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Rheumatoid arthritis and metal compounds - Perspectives on the role of oxygen radical detoxification

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Rheumatoid arthritis (RA) is characterised by migration of activated phagocytes and other leukocytes into synovial and periarticular tissue. Activated oxygen species and other mediating substances from triggered phagocytes appear to exacerbate and perpetuate the rheumatoid condition. Iron excesses are capable of aggravating the arthritic inflammation, probably through their pro-oxidant potentials. In contrast, therapeutically given gold salts, through a lysosomal loading of the metal, inhibit the triggered cells, thereby reducing the toxic oxygen production. Pharmacological doses of zinc also may immobilise macrophages. Furthermore, the copper-zinc-containing enzyme SOD (superoxide dismutase) can act as a scavenger of toxic oxygen in the tissues. Therapeutic remission of RA has been obtained following intraarticular administration of SOD. Intramuscular administration of copper complexes has induced remission in about 60% of RA patients in open studies. Another drug, penicillamine, that protects cellular membranes against toxic oxygen in vitro, is presumed to act as an antirheumatic via the SOD mimetic activity of its copper complex. Thiomalate and other thiols may possess similar activities. Selenium compounds also may act as oxygen radical scavengers. A significant alleviation of articular pain and morning stiffness was obtained following selenium and vitamin E supplementation in a double-blind study on RA patients. The observations reviewed here indicate that metal compounds and other antioxidants can reduce the rheumatic inflammation by reducing the cellular production and/or concentration of toxic oxygen species.
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S
CH
CH
2
COOH
COOH
Au SH
CH
CH
2
COOH
COOH
Gold thiomalate Thiomalate
Rheumatoid arthritis and metal
compounds—perspectives on the role of oxygen radical
detoxification
Jan Aaseth
*a
, Margaretha Haugen
b
and Øystein Førre
b
a
Medical Department, Kongsvinger Hospital, 2200 Kongsvinger, Norway
b
Rikshospitalet, The National Hospital of Norway, Oslo Sanitetsforening Rheumatism Hospital,
Oslo, Norway
Rheumatoid arthritis (RA) is characterised by migration
of activated phagocytes and other leukocytes into synovial
and periarticular tissue. Activated oxygen species and
other mediating substances from triggered phagocytes
appear to exacerbate and perpetuate the rheumatoid
condition. Iron excesses are capable of aggravating the
arthritic inflammation, probably through their
pro-oxidant potentials. In contrast, therapeutically given
gold salts, through a lysosomal loading of the metal,
inhibit the triggered cells, thereby reducing the toxic
oxygen production. Pharmacological doses of zinc also
may immobilise macrophages. Furthermore, the
copper–zinc-containing enzyme SOD (superoxide
dismutase) can act as a scavenger of toxic oxygen in the
tissues. Therapeutic remission of RA has been obtained
following intraarticular administration of SOD.
Intramuscular administration of copper complexes has
induced remission in about 60% of RA patients in open
studies. Another drug, penicillamine, that protects cellular
membranes against toxic oxygen in vitro, is presumed to
act as an antirheumatic via the SOD mimetic activity of
its copper complex. Thiomalate and other thiols may
possess similar activities. Selenium compounds also may
act as oxygen radical scavengers. A significant alleviation
of articular pain and morning stiffness was obtained
following selenium and vitamin E supplementation in a
double-blind study on RA patients. The observations
reviewed here indicate that metal compounds and other
antioxidants can reduce the rheumatic inflammation by
reducing the cellular production and/or concentration of
toxic oxygen species.
Keywords: Copper; zinc; selenium; gold; thiols; trace
elements; phagocytes; leukocytes; macrophages; rheumatoid
arthritis
The pathological hallmark of rheumatoid arthritis (RA) is a
persistent inflammation in synovial membranes of joints. This
leads to a gradual destruction of the supporting structures of the
joints, such as bone and cartilage, a process that ceases only if
a remission occurs.
It is surprising that active RA can be brought to remission by
treatment with metal compounds such as gold or copper
complexes or with metal-complexing agents such as penicil-
lamine or 5-aminosalicylate. In some way, the remission-
inducing agents must interfere with crucial mechanisms
underlying the chronicity of the disease. Recent research
indicates that activated tissue macrophages and blood mono-
cytes invading the synovial tissue play a central role in the early
steps of pathogenesis and chronification of RA.
1
Important
signal substances derived from the activated macrophages are
the free oxygen radicals (superoxide and hydrogen peroxide)
and the cytokines such as tumour necrosis factor-a (TNF-a).
Apparently, these mediating substances play key roles in the
progression of the rheumatoid inflammation.
2
Another possible
source of free oxygen radicals is related to the anoxic
reperfusion reactions that may accompany excessive motions of
affected joints.
3
The aim of this paper is to discuss traditional
and new pharmacological approaches that makes use of metal
compounds and chelators that are presumed to interact with the
generation or toxicity of activated oxygen species.
Gold compounds
The first clinical tests of gold around 1925 were precipitated by
in vitro studies of the bacteriostatic effect towards bacilli of gold
and other metals. Since RA was assumed to be an infectious
disease, some patients suffering from RA were included in a
programme of clinical testing of the heavy metals. These open
studies led to the introduction of gold complexes as remission
inducing agents by a French physician, Forestier.
4
However, it was not until over 30 years later, in a report of the
British Rheumatism Council in 1960, that gold therapy was
shown to be clinically efficient in a controlled study.
5
Nevertheless, already in the early 1930s it was observed that the
most applicable gold compounds consisted of gold and sulfur-
containing complexing agents. The compound most used in
clinical medicine has been gold thiomalate (Myocrisin)
(Fig. 1).
Astonishingly, these gold(i) complexes have only a weak or
negligible anti-inflammatory action in animal models, although
their antirheumatic effect has now been documented. This
indicates that gold has a specific action in RA, perhaps on some
basic mechanism underlying the perpetuating nature of this
disease. However, the clinical use of sulfur–gold has been
limited, to some extent, by its toxic reactions. Further, it has to
be given by weekly intramuscular injections, which may be
inconvenient for patients. This has led to the introduction of the
lipophilic gold compound auranofin, which can be administered
orally.
After absorption the gold complex is not stable in vivo, the
gold cation being released from the complexing agent. We have
found that gold(i) thiomalate dissociates rapidly in blood
plasma, gold being chelated by albumin and thiomalate being
liberated in the free thiolate form.
6
Presented at The Sixth Nordic Symposium on Trace Elements in Human Health and
Disease, Roskilde, Denmark, June 29–July 3, 1997.
Fig. 1 Formulae of gold thiomalate and thiomalate.
Analyst, January 1998, Vol. 123 (3–6) 3
In vivo, thiomalate and gold have different metabolic
behaviours, and it has been suggested that gold thiomalate
injections, in fact, involve simultaneous treatment with two
different drugs, viz., the thiol moiety in addition to gold itself.
6
After repeated administration, gold is concentrated in the
kidneys, liver, spleen and synovial tissue.
7
It is easily taken up
by the macrophages, and ultrastructural studies have shown that
gold is deposited almost exclusively in the lysosomes.
8
Subsynovial macrophages in untreated RA are characterised
by a remarkable increase in the number of lysosomes,
explaining the striking accumulation of gold in these cells in
RA.
9
Such activated macrophages characterising RA are
reported to generate superoxide and peroxides that are dis-
charged along with the cytokines. The activity of synovial
macrophages and granulocytes of RA patients appears to be
lowered in the presence of gold salts.
10
Presumably, such
immobilisation of cells and lysosomes can decrease the
discharge of toxic oxygen and cytokines. Also, it has been
reported that auranofin can inhibit the induction of TNF-a from
the macrophages.
11
Selenium
Low selenium levels have previously been reported in blood
plasma and cells from patients with RA.
12,13
The most
important biological function of selenium is attributed to its
presence in the enzyme glutathione peroxidase (GSH-Px),
which is a crucial factor in the cellular defence against toxic free
radicals. Although oxygen radical formation may be of
significance in the pathogenesis of RA, no significant clinical
improvement was obtained when using nutritionally adequate
or moderate doses of selenium supplementation, up to about
250 mg d
21
.
14
We have undertaken a double blind clinical study
to test if higher doses of selenium might exert disease-
modifying efficacy in RA.
Forty-seven patients with classical or definite RA (ARA
criteria) were randomly allocated to a treatment or placebo
group (Table 1). The study was double-blind. In the treatment
group all patients received 600 mg d
21
of selenium, as a
selenomethionine-containing yeast, for 8 months. The control
group received placebo tables for the first 4 months, and the
following 4 months they received 600 mg d
21
of selenium, the
same as in the selenium group. All tablets were enriched with
vitamin E because this vitamin has been reported to protect
against toxicity of high selenium doses.
15
The patients were
examined at the start of the study and after 4 and 8 months of
treatment.
To assess the disease activity, the following clinical variables
were measured: articular index,
16
grip strength in right and left
hands, morning stiffness in minutes, number of swollen joints
and ESR.
The Wilcoxon two-sided paired test was used for longitudinal
intra-group comparisons and Wilcoxon rank sum test for inter-
group comparisons.
Statistical analyses of clinical and laboratory parameters of
disease activity after the first 4 month period of the selenium
treatment revealed no signs of improvement or deterioration
(5% significance level) compared with the control group. The
same result was found in the control group after 4 months with
600 mg d
21
of supplementation with selenium. A significant
improvement in articular pain index (modified Ritchie test),
grip strength of left hand and morning stiffness were, however,
seen after 8 months with supplementation (Table 2). No signs of
serious toxic side effects were seen, clinically or biochem-
ically.
17
The concentrations of selenium in serum and whole blood
were significantly raised by the treatment. Serum Se values
reached a plateau around 500 mg l
21
, whereas whole blood
selenium continued to increase above 600 mg l
21
(Fig. 2).
This double-blind clinical study indicates that long-term
treatment with pharmacologically high doses of selenium (600
mg d
21
) reduces the articular pain index and morning stiffness
in cases of RA. The lack of response following treatment with
lower doses or a shorter treatment period indicate that the
apparent clinical efficacy is related to an intracellular accumu-
lation of unphysiologically high selenium amounts and not only
a simple restoration of the antioxidant potential of the cells. It
has been reported that pharmacological doses of organic
selenium have cytostatic properties in leukaemia diseases.
18
Hence it is tempting to speculate whether an immunomodulat-
ing effect of the present doses of selenium results from
pharmacological interferences with cellular processes in white
blood cells, presumably in the macrophages and/or granulo-
cytes. It is not likely that the E-vitamin enrichment contributed
to the results observed in this study owing to the relatively low
doses involved. As suggested in recent review by Tarp,
19
not
only the macrophages but also the polymorphonuclear leuko-
cytes might be important target cells for oxygen radical
scavengers such as selenium compounds.
Table 1 Patients’ characteristics at inclusion
Control
Selenium group
Number of patients 25 22
Female/male 20/5 17/5
Age/years (mean and range) 51.9 52.1
(20–66) (21–77)
Disease duration/months (mean and
range) 80 142
(3–360) (6–480)
Table 2 Clinical and laboratory variables recorded at inclusion and after 8
months of treatment [mean and (in parentheses) SEM]
Selenium group Control group
At 8 At 8
Variable inclusion months inclusion months
Articular index 17.2 (1.8) 9.8
*
(1.7) 15.7 (1.7) 12.0 (2.1)
Grip strength, right hand/
mmHg 57 (7) 80 (9) 63 (8) 81 (11)
Grip strength, left hand/
mmHg 50 (7) 68
*
(6) 66 (9) 78 (11)
Morning stiffness/min 76 (10) 38
*
(8) 86 (10) 71 (13)
Number of swollen joints 8.8 (1.2) 7.3 (1.3) 9.5 (1.5) 10.9 (2.4)
Erythrocyte sedimentation
rate 38 (4) 44 (6) 34 (4) 39 (6)
*
Compared with the value at the start of the study, p < 0.01.
Fig. 2 Selenium concentrations (mean values) in A, whole blood; B,
serum; and C, placebo, during the study.
4 Analyst, January 1998, Vol. 123
SH
C
CH
COOH
CH
3
SeCH
3
C
C
CH
Penicillamine Selenomethionine
CH
3
NH
2
H H
HH
COOH
NH
2
Copper
Forestier
20
was among the first to report that a copper complex,
Cupralene, was effective in the treatment of rheumatoid
arthritis. Based on open studies, he concluded in 1949 that
‘Copper salts are effective in the treatment of rheumatoid
arthritis. They give better results than gold salts in the early
stages of the disease. In cases of longer standing, they must be
used if there is gold intolerance or gold resistance, but whenever
gold salts are tolerated they are to be preferred’.
These positive results with copper complexes were supported
by the studies of other workers.
21,22
Hangarter and Lubke
22
treated more than 600 patients suffering from RA with copper
salicylate and reported that 65% became symptom free, 23%
improved and 12% of the patients remained unchanged. No
serious toxic disturbances were recorded in association with the
treatment. Their studies were not controlled, however, and their
reports are difficult to evaluate. Although extensive evaluations
of copper complexes in animal models have been undertaken,
23
double-blind clinical studies on copper complexes in rheuma-
toid arthritis are still lacking.
When discussing clinical treatment with copper-containing
agents, the clinical use of the anti-inflammatory copper-
dependent metalloenzyme superoxide dismutase (SOD), should
also be commented upon. Bovine SOD has been shown to
reduce inflammation when given intra-articularly into the joints
of RA patients. The discovery and evaluation of this agent may
provide insights into the biochemical mechanisms of actions for
all copper compounds.
24
It is found that RA is usually
associated with decreased intracellular SOD activity.
25
This is
interesting since SOD has anti-inflammatory activity. It is
known that the cytosolic SOD is a copper/zinc-containing
enzyme. Ceruloplasmin and therapeutic copper complexes have
been shown to possess SOD-like activity.
23
Hence the demon-
strated physiological rise of ceruloplasmin in RA is suggested to
represent a protective response. Consistent with this, a lack of
rise of ceruloplasmin may increase the risk of chronic disease,
as seen in copper-deficient animals with adjuvant arthritis.
23,26
Biochemically, SOD can act protectively by detoxifying
superoxide radicals discharged from activated phagocytes. The
less toxic product H
2
O
2
thus formed can be further degraded by
glutathione peroxidase in the presence of glutathione. The
clinical use of bovine SOD has, however, been abandoned
because it is considered to induce antibody formation.
Other metal complexes
The well documented antirheumatic efficacy of the chelating
agent penicillamine
27
is still of theoretical interest, although the
practical usefulness of this drug is limited by its pronounced
tendency to induce toxic side reactions. It is noteworthy that the
chemical structure of penicillamine, and also its clinical effect
profile, resemble those of gold thiomalate. Selenomethionine,
which was used in our clinical study described above, is
structurally related to penicillamine (Fig. 3).
Penicillamine is also presumed to mediate its antirheumatic
effects via an inhibiting effect on synovial tissue macrophages,
analogues to the proposed mechanism of action of gold
complexes. It inhibits macrophage migration and stabilises the
lysosomal membrane,
28,29
thus reducing the induction of pro-
inflammatory cytokines and oxygen free radicals. Being a
strong copper chelator, it rapidly ties up free copper ions,
forming a complex that acts as an efficient superoxide
dismutating catalyst.
23
Another strong copper-binding agent with anti-inflammatory
properties is 5-aminosalicylate, which is delivered into tissues
on the degradation of the antirheumatic drug sulfasalazine.
Again, the superoxide dismutase mimetic activity of the copper
chelate may contribute to its therapeutic potency.
23
In addition,
aminosalicylate is capable of chelating free iron(iii) cations.
This property is relevant since the presence of catalytic amounts
of free metal ions in an extracellular mixture of H
2
O
2
and
superoxide leads to a spontaneous interaction that gives rise to
the extremely reactive hydroxyl radical. Thus, the ultimate
consequences of the radical release accompanying respiratory
bursts of invading leukocytes depend on the iron status in the
tissue.
High doses of zinc salts led to significant improvements in
symptoms of rheumatoid arthritis in a clinical trial,
30
but
controversial results have been reported.
31
. When reaching into
the intracellular space, zinc is a potent inductor of metal-
lothionine, which is a protein tying up both copper and zinc, and
which is also reported to act as an oxygen radical scavenger in
biological systems.
23
Conclusion
Rheumatoid arthritis is characterised by increased activity of
macrophages, which in cooperation with other inflammatory
cells infiltrates the synovial tissue. The activated macrophages,
monocytes and granulocytes generate reactive forms of oxygen
which have been suggested to be mediators of inflammation,
together with the pro-inflammatory cytokines, particularly
TNF-a. It is tempting to hypothesise that TNF-a is an enzyme
inhibitor acting on SOD and GSH-Px in RA. Recently,
administration of TNF-a antibodies has been used therapeuti-
cally with good results.
2
Gold is accumulated in the lysosomes
of the macrophages, which are thereby immobilised, causing an
arrest of the pro-inflammatory signaling. Zinc in high doses can
also immobilise macrophages. Gold, zinc and copper can induce
synthesis of the sulfhydryl-rich protein metallothionein. Copper
is a component of the cytosolic enzyme SOD, and several
copper-containing molecules including ceruloplasmin possess
SOD activity. The anti-inflammatory activity of pharmaco-
logical copper complexes is attributed to their SOD activity.
The therapeutic effects of penicillamine, may also be related to
an antioxidative or membrane-protecting action. Increased
intracellular levels of the selenium-containing enzyme GSH-Px
can also accelerate the breakdown of reactive oxygen. Further
research to evaluate the possible therapeutic effects of oxygen
radical detoxification and of selenium supplementation in high
doses in RA is of interest.
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Paper 7/04840H
Received July 8, 1997
Accepted October 13, 1997
6 Analyst, January 1998, Vol. 123
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