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Observations on the course and treatment of systemic lupus erythematosus.

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Observations on the Course and Treatment of Systemic
Lupus Erythematosus
By MORRIS
ZIFF, PAULESSERMAN
AND CURRIER
MCEWEN
Long-term clinical and laboratory studies
of 24 cases of systemic lupus erythematosus provide additional information concerning the nature of this polysymptomatic disease. Positive rheumatoid serologic tests were observed in 28 per cent
of patients tested. Antimalarial drugs
seemed to benefit most patients.
Perdurative studios clinic e labotatorial
in 24 casos de systemic lupus erythematose provide informationes additional in
re le natura d e iste morbo polysymptomatic. Le tests rheumato-serologic esseva
positive in 28 pro cento del casos assi
stiidiate. Drogns antimalarial pareva
beneficiar certes del patientes.
T
WO FACTORS have influenced the apparent life history of systemic lupus
erythematosus (S.L.E.) in recent years. The application of the L.E. cell
test as a diagnostic aid has brought milder forms of the disease under observation. The introduction of steroid therapy has prolonged life by tiding patients
over acute crises and has permitted observation of the disease through repeated episodes of remission and relapse. It is accordingly, of value to review
certain aspects of the course of S.L.E., as observed during recent years in the
light of these new influences.
The reports of benefit from the use of antimalarials*-*in the treatment of
chronic discoid lupus erythematosus suggested ii trial of these drugs in the
treatment of the disseminated form of the disease. Our experience gives support to the view that qiiinacrine and chloroquine are effective agents when
used in combination with adrenal steroids. These results, previously reported
in abstract," are presented here in detail. Additional information pertinent to
the long-term management of S.L.E. by steroid and combined therapy is
also presented.
PATIENT
SAMPLE
Between 1950 and 1956, 24 patients with S.L.E. were observed on the Third Medical
Division ( New York University) of Rellevrio Hospital. Some patients had been treated
previously at other institutions, hut all were under oiir observation for the major part of
their clinical course, which ranged from sevcral months to five years. There were 20
females and four males; the agc at onset ranged between 13 and 61 (table 1); 15 of the
patients were white, eight negro, and one Chinese.
Duration of dbease.-This has brcn dated from the time of the first evidence of systemic
manifestations. Periods of prior discoid lripiis erytheniatosns in foiir patients and a prolonged arthritis resembling rheumatoid arthritis, in one. were not included in dating the
From the Department of Aferlicinc cind Study Group on Rheumatic Diseases, New York
University College (if Medicine, New Y o i k , N . Y.
Supported by grants from the i\.lasotric Founrtation for Medical Research cind Human
Welfare ( i d the Natiotuil Institute of Arihritis and A1 etabolic Diseases, U . S . P . 1 l . S . Grunt
A-679.
One of the authors (7if.Z.) i s Senior Znwstigcrtor, Arthr
cind Rheumatism Foundation.
332
333
S.L.E.: OBSERVATIONS ON COURSE AND TREATMENT
TABLE1.-Age
ut Onset of Systemic Lupus Erythematosus
Aae
f w e .)
Number of
Patients
10-20
2130
31-40
41-50
51-70
6
8
5
2
3
onset. Duration ranged between six months and nine years (table 2). The longest period
of survival in the surviving group was 5.5 years.
Seoertty of diseclse.-When the activity of the disease was graded on a 1 + to 4+ scale
according to the criteria listed below, 19 of the 24 patients showed 4-1 activity at some
time in their course, two patients 3+ activity, and three 2+ activity. The severity varied
markedly in individual patients, ranging in some between 4+ and 0.
Manifestations.-The manifestations of S.L.E. were graded as follows:
GRADE
++++
+++
++
+
0
Acute, life-threatening illness (lupus crisis),
Severe illness, with temperatures above 102" F., and accompanied by
severe manifestations usually in more than one organ system.
Moderately severe illness involving one or more organ systems with temperatures up to 102" F.
Mild illness with low-grade fever and minor manifestations in one or more
organ systems.
Clinical remission, with or without maintenance therapy, except for the
fact that the erythrocyte sedimentation rate may remain elevated and
the L.E. cell test positive.
Laborutoly methods.-The
following determinations were done at regular intervals:
erythrocyte sedimentation rate ( E.S.R. ) by the Westergren method; C-reactive protein test;
L.E. cell test by the Zimmer-Hargraves clot method' and by a modification5 of the method
of Schultz, Baum and Ziffa; Coombs test; measurement of phenolsulfonphthalein excretion
and endogenous creatinine clearance; and sensitized sheep cell agglutination and inhibition
tests on the euglobulin fraction.'
Management.-During the acute stages of the disease, prednisone in doses of 40 to 60
mg. daily or cortisone in comparable doses was administered to suppress the acute manifestations rapidly. In extremely ill patients, higher doses were administered during periods
of marked activity. In the case of psychotic patients, electroshock treatment was added to
the regimen when indicated.
To evaluate the effect of antimalarials, the following plan of treatment was carried out.
After the acute symptoms were controlled with steroids, the dosage of the latter was
gradually reduced, i.e., by 2.5 mg. decrements every two days in the case of prednisone
or by 12.5 mg. in the case of cortisone, until the lowest possible dose capable of suppressing clinical signs of activity was reached. At this point, chloroquine diphosphate (Aralen)
TABLE2.--Uirrotion
of
Systemic
~ U p f l SErythetncltostls
in 24 Patients
Number of Patients
Years
0-2
2-4
4-6
Ala've
Dead
Total
5
5
2
2
1
10
10
5
3
'
6
0
6-10
Total
14
"Whereabouts of one patient unknown.
8
1
24
334
ZIFF, ESSERMAN AND MC EWEN
in a dosage of 500 mg. daily or Atahrine in a dosage of 100 mg. daily was added to the
regimen. Usiially these were administered for ten days, and then further reduction of the
steroid dosage at a rate of approximately 2.5 mg. every two to three days was initiated.
When the lowest effective dosage level of \teroid was reached, the patient waq discharged
to the Out-Patient Department on the required maintenance dose of steroid plr~s cither
chloroquine (500 mg. daily) or Atnbrine ( 100 mg. daily).
At each out-patient visit, an attempt was made to reduce the dosage of strroid. On
occasion, the antimalarial drug was withdrawn to evaluato its potentiating effect. In R
few patients, steroid was eliminated and chloroquine alone c o n t i n l d Two patients were
treated with chloroquine alone from the onset.
OBSERVAT~ONS
Type of onset.-Polyarthritis was the most common initial manifestation
(table 3), occurring in 50 per cent of the patients. It was frequently present
for considerable periods prior to diagnosis, in six instances between three and
30 years. Facial rash led to early diagnosis in the five patients in whom it occurred. In two patients, the presenting clinical picture was that of acute nephritis and in one a biologic false positive reaction for syphilis was found prior
to the onset of symptoms. Four patients had had discoid lupus erythematosus
prior to the onset of S.L.E. (table 4 ) for periods ranging from five to 31 years.
Patterns of recurrent activity.-The utilization of suppressive therapy has
provided an opportunity to observe the disease in a number of episodes of remission and exacerbation. It was noted that there were characteristic patterns
of recurrent activity for individual patients. For example (table S), one patient
had arthralgias, facial rash arid mouth ulceration with development of mild
activity, and on each of the six occasions that she had a severe relapse she
developed high fever with psychosis, in addition. Knowledge of the characteristic manifestations of recurring activity for each patient was a distinct help
in management because it permitted anticipation of an exacerbation sooner
than otherwise.
Arthritis
Nineteen patients had some form of joint manifestation in the course of their
disease. Four had arthralgias only, four acute transient polyarthritis, five moderately prolonged episodes of arthritis, and six chronic deforming arthritis
resembling that seen in rheumatoid arthritis.
In the latter six patients, the chronic arthritis had existed from four to 30
years prior to the emergence of systemic manifestations of S.L.E. Until this time
TABLE3.-lnitMl
Mutlifes$ations of Systemic Lupus Erythematosus
_-
Number
Manifestat ion
Polyarthritis
Facial rash"
Discoid lupus erythematosus
"Nephritis"
Biologic false positive test
for syphilis
"Not including discoid facial rash.
of
l'ntients
RPfore Diagnosis
Median Duration
Range of Duration
Refore Diagnoeis
(YrS.)
(YrS.1
2
1.3
0-30
0-0.8
130
0.8-2
1
1
?
12
5
4
1
0
c
S.L.E.:
335
OBSERVATIONS ON COURSE AND TREATMENT
TABLE
4.-Systemic
Patiewi
Lupus Erythemutosi~sFollowing Chronic Diwoid Lupus Erythetnutosus
Age
Duration
Discoid
Disease
(Yrs.)
hl
54
31
F
16
5
Sex
Clinical
Evidence of
Dissemina Lion
L.E.
Cell
Tent
+
~
AX.
-___J.C.
R.V.
I?
32
EM.
F
32
Arthralgia, Fever,
C.H.F., Hematuria,
Elevatrd E.S.R.,
Elevated B.U.N.
Psychosis, Arthritis,
-0
Fever, Retinopathy,
Hematuria,
Elevated E.S.R.
12
Psychosis, Arthralgia,
Fever, Retinopathy,
Splenomegaly,
Leucopenia, Ilematuria,
-- Elevated E.S.R.
7
.4rthritis, Fever,
Lencopenia,
Elevated E.S.R.
+
Length of Time
Front Onset
of Hormone
Therapy to
Death (Hoe.)
9
___15
24
+ ______
24
'S.L.E. proved at autopsy.
TABLE5.-Chnrmteristic
Patient
Patterns of Recrrrrrnt Activity in Three Patients
Additional
Sqmptonur
Mild Activity
G.R.
Low grade fever; Arthralgias; Facial
rash; Ulcerations of buccal mucosa
and hard palate.
High Fever
Psychosis"
P.McC.
Arthralgias; Salivary gland enlargement and tenderness; Pigmented facia1 lesions.
A.McK.
Low grade fever; Arthralgias.
High Fever
Psychosis
Facial rash
Acute arthritis
High Fever
Pnmmonia
Pleiirisv
N o . of
Times
Repeated
-6
3
3
'Attempted suicide on three occasions.
they had been considered to have rheumatoid arthritis. In three, x-ray changes
like those seen in rheumatoid arthritis were present. In three of the five patients
of this group on whose sera the sensitized sheep cell agglutination test was
carried out, the test was positive. The manifestations which were taken as
evidence for the diagnosis of S.L.E. in the six patients are given in table 6. It
is to be noted that in all cases there was evidence of systemic disease in addition to a positive L.E. cell test.
Sensitized sheep cell agglutination tests were done on the euglobulin fraction of the serum of 18 patients (table 7 ) who had had some form of joint
manifestation in the course of their disease. Four, or 22 per cent, showed positive tests by the direct agglutination procedure and five, or 28 per cent, by the
-
j ~c~ISTOPY.E-9'S
.
HCISPITAL
336
ZIFF, RSSEHMAN A N D MC EWEN
TABIX6.---S~stemic Munifestutions at Time of Diugnosb of S.L.E. in Patients
with Prcceding Chronic Arthritis"
m 1ien I
Diiration Pn'or
Arthritir
(years )
B.S.
Type of
Arthritts
-___
chronic
deforming
chronic
deforming
chronic
deforming
chronic
deforming
31
R.S.
9
P.C.
5
K.J.
4
C.R.
5
Apylutination
Tent
+
Systemic?
Manifestations
Myocarditis, pericarditis
pneumonia, pleurisy
Fever, myocarditis, renal
disease
Fever, rash, alopecia, renal
disease, myocarditis
Continued high fever, renal
disease, congestive heart
failure
High fever, pleurisy
-_
+
-
+
chronic
deforming
N.n.1
Fever, rash, confirmatory
chronic
C.N.
4.5
deforming
autopsy findings!
-"All patients had positive L.E. cell tests at tinie of diagnosis of S.L.E.
t Splenic arteriolar cuffing, pericarditis, pleurisy.
1N.D. = not done.
TABLEi'.-Sen.dtized
Jrnnt
Manrfestation
Arthralgias
Acute
transient
Moderately
prolonged
Chronic
Total
Sheep Cell Agglutination und Inhihition Tests in
Systemic Lupus Erythemutosics
N o . of
Patients
Inhihition
Agglutinn f ion
Pos.
Neg.
PO%
4
0
4
0
4
4
0
4
0
4
5
5
18
1
3
4
4
2
2
14
3
3
2
13
5
Neg.
inhibition method. The titer of the agglutination test did not vary with the
clinical activity of the disease.
It is noteworthy that all of the patients with a positive sheep cell agglutination test fell into a group that had either a prolonged course of arthritis or
chronic rheumatoid-like arthritis. It would appear, therefore, that the more
pronounced the arthritis in patients with S.L.E. the more likely i s the agglritination test to be positive. An exception to this, however, was seen in one
patient who had had chronic deforming arthritis of the hands for four years
with a negative agglutination test.
In recent years the dividing line between S.L.E. and rheumatoid arthritis
has become less distinct. A number of investigatorsR*"have reported a signifi
cant incidence of positive L.E. tests in patients with classic rheumatoid arthritis. In this clinic," eight patients of 70 tested have given positive tests, an
incidence of eleven per cent. In the positive sheep cell tests here reported, we
see evidence of the overlap of the serum abnormalities of the two diseases from
the other direction.
S.L.E.: OBSERVATIONS ON COURSE AND TREATMENT
337
Psychosis*
There was a higher incidence of psychosis in this group than in other series
(table 8 ) , since psychosis was present in 13 of 24 patients or 54 per cent. This
reflects the unusual circumstance that the N.Y.U. Division of Bellevue Hospital has psychiatric wards to which psychotic patients known to have S.L.E.
were transferred from other institutions.
The effects of steroid therapy on the course of psychosis (table 9) were
studied in eleven patients. The psychiatric diagnosis at the time of admission
in eight patients was “steroid-induced psychosis.” In the other three, who had
not received previous steroid therapy, the diagnosis was “organic psychosis
caused by S.L.E.”
In the first group of eight patients with the diagnosis of steroid-induced
psychosis, six improved dramatically when the steroid dosage was raised to
levels adequate to control the activity of the disease, although three received
electroshock therapy concomitantly. All three patients in the second group,
with the diagnosis of organic psychosis caused by S L E . , improved draniatically when treated with steroids in adequate dosage. In no patient did an
increase in the dosage of steroid aggravate the psychosis. The fact that improvement occurred in nine of eleven patients following administration of
steroid in a dosage adequate to control clinical activity suggests strongly that
many, if not most, psychoses in patients with S.L.E. are due to the activity of
the disease rather than to the steroid. Doubtless there are patients in whom
psychosis is either steroid-induced or caused by latent psychoses of other types
which become overt under the stress of serious illness. In such patients, it
would be anticipated that suppressive therapy adequate to control physical
symptoms would not alleviate the psychosis.
H e r d DZseme
This was graded according to the following criteria.
Minirnul to mild renu1 diseuse: Presence of iiiiniiiiiil iiriniiry findings \uch as 1+
to 2+ albuniinuria with or without occasional microscopic heinaturia; no decrease
in phenolsulfonphthalein ( P.S.P.) ewretion and creatinine clearance; nonnal
B.U.N.
Moderute renu1 disease: Presence of inoderately severe urinary findings such as 3+
to 4+ albuminuria with or without persistent microscopic hematuria; P.S.P.
excretion between 10 and 20 per cent in 15 minutes or a creatinine clearance
between 50 to 75 cc. per minute; B.U.N. normal.
Seljsre renul diseuse: Urinary findings which vary between moderate and severe;
P.S.P. excretion less than 1 0 per cent in 15 minutes, or creatinine clearance less
than 50 cc. per minute, or B.U.N. elevated.
Progression.-Four patients (table 10) did not demonstrate evidence of
renal involvement at any time during observations over periods of 6, 12, 36, and
60 months. There was no albuminuria, and endogenous creatinine clearance,
*A detailed report of this phase of the study is being prepared by Dr. Marvin Stem of
the Department of Psychiatry, who was responsible for the psychiatric care of the patients.
338
ZIFF, ESSERMAN AND MC EWEN
TABLEb.-Reported
Incidence of Psychosis in Systemic Lupus Etythernutosus
Sen'=
_____
1. Ziff, Esserman and McEwen'
No. Patients
<nSeriea
No. with
Pwchoain
Peychoas
%with
24
13
54
62
15
24
105
20
19
44
4
9
-
(1956)
2. Diibois"'
(1953)
3. Harvey et al."
(1955)
4. Jessur et al?*
(1953)
TABLE
9.-Effects
Initial Diaanoein
of Pnychoaim
of
Steroid Therapy
No. of
Pts.
Steroid-induced
psychosis
3
Organic psychosis
caused by S.L.E.1
3
on
Psychosis tn Eleven Patients'
Remlts Followinn
Increased Steroid Doaaoe
Courne
No. Pta.
Cleared
Cleared with
concomitant
electroshock
Ihubtfully improved
Unimproved
3
Cleared
3
3
1
1
'One patient with senile psychosis did not receive steroids; a rrcond was treated elsewhere with undetermined results. These are not included here.
t No prior steroid therapy.
P.S.P. excretion and B.U.N. remained within normal limits. Eight showed
minimal to mild renal disease when first observed, and after a period of observation ranging from six months to nine years (average 3.9 years) only three
patients showed progression of this manifestation. Twelve patients had moderate renal disease at the outset, and when observed for six months to five years
(average 2.7 years) only two showed evidence of progression. The latter two
ultimately died of uremia, one after one yeiir and the second after 2.5 years
despite administration of steroids in doses adequate to suppress other clinical
evidence of S.L.E. In two patients the disease began with the clinical picture
of acute nephritis, which subsided concomitantly with administration of
steroid, leaving mild to moderate urinary findings.
It was an unexpected finding that in the entire group of 24 patients of whom
20 had renal disease when first examined, only five showed evidence of progression of renal involvement during the period of observation. It would
S
may
appear from this that the renal changes in systemic ~ L I ~ Uerythematosus
go for long periods without progression in many patients. The data are not
sufficient, however, to permit conclusions as to whether steroid or combined
therapy was effective in preventing progression. Hypertension was manifested
by only five patients, and by four of these only while receiving moderate to
large dosage of steroids. Detailed observations on the effect of steroids on
blood pressure are available on 12 patients who were receiving maintenance
doses of cortisone above 100 mg. daily or 85 to 40 mg. of prednisone daily.
339
S.L.E.: OBSERVATIONS ON COURSE AND TREATMENT
TABLE10.-Progression of Hem1 Disease in 24 Patients with Systemic Lupus Erythematosus
Renal Status
.when Renal Mseaac
First Observed
No renal disease
Minimal to mild
renal disease
Renal StatuR
when Lant Observed
No. of
Pts.
No. of
Pts.
4'
No renal disease
~~Minimal renal disease
8t
Moderate renal disease
Severe renal disease
4
Minimal renal disease
Moderate renal disease
Severe renal disease
1
9
~12#
Moderate renal disease
TOTAL
No. with
Progsesmun
0
.
5
2
1
3
2
I.
24
5
Average duration of observation:
'2.4 yrs. ( 0 ~ 5 - 5 )
t3.9 yrs. (0.5-9)
42.7 yrs. (0.5-5)
Two patients without renal involvement showed no rise in blood pressure. In
four of ten patients with moderate renal disease, the blood pressure rose to
hypertensive levels but returned to normal when the dosage of steroid was
reduced with the aid of adjuvant chloroquine therapy. One patient who had
previously had normal blood pressure developed diastolic hypertension, which
was sustained even after reduction of the dosage of steroid.' In the rest the
blood pressure remained within normal limits.
Fluctuating a1buminuria.-Of interest was the observation that the degree
of albuminuria fluctuated between 3f and 0 in six patients in a manner unrelated to other evidence of disease activity. The urine of a typical case, for
example, contained significant amounts of albumin (1+ to 3 f ) when
examined monthly over approximately two years. Subsequently albumin could
riot be detected on three different occasions for periods as long as five months.
The degree of albuminuria was not related to the over-all activity of the
disease at the time.
Laboratory Findings
L.E. cell tests.-All but one patient had repeatedly positive tests in all phases
of activity by both the Zimmer-Hargraves procedure and the modified serum
test of Fallet and Ziff.z The single exception, who was tested only on several
occasions, showed findings characteristic of S.L.E. on autopsy. In some patients
the number of L.E. cells were roughly correlated with clinical activity but
frequently patients in therapeutic clinical remission showed strongly positive
tests.
Erythrocyte sedimeniution rate.-Systematic data on the effect of therapy
on the E.S.R. are available for 17 patients. In 10 of these, there was a significant
fall in the E.S.R. (average fall of 25 mm. or greater) following treatment for
six to 45 months, and all of these patients attained a clinical remission either
~
~~
~~
'A second patient, not tabulated here, in whom the blood pressure did not
the dosage of steroid was reduced, has recently been observed.
fall when
340
%IFF, ESSERMAN AND M C EWEN
with or without concomitant therapy. The E.S.R. reached normal levels in
three of this group. Of seven patients in whom the E.S.R. did not fall significantly, two are in clinical remission on therapy, three have died. one is in
uremia, and one has been lost to the study.
The E.S.R. was only an approximate index of the response to therapy, as
evidenced by the fact that two patients attained clinical remission without
fall in sedimentation rate, and in seven others, who attained remission of symptoms, it remained distinctly elevated. It is possible that higher doses of steroids
would have suppressed the E.S.R. further, but in the treatment of the present
group of patients, dosage was regulated on the basis of clinical symptomatology rather than on the level of laboratory indices.
(;-reactive protein test.-Repeated determinations13 in fourteen patients
showed positive tests in ten and negative tests in four before institution of antimalarial and steroid therapy.* The changes in level of the C-reactive proteiii
were studied over an average period of 33 months of treatment (five to 45
months). At the end of this time, the three patients with active disease, as
indicated by clinical symptoms, showed positive tests, while among the eleven
patients in clinical remission (of whom eight were receiving steroids or chloroquine or both at the time) five gave positive tests and six negative.
It is of interest that four of the six patients in remission who had negative
C-reactive protein tests continued to have elevated sedimentation rates. I t
appeared, therefore, that the C-reactive protein concentration, though it paralleled both the clinical activity and the erythrocyte sedimentation rate,
reached normal levels in some cases while the E.S.R. remained elevated. The
reverse was not observed.
Albumin-globulin ratio.--Nine of 17 patients had reversed ratios hefore
therapy in which the albumin concentrations were low and the globillin coiicentrations frequently high. Six of the nine patients with initially reversed
A/C ratios experienced clinical remission with treatment, and all s h o w d return of the ratio to normal. In three the follow-up was not adequate. Thus, it
appeared that the A/G ratio paralleled clinical activity rather closely.
Coonibs test.-Of the ten patients who were tested by the direct Coo~nLs
test, only one had a positive result.
RESULTS
OF COMBINED
THERAPY
The dosage levels of steroid required to maintain adequate suppression of
the acute manifestations of S.L.E. are frequently high, and may be acc0111panied by serious side effects. In the patients here reported, it was possihle to
maintain adequate control of S.L.E. activity with significantly lower doses of
steroids after the administration of antimalarial drugs. This has made possible
prolonged administration of steroids at relatively low dosage levels and t t r l t ,
with less unfavorable side effects.
When chloroquine alone was administered to two patients with milt1 systemic activity (+),the disease appeared to be satisfactorily controlled, but
___
~
_
_
~
_
*Two of these patients arc not included in table 1 1 becanse one began strroid and chloro
quiiie therapy siniultarieously and a second received cliloroquiiie alone.
341
S.L.E.: OBSFAVATlONS ON COURSE AND TREATMENT
++++)
two patients with marked activity (
were not benefited. The failure
to observe improvement in more severely ill patients when chloroquine was administered alone led to studies of the effects of antimalarials when used concomitantly with steroids.
Antimalarials were administered to thirteen patients in conjunction with
steroids. The severity of the disease was classified as 4+ in ten of these and
3+ in the remainder. In order to evaluate the potentiating effect of the antimalarial drugs on the action of steroids, the steroid alone, either cortisone or
prednisone, was first administered to twelve patients (table 11) in a dosage
sufficient to control the activity of the disease.*
Following a variable period, usually several weeks, during which the patient
was brought under control, reduction of the dosage of steroid was carried out
stepwise (12.5 mg. every second day in the case of cortisone and 2.5 mg. in the
case of prednisone) until the lowest maintenance dosage of steroid necessary
to control symptoms was established. Effective control was considered to be
established when the patients were afebrile and otherwise asymptomatic except for minor residual joint symptoms. Continued elevation of acute phase
indices also was not infrequently present. At this point, chloroquine, or in two
cases Atabrine (see table 11), was added to the regimen. It was seen that
in these twelve patients, administration of the antimalarial drug was associated
in eleven instances with a considerable reduction of the required maintenance
suppressive dose of steroid. This occurred in all cases within approximately
six weeks from the start of the antimalarial therapy. Combined therapy has
been continued satisfactorily in 10 patients for periods ranging from six months
to two years. At the present time, all of these are asymptomatic (table 11).
With clinical remission, as indicated above, the sedimentation rate, C-reactive
protein test and A/G ratio showed considerable improvement in nine individuals and reached normal levels in three.
Combined therapy with chloroquine and prednisone was maintained in one
patient throughout the course of a successful pregnancy, and in a second with
renal tuberculosis these drugs were administered along with isoniazid, streptomycin and paraamino salicylic acid. Two of the thirteen have died, and one
continues to have active disease and is in uremia.
Of the two patients with mild activity who were treated successfully with
chloroquine alone, one, whose disease was manifested by a skin rash, mild
arthritis and albuminuria, has been satisfactorily maintained on chloroquine
for 17 months with subsidence of rash and joint symptoms but not of the
albuminuria. The second patient, who had fever, chronic polyarthritis, and
albuminuria, became asymptomatic following tieatment with chloroquine for
two months, and has remained so for two years, although the albuminuria
persists. L.E. tests remain positive in both. Two patients with markedly active
disease showed no significant improvement on chloroquine alone, as noted
above.
In three patients with markedly active (
disease who were receiving combined maintenance therapy with chloroquine and prednisone, system-
++++)
-
*The thirtarritli individual received cortisone with chloroquine from the start.
342
ZIFF, ESSERMAN AND MC EWEN
TABLE11.-Effect
of
__--
-
- -.
Chloroquine (or -4tabrine) on hlaintenance Dosage
of Steroid in Zwelce Pntients
Loweat Maintenanre Donagc
Z'atient
Before
Antimahiial
Drug Img. )
____.___
__I____________.___
~
G.H.
h1.C.
c
c
100
M.I.
E.M.
C
50
75
200
75
200
200
100
P.McC.
AA1cK.f
1'.C. f
A.M.
R.A.
N.B.
F.G.
c
c
c
c
c
H
1'
P
0"
P 15O
H 20
0
25
60
- ______
C = Cortibonc; H = Hydrocortisorie, 1'
"Antimalarial therapy tliscontinued.
1 Received Atabrinc.
{Died siibsrquently.
r
___.__
--
C 50"
C 50
c 25
C 50
C 25"#
c 37.54
C 25
300
C 175
C: R .
-
After
Antimalarial
Druw (mg. )
0
Prednisone
atic attempts were made to evaluate the effects of withdrawal of the chloroquine while maintaining the prednisone dosage unchanged. Exacerbation of
symptoms occurred in all three after periods of one to three months.
The current status of 13 patients who received combined therapy with
steroids and antimalarials is shown in table 12.
Toxic effects.-One of the two patients who received Atabrine had mild
blurring of vision which d i s a p p r e d on interrupting therapy and did not return when therapy wws resumed with chloroquine. Urticaria1 rashes were noted
in five of 14 patients who received chloroquine. Three had mild conjunctivitis.
In only one case were the urticaria1 symptoms severe enough to cause cessation of chloroquine iidministration. Atabrine was satisfactorily substituted in
this patient. Occasionally, nausea and heartburn were noted after ingestion of
chloroquine, but these were of mild degree, and were controlled by reducing
dosage to one tablet a day or by stopping therapy temporarily.
CompZicntions.-There were thirteen serious complications in ten patients.
These fell into three categories: infection, uremia and thrombosis of major
vessels (table 13).
Severe pyogenic infections were noted in five patients, of whom four died.
Only one of the patients who died had had the benefit of adjuvant antiinalarial
therapy. In three, the serious nature of the infection was not recognized until
autopsy. The infections included septicemia due to hemolytic streptococcus,
staphylococcic arthritis with septicemia and multiple small lung abscesses.
Tuberculosis occurred in three individuals, of whom one had received adjuvant antimalarial therapy. In one, the occurrence of renal findings was first
ascribed to the S.L.E. and in another the presence of disseminated tuberculosis
became known at autopsy.
Although superimposed infection has been known to be a frequent compli-
343
S.L.E.: OBSERVATIONS ON COURSE AND TREATMENT
TABLE12.-Present
Status of Thirteen Putients W h o Have Received Combined Therapy
NO.'
Statun
Pts.
In clinical remission
On: No therapy
Chloroquine alone
Steroid alone
Combined therapy
Active disease
2
2
2
10
Luboratwy Indiecn
of Inpammatio~if
NO.
Pta.
Within nonnal limits
Improved$
Essentially unchanged
4
3
6
1
~.
in uremia )
Deaths:
Uremia
Cerebellar hemorrhage
1
Worsened
1
2
Worsened
Improved
1
1
'One patient is not included in the previous table because steroid and antimalarial
therapy were begun simultaneously.
fImprovement recorded when: E.S.R.fell 23 mm. (E.S.R. > 30 nim. initially). C.R.P.
fell 2 units. A/C ratio reverted to normal.
4 Where urinary abnormalities were present, these did not necessarily disappear or
improve.
TABLE13.--Complicatu~ns in 10
of
24 Patients uith Systemic Lupus Eythemutosuu'
No. of
Complicatima
t'atienta
______.
Tupe
infection
5
Hemolytic streptococcal septicemia;t staphylococcal arthritis; t multiple lung abscesses; multiple buttock abscesses; recurrent pyelonephritis
Pyogen ic
Tuberculosis
3
Renal; pulmonary; disseminated.
Vascular
reactions
2
Cerebellar thrombosis and hemorrhage; thrombosis with
gangrene of extremity.
Uremia#
3
-
'Three patients showed two coinplications each.
tThese infections were fatal.
]Living, 1; dead, 2 (one of other cmse).
cation of S.L.E. in the past, it is likely that its incidence and severity have increased since the advent of steroid therapy. The problem is further complicated by the fact that serious infcctions may go unrecognized either because
their symptoms are ascribed to the S.L.E. or because they have been suppressed by steroid therapy.
Deaths.-There were ten deaths (table 14), only two of which occurred in
the group of 13 individuals who received combined therapy. Two patients
died in lupus crisis, two with septicemia, one with a cerebellar thrombosis and
hemorrhage, one in uremia and four of unidentified cause.
One of the deaths in lupus crisis occurred in the early days of the study, and
a second in another hospital before adequate therapy was instituted. It is the
impression of the authors that this type of death is usually preventable when
the patient is closely supervised. Both of the above instances of fatal septicemia
were recognized during life, although their severity was not appreciated till
autopsy. It may be assumed that these infections were complications of steroid
therapy.
344
ZIFF, ESSERMAN AND MC EWEN
TABLE14.--Cause
of Denth in 10 of 24 Patients with Systemic Lupus Erythemotosus
No.
Catrae
2
Lupus crisis
Septicemia
Cerebellar thrombosis and lieinorrhaye
Uremia
Cause unknown
2
1
Total
1
4
10
The progression of renal failure in tlie patient who died in uremia was unaffected by increasing the dosage of prednisone from 30 to 60 mg. daily.
Two patients, as mentioned, died while receiving combined therapy. One,
a negro woman of 31, demonstrated ii cerebellar venous hemorrhage arid
thrombosis at autopsy. Hypertension dependent on the dosage level of steroid
had been present. The second patient, who died in uremia, had previously
developed bilateral arterial thronihosis of the lower extremities, necessitating
amputation of one leg. The experience in these two patients plus subsequent
experience with patients not included in this series suggests that vascular
thrombosis may be a relatively frequent imd serious complication of S.L.E.
during prolonged steroid administration, either as a result of the disease per se
or of the therapy.
Assuming that lupus crisis and infection are recognizable and controllable
in the closely supervised patient, it would appear from the above experience
that the major hazards to long survival in S.L.E. are the development of iiremia
and vascular thrombosis. This does not imply that renal disease which has not
reached the stage of uremia is necessarily rapidly progressive.
In the past three years in a group of sixteen closely siipervised patients, of
whom thirteen received combined therapy with steroids and antimalarials,
there have been only two deaths, oiie in uremia arid oiie following cerebellar
vascular thrombosis.
DISCUSSION
The group of patients in wlioin tlie diagnosis of S.L.E. is currently being
made has increased in size. This is due in part to the introduction of the L.E.
cell test, as a result of which milder and atypical cases are being included.
Though the significance of a positive L.E. cell test is occasionally open to
differing interpretations, it appears inevitable that the use of this test will increase the number of patients included under the diagnosis of S.L.E. This,
along with the use of steroid and antimalarial therapy, has so changed the
course of the disease that it is necessary to revise previous concepts of it.
Though nineteen of the 24 patients in the present series had an acute, lifetlireatening episode chiiracteristic of full-blown S.L.E. at some time in their
course, it is noteworthy that many demonstrated atypical patterns at the onset
of their disease. Four patients, for instance, had chronic discoid lupus erythematosus for long periods before dissemination. Five patients had episodes
of moderately prolonged arthritis and five had chronic arthritis resembling
s.L.E.: OBSERVATIONS
ON CoimsE AND TREATMENT
345
rheumatoid arthritis prior to the diagnosis of S.L.E. The sensitized sheep cell
agglutination test was positive in five of the latter ten individuals. Whether the
sheep cell agglutination test was positive or negative appeared to be related
to the degree of arthritis present.
It should be pointed out that in spite of a history of arthritis and the presence
of a positive L.E. cell test, the diagnosis of S.L.E. was not made except in the
presence of convincing evidence of systemic disease (table 6). It is not known
whether the L.E. cell test was positive prior to the development of systemic
symptoms in those patients with a long history of arthritis. The fact that the
five patients who might well have been regarded as having had rheumatoid
arthritis for long periods acquired the features of S.L.E. raises a question about
prognosis in patients with uncomplicated rheumatoid arthritis and positive
I,.E. cell tests who now are so commonly seen.6,8,n
It is of interest in this connection that of 72 patients with uncomplicated
rheumatoid arthritis studied in this clinic, eight had positive L.E. cell tests.6
Thus, the relatively high incidence of positive sensitized sheep cell agglutination tests in patients with S.L.E. (table 7) and positive L.E. tests in patients
with rheumatoid arthritis, along with the other manifestations in common, such
as polyarthritis, biologic false positive test for syphilis14 and Raynaud's phenomenon,l'.lE all point to a close relationship between the two diseases.
It has been reported12v1sthat chronic discoid lupus erythematosus mav become systemic. Jessar and co-workers]' have reported that 26 per cent of their
patients with S.L.E. had previously had the chronic discoid disease. In the
present series, four patients had had the discoid form of the disease, one for
thirty years prior to dissemination. The fact that all died within two years of
the time of dissemination suggests the possibility that this type of S.L.E. may
be a severe form of the disease. Such a conclmion is not warranted on the basis
of a few cases, but further observation regarding the possibility is indicated.
Renal impairment was not clearly progressive in most patients during the
period of observation. In only five of 24 was there observable progression, and
four patients who had no evidence of renal disease at the onset had not yet
developed this manifestation after an average period of observation of 2.4
years. Two patients with the nephrotic syndrome lost their edema on steroid
therapy7 and aside from persistent albuminmia, there was no measurable impairment of renal function. It would appear from this that the nephrotic phase
of lupus nephritis may respond well to steroid therapy and is not necessarily
associated with a grave prognosis.
Three patients developed uremia, and two of these are dead. Limited experience available from these patients and others not reported here indicates that
once renal insufficiency has progressed to uremia, treatment with steroids in
doses up to 60 mg. of prednisone daily does not affect the subsequent cotme.
Though most of the deaths in this series have resulted from acute events such
as infection, lupus crisis and vascular complications, the chronic process which
appears to threaten the patient most seriously is nephritis. It remains to be seen
whether adequate maintenance therapy with steroid inhibits the rate of pro-
346
ZIFF, ESSERMAN AND MC EWEN
gression of renal disease. It is the conclusion of Muehrcke and co-workers'?
that suppressive therapy with steroids does not prevent this progression.
It is recognized that the administration of steroids raises the blood pressure
in a significant proportion of patients with renal disease and often without. It
is not surprising, therefore, that half of the patients with renal involvement in
this series developed diastolic hypertension, which in most cciscs subsided
when it was possible to reduce or eliminate steroid therapy.
Thc h$h incidence of psychosis in the patients reported here is a consequence of the special circumstance that they were drawn in goocl part from
a medical psychiatric service. Nevertheless, the iiicidence of psychosis reported
by others has ranged between nine and 24 per cent.1r'.'2-1x
There are at least
three factors which may contribute to the development of psychotic behavior in patients with S.L.E. Central nervous lesions have been frequently
described'1'.21in the form of disseminated areas of encephalomalacia, which
inay be associated with endarteritis of small arteries of the brain.'" Second, the
administration of steroids is known to induce psychosis in some individuals,
and third, the factor of psychologic stress resulting from the impact of a grave
illness may predominate. In the latter group, there may be some patients with
latent psychosis whose underlying mental illness is uncovered by the psychologic stress.
It is of interest that three of the eleven patients with psychosis had symptoms
of an organic brain syndrome which cleared concomitantly with suppression of
L.E. activity by adequate doses of steroids. Furthermore, three patients in
whom the diagnosis of steroid-induced psychosis had previously been made
also cleared when control of physical symptoms had been achieved by raising
steroid dosage, after an attempt to treat the psychosis by lowering the dosage
of steroids had been followed by no improvement. Three other patients previously thoright to have steroid-induced psychosis cleared with concomitant
shock therapy when control of the physical symptoms was achieved by the aid
of steroids. That steroid therapy was not a causative factor in the psychotic
behavior of the latter patients is suggested by the fact that dramatic improvement occurred following shock therapy although steroids were maintained at
the same or higher dosage levels.
The above observations indicated that in this group of patients with S.L.E.
and psychosis, the latter was most often a manifestation of the underlying
disease. Our experience suggests that adequate suppressive doses of steroids
he administered when psychosis occurs in the presence of symptoms of activc
disease. When the patient has been violent and uncooperative, the employment
of electroshock in conjunction with increased steroid dosage has resulted in
satisfactory remission of the psychotic episode. In the presence of osteoporosis
following prolonged steroid administration, the me of electroshock shorild be
approached with caution. Patients in whom a psychotic episode is unaccompanied by active symptoms of S.L.E. appear to have a less favorable prognosis.
Not infrequently these patients are young women whose defenses have been
broken down by the impact of illness, and in whom organic mental changes
play a minor role.
S.L.E. : OBSERVATIONS ON COURSE AND 1’REATMENT
347
Close supervision is of paramount importance in the treatment of S.L.E. It
is frequently necessary to distinguish early between increased disease activity
and infection. This problem is difficult in that the symptoms of S.L.E. imitate
those of infection, and because steroid therapy may modify the usual manifestations of infection. Three of five patients who died and were autopsied
showed evidence of severe infection unrecognized during life. When proper
antibiotic treatment is instituted, steroid dosage does not have to be reduced
in most instances. When there is no adequate antibiotic, as in the case of the
so-called “hospital staphylococcus infcetion,” the continuation of steroid
therapy in high dosage presents a serious danger.
Close supervision also makes it possible to prevent a life-threatening relapse. Intimate knowledge of the characteristic pattern of relapse for each
patient, described previously for our series (table S),permits early recognition
of the relapse.
The value of close supervision has been clearly demonstrated in this study
in terms of a decrease in the number of hospital admissions for recurrence of
activity and a diminution in the incidence of psychotic episodes in well controlled patients.
It should be pointed out, in assessing the significance of the decrease in the
maintenance dose of steroid following the addition of chloroquine or Atabrine
to the regimen, that no control data are available in which a placebo was used
in place of the antimalarial. This type of control is necessary to rule out the
factor of time in contributing to the eventual lowering of the maintenance
dosage. Control data were not obtained because most patients were seriously
ill and because a sufficient number of patients was not available. It was believed, moreover, that the initial lowering of the dosage of steroid before addition of antimalarials was sufficiently gradual and prolonged to make it unlikely
that the additional time involved in the ten day period during which antimalarial was added was a factor in permitting subsequnt lowering of the steroid
dose. It should also be pointed out that care was taken to be certain that the
patient was observed for a sufficient period to be sure that when symptoms
flared prior to the addition of the antimalarial, they were the result of relapse
and not of rebound. These precautions together with the high incidence of
favorable results observed tend to overcome, at least in part, the deficiency of
the lack of a control series and lead us to believe that this type of therapy holds
promise and deserves further evaluation. It is our impression that the patients
in the present series receiving steroids and adjuvant antimalarial therapy were
better controlled with lower steroid dosage and with less side effects than
previously observed in comparable individuals on steroid alone. Evidence of
the value of antimalarials in the treatment of S.L.E.has already been reported
by
who concluded that 80 per cent of milder cases are benefited by
antimalarials alone, and that their synergistic use with steroids often makes
possible a reduction of the steroid dose.
The mechanism by which antimalarials are of benefit in the treatment of
S.L.E. is unknown. The effects noted were relatively slow in onset. It is, therefore, unlikely that they act directly on the inflammatory reaction. Dubois2s has
348
ZIFF, ESSERMAN AND M C EWEN
shown that the L.E. phenomenon is inhibited in vitro by Atabrine at concentrations which might well exist in the patient's leukocytes during therapy.
Holman and Kunkel" have observed that the ability of white cell nuclei to
absorb the L.E. factor from serum, a vital step in the L.E. cell reaction. is
blocked by prior treatment of the nuclei with Atabrine.
There is reason to believe that the blocking of the L.E. cell reaction by an
;igent such as Atabrine could play a significant role in the amelioration of
S.I,.E. since the I,.E. cell body of the peripheral blood smear is not an isolated
manifestation of the effects of the L.E. factor. The hematoxylin bodies described by Klemperer and co-workers2zin a number of organs and tissues of
patients with S.L.E. show staining characteristics which are similar to those
of the L.E. cell body, and suggest that the effects of the L.E. factor are exerted
in the tissues as well as in the serum. Recently, Friouz'{ and Holborow, Weir
and Johnsonzi have shown by the fluorescent antibody technic that the L.E.
factor does in fact possess the capacity to react in vitro with nuclei of tissues
such as kidney cortex, thyroid gland, skin, heart muscle and spleen. It has bcen
suggested by the latter authors that the L.E. cell factor acts much as though
it were an antibody to the nuclear material of white cells and tissue cells. An
L.E. cell type of reaction could be expected to occur in tissue, therefore, either
with desoxyribonucleoprotein liberated in the process of cellular turnover or
with the nucleus of the intact altered cell directly. Either the resulting nucleoprotein-L.E. factor complex or the products of cellular breakdown could
conceivably lead to tissue inflammation. An agent capable of interfering with
the reaction between L.E. factor and nuclear material in the tissues might then
prevent this inflammatory reaction. The lag in the effects of antimalarials
\voiild be explained in terms of the time necessary to build up adequate tissue
concentrations of these drugs.
SUMMARY
1, The course of twenty-four patients with systemic lupus erythematosus is
described. Thirteen were treated with both steroids and antimalarial drugs
(chloroquine or Atabrine) and the remainder with steroid or antimalarial
drugs alone. Following the addition of antimaltirials to the regimen the required maintenance dose of steroid was significantly lower in 11 of 12 patients.
2. Chronic arthritis was present in some patients for many years before the
development of systemic symptoms. The sheep cell agglutination test bv thc
inhibition method was positive in 28 per cent of patients tested. The positive
tests were observed in those patients in whom a chronic form of arthritis was
present together with systemic manifestations of S.L.E.
3. Psychosis was, in most cases, related to the activity of systemic lupus
erythematosus, and improved when symptoms were controlled.
4. Renal involvement progressed in only five of 24 patients during the period
of observation. Hypertension was related in most cases to the presence of renal
disease and to the dose of steroid administered.
5. Though the likelihood of death due to infection and lupus crisis appeared
S.L.E.: OBSERVATIONS ON COURSE AND TREATMENT
349
to be decreased with combined therapy and close supervision, the development of uremia and vascular thrombosis, on the other hand, occurred in spite
of these measures.
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8.
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Ziff, M., Brown, P., Lospalluto, J., Badin,
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C. L., and Pollak, V. E.: Lupus
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ZIFF, ESSERMAN AND M C E W E N
of systemic and discoid liipus erythematosus. A.M.A. Arch. Int. Med. 94:
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24. Holman, H. R. and Kunkel, H. G.: Af-
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19.56.
.-. -
Arch. Path. 493,503,
26. Friou, G . : Communication to the ninth
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finity between the lupus erythematosus
serum and factor and cell nuclei and
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-, 1957.
son, C . I).: A serum factor in lupus
25. Klemperer, P., Gueft, B., Lee, S., Leuchc,rytht.m;itosiis with allhit, for tissue
tenberger, C. and Pollister, A.: Chemniidei. Brit. Med. J. ii:732, 19.57.
ical changes of wiite lup~isrrythema~~
~
~
Morris Ziff. Ph.D., M.D., fornierly Associcite Professor of Medicine, New York Uniuersittl College of Medicine, New York,
N.Y.: presently Professor of Internti1 Medicine, University of
Texas Southwestern Mecliccil School, Dallas, Tex.
Paul Essermun, M.D., Assiutunt Clinical Professor of Medicine,
New York Uniuresity College of Medicine, New York, N . Y .
Currier McEwen, M.D., Associate Professor of Medicine, New
York University College of Medicine, New York, N . Y .
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