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ARTHRITIS & RHEUMATISM
Vol. 46, No. 11, November 2002, pp 3102–3114
© 2002, American College of Rheumatology
LETTERS
1. American College of Rheumatology Subcommittee on Rheumatoid
Arthritis Guidelines. Guidelines for the management of rheumatoid
arthritis: 2002 update. Arthritis Rheum 2002;46:328–46.
2. Patrono C, Coller B, Dalen JE, FitzGerald GA, Fuster V, Gent M,
et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2001;119 Suppl:39S–63S.
3. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R,
Davis B, et al, VIGOR Study Group. Comparison of upper
gastrointestinal toxicity of rofecoxib and naproxen in patients with
rheumatoid arthritis. N Engl J Med 2000;343:1520–8.
4. Konstam MA, Weir MR, Reicin A, Shapiro D, Sperling RS, Barr E,
et al. Cardiovascular thrombotic events in controlled, clinical trials
of rofecoxib. Circulation 2001;104:2280–8.
5. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T,
Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid
arthritis: the CLASS study: a randomized controlled trial. JAMA
2000;284:1247–55.
6. Garcia Rodriguez LA, Varas C, Patrono C. Differential effects of
aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the
primary prevention of myocardial infarction in postmenopausal
women. Epidemiology 2000;11:382–7.
7. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco
S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet
effects of aspirin. N Engl J Med 2001;345:1809–17.
8. Garcia Rodriguez LA, Hernandez-Diaz S. The risk of upper
gastrointestinal complications associated with nonsteroidal antiinflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents. Arthritis Res 2001;3:98–101.
DOI 10.1002/art.10505
Aspirin antiplatelet therapy and nonsteroidal
antiinflammatory drugs: comment on the 2002 update
of the American College of Rheumatology Guidelines
for the Management of Rheumatoid Arthritis
To the Editor:
In the 2002 update of the American College of Rheumatology Guidelines for the Management of Rheumatoid
Arthritis (1), the authors stress the need for antiplatelet
therapy with low-dose aspirin for patients at risk for cardiovascular disease who are taking selective cyclooxygenase-2
(COX-2) agents, reasoning that, unlike nonselective nonsteroidal antiinflammatory drugs (NSAIDs), the selective COX-2
inhibitors have no effect on platelet adhesion or aggregation.
This seems to imply that antiplatelet therapy with aspirin is
required only when selective COX-2 inhibitors are used. I
believe nonselective NSAIDs neither ensure appropriate antiplatelet prophylaxis, nor do they appear better than selective
COX-2 inhibitors for patients at cardiovascular risk who are
receiving concomitant aspirin antiplatelet therapy.
Unlike the potent and irreversible inhibition of platelet
COX-1 induced by aspirin, the antiplatelet effect of NSAIDs is
highly variable and depends on two factors: their potency for
inhibiting COX-1 at pharmacologic doses and their half-life
(2). Thus, neither NSAIDs with a short half-life, such as
ibuprofen, nor those with a relatively low COX-1 inhibitory
effect, such as diclofenac, provide efficient and sustained
antiplatelet therapy. Only drugs with a long half-life and a
potent COX-1 inhibitory effect, such as indobufen, flurbiprofen, and naproxen, have been suggested to be potentially useful
as antiplatelet agents (2). This may explain the observation of
a higher rate of thrombotic events with rofecoxib than with
naproxen in a large trial (3), something not observed when
rofecoxib or celecoxib is compared with other nonselective
NSAIDs (4,5). However, due to the reversibility of the antiplatelet effect of NSAIDs, the cardioprotective effect of these
drugs as shown in clinical trials, where compliance with the
dose and treatment schedule is usually better, does not necessarily apply to clinical practice, where intermittent use by
patients is common. Accordingly, epidemiologic studies have
failed to demonstrate cardioprotective effects of NSAIDs, in
contrast with aspirin (6).
Furthermore, recently published data demonstrate
that in patients taking aspirin, ibuprofen antagonizes the
irreversible platelet inhibition induced by aspirin, whereas
other drugs with lower COX-1 inhibitory effects, such as
diclofenac or rofecoxib, do not interfere with aspirin’s effects
(7). An additional matter of concern when using aspirin with
NSAIDs is their synergistic action in terms of gastrointestinal
toxicity, something that has not been sufficiently evaluated for
COX-2 selective drugs (8).
In conclusion, neither relying on the antiplatelet effect
of NSAIDs in patients at cardiovascular risk, nor using
NSAIDs instead of selective COX-2 inhibitors when low-dose
aspirin is needed, can be recommended based on available
evidence.
DOI 10.1002/art.10707
Hidden hazards and practical problems: comment on
the 2002 update of the American College of
Rheumatology Guidelines for the Management of
Rheumatoid Arthritis
To the Editor:
The remarkable proliferation of improved diagnostic
tests, disease activity measurements, and effective yet potentially toxic therapies more than justifies the 2002 update of the
American College of Rheumatology Guidelines for the Management of Rheumatoid Arthritis (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines.
Guidelines for the management of rheumatoid arthritis: 2002
update. Arthritis Rheum 2002;46:328–46). Although individuals may argue about some of the details of the guidelines, in
general I believe members of our College will welcome and
appreciate the comprehensive and organized document prepared by the Subcommittee on Rheumatoid Arthritis Guidelines.
As a practicing physician in a small office, however, I
am concerned about two things. The first concern arises from
some of the language used in the sections devoted to documentation, for by now, not only have most rheumatologists
read these guidelines, but so have most third-party payers and
malpractice attorneys. When “guidelines” such as these are
couched in terms like “should document” and “must assess”
and are published under the imprimatur of the American
College of Rheumatology (ACR), they may become much
more than just guidelines; they may become requirements.
One need only consider how the original intent of ACR
classification criteria for various diseases has been misinter-
José L. Pablos, MD
Hospital 12 de Octubre
Madrid, Spain
3102
LETTERS
3103
preted and misused, to understand the point I am trying to
make.
Second, I wonder if, as they wrote the documentation
recommendations, the members of the Subcommittee considered their potential impact on the actual clinical practice of
rheumatology. Had they done so, then along with the guidelines perhaps would have come practical suggestions to enable
us to fulfill the Subcommittee’s documentation goals, for
example, a template acceptable to Medicare which would
sufficiently document the history, physical examination, joint
count, initial and interval laboratory monitoring results, imaging reports, Health Assessment Questionnaire findings, global
assessments, pain, fatigue, and stiffness scores, and impressions and plans, all within the constraints of the usual 1-hour
consultation and 15–20-minute return visit times we have to
devote to our patients. By the time such recommended documentation, as currently outlined in the guidelines, is completed
to the satisfaction of the Subcommittee (not to mention the
other interested parties), there will be no time left to actually
talk to our patients about what is going on in their lives, the
changing evolution and course of their disease, and the therapeutic changes we might suggest, and their ramifications.
Documentation, while important, has become so cumbersome and burdensome that it impairs a physician’s ability to
provide good medical care. Computerization of records is not
necessarily the answer: most of the computerized records I
receive from primary care physicians (which supposedly comply with current Medicare rules) are so burdened with repetitive negative and unchanging data as to make them unreadable.
Perhaps teaching institutions and large groups have the
time, money, and manpower to meet the standards implied by
these guidelines. As for the rest of us (who now better
understand how frustrated states feel when the federal government imposes unfunded mandates), we would appreciate the
Subcommittee now turning its attention to formulating a
practical way for us to comply with its goals, serve our patients,
and avoid (or at least satisfactorily reply to) third-party audits
while at the same time limiting our legal liabilities.
Sidney R. Block, MD
Bangor, ME
DOI 10.1002/art.10506
Reply
To the Editor:
One of the benefits of the exercise of the creation,
dissemination, and critical review of treatment guidelines is to
highlight gaps in evidence and focus attention on areas where
well-designed studies are needed to clarify areas of uncertainty. The points made by Dr. Pablos are well-taken and raise
important issues surrounding the risks and benefits of treatment with selective and nonselective NSAIDs in rheumatoid
arthritis (RA) patients and other patient populations (1).
We would suggest that additional evidence, preferably
from randomized controlled trials, is needed to address the
following questions: 1) Does low-dose aspirin negate the
gastrointestinal (GI)–protective effect of the coxibs over the
nonselective NSAIDs, as suggested by data from the Celecoxib
Long-Term Arthritis Safety Study (2)? Is this a class effect of
the coxibs? 2) Do coxibs and/or nonselective NSAIDs negate
the cardioprotective benefits of low-dose aspirin (3)? If so,
which ones have this effect? 3) For older patients who need an
NSAID for osteoarthritis (OA) or RA, and need low-dose
aspirin for cardioprotection but are at higher risk for NSAIDinduced adverse GI events, is the safest regimen a combination
of low-dose aspirin and/or a proton pump inhibitor with either
a coxib or a nonselective NSAID?
Data from longitudinal cohort studies may be needed
to determine the following: 1) In clinical practice, what is the
effectiveness (versus efficacy in clinical trials) of various nonselective NSAIDs in terms of cardioprotective benefits as
compared with low-dose aspirin in patients receiving long-term
NSAID treatment for OA or RA? 2) In clinical practice, what
is the effectiveness (versus efficacy) of the coxibs versus
nonselective NSAIDs in terms of greater GI safety. Is this a
class effect for all coxibs?
In response to the comments of Dr. Block, the Subcommittee on Rheumatoid Arthritis Guidelines agrees that
increasing documentation requirements for each clinical encounter have placed new and onerous burdens on the rheumatology practitioner. However, these challenges are generated not by practice guidelines, but rather by larger economic
forces. It is Medicare and private payers who have linked
provider reimbursement to level of service coding and, more
recently, to documentation of the clinical encounter. In an
effort to assist members in meeting these requirements, the
ACR has created written documentation templates, provided
multiple training sessions in Evaluation and Management
coding, and is in the process of evaluating new practice
management technologies such as electronic medical records
and handheld devices. Many of these newer technologies use
software templates for structured data entry that are designed
to calculate and suggest a level of service based on the
documentation of the visit. Information about these activities
is accessible through the ACR Web site and the Socioeconomic Affairs Department.
While we are sympathetic with the points raised by Dr.
Block, we believe practice guidelines cannot be compromised
by concerns about their being misused by legal professionals.
These guidelines are indeed just guidelines and should never
be “requirements” that substitute for good clinical judgment.
The primary purpose, as Dr. Block affirms, was to update the
RA guidelines to address clinical changes in the treatment of
the disease.
C. Kent Kwoh, MD
Larry G. Anderson, MD
Jerry M. Greene, MD
Dorothy A. Johnson, DNSc, FNP
James R. O’Dell, MD
Mark L. Robbins, MD, MPH
W. Neal Roberts, Jr., MD
Robert W. Simms, MD
Robert A. Yood, MD
American College of Rheumatology Subcommittee
on Rheumatoid Arthritis Guidelines
1. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events
associated with selective COX-2 inhibitors. JAMA 2001;286:954–9.
2. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T,
Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid
3104
LETTERS
arthritis: the CLASS study: a randomized controlled trial. JAMA
2000;284:1247–55.
3. Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco
S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet
effects of aspirin. N Engl J Med 2001;345:1809–17.
DOI 10.1002/art.10490
Intolerance to caffeine may increase susceptibility to
rheumatoid arthritis: comment on the article by
Mikuls et al
To the Editor:
In the interesting report by Mikuls et al (1) on the
independent and positive association between decaffeinated
coffee and rheumatoid arthritis (RA), the authors discuss
various reasons for the association, all implicating decaffeinated coffee. However, they did not consider the alternative
explanation that those who are intolerant to caffeine may be
more susceptible to developing RA. Rather than decaffeinated
coffee, it may be the need to use decaffeinated coffee that
defines the group at risk.
Caffeine increases cortisol levels (2). RA patients have
deficient cortisol responses due to a poorly functioning
hypothalamic–pituitary axis (3). They can be expected to be
hypersensitive to cortisol, just as those with hypothyroidism are
hypersensitive to thyroxine. Insomnia, hyperactivity, and other
central nervous system manifestations of hypersensitivity to
cortisol, a central nervous system stimulant, would encourage
the use of decaffeinated beverages. This hypersensitivity is in
accord with the observed hypersensitivity of RA patients to the
therapeutic and toxic effects of corticosteroids (4).
The authors’ findings are no less interesting with this
alternative explanation, because it supports decreased resistance to stress, i.e., a deficient hypothalamic response to severe
inflammation and other stressors, as the critical feature predisposing one to RA. This has been described as well in the
Lewis rat, an animal model of RA. Diminished pituitary–
hypothalamic axis function is observed in this model, in which
a severe, chronic, proliferative, and erosive inflammatory
polyarthritis develops after injection of streptococcal cell wall
antigen (5). The condition cannot be induced in the histocompatible F344 rat, which has a normal hypopituitary–
hypothalamic axis. Replacement doses of corticosteroids significantly suppress the severity of the arthritis. Thus, the
authors of the present study may be identifying a subset that is
not only prone to developing RA but one in which the disease
may be averted or attenuated by replacement doses of steroids.
So why does regular coffee, which increases cortisol
levels, not decrease the severity of RA? Unfortunately, regular
coffee also inhibits adenosine receptors (6). Adenosine, a sleep
promoter (7), is also a powerful suppressor of inflammation
(8,9); the inhibition of adenosine by coffee, although adding to
the wakefulness induced by cortisol, would tend to counter its
antiinflammatory action.
The authors are to be commended for their long-term
comprehensive study of coffee, which has opened the door to
links between coffee, an everyday beverage, and RA. These
links are fascinating and warrant further study.
Hugh McGrath, Jr., MD
Louisiana State University
Medical Center
New Orleans, LA
1. Mikuls TR, Cerhan JR, Criswell LA, Merlino L, Mudano AS,
Burma M, et al. Coffee, tea, and caffeine consumption and risk of
rheumatoid arthritis: results from the Iowa Women’s Health Study.
Arthritis Rheum 2002;46:83–91.
2. Lovallo WR, Al’Absi M, Blick K, Whitsett TL, Wilson MF.
Stress-like adrenocorticotropin responses to caffeine in young
healthy men. Pharmacol Biochem Behav 1996;55:365–9.
3. Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS.
Defective hypothalamic response to immune and inflammatory
stimuli in patients with rheumatoid arthritis. Arthritis Rheum
1992;35:1281–8.
4. Firestein GS. Etiology and pathogenesis of rheumatoid arthritis. In:
Kelley WN, Harris ED, Ruddy S, Sledge CB, editors. Textbook of
rheumatology. 5th ed. Philadelphia: WB Saunders; 1997. p. 851–97.
5. Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ,
Gold PW, et al. Inflammatory mediator-induced hypothalamicpituitary-adrenal axis activation is defective in streptococcal cell
wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci U S A
1989;86:2374–8.
6. Radulovacki M, Miletich RS, Green RD. N6 (L-phenylisopropyl)
adenosine (L-PHA) increases slow-wave sleep (S2) and decreases
wakefulness in rats. Brain Res 1982;246:178–80.
7. Van Dongen HP, Price NJ, Mullington JM, Szuba MP, Kapoor SC,
Dinges DF. Caffeine eliminates psychomotor vigilance deficits from
sleep inertia. Sleep 2001;24:813–9.
8. Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue
damage. Nature 2001;414:916–20.
9. Cronstein BN, Montesinos MC, Weissmann G. Salicylates and
sulfasalazine, but not glucocorticoids, inhibit leukocyte accumulation by an adenosine-dependent mechanism that is independent of
inhibition of prostaglandin synthesis and p105 of NF␬B. Proc Natl
Acad Sci U S A 1999;96:6377–81.
DOI 10.1002/art.10491
Reply
To the Editor:
We thank Dr. McGrath for his interest in our report
and compliment him on his novel hypothesis. His theory, that
patients with a relative cortisol deficiency, who are perhaps
more prone to developing rheumatoid arthritis (RA), may
have a heightened sensitivity to cortisol and thus avoid caffeine
intake due to its adrenal-stimulating effects, is provocative.
Although his hypothesis may ultimately prove correct,
our findings are not entirely consistent with this explanation.
Specifically, we observed no association (relative risk ⫽ 0.94;
95% confidence interval 0.58–1.52 for highest quartile) between daily caffeine intake and the development of RA. If the
proposed hypothesis were true, one might anticipate women
who are less sensitive to the effects of caffeine to have a
significantly lower risk for RA. Moreover, we observed only a
modest inverse correlation between daily caffeine intake and
decaffeinated coffee consumption (r ⫽ ⫺0.3), suggesting that
caffeine intake and decaffeinated coffee drinking were not
necessarily mutually exclusive behaviors in this cohort. Notwithstanding, our data may be underpowered to detect a
protective association between caffeine intake and RA risk, if
such an association truly exists.
LETTERS
3105
The association of decaffeinated coffee use with RA,
also reported by investigators from the Black Women’s Health
Study (Formica MK, Palmer JR, Rosenberg L, McAlindon TE.
Lifestyle factors associated with development of rheumatoid
arthritis: results from the Black Women’s Health Study [abstract]. Arthritis Rheum 2001;44 Suppl 9:S376), represents a
novel finding and, as suggested by Dr. McGrath, warrants
further investigation to define the mechanism underlying this
putative association.
Ted R. Mikuls, MD, MSPH
James R. Cerhan, MD, PhD
Lindsey A. Criswell, MD, MSPH
Linda A. Merlino, MSc
Kenneth G. Saag, MD, MSc
University of Alabama at Birmingham
DOI 10.1002/art.10507
Importance of T cells in rheumatoid synovitis:
comment on the review by Firestein and Zvaifler
To the Editor:
In 1990, Firestein and Zvaifler wrote a cogent editorial
on the limited role of T cells in rheumatoid (RA) synovitis,
which remains a landmark in our understanding of the disease
(1). The sequel (2) reaffirms the evidence, but the conclusions
fail on the central question: “why does she have RA and not
he?”
Firestein and Zvaifler show that rheumatoid synovitis
is not due to a local T cell effector mechanism. They could add
that there is little evidence for T cell autoreactivity in RA.
Neither point, however, is incompatible with the evidence from
HLA–DR4 studies that RA is a T cell–dependent adaptive
immune response (3).
A systemic T cell–dependent response can initiate
distant inflammation through antibody. It is now generally
accepted that immune complexes generate inflammation not
through complement, but by inducing cytokine release via IgG
Fc␥ receptor type III (Fc␥RIII) (4). Unlike autoreactive T
cells, immune complexes small enough to traverse endothelium are abundant in RA, and Fc␥RIII is selectively expressed
in synovium (5). Many rodent models of RA have now been
shown to be antibody and Fc␥RIII dependent (6,7). That
adjuvant used to boost an adaptive immune response may also
have an early activating effect on synovial cells through Tolllike receptors is probably a red herring. Another red herring,
as Firestein and Zvaifler effectively point out, is that synovial
macrophage cytokine release tends to recruit bystander “Th1”
cells.
It is very difficult to explain the extraarticular manifestations of RA without immune complexes. The distribution of
Fc␥RIII indicates that pericarditis, nodules, and synovitis
should all have the same origin (5). Tissue-specific amplification mechanisms almost certainly apply in synovium and bone
marrow (8), but it is difficult to justify two means of initiation
where one will do.
The flaw in the common assumption that T cell–
dependent autoimmune responses require autoreactive T cells
is more subtle. The most consistent immune response in RA,
rheumatoid factor production, is almost certainly T cell depen-
dent, but there is no T cell autoreactivity to IgG. This paradox
is explained by the ability of rheumatoid factor B cells to
obtain help from T cells recognizing foreign antigen (9,10).
Evidence from other disorders also suggests that T cell responses to autoantigens may not determine corresponding
autoantibody production (11,12). “Loss of T cell tolerance”
may not apply.
Stastny not only confirmed the role of genes in RA (3),
but also pointed out that the other factors may be not
environmental, but stochastic (random). Genes, and probably
smoking, set thresholds, but the kinetics of disease initiation
are of a sequence of internal stochastic events. Studies of
monozygotic twins suggest that a rate-limiting event occurs
approximately once in 200 woman-years (4 adult lifetimes)
(13). Scandinavian studies of antibody profiles evolving over
several years before diagnosis indicate that other random
events, occurring every few months or years, are probably
involved (14). They also confirm that an adaptive response
comes before synovitis, and it is an antibody response.
Firestein and Zvaifler suggest that B cell activation is
due to “undefined processes.” These processes may have
remained undefined because they are engineered by the B cells
themselves. “Anti-foreign” B cells control their own activation
by interacting with antigen through surface and secreted
antibody. Autoreactive B cells should not, but if a rare subset
can do so through abnormal means, including the way rheumatoid factor B cells obtain T cell help, they will be selfperpetuating, and the kinetics of autoimmunity become comprehensible. Plausible mechanisms are not hard to identify
(10). The generation of all antibody species is random. Antibodies able to subvert all control mechanisms and initiate RA
might well arise only once in 200 woman-years, being what
survival pressures will allow. Recruitment of other clones to
create clinical disease might well take months or years. In
advanced RA, B cell depletion often lowers the C-reactive
protein level to normal as autoantibody levels fall (15,16).
Relapse occurs following B cell return, but again, may evolve
over many months.
Firestein and Zvaifler are right to argue that T cells in
rheumatoid synovitis are largely bystanders, but the answer to
their question “what comes before T cells” is well documented
(14): it is antibody.
Jonathan C. W. Edwards, MD
University College
London, UK
1. Firestein GS, Zvaifler NJ. How important are T cells in chronic
rheumatoid synovitis? [editorial]. Arthritis Rheum 1990;33:
768–73.
2. Firestein GS, Zvaifler NJ. How important are T cells in chronic
rheumatoid synovitis? II. T cell–independent mechanisms from
beginning to end. Arthritis Rheum 2002;46:298–308.
3. Stastny P. Association of the B cell alloantigen DRw4 with
rheumatoid arthritis. N Engl J Med 1978;298:869–72.
4. Janeway CA, Travers P, Walport M, Capra JD. Allergy and
hypersensitivity. In: Immunobiology, 4th ed. London: Elsevier
Science; 1998. p. 478–80.
5. Bhatia A, Blades S, Cambridge G, Edwards JCW. Differential
distribution of Fc␥RIIIa in normal human tissues and co-localization with DAF and fibrillin-1: implications for immunological
microenviroments. Immunology 1998;94:56–63.
6. Matsumoto I, Staub A, Benoist C, Mathis D. Arthritis provoked by
3106
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Kleinau S, Martinsson P, Heyman B. Induction and suppression of
collagen-induced arthritis is dependent on distinct fcgamma receptors. J Exp Med 2000;191:1611–6.
Edwards JCW. Synovium. In: Klippel JH, editor. Primer on the
rheumatic diseases. 12th ed. Atlanta: Arthritis Foundation; 2001.
p. 22–6.
Roosnek E, Lanzavecchia A. Efficient and selective presentation
of antigen-antibody complexes by rheumatoid factor B cells. J Exp
Med 1991;173:487–9.
Edwards JCW, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 1999;97:1868–96.
Kuwana M, Feghali CA, Medsger TA Jr, Wright TM. Autoreactive
T cells to topoisomerase I in monozygotic twins discordant for
systemic sclerosis. Arthritis Rheum 2001;44:1654–9.
Davies ML, Taylor EJ, Gordon C, Young SP, Welsh K, Bunce M,
et al. Candidate T cell epitopes of the human La/SSB autoantigen.
Arthritis Rheum 2002;46:209–14.
Ollier WE, MacGregor A. Genetic epidemiology of rheumatoid
disease. Br Med Bull 1995;51:267–85.
Halldorsdottir HD, Jonsson T, Thorsteinsson J, Valdimarsson H.
A prospective study on the incidence of rheumatoid arthritis
among people with persistent increase of rheumatoid factor. Ann
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Edwards JCW, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology 2001;40:205–11.
Leandro MJ, Edwards JCW, Cambridge G. Clinical outcome in 22
patients with rheumatoid arthritis treated with B lymphocyte
depletion. Ann Rheum Dis. In press.
DOI 10.1002/art.10508
Reply
To the Editor:
We thank Dr. Edwards for his thoughts on RA and
appreciate the fact that there are more similarities than
differences between his view and our own. He acknowledges
that elements of the innate immune system play a critical role
in the initiation phase of inflammatory arthritis. His particular
focus is the engagement of Fc␥ receptors on synovial intimal
cells by immune complexes “small enough to traverse endothelium.” Presumably the autoantibodies in these complexes
are produced in peripheral sites, gain access to the joints, and
induce synovitis. This view is supported by rodent models of
inflammatory arthritis caused by antibodies directed against
type II collagen or glucose-6-phosphate isomerase, which
require Fc␥RIII and components of the alternative (not the
classical) complement pathway (1). However, experimental
arthritis is not necessarily RA (2).
The idea that immune complexes are important in the
pathogenesis of RA joint inflammation hearkens back to
concepts popular in the 1960s. Then, however, the emphasis
was on the production of IgG and IgM antibodies by immune
cells in the synovium; these formed large intraarticular immune complexes, engaged the classical complement system,
and were removed by phagocytosis (for review, see ref. 3). The
demonstration of complexes containing immunoglobulins,
LETTERS
rheumatoid factor, and early complement components in
Fc␥R-bearing synovial fluid leukocytes and phagocytic intimal
lining cells formed the basis for the notion that RA might be
“an extravascular immune complex disease” (4). Indeed, it
remains true that seropositive RA is the only form of chronic
inflammatory arthritis associated with unequivocal consumption of early complement components in joint effusions.
While we would agree that autoantibodies represent
one potential mechanism for the initiation of synovitis, there is
insufficient evidence to exclude an equally important role for
engagement of Toll-like receptors, mannose receptors, or
other primitive host defense mechanisms. Experimental evidence bearing on these facets of innate immunity will be
clarified in future studies. The subsequent influx of immune
and inflammatory cells into the joint could lead to either
transient or persistent inflammation depending on the sex or
genetic makeup of the individual, enviromental influences, and
other still-to-be-defined factors.
The production of autoantibodies in advance of clinical
features of RA is well established (5), but does this mean that
self-directed humoral responses are the only form of immunity
(innate or acquired) that can prepare the synovium for subsequent invasion? The risk of developing RA in individuals who
are persistently seropositive for rheumatoid factor is intriguing, and Dr. Edwards’ explanations are provocative. We anticipate, however, that the conversion from seropositivity to joint
disease is likely to be more complex and will depend on a
number of stochastic events (even including autoantibodies) as
he suggests. Alternative mechanisms are also needed to explain the onset of RA in seronegative patients who later
convert to seropositivity (6).
In any case, we have once again stepped into the fray
by fine-tuning our model of the initiation and perpetuation of
RA. Our intent is to be provocative and raise questions, rather
than answer all of them. Hopefully, this model will provide an
impetus for dissecting the undefined mechanisms that lead to
this uniquely human destructive arthritis.
Gary S. Firestein, MD
Nathan J. Zvaifler, MD
University of California, San Diego
School of Medicine
La Jolla, CA
1. Matsumoto I, Maccioni M, Lee DM, Maurice M, Simmons B,
Brenner M, et al. How antibodies to a ubiquitous cytoplasmic
enzyme may provoke joint-specific autoimmune disease. Nat Immunol 2002;3:360–5.
2. Corr M, Firestein GS. Innate immunity as a hired gun: but is it
rheumatoid arthritis? J Exp Med 2002;195:F33–5.
3. Zvaifler NJ. The immunopathology of joint inflammation in rheumatoid arthritis. Adv Immunol 1973;16:265–336.
4. Zvaifler NJ. Rheumatoid synovitis: an extravascular immune complex disease. Arthritis Rheum 1974;17:297–305.
5. Halldorsdottir HD, Jonsson T, Thorsteinsson J, Valdimarsson H. A
prospective study on the incidence of rheumatoid arthritis among
people with persistent increase of rheumatoid factor. Ann Rheum
Dis 2000;59:149–51.
6. Dixon AStJ. Rheumatoid arthritis with negative serologic reaction.
Ann Rheum Dis 1960;19:209–28.
LETTERS
3107
DOI 10.1002/art.10570
Genetic drift as an explanation for the reduced
incidence of rheumatoid arthritis
To the Editor:
With great interest we read the unique report by
Doran et al on the decreasing incidence of rheumatoid arthritis
(RA) (1). In the thoughtful accompanying editorial, Silman
indicated that the most likely explanation for the worldwide
trend of decline in incidence is a birth cohort effect (2). Since
this effect is apparent in various populations such as American
whites, Pima Indians, Finnish, and Japanese patients, the
explanation should be a factor that had an identical effect in all
populations throughout the world in the birth cohorts from
1880 to 1950. Such an effect could be either an environmental
effect or an effect caused by a change in the population
genome. We propose that this last explanation may be (partly)
responsible for the decrease in incidence of RA.
In previous times, human reproductive success was
very unevenly distributed, with a minority of fertile women
who gave birth to the majority of newborns. For example, in
the 1912 Australian census, 50% of the children were the
offspring of 1 in 7 of the women (3). However, in recent times
this predominance steadily decreased since both fertile and
less fertile women have equally contributed to the next generation.
Genetic factors partly control fertility. Recently, we
identified one of those factors, a high innate interleukin-10
(IL-10) production is associated with high fertility (4). Thus,
before 1880, strong pressure within the genetic composition of
the population was present that favors high IL-10 production.
We previously demonstrated that IL-10 production is related
to the composition of the IL-10 locus as defined by microsatellites; more specifically, the IL-10 R3 haplotype is associated
with reduced IL-10 production (5). Moreover, we demonstrated that IL-10 R3 protects against RA in different ethnic
populations (Scottish [Glasgow, UK]: odds ratio [OR] 0.6, 95%
confidence interval [95% CI] 0.39–0.92; British [Oxford, UK]:
OR 0.58, 95% CI 0.38–0.87; African American [Atlanta, GA]:
OR 0.38, 95% CI 0.18–0.84) (6).
The fact that the number of children per woman has
decreased in the birth cohorts from 1880 to 1940 must have
had the consequence that more women with a genetic makeup
for impaired fertility contributed to the offspring. With respect
to the IL-10 locus, this must have led to an increase of IL-10
R3 (which protects against RA) in the general population. This
genetic drift may explain the lower incidence of RA in those
born in the birth cohorts after 1880.
Tom W. J. Huizinga, MD, PhD
Suzanne Linn-Rasker, MD
Leroy R. Lard, MD
Rudi G. J. Westendorp, MD, PhD
Leiden University Medical Center
Leiden, The Netherlands
1. Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE.
Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;
46:625–31.
2. Silman AJ. The changing face of rheumatoid arthritis: why the
decline in incidence? Arthritis Rheum 2002;46:579–81.
3. Cummins J. Evolutionary forces behind human infertility [letter].
Nature 1999;397:557–8.
4. Westendorp RG, van Dunne FM, Kirkwood TB, Helmerhorst FM,
Huizinga TW. Optimizing human fertility and survival [letter]. Nat
Med 2001;7:873.
5. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG,
Huizinga TW. Interleukin 10 secretion in relation to human IL-10
locus haplotypes. Proc Natl Acad Sci U S A 1998;95:9465–70.
6. Eskdale J, McNicholl J, Wordsworth P, Jonas B, Huizinga T, Field
M, et al. Interleukin-10 microsatellite polymorphisms and IL-10
locus alleles in rheumatoid arthritis susceptibility [letter]. Lancet
1998;352:1282–3.
DOI 10.1002/art.10488
Successful rechallenge with anti–tumor necrosis factor
␣ for psoriatic arthritis after development of
demyelinating nervous system disease during initial
treatment: comment on the article by Mohan et al
To the Editor:
We read with interest the article by Mohan et al about
the occurrence of neurologic events during anti–tumor necrosis factor ␣ (anti-TNF␣) therapy for inflammatory arthritides
(1). Using the criteria proposed by Miller et al (2), Mohan and
colleagues concluded that there were enough elements in their
series to support the notion of an association between antiTNF␣ therapy and neurologic complications. Although they
pointed out that reported cases were few, they recommended
discontinuation of anti-TNF␣ agents when neurologic signs
appear. We report herein the case of a 34-year-old man with
severe psoriatic arthritis and very extensive skin involvement
who developed a recurrence of Guillain-Barré syndrome during anti-TNF␣ treatment, followed later by a successful rechallenge.
The patient’s disease began in 1986, when he was 19
years old, with polyarthritis, balanitis, and sacroiliac pain with
radiologically evident sacroilitis, without skin disease. He was
diagnosed at another institution as having reactive arthritis and
treated elsewhere with corticosteroids. After 6 months, he
developed a right facial palsy and instability while walking. On
examination, ataxia, areflexia, and external ophthalmoplegia
were observed. Electromyography demonstrated a generalized
motor polyradiculoneuropathy. The cerebrospinal fluid (CSF)
was normal, as were findings on computed tomography (CT) of
the brain. Guillain-Barré syndrome (Miller-Fisher variety) was
diagnosed, and he was treated with plasmapheresis and highdose corticosteroids. After 2 months, the Guillain-Barré syndrome had completely resolved.
In the subsequent years, the patient had several flares
of polyarthritis, treated with prednisone at various doses and
nonsteroidal antiinflammatory drugs. In 1990, a typical and
extensive psoriatic rash appeared, and methotrexate (MTX)
therapy was started, with continuation of the steroids. During
the next 9 years, he experienced a severe decline in functional
capacity because of sustained polyarthritis and extensive cutaneous involvement, and had to leave his job. His erythrocyte
sedimentation rate and C-reactive protein level were persistently elevated. He was referred to our institution in 1996. We
3108
LETTERS
tried several therapeutic approaches to control the disease
activity: high-dose MTX, cyclosporine, MTX plus azathioprine, MTX plus mycofenolate, and azathioprine plus mycofenolate, without improvement in either the articular disease
or the skin involvement.
In March 2000, the patient received his first dose of
infliximab (200 mg), with an impressive response: 2 weeks after
treatment, the joint and skin disease had resolved completely.
A second dose of infliximab (100 mg) was given in May.
In June 2000, he reported weakness in his legs, which
quickly extended to the upper limbs and to respiratory muscles. After 2 days, he was placed on mechanical ventilatory
support. Electromyography showed evidence of a demyelinating motor polyradiculoneuropathy. Magnetic resonance imaging of the cervical spine showed inestability at the C1–C2 level
without evidence of myelopathy. A brain CT scan yielded
normal results. CSF analysis revealed a glucose level of 49
mg/dl and a protein level of 54 mg/dl, with no leukocytes.
Guillain-Barré syndrome was diagnosed, and all therapy was
discontinued. Intravenous immunoglobulin was administered
(2 gm/kg in 5 days), and the patient recovered fully after 3
weeks.
One month later, the patient began to experience joint
pain again, and, fearing a recurrence of his devastating disease,
he requested that infliximab treatment be reinstituted. After
discussing with him the uncertainty of this trial, we reinstituted
the treatment, but in lower doses than used previously. In July
2000, he received 100 mg of infliximab. His joint pain disappeared and since then, he receives infliximab 100 mg once
every 3 months, plus MTX 15 mg/week. He has no joint pain,
and the only skin symptom is hyperpigmentation in some areas.
He has resumed normal employment in an office.
There are several reports in the literature about recurrences of Guillain-Barré syndrome 1–25 years after the first
episode (3,4). Most of those recurrences were clinically similar
to the initial episode. Some of them seemed to be related to a
viral infection (5). Our patient had a variant of a GuillainBarré syndrome years before the start of anti-TNF␣ therapy.
The recurrence might have been elicited by the blockade of
TNF␣ or it might have been part of the natural history of the
disease. The successful rechallenge with infliximab suggests
that the latter could be the case. If so, then there might be
differences among the various demyelinating diseases with
regard to TNF blockade sensitivity. It is notable that the
patient had such a good response with the low doses used. It
might also be that these doses were sufficient to treat his
condition but not high enough to elicit neurologic disease.
However, even though our patient did not have any
problems with the rechallenge, we do not believe we can make
a definitive conclusion about how to continue therapy after the
appearance of a demyelinating disease in the course of antiTNF␣ treatment.
Marcela Cisternas, MD
Miguel Gutiérrez, MD
Sergio Jacobelli, MD
Pontificia Universidad Católica de Chile
Santiago, Chile
1. Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G,
Crayton H, et al. Demyelination occurring during anti–tumor
2.
3.
4.
5.
necrosis ␣ therapy for inflammatory arthritides. Arthritis Rheum
2001;44:2862–9.
Miller FW, Hess EV, Clauw DJ, Hertzman PA, Pincus T, Silver
RM, et al. Approaches for identifying and defining environmentally
associated rheumatic disorders. Arthritis Rheum 2000;43:243–9.
Taly AB, Gupta SK, Anisya U, Shankar SK, Rao S, Das KB, et al.
Recurrent Guillain Barre’s syndrome: a clinical, electrophysiological and morphological study. J Assoc Physicians India 1995;43:
249–52.
Combes A, Goulon M. Recurrence of Guillain-Barre syndrome.
Ann Med Interne (Paris) 1992;143:515–8.
Jacobs BC, Rothbarth PH, van der Meche FG, Herbrink P, Schmitz
PI, de Klerk MA, et al. The spectrum of antecedent infections in
Guillain-Barre syndrome: a case-control study. Neurology 1998;51:
1110–5.
DOI 10.1002/art.10489
Reply
To the Editor:
In our case series, 4 patients had a flare of previously
existing multiple sclerosis (MS) following administration of
anti-TNF␣ therapy, as demonstrated in Table 1. However, in 3
of the 4 patients, the disease had remained completely quiescent for several years after initial diagnosis and flared only
after institution of anti-TNF␣ therapy. Patient 4 had had
several flares between diagnosis of MS and initiation of
anti-TNF␣ treatment. However, the flare that occurred after
anti-TNF␣ therapy was longer and more severe. Three patients
in the reported series who continued to receive anti-TNF␣
therapy experienced worsening neurologic symptoms, while
the rest, who discontinued these agents, had partial or complete resolution.
Relapses in both Guillain-Barré syndrome (Romano
JG, Rotta FT, Potter P, Rosenfeld V, Santibanez R, Rocha B,
et al. Relapses in the Guillain-Barre syndrome after treatment
with intravenous immune globulin or plasma exchange. Muscle
Nerve 1998;21:1327–30) and MS (Amato MP, Ponziani G,
Bartolozzi ML, Siracusa G. A prospective study on the natural
history of multiple sclerosis: clues to the conduct and interpre-
Table 1. Flares of multiple sclerosis (MS) after treatment with
anti–tumor necrosis factor ␣ (anti-TNF␣)
Patient with
preexisting
MS
Duration
between
diagnosis of
MS and
flare, years
Duration of
anti-TNF␣
treatment
prior to
flare, months
1
10
10
2
26
12
3
4
5
4
6
1
Outcome
Partial resolution at
4 months
Complete resolution
at 3 months
Continued symptoms
at 6 months
Partial resolution at
3 months
LETTERS
3109
tation of clinical trials. J Neurol Sci 1999;168:96–106), both of
which are considered to be autoimmune disorders directed
against central and peripheral myelin components, respectively, have been described. However, in Cisternas et al’s
patient the fact that the relapse occurred within 3 months of
initiation of anti-TNF␣ therapy, after being quiescent for 14
years (1986–2000), increases the likelihood of a true association. Hence, we reiterate that it would be prudent to discontinue anti-TNF␣ therapy in such a situation until the underlying etiology can be better delineated. Furthermore, the
occurrence of a positive rechallenge phenomenon in patients
such as patient 2 in our report, as well as more reports to the
Food and Drug Administration of such events (personal
communication), suggest that rechallenge is associated with a
significantly increased risk of recurrence, even with a lower
dose of the drug. Therefore, we believe rechallenge should be
avoided unless no other treatment options are available.
Niveditha Mohan, MBBS
Thomas R. Cupps, MD
Georgetown University Medical Center
Washington, DC
DOI 10.1002/art.10414
A nonsense mutation in exon 2 of the DNase I gene is
not present in UK subjects with systemic lupus
erythematosus and Graves’ disease: comment on the
article by Rood et al
To the Editor:
The identification of genetic loci conferring susceptibility to the development of systemic lupus erythematosus
(SLE) is important for our understanding of the disease
process and the ultimate design of new therapies. Rood et al
recently reported not only association between the HLA gene
region on chromosome 6p21 and SLE but also an independent
association with tumor necrosis factor ␣ (1). While the major
histocompatibility complex (MHC) genes are inextricably
linked with the autoimmune disease process, they have so far
remained intractable to therapeutic modulation through peptide mimics. Identification of non-MHC loci, therefore, may
hold the key to the development of novel therapies.
The DNase I gene (DNASE1) on chromosome 16p13.3
(2) encodes an enzyme that hydrolyzes DNA forming deoxyribonucleotides. A murine model has shown that
DNase I–deficient mice have an increased incidence of SLE,
with classic findings including the presence of autoreactive
antibodies and glomerulonephritis in a DNase I-dose–
dependent manner. This suggests that DNase I could prevent
the expansion of lymphocytes responsive to nucleosomal antigens, which contribute to SLE, by the removal of DNA from
soluble or deposited autoantigenic nucleoprotein complexes
(3). DNase I is, therefore, a potential target for therapeutic
modulation.
A heterozygous nonsense mutation in DNASE1 was
reported in 2 of 20 female Japanese patients with SLE,
resulting in an A3 G transversion in exon 2 at position 172 of
the coding sequence, leading to the generation of a stop codon
within the DNASE1 sequence (4). This resulted in decreased
DNase I activity and an increased IgG titer against nucleoso-
mal antigens, suggesting that DNASE1 could be involved not
only in the genetic susceptibility to SLE but also the autoimmune disease process in general. The presence of a
DNASE1 mutation could potentially identify a subgroup of
patients with SLE with specific disease characteristics relating,
for example, to progression of disease, prognosis, or response
to therapy. The aim of this study, therefore, was to determine
whether the A3 G mutation of DNASE1 plays a role in the
genetic susceptibility to the development of SLE and the
autoimmune disease process in a Caucasian UK population.
One hundred eighty-two patients (12 of whom had a
history of autoimmune thyroid disease) were recruited from
the SLE clinic at the University Department of Rheumatology,
Queen Elizabeth Hospital, Birmingham. Patients fulfilled the
American College of Rheumatology criteria for the classification of SLE (5). Two hundred ninety-one patients with autoimmune hyperthyroidism (Graves’ disease), 5 of whom had a
family history of SLE, were recruited from thyroid clinics, as
described previously (6). Ethnically matched control subjects
(285) with no family history of autoimmune disease, recruited
as previously described, were also used (6). The study was
approved by the local ethics committee and all subjects gave
informed, written consent.
Genomic DNA was extracted from whole blood using
the Bacc II DNA extraction kit from Nucleon Biosciences
(Lanarkshire, UK). Amplification of the target DNA in exon 2
of DNASE1 was carried out by polymerase chain reaction
(PCR) and the resulting products were subjected to restriction
fragment length polymorphism (RFLP) analysis with Nsp I
using conditions previously described (4). To verify the Nsp I
assay, RFLP was performed on a sample of DNA (HLA–
DQB1*0602 cloned into the pCIneo expression vector) containing 6 Nsp I sites. Genotyping results obtained by PCRRFLP were verified by subjecting 15 randomly selected
samples to sequence analysis using the ABI Prism 377 DNA
sequencer (Applied Biosystems, Warrington, UK). Unambiguous genotyping data were obtained on all samples. The A3 G
mutation in exon 2 of DNASE1 was not found in any of the 758
subjects studied.
Although the A3 G mutation of DNASE1 has been
shown to be associated with decreased DNase I activity and a
high IgG titer against nucleosomal antigens in 2 Japanese
patients with SLE (7), we examined 1,516 human chromosomes, including 364 in subjects with SLE, and found no
evidence to suggest that this plays a role in the development of
SLE in a Caucasian UK population. There are a number of
factors that could explain the observed differences between the
Japanese and UK populations. First, it is possible that the
A3 G mutation is in linkage disequilibrium with another gene
or haplotype that is associated with SLE in the Japanese
population but not in the UK population. Second, certain
genes may lead to the development of autoimmune disease in
specific ethnic/geographic populations only. For example,
chromosome 1p36 is linked to SLE in a Mexican American
population but not in a Caucasian population (8). Third, the
A3 G mutation may have produced a rare form of SLE in 2
Japanese subjects. Finally, however, it is worth noting that no
further A3 G mutations were found in a second cohort of 180
Japanese patients, raising the possibility of a false positive
result in the original data set (Yasutomo K: personal communication).
3110
LETTERS
In conclusion, further studies are required to determine the mechanisms behind the role of the MHC in SLE and
other autoimmune diseases. However, the study of non-MHC
candidate genes is also important. Although the A3 G mutation in DNASE1 does not appear to be associated with SLE or
the autoimmune disease process in the UK, this and other
functional candidates require detailed investigation if novel
disease-modifying therapies are to be identified.
Matthew J. Simmonds, BSc
Joanne M. Heward, PhD
M. Ann Kelly, PhD
Amit Allahabadia, MD
Helen Foxall, BSc
Caroline Gordon, MD, FRCP
Jayne A. Franklyn, PhD
University of Birmingham
Queen Elizabeth Hospital
Stephen C. L. Gough, MD, FRCP
University of Birmingham
Birmingham Heartlands Hospital
Birmingham, UK
1. Rood MJ, van Krugten MV, Zanelli E, van der Linden MW,
Keijsers V, Schreuder GM, et al. TNF-308A and HLA–DR3 alleles
contribute independently to susceptibility to systemic lupus erythematosus. Arthritis Rheum 2000;43:129–34.
2. Yasuda T, Nadano D, Iida R, Takeshita H, Lane SA, Callen DF, et
al. Chromosomal assignment of the human deoxyribonuclease I
gene, DNASE 1 (DNL1), to band 16p13.3 using the polymerase
chain reaction. Cytogenet Cell Genet 1995;70:221–3.
3. Napirei M, Karsunky H, Zevnik B, Stephan H, Mannherz HG,
Moroy T. Features of systemic lupus erythematosus in Dnase1deficient mice. Nat Genet 2000;25:177–81.
4. Yasutomo K, Horiuchi T, Kagami S, Tsukamoto H, Hashimura C,
Urushihara M, et al. Mutation of DNASE1 in people with systemic
lupus erythematosus. Nat Genet 2001;28:313–4.
5. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, et al. The 1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 1982;25:1271–7.
6. Heward JM, Nithiyananthan R, Allahabadia A, Gibson S, Franklyn
JA, Gough SC. No association of an interleukin 4 gene promoter
polymorphism with Graves’ disease in the United Kingdom. J Clin
Endocrinol Metab 2001;86:3861–3.
7. Gordon C, Salmon M. Update on systemic lupus erythematosus:
autoantibodies and apoptosis. Clin Med 2001;1:10–4.
8. Shai R, Quismorio FP Jr, Li L, Kwon OJ, Morrison J, Wallace DJ,
et al. Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families. Hum Mol Genet 1999;8:
639–44.
DOI 10.1002/art.10484
Antioxidant treatment decreases the titer of
circulating anticardiolipin antibodies: comment on the
article by Sambo et al
To the Editor:
Sambo et al described an enhanced oxidative stress in
scleroderma and the maintenance of scleroderma fibroblast
phenotype by the constitutive up-regulation of reactive oxygen
species generation through the NADPH oxidase complex
pathway (1). Previous reports indicated that an enhanced
oxidative stress could also be linked to the formation of
anticardiolipin antibodies (aCL) in autoimmune diseases. In
particular, an interesting hypothesis suggested that aCL bind
exclusively to the peroxidized molecule, indicating that these
antibodies recognize epitopes derived from phospholipid oxidation (2). Furthermore, a close association between antiphospholipid antibodies (aPL) and in vivo markers of lipid peroxidation (3) has been demonstrated. To explore this hypothesis
in aPL-positive patients, we undertook an interventional study
to assess whether antioxidant treatment is able to affect the
serum titer of aCL.
We studied 14 consecutive outpatients (12 women and
2 men; age 24–49 years) who were positive for aCL, with a titer
of 14–120 IgG phospholipid units (GPL units) or IgM phospholipid units (MPL units); among these patients, 8 were also
positive for lupus anticoagulant (LAC). Six of 14 aPL-positive
patients had primary antiphospholipid syndrome (primary
APS) with a history of arterial and/or venous thrombosis in the
previous 12–25 months. The remaining 8 patients had systemic
lupus erythematosus, and 1 of these patients had had a
thromboembolic stroke 19 months previously. At the time of
the study, all patients with a previous episode of arterial
thrombosis were treated with aspirin (100 mg/day). The 3
patients who had had an episode of venous thrombosis in the
previous 15–25 months discontinued the anticoagulant treatment spontaneously ⬃6 months before their inclusion into the
study.
The study was approved by the Internal Review Board
and Ethics Committee. Patients positive for aPL were randomly treated with (group 1; n ⫽ 7) or without (group 2; n ⫽
7) antioxidant supplementation (vitamin E at 900 IU/day,
vitamin C at 2,000 mg/day). Clinical and laboratory parameters
were evaluated before and after 4–6 weeks of treatment. An
enzyme-linked immunosorbent assay validated in an international workshop was used for measurement of aCL. Patients
were considered positive for IgG or IgM aCL when the serum
concentration was ⬎10 GPL units or ⬎10 MPL units, respectively (4). Patients were considered positive for aPL if aCL
and/or LAC were detected on two separate occasions at least
2 months apart. Levels of LAC, fibrinogen, prothrombin
fragment 1⫹2 (F1⫹2), serum tumor necrosis factor ␣ (TNF␣),
and plasma vitamin E and vitamin C were assayed as previously
described (5).
Previous study showed that the sample would have to
consist of at least 6 patients in each group (␣ ⫽ 0.05 and 1 ⫺
␤ ⫽ 0.90) (6), assuming that antioxidant treatment reduced
F1⫹2, a marker of thrombin generation in vivo, by 40% (4).
We postulated that the same sample size was necessary to
observe at least 40% reduction in aCL circulating titer. The
statistical analysis was performed by appropriate t-test. The
linear regression test was used to study the different correlations. The effect of treatment was analyzed by two-way
repeated-measures analysis of variance (ANOVA). Data were
presented as the mean ⫾ SD and median and range. Only
2-tailed probabilities were used for testing statistical significance. P values less than 0.05 were considered significant.
The two treatment groups were homogeneous for age,
sex, disease activity, previous thrombosis, primary APS, and
corticosteroid and aspirin treatment, as well as for circulating
levels of aCL, F1⫹2, and plasma vitamins E and C (Table 1).
In order to assess the oxidative stress in the whole aPL group,
LETTERS
3111
Table 1. Clinical and laboratory characteristics of patients enrolled (group 1) or not (group 2) for vitamin E and vitamin C supplementation*
Group 1 (n ⫽ 7)
Before treatment
After treatment
Age in years, mean ⫾ SD
35 ⫾ 1
–
Men
1 (14)
–
Primary APS
3 (43)
–
Active disease
2 (29)
2 (29)
Thrombosis
4 (57)
4 (57)
Corticosteroid treatment, prednisone
2 (29)
2 (29)
5–15 mg/day or
methylprednisolone 4–24 mg/day
Aspirin treatment, 100 mg/day
2 (29)
2 (29)
Fibrinogen in mg/dl, mean ⫾ SD
261 ⫾ 40.9
258 ⫾ 42
TNF in pg/ml, median (range)
186.2 (94.6–290.4) 161.8 (84.9–280.4)
aCL, median (range)§
32 (16–120)
8 (3–100)
F1⫹2 in ␮moles, mean ⫾ SD
1.99 ⫾ 0.44
1.19 ⫾ 3.4
Vitamin E in ␮moles/liter, mean ⫾
14.5 ⫾ 3.4
39.7 ⫾ 7.7
SD
Vitamin C in ␮moles/liter, mean ⫾
16.1 ⫾ 7.0
26.3 ⫾ 9.3
SD
P†
P, difference
between groups
after treatment‡
–
–
–
⬎0.05
⬎0.05
⬎0.05
–
–
–
–
–
–
⬎0.05
⬎0.05
⬎0.05
⬎0.05
⬎0.05
⬎0.05
–
⬎0.05
⬎0.05
⬍0.05
⬍0.05
⬍0.05
⬎0.05
⬍0.05
Group 2 (n ⫽ 7)
P†
–
–
–
⬎0.05
⬎0.05
⬎0.05
Before treatment After treatment
36 ⫾ 11
1 (14)
3 (43)
1 (14)
3 (43)
1 (14)
–
–
–
1 (14)
3 (43)
1 (14)
⬎0.05
2 (29)
2 (29)
⬎0.05
263 ⫾ 39
258 ⫾ 40
⬎0.05 189.2 (96.4–248.6) 177.6 (85.7–282)
0.016
50 (14–100)
50 (9–100)
0.016
1.96 ⫾ 0.48
2.02 ⫾ 0.33
0.016
14.9 ⫾ 4.3
16.6 ⫾ 3.8
0.016
17.8 ⫾ 8.9
17.2 ⫾ 8.6
* Except where indicated otherwise, values are the number (%) of patients. APS ⫽ antiphospholipid syndrome; TNF ⫽ tumor necrosis factor; aCL ⫽
anticardiolipin antibodies; F1⫹2 ⫽ prothrombin fragment 1⫹2.
† Wilcoxon signed rank test.
‡ In percentages of change from baseline, by Mann-Whitney U test.
§ In IgG phospholipid units or IgM phospholipid units.
we compared plasma levels of vitamins E and C of aPLpositive patients with those of 20 healthy subjects (18 women
and 2 men; age 22–51 years) matched for age and sex.
Compared with controls, aPL ⫽ positive patients had significantly lower levels of vitamin E (mean ⫾ SD 14.7 ⫾ 6.8
␮moles/liter versus 38.9 ⫾ 4 ␮moles/liter; P ⬍ 0.0001) and
vitamin C (16.9 ⫾ 7.8 ␮moles/liter versus 40 ⫾ 16.7 ␮moles/
liter; P ⬍ 0.0001). Vitamin E (r ⫽ ⫺0.63, P ⬍ 0.02) and vitamin
C (r ⫽ ⫺0.65, P ⫽ 0.01) were significantly inversely correlated
with circulating levels of F1⫹2 in aPL ⫽ positive patients. In
subjects not assigned to antioxidant treatment, no changes in
values of clinical and laboratory variables were observed at the
end of treatment. Conversely, patients assigned to antioxidants
showed significant decreases in aCL titer and in levels of F1⫹2
and significant increases in plasma levels of both vitamin E and
vitamin C (Table 1). In all patients treated with antioxidants,
we observed a mean decrease in aCL titer of 61% (range
16–84%). The ANOVA confirmed significant decreases in
aCL titer (P ⫽ 0.01) and F1⫹2 plasma levels (P ⫽ 0.0001) and
significant increases in levels of vitamin E (P ⫽ 0.0001) and
vitamin C (P ⫽ 0.0001) after antioxidant treatment.
We can reasonably exclude the possibility that change
in disease activity could account for the decrease in aCL titer,
since levels of TNF␣ and fibrinogen (two markers of disease
activity) as well as clinical characteristics were not modified at
the end of treatment. The decrease in aCL titer could therefore be considered an effect of antioxidant treatment, thus
supporting the hypothesis that oxidative stress plays a central
role in the formation of aCL. However, further study is
necessary to assess the intrinsic mechanism by which oxidative
stress gives rise to formation of new phospholipid epitopes
in vivo. Antioxidant treatment may be of clinical value in
antiphospholipid syndrome (APS), by virtue of a potential
antithrombotic effect. In fact, consistent with previous findings, we observed a reduced rate of thrombin generation that
can be interpreted to be a consequence of reduced lipid
peroxidation and/or reduced aCL titer (3,5). Should findings of
this pilot study be confirmed in a larger study, reducing
oxidative stress may represent a new strategy for the treatment
of APS.
D. Ferro, MD
L. Iuliano, MD
F. Violi, MD
G. Valesini, MD
F. Conti, MD
“La Sapienza” University of Rome
Rome, Italy
1. Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini G,
et al. Oxidative stress in scleroderma: maintenance of scleroderma
fibroblast phenotype by the constitutive up-regulation of reactive
oxygen species generation through the NADPH oxidase complex
pathway. Arthritis Rheum 2001;44:2653–64.
2. Horkko S, Miller E, Dudl E, Reaven P, Curtiss LK, Zvaifler NJ, et
al. Antiphospholipid antibodies are directed against epitopes of
oxidized phospholipids: recognition of cardiolipin by monoclonal
antibodies to epitopes of oxidized low density lipoprotein. J Clin
Invest 1996;98:815–25.
3. Iuliano L, Praticò D, Ferro D, Pittoni V, Valesini G, Lawson J, et
al. Enhanced lipid peroxidation in patients positive for antiphospholipid antibodies. Blood 1997;90:3931–5.
4. Harris EN, Gharavi AE, Patel SP, Hughes GRV. Evaluation of the
anticardiolipin antibody test: report of an international workshop
held 4 April 1986. Clin Exp Immunol 1987;68:214–9.
5. Praticò D, Ferro D, Iuliano L, Rokach J, Conti F, Valesini G, et al.
Ongoing prothrombotic state in patients with antiphospholipid
3112
antibodies: a role for increased lipid peroxidation. Blood 1999;93:
3401–7.
6. Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin
inhibits the monocyte expression of proinflammatory cytokines in
patients with hypercholesterolemia. J Am Coll Cardiol 2000;36:
427–31.
DOI 10.1002/art.10483
Role of T cells in the pathogenesis of osteoarthritis
To the Editor:
We read with interest the review by Pelletier et al (1).
This is a timely article suggesting that osteoarthritis (OA) is an
inflammatory disease and that the traditional view by rheumatologists that OA is a noninflammatory disease should be
reconsidered and the disease should be reclassified.
In their review, Pelletier et al (1) cited macrophages as
the exclusive source of inflammation in OA. However, the role
of T cells in the inflammatory process has not been considered.
We (2–7) and others (8–10) have provided evidence that T cell
infiltrates are frequently detected in the synovial membrane
(SM) of patients with OA (2,8–10). These infiltrates are often
angiocentric (4) and are associated with activation of local
vascular endothelial cells, as suggested by the increase in
expression of E-selectin (10). In patients with advanced OA, T
cell infiltrates in the SM exhibit a nodular pattern in 37% (9)
to 65% (2) of the patients and express early (CD69), intermediate (CD25), and late (CD45RO, HLA–DR) activation antigens (2). Additionally, T cell cytokine transcripts of the Th1
type interferon-␥ (IFN␥) and interleukin-2 (IL-2) and IL-10
were found in the SM of patients with OA, whereas IL-4 and
IL-5 were not detected (2). There were no statistical differences in the levels of IFN␥ and IL-2 transcripts in the SM
between patients with rheumatoid arthritis (RA) and OA,
when normalized for T cell number equivalents (2). However,
when the levels of IFN␥ transcripts were normalized for total
cell number equivalents, they were lower in OA than in RA.
The presence of substantial proportions of T cells expressing
early, intermediate, and late activation antigens and of the Th1
cytokine pattern (2) in chronic SM lesions of patients with OA
strongly suggests that T cells at least contribute to chronic
inflammation in these patients. This Th1 response may be
driven by macrophages.
Macrophages and synovial lining cells express IL-12, a
cytokine that drives the Th1 immune response (3). OA synovial
fluid exhibits increased levels of macrophage inflammatory
protein 1␤ (11), a ligand for the chemokine receptor CCR5,
present on Th1 cells (12). Although these findings may be
explained by a nonspecific activation of T cells, we have
demonstrated (6,7) the presence of oligoclonal populations of
T cells in the SM of 4 out of 5 patients with advanced OA.
Amplification of ␤-chain T cell receptor (TCR) transcripts
from the SM of patients with OA by either nonpalindromic
adaptor polymerase chain reaction (PCR) or V␤-specific PCR
(13), followed by cloning and sequencing of the amplified
transcripts, revealed substantial proportions of identical
␤-chain TCR transcripts, suggesting the presence of oligoclonal populations of T cells. These results strongly suggest
that T cells have undergone antigen-driven proliferation and
clonal expansion in situ in the SM of patients with OA, in
LETTERS
response to as-yet-unidentified antigens. These antigen(s) are
not known, but one study suggested a self-reactive immune
response to chondrocyte membrane components (14).
Like other conditions of chronic T cell activation (15),
such as RA (16), systemic lupus erythematosus (17), and
tumor-infiltrating lymphocytes (18), T cells in the SM of
patients with OA show decreased expression of CD3-␨ chain
transcripts and protein (5). The inflammation in OA may not
be confined within the joints. One study described perivascular
lymphocytic infiltrates in muscle biopsies of 18% of patients
with OA (19). Activated T cells, through cell contact–
dependent interaction or through soluble mediators (20), can
stimulate monocytes to produce cytokines (21). In rheumatoid
synovitis, T cells were found to be largely responsible for the
production of metalloproteinase (22).
All these results taken together strongly suggest that a
T cell immune response occurs in OA (6). Substantial evidence
has been accumulated suggesting that OA is an inflammatory
disease. The traditional view that OA is a noninflammatory
disease must be revised. We believe that it is difficult to explain
the chronic inflammation that is observed in the SM of patients
with OA without a role for T cells and a role for putative
antigen(s) in the initiation and propagation of the disease.
Lazaros I. Sakkas, MD, PhD
Temple University School of Medicine
Philadelphia, PA
and Thessaly University School of Medicine
Larisa, Greece
Chris D. Platsoucas, PhD
Temple University School of Medicine
Philadelphia, PA
1. Pelletier JP, Martel-Pelletier J, Abramson SB. Osteoarthritis, an
inflammatory disease: potential implication for the selection of
new therapeutic targets. Arthritis Rheum 2001;44:1237–47.
2. Sakkas LI, Scanzello C, Johanson N, Burkholder J, Mitra A,
Salgame P, et al. T cells and T-cell cytokine transcripts in the
synovial membrane in patients with osteoarthritis. Clin Diagn Lab
Immunol 1998;5:430–7.
3. Sakkas LI, Johanson NA, Scanzello CR, Platsoucas CD. Interleukin-12 is expressed by infiltrating macrophages and synovial lining
cells in rheumatoid arthritis and osteoarthritis. Cell Immunol
1998;188:105–10.
4. Sakkas LI, Scanzello CR, Katsetos CD, Johanson NA, Platsoucas
CD. Angiocentric inflammation in the synovial membrane (SM) in
osteoarthritis. Rheumatology 2000;39 Suppl:117.
5. Sakkas LI, Koussidis GA, Avgerinos ED, Platsoucas CD. Decreased expression of CD3zeta chain in the synovial membrane in
osteoarthritis. Rheumatology 1999;39 Suppl:217.
6. Scanzello CR, Sakkas LI, Johanson NA, Platsoucas CD. Oligoclonal populations of T-cells infiltrate the synovial membrane
(SM) of patients with osteoarthritis (OA) [abstract]. Arthritis
Rheum 1999;43 Suppl 9:S257.
7. Scanzello C, Sakkas LI, Johanson N, Platsoucas CD. Clonally
expanded T cells in the synovial membrane of patients with
osteoarthritis. Scand J Immunol 2001;54 Suppl 1:59.
8. Linblad S, Hedfors E. Arthroscopic and immunohistologic characterization of knee joint synovitis in osteoarthritis. Arthritis
Rheum 1987;30:1081–8.
9. Smith MD, Triantafillou S, Parker A, Youssef PP, Coleman M.
Synovial membrane inflammation and cytokine production in
patients with early osteoarthritis. J Rheumatol 1997;24:365–71.
LETTERS
10. Koch AE, Turkiewicz W, Harlow LA, Pope RM. Soluble Eselectin in arthritis. Clin Immunol Immunopathol 1993;69:29–35.
11. Koch AE, Kunkel SL, Shah MR, Fu R, Mazarakis DD, Haines
GK, et al. Macrophage inflammatory protein-1␤: a C-C chemokine in osteoarthritis. Clin Immunol Immunopathol 1995;77:
307–14.
12. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B,
Chizzolini C, et al. CCR5 is characteristic of Th1 lymphocytes.
Nature 1998;391:344–5.
13. Slachta CA, Jeevanandam V, Goldman B, Lin WL, Platsoucas CD.
Coronary arteries from human cardiac allografts with chronic
rejection contain oligoclonal T cells: persistence of identical
clonally expanded TCR transcripts from the early post-transplantation period (endomyocardial biopsies) to chronic rejection (coronary arteries). J Immunol 2000;165:3469–83.
14. Alsalameh S, Mollenhauer J, Hain N, Stock KP, Kalden JR,
Burmester GR. Cellular immune response toward human articular
chondrocytes: T cell reactivities against chondrocyte and fibroblast
membranes in destructive joint diseases. Arthritis Rheum 1990;33:
1477–86.
15. Krishnan S, Warke VG, Nambiar MP, Wong HK, Tsokos GC,
Farber DL. Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of
CD3␨ expression. Blood 2001;97:3851–9.
16. Matsuda M, Ulfgren AK, Lenkei R, Petersson M, Ochoa AC,
Lindblad S, et al. Decreased expression of signal-transducing
CD3␨ chains in T cells from the joints and peripheral blood of
rheumatoid arthritis patients. Scand J Immunol 1998;47:254–62.
17. Liossis SN, Ding XZ, Dennis GJ, Tsokos GC. Altered pattern of
TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells
from patients with systemic lupus erythematosus. J Clin Invest
1998;101:1448–57.
18. Finke JH, Zea AH, Stanley J, Longo DL, Mizoguchi H, Tubbs RR,
et al. Loss of T-cell receptor ␨ chain and p56lck in T-cells
infiltrating human renal cell carcinoma. Cancer Res 1993;53:
5613–6.
19. Voskuyl AE, van Duinen SG, Zwinderman AH, Breedveld FC,
Hazes JM. The diagnostic value of perivascular infiltrates in
muscle biopsy specimens for the assessment of rheumatoid vasculitis. Ann Rheum Dis 1998;57:114–7.
20. Aarvak T, Chabaud M, Miossec P, Natvig JB. IL-17 is produced by
some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol 1999;162:1246–51.
21. Sebbag M, Parry SL, Brennan FM, Feldmann M. Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-␣, but not interleukin-10:
possible relevance to pathophysiology of rheumatoid arthritis. Eur
J Immunol 1997;27:624–32.
22. Klimiuk PA, Yang H, Goronzy JJ, Weyand CM. Production of
cytokines and metalloproteinases in rheumatoid synovitis is T cell
dependent. Clin Immunol 1999;90:65–78.
DOI 10.1002/art.10528
Benefit or risk of aspirin treatment of giant cell
arteritis: comment on the article by Weyand et al
To the Editor:
Weyand et al (1) document the efficacy and perhaps
even superiority of acetylsalicylic acid (aspirin) for normalizing
major immunomodulators in giant cell arteritis. Although
proinflammatory cytokines were suppressed, past clinical experience must also be respected. Suppression of immunomodulation and, specifically, suppression of the erythrocyte
sedimentation rate are major criteria for monitoring activity of
3113
disease and tailoring the corticosteroid treatment regimen.
Aspirin does alter those parameters, but past clinical experience illustrates one major lapse: contrary to the experience
with corticosteroids, aspirin does not prevent blindness (2–6).
Weyand et al present an intriguing perspective on a
potential mechanism of action of aspirin, but caution is required in applying this information to clinical management of
patients with giant cell arteritis.
Bruce M. Rothschild, MD
Arthritis Center of Northeast Ohio
Northeastern Ohio Universities College of Medicine
Youngstown, OH
1. Weyand CM, Kaiser M, Yang H, Younge B, Goronzy JJ. Therapeutic effects of acetylsalicylic acid in giant cell arteritis. Arthritis
Rheum 2002;46:457–66.
2. Chavany JA, Taptas JN. A propos d’un cas d’arterite temporale.
Presse Med 1948;56:835–45.
3. Harrison CV. Giant cell or temporal arteritis: a review. J Clin
Pathol 1948;1:1–24.
4. Kalliomaki JL, Lauren PA. Development of temporal arteritis in a
patient with rheumatoid arthritis during treatment with indomethacin. Acta Rheum Scand 1965;11:131–6.
5. Fernandez-Herlihy L. Polymyalgia rheumatica. Semin Arthritis
Rheum 1971;1:236–45.
6. Hunder GG, Disney TF, Ward LE. Polymyalgia rheumatica. Mayo
Clin Proc 1969;44:849–75.
DOI 10.1002/art.10523
Reply
To the Editor:
We agree with Dr. Rothschild’s cautionary note that
glucocorticoids are the gold standard in the treatment of giant
cell arteritis (GCA), and it was certainly not the intention of
our experimental study to advocate replacing corticosteroids
with aspirin. However, we also feel the need to optimize
current treatment with glucocorticoids (1–3); to accomplish
that goal, targeting of relevant pathomechanisms will be
necessary. One of the critical pathways is the tissue production
of interferon-␥ (INF␥) (4,5), which is relatively spared by
corticosteroids but is targeted by acetylsalicylic acid (3).
Tissue ischemia in GCA results from aggressive intimal
hyperplasia, which cannot be reversed by any immunosuppressive or antiinflammatory interventions (6). It is correct that the
frequency of visual ischemic symptoms and blindness has
decreased since the introduction of glucocorticoids for treatment. However, it is also common experience that even in
patients receiving corticosteroids, especially the low doses used
to manage polymyalgia rheumatica, sporadic cases of fullblown arteritis and blindness can occur. The anecdotal cases
cited by Dr. Rothschild, therefore, have only limited value.
Controlled studies on the use of aspirin are not yet available.
More importantly, most of the patients referenced by Dr.
Rothschild had polymyalgia rheumatica (7–10) and were receiving nonsteroidal antiinflammatory agents, such as indomethacin and phenylbutazon, not aspirin. Our experiments
clearly show that the action of aspirin on IFN␥ production is
not related to its cyclooxygenase inhibitory activity. Indeed,
indomethacin could not suppress tissue IFN␥.
3114
LETTERS
Our molecular experiments demonstrated that corticosteroids and aspirin have distinct targets. These 2 agents
should complement each other, not replace each other. In fact,
each of them could have unique benefits in terms of inhibiting
the different components of the GCA syndrome. Aspirin is
minimally effective in inhibiting transcription of nuclear
factor–dependent cytokines, such as interleukin-1 (IL-1) and
IL-6. It may, therefore, not have an immediate effect on the
production of these monokines in the vessel wall. It is also
likely much less effective than corticosteroids in treating the
acute-phase response and the systemic component of GCA
and polymyalgia rheumatica. However, aspirin reduces IFN␥
production in the vessel wall and may, therefore, be able to
suppress the progression of intimal hyperplasia. In short-term
treatment of GCA, the major benefit of aspirin may relate to
its ability as a platelet aggregation inhibitor. In long-term
treatment, aspirin may have a role as a steroid-sparing agent,
but it will not replace the need for corticosteroids. Naturally,
such treatment recommendations cannot be based solely on
experimental models but need to be tested in clinical studies.
Cornelia M. Weyand, MD
Jörg J. Goronzy, MD
Mayo Clinic
Rochester, MN
1. Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ.
Treatment of giant cell arteritis: interleukin-6 as a biologic marker
of disease activity. Arthritis Rheum 2000;43:1041–8.
2. Weyand CM, Fulbright JW, Evans JM, Hunder GG, Goronzy JJ.
Corticosteroid requirements in polymyalgia rheumatica. Arch
Intern Med 1999;159:577–84.
3. Brack A, Rittner HL, Younge BR, Kaltschmidt C, Weyand CM,
Goronzy JJ. Glucocorticoid-mediated repression of cytokine gene
transcription in human arteritis-SCID chimeras. J Clin Invest
1997;99:2842–50.
4. Weyand CM, Goronzy JJ. Pathogenic principles in giant cell
arteritis. Int J Cardiol 2000;75 Suppl 1:S9–S15; discussion S17–9.
5. Weyand CM, Goronzy JJ. Arterial wall injury in giant cell arteritis.
Arthritis Rheum 1999;42:844–53.
6. Kaiser M, Weyand CM, Bjornsson J, Goronzy JJ. Platelet-derived
growth factor, intimal hyperplasia, and ischemic complications in
giant cell arteritis. Arthritis Rheum 1998;41:623–33.
7. Harrison CV. Giant cell or temporal arteritis: a review. J Clin
Pathol 1948;1:1–24.
8. Kalliomaki JL, Lauren PA. Development of temporal arteritis in
patients with rheumatoid arthritis during treatment with indomethicin. Acta Rheum Scand 1965;11:131–6.
9. Fernandez-Herlihy L. Polymyalgia rheumatica. Semin Arthritis
Rheum 1971;1:236–45.
10. Hunder GG, Disney TF, Ward LE. Polymyalgia rheumatica. Mayo
Clin Proc 1969;44:849–75.
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