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.