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Pulmonary toxicity with gold therapy.

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347
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CASE REPORT
PULMONARY TOXICITY WITH GOLD THERAPY
TERRY E. PODELL, JAMES R. KLINENBERG, LOUIS S. KRAMER, and HARVEY V. BROWN
Several adverse reactions are seen with gold
therapy in rheumatoid arthritis (RA). Approximately
80% of such reactions are inconsequential, consisting of
pruritis, rash, stomatitis, eosinophilia, and mild proteinuria (1,2). Nitritoid reactions are also frequent with the
thiomalate preparation and usually occur early in the
course of treatment. More severe reactions include
thrombocytopenia, leukopenia, pancytopenia, nephrotic
syndrome, and exfoliative dermatitis. In addition, cholestatic jaundice (3), enterocolitis, corneal chrysiasis,
and peripheral neuropathy have been reported. It is not
clear that any of the adverse effects are dose related
(43). Recently, several cases of diffuse pulmonary injury associated with gold therapy have been reported.
We report here an additional case of this severe but reversible condition.
CASE REPORT
A 74-year-old white woman with a 25-year history of classic rheumatoid arthritis was first begun on
gold sodium thiomalate (Myochrysine) on May 16,
From the Department of Medicine, Cedars-Sinai Medical
Center and UCLA School of Medicine, Los Angeles, California.
Terry E. Podell, MD: Rheumatology Fellow, Cedars-Sinai
Medical Center; James R. Klinenberg, MD: Director, Department of
Medicine, Cedars-Sinai Medical Center, Professor and Vice-Chairman, Department of Medicine, UCLA School of Medicine; Louis S.
Krarner, MD: Chief of Staff, Cedars-Sinai Medical Center, Associate
Clinical Professor of Medicine, UCLA School of Medicine; Harvey V.
Brown, MD: Associate Director Pulmonary Division, Cedars-Sinai
Medical Center, Assistant Professor, Department of Medicine, UCLA
School of Medicine.
Address reprint requests to James R. Klinenberg, MD, Director, Department of Medicine, Cedars-Sinai Medical Center, Los
Angeles, California 90048.
Submitted for publication August 13, 1979; accepted in revised form October 24. 1979.
Arthritis and Rheumatism, Vul. 23, Nu. 3 (March 1980)
1978, after trials on salicylates, indomethacin, and
ibuprofen failed to relieve her hand and bilateral knee
pain. She was given a test dose of 10 mg intramuscularly, followed in 1 week by a 25 mg dose and
then 50 mg each week, with a good response. Except for
I + proteinuria on one occasion and a persistent eosinophilia, weekly urinalysis and CBC were within normal
limits. Treatment was interrupted briefly on two occasions because of pruritis and stomatitis. There was definite improvement in the patient's hand and knee pain.
On August 5, 1978, after a total dose of 395 mg,
she was admitted to Cedars-Sinai Medical Center because of shortness of breath and epigastric pain. There
was no cough, fever, or sputum production. She had no
history of tuberculosis, recent travel, or exposure to industrial pollutants, pets, or infectious disease. By August 14 the patient's shortness of breath had worsened.
Physical examination revealed a temperature of 98.6"F,
pulse of 88, and blood pressure of 150/95. There were
occasional fine rales at the left base and a grade I W I
systolic murmur at the apex. There were no gallops and
no jugular venous distension. Classic changes of rheumatoid arthritis were present, including diffuse swelling
of all metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, Swan-neck deformities, ulnar
deviation, subluxations, and flexion contractures of
both elbows. There were no nodules. Chest film on admission showed widespread interstitial and early alveolar infiltrates with normal pulmonary vasculature and
cardiac size and an old elevation of the right hemidiaphragm. The most recent previous chest film on May
4, 1977 was clear.
The white blood cell count was 8,400 with 73%
polymorphonuclear leukocytes, 14% lymphocytes, 8%
eosinophils, and 5% monocytes. On August 9, the pa-
348
Figure 1. Chest roentgenogram 4 days after admission showing widespread interstitial and alveolar infiltrates, markedly increased since
admission, with normal pulmonary vasculature and cardiac size and
an old elevation of the right hemidiaphragm.
tient developed a diffuse pruritic maculopapular rash
and severe shortness of breath. The chest film showed
progression of the pulmonary infiltrates (Figure I), despite a trial of diuresis with Lasix and digitalization. On
examination, the rales had extended to the lower twothirds of both lung fields posteriorly, and an arterial
blood gas showed a pH 7.37, PCO, 54 mm Hg, and Po,
60 mm Hg on 5 liters/minute of oxygen by nasal cannula.
On August 15, fiberoptic bronchoscopy with five
transbronchial biopsies of the left lower lobe was performed which showed minimal non-specific inflammation in the bronchial mucosa only, with normal alveoli.
Results of cytology and cultures of bronchial washings
were negative. Other test results included cold agglutinin titers of < 1 :4, mycoplasma complement fixation titer of < 1 :8, and negative complement fixation for coccidiomycosis. Results of an ANA and latex fixation
were negative (it is not known whether she ever had a
positive rheumatoid factor in the past), and Westergren
sedimentation rate was 36.
The patient's severe dyspnea continued, and she
was started on corticosteroids on August 17 with 125 mg
of Soh-medrol intravenous push, followed by 50 mg of
Medrol orally each day. By August 20 the patient was
no longer short of breath and there were only bibasilar
rales. The chest film did not show significant clearing
until August 26. The rash and eosinophilia disappeared
with the steroid treatment and the blood gas improved
to pH 7.47, Pco2 38 mm Hg, and Po, 60 mm Hg on
room air. An upper gastrointestinal series (UGI) was
CASE REPORT
performed but findings were normal, and the etiology of
the abdominal pain (which had decreased) was not
found. She was discharged on 40 mg/day of Medrol on
September 2, 1978.
One week later on September 9, the patient's epigastric pain worsened and she was readmitted to the
hospital. A repeat UGI showed an ulcer in the pre-pyloric antral area of the stomach with confined posterior
perforation. Elevated amylase and lipase values were
noted. She was treated medically with resolution of the
problem. On doses of Medrol tapering over 1 month,
she continued to be free of dypsnea, rales, rash, and eosinophilia, and her chest film totally cleared (Figure 2)
except for some increased interstitial markings at the
left base that probably represented chronic changes.
Despite discontinuance of steroids and all other antiinflammatory drugs, her arthritis remained almost totally quiescent. The prednisone was discontinued by
November 1978 without further problems.
DISCUSSION
We have described a patient with seronegative
rheumatoid arthritis who developed respiratory failure
secondary to an extensive pulmonary hypersensitivity
reaction after receiving 395 mg of gold. Within 4 days of
beginning steroids the patient was symptom-free, and
within 10 days her chest film showed significant improvement, with total clearing by 3 weeks. The prednisone was tapered over 3 months and discontinued without recurrence. The differential diagnosis included
pneumonia, congestive heart failure, pulmonary vascu-
Figure 2. Clearing of the chest roentgenogram 1 month after initiation
of steroid treatment.
CASE REPORT
litis, rheumatoid interstitial fibrosis, and gold-induced
pulmonary injury in the form of a PIE syndrome (pulmonary infiltrates with eosinophilia). The lack of fever
or leukocytosis and the failure to demonstrate organisms with extensive culturing, transbronchial biopsy,
and serologies suggested this was not an infectious process. The lack of response to diuretics and digitalization
along with the absence of clinical signs of heart failure
was evidence against this diagnosis. The negative results
of the lung histology, only mild elevation of the sedimentation rate, and seronegativity (19) argued against a
vasculitis. The acute onset, normal lung histology, and
rapid recovery made rheumatoid fibrosis unlikely. Finally, the striking similarity of symptoms, chest film,
histology, and course to previously reported cases favored a diagnosis of gold-induced pulmonary injury.
Savilahti (6) first reported a case of diffuse pulmonary injury associated with gold therapy in 1948.
Winterbauer, Wilske, and Wheelis (7) reported two
cases in 1976. Geddes and Brostoff described another
case in 1976 (8), and Gould, McCormack, and Palmer
reported three cases in 1977 (10). Finally, Scharf, Nahir,
Kleinhaus, and Barzilai (21) reported an additional case
in 1977.
Four of the previous eight reported patients with
gold-induced pulmonary damage had eosinophilia (300
eosinophils/mm’), which our patient also had. Eosinophilia has been seen at times in rheumatoid arthritis
(13,18), especially in association with vasculitis, nodules, pleuropericarditis, and pulmonary fibrosis. It has
been estimated to occur in 5% to 40% of cases treated
with gold but is often transient (1,14). In one study (14)
patients receiving gold who developed eosinophilia had
a higher incidence of developing other side effects (55%)
than those without eosinophilia ( 1 1%). The five cited
cases with eosinophilia also fulfill the criteria for PIE
(pulmonary infiltration with eosinophilia) syndrome. Of
the five major categories (15) of PIE syndrome-Loffler’s syndrome, chronic eosinophilic pneumonia, asthmatic eosinophilia, parasitic diseases, and vasculitis-a
diagnosis of chronic eosinophilic pneumonia best fits
these cases (16). However, drug reactions are well
known to cause the PIE syndrome and may or may not
fit perfectly into one of the five categories. When such
cases do, it is usually Loffler’s syndrome which they resemble most. In the cases of gold-induced pulmonary
damage, the symptoms were more severe (including one
death) and the roentgenographic abnormalities more
protracted that is usual for Loffler’s syndrome but not
unlike that of chronic eosinophilic pneumonia. As in
the latter illness, there has been a female preponderance
349
in the cases cited. However, this may not be significant
in view of the 2.5: I female predominance seen in rheumatoid arthritis.
Six of the 8 reported cases of gold-induced pulmonary damage exhibited skin rashes at or near the
time of respiratory difficulty. When described, the
rashes were erythematous, maculopapular, pruritic, and
generalized-consistent with adverse reactions to gold.
The incidence of skin rashes from gold has been as high
as 53% in one series (17).
It is noteworthy that our patient demonstrated
significant carbon dioxide retention at her most acute
phase of illness. This was not demonstrated in the few
previous cases where blood gas results are given, although the patient reported by Scharf et a1 showed significant hypoxemia (2 I).
The use of corticosteroids allowed a rapid recovery in all cases when they were used except for Gedde’s
patient (8), who apparently improved only slowly and
who received the smallest dose ( I 5 mg/day prednisone),
and the patient of Gould et a1 (lo), who died of a myocardial infarction within hours of starting therapy. In
the other steroid-treated cases there was dramatic resolution of dyspnea and rales (often in a few days) with
slightly less dramatic clearing of pulmonary infiltrates
roentgenographically (usually in a few weeks). Rash
and eosinophilia, when present, also usually responded
quickly. However, the appropriate dose and duration of
therapy are not yet clear and may, in fact, vary with the
individual. In the 6 cases reported in which steroids
were used, dosages varied from 15 mg/day of prednisone to 200 mg/day (equivalent to 250 mg prednisone)
of methylprednisolone. The shortest duration of therapy
was 2 weeks (7), although the patient relapsed and was
given 4 additional months of therapy. It appears likely
that 14 months of tapering steroid doses with initial
doses of at least 30-60 mg prednisone equivalent, and
perhaps intravenous boluses of 150-250 mg prednisone
equivalent for the first dose, may be most effective, but
this must be borne out by further reports.
As in previous cases, our patient’s total gold dose
was rather small (395 mg). The largest dose given to the
previously reported patients was 1.06 gm (6) and the
smallest was 175 mg (21), with a mean of 552 mg. This
would take 5-20 weeks to reach when gold is given in
the usual manner.
British antilewisite (BAL) was tried in only one
case (6) with apparent success. This drug should be reserved for life-threatening circumstances because of its
ability to cause hypertension, convulsions, and coma. It
is also potentially nephrotoxic.
CASE REPORT
350
REFERENCES
1. Gottlieb NL: Chrysotherapy. Bull Rheum Dis 27:912-
917, 1977
2. Ehrlich GE: Remittive pharmaceutical agents, Rheumatic
Diseases. Edited by W Katz. First edition. Philadelphia,
JB Lippincott Co, 1977, p 901
3. Favreau M: Hepatic toxicity associated with gold therapy.
Ann Intern Med 87:717-719, 1977
4. Furst DE: A double blind trial of high versus conventional dosages of gold salts for rheumatoid arthritis. Arthritis Rheum 20:1473-1480, 1977
5. Sharp JT: Comparison of two dosage schedules of gold
salts in the treatment of rheumatoid arthritis. Arthritis
Rheum 201 179-1 191, 1977
6. Savilahti M: Pulmonary complication following use of
gold salts. Ann Med Int Fenn 37:263-266, 1948
7. Winterbauer RH, Wilske KR, Wheelis RF: Diffuse pulmonary injury associated with gold treatment. N Engl J
Med 294:919-921, 1976
8. Geddes DM, Brostoff J: Pulmonary fibrosis associated
with hypersensitivity to gold salts. Br Med J 2: 1444, 1976
9. Denman EJ, Denman AM: The lymphocyte transformation test and gold hypersensitivity. Ann Rheum Dis
27582-588, 1968
10. Gould PW, McCormack PL, Palmer OG: Pulmonary
damage associated with sodium aurothiomalate therapy. J
Rheumatol 4:3, 1977
11. Sidorenkhov MI, Tyumkin VS: A case of eosinophilic
pneumonia after chrysanol treatment. Teve Avkh 110111, 1965
12. Vaccarezza RF, Pavlovsky A: Bronchopulmonary allergy
produced by gold salts: Loeffler’s syndrome with disseminated foci and micronodulary picture (abstract). JAMA
131:1250, 1946
13. Panush RS: Eosinophilia associated with rheumatoid arthritis. Ann Intern Med 75:199, 1971
14. Davis P, Hughes GRV: Significance of eosinophilia during gold therapy. Arthritis Rheum 17:964-968, 1974
IS. Scully SE: Presentation of a case. N Engl J Med 297:155161, 1977
16. Lillington GA, Jamplis R W A Diagnostic Approach to
Chest Diseases: Differential Diagnosis Based On Roentgenographic Patterns. Second edition. Baltimore, The
Williams and Wilkins Co, 1977, pp 541-555
17. Browning JS, Rice RM, Lee WV, Baker LM: Gold therapy in rheumatoid arthritis. N Engl J Med 237:428-431,
1947
18. Winchester RJ, Litwin SD, Koffler D, Kunkel HG: Observations on the eosinophilia of certain patients with
rheumatoid arthritis. Arthritis Rheum 14:650-665, 1971
19. Mongan ES, Cass RM, Jacox RF, Vaughn JH: A study of
the relationship of seronegative and seropositive rheumatoid arthritis to each other and to necrotizing vasculitis.
Am J Med 47:23-33, 1969
20. Mongan ES, Atwater EC: A comparison of patients with
seropositive and seronegative rheumatoid arthritis. Med
Clin North Am 52:533-539, 1968
21. Scharf J, Nahir M, Kleinhaus U, Barzilai D: Diffuse pulmonary injury associated with gold therapy. JAMA
237:2412, 1977
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