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Treatment decisions in systemic lupus erythematosus.

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283
TREATMENT DECISIONS IN
SYSTEMIC LUPUS ERYTHEMATOSUS
CODY K. WASNER and JAMES F. FRIES
Rheumatologists and nephrologists were surveyed, by the use of specifically designed case histories,
regarding their management of selected aspects of systemic lupus erythematosus (SLE). Treatment was individualized on a case by case basis by the vast majority of
respondents. There was agreement on the initial treatment of SLE involving mild arthritis, active nephritis, or
central nervous system disease and on steroid tapering
practices. There was disagreement about treatment of a
“serologic flare” and the management of late-stage nephropathy. Academic centers were more selective and
less aggressive than practicing subspecialists. Areas of
concordance document current standard treatment
practices but sometimes show dissociation between the
degree of consensus and the level of available medical
knowledge.
Systemic lupus erythematosus (SLE), a multisystem disease of variable manifestations, is characterized by exacerbations and remissions, frequently involving different organ systems. Treatment can differ
drastically between patients at different stages and with
different presentations. To help determine how these
various situations are treated by practicing physicians
and how clinical and laboratory information influences
these decisions, the following survey was undertaken.
Supported in part by the Northern California Chapter of the
Arthritis Foundation.
Address reprint requests to Cody K. Wasner, MD, Division
of Clinical Immunology and Rheumatology, University of Alabama
in Birmingham, University Station, Birmingham, Alabama 35294.
Submitted for publication July 20, 1979; accepted in revised
form November 15, 1979.
Arthritis and Rheumatism, Vol. 23, No. 3 (Marcb 1980)
METHODS
Eight clinical histories were carefully constructed to
represent problems faced in the treatment of systemic lupus
erythematosus patients. Physicians were given pertinent laboratory and clinical information and asked to select the initial
appropriate treatment from different treatment alternatives.
The survey questionnaire was sent to 100 rheumatologists (of
approximately 600 listed), 100 nephrologists (of approximately 800 listed), and 100 allergist-immunologists (of approximately 1200 listed) selected at random from the Directory of Medical Specialists ( 1 ) .
This directory of subspecialty certification represents
well over 99% of those certified for 1975-1976. Ten university
or academically affiliated medical centers well known for their
work in SLE and with large SLE patient populations were
also sampled. Their rheumatology program directors were
asked to respond with management most typical for their institution. No followup requests were sent, and the only incentive for returning the questionnaire was that a report of the
results would be sent to those who responded.
RESULTS
Of the 100 rheumatologists, 61 responded and 5
were returned (not forwardable). Thirty-six of the 100
nephrologists responded, 7 were returned (not forwardable), and 3 returned saying they did not treat SLE patients. Certified allergists frequently reported they did
not manage SLE patients, and less than 10% of those
sampled answered the entire questionnaire. The results
from this group were not further analyzed. The mean
number of SLE patients followed per year was 20
(range 3-75) for rheumatologists and 9 (range 0-30) for
nephrologists while the average number of years since
training was 7 (range 1-22) and 8 (range 0-30) respectively.
The following directions were provided. “To
help assess tre’atment philosophy we have prepared ex-
284
WASNER AND FRIES
1
I
I
I
60 KG PATIENT
ACTIVE MEMBRANOPROLIFERATIVE NEPHRITIS
W
z
E
2
0
w
9
RHEUMATOLOGISTS
NEPHROLOGISTS
0
30 -
0
40
10 -
-
20
I
I
1
1MO
ZMO
3M0
I
1
I
4M O
5M0
6M0
Figure 1. For case 7, steroid tapering schedules chosen in mg/day of
prednisone over a 6 month course of treatment. Brackets are standard
errors.
amples of eight typical problems faced in treatment of
SLE. All the pertinent history have been verified. Please
list initial treatment responses which would be most
typical of your experience. You may use more than one
treatment in each case, or no treatment. Please respond
regardless of how often you have actually encountered
this clinical situation.” Treatment alternatives for the
first 6 cases were 1) acetylsalicylic acid (ASA) or other
nonsteroidal drugs, 2) prednisone or its equivalent, 3)
immunosuppressive or cytotoxic drugs, or 4) no treatment. Other options could be written in. Summarized
case histories and results follow. The patient was a 60 kg
woman for all cases.
Case one: Mild arthritis and mild rash. A young
female with mild rash and metacarpophalangeal arthritis had normal renal function and serologies (except for
a positive FANA). She had no previous treatment.
Rheumatologists (98%) and nephrologists (100%) uniformly agreed that the treatment for mild arthritic
symptoms of SLE should involve aspirin and/or hydroxychloroquine and should not involve prednisone.
Case two: Early nephritis. A patient with normal
creatinine and creatinine clearance and no previous
treatment developed a mildly abnormal complement
and DNA binding and a urinalysis containing 3+ protein, and 6 RBC/HPF. Kidney biopsy was refused.
Findings of early nephritis resulted in prednisone being
chosen in the majority of cases (Table I). The dose selected was quite variable, ranging from 15 to 80 mg/day
with 42% choosing 40 mg or less. Twenty-one percent
withheld prednisone at this time; comments indicated
that the respondents would watch closely and gather serial information, mesumablv to establish a trend before
treatment.
Case three: Active progressive nephritis. A
creatinine rise from 1.0 mg%
- to 1.5 mg%
- in 2 months
with many RBC casts in the urine and 3.6 gm of protein/24 hours highlighted this patient’s problems. Her
blood pressure was normal. Serum C3 was reduced and
DNA binding was increased. Active nephritis was uniformly treated with prednisone (Table 1) with 36% of
the nephrologists adding immunosuppressives, compared to 8% of the rheumatologists.
Case four: “Serologic flare.” This patient, after
6 months of mild arthritis controlled by ASA, had normal renal function and urinalysis. Serial serologies over
the last 3 months had shown C3 decreasing to low levels
and DNA binding increasing to abnormally high levels.
Case 4 was controversial, with no consensus on the appropriate treatment (Table 1). Forty-three percent of
rheumatologists and 53% of nephrologists chose prednisone as their treatment but when the decision to treat
was made, there was still a wide range of variability in
the prednisone dosage chosen (15-60 mg/day).
Case five A C N S episode. A patient with mild
arthritis, pleurisy, and normal renal function for the last
,.
Table 1. Treatment responses (percent)
Case
Respondent
Prednisone
Early nephritis (case 2)
Rheumatologists
Nephrologists
Rheumatologists
Nephrologists
Rheumatologists
Nephrologists
Rheumatologists
Nephrologists
R heumatologists
Nephrologists
82
60
90
64
43
57
92
76
56
23
Active nephritis (case 3)
“Serologic Bare“ (case 4)
CNS disease (case 5)
Late stage nephropathy
(case 6)
_ _ ~ _ _ _ _
Prednisone
and immunosuppressives
Aspirin
or
no treatment
-
18
31
9
9
36
21
16
26
-
57
43
8
3
28
51
TREATMENT OF SLE
18 months presented with two seizures (grand mal).
Evaluation revealed a low grade fever and central nervous system (CNS) finding of increased protein, 9
lymphs, and no organisms. CAT scan showed no abnormal findings. Treatment was started with antibiotics and
anticonvulsants. The patient had not been on immunosuppressants or steroids in the past. High dose prednisone (mean 140 mg/day) was chosen by the vast majority of the physicians (range 40-2000). Twenty-one
percent of the nephrologists would add immunosuppressives (Table 1).
Case five B: CNS episode, progressive. In spite
of treatment, the patient became semicomatose and developed a right hemiparesis over 3 days. In this situation, prednisone was uniformly increased to over 200
mg/day with 22% of rheumatologists and 30% of nephrologists adding immunosuppressives.
Case six: Late stage nephropathy. After 8 years
of lupus nephritis, this patient had azotemia and hypertension. With previous steroid treatment, serum creatinine was 3.5 mg% (one year ago), but she had no treatment or followup for this last year and now returns with
a creatinine of 7.8 mg%. She has minimal arthritis and
no skin rash. Serum C3 is 85 mg% (normal 110-200),
DNA binding is 15% at 1 : 10 (normal t20), and urine
sediment reveals 2+ protein, 3 RBC/HPF, and no casts.
A patient with late stage nephropathy was another difficult area for respondents. They were divided
between attempting treatment or no treatment and
whether or not to use immunosuppressives (Table 1).
Those recommending no treatment frequently suggested dialysis as an alternative.
Case seven: Steroid treatment. Respondents
were asked to construct a steroid treatment schedule for
a patient with early diffuse membranoproliferative SLE
nephritis and no previous treatment. They were to assume a “typical” clinical response over the 6-month period. Figure l shows that both physician groups demonstrated similar tapering practices. Dosage schedules
differed however, with rheumatologists using divided
daily doses more frequently (12 to 18%) and using alternate day schedules less frequently, (24 to 44%).
Case eight: Flare on treatment. A patient on tapering prednisone doses, after a flare of lupus nephritis
3 months ago, now develops early cushingoid changes,
active urinary sediment, rising creatinine, arthritis, noninfectious fever, and pleurisy. Treatment was modified
by all respondents. Prednisone was increased by all and
immunosuppressives were added by 73%. Azathioprine
was used most frequently, followed by cyclophosphamide, and chlorambucil by a few physicians.
285
Table 2. Comparison of treatment by physicians at University
Centers to treatment by specialists
Prednisone used (%) by
97 specialists
Case I: Mild SLE
Case 2: Early nephritis
Case 3: Severe nephritis
Case 4: Serologic flare.
Case 5: CNS lupus
Case 6: Late nephropathy’
Case 8: Flare on treatment?
2
19
97
46
93
64
19
10 academic
centers
0
I0
90
10
70
22
80
P c 0.4 Fisher exact test.
t Immunosuppressives used (%).
University treatment compared. The comparison
of treatment at university centers with that of the specialists who responded can be seen in Table 2. Significant differences in treatment practices were seen in case
4 and case 6.
Analysis of the results in relation to the number
of years since training, location of training, or number
of SLE patients seen per year revealed no clear pattern.
DISCUSSION
Treatment practices varied widely depending on
the individual characteristics of each case. The degree
of agreement between specialists is striking especially in
the case of CNS lupus. Although studies demonstrating
the benefit of steroids in CNS lupus have never been
performed, clearly the consensus of those responding is
that prednisone should be used, in high doses, in this
situation. This phenomenon may represent desperation,
but the dissociation between knowledge and certainty of
treatment (as expressed in consensus) is striking.
A difficult problem was presented in case 4
where a serologic flare occurred in the absence of symptoms. This difficulty can be seen not only by lack of
agreement on treatment but by the wide range of dosages selected once one had decided to treat. Recently,
Gladman et a1 (2) reported a series of patients followed
for over 10 years with markedly abnormal serologic values but no clinical signs of disease. The results suggest
that this subset of patients does not necessarily need
prednisone treatment. The university centers apparently
agree with this conclusion, most (900/0)of them choosing
not to treat the patient of case 4. It is interesting that
these centers were instrumental in popularizing these
serologic tests as an early guide to treatment, yet now
pay less attention to the results than do the practicing
specialists.
286
Differences between different specialty groups
occurred in a few instances with nephrologists using immunosuppressives more frequently in some instances,
using alternate day steroids earlier and more frequently,
and treating late stage lupus nephropathy less aggressively. Nephrologists of course see a somewhat different
population of patients. Late stage nephropathy patients,
with whom nephrologists are familiar, have frequently
failed on steroids and are referred for dialysis, and thus
less corticosteroids might be used in this situation. Or,
nephrologists may be more familiar with the failure to
respond to medical therapy in this setting and less reluctant to switch reliance to dialysis procedures.
These results should be considered only an approximation of treatment practices. The return rate of
the questionnaire, although high, suggests some selection biases. Those familiar with the disease seemed
more likely to respond; for example, allergists had a
very low return rate and those allergists responding said
they rarely saw SLE patients. Rheumatologists, who on
the average saw the most SLE patients, also had the
highest return rate. Sampling from the Direcrory of
Medical Specialists also eliminated many physicians in
practice before the advent of subspecialty boards, those
choosing not to be certified, and those just recently
graduated. A cross section of experience was obtained,
however, with over 33 different training programs and
all major geographic areas of the United States represented.
Questionnaire responses give a picture of how a
sample of subspecialists respond to certain clinical and
WASNER AND FRIES
laboratory features of SLE. Responses suggest that even
in some areas which have been difficult to study, such as
CNS lupus, there is still a consensus upon treatment. In
other areas such as serologic flare of disease without
clinical disease, or in late stage nephropathy, disagreement remains concerning the best treatment, despite growing evidence and academic center perception
that corticosteroid treatment should be employed very
selectively, if at all, in these settings.
Surveys of treatment philosophy, as in this study,
ofl'er a means to estimate the community standard of
treatment at a particular time, and to suggest areas in
which distribution of new medical knowledge should be
improved through medical school or postgraduate education. We hope this sample technique, using specific
model cases, has further applicability, especially in diseases and treatment areas where controlled trials are not
available.
ACKNOWLEDGMENTS
We thank the rheumatologists, nephrologists, and allergists who responded to our survey.
REFERENCES
I . Directory of Medical Specialists, 1975- 1Y76. Fifteenth edition. Chicago, Marquis Who's Who, 1976
2. Gladman DD, Urowitz MD, Keystone EC: Serologically
active clinically quiescent SLE: a discordance between
clinical and serological features. Am J Med 11:210-216,
1979
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