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No firm basis to advocate auranofin in the treatemnt of juvenile rheumatoid arthritis.

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LETTERS
Table 1. Characteristics of 10 patients with dermatomyositis treated with cyclosporin A (CsA)*
Patient
Agelsex
1
2
3
4
5
6
7
8
9
10
45lF
391F
231F
35lF
58IM
61lF
4QlF
47lM
291F
Years of
disease
Earlier
treatment
Dosage of CsA
(mglkglday),
initiallmaintenance
2
5
16
5
Pred., AZA
Pred., AZA
Pred., AZA
Pred., AZA
Pred.
Pred., AZA
Pred .
Pred., AZA
Pred., AZA
Pred.
512
512.5
512
513.5
513
513
512
513.5
513.5
512.5
1
2
0.5
2
38lF
* Pred.
=
prednisone; AZA
1
2
=
-
Laboratory values in the 10 patients before cyclosporin A
(CsA) treatment and 3 months after the initiation of treatment
Table 2.
After
CK, unitslliter
LDH, unitslliter
T4+ (CD4+) cells, %
T8+ (CD8+) cells, %
Improvement
50
50
30
30
40
200
100
25
20
25
25
25
0
25
30
30
20
0
0
0
Remarkable
Remarkable
Remarkable
Good
Good
Remarkable
Remarkable
Remarkable
Good
Good
treatment
952 (200-4,200)
706 (329-2,380)
56.8 (51.9-60.2)
31.3 (11-45.2)
77 (10-310)
235 (26W72)
52 (40-60)
29 (1 2 4 0 )
=
had returned to normal after 3 months of treatment (mean
CK level 952 unitdliter pretreatment, 77 units/liter at 3
months; mean LDH level 706 unitdliter pretreatment, 235
units/liter at 3 months) (Table 2). Plasma creatinine and
blood urea nitrogen levels in the 10 patients remained low.
Blood pressure and kidney and liver function remained
stable throughout treatment.
After a treatment period of 3-12 months, remarkable
symptomatic improvement has been maintained in these
patients. These 10 cases show that cyclosporin A, even in
low doses, can be an effective treatment in patients with
acute forms of dermatomyositis (3), with no increased risk of
adverse effects compared with those associated with other
drugs (4).
Katalin Danko, MD
Gyula Szegedi, MD, PhD
University Medical School
Debrecen, Hungary
Zabel P, Leimenstoll A, Gross WL: Cyclosporin for acute
dermatomyositis (letter). Lancet I:343, 1984
Ruffel B: Pharmacology of cyclosporine: pharmacological reviews (abstract). Am SOCPharm Exp Ther 318:408, 1989
Alijotas J , Borquinero J , Ordi J , Vilardell R: Polymyositis and
cyclosporin A (letter). Ann Rheum Dis 49:66, 1990
Palestine AG, Nussenblatt RB, Chan CC: Side effects of systemic Cyclosporin in patients not undergoing transplantation.
Am J Med 77:652456, 1984
3 months
of CsA
Pre-CsA
treatment
* Values are the mean (range). CK
lactate dehydrogenase.
Dosage of Pred.
3 months after
initiation of
CsA (mglday)
azathioprine.
with cyclosporin A (CsA) in patients with DM (I). The primary
clinical use of CsA has been its application as an immunosuppressive agent in patients undergoing organ transplantation,
but its use in autoimmune diseases (e.g., rheumatoid arthritis,
systemic lupus erythematosus, DM) is increasingly being explored (2). Herein we describe the clinical courses in 10
patients with DM that was treated with CsA.
In 7 of the 10 patients, azathioprine treatment had
been tried but was discontinued because of side effects or
lack of efficacy. All 10 required prednisone treatment for
control of their disease. CsA treatment was initiated at 5
mg/kg/day, and the dosage was thereafter adjusted to maintain a whole blood level of 150-250 ng/ml. In most patients,
a maintenance dosage of 2-3.5 mglkglday was sufficient. The
duration of DM at the time of initiation of CsA treatment
ranged from 6 months to 16 years (Table 1).
Good clinical response was obtained within the first
week of treatment. The patients have now been receiving
CsA for 3-12 months (mean 5.6 months). Minor side effects
occurred in 3 of the 10 patients (hypertrichosis in 2, nausea
in 1). These abnormalities were reversed after the dosage of
the drug was decreased.
Levels of creatine kinase (CK) and lactate dehydrogenase (LDH), which were elevated before CsA treatment,
Variable*
Dosage of Pred.
at the time of
initiation of
CsA (mglday)
creatine kinase; LDH
=
No firm basis to advocate auranofin in the treatment
of juvenile rheumatoid arthritis
To the Editor:
We are writing to comment on the recent article by
Giannini et a1 (1) regarding the treatment of juvenile rheu-
LETTERS
935
matoid arthritis (JRA) with auranofin. There are a number of
problems with the study, which, we believe, call the reported findings into question.
The conclusions drawn by the authors are not supported by the statistics presented in the paper. The only
differences that were statistically significant were intertreatment differences in articular indices before therapy.
Despite this fact, the authors conclude that the “clinical
efficacy of auranofin is modestly higher than that of placebo
in the treatment of JRA, as evidenced by the consistent
trends observed in the data.” In fact, there are no significant
differences in outcome between the two treatment groups in
this study. All 95% confidence intervals for the differences
between auranofin response and placebo response, for both
3-month and 6-month observations, include zero (see their
Table 5). Furthermore, the authors do not define the concept
of “trend,” and its use is inappropriate and misleading.
In their discussion of their findings, the authors
address what they believe are “inordinately high placeboresponse rates” observed in this study, as well as in their
prior study of penicillamine and hydroxychloroquine (2),
that “precludes the detection of statistically significant differences in efficacy between that regimen [placebo] and the
active agent, regardless of sample size.” It is curious that
they view this phenomenon as due to “inordinately high
placebo-response rates,” without considering the alternative
explanation that these slow-acting antirheumatic drugs offer
no statistically significant, and questionable clinically significant, therapeutic benefit over placebo.
Another explanation offered for the lack of statistically significant inter-treatment group differences was the
duration of chrysotherapy that was chosen for the study.
They suggest that the “results may have been different if this
study were allowed to proceed for an additional 6-12
months.” However, the 6-month period they used conforms
to that of most studies of disease-modifying antirheumatic
drugs.
We are concerned that studies such as this are
published, and then later cited and taken at face value for use
in clinical decision making. The issue being studied is a
clinically important one; however, because of flawed interpretation, the conclusion of “modestly higher” clinical
efficacy of auranofin is not supported by the data.
Lindsey A. Criswell, MD
Patricia P. Katz, PhD
Basia B. Tack, RN, MSN
University of California
Sun Francisco, C A
1. Giannini E H , Brewer EJ Jr, Kuzmina N , Shaikov A, Wallin B,
for the USA Pediatric Rheumatology Collaborative Study Group
and the USSR Cooperative Children’s Study Group: Auranofin in
the treatment of juvenile rheumatoid arthritis: results of the
USA-USSR double-blind, placebo-controlled trial. Arthritis
Rheum 33:466-476, 1990
2. Brewer EJ, Giannini E H , Kuzmina N , Alekseev L: Penicillarnine
and hydroxychloroquine in the treatment of severe juvenile
rheumatoid arthritis: results of the USA-USSR double-blind
placebo-controlled trial. N Engl J Med 314:1269-1276, 1986
Reply
To the Editor:
Quite obviously we provided sufficient detail of
methods and results for Criswell and colleagues to formulate
their own interpretation of the therapeutic utility of oral gold
in the treatment of juvenile rheumatoid arthritis. It is patronizing to believe other readers of our article are less capable
of doing the same. The generally accepted usage of the term
“trend” is “in the direction of, drift, or tendency,” and we
believe its use in the article is entirely appropriate. We think
that the article is painstakingly clear about when and where
statistical differences were and were not detected.
This trial represents a collaborative effort by 24
centers in two countries, and is the largest study of oral gold
therapy in children to date. It is not likely to be repeated.
Results from these studies must be reported in the literature
to assist practitioners in clinical decision making.
Edward H. Giannini, DrPH
Children’s Hospital Medical Center
Cincinnati, OH
Earl J. Brewer, Jr., MD
Houston, TX
On the structure of human autoantibodies
To the Editor:
I would like to comment on the report by Barnes and
coworkers of a V,4 origin of the dually autoreactive monoclonal IgM-rheumatoid factor, BLA (1). Only in the last few
years has it been understood how the known heavy (H) chain
variable (V) region gene families relate to the earlier protein
classification system of Kabat et al (2), which used amino
acid homologies of H chain V region sequences to assign 3
subgroups: I, 11, and 111.
‘To address the issue of the V gene family origins of
monoclonal autoantibodies, my colleagues and I have developed a growing panel of antipeptide serologic reagents to V
region determinants. By analysis of reactivity with related
synthetic peptides and H chains of known sequence from all
V, families, we have demonstrated that the reagent initially
designated anti-PHII, and subsequently renamed anti-V,4FRl, identifies a determinant commonly expressed by the
products of genes of the V,4 family (3). In addition, separate
reagents have been created that discriminate all other V,
families, including the products of the protein subgroup
11-related V,2 family and the single-member V,6 family (3).
These reagents were used to characterize the second
major set of idiotypically related monoclonal rheumatoid
factors, which represent -20% of the monoclonal rheumatoid factors that occur in mixed cryoglobulinemia and Waldenstrom’s macroglobulinemia. These circulating autoantibodies have VH4-encoded H chains that bear the idiotope
identified by the LCl murine antiidiotype and are associated
with VKIIIa light chains identified by the murine 6B6.6
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