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Laboratory tests as predictors of flares in systemic lupus erythematosusComment on the article by Esdaile et al.

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LETTERS
393
child early in the course of disease is supportive of further
study of the use of type I1 collagen in individuals early in their
illness.
Clearly, a pilot study lacking a placebo group is not
capable of determining whether clinical improvements are the
consequence of therapy or represent spontaneous changes in
disease activity. The favorable results obtained in this pilot
study, however, provide the basis for a blinded, placebocontrolled trial to further explore the potential benefits of oral
type I1 collagen in the treatment of JRA.
Martha L. Barnett, MD
David E. Trentham, MD
Beth Israel Hospital
Haward Medical School
Boston, MA
Laboratory tests as predictors of flares in systemic
lupus erythematosus: comment on the article by
Esdaile et a1
within 1 week, which was evaluated together with the previous
samples within the same assay. In case a significant rise of
anti-dsDNA occurred, the patient was randomized to receive
either direct treatment with corticosteroids or to not receive
any treatment at that time.
During the study period, 110 patients either did not
show a significant rise in anti-dsDNA levels or showed persistently negative results. Six of these patients developed a
relapse. There were 46 patients who demonstrated a significant
rise in their anti-dsDNA levels. Of the latter patients, 22 were
randomized to receive early treatment and only 2 of them
developed a relapse, whereas in the group of patients who were
not treated at the time of the rise, 20 of 24 relapsed. Total and
mean daily dose of corticosteroids during the study period
were comparable in both groups. These data not only confirm
our previous findings, that rises of anti-dsDNA are related to
subsequent relapses, but also show the clinical significance of
measuring levels of anti-dsDNA in the followup care of
patients with SLE.
C. G. M. Kallenberg, MD
H. Bootsma, MD
P. E. Spronk, MD
E. J. ter Borg, MD
R. H. W. M. Derksen, MD
L. Kater, MD
University Hospitals of Groningen and Utrecht
Groningen and Utrecht, The Netherlands
To the Editor:
We read with great interest the article by Dr. Esdaile
and colleagues, in which, from their analysis (l),the authors
concluded that fluctuations in laboratory test values are poor
predictors of disease exacerbations in systemic lupus erythematosus (SLE). This conclusion was based on a retrospective
analysis in which results of laboratory tests were evaluated at 9
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In a previous study (2) referred to by Esdaile et al, we
systemic lupus erythematosus: why some tests fail. Arthritis Rheum
39:370-378, 1996
prospectively followed up a cohort of 72 SLE patients. Plasma
2. Ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CGM:
samples were drawn from these patients every 4 weeks and
Measurement of increases in anti-double-stranded DNA antibody
assessed for levels of anti-double-stranded DNA (antilevels as a predictor of disease exacerbation in systemic lupus
dsDNA) by 3 different assays, and for complement C3 and C4
erythematosus: a long-term, prospective study. Arthritis Rheum
fractions. In those patients who were positive for anti-dsDNA
33:634-643, 1990
at the time of a flare (82%), flares were predicted by a rise in
3. Bootsma H, Spronk PE, Limburg PC, Gmelig Meyling FHJ, Kater
levels of anti-dsDNA in 87% of patients when the '''1 recomL, Derksen RHWM, Kallenberg CGM: Prevention of relapses of
binant dsDNA Farr assay was used. The other tests used to
systemic lupus erythematosus by treatment with corticosteroids
detect anti-dsDNA levels (enzyme-linked immunosorbent asbased on changes of anti-ds DNA levels: a long-term controlled
prospective study (abstract). Arthritis Rheum 37 (suppl 9):S368,
say and indirect immunofluorescence) and those used to
1994
determine C3 and C4 fractions were less sensitive.
4. Bootsma H, Spronk PE, Derksen R, de Boer G, Wolters-Dicke H,
In this study, inter- and intraassay variability in all test
Hermans J, Limburg P, Gmelig Meyling F, Kater L, Kallenberg C:
results were carefully controlled and significant rises were
Prevention of relapses in systemic lupus erythematosus. Lancet
predefined, based, in part, on the variabilities of the assays
345:1595-1599, 1995
themselves, which are not mentioned in Dr. Esdaile's study.
Median time between a significant rise in levels of anti-dsDNA
and flare of the disease was 10 weeks. This means that most of
the rises would have gone undetected if the analysis had been
To the Editor:
restricted to test results at 9, 6, and 3 months preceding the
We appreciate the interest of Dr. Kallenberg and
relapse, as was performed in Dr. Esdaile's study.
colleagues in our article, which described the ability of 9
The usefulness of our approach was shown in a recent
individual laboratory tests, performed in a hospital's clinical
study, the results of which were presented at the 1994 annual
laboratories, to predict subsequent flares in activity of SLE. In
scientific meeting of the American College of Rheumatology
their letter, Kallenberg et a1 principally review their work on
(3) and were published last year (4); this study was not
anti-dsDNA tests performed in a research setting. As they
mentioned by Dr. Esdaile et al. In this study by Bootsma et al,
note, we cited their study (l),which found that determinations
performed in 2 university hospitals, we prospectively followed
of anti-dsDNA levels using a standardized assay performed at
up 156 SLE patients. Their plasma was assessed for levels of
least monthly was highly predictive of subsequent flares in
anti-dsDNA using the aforementioned Farr assay every 4
disease activity. We also cited the work of Swaak et a1 (2,3),
weeks. Again, significant rises were predefined and, once they
who found that measurement of anti-dsDNA levels was of
occurred, were reconfirmed by another plasma sample taken
LETTERS
394
value in predicting flares in SLE activity, and also referenced
studies by Abrass et a1 (4) and Petri et a1 (5) that did not
achieve these results.
We did not cite the article by Bootsma et a1 (6),
although it has been cited in a forthcoming article that focuses
specifically on the role of immunologic tests in predicting
disease exacerbations in SLE (7). As Kallenberg et a1 note,
there were significantly more relapses in the conventional
treatment group than in the early treatment group in the study
by Bootsma et al. Relapses were classified as minor or major.
The majority of the relapses in the conventional treatment
group (13 of 20 relapses) were minor. No patient in the early
treatment group sustained a minor relapse. It is important to
note that the definition of a minor relapse was based on the
need to start administration (or presumably, increase the dose)
of prednisone or immunosuppressive agents. When a patient’s
anti-dsDNA level rose, he or she was randomized to receive
either early treatment or conventional treatment. Those randomized to receive early treatment had their dose of prednisone increased by 30 mg/day immediately. Thus, the patients
in the early treatment group would be unlikely to need a
further increase in the dose of prednisone and would be almost
ineligible to have a minor relapse. When the anti-dsDNA level
rose, those randomized to the conventional treatment group
did not have their dose of prednisone raised until after they
had a relapse. In that case, according to their definition, the
outcome could be counted as a minor relapse.
The similarity in the definition for the treatment
intervention and for the outcome poses something of a problem for interpreting the results. The astute clinician is likely to
ask: Did the use of prednisone early, before a clinical relapse
occurred, result in less prednisone being used? In their letter,
Kallenberg et a1 state that the “total and mean daily dose of
corticosteroids during the study period were comparable in
both groups.” However, in the text of the article by Bootsma et
al, the authors report that the “mean daily doses of prednisone
differed significantly between the conventional and early treatment groups (median 10.0 vs 15.3 mg/day; p = 0.025). The
cumulative doses of prednisone did not differ significantly
(4515 vs 8052 mg; p = 0.068)” (6). Thus, while early intervention with prednisone following a rise in anti-dsDNA level
reduces subsequent clinical relapses, it does so at the cost of an
increased dose of prednisone. Whether or not this is desirable
is moot. Nonetheless, we do agree that this is an important
study.
John M. Esdaile, MD, MPH
University of British Columbia
Vancouver, British Columbia, Canada
Michal Abrahamowicz, PhD
Lawrence Joseph, PhD
Todd MacKenzie, Msc
Yin Li, MSc
Deborah Danoff, MD
McGill University
Montreal, Quebec, Canada
1. Ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenberg CGM:
Measurement of increases in anti-double-stranded DNA antibody
levels as a predictor of disease exacerbations in systemic lupus
erythematosus: a long-term, prospective study. Arihritis Rheum
33:634-643, 1990
2. Swaak AJG, Groenwold J, Aarden LA, Statius van Eps LW,
Feltkamp TEW: Prognostic value of anti-dsDNA in SLE. Ann
Rheum Dis 41:388-395, 1982
3. Swaak AJG, Groenwold J, Bronsveld W Predictive value of
complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis 45:359-366, 1986
4. Abrass CK, Nies KM, Louie JS, Border WA, Glassock RJ: Correlation and predictive accuracy of circulating immune complexes
with disease activity in patients with systemic lupus erythematosus.
Arthritis Rheum 23:273-282, 1980
5. Petri M, Genovese M, Engle E, Hochberg M: Definition, incidence,
and clinical description of flare in systemic lupus erythematosus: a
prospective cohort study. Arthritis Rheum 34:937-944, 1991
6. Bootsma H, Spronk PE, Derksen R, de Boer G, Wolters-Dicke H,
Hermans J, Limburg P, Gmelig Meyling F, Kater L, Kallenberg C:
Prevention of relapses in systemic lupus erythematosus. Lancet
345:1595-1599, 1995
7. Esdaile JM, Joseph L, Abrahamowicz M, Li Y, Danoff D, Clarke
AE: Routine immunologic tests in systemic lupus erythematosus: is
there a need for more studies. J Rheumatol (in press)
Dermatomyositis, hepatocarcinoma, and hepatitis C:
comment on the article by Weidensaul et a1
To the Editor:
Weindensaul et al reported the association of polymyositis (PM), anti-Jo-1 antibodies, pulmonary fibrosis, and
hepatitis C infection (1). We describe herein the association of
anti-Jo-1 antibodies, dermatomyositis (DM), and hepatocarcinoma in a patient with hepatitis C infection.
The patient, a 73-year-old man, was admitted to the
hospital with progressive painless musculoskeletal symptoms
and dysphonia. Beginning 3 months before admission, weakness of his shoulders, arms, and legs and problems in swallowing food had gradually developed. There was no fever,
Raynaud’s phenomenon, or arthritis, and he had no history of
liver disease or blood transfusions.
On examination, he generally appeared well, but heliotropic erythema, Gottron’s papules, and a nontender hepatomegaly of 20 cm were present. Musculoskeletal evaluation
revealed marked weakness of all proximal muscle groups.
Results of a complete blood cell count were normal.
The creatine phosphokinase level was 545 units/liter (normal
50-150), and liver function test results were normal. Thyroid
function was normal, and findings of a serologic evaluation for
human immunodeficiency virus was negative. Fluorescent
antinuclear antibodies were positive at titer of 1:320 with
a speckled pattern, and anti-Jo-l antibodies were positive by
immunodiffusion. Cryoglobulins were negative. Electromyographic findings were compatible with proximal myopathy.
Muscle biopsy showed a predominantly lymphocytic infiltrate
in the perivascular and interstitial areas surrounding myofibrils
with minimal fiber destruction, compatible with DM. Chest
radiography results were normal.
Abdominal echography and tomography showed a left
liver mass of 8 cm. Biopsy revealed neoplastic cells of a
hepatocarcinoma. The a-fetoprotein level was 1,140 units/liter
(normal <lo), hepatitis B virus antigen was negative, and
hepatitis C virus (HCV) antibodies were positive by enzymelinked immunoabsorbent assay. Hepatitis C viremia was confirmed by the detection of HCV messenger RNA using reverse
transcriptase polymerase chain reaction amplification.
Treatment with steroids and azathioprine was started,
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