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Polymyositis and aplastic anemia a report of a case.

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ARTHRITIS ROUNDS (2)
Polymyositis and Aplastic Anemia
A Repori o f a Case
.
.
By L. A HEALEY
The appearance of aplastic anemia in
a seventyone year old man with polymyositis is described. The pancytopenia
was unrelated to drugs and was fatal.
Autopsy confirmed both diagnoses and
disclosed no occult neoplasm. Although
its association with visceral malignancy
is well known, the occurence of polymyositis and aplastic anemia in the same
patient has been reported but once
before.
Es describite le apparition de anemia
aplastic in un masculo de septanta-duo
annos de etate qui esseva afficite de
polyomyositis. Le pancytopenia esseva
attribuibile a nulle pharmaco e se provava mortal. Le necropsia confirmava
ambe diagnoses e revelava nulle occulte
neoplasma. Ben que su association con
maligiiitates visceral es ben cognoscite,
le occurrentia de polyomyositis e de
anemia aplastic in le mesme subject0 se
trova reportate in le litteratura non plus
que un sol vice.
T
HE OCCURRENCE OF POLYMYOSITIS (or dermatomyositis) and
aplastic anemia in the same patient is most unusual, only two such instances having been reported. In a description of the pathology of dermatomyositis in 1949, Page1 mentioned an aplastic bone marrow as an autopsy
finding in a young boy with the disease. The clinical features or bIood counts
are not inc1uded.l In 1959, Duncan et al. reported a case of dermatomyositis
and aplastic anemia. The patient was a fifty-three year old man who had had
the muscular symptoms for one year when he developed the pancytopenia
and died three months later. Post-mortem examination confirmed both diagnoses.2
Since this combination has been observed so rarely, the following case is
reported.
CASEREPORT
The patient, a 71 year old white man, was first seen in August 1961, complaining of.
progressive weakness and stiffness of six months duration. Although he had continued to
work on a road maintenance crew, he had difficulty raising a loaded shovel or lifting
heavy objects. Climbing stairs and rising from a chair required great effort. He had
very little pain, but stiffness of all his joints, particularly in the arms and hands, was
persistently troublesome. His weight had fallen from 155 to 130 pounds with the illness
but he had not experienced any dysphagia or regurgitation.
In the past, he had enjoyed good health. Three years previously, his varicose veins had
been stripped and the next year, an inguinal hernia was repaired. Both operations were
uneventful, except for the persistence of dependent edema of his legs which was most
pronounced after working or standing. Blood counts and other tests performed at the
time of the operations were normal.
.
In March 1961, he was given hydroflumethiazide, 25 mgni. daily, for the edema. One
month later, he was hospitalized because of the persistence of the edema plus the complaints of weakness, stiffness, aches and weight loss. Generalized swelling of both hands,
275
AHTIiRITIS AND
RHEUMATISM,V O L . 7 , NO. 3
(JUNE),
1964
276
L. A. HEALEY
tenderness of the metacarpophalangeal joints without inflammation and 3 f edema of both
lower legs were noted. His hemoglobin was found to be 11.5 Gms. per cent and his
white blood cell count was 10,300 per cubic millimeter with a normal differential count.
The stained peripheral blood smear was described as normal. When the sefum uric acid
was elevated ('6.5 mgm. per cent), the symptoms were ascribed to gout.
The edema of the legs cleared without diuretics while in the hospital, and he was discharged taking a combination tablet of colchicine 0.5 mgm. and probenecid 0.5 Gm.
daily. He took this tablet and no other medication until one week before he was seen in
August, when he discontinued it because a rash appeared on his legs. Coincident with
the rash, he had noted marked fatigue and dyspnea on slight exertion in addition to the
persistent muscular stiffness and weakness.
On physical examination, he appeared elderly and chronicaly ill. The skin was pale
and sallow but there was no atrophy or tautness. No periorbital swelling or discoloration
was present nor were subcutaneous nodules. Below the knees, both legs were covered
with petecchiae and brawny edema was evident. No lymph nodes were palpable and
the thyroid, liver and spleen were not enlarged. The lungs were clear. Blood pressure
was 170/70 mm. and the pulse rate was 90/min. and regular. A grade iii blowing systolic
murmur was heard over the precordium.
He had pronounced weakness, particularly of the proximal muscles in the arms and
legs and could not rise from a chair without assistance. No tenderness or hypertrophy
of muscles could be found, but the muscles and subcutaneous tissue of the forearms felt
hard on palpation. Joints were not swollen, tender or deformed but motion was restricted.
Shoulder abduction was poor and h e could not fully extend the elbows, hips or knees.
Flexion and extension of the wrist were limited to 10" in each direction. The subcutaneous
tissues of the hands were puffy and swollen and he could not clench his fists. Apart from
the weakness, the neurologic examination revealed no abnormality.
Laboratory studies showed the hemoglobin was 5 Gms. per cent and the hematocrit
was 14 per cent. There were 45,000 platelets and 4500 leucocytes per cubic millimeter,
47 per cent neutrophils, 51 per cent lymphocytes and 2 per cent eosinophils. The sedimentation rate was 160 mm. in one hour (Westergren). Serum transaminase levels were
not elevated and L.E. cell preparations, latex agglutination and serologic test for syphilis
were negative. Serum uric acid measured 3.5 mgm. per cent. On paper electrophoresis of
the serum proteins, the albumin measured 4.0 Gms. and the gamma globulin 2.2 Gms.,
but no abnormal globulins were present.
X-rays of the chest and gastrointestinal tract disclosed no neoplasm. The only abnormality was noted in the esophagus when barium was swallowed. The swallowing reflex was
normal, but in the lower two-thirds of the esophagus, peristalsis was absent and the barium
pooled in the dilated lumen. Except for some degenerative changes in the distal interphalangeal joints of the hands, the radiologic appearance of all joints was normal.
Skin and muscle of the biceps area and anterior thigh were biopsied. Microscopically,
the skin showed only epidermal atrophy. Sections of muscle revealed swelling of some
fibers with loss of striations and atrophy of other fibers. Lymphocytes were abundantly
present surrounding muscle fibers and blood vessels. No arteritis was seen.
It was evident that the anemia was not due to blood loss or hemolysis. The cells appeared normocytic and normochromic, the stools did not contain blood, serum bilirubin
was not increased and the reticulocyte count was 0.8 per cent. Marrow aspirate obtained
from the sternum and iliac crest revealed marrow arrest; very few formed elements were
present. There were no abnormal cell aggregates.
Treatment with prednisone (60 to 80 mgm./day) and parenteral testosterone was ineffective in producing a remission and the anemia was compounded by frequent episodes
of bleeding. Repeated transfusions were necessary to maintain th hemoglobin in the range
of 7 grams. Finally, after three months, he was admitted to the hospital with massive
gastrointestinal bleeding, a fever of 105" (F.), and died. The final blood count showed a
277
POLYMYOSITIS AND APLASTIC ANEMIA
hemoglobin of 4 Gms. per cent, only 315 platelets and 2600 leiicocytes per cubic millimeter, 9 per cent neutrophils and 91 per cent lymphocytes.
Postmortem examination disclosed bronchopneumonia and diffuse gastrointestinal bleeding without any localized ulceration. The biopsy findings in the skin, muscle and bone
marrow were confirmed. No evidence of malignancy or leukemia was present.
DISCUSSION
The diagnosis of polymyositis in this patient is based on the clinical picture
of marked muscle weakness, particularly of the proximal muscle groups,
limitation of joint motion due to muscular contractures in the absence of
arthritis or radiologic joint changes, and the findings of swelling, atrophy
and fibrosis of fibers with lymphocytic infiltration seen in the muscle biopsy.
There were no changes in the skin to suggest scleroderma nor were the rash
and edema specific for the diagnosis of dermatomyositis. However, the pathologic process in the muscles is felt to be the same in polymyositis and dermatomyositis, regardless of the presence or absence of dermatologic manifestation~.~
The elevation of the serum uric acid, a known effect of the administration
of all thiazide diuretics, led to an erroneous diagnosis of gout. When hydroflumethiazide was stopped, the serum uric acid level was normal.
Polymyositis beginning in the eighth decade, although unusual, has been
observed previously. When the disease begins after middle age, it is frequently associated with an occirlt malignancy3 but none was present in this patient.
Radiologic demonstration of absent peristalsis in the lower esophagus has
been described in polymyositis as well as in scleroderma, although weakness
of the laryngeal muscles with consequent difficulty in swallowing is more
~ o m m o nThis
. ~ patient had no symptoms attributable to the lack of peristalsis.
The possibility that the aplastic anemia might have been due to a drug
was considered, but does not seem likely. Thiazide derivatives have been
implicated in thrombocytopenia and leukopenia5 b J t the interval of. five
months between the time when the hydroflumethazide was stopped and the
appearance of the anemia weighs heavily against its being the causative
agent. It is certain that he did not receive phenylbutazone or gold compounds
or any of the other medications known to cause aplastic anemia. Such toxicity
has not been observed with colchicine or probenecid which were the medicines he was taking.
Both polymyositis and aplastic anemia are uncommon diseases but their
rare occurrence in the same patient may merely represent the incidence expected through chance. Since the etiology of both conditions is unknown, no
speculation regarding their relationship seems reasonable.
SUMMARY
A 71 year old man with polymyositis developed fatal aplastic anemia. The
appearance of both these diseases in the same patient has been reported but
once before.
278
L. A. HEALEY
REFERENCES
1. l’agel, W., Woolf, A. L., and Asher, R.:
Histological observations on dermatomyositis. J. Path. & Bact. 61:403, 1949.
2. Duncan, P. R., Harvey, P. W., and Seville,
R. H.: Derinatomyositis presenting as
aplastic anemia. Brit. J. Dermat. 71:
‘
344, 1959.
3. Pearson, C . M.: Polymyositis and dcrmatomyositis. Bull. Rheum. 13s. XII: 269,
1962.
4. Donoghue, F. E., Winkelmann, R. K., and
Moersch, H. J.: Esophageal defects in
dermatomyositis. Ann. Oto. Rhin.
Laryn. 69: 1139, 1960.
5. Zuckerman, A. J., and Chazan, A. A.:
Agranulocytosis with throinbocytopenia
following chlorothiazidc therapy. Brit.
M. J. 1:1338, 1958.
Discussion
THE EXTREME RARITY with which both
polymyositis and aplastic anemia have occurred in the same patient has been emphasized by Dr. Healey in the preceding case
report. In the nearly 60 cases of either polyor dermatomyositis that I have followed
during the past several years, anemia has not
been it significant clinical problem in any of
them, and leukopenia or thrombocytopenia
were not observed. In the present case,
there is almost no doubt that a clinical diagnosis of chronic polyinyositisl can he made.
In this form, the progression of the diseass
process is insidious, fibrosis and contractures
of muscles appear commonly, and there occurs a distinct overlap between niyositis and
the clinical features of rheumatoid arthritis
on the one hand and scleroderma on the
other. Many of these aspects are noted in the
present case, in which contractures, pain in
the regions of joints, and radiographic esophageal changes are all described. It would
have been helpful to have had the report of
an electromyographic study or to have
found elevation of the serum levels of some
enzymes. In the very chronic cases, however,
only a few selected enzymes, such as aldolase, may be slightly raised. However, they
were not looked for.
Tlie main problem, then, is the concurrent
presence of the aplastic anemia. its cause
and its association (if any 1 with polymyositis. In a recent report, Havard and Scott2
have carefully analyzed 101 cases of aplastic
or refractory anemia and havc conclndecl
that t l i e s ~anemias compose a heterogeneons
group in which the rolo of the hone marrow
cellnlarity and responsiveness, a low grade
hemolysis, the status of splenic function and
other factors each vary in individual cases
so that the only common links are an ignorance as to the underlying cause and failure
of response to available treatment. In none
of their cases was a myopathic weakness
mentioned, which again stresses the individuality of these two conditions. Although it
is tempting and often satisfying to explain
various clinical manifestations of rare syndromes on a common or single cause, I believe that in the present case such is not
possible with the clinical and pathological
information that we possess today on each
of these conditions. Hence, I agree with Dr.
Healey’s reluctance to speculate about an
intcrrelationship between thein, and with his
conclusion that they probably represent
the occurrence to two coincidental disorders
in a single individual. I likewise agree that
contact with the few drugs this patient took
was too brief, and the bone marrow depression too persistent to be rationally explained
on this basis.
Since we are at the moment engaged in an
intellectual exercise concerning a disease
of the skeletal musculature and the hematological tissues, what other processes could
conceivably affect both of these tissues, produce symptoms in each of them and thereby
link these two rare and apparently unrelated
disorders to a common cause? I could think
of two further possibilities, neither of which
seems to be too likely in the case under discnssian. but either of which cannot be fully
dismissed. A ) MyasthcniLi gravis, a disorder
in which miiscle weaknws is proniinent. has
been associated with n benign or riialigiiant
thynioma in a significant number of cases.
In fact, it is now considered in many quar-
279
POLYMYOSITIS AND APLASTIC ANEMIA
ters as an autoimmune disease.3 Admittedly,
the weakness of myasthenia gravis is usually
variable, being intensified by exertion and
relieved by rest. However, in certain cases
a relatively constant amount of myopathic
weakness has been noted so that permanent
inyopathic features are not unheard of.
Furthermore, the rare but unequivocal
association of hyporegenerative anemia4
and pancytopenia5 with a benign thymoma is
to be noted. In the present case it would
have been reassuring to have known the rcsults of a Tensilo& test or to have had R
clear statement about the absence of thymic
tissue. €3) Carcinoma is occasionally responsible, in a manner yet to be clarified,
for refractory anemia which is not due to
direct bone marrow invasion. Moreover, the
incidence of polymyositis in conjunction
with carcinoma is much greater, especially in
men over 40 years of age,l than would be
expected by mere chance association of
these two conditions. Hence, a causal relationship is implied. In one of our cases of
progressive dermatomyositis, which was also
refractory to corticosteroid treatment, an
occult carcinoma of the lung was only found
at autopsy after routine histological sections
of the mediastinal nodes had revealed the
presence of tumor. Whether such an occult carcinoma could have been present in
the case under discussion here seems unlikely, and yet is worthy of passing mention.
CARL M. PEARSON
REFERENCES
1. Pearson, C. M.: The patterns of poly2.
3.
4.
5.
myositis and their responses to treatment. Ann. Int. Med. 59:827, 1963.
Havard, C. W . H., and Scott, R. B.:
Refractory anemia. A disease or a syndrome. Lancet 1:461, 1963.
White, R. G., and Marshall, A. H. E.:
The autoimmune response in myasthenia gravis. Lancet 2:120, 1962.
Soutter, L., and Emerson, C. P.: Elective
thymectomy in the treatment of aregenerative anemia associated with
monocytic leukemia. Am. J. Med. 28:
609, 1960.
Barnes, R. D. S., and O’Gorman, P.: Two
cases of aplastic anaemia associated
with tumours of the thymus. J. Clin.
Path. 15:264, 1962.
DR. HEALEYis to be congratulated on his
excellent report of a most unusual occurrence of polymyositis and aplastic anemia
in the same patient. The weakness of the
proximal groups of muscles, the histologic
evidence of muscular degeneration and inflammation and the demonstration of only
a few formed elements in the bone marrow
support the diagnoses. Might these conditions be related? The only potential common denominator that this discussant can
call to mind is a neoplasm, which might
have explained both the myopathy and pancytopenia. There is a great deal of current
interest in the association of thymoma with
hoth polymyositis and aplasia of bone marrow. Postmortem examination presumably excluded these possibilities.
The cause of polymyositis is, of course,
totally unknown. And while the cause ot
aplastic anemia is often similarly unidentified, the list of drugs and chemicals which
can cause an acellular marrow seems to
grow with every report on the subject. Despite the patient’s denial, it is not unlikely
that he was exposed to some toxic substance
which poisoned his marrow. In this connection and for purposes of this discussion,
I would take mild issue with Dr. Healey
in his assertion that colchicine does not
cause aplastic anemia. That colchicine can
do this has been shown frequently following its administration in large and toxic
doses for the treatment of cancer.12 The
inhibiting-effect of colchicine upon mitosis
is well established. To my knowledge aplastic anemia has not been observed following
the use of colchicine in the usual anti-gout
doses, although I suppose this could occur.
There have been several instances of
agranulocytosis following the use of colchicine analogs in acute gouty arthritis.3 I
have seen one patient whose fatal aplastic
anemia followed the intravenous administration for acute gout of one of these analogs,
desacetylmethlcolchicine ( Colcemid ) .
EPHRAIMP. ENGLEMAN
REFERENCES
1. Brown, W. O., and Seed, L.: Effect of
Colchicine on human tissues. Amer. J.
of Clin. Path. 15:189, 1945.
2. Eigsti, 0. J., and Dustin, P.: Colchicine.
(Iowa State College Press) 183, 1955.
280
3. Wallace, S. L.: Colchicine analogs in the
treatment of acute gout. Arth. & Rheum.
2:389, 1959.
THISELDERLY PATIENT has a proposed relationship between aplastic anemia and polyinyositis. As the author has noted this relationship is most unusual, and he refers to
2 reports in the literature that have incomplt.te documentation of the clinical course.
The patient in this report during the 5
months prior to the onset of pancytopenia
had received colchicine and probenecid.
Thc author is reluctant to incriminate these
drugs. I would agree that the historical we
of colchicine would make it an unlikely offender. Can we accept such a benign status
for probenecid?
This drug was introduced into active clinical use a decade ago. Since that period
there have been repeated reports regarding
mild gastrointestinal irritation; i.e., pyrosis
and mild epigastric'pain.1 In addition a small
group of patients with skin rashes have been
observed following short or prolonged use of
probenecid. One patient has been described
with drug fever as well as eosinophilia.1
These reports imply that we have a potential but rare drug offender. Since the
basic structure of this uricosuric agent is
related to sulfonamides, it would be expected that similar drug reactions could be
encountered.
In rare instances serious complications
have been associated with this drug. These
relationsliips vary from induction of the
nephrotic syndrome2 to liver necrosis.3 In
the series of cases of acquired aplastic anemia
by Scott et al., one patient receiving probenecid and penicillin developed an aplastic anemia.4 This reviewer believes that the reports of cellular toxicity already imply that
wc may expect a similar spectrum of response that has accumulated slowly with
the sulfonamide drugs during the past 25
years. Certainly this complication could be
attributed to the 5 months of probenecid
therapy. Probably this type of reaction should
be on file with Registry of Blood Dyscrasias.5 While we cannot with certainty attribute this particular case of aplasia to a
specific drug, only the accumulated experience will tell us the rare dangerous con+
plications of the drugs we are willing to
L. A. HEALEY
use readily.
The onset of pancytopenia may be insidious, especially when the patient has
limited activity from muscular weakness.
It is unusual to see bone marrow aplasia
after the age of seventy. Most patients
would have an acquired type of aplasia in
this age group; the great majority related
to drug ingestion.
The report by Pagel et al. in this report
herein refers to a 13 year old boy with prolonged fever. \Ye may wonder what antipyretic drugs could have been used that
might have been insulting to the bone
marrow. This comment does not propose
to ignore the suggestion that aplasia may bc
related to polymyositis. Rather this is a plea
for all physicians to recognize that many
drugs in common use do have rare complications that may be of the same order of
possibility as noted in this case report.
This poses a dilemma that will remain nnsolved with our present techniques of evalnating cytological toxicity.
FRANKH. GARDNER
REFERENCES
1. Bartels, E. C., and Matossian, G. S.:
Gout-A
six year follow-up on Probenecid (Benemid) therapy. Arthritis
and Rheum. 2:193, 1959.
2. Ferris, T. F., Morgan, W. S., and Levitin,
H.: Nephrotic syndrome caused by
Probenecid. New England J. Med. 265:
381, 1961.
3 . Reynolds, E. S., Schlant, R. C . , Gonick,
H. C., and Dammin, G. J.: Fatal inassive necrosis of the liver as a nianifestation of hypersensitivity to Probenecid.
New England J. Med. 265:592, 1957.
4. Scott, J. L., Cartwright, G. E., and Wintrobe, M. M.: Acquired aplastic anemia;
an analysis of thirty-nine cases and
review of the pertinent literature. Medicine 58:119, 1959.
5. Erslev, A. J., and Wintrobe, M. M.: Detection and prevention of drug-induced
blood dyscrasias. J.A.M.A. 181:114,
1962.
IT IS quite true we cannot be certain the
pancytopenia in this patient was not due
to drugs, but as Dr. Gardner points out,
such a hematologic complication of pro-
281
POLYMYOSITIS AND APLASTIC ANEMIA
benecid would be rare, if not unique. Following his suggestion, this case is being reported to the Registry of Blood Dyscrasias.
The antimitotic effect of colchicine is usually dose-related and thus depression of the
white and red blood cells more likely io
occur when the drug is given intravenously
and in large doses. This man took one 0.5
mgm. tablet daily which is a small dose
indeed. Recently we have seen a 36 year old
man with gout who developed a severe aregenerative anemia (hematocrit 18 per cent )
without leukopenia while taking 1.0 mgm.
of colchicine a day. However, it is not pos\ible to prove or disprove a causal relation
in these instances.
Anemia, leukopenia, thronibocytopenia,
arteritis, splenomegaly and other visceral
inanifestations are not unusual in systemic
lupus erythematosus or rheumatoid arthritis.
Their rarity in polyniyositis is puzzling when
one considers the frequent similarities of
polymyositis to the other two diseases, especially early in the course. The profound
marrow failure in this case is not considered
to be a manifestation of the connective tissue disease.
The question of a thymoma raised by Dr.
Engleman and Dr. Pearson is very pertinent.
At post-mortem examination, the neck and
upper mediastinurn were investigated and
no thymoma or thymic tissue was present.
An asymptomatic neoplasm would have unified the disparate elements of this illness
and if detected, its removal might have led
to a remission of both the myositis and the
anemia. Despite diligent search before
death and after, none was found. If present
in this patient, the neoplasm was truly ocL. A. HEALEY
cult.
L. A. Healey, Formerly, Staff Physician, The Community Hospitat at Glen Cove, N . Y.; Presently, Instructor in Medicine,
University o f Washington, Seattle, Washington.
Carl M . Pearson, M.D., Associate Professor of Medicine, The
Center for the Health Sciences, University of California, Los
Angeles, California.
Ephraim P. Engleman, ILI.D., Director Arthritis Clinical Study
Center and Rheumatic Disease Group, University of California School of Medicine, San Francisco, California.
Frank H. Gardner, M.D., Peter Bent Brigham Hospital, Boston, hlassachusetts.
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