LETTERS TO THE EDITOR 473
Wedgewood that not only did we apply the
ac-tuarial analysis to our own experience in iupus
erythematosus but piior to that we also used it
to study the outcome of chronic ulcerative coli-tis in children.’
G. B. STIciuER, M.D.
E. C. BURKE, M.D.
REFERENCES
1. Meislin, A. G., and Rothfield, N. : Systemic
lupus erythematosus in childhood : Analysis of
42 cases, with comparative data on 200 adult
cases followed concurrently. PEDIATRICS, 42: 37, 1968.
2. Hagge, W. W., Burke, E. C., and Stickler,
C. B.: Treatment of systemic lupus
erythe-matosus complicated by nephritis in children.
PEDIATRICS, 40:822, 1967.
3. Good, R. A., Venters, H., Page, A. R., and
Good, T. A. : Diffuse connective tissue
dis-eases in childhood with a special comment on
connective tissue diseases in patients with
agammaglobulinemia. J. Lancet, 81:192,
1961.
4. Michener, \V. M., Gage, R. P., Saner, W. G.,
and Stickler, G. B. : The prognosis of chronic
ulcerative colitis in children. New Eng. J.
Med., 265:1075, 1961.
EDIToR’s NOTE : Doctors Meislin and
Roth-field comment as follows:
So long as the diagnosis of SLE is based on
an overall view of the entire clinical picture
with assistance from various laboratory tests
such as LE cells, antinuclear antibodies, and
skin and renal biopsies, there will be problems
in arrivmg at a definitive diagnosis and the
in-evitable semantic arguments” will continue to
arise. We welcome Drs. Stickler and Burke’s
letter, which provides the opportunity to fur-tlier clarify our concept of SLE.
Criteria for diagnosis of SLE were set forth
in our second paragraph of the section entitled
Discussion,1 in as precise a manner as we feel
tile disease permits at the present state of
knowledge. We further stated, “all patients
fulfilled tile criteria set forth by Dubois.”2
In-deed, our criteria were more restrictive than
Dubois’ since we specifically included multiple
system involvement as a prerequisite for
diag-nosis and inclusion in our series. This we feel
automatically excluded cases of RA with
posi-tive LE cell test and discoid LE with positive LE cell test (though three cases of discoid lupus which evolved into SLE were included in our series).
Our concept of “rheumatoid arthritis with a
positive LE cell test” is not firm, and we
ap-proach tile entire subject with profound
humil-ity. Judging from the frequently reported
de-layed appearance of multi-system involvements
and the frequently delayed emergence of SLE,
it would not surprise us if this entity were to
become another of the many faces of SLE.
Nonetheless, we agree with Dubois and with
the correspondents that it is important to keep
this group separate and excluded from SLE, as
we have done. Perhaps renal biopsies would be
helpful in resolving the nature of this problem
as suggested by the work of Poilak, et al. and
Dubois alld n’5
We deliberately avoided the term,
drug-in-duced lupus, employing drug-associated or
drug-related disease instead, since we are not
certain of the etiologic relationship, something
we speculated upon in our article. Four cases
of possible drug-related disease were included
in the series (three treated with INH and one
On anti-convulsants
)
. Three of these fourexpe-rienced progressive active disease, two with
fatal outcomes, following discontinuation of
drug therapy as stated in our discussion. This
represents a much graver prognosis than
cx-pected from “drug induced lupus,”0 indeed it
is a poorer prognosis than we observed in the
non-drug related disease.
Seven of 39 patients had BUN elevation by
the time of diagnosis and renal disease was
considered present in 22 of 42 patients at
diag-nosis based upon urinalyses. The overall
mci-dence of renal disease was 29 of 41 cases, or
71% of cases followed. This incidence is lower
than that reported in most pediatric series
(Table I) . Variation exists and the published
series are small, but it is remarkable that four
of the six series indicate renal involvement
within relatively narrow limits of 71 to 82% of
cases. Noteworthy are the different bases for
defining renal disease-urinalysis, Addis count,
renal function tests, and renal biopsies-which appear to be relevant to the incidence of renal disease reported.
The incidence of renal involvement in repre-sentative adult series of SLE varies from 46.1% to 65t.8 Our own experience in a previous study
showed renal disease in 29 of 52 lupus patients
(56%) ages 8 to 80, all present at the first
ob-servation,9 and in our current studyl 51 of
200 adults had lupus nephritis. Though age
.lge (yr)
5-13
5-15 3-15 6-19 2-16
<15
4-18
<14 <15 1
25
‘27
TABLE 1
INcIl)EN(E OF RF:N%I. INVOLvEMENT IN (‘iiiimioon SLE
‘Vu,,,ber ,
Renal ‘c 11(0(11
of . . t 010 iiu’nl.v
- Dtsea.c Dixea.se
Patzen1.
11 5 451 Lower incidence than heart or lung illvolvelnent.
15 10 67% Throughout course.
41 ‘29 7l/ ‘2’2/4 (5’2%) at onset; based on clinical findings.
‘21 15 71% 56/9() in total series, ages 6-70.
30 3 77% Renal involvenient questionable in four cases
with no significant proteinuria.
.5’2 Inclusive of the 35 cases repoited in 1963,6 vlich iflclude(l seven cases of “drug-induced liipus.”
18 Characteristic cases of SLE with uiiiforni clinical iIfl(l lal) pi(ture.
37 33 89’
11 ii looc/2) l4nse(l on 1)iol)sies and electron Illicroscopic
studies; three of 1 1 ilad nornial uriiies
474 LETTERS TO THE EDITOR
indicated 110 correlation between age and
in-cidence of renal disease.bo
The correspondents’ criteria for diagnosis”
are identical with our own, except that lOfYt
of their patients had positive LE preps and
ESR elevation while our figures were 90% and
80%, respectively, by the time of diagnosis. Of
the four patients in our series with negative LE
preps at diagnosis, three subsequently
devel-oped positive LE preps, and one had skin,
sub-cutaneous nodule, and renal biopsies
compat-ible with SLE, strongly positive ANA, and died
within 6 months of diagnosis of renal failure
and pneumonia. All had serious multisystem
disease and indicate to US tile propriety of
mak-illg the diagnosis of SLE in the absence of a
Positive LE prep, if other overwhelming
cvi-dence of the disease is present. Newer
tech-niques, such as antinuclear antibody
determina-tiOIls, may enhance the reliability of diagnosis,
but complete accuracy awaits the isolation of
an etiological agent.
We are therefore compelled to dispute the
statement that we are presenting “data on a
group of diseases considered to be SLE.” What
we may very well be doing is broadening the
clinical spectrum of juvenile SLE as seen by
Drs. Stickler and Burke. With the description of the LE cell phenomenon at the Mayo Clinic
in 1948,12 the concept of SLE was enlarged
from a rare, fulminating disorder of
pleo-morphic nature. Our study simply supports the
case against the more restricted concept of
childhood SLE as a generally rapidly fatal
dis-ease, almost invariably associated with severe
renal disease.
Our statement that proteinuria and hematu-na were present in “most patients’ applied to
a discussion of patients with renal disease and
not to the entire series. We apologize for the
ambiguity.
All attempt should be made to explain tile
differences observed in childhood SLE in New
York and Minnesota. We cannot exclude the
possibility of geographical differences, and the
entire ecology of SLE bears illvestigation. For example, the incidence of SLE in Rochester,
Minnesota, has been reported to be greater
tilall ill New York City or Sweden;1’ and its
in-cidence in England is lower than ill the United
States.” Also, racial differences may exist.”
Almost half of our series were non-Caucasian. A point must also be made for geographical
and institutiollal i)ias. A large, rural, referral
center will attract more seriously ill patients
with poorer prognosis, whereas the urban mcd-ical center such as our OW with its
surround-ing dense population viIl draw a broader
spec-trum of freshly diagnosed disease-from
be-nign to rapidly fatal-though criteria for
diag-nosis remam the same.
Therapy was described in detail with
spe-cific dosage schedules under the heading
enti-tied “Treatment.” Empirical therapy was that dosage sufficient to control disease activity. All
patients were treated with prednisone, most
with antimalarials as well; therefore, we were
LETTERS TO THE EDITOR 475
the disease. At present, our clinical impression is that long-term chioroquine treatment is
help-ful in controlling disease activity. Since no
con-trolled studies were done, we cannot offer
ob-jective evidence for this impression. Analysis of
chloroquine effect is currently under study in
patients whose drug was discontinued due to
ocular toxicity.”
Actuarial treatmeilt of the data and
compu-tatioll of life tables and survival rates are not
lldW to the medical literature” nor to SLE.””
However, we feel that construction of survival
models based on a numerically small
experi-ence renders the data more intelligible than
re-porting raw survival probai)ihties based on
similar numbers. The models also permit more
meaningful graphic comparison between series
of patients when survival data is treated in the
same way.
AARON G. MEISLIN, M.D.
NAOMI ROTHFIELD, M.D.
REFERENCES
1. Meislill, A. G., and Rothfield, N. : Systemic
lupus erythematosus in childhood. Analysis
of 42 cases, Witil comparative data on 200
adult cases followed concurrently.
PEDIAT-RICS, 42:37, 1968.
2. Dubois, E. L. : Lupus Erythematosus. New
York: McGraw-hill Inc., 1966.
3. Kievitz, J. H., Gosiings, J., Shuit, H., and
Hijmans, W. : Rheumatoid arthritis and the
positive L.E. cell phenomenon. Ann. Rileum. Dis., 15:211, 1956.
4. Pollak, V. E., Pirani, C. L., Steck, I. E., and
Kark, R. M. : The kidney in rheumatoid ar-thritis: Studies by renal biopsy. Arthritis
Rheum., 5:1, 1962.
5. Berman, L. B., and Dubois, E. L. : Renal
biopsy in rheumatoid arthritis with L. E.
cells. (Ahst.) Arthritis Rheum., 5:283, 1962.
6. Jacobs, J.: Systemic lupus erythematosus in
childhood. PEDIATRICS, 32:257, 1963.
7. Dubois, E. L., and Tuffanelli, D. : Clinical
manifestations of systemic Itipus
erythemato-5115. J.A.M.A., 190:104, 1964.
8. lIarvey, A. I., Shulman, L. E., Tumult, A.,
Conley, C. L., and Schoenricll, E. H. :
Svs-temic lupus erytllenlatOsus : Review of the
literature and clinical analysis of 138 cases.
Medicine, 33:291, 1954.
9. Rothfleld, N., McCluskey, H. T., and Baldwin,
I). S. : Renal disease in systemic lupus
er\-thematosus. New Eng. J. Med., 269:537,
196.3.
10. Urowitz, M. B., Stevens, M. B., and Shulnlan,
L. E. : The influence of age of the clinical Pattern of systemic lupus erythematosus.
(Abst.) Arthritis Rheum., 10:319, 1967.
11. Hagge, \V. W., Burke, E. C., and Stickler,
G. B.: Treatment of systemic lupus
erythe-matosus complicated by nephritis in
chil-dren. PEDIATRICS, 40:822, 1967.
12. Hargraves, M., Richmond, H., and Morton, R.:
Presentation of two bone marrow elements:
The “tart” cell and L. E. Cell. Proc. Staff
Meet. Mayo Clin., 23:25, 1948.
13. Nobrega, F. T., Ferguson, R. H., Kurland, L. T.,
and Hargraves, M. : Population studies of
the rheumatic diseases. In Bennett, P. II.,
and Wood, P. H. N., ed. : Exerpta Medica
Foundation, 1968.
14. Bywaters, E. G. L., and Scott, J. T. : Progress
in clinical rheumatology. in Dixon, A. S. J.,
ed. : Systemic Disease of Connective Tissues.
Boston: Little, Brown and Company, p. 130, 1964.
15. Siegel, M., and Lee, S. L. : The epidemology
of systemic lupus erythematosus: Results of
a population study in New York City.
Pro-ceedings of the Third International
Sympo-sium on Population Studies of the
Rheu-inatic Diesases, New York, June 1966.
16. Rothfield, N. : Unpublished data.
17. Berkson, J., and Gage, R. P.: Calculation of
survival rates for cancer. Proc. Staff Meet. Mayo Clin., 25:270, 1950.
18. Merrell, M., and Shulman, L. E. :
Determina-tion of prognosis in chronic disease illu5-trated by SLE. J. Chronic Dis., 1 : 12, 1955. 19. Kellem, R. E., and Haserick, J. R.: SLE-A
statistical evaluation of mortality’ based on a
consecutive series of 299 patients. Arch. In-tern. Med., 113:92, 1964.
20. Zetterstroni, R., and Bergiund, C. : Systemic lupus erythematosus in childhood: a clinical
study. Acta Paediat. ( Stockholm), 45:189,
1956.
21. Grihetz, D., and Henley, W.: Systemic lupus
erythematosus in childhood. J. Mount Sinai
Hosp. N.Y., 26:289, 1959.
22. Soffer, L. J., Southren, A. L., Weiner, H. E.,
and Wolf, R. L. : Renal manifestations of
systemic lupus erytheniatosus : a clinical and
pathologic study of 90 cases. Ann. Intern.
Med., 54:215, 1961.
23. Hanson, V., and Kornreich, H. : Systemic
rheu-nlatic disorders in childhood. Bull. Rheum.
Dis., 17:435, 1967.
24. Jacobs, J. C. : Lupus erythematosus with
ne-phritis. PEDIATRICS, 42:369, 1968.
25. Peterson, R. D. A., Vernier, R. L., and Good,
R. A. : Lupus erythematosus. Pediat. Clin. N. Amer., 10:941, 196,3.
26. Cook, C. D., Wedgwood, R. J. P., Craig, J. M.,
Ilartmann, J. R., and Janeway, C. A.:
Svs-temic inpus erytllenlatosus. Description of
37 cases in children and a discussion of
endocrine tilerapy in 32 of the cases.