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Serologic Abnormalities in Systemic Lupus Erythematosus Associated with Viral Hepatitis and Tuberculosis.

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Serologic Abnormalities in Systemic Lupus Erythematosus
Associated with Viral Hepatitis and Tuberculosis
Kent W. Salisbury, Paul H. Plotz, Paul V. Holland, Alfred D. Steinberg and
Mark Peppercorn
A 38-year-old Turkish woman with the clinical diagnosis of systemic lupus
erythematosus but with negative LE cell tests developed a positive LE cell
test and anti-DNA and anti-RNA antibodies coincident to manifestations of
serum hepatitis. Tuberculosis, present at the same time, may have been an
additional factor.
It has often been suggested that systemic
lupus erythematosus (SLE) and other autoimmune diseases are the result of altered immunity to naturally occurring viral infections.
There are increased titers of antibodies to several groups of human viral pathogens in
patients with SLE (1-3), and tubuloreticular
structures, possibly related to virus infection (4), are found in the kidneys (5),
skin (6), liver (7) and circulating leukocytes (8)
from patients with SLE. The infection of NZB/
NZW mice with some viruses accelerates the
course of their lupus-like illness (O), and the
anti-RNA antibodies from patients with SLE
and from NZB/NZW mice are inhibited better
by naturally occurring viral RNA than by synthetic polynucleotides (10).The effect of known
viral illness in the course of SLE, however, has
received little careful study.
We have recently observed a 38-year-old female with clinical SLE in whom the serologic
parameters of SLE developed for the first time
during an episode of HB Ag (Australia antigen)
positive serum hepatitis. Disseminated tuberculosis was present coincident to the hepatitis and
continued to be a problem after the hepatic and
serologic abnormalities had cleared.
From the Arthritis and Rheumatism Branch, National
Institute of Arthritis, Metabolism and Digestive Diseases,
and the Clinical Center Blood Bank, The National Institutes of Health, Bethesda, Md.
KENT w. SALISBURY, MD: Department of Medicine, Cardiac Unit, Massachusetts General Hospital, Boston, Mass;
PAUL H. PLOTZ, MD: Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism and Digestive Diseases, The National Institutes of Health, Bethesda, Md;
PAUL v. HOLLAND, MD: Clinical Center Blood Bank, The
National Institutes of Health, Bethesda, Md; ALPRED D.
STEINBERG, MD: Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism and Digestive Diseases, The National Institutes of Health, Bethesda, Md;
MARK PEPPERCORN, MD: Department of Medicine, Beth Israel Hospital, Boston, Mass.
Reprint requests should be addressed to: Dr. Paul H.
Plotz, Building 10, Room 9N218, The National Institutes
of Health, Bethesda, M d 20014.
Submitted for publication Nov 15, 1972; accepted Jan 8,
1973.
AG, a 38-year-old Caucasian Turkish female nurse, was
referred to The National Institutes of Health (NIH) for
evaluation of fever and hemolytic anemia. At age 18 (1953)
she developed morning stiffness and swelling of her fingers
and was told she was anemic. She had one normal pregnancy with the delivery of a full-term infant in 1963. Over
the next 6 years she had 4 miscarriages. After one of these
in 1968, she developed fever and generalized polyarthritis
and was told she had rheumatoid arthritis. She had had
Raynaud’s phenomenon. There was no history of tuberculosis though the tuberculin skin test was known to be
positive.
In May 1970, after a 6-month pregnancy, she delivered a
premature infant who subsequently died. Soon thereafter
she developed fevers (39O C), anorexia, hemolytic anemia,
hepatosplenomegaly and recurrent severe polyarthritis most
marked in left wrist and hand. The hematocrit was 13%;
the Coombs’ test was negative. There were mild pyuria and
albuminuria, high ESR, normal bilirubin, single values of
CASE REPORT
406
Arthritis and Rheumatism,Vol. 16, No. 3 (May-June 1973)
SEROLOGIC ABNORMALITIES IN SLE
SGPT 65 and SGOT 30, normal albumin and globulin, but
with mildly elevated gammaglobulin by paper electrophoresis. Liver biopsy was interpreted as normal. X-rays
showed only sltghtporosu of her left hand and wrist. A test
for rheumatoid factor and repeated LE preps were negative.
She was felt to have rheumatoid arthritis and was treated
from September 1970 to February 1971 with corticosteroids, salicylates, antibiotics and cyclophosphamide.
During the same period she received 12 .blood transfusions.
Her hematocrit stabilized, but fevers, arthritis, anorexia
and hepatosplenomegaly persisted, and she was referred to
the NIH.
On her arrival at the end of March 1971, approximately
3 months after her last transfusion, she appeared acutely
and chronically ill. Her temperature was 38.5"C. The liver
and spleen were enlarged 1 to 2 fingerbreadths below the
costal margins. There was widespread polyarthritis which
was symmetric and mild except for marked swelling and
tenderness of the left wrist. Admission laboratory data were
as follows: hematocrit 31%; hemoglobin 10.6 g/100 ml;
reticulocytecount 2%;white blood count 3800/cu mm, with
79 polymorphonuclears, 1 band, 16 lymphocytes, 2 monocytes, 1 eosinophil and 1 basophil; erythrocyte sedimentation rate (ESR) 120 mm/hr (Westergren); platelet count
289,OOO/cu mm; direct Coombs' test was weakly positive,
total protein 7.5 g%, with albumin 3.4 g%; and gammaglobulin was 2.5 g% by paper electrophoresis. The urine
sediment contained 1 to 5 red blood cells and 1 1 to 20 white
blood cells per high-powered field; there were notasts or
proteinuria. Total bilirubin was 0.3 mg/100 ml, alkaline
phosphatase 74 IU, SGOT 44 and SGPT 18. Haptoglobin
was 262 mg% and VDRL was negative. C3 was 150 mg%,
the bentonite flocculation test for rheumatoid factor was
negative and two LE preps were negative. Chest x-ray demonstrated a calcified right hilar lymph node. On the basis of
the history, physical examination and laboratory tests, the
patient was thought to have SLE.
The remainder of the clinical and laboratory course is
summarized in Figure 1. At the end of Week 1 the patient
began to develop the classic syndrome of acute viral hepatitis with nausea, vomiting and anorexia, and her liver enlarged further and became tender. Her generalized arthritis
increased in severity. HBAg was identified in the serum at a
1:256 titer [counterelectrophoresis(1 l)] and liver function
tests revealed the pattern of hepatocellular injury.
Between the end of Week 1 and the end of Week 3 the
liver function abnormalities rose to their highest level.
Jaundice appeared during Weeks 2 and 3. The symptoms of
hepatitis had regressed significantly at the end of Week 2.
By the end of Week 4 the transaminases were normal and
remained so thereafter. HBAg disappeared finally 4 months
after the onset of hepatitis. At no time was antibody to
HBAg detected by radioimmunoassay or complement fixation.
When jaundice appeared, LE cells were found for the
first time during her long illness. Antibodies to native
double-stranded DNA, which were not present in significant amounts in Week 1, rose to high levels by the end of
Week 4 (Figure 1). Antibodies which reacted with synthetic
double-stranded RNA (poly I.poly C) were likewise absent in Week 1, but rose to significant levels during the
acute phase of hepatitis. Inhibition studies with synthetic
6
600
2
Fig 1. HBAg was measured by
counterelectrophoresis (11). ToLa1 bilirubin ( 0 ---*) and SGOT
(0-0) were also measured. Anti-DNA (0-0)
and anti-RNA
(.---.)
were measured by a
modification of the Farr technic
allowing quantitation of the
amount of antibody (12). The
antigen for anti-DNA was native
double-stranded DNA from KB
cells: the antigen for RNA was
polyinosinic. polycytidylic acid.
400 v)
sg
55-
2
200
0
0
w
0
J'
APih
0 .1ot t
Arthritis and Rheumatism,Voi. 16, No. 3 (May-June 1973)
t t
I
MAY
*
0
JUlNE
0
2
o +
'M
AUG OCT
407
SALISBURY ET AL
negative LE preps prior to the hepatitis, the
diagnosis seemed reasonable, though based on
only three rather than four of the proposed criteria (13). The possibility that tuberculosis
could account for the entire 20-year illness deserves consideration. We find that possibility
unlikely because recurrent symmetric polyarthritis over many years and Raynaud's phenomenon are not a part of tuberculosis. Furthermore, although hemolytic anemia probably
occurs in tuberculosis, documented cases in
which the tuberculosis did not follow therapy
for the anemia are exceedingly rare (14). Far
more likely is the possibility that the steroids
and cyclophospharnide administered in the
prior year and a half reactivated the known old
primary tuberculosis.
T h e presence of hepatosplenomegaly with a
normal liver biopsy and a single borderline abnormality of SGPT during a flare of disease activity prior to her admission to the NIH are
consistent with the minor abnormalities of liver
function occasionally associated with SLE (1 5).
During profound hemolysis prior to her admission the bilirubin had never exceeded 1.2 mg%.
Shortly after admission to the NIH, about 3
months after her most recent transfusion, she
developed a mild case of hepatitis with elevated
transaminases and bilirubin and the presence of
HBAg. Despite the complex nature of her underlying connective tissue disease and the widespread tuberculosis that became evident as the
hepatitis resolved, the hepatitis itself pursued a
benign course, much as it would in a healthy
person. In the wake of the hepatitis the serologic abnormalities of SLE first became manifest and declined soon after the hepatitis did.
The occurrence of a positive LE prep during
uncomplicated viral hepatitis is apparently
rare. In the cases reported, (16, 17) the LE prep
DISCUSSION
appeared during relapses, and there was the
T h e clinical diagnosis of SLE in this patient strong suggestion in both cases that the illnesses
was made prior to the onset of hepatitis and was were related to sulfadimethoxine-induced hebased on long-standing fever, symmetric, non- patic injury. The appearance of anti-DNA and
deforming polyarthritis, hemolytic anemia and anti-RNA in response to HBAg-positive and
Raynaud's phenomenon. Despite repeatedly HBAg-negative hepatitis is presently under
polyinosinic .polycytidylic acid and native and heat-denatured KB cell DNA established the specificity of the antiDNA and anti-RNA antibodies (12). Fluorescent antinuclear antibody, which was weakly positive at the end of
Week 1, k a m e strongly positive. Antibodies to mitochondria and smooth muscle were absent repeatedly. During the
acute phase of her hepatitis, serum C3 fell to 80 mg%. Her
hematocrit feH slightly. to 25%, reticulocyte. count rose to
5.270, serum haptoglobin declined to 23 mg% and the direct Coombs' test, which had been weakly positive, became
strongly positive (non-7 type).
From Weeks 3 to 5, as her hepatitis resolved clinically
and chemically, the LE prep reverted to negative, C3 rose to
normal and hematocrit rose and reticulocyte count fell.
Anti-RNA antibodies diminished to insignificant levels by, ,
Week 8 while anti-DNA gradually declined to the normal 1.
range by Week 16.
Early in Week 4 the clinical course was complicated by
the onset of acute meningitis and a left facial palsy. Lumbar
puncture demonstrated low sugar, high protein and 102
white blood cells, of which 55% were lymphocytes. The
patient was treated with INH", ethambutol and streptomycin for suspected tuberculosis at the end of Week 4. In addition, she was given prednisone, 30 mg/day, and a brief
course of ampicillin. Routine spinal fluid cultures and stains
were negative for bacteria and fungi, but subsequently
Mycobocferium fuberculosis were isolated. M fuberculosis
was also cultured from a urine obtained in Week 1. HBAg
was present in the spinal fluid for 2 weeks after the onset of
meningitis.
The meningitis improved rapidly but additional problems developed. Although the polyarthritis disappeared, the
left wrist worsened and x-rays showed new destructive lesions in the bones. A synovial biopsy in Week 12 demonstrated granulomata and culture was positive for M tuberculosis. While on ethambutol, INH and streptomycin,
she had the recurrence of acute tenosynovitis of her left
wrist followed 2 weeks later by the recurrence of acute meningitis. Spinal fluid culture again demonstrated M tuberculosis sensitive to the administered drugs. The LE prep was
found to be positive once after her recurrent acute meningitis. The patient improved considerably with an increase
in dosage of her antituberculous therapy. She returned to
Turkey in October 1971 and was reported to have died
there several months later. No details of her final illness
could be obtained.
408
Arthritis and Rheumatism, Vol. 16, No. 3 (MayJune 1973)
SEROLOGIC ABNORMALITIES IN SLE
study in our laboratory. Although chronic
hepatitis is often associated with a positive LE
prep, the prior and subsequent tests of liver
function and the history do not suggest that thic
was the patient’s underlying illness.
Despite a growing interest in viral immunity
in systemic lupus as an indicator of enhanced
antibody formation and as a source for cross reacting anti-DNA or anti-RNA antibodies, there
are few observations on the course of viral illness in patients with SLE. In the account by
Appelbaum et a f , of viral hepatitis in patients
with SLE (18), 1 patient seems to have had
chronic active hepatitis with a positive LE prep.
Another, who had SLE with a negative LE
prep, did not develop a positive LE prep during
the course of severe hepatitis.
The onset of chronic hepatitis with or without a positive LE prep is frequently indistinguishable from viral hepatitis (19).
Whether the progression of acute hepatitis to
LE positive chronic hepatitis is due to the effect
a lupus diathesis on viral hepatitis, or the diseases are wholly different, is moot. Druginduced hepatitis may be indistinguishable from
LE positive fupoid hepatitis, as in some of the
cases of oxyphenisatin-induced hepatitis (20).
In the view of Soloway et a1 (21), the appearance of a positive LE prep in chronic hepatitis
merely correlates with the severity of the illness.
Although it is possible that the serologic abnormalities in this patient developed coincidentally during hepatitis (there is no reason to believe that they caused the hepatitis), that seems
unlikely. A severe flare of her illness in Turkey
was associated with repeatedly negative LE
preps. Unfortunately, sera from that admission
were not available for measurement of antiDNA. Perhaps tuberculosis, by an adjuvantlike effect, contributed to the development of the
serologic changes (3).
The interest of this case lies in the documentation, in a patient with clinical SLE, of the
waxing and the waning of serologic manifestations of lupus in conjunction with a viral illness
and tuberculosis. This supports the idea that
immune responses to infectious illnesses have a
pathogenetic role in SLE.
ACKNOWLEDGMENTS
We are grateful to Professor 0. Fethi Tezok of the Gul-
hane Military Medical Academy, Ankara, Turkey, for referring this patient to The National Institutes of Health; to
Dr. Sheldon Wolff of the National Institute of Allergy and
Infectious Disease for allowing us to study her; and to Dr.
Kemal Ishak of the Armed Forces Institute of Pathology for
performing fluorescent antibody studies.
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Science 168:982-984,1970
2. Hollinger FB, Sharp JT, Lidsky M D , et al: Antibodies to viral antigens in systemic lupus erythematosus. Arthritis Rheum 14:l-11, 1971
3. Hurd ER, Dowdle W, Casey H, et al: Virus antibody levels in systemic lupus erythematosus.
Arthritis Rheum 15:267-274,1972
4. Pincus T, BlacMow NR, Grimley PM, et al:
Glomerular microtubules of systemic lupus erythematosus. Lancet 2:1058-1061, 1970
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18. Appelbaum JJ, Job H, Kern F: Hepatitis associated with disseminated lupus erythematosus.
Gastroenterology 40:766-771, 1961
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Arthritis and Rheumatism, Vol. 16, No. 3 (May-June 1973)
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