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

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2083
LETTERS
American Board of Medical Specialties to adopt the concept of
recertification. Certification has been and will continue to be
important in the managed care arena, and memberships,
contracts, and reimbursement will be dependent on such. In
addition to the ABIM’s certification and recertification, the
American Medical Association is in the process of establishing
a physician performance assessment program. Market and
consumer pressures for physician accreditation are great, and
it is best that our peers in medicine administer these programs,
rather than some private or governmental agency, with the
attendant financial and/or political consequences. This is not
the time to challenge a system that has been developed by and
is administered by our own peers.
Certification and recertification are imperfect measures of high-quality, compassionate patient care. The ACR
needs to be certain that academic, clinical, and research
rheumatologists assist the ABIM in this evolutionary testing
process and that we properly prepare our members for certification and recertification examinations. I would encourage
the ACR members in Mississippi and elsewhere in the US
(including those of us who were certified prior to 1990) to
prepare for the examinations, pass the examinations, and
position ourselves for the challenges that lie ahead in a
changing health care system. “United we stand-divided we fall!”
Arthur L. Weaver, MD, FACP, FACR
Lincoln, NE
President, American College of Rheirtnatology
Comment on the American College of Rheumatology
guidelines for osteoarthritis of the knee and hip
To the Editor:
T h e American College of Rheumatology (ACR)
guidelines on the treatment of osteoarthritis (OA) of the knee
and hip summarized in ACR News (October 1995; 14[10]:1-3)
contain a number of thoughtfully developed approaches to the
comprehensive care of osteoarthritic disorders that are particularly relevant to O A of the knee and hip. They also contain
one item that I felt was not as carefully thought out and is
potentially detrimental to the management of OA of the hip.
The guideline in question is, “The efficacy of intra-articular
corticosteroid injections in hip osteoarthritis has not been
studied. In some patients, however, these injections are useful.
This technically difficult procedure should be performed by a
rheumatologist, orthopedist, or radiologist under fluoroscopic
guidance.”
I have done well over 500 intraarticular hip joint
injections in the past 30 years without fluoroscopic guidance.
These injections have been performed to relieve pain and
improve function in patients with O A of the hip. In the
majority of cases, they have met their objectives without
complications. Granted, there are times when one cannot
aspirate synovial fluid for analysis. Where this is critical, as in
the diagnosis of septic arthritis or possibly a crystal-induced
arthropathy, fluoroscopic confirmation of needle placement is
an appropriate option. The technique of intraarticular hip joint
injection is illustrated in Moskowitz’s Osteoarthritis Diagnosis
and Medical/Surgical Management (Second edition. Philadel-
phia, WB Saunders, 1992, p. 505). The illustration is taken
from Steinbrocker and Neustadt’s Aspiration and Injection
Therapy In Arthritis and Musculoskeletal Disorders: A Handbook
on Technique and Management (New York, Harper and Row,
1972). The hip injection technique is straightforward, and if the
anatomic landmarks are carefully observed, the injection is
only slightly more difficult than injecting a knee or shoulder
joint.
The publication of these criteria impose upon the
patient (and/or the managed care provider) increased cost and
radiation exposure and create a third problem for the clinician,
which is that not to follow the guidelines would make him o r her
vulnerable to malpractice litigation.
I strongly urge that this matter be rethought and
revised, lest unintended consequences befall many of us who
endeavor to provide the best possible treatment for our
patients with OA o r noninfectious inflammatory arthropathies
of the hip joint. Intraarticular hip joint injections can be
performed in order to avoid or defer surgery in patients in
whom this option either is not desired or is contraindicated, to
minimize the risk of nonsteroidal antiinflammatory drugs, and
to help relieve pain and improve function when acetaminophen or other drugs are not adequate.
Robert L. Swezey, M D
The Arthritis and Back Pain Center
Santa Monica, CA
Laboratory tests as predictors of disease
exacerbations in systemic lupus erythematosus:
comment on the article by Esdaile et al
To the Editor:
In their article on the use of laboratory parameters as
predictors of disease exacerbations in systemic lupus erythematosus (SLE), Esdaile and colleagues reached the conclusion
that frequent testing of serum samples is not necessary because
parameters such as anti-DNA do not fluctuate in relation to
disease activity (1). This conclusion takes us at least 20 years
back in time, to when this concept generally prevailed. However, during the last 20 years, many groups have shown the true
existence of such correlations, provided that precise criteria
about the definition of exacerbation, serum sampling, and
laboratory methodology have been met. This is exactly where
the analysis by Esdaile and coworkers failed.
In 1979, Swaak and colleagues published the first study
in which a longitudinal approach involving anti-DNA measurement was used to follow up patients with SLE (2). In this study,
it was found that exacerbations of SLE can be predicted on the
basis of increasing anti-DNA levels. These findings were later
extended (3,4). Subsequently, it was found that the correlation
between onset of disease exacerbation and peak in anti-DNA
level depended, in part, on a qualitative parameter, i.e., the
avidity of the anti-DNA. Although high-avidity anti-DNA, as
measured with the Farr assay, correlated very well with clinical
exacerbations, low-avidity anti-DNA did not (5,6).
More recently, the correlation between anti-DNA levels and clinical exacerbations was confirmed by Ter Borg and
colleagues (7,8). Last year, Bootsma et a1 even published a
study in which they showed that relapses of clinical flares of
2084
LETTERS
SLE can be prevented by starting treatment of the patients in
an early phase based on increasing anti-DNA levels (9).
Several points may explain why Esdaile et a1 failed
where others have succeeded. In the first place, the definition
of exacerbations in SLE has to be concise. Esdaile and
colleagues performed a retrospective study of patients seen
between 1977 and 1992. They used a 6-point rise in the SLE
Disease Activity Index (SLEDAI) score over a 3-9-month
period as the definition of a flare. However, they must have
accredited SLEDAI points to patients retrospectively, since
the index did not exist at the time they sampled their patients
(10,ll). This being very dangerous in and of itself, the situation
becomes more complicated because the SLEDAI is meant as a
method of expressing the disease activity at one point in the
course of the disease, and, therefore, is difficult to use as a
scoring system to identify clinical exacerbations.
Second, to obtain reliable measurements of anti-DNA
levels, the test that is used (Farr assay) must be quantifiable. A
mere 1-sample measurement and expression in percentage
binding (between 0 and 100) is unacceptable as a means of
quantitation. Sera must be titrated and the level of anti-DNA
expressed in IU/ml (based on the World Health Organization
standard WoBO [ 121) to allow comparison of antibody levels.
Esdaile and colleagues, unfortunately, did not express antiDNA levels in such a way.
A third point of relevance is the frequency of serum
sampling. To obtain good insight regarding fluctuations in
anti-DNA levels, it is indeed of great importance to sample
sera from individual patients in regular, small intervals. This
implies measurement of anti-DNA at least every 4-6 weeks.
The authors compared the mean of values obtained 9,6, and 3
months before the flare. Furthermore, we and others have
reported several times in the literature that it is not the level of
anti-DNA that indicates upcoming exacerbations, but the
change in anti-DNA level. Therefore, each patient has to be
evaluated separately, as opposed to calculating mean levels
and comparing them as Esdaile and colleagues have done.
In conclusion, we believe that we have answered the
question posed as a subtitle on the article by Esdaile and
colleagues: some tests fail because they are not performed
adequately. The readers of Arthritis & Rheumatism should be
aware that prospective, longitudinal measurement of serologic
parameters in SLE, provided that it is performed properly, can
be of great value to the clinician and may even help to prevent
exacerbations by providing a point in time when therapy might
be started.
Ruud J. T. Smeenk, PhD
Lucien A. Aarden, PhD
Central Laboratory of the Netherlands Red Cross Blood
Transfusion Senice
Amsterdam, The Netherlands
Tom J. G. Swaak, MD, PhD
Dr. Daniel den Hoed Clinic
Rotterdam, The Netherlands
1. Esdaile JM, Abrahamowicz M, Joseph L, MacKenzie T, Li Y,
Danoff D: Laboratory tests as predictors of disease exacerbations
in systemic lupus erythematosus: why some tests fail. Arthritis
Rheum 39:370-378, 1996
2. Swaak AJG, Aarden LA, Statius van Eps LW, Feltkamp TEW:
Anti-dsDNA and complement profiles as prognostic guides in
systemic lupus erythematosus. Arthritis Rheum 22226-235, 1979
3. 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
4. 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
5. McGrath H Jr, Biundo JJ Jr: A longitudinal study of high and low
avidity antibodies to double-stranded DNA in systemic lupus
erythematosus. Arthritis Rheum 28:425-430, 1985
6. Nossent JC, Huysen V, Smeenk RJT, Swaak AJG: Low avidity
antibodies to dsDNA in SLE:a longitudinal study of their clinical
significance. Ann Rheum Dis 48:677-682, 1989
7. Ter Borg W, Horst G, Hummel EJ, Limburg PC, Kallenberg
CGM: Measurement of increases in anti-double-stranded DNA
antibody levels as a predictor of disease exacerbation in systemic
lupus erythematosus: a long-term, prospective study. Arthritis
Rheum 33:634-643, 1990
8. Ter Borg EJ,Horst G, Hummel E, Limburg PC, Kallenberg CGM:
Rises in anti-double stranded DNA antibody levels prior to
exacerbations of systemic lupus erythematosus are not merely due
to polyclonal B cell activation. Clin Immunol Immunopathol
59:117-128, 1991
9. Bootsma H, Spronk P, 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. L'mcet
345: 1595-1599, 1995
10. Bombardier C, Gladman DD, Urowitz MB, Caron D, Hsing
Chang C, and the Committee on Prognosis Studies in SLE:
Derivation of the SLEDAI: a disease activity index for lupus
patients. Arthritis Rheum 35630-640, 1992
11. Hawker G, Gabriel S, Bombardier C, Goldsmith C, Caron D,
Gladman D: A reliability study of SLEDAI: a disease activity
index for systemic lupus erythematosus. J Rheumatol20:657-660,
1993
12. Feltkamp TEW. Kirkwood TBL, Maini RN, Aarden LA: The first
international standard for antibodies to dsDNA. Ann Rheum Dis
47:740-746, 1988
To the Editor:
We welcome the opportunity to reply to the letter by
Smeenk and colleagues. Our article addressed the value of 9
commonly ordered hematologic and immunologic tests for
predicting lupus exacerbations. Smeenk et a1 express concern
that we were not able to reproduce their results (1,2) and the
work of others (3) with regard to changes in 1 of the parameters we evaluated, levels of anti-double-stranded D N A
(anti-dsDNA).
Smeenk et al suspect that we had calculated the
SLEDAI (4) scores retrospectively. There is no need to suspect
this, since we stated that we had done so in the Patients and
Methods section, and that this was one reason for using the
SLEDAI. We also presented, in some detail, our efforts to
validate that a change in the SLEDAI of 6 points was an
indication of actual exacerbation, described the modifications
that we made to the SLEDAI to increase the validity of our
determination that a flare was present, and reported that we
had reviewed every flare identified, blinded to laboratory data
(except for urinalysis data), to confirm that no errors had
occurred. Finally, as was noted in our article, others have
LETTERS
considered a flare to be a rise in the SLEDAI of 2 2 or -3
(5,6). Thus, given the reduced maximum of our modified
SLEDAI (maximum 74 rather than l05), a rise of 6 almost
certainly represented a flare.
Smeenk et a1 also suggest that the study was retrospective. In fact, as was stated in our article, we collected the data
prospectively using standardized forms and definitions. We
had not noted that 1 of the authors (JME) had participated as
a member of the committee that developed the SLEDAI in
1985, that the SLEDAI definitions were based on the American College of Rheumatology glossary, which was developed,
in part, by this same author (7,8), or that these same definitions
were the basis for the prospective collection of data for the
lupus registry. The sole reason for obtaining the number of
laboratory tests we did, with the frequency we did, was with a
view to testing their clinical value. We required permission to
do so from the Director of the Immunology Laboratory, on the
understanding that we would evaluate the clinical utility of the
tests.
Smeenk et a1 suggest that the SLEDAI is meant as a
“method of expressing the disease activity at one point in the
course of the disease, and, therefore is difficult to use as a
scoring system to identify clinical exacerbations.” This statement does not reflect the intent of the committee that developed the SLEDAI in 1985. Furthermore, it is contradicted by
a 1992 article that provides a description of the SLEDAI (4),
and by subsequent studies that have found the SLEDAI to be
an appropriate measure for assessing changes in disease activity in SLE (5,9-11).
Smeenk and colleagues point out, quite correctly, that
Swaak et a1 (1,2) and Ter Borg et a1 (3) have found that
anti-dsDNA levels are a predictor of flares. We noted this and
cited other studies that did not reach this conclusion. Swaak et
a1 found that anti-dsDNA, expressed as unitdm1 after comparison against a standard, and measured every 4-6 weeks, was
100% sensitive and 100% specific for both nephritis and
non-nephritis flares. Ter Borg et a1 found that anti-dsDNA,
expressed as units/ml after comparison against the W0/80
standard, and measured monthly, was >90% sensitive and
specific for nephritis flares. These results are exceptional for
any laboratory test in any disease. We agree that the more
frequent testing and the use of a standard may have contributed to the better results reported by these authors for
anti-dsDNA levels. Given the costs of performing immunologic tests in North America, the increased concern about how
limited health care dollars are spent, and the out-of-pocket
costs to patients for monthly visits, it seems reasonable to
demand a greater degree of certainty before advising physicians that monthly testing for anti-dsDNA levels against a
standard is necessary. Further work to test the specific hypothesis seems required. We have discussed these issues in detail in
a companion paper (12).
In addition, Smeenk et a1 seem confused about our
analytic methods. We and the reviewers believed that we had
presented the analytic techniques in excruciating detail.
Briefly, we did not evaluate overall means as a method of
predicting flares in individual patients. The laboratory test data
at 9, 6, and 3 months before a flare were evaluated for each
patient as an individual and were analyzed to identify whether
any systematic pattern of within-patient changes preceded the
flare. The mean values at the time of first flare and over the
2085
entire disease course were presented as part of our evaluation
of why laboratory tests are so frequently considered useful in
cross-sectional studies, while longitudinal studies have produced what we referred to as inconsistent results.
John M. Esdaile, MD, MPH
Mary Pack Arthritk Centre
and Vancouver Hospital
University of British Columbia
Vancouver, BC, Canada
Michal Abrahamowicz, PhD
Lawrence Joseph, PhD
Todd MacKenzie, MSc
Yin Li, MSc
Deborah Danoff, MD
Montreal General Hospital
McGill University
Montreal, Quebec, Canada
1. Swaak AJG, Groenwold J, Aarden LA, Statius van Eps LW,
Feltkamp TEW: Prognostic value of anti-dsDNA in SLE. A n n
Rheum Dis 41:388-395, 1982
2. Swaak AJG, Groenwold J, Bronsveld W: Predictive value of
complement profiles and anti-dsDNA in systemic lupus erythematosus. A n n Rheum Dis 45:359-366, 1986
3. Ter Borg EJ, Horst G, Hummel ELI, Limburg PC, Kallenberg
CGM: Measurement of increases in anti-double-stranded DNA
antibody levels as a predictor of disease exacerbation in systemic
lupus erythematosus: a long-term, prospective study. Arthritis
Rheum 33:634-643, 1990
4. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH,
and the Committee on Prognosis Studies in SLE: Derivation of the
SLEDAI: a disease activity index for lupus patients. Arthritis
Rheum 35:630-640, 1992
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. Urowitz MB, Gladman DD, Farewell VT, Stewart J, McDonald J:
Lupus and pregnancy studies. Arthritis Rheum 36:1392-1397,1993
7. American Rheumatism Association Glossary Committee: Dictionary of the Rheumatic Diseases. Volume I: Signs and Symptoms.
New York, Contact Associates, 1982
8. American Rheumatism Association Glossary Committee: Dictionary of the Rheumatic Diseases. Volume 11: Diagnostic Testing.
Bayport, New York, Contact Associates, 1985
9. Guzman J, Cardiel MH, Arce-Salinas A, Sanchez-Guerrero J,
Alarcon-Segovia D: Measurement of disease activity in systemic
lupus erythematosus: prospective validation of 3 clinical indices. J
Rheumatol 19:1551-1558, 1992
10. Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Bombardier
C, Isenberg D, Kalunian K, Liang MH, Maddison P, Nived 0,
Richter M, Snaith M, Symmons,D, Zoma A: Sensitivity to change
of 3 systemic lupus erythematosus disease activity indices: international validation. J Rheumatol 21:1468-1471, 1994
11. Fortin PR, Abrahamowicz M, Danoff D: Small changes in outpatient lupus activity are better dekected by clinical instruments than
by laboratory tests. J Rheumatc$22:2078-2083, 1995
12. Esdaile JM, Joseph L, Abrahadbwicz M, Li Y, Danoff D, Clarke
AE: Routine immunologic tests@ systemic lupus erythematosus:
is there a need for more studied J Rheumatol (in press)
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