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Neoplasia and Cyclophosphamide.

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Neoplasia and Cyclophosphamide
To the Editor:
Well-documented evidence from animal
experiments and in human renal transplant
recipients reveals an increased incidence of
malignancy with administration of immunosuppressive agents. Such neoplasms have
usually involved the lymphoreticular system (1-3). Recently their occurrence has
aroused growing concern about the increasing
use of immunosuppressive type agents in the
treatment of severe nonmalignant disease such
as rheumatoid arthritis (4).
The most recent report related the occurrence
of neoplasia in 5 patients under treatment with
cyclophosphamide (5). There were 2 reticulum
cell sarcomas of the stomach, 1 chronic lymphocytic leukemia, 1 acute stem cell leukemia, and
1 Hodgkin’s Disease.
It has been suggested (6,7) that a formal tumor registry be established in order to document those patients with rheumatoid arthritis
who have developed malignancy while under
treatment with immunosuppressive agents. In
consonance with this view, we are recording
two instances of neoplastic disease, not involving the lymphoreticular system, in men under treatment with cyclophosphamide for severe
rheumatoid arthritis.
Case 7: A 55-year-old boilermaker, was first
seen in April 1968 with a history of arthralgia
of 15 years duration and evidence of classical
active rheumatoid arthritis of 2 years duration.
He had smoked 1 to 2 packs of cigarettes daily
for 40 years. His mother had died of cancer
(primary site unknown) at age 45. When first
seen he had been unable to work for several
months because of the severity of the arthritis.
On a comprehensive regimen of management,
including physical therapy, salicylates, and
chrysotherapy he improved sufficiently to return to work. By May 1969, however, despite
continuation of the above regimen, and the ad424
dition of 10 mg of prednisone daily, his condition deteriorated. The activity of the rheumatoid process increased so that once again he was
nearly bedfast and hospitalization was required. In the hospital, studies again only confirmed the existence of severely active, classical
rheumatoid arthritis. The erythrocyte sedimentation rate was markedly accelerated and the latex titer (for rheumatoid factor) was negative,
as it always had been.
Serum protein electrophoretic studies, the total leukocyte count and its morphology, as well
as the biochemical profile were entirely normal.
LE cell preparations and antinuclear antibody
tests were normal. At no time did he present
evidence of psoriasis, spondylitis, or any other
variant of rheumatoid arthritis.
In May 1969 therapy with cyclophosphamide, 50 mg daily, was initiated. The dose
was gradually increased over the following
2 months to 150 mg daily. Within 4 months
he was improved sufficiently to return to
his job. The dose of prednisone was reduced
gradually and discontinued in December 1969.
Over a period of 23 months he received 74 g of
cyclophosphamide in doses ranging between
100 and 150 mg daily.
In April 1971 he was readmitted to the hospital because of the sudden onset of severe pain
in the chest and ribs. Roentgenograms disclosed
multiple areas of neoplastic disease in the lungs,
and there were also lytic lesions in ribs and vertebral fractures. Previous roentgenograms of
the chest in April 1968 and May 1969 disclosed
only slight increase in hilar markings and mild
chronic fibrotic pulmonary changes. Bloody
fluid (800 cc) was removed from the right hemithorax. A pleural biopsy revealed a poorly differentiated adenocarcinoma. A comprehensive
search for any other primary neoplastic lesion
was negative. The patient’s condition deteriorated rapidly and he expired on May 5, 1971.
An autopsy could not be obtained.
Case 2: A 61-year-old construction foreman,
Arthritis and Rheumatism, Vol. 16, No. 4 (July-August 1973)
was first seen in March 1966 with a history of
arthritis of 10 years duration. He had worked
outside for 35 years with considerable exposure
to sunlight and had smoked two packs of cigarettes daily for over 20 years.
The examination revealed classical rheumatoid arthritis with typical rheumatoid deformities. The latex titer was positive in a dilution
of 1:320. Initially, he managed quite well on a
conservative program which included physical
therapy, salicylates and chrysotherapy. Later,
however, despite adherence to a comprehensive
program of therapy, which also included prednisone (12.5 mg daily), the activity of his arthritis increased and progressed to the point where
he was barely able to handle his activities of
daily living.
He was admitted to the hospital where the
following studies were performed and found to
be normal: serum protein electrophoresis, total
leukocyte count and its morphology, biochemical profile, LE preparation and antinuclear antibody test.
He was then started on cyclophosphamide in
June 1969. Over the subsequent 35 months the
patient received a total of 58.5 g of cyclophosphamide.
His dose of cyclophosphamide averaged 50
mg/day. By March 1970 his condition was improved considerably, and by February 1971 the
dose of prednisone was reduced to 5 mg/day
and the cyclophosphamide to 50 mg every other
On April 11, 1972 a hard mass was noted on
the right side of his neck, associated with swelling of the right side of the face. He was admitted
to the hospital where a biopsy of the retromolar
area revealed a squamous cell carcinoma, with
spread to the right jugulodigastric area. Cobalt
therapy was instituted, but he died on July 15,
1972. The autopsy confirmed the above diagnosis and generalized rheumatoid arthritis.
Special immunologic studies performed by
Dr. Alan Winkelstein in the course of a survey
of a group of patients on cyclophosphamide
showed in both of the above patients, as in most
of our rheumatoid patients on cyclophosphamide, an absolute lymphopenia and decreased response to phytohemagglutinin (8).
Chromosome studies by Dr. Howard Nankin
on the peripheral lymphocytes in Case 2 did
show some abnormalities similar to chromosome changes noted in other patients taking cyclophosphamide (9).
Obviously, the relation between the neoplasia in these two cases and the drugs administered remains unanswered and, at most, only
speculative-but worthy of reporting.
Rheumatology Division of the Department
of Comprehensive Medicine
St. Margaret Memorial Hospital and
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
1. Penn I, Halgrimson CG, Starzl TE: DeNovo ma-
lignant tumors in organ transplant recipients.
Transplant Proc 3:773-778, 1971
2. Walker D, Gill J J, Carson JM: Leiomyosarcoma
in a renal allograft recipient treated with immunosuppressive drugs. JAMA 215:2084-2086,
3. Fahey JL: Cancer in the immunosuppressed
patient. Ann Intern Med 75:310-312,1971
4. Steinberg AD, Plotz PH, Wolf SM, et al: Cytotoxic drugs in treatment of nonmalignant diseases. Ann Intern Med 76:619-642, 1972
5. Fosdick WM: Discussion at the eighteenth interim scientific session of the American Rheumatism Association, Pittsburgh, Pennsylvania, Dec
I972 (and personal communication)
6. Lipsmeyer, EA: Development of malignant cerebral lymphoma in a patient with systemic lupus
erythematosus treated with immunosuppression.
Arthritis Rheum 15:183-186,1972
Arthritis and Rheumatism, Vol. 16, No. 4 (July-August 1973) .
7. Decker JL, The recognition of drug effects. Ar-
thritis Rheum 15:187-189, 1972
8. Winkelstein A, Mikulla JM, Nankin HR, et al:
Mechanisms of immunosuppression: Effects of
cyclophosphamide on lymphocytes. J Lab Clin
Med 80:506-513,1972
9. Tolchin SF, Winkelstein A, Rodnan GP, et al:
Chromosome abnormalities resulting from cyclophosphamide therapy in rheumatoid arthritis
and progressive systemic sclerosis. Arthritis
Rheum 16:135, 1973 (Abstract)
Antibody Titers in SLE
To the Editor:
We have read with much interest the report
on “Epstein-Barr Virus Antibody Levels in
Systemic Lupus Erythematosus” by Phillips
and Hirshaut (Arthritis Rheum 16:97-101,
1973). In it they state that they have failed to
confirm our previous report of elevated EBV
antibody titers in SLE (Lancet 1:167-168,
1971) even when using the same cell line, the
EB3 line, as the antigen source as we used.
They point out, however, that the geometric
mean titer (GMT) in their 50 SLE patients at
log 2 of 7.84 (1:230) was almost exactly that
found by us in our matched sera of 34 patients
with a G M T of 1:216.8. The differences lie in
the control group. In their blood bank donors
the G M T was log 2 of 7.32 (1:160), whereas
ours in patients with tuberculosis was 1:35.3.
In a subsequent extension of our study we found
a G M T of 1:61.9 in 255 controls mostly drawn
from a blood donor group (Ann Rheum Dis 32:
238,1973). The Henles’ report an extensive experience with the EB3 cell line with a G M T of
1:37 for anti-EBV antibody in 489 healthy controls (J Nutl Cancer Znst 43:147, 1969). T h e
titers found in SLE are definitely elevated as
compared to most control groups and in the
range of those observed in Hodgkin’s disease.
A second difference is the way that titers under 1 :10 are handled. We eliminate them from
our calculation of the G M T , as do the Henles,
as we are interested as to whether antibody levels are elevated in those who have demonstrable
antibody. Phillips and Hirshaut, however, have
assigned an arbitrary value of 1:5 to this group
and included them in the G M T . As it is not
stated how many SLE or control sera lacked demonstrable antibody, the effect of their treatment of the data is unknown except that such
inclusion lowers the G MT .
They also regard the elevated IgG levels to be
the cause of elevated viral antibody levels as a
part of a generalized hyperreactivity. We view
the events in the opposite direction, i.e., that the
elevated IgG levels are the result of viral multiplication and that the relationship is specific
and selective because many other antibody levels are not elevated in SLE.
We hope that ways will be found to resolve
these differences so that EB virus may be vigorously pursued as one of the possible causative
agents in SLE, if the evidence merits it, or abandoned, if the results are negative. One approach
is for the National Institute of Arthritis and
Metabolic Disease or Lupus Foundation to organize a double-blind cooperative study of SLE
sera from patients with known clinical activity
and a carefully chosen control group among
those persons whose activity is involved in this
issue. We would be happy to participate in this
type of evaluation.
Yale University School of Medicine
N e w Haven, Connecticut
lntraarterial Reserpine
To the Editor:
I should like to report a unique experience
with the use of intraarterial reserpine that is not
cited in the literature to the best of my knowledge.
A 45-year-old white female was hospitalized
from April 23 to May 9, 1973, for pneumonitis.
Arthritis and Rheumatism,Vol. 16,No. 4 (July-August 1973)
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neoplasia, cyclophosphamide
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