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Influence of cytotoxic agents on the development of lymphoid neoplasms in connective tissue diseases.

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the increased incidence of malignancy in SLE with and
without immunosuppressive drug treatment warrants
close observation of these patients for tumor development.
Medical Service
Brooklyn VA Medical Center
Brooklyn, N Y 1 1 209
Department of Medicine
Downstate Medical Center
State University of New York
Brooklyn N Y I 1 203
Cohen AS, Reynolds WE, Franklin EC, et al: Preliminary
criteria for the classification of systemic lupus erythematows. Bull Rheum Dis 21:643-648, 1971
Lewis RB, Castor CW, Knisley RE, Bole G G : Frequency
of neoplasia in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 19:1256-1260, 1976
Canoso JJ, Cohen AS: Malignancy in a series of 70 patients
with systemic lupus erythematosus. Arthritis Rheum
17383-388, 1974
Penn I, Starzl TE: Immunosuppression and cancer. Transplant Proc 5:943-947, 1973
Inffuence of cytotoxic agents on the
development of lymphoid neoplasms in
connective tissue diseases
To the Editor:
We recently reviewed 29 patients seen at the
Mayo Clinic from 1965 through 1975 who developed a
lymphoid neoplasm following an established connective
tissue disease (1). In this group there were 19 patients
with rheumatoid arthritis, 4 with psoriatic arthritis, 2
with Sjogren’s syndrome, 2 with scleroderma, 1 with
systemic lupus erythematosus, and 1 with ankylosing
spondylitis. Of the 29 patients studied, 12 had malignant lymphoma with diffuse large cell morphology, one
of which was an immunoblastic cell type, 6 had lymphocytic lymphomas, 2 had Hodgkin’s disease, 3 had
plasma cell myelomas, and 6 had chronic lymphocytic
In this group of 29 cases, 2 patients were receiving agents which might be suspected of inducing oncogenesis. One patient had ankylosing spondylitis and
at age 21 was treated with x-ray therapy to the spine.
Fifteen years later he developed a lymphoma involving
the stomach and bone. The other patient who had psoriatic arthritis had been treated with methotrexate for 1
year, and 4 years later the patient developed Hodgkin’s
disease. None of the 29 patients had taken azathioprine
or cyclophosphamide prior to the development of the
lymphoid neoplasm.
There have been reports of neoplasms occurring
in patients with connective tissue diseases. Lymphoid
neoplasms and multiple myeloma have been reported in
patients with rheumatoid arthritis; however we do not
know if the incidence of these neoplasms is actually increased in this population (2,3). Neoplasms and particularly carcinomas are apparently more frequent in patients with systemic lupus erythematosus (3). There is
an increased frequency of lymphoid neoplasms in patients with Sjogren’s syndrome (4). In these reports the
induction of the neoplasms may have been influenced in
some cases by the prior use of cytotoxic agents.
There have been case reports of the development
of neoplasms, including lymphomas, leukemias, and
carcinomas, in patients with connective tissue diseases
following the use of cytotoxic agents (5,6). However, in
our patients we cannot implicate the use of cyclophosphamide or azathioprine in the development of the lymphoid neoplasms.
Mayo Clinic
200 First Street, S W
Rochester, Minnesota 55901
I . Banks PM, Witrak GA, Conn DL: Lymphoid neoplasia
following connective tissue diseases. Mayo Clin Proc
54:104-108, 1979
2. Zawadski ZA, Benedek TG: Rheumatoid arthritis, dysproteinemic arthropathy, and paraproteinemia. Arthritis
Rheum 12:555-568, 1979
3. Lewis RB, Castor CW, Knisley RE, Bole GG: Frequency
of neoplasia in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 19:1256- 1260, 1976
4. Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R,
Kimberly RP, Budman DR, Costa J, Decker JL, Chused
TM: Increased risk of lymphoma in sicca syndrome. Ann
Intern Med 892388-892, 1978
5 . Alexson E, Brandt KD. Acute leukemia afler azathioprine
treatment of connective tissue disease. Am J Med Sci
273:335-340, I977
6. Seidenfeld AM, Smythe HA, Ogryzlo MA, Urowitz MB,
Dotten DA: Acute leukemia in rheumatoid arthritis treated
with cytotoxic agents. J Rheumatol3:295-304, 1976
Ankylosing spondylitis sine sacroiliitis
To the Editor:
Regarding my recent report, “Ankylosing spondylitis sine sacroiliitis” (Arthritis Rheum 22:303-304,
1979), I would like to take this opportunity to apologize
to Dr. Don E. Cheatum for not referring to his earlier
contribution entitled ‘Ankylosing spondylitis’ without
sacroiliitis in a woman without the HLA B27 antigen”
(J Rheumatol 3:420-425, 1976). The recognition of two
such cases suggests that the phenomenon may be more
widespread than hitherto considered.
Stanford University Medical Center
Stanford California
Coexistent gout and rheumatoid arthritis: “A
red marker?”
To the Editor:
Wallace et a1 recently reported a case of probable coexistence of rheumatoid arthritis (RA) and gout
(1). A few comments deserve to be added concerning
the interesting questions raised in the conclusion of that
1. Are the RA factor coated crystals less inj?ammatory? Ingestion of IgG-rheumatoid factor (IgG-RF)
complexes rather than opsonization of crystals by these
complexes may be important in the production of a cellular phagocytic defect. Peripheral blood and synovial
fluid neutrophils from patients with rheumatoid arthritis showed a significant decrease of phagocytosis and
chemotaxis (2-4). Normal peripheral blood neutrophils
that had ingested preformed IgG-RF complexes exhibited significantly less yeast phagocytic capacity than
control cells or cells preincubated with the individual
complex components .(4). One might surmise therefore
that altered proteins or RA factors coated on the surface
of crystals play a role in the chronicity of tophaceous
gouty arthritis simulating RA. This could be one of the
factors leading to chronic synovitis in rabbits injected
with urate crystals (5).
In clinical practice, rheumatoid factors encoun-
tered in gouty patients seem to correlate best with the
presence of liver disease, most often alcoholic (6). This
may contribute to a diagnostic error in chronic cases of
gouty arthritis. Despite the theory cited above, acute or
chronic gouty arthritis does not seem to be less inflammatory in these patients.
The prevalence of rheumatoid factors is about
30% in patients with chronic tophaceous gout and about
10% in patients with nontophaceous gouty arthritis (7).
In 13 possible cases of gout and RA reported in the last
40 years (1,8,9), tophaceous gout was observed in 11
cases (85%) and positive RF in 7 cases (54%). Talbott
recently reported 44 patients with definite gout, of
whom 61% had tophaceous gout and 23% had rheumatoid factors (8).
2. Are the crystals themselves immunosuppressive?
Experiments with animal models do not allow a clear
answer so far. In a recent study two groups of 20 rats
were used: one group was fed a standard diet and the
other received an oxonate diet which produces hyperuricemia. Ten rats in each group were injected with sodium urate crystals (0.5 mg in 0.1 ml NaClO.85%) in the
right hindpaw once a week for 5 consecutive weeks.
One week after the last urate injection, all the rats were
then injected with Freund’s adjuvant in the left hindpaw. In rats fed a standard diet, prior urate crystal injections significantly increased the induced polyarthritis
(P c 0.01). There was a slight decrease of the induced
polyarthritis (P= 0.20) in hyperuricemic rats that have
received urate crystal injections (10). The repetitive injections of urate crystals in joints of rabbits have shown
the production of a chronic synovitis comparable to
rheumatoid or Glynn synovitis ( 5 ) . Such a reaction
makes us wonder if the same situation could not happen
in human chronic tophaceous gouty arthritis. Biopsy of
the synovial membrane could very well then be misleading. Therefore, we should require other kinds of
hard data since chronic synovitis in gout can simulate
RA not only clbically but histopathologically (1 1). Furthermore, a preliminary study on 40 gouty patients
matched with 40 healthy controls did not show any difference in the cellular immunity (10).
3. Do conditions associated with decreased cellular
immunity alter the negative association between gout and
RA? In the literature review Wallace et a1 stated that the
first conclusive example of coexistent gout and RA was
reported in 1966 by Owen (12). The fibrotic lesion of the
lung had been attributed to tuberculosis but the patient
died from lung cancer (13). Conditions associated with
a disturbed immunity such as Felty’s syndrome and
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development, neoplasms, connection, agenti, lymphoid, disease, cytotoxic, tissue, influence
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