of various microorganisms, affect complement activation, inhibit chemotactic responses of human monocytes, and inhibit various lymphocyte functions.15,28 After chronic administration, gold distribution and tissue concentrations vary considerably. In general, gold is concentrated in the kidneys, liver, and spleen. Gold is easily taken up by macrophages, with ultrastructural studies demonstrating that gold is deposited almost exclusively in the lysosomes. Relatively low concentrations of gold are detected in synovial membrane and articular cartilage, suggesting that small amounts of gold are required to achieve a therapeutic res~1t.l~ Interestingly, the three gold compounds used in clinical practice all consist of gold bound to a sulfhydryl gr0up.l After gastrointestinal absorption, the gold complex is not stable. In vivo, the gold cation is released from the complex, with rapid chelation by albumin. Some studies have suggested that the thiol moiety may have beneficial effects independent of the gold c~mponent.~ The efficacy of the three gold compounds-parenteral aurothioglucose, sodium gold thiomalate, and oral auranofin-in the treatment of RA is beyond the scope of this article but has recently been reviewed elsewhere.'O, 11, 31 Recently, the prospect of beneficial effects from topical gold has attracted considerable attention. To examine the hypothesis that gold rings might delay development of articular erosions in patients with RA, gold ring wearers were compared with non-ring wearers with regard to erosions at the left fourth metacarpophalangeal (MCP) or proximal interphalangeal (PIP)joints. Thirty ring wearers and 25 non-ring wearers were evaluated. The median Larsen score in the fourth MCP joint of the left hand of ring wearers was significantly less than in their own right fourth MCP and the equivalent joint of the left hand in non-ring wearers. A similar difference was noted in the adjacent middle finger MCP. The authors believed that these results support the hypothesis that gold
934
ROSENSTEIN & CALDWELL
could be transported percutaneously and via lymphatics "downstream" to the more proximal MCP joint sufficiently to delay articular erosions.18 The explanation for the "spreading" of effects to adjacent fingers is not explained. More extensive studies are required to corroborate these findings and evaluate whether this effect is simply a reflection of ring wearers and not a consequence of the constitution of the ring.
CONCLUSIONS
The importance of macrophages in the rheumatoid process has been well substantiated. In addition to the production of pro-inflammatory cytokines, macrophages contribute to the production of reactive forms of oxygen, which contribute to the inflammatory process. It is tempting to theorize that the effects of the trace metallic elements may be through mechanisms that control macrophage function and the proinflammatory effects of the toxic oxygen metabolites. Gold, zinc, and copper can induce synthesis of metallothioneins. Copper is a component of superoxide dismutase, and the major copper-containing protein, ceruloplasmin, which has anti-inflammatory properties. In high doses, zinc can immobilize macrophages. Gold accumulates in macrophage lysosomes and may have more direct anti-oxidative effects.l, This paradigm offers a convenient concept for the potential effectiveness of trace metal supplementation. Unfortunately, other than for gold-sulfhydryl compounds, there exists a chronic deficiency of solid scientific information about any role of trace metallic elements, whether they are administered parenterally, orally, or topically as therapeutic agents in the management of 14, 23, 26 Further studies are necessary to determine which of these modalities have therapeutic effects and to identify those patients who are most likely to benefit from them.
References 1. Aaseth J, Haugen M, Forre 0 Rheumatoid arthritis and metal compounds-perspectives on the role of oxygen radical detoxification. Analyst 1233-6, 1998 2. Auer DE, Seawright AA: Copper salicylate and copper phenylbutazone as topically applied anti-inflammatory agents in the rat and horse. J Vet Pharmacol Ther 136775, 1990 3. Cimmino MA, Mazzucotelli A, Rovetta G, et al: The controversy over zinc sulphate efficacy in rheumatoid and psoriatic arthritis. Scand J Rheumatol 13:191-192, 1984 4. Davis P: Penicillamine metal chelates and their possible importance in rheumatoid arthritis-a brief review. Clin Invest Med 7:41-44, 1984 5. Gerber DA: Inhibition of the denaturation of human gamma globulin by a mixture of u-penicillamine disulfide and copper. J Pharmacol27469472,1978 6. Grootveld M, Blake DR, Sahinoglu T, et al: Control of oxidative damage in rheumatoid arthritis by gold(1)-thiolate drugs. Free Rad Res 10:199-220, 1990
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935
7. Honkanen V, Konttinen YT, Sorsa T, et a1 Serum zinc, copper and selenium in rheumatoid arthritis. J Trace Elem Electrolytes Health Dis 5261-263, 1991 8. Jantti J, Vapaatalo H, Seppala E, et a1 Treatment of rheumatoid arthritis with fish oil, selenium, vitamins A and E and placebo [abstract]. Scand J Rheumatol 20:225, 1991 9. Jellum E, Munthe E: Fate of the thiomalate part after intramuscular administration of aurothiomalate in rheumatoid arthritis. Ann Rheum Dis 41:431432, 1982 10. Jones G, Brooks PM. Injectable gold compounds: An overview. Br J Rheumatol35:11541158, 1996 11. Kean WF, Hart L, Buchanan W W Aumaofin. Br J Rheumatol36:560-572, 1997 12. Kose K, Dogan P, Kardas Y, et a 1 Plasma selenium levels in rheumatoid arthritis. Biol Trace Elem Res 5351-56, 1996 13. Kremer J M Nutrition and rheumatic diseases. In Kelly WN, Harris ED, Ruddy S, et a1 (eds): Textbook of Rheumatology, ed 5. Philadelphia, WB Saunders, 1997, pp 521-533 14. Lewis AJ: The role of copper in inflammatory disorders. Agents Actions 15:513-519, 1984 15. Lipsky PE, Ziff M Inhibition of antigen- and mitogen-induced human lymphocyte proliferation by gold compounds. J Clin Invest 59:455466, 1977 16. Lipsky PE, Ziff M Inhibition of human helper T cell function in vitro by D-peniCillamine and CuSO,. J Clin Invest 65:1069-1076,1980 17. Mattingly PC, Mowat AG: Zinc sulphate in rheumatoid arthritis. Ann Rheum Dis 41:45&457,1982 18. Mulherin DM, Struthers GR, Situnayake R D Do gold rings protect against articular erosion in rheumatoid arthritis? Ann Rheum Dis 56:497499, 1997 19. Naveh Y, Schapira D, Ravel Y, et al: Zinc metabolism in rheumatoid arthritis: Plasma and urinary zinc and relationship to disease activity. J Rheumatol24:643-646, 1997 20. ODell JR, Lemley-Gillespie S, Palmer WR, et al: Serum selenium concentrations in rheumatoid arthritis. Ann Rheum Dis 50:376-378, 1991 21. Peretz AM, Neve JD, Famaey JPP: Selenium in rheumatic diseases. Semin Arthritis Rheum 20305-316,1991 22. Petersson I, Majberger E, Palm S, et al: Treatment of rheumatoid arthritis with selenium and vitamin E [abstract]. Sand J Rheumatol 20218, 1991 23. Rafter GW: Rheumatoid arthritis: A disturbance in copper homeostasis. Med Hypotheses 22:245249, 1987 24. Rasker JJ, Kardaun SH: Lack of beneficial effect of zinc sulphate in rheumatoid arthritis. Scand J Rheumatol 11:168-170, 1982 25. Simkin PA: Oral zinc sulphate in rheumatoid arthritis. Lancet 2:539-542, 1976 26. Simkin PA: Zinc, again. J Rheumatol24626-627,1997 27. Tarp U:Selenium in rheumatoid arthritis. A review. Analyst 120:877-881, 1995 28. Ugai K, Ziff M, Lipsky PE: Gold-induced changes in the morphology and functional capabilities of human monocytes. Arthritis Rheum 22:1352-1360, 1979 29. Walker WR, Beveridge SJ, Whitehouse Mw: Dermal copper drugs: The copper bracelet and Cu(I1) salicylate complexes. Agents Actions Suppl 8:359-367, 1981 30. Whitehouse W ,Walker WR Copper and inflammation. Agents Actions 8235-90, 1978 31. Wolfe F: The curious case of intramuscular gold. Rheum Dis Clin North Am 19:173187, 1993 32. Zoli A, Altomonte L, Caricchio R, et al: Serum zinc and copper in active rheumatoid arthritis: Correlation with interleukin 1 p and tumour necrosis factor a.Clin Rheumatol 17:378-382, 1998
Address reprint requests to Elliot D. Rosenstein, MD Arthritis and Rheumatic Disease Center Saint Bamabas Medical Center 200 South Orange Avenue Livingston, NJ 07039
0889-857X/99 $8.00
+ .OO
TRACE ELEMENTS IN THE TREATMENT OF RHEUMATIC CONDITIONS Elliot D. Rosenstein, MD, and Jacques R. Caldwell, MD
The oft-quoted Ebers papyrus, a therapeutic compendium from the eighteenth Dynasty of ancient Egypt (about 1500 BC), is one of the first known citations of the use of trace elements, particularly various metallic compounds, for relief of musculoskeletal disorders. Verdigris (basic copper acetate), blue vitriol (copper(I1) sulfate), and pulverized metallic copper were recommended as topical therapies for rheumatic pains.3o The role of these trace elements in chronic inflammatory conditions such as rheumatoid arthritis (RA) is of great interest because many of them are co-factors in metabolic processes involving collagen and bone or immune system function.*,7, 13, 32 Studies of the nutritional status of patients with active RA frequently demonstrate deficiencies in these "micronutrients," in Earticular various metallic elements, including copper, zinc, selenium, and magnesium.', l3 The increase in levels of proinflammatory cytokines such as interleukin-1 (IL-1), tumor necrosis factora (TNF-a) and IL-6 seen in the setting of active RA may affect the availability of these elements by inducing the production of metalbinding proteins, metallothioneins, in the liver or intestine.32The increased metallothionein production may result in sequestration of these
From the Arthritis and Rheumatic Disease Center and Division of Rheumatology, Saint Bamabas Medical Center, Livingston, New Jersey (EDR); Department of Medicine, Mount Sinai School of Medicine, New York, New York (EDR); Halifax Clinical Research Institute, Daytona Beach (JRC), Gainesville Clinical Research Center; and the Department of Medicine, University of Florida (JRC), Gainesville, Florida
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 25 NUMBER 4 * NOVEMBER 1999
929
930
ROSENSTEIN & CALDWELL
metal ions so that they are unavailable to peripheral tiss~es.~, 13, 32 In peripheral tissues, including within inflammatory cells, many of these trace metallic elements are incorporated into antioxidant enzymes. Antioxidant metalloenzymes interfere with the production of free radicals by inactivating reactive oxygen molecules in tissues and immune cells. Although the physiologic role for these trace elements may be reasonably well substantiated, their therapeutic usefulness is less compelling.
COPPER
Arthritis patients have worn copper amulets, anklets, and bracelets for thousands of years, and their use continues today as a folk remedy, despite the skepticism of most Most serum copper is bound to ceruloplasmin, the levels of which increase as part of the acute phase response. Ceruloplasmin has been shown to have antioxidant properties, including binding superoxide. The levels of both copper and ceruloplasmin have been shown to positively correlate with levels of IL-lP and TNF-a.32 Despite this, the role of copper in inflammatory processes remains quite obscure. Both pro- and anti-inflammatory effects of copper have been documented. Because all soluble copper is bound in physiologic environments, the oxidation state of copper, monovalent copper(I), or divalent copper(II), may determine differing phlogistic effects. It may, in fact, be their respective ligands rather than the metallic portions of the molecules that mediate the inflammatory response to copper Along with zinc and manganese, copper has been shown to be an essential cofactor for antioxidant metalloenzymes such as cytoplasmic superoxide dismutase, which plays an essential role in inhibiting free radical damage. Other copper-dependent enzymes have been identified in lymphocytes, including cytochrome C oxidase and sulfhydryl oxidase.16Despite the importance of these enzymes, dietary intake of copper and other heavy metals does not enhance their antioxidant activity once saturated, leaving the mechanism of action of copper un~1ear.l~ The therapeutic benefit of penicillamine had been attributed in part to the chelation of copper salts.5 The complex of D-penicillamine-copper(1) has been shown to suppress arthritis in animal models, however, in addition to suppressing mediators of inflammation such as lysosomal enzymes, prostaglandins, and the oxidative metabolites of the respiratory b ~ r s t . ~ Whitehouse and Walker30 detected modest anti-inflammatory and antiarthritic effects of a variety of copper salts in rats. Of interest, copper complexes of nonsteroidal anti-inflammatory drugs have been demonstrated to be more active than the nonsteroidal anti-inflammatory
TRACE ELEMENTS
931
drugs themselves, although the clinical significance of this observation remains unclear. Copper salicylate has been shown to have analgesic and anti-inflammatory effects when administered either systemically or topically in experimental animal models of arthritis. In the rat, copper salicylate and copper phenylbutazone were superior anti-inflammatory agents compared with either salicylate or phenylbutazone, respectively.2 In humans, when copper salicylate is topically applied, higher plasma salicylate levels are established than when the equivalent amount of salicylic acid is applied.29 Copper has been documented to dissolve in human sweat, and soluble copper can permeate through skin. Copper jewelry worn in contact with the skin has been documented to lose weight (up to 13 mg/mo)?O The potential therapeutic value of copper bracelets was examined in a poorly controlled trial, using questionnaires and psychological parameters as outcome measures. Walker et alZ9performed a comparison of patients with self-diagnosed "arthritis" or "rheumatism" who wore copper bracelets, anodized aluminum bracelets resembling copper, or no bracelets at all. Of 77 evaluable subjects, a significant number of patients noted symptomatic improvement with the copper bracelets (copper vs aluminum, P < 0.01). They obtained a 93% response rate from 323 patients and noted that those who wore copper bracelets felt worse without them (P < 0.02). Although these results do not inspire one to suggest purchasing copper bracelets, this is the only existing attempt to evaluate this common alternative i~eatrnent.2~ SELENIUM
Selenium is an' essential component of the enzymes glutathione peroxidase and phospholipid hydroperoxidase, which catalyze the reduction of organic and inorganic peroxides as well as hydroperoxides derived from arachidonic acid metabolism and modulate superoxide and hydrogen peroxide generati~n.'~ Selenium has been suggested to have antimutagenic, antiproliferative, anti-inflammatory, antiviral, and zo Abnormalities in the serum, blood, and immunomodulatory effects.1z* red blood cell concentration of selenium have been noted in studies of RA patients. When compared with those of healthy controls, selenium concentrations have been noted to be relatively low, with a mean reduc20, 27 It has been observed that selenium tion of approximately levels drop in response to inflammation, including acute bacterial infections in people and adjuvant arthritis in rats, as well as in comparisons 27 Low activity of of RA patients with active versus quiescent disease.20* glutathione peroxidase has been found in serum, red blood cells, and neutrophils of patients with active RA. Interestingly, despite long-term
932
ROSENSTEIN & CALDWELL
supplementation with selenium, the activity of neutrophil glutathione peroxidase remained suppressed, although that of other isozymes imAfter an open trial of 10 RA patients suggested clinical improvement with sodium selenite supplementation, a double-blind study of 40 patients with active RA h-eated for 6 months with 256 rJ.gof yeast selenium revealed no clinical or laboratory improvement, although, as expected, serum and red blood cell levels of selenium had The results of two subsequent studies (published in abstract form) that examined selenium supplementation compared with vitamin A, vitamin E, or n-3 fatty acid supplementation did not demonstrate beneficial effects of selenium therapy.s,22 Peretz et al?' however, treated 8 patients with recent onset RA using 200 bg of yeast selenium for 3 months and found a significant reduction in articular pain and joint score. Aaseth et all treated 25 patients with 600 bg of selenium for 8 months in a double-blind study compared with 22 placebo-treated patients who were switched to selenium after 4 months. After the initial 4-month controlled portion of the study, no clinical differences were seen between the two groups. After the full 8 months of supplementation, however, significant improvements in articular pain index, grip strength (left hand only), and morning stiffness were noted in the long-term-treated population.' The therapeutic benefits of oral selenium supplementation appear to be quite limited. The unresponsiveness of neutrophil glutathione peroxidase to selenium supplementation may play some role in the continued inflammation seen in these patients.
ZINC
Low serum zinc levels have been reported in patients with RA, although correlation with disease activity has been incon~istent.'~, 25 A recent report of RA patients has demonstrated a negative correlation between proinflammatory cytokine levels (IL-lp, TNF-a) and serum zinc Reports of defective absorption of zinc in RA have recently appeared, but there remains significant controversy over whether these findings are a reflection of true zinc deficiency or instead indicate changes in zinc-protein binding.I9 Zinc deficiency has been demonstrated to blunt lymphocyte proliferation, inhibit delayed cutaneous hypersensitivity, reduce natural killer cell activity, and slow neutrophil chemotaxis. The importance of zinc to normal immune function, the anti-inflammatory effects of zinc preparations in chronic models of inflammation, and the role of zinc as a cofactor in collagen ~ynthesis'~ have prompted many investigations of the therapeutic role of zinc supplementation in RA. Simkin25treated 24 refractory chronic RA patients with 220 mg of zinc sulfate administered
TRACE ELEMENTS
933
three times daily, observing improvement in walking time, patient global assessment of disease activity, duration of morning stiffness, and joint 17, 24 swelling.25Subsequent investigators could not repeat these res~lts.~, Although there is no consensus about the potential role of zinc supplementation at this time, Simkinz6has suggested that zinc supplementation may only be beneficial is those patients who are deficient in zinc.
Gold has been used for the treatment of rheumatic diseases since the late 1800s. Although complex gold compounds are used therapeutically, their mechanism of action is poorly understood. Although not incorporated into antioxidant enzymes like other trace metals, gold compounds have been demonstrated to inhibit growth of various microorganisms, affect complement activation, inhibit chemotactic responses of human monocytes, and inhibit various lymphocyte functions.15,28 After chronic administration, gold distribution and tissue concentrations vary considerably. In general, gold is concentrated in the kidneys, liver, and spleen. Gold is easily taken up by macrophages, with ultrastructural studies demonstrating that gold is deposited almost exclusively in the lysosomes. Relatively low concentrations of gold are detected in synovial membrane and articular cartilage, suggesting that small amounts of gold are required to achieve a therapeutic res~1t.l~ Interestingly, the three gold compounds used in clinical practice all consist of gold bound to a sulfhydryl gr0up.l After gastrointestinal absorption, the gold complex is not stable. In vivo, the gold cation is released from the complex, with rapid chelation by albumin. Some studies have suggested that the thiol moiety may have beneficial effects independent of the gold c~mponent.~ The efficacy of the three gold compounds-parenteral aurothioglucose, sodium gold thiomalate, and oral auranofin-in the treatment of RA is beyond the scope of this article but has recently been reviewed elsewhere.'O, 11, 31 Recently, the prospect of beneficial effects from topical gold has attracted considerable attention. To examine the hypothesis that gold rings might delay development of articular erosions in patients with RA, gold ring wearers were compared with non-ring wearers with regard to erosions at the left fourth metacarpophalangeal (MCP) or proximal interphalangeal (PIP)joints. Thirty ring wearers and 25 non-ring wearers were evaluated. The median Larsen score in the fourth MCP joint of the left hand of ring wearers was significantly less than in their own right fourth MCP and the equivalent joint of the left hand in non-ring wearers. A similar difference was noted in the adjacent middle finger MCP. The authors believed that these results support the hypothesis that gold
934
ROSENSTEIN & CALDWELL
could be transported percutaneously and via lymphatics "downstream" to the more proximal MCP joint sufficiently to delay articular erosions.18 The explanation for the "spreading" of effects to adjacent fingers is not explained. More extensive studies are required to corroborate these findings and evaluate whether this effect is simply a reflection of ring wearers and not a consequence of the constitution of the ring.
CONCLUSIONS
The importance of macrophages in the rheumatoid process has been well substantiated. In addition to the production of pro-inflammatory cytokines, macrophages contribute to the production of reactive forms of oxygen, which contribute to the inflammatory process. It is tempting to theorize that the effects of the trace metallic elements may be through mechanisms that control macrophage function and the proinflammatory effects of the toxic oxygen metabolites. Gold, zinc, and copper can induce synthesis of metallothioneins. Copper is a component of superoxide dismutase, and the major copper-containing protein, ceruloplasmin, which has anti-inflammatory properties. In high doses, zinc can immobilize macrophages. Gold accumulates in macrophage lysosomes and may have more direct anti-oxidative effects.l, This paradigm offers a convenient concept for the potential effectiveness of trace metal supplementation. Unfortunately, other than for gold-sulfhydryl compounds, there exists a chronic deficiency of solid scientific information about any role of trace metallic elements, whether they are administered parenterally, orally, or topically as therapeutic agents in the management of 14, 23, 26 Further studies are necessary to determine which of these modalities have therapeutic effects and to identify those patients who are most likely to benefit from them.
References 1. Aaseth J, Haugen M, Forre 0 Rheumatoid arthritis and metal compounds-perspectives on the role of oxygen radical detoxification. Analyst 1233-6, 1998 2. Auer DE, Seawright AA: Copper salicylate and copper phenylbutazone as topically applied anti-inflammatory agents in the rat and horse. J Vet Pharmacol Ther 136775, 1990 3. Cimmino MA, Mazzucotelli A, Rovetta G, et al: The controversy over zinc sulphate efficacy in rheumatoid and psoriatic arthritis. Scand J Rheumatol 13:191-192, 1984 4. Davis P: Penicillamine metal chelates and their possible importance in rheumatoid arthritis-a brief review. Clin Invest Med 7:41-44, 1984 5. Gerber DA: Inhibition of the denaturation of human gamma globulin by a mixture of u-penicillamine disulfide and copper. J Pharmacol27469472,1978 6. Grootveld M, Blake DR, Sahinoglu T, et al: Control of oxidative damage in rheumatoid arthritis by gold(1)-thiolate drugs. Free Rad Res 10:199-220, 1990
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Address reprint requests to Elliot D. Rosenstein, MD Arthritis and Rheumatic Disease Center Saint Bamabas Medical Center 200 South Orange Avenue Livingston, NJ 07039