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D-penicillamine-induced lupus erythematosus.

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BRIEF REPORT
D-PENICILLAMINE-INDUCED LUPUS ERYTHEMATOSUS
RAYMOND J. ENZENAUER, STERLING G.WEST, and ROBERT L. RUBIN
We describe a patient who presented with polyarthritis, pleurisy, rash, and a positive antinuclear
antibody result after 5 years of D-penicillamine therapy.
D-penicillamine-induced antinuclear antibodies were
mainly high-titer IgG directed against the (H2A-H2B)DNA complex. Weak IgM activity with H1 and H2B was
also observed. Withdrawal of D-penicillamine therapy
resulted in improvement in clinical symptoms and gradual resolution of serologic abnormalities.
Several drugs have been implicated in causing a
clinical illness with features resembling those of systemic lupus erythematosus (SLE) (1). D-penicillamine
has been reported to cause several autoimmune phenomena, including a syndrome that meets criteria for
SLE (2). We report a case of well-documented Dpenicillamine-induced LE, in which the characteristics of the autoantibodies produced during the disease
course were investigated.
Case report. The patient, a 50-year-old white
woman, was admitted to Fitzsimons Army Medical
Center in March 1987 for evaluation of pleuritic chest
The opinions or assertions contained herein are the private
views of the authors and are not to be construed as official or as
reflecting the views of the Department of the Army or the Department of Defense.
From the Rheumatology Service, Fitzsimons Army Medical Center, Aurora, Colorado, and Scripps Clinic and Research
Foundation, La Jolla, California.
Raymond J. Enzenauer, MD: Fitzsimons Army Medical
Center; Sterling G. West, MD: Fitzsimons Army Medical Center;
Robert L. Rubin, PhD: Scripps Clinic and Research Foundation.
Address reprint requests to Sterling G. West, MD, Chief,
Rheumatology Service, Department of Medicine, Fitzsimons Army
Medical Center, Aurora, CO 80045.
Submitted for publication February 21, 1990; accepted in
revised form May 15, 1990.
Arthritis and Rheumatism, Vol. 33, No. 10 (October 1990)
pain and dyspnea on exertion. The patient had a
25-year history of seropositive, erosive rheumatoid
arthritis (RA), which was treated with several nonsteroidal medications. Previous remittive therapy with
antimalarial drugs and gold salts was discontinued due
to retinal toxicity and rash, respectively. In 1981, she
was started on a regimen of D-penicillamine, with
good control of her arthritis symptoms after achieving
a dosage of 750 mg/day. In 1983, with her arthritis
under control, serologic evaluation showed a positive
rheumatoid factor titer of 1540 and a negative antinuclear antibody (ANA) test result.
In June 1986, the patient reported increasing
arthritis of her wrists, ankles, and knees, with intermittent fever and increasing fatigue. She also experienced pleuritic chest pain, with progressive dyspnea
on exertion. She denied having any of the following:
cough, sputum production, muscle weakness, dysphagia, gastroesophageal reflux symptoms, or tobacco
abuse. Results of a chest radiograph and computed
tomography performed in January 1987 revealed bilateral pleural effusions. Pulmonary function tests revealed a combined obstructive/restrictive defect. The
patient was referred to Fitzsimons Army Medical
Center in February 1987 for further evaluation.
At admission, the patient’s vital signs were
normal. Pertinent abnormalities found on physical
examination included decreased breath sounds and
basilar rales posteriorly in both lungs, nonreducible
swan-neck deformities and ulnar deviation with swelling and tenderness of the small joints of both hands,
wrists, and feet, and vitiligo of the skin of both upper
extremities.
The laboratory evaluation showed the following
values: hematocrit 41%, hemoglobin 13.7 gm/dl, leu-
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BRIEF REPORTS
Table 1. D-peniciUamine-induced lupus erythematosus antibody activity*
ELISA reactivity to antigen
March 1987
May 1988
August 1988
March 1989
Antigen
IgG
IgM
IgG
IgM
IgG
IgM
IgG
IgM
H2A-H2B
(HZA-HZBbDNA
Denatured DNA
HI
H2A
H2B
H3
H4
0.05
5.90
0.23
0.03
0
0.04
0
0
0.05
0.11
ND
0.77
0.32
0.49
0
0.07
0.01
0.06
0.08
ND
0.73
0.17
0.48
0.01
2.45
0.10
0.08
0
0
0
0
0.03
0.03
ND
0.14
0.00
1.07
0.00
0.00
0
0.11
0
0
0.00
0.01
ND
0.08
0
0
0
0
5.64
0.00
0.48
0.01
0.12
0
0
0
0.13
0
0.16
0
0
* Values are optical density units: normal <O. 1 for IgG and ~ 0 . for
2 IgM. ELISA = enzyme-linked
immunosorbent assay; ND = not determined.
kocyte count 5,300/mm3, with a normal differential cell
count and a normal platelet count. Results of blood
chemistries, coagulation studies, and a urinalysis were
within normal limits. Serologic evaluation showed an
elevated Westergren erythrocyte sedimentation rate of
46 m d h o u r , a C-reactive protein level of 4.9 mg/dl
(normal <0.6), and a positive ANA titer of 21540,
with a homogeneous pattern. Results of tests for
complement levels and immunoglobulins, and a serum
protein electrophoresis were within normal limits.
A chest roentgenogram showed pleural thickening, and gallium scanning showed mild increased pleural uptake. Joint radiographs showed erosions of the
small joints of the hands, wrists, and feet, consistent
with the presence of RA.
At this time, the rheumatology service was
contacted, and on the basis of the clinical signs and the
positive ANA, a diagnosis of D-penicillamineinduced
L E was made, and the medication was discontinued
(March 1987). Over the next several weeks, the patient’s arthritis and pulmonary symptoms improved.
Azathioprine therapy, at 50 mg/day, was begun to
prevent reactivation of her RA. The patient has been
followed for the past 3 years, and there has been no
recurrence of her symptoms. Since September 1988,
her ANA test results have been negative.
Laboratory methods and results. Serum samples
were obtained at the time the patient was admitted to
the medical center and at various intervals after discontinuation of D-penicillamine, while the patient was
asymptomatic. Antibodies to nuclear antigens were
detected on 4 pm-thick sections of mouse kidney by
indirect immunofluorescence. Serum samples were
examined for antibodies to native double-stranded
DNA (dsDNA) by a Millipore (Bedford, MA) binding
technique, for antibodies to nonhistone antigens (Sm,
nuclear RNP, SS-A, SS-B) by double immunodiffusion, and for antibodies to histones and denatured
DNA by enzyme-linked immunosorbent assay
(ELISA), as previously described (3).
Serum samples were collected at admission and
2, 5 , and 18 months after the patient’s discharge from
the hospital. ANA was positive on admission, weakly
positive 5 months after discharge, and negative 18
months after discharge.
ELISA analysis of the serum sample obtained
on admission showed slightly elevated antibody activity to total histones, using a polyvalent detecting
reagent. The serum did not contain antibodies to
dsDNA or the nonhistone antigens Sm, nuclear RNP,
SS-A, or SS-B. After D-penicillamine was discontinued, antibody activity to total histones decreased and
became undetectable in subsequent serum samples.
Results of testing for antibody activity to individual histones, histone complexes, and denatured
DNA are shown in Table 1. At the time of admission,
exclusive and highly elevated IgG reactivity was observed with the (H2A-H2BkDNA complex. Weak
IgM binding to H1, H2B, and H2A was also detected.
After discontinuation of D-penicillamine therapy, IgG
anti-(H2A-H2B)-DNA gradually declined as the
symptoms resolved, reaching one-fifth the original
level after 2 years.
Discussion. Definitive criteria for the diagnosis
of drug-induced LE have not been established. The
appearance of LE-like symptoms and a positive ANA
test after long-term consumption of a drug and their
resolution after drug withdrawal are highly suggestive
of a drug-induced syndrome (1). Our case satisfies
1584
these criteria and is consistent with previously reported cases of D-penicillamine-induced LE (2).
Review of the English literature shows that
cases of suspected D-penicillamine-induced LE have
been reported in patients with RA (2,4,5), Wilson’s
disease (6,7), and cystinuria (8). These patients had
received D-penicillamine for 1-48 months before
symptoms appeared. Dosages ranged from 250 mg to
1,000 mg per day in RA patients and 2-3 gm per day in
patients with Wilson’s disease.
D-penicillamine-induced LE was first described in patients with RA by Harkcom et al in 1978
(9) and has been subsequently reported in several RA
patients (2,4,5). The frequency of D-penicillamineinduced LE in RA has been reported to be as high as
2% (2), which is consistent with the frequency found in
patients taking D-penicillamine for Wilson’s disease
(7). The most common clinical manifestations include
pleurisy, increased polyarthritis, leukopenia, and
thrombocytopenia; neurologic and renal involvement
are both uncommon (2). Laboratory abnormalities
include positive ANA and LE cells, with hypocomplementemia and antibodies to dsDNA occasionally seen
(2,5,9). Most D-penicillamine-induced syndromes occur between the sixth and twelfth months of therapy
(4), although symptoms have been reported in RA
patients after only 5 weeks of treatment (5).
ANA are consistently found in the sera of
patients with drug-induced LE. Antibodies to denatured DNA are also commonly observed as a side
effect of therapy with various drugs (1). In patients
with LE due to hydralazine (lo), procainamide (1 I),
quinidine (12), and methyldopa (13) therapy, the ANA
have been shown to be directed primarily against
histone components of the nucleus. This contrasts
with the findings in patients with idiopathic SLE, in
whom antibodies against histones, as well as dsDNA
and nonhistone proteins, are detected (14). Antibodies
to dsDNA have been rarely reported in patients receiving D-penicillamine (2,15,16). Antibodies to
dsDNA are generally regarded as highly specific for
idiopathic SLE (14) and are not found in drug-induced
LE caused by other medications (I7,lS). The ANA
profile in our patient showed only antihistone specificity,
without antibodies to dsDNA and nonhistone proteins.
Antihistone antibody specificity in D-penicillamine-induced LE has not been studied extensively.
While specificity for HI has been reported in 1 patient,
another patient had elevated levels of binding to all
histones (16). In our patient, the histone-reactive antibodies were remarkably restricted in specificity to
BRIEF REPORTS
the (H2A-H2B)-DNA complex. These antibodies
failed to react with the component histones H2A and
H2B, the H2A-H2B complex, or with dsDNA, which
suggests that a conformational antigenic determinant
or an epitope created by adjacent contact regions in
the quarternary structure was generated when this
nucleoprotein particle was formed. The H2A-H2B
complex has been previously shown to have unique
antigenicity in patients with procainamide-induced LE
(1 l), and recent data indicate that these antibodies
display enhanced reactivity when the H2A-H2B complex is associated with dsDNA (19). Furthermore,
anti-(H2A-H2B)-DNA antibodies have been detected
in approximately 50% of patients with LE induced by
quinidine (19). The finding that the immune response
in the patient described here was also restricted to the
(H2A-H2B)-DNA complex adds D-penicillamine to
the list of drugs capable of inducing this autoantibody
specificity.
REFERENCES
I. Harmon CE, Portanova JP: Drug-induced lupus: clinical
and serological studies. Clin Rheum Dis 8:121-135, 1982
2. Chalmers A, Thompson D, Stein HE, Reid G, Patterson
AC: Systemic lupus erythematosus during penicillamine
therapy for rheumatoid arthritis. Ann Intern Med 97:
659-663, 1982
3. Rubin RL: Enzyme-linked immunosorbent assay for
anti-DNA and anti-histone antibodies, Manual of Clinical Laboratory Immunology. Edited by NR Rose, H
Friedman, J L Fahey. Washington, DC, American Society for Microbiology, 1986
4. Camus JP, Homber JC, Crouzet J: Autoantibody formation in d-penicillamine-treated rheumatoid arthritis. J
Rheumatol [Suppl] 7:80-83, 1981
5. Thorvaldson J: Penicillamine-induced lupus-like reaction in rheumatoid arthritis and vasculitis. Dermatologica 162:277-280, 1981
6. Elsas LJ, Hayslett JP, Spargo BH, Durant JL, Rosenberg LE: Wilson’s disease with reversible renal tubular
dysfunction. Ann Intern Med 75:427433, 1971
7. Walshe JM: Penicillamine and the SLE syndrome. J
Rheumatol [Suppl] 8: 155-160, 1981
8. Oliver I, Liberman UA, de Vries A: Lupus-like syndrome induced by penicillamine in cystinuria (letter).
JAMA 220588, 1972
9. Harkcom TM, Conn DL, Holley KE: D-penicillamine
and lupus erythematosuslike syndrome (letter). Ann
Intern Med 89: 1012, 1978
10. Portanova JP, Rubin RL, J o s h FG, Agnello VD, Tan
EM: Reactivity of anti-histone antibodies induced by
procainamide and hydralazine. Clin Immunol Immunopathol 25:67-79, 1982
BRIEF REPORTS
1 1 . Totoritis MC, Tan EM, McNally EM, Rubin RL: Association of antibody to histone complex H2A-H2B with
symptomatic procainamide-induced lupus. N Engl J
Med 318:1431-1436, 1988
12. West SG, McMahon M, Portanova JP: Quinidineinduced lupus erythematosus. Ann Intern Med 100:84&
842, 1984
13. Nordstrom DM, West SG, Rubin RL: Methyldopainduced systemic lupus erythematosus. Arthritis Rheum
32~205-208, 1989
14. Tan EM: Antinuclear antibodies: diagnostic markers for
autoimmune disease and probes for cell biology. Adv
Immunol 44:93-151, 1989
IS. Webb J , Pollard KM: Induction of DNA-antibodies by
d-penicillamine. Clin Exp Rheumatol 3:213-219. 1985
1585
16. Hobbs RN, Clayton A-L, Bernstein RM: Antibodies to
the five histones and poly(adenosine diphosphateribose) in drug-induced lupus: implications for pathogenesis. Ann Rheum Dis 46:408-416, 1987
17. Hughes GRV, Rynes RI, Gharavi A, Ryan PFJ, Sewell
J, Mansilla R: The heterogeneity of serologic findings
and predisposing host factors in drug-induced lupus
erythematosus. Arthritis Rheum 24: 107&1073, 1981
18. Fritzler MJ, Tan EM: Antibodies to histones in druginduced and idiopathic lupus erythematosus. J Clin
Invest 62:560-567, 1978
19. Burlingame RW, Rubin RL: Anti-histone antibody induction by drugs implicates autoimmunization with nucleohistone (abstract). Arthritis Rheum 32 (suppl4):S22,
1989
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