Thymoma, myasthenia gravis, erythroblastopenicanemia and systemic lupus erythematosus in one

patientH. L. N. MacKechnie, m.d., A. H. Squires, m.d., f.r.c.p.[c], M. Platts, m.d., f.r.c.p.[c] andW. Pruzanski, m.d., f.r.c.p.[c], f.a.c.p., Toronto

Summary: A 50-year-old woman whoinitially had myasthenia gravissubsequently presented with thymoma,erythroblastopenic anemia andsystemic lupus erythematosus during17 years of follow-up. In a reviewof the literature no similar documentedcases were found, although 14 patientswere reported with three of the abovediseases, two also having positive LEcell tests. An association of severalautoimmune disorders in one patientmay be more frequent than was

previously believed.

Resume: Thymome, myasthenie grave,Srythroblastope'nie et lupus eryth6mateuxdissSmine observes chez une maladeUne femme de 50 ans qui avait

anterieurement souffert d'une myastheniegrave presenta subsequemment un

thymone, une erythroblastopenie et un

lupus erythemateux disseminependant les 17 ans ou elle a ete suivie.Une revue de la litterature sur lesujet n'a pas permis de decouvrirun seul cas identique, bien qu'on aitsignale trois des pathologiessusmentionnees chez 14 malades,dont deux avaient egalement descellules LE. Nous concluons que lacoexistence de plusieurs maladiespar auto-immunisation peutse rencontrer chez un meme maladeplus souvent qu'on ne le croyaitauparavant.

The coexistence of thymoma with var¬ious autoimmune disorders has frequent¬ly been reported. For 17 years we havekept under our surveillance a patientin whom were associated thymoma,myasthenia gravis, erythroblastopenicanemia and systemic lupus erythema¬tosus. The occurrence of these four con¬

ditions in the same person, to our

knowledge, has never been well docu-

From the Immunoproteins Research Laboratoryof the University of TorontoRheumatic Disease Unit,Departments of Medicine and Pathologyof The Wellesley Hospital, Toronto

Supported by Grant-in-aid of theCanadian Arthritis and Rheumatism SocietyReprint requests to: Dr. W. Pruzanski,The Wellesley Hospital, 160 Wellesley St. E.,Toronto 5, Ont.

mented. Siguir et al1 in 1969 and Zou-panos, Saegesser and Schneider2 in 1970each reported a patient with thymoma,myasthenia gravis and erythrocyteaplasia. Although both patients ex-hibited the LE cell phenomenon, no

definite clinical or pathological evid¬ence of systemic lupus erythematosuswas provided.Case report

J. M. was admitted to hospital for thefirst time in January 1954 when she was

aged 33. She had not been feeling wellfor approximately three months and was

mentally depressed. Since childhood shehad developed urticaria during the straw-berry season; otherwise she had enjoyedgood health. Her family history was non-

contributory. Results of the physical ex¬amination were negative. She was treatedwith insulin shock and psychotherapy, andwas able to return to her job.

In March 1955 she was referred to theOntario Department of Health with a

five-month history of muscular weakness,mainly of proximal type, ptosis of theright upper lid and mild dysphagia, theonset of which followed an upper respira¬tory illness. The diagnosis of myastheniagravis was made and the patient wastreated with prostigmine. The weaknessprogressed, however, and she developedmild shortness of breath on walking oneblock. A chest radiograph showed thepresence of a shadow 5 cm. in diameterinterpreted as a thymic mass. The patientreceived cobalt irradiation of 3000 radsand a remarkable shrinkage of the masstook place. Over the next three years herstate remained unchanged.

In 1958 the patient's condition deteri¬orated. The complaints mentioned were

persistent but there was no diplopia, dys-arthria or leg weakness. Slight exacerba-tions of myasthenia followed one to threerespiratory infections per year, and weretreated with Mytelase chloride® (am-benonium chloride) 12.5 mg. four timesdaily.

In 1960 the patient first noticed blanch-ing and numbness of the fingertips on

exposure to cold. In 1963 she began no-

ticing increasing fatiguability, shortness ofbreath and postural vertigo, and was ad¬mitted to hospital. On admission she re¬lated a history of arthralgia and inter¬mittent swelling of the proximal inter-phalangeal joints. She looked chronicallyili and her speech was slurred. Myopathic

facies and ptosis of the right eyelid wereevident. Blood pressure was 125/85 mm.

Hg; pulse was 100 and regular. A freelymobile thyroid nodule, 3 cm. in diameter,was found. There was no hepato- or

splenomegaly or lymphadenopathy. Onexamination the skin appeared normal.Full extraocular movements were present.The uvula was directed to the right. Therewas weakness of the muscles of the neckand arms, more prominent proximallythan distally, especially on the right side.Sensation and reflexes were normal.Hemoglobin was 8.9 g./100 ml., reticu-

locytes 0.05%. The leukocyte count was8100/c. mm. with a normal differentialcount, and the platelet count was 457,000/c. mm. ESR was 113 mm. in the firsthour. Bone marrow was hypocellular withcomplete absence of erythrocyte pre-cursors. Albumin was 4.06 g./lOO ml.,gamma globulin 1.76 g./lOO ml. Anti-nuclear factor test was positive. LE celltest was strongly positive on three occa¬sions. Latex test was non-reactive. BUNwas normal. PBI and radioactive iodineuptake were normal. A thyroid scanshowed a functioning nodule in the leftlobe.

FIG. 1.Lymphorrhage in right deltoidmuscle biopsy. Lymphocytes in connectivetissue between striated muscle fibres.x 200

CMA JOURNAL/OCTOBER 20, 1973/VOL. 109 733

She was given 1500 ml. of whole blood.The reticulocyte count was unaffected bythe discontinuation df Mytelase chlorideor the later administration of Mestinon®(pyridostigmine bromide). Methandroste-nolone was begun but no response oc¬curred.Over the next year her hemoglobin was

kept at a normal level with transfusionsof packed cells, two units being givenevery two to three months.

In May 1964 the patient was read-mitted. The physical findings were un¬

changed. Hemoglobin was 10.1 g./lOOml., ESR 72 mm. in the first hour. Serumprotein electrophoresis was normal. LEcell test was strongly positive. Both Kelland thyroid antibodies were found. Uri¬nalysis yielded normal findings. Electro-myography showed a typical myastheniepattern. A biopsy of the right deltoidmuscle showed minimal myopathicchanges with lymphorrhages (Fig. 1). Re-peat bone marrow aspiration showedmarked erythroid hypoplasia. A course ofprednisone 60 mg. per day resulted inreticulocytosis, rise in hemoglobin (Fig. 2)and prominent increase in erythroid ele-ments in the bone marrow. The LE celltest became negative. However, the myas¬thenia relapsed and the patient developedpolydypsia with glycosuria. Prednisonewas gradually reduced to 5 to 10 mg./day, and instead of Mytelase chloride,Mestinon timespan® was given with ex¬cellent results. The LE cell test remainednegative until September 1965.

In 1967 her serum test was negativefor anti-DNA, weakly positive for anti-SS DNA and strongly positive for freeDNA. Hemoglobin fluctuated from 8 to12 g./lOO ml. without blood transfusionsuntil April 1970 when the patient devel¬oped intermittent arthralgia of hands andwrists and a pericardial friction rub.Hemoglobin was 10.4 g./lOO ml. and theLE cell test became strongly positive.Prednisone was increased to 20 mg./dayand by August 1970 the friction rubwas gone. Prednisone was then reducedto 10 mg./day.

In August 1971 she was hospitalizedfor the last time, with complaints ofgeneralized muscle weakness and shortnessof breath on exertion. She had somedifficulty with chewing and occasionalregurgitation. There was no history ofparoxysmal nocturnal dyspnea and onlyoccasional swelling of the ankles at theend of the day.

She appeared chronically ili. On ex¬amination, the chest was clear; a leftparasternal ejection murmur was heard,maximal at the second to fourth inter-space. There was no hepato- or spleno-megaly or lymphadenopathy. Neurologicalexamination revealed easily fatigued eyemuscles with slight ptosis of both uppereyelids, and the neck and arm weaknesspreviously noted. The thyroid nodule wasunchanged.Hemoglobin was 6.2 g./lOO ml., ESR

92 mm./hr., Coombs' test, direct andindirect, was negative. No antibodies werefound against DNA or single strandedDNA. No free circulating DNA was de-tected. The total hemolytic complementwas 178 CHU50 (normal range 180-260CHU50). Ham's test for hemolysis was

negative and osmotic fragility was normal.Calcium was 8.9 mg., phosphate 4.0 mg.,bilirubin 0.7 mg., BUN 24 mg. and crea¬tinine 0.65 mg./100 ml. Urinalysis yieldednormal findings. Two 24-hour urine col-lections showed protein values up to 168mg./24 hours. Creatinine clearance variedfrom 44.9 to 55.4 ml./min. ECG showednonspecific abnormalities. Thyroid scanshowed slightly decreased uptake at theperiphery of the right lobe, but the 24-hour value for total uptake was normal,

29%, and the T4 level was 6 Mg./100 ml.Bone marrow showed severe erythroidhypoplasia with myeloid:erythroid ratioof 100:1 (Fig. 3). A further course ofprednisone, 100 mg. per day, was givenin an attempt to induce a remission inthe erythroblaatopenia. However, therewas no reticulocytic response and thehemoglobin continued to fall (Fig. 2). Anaortic systolic and diastolic murmur wereheard, the latter for the first time.

In October 1971 the patient developedPREDNISONE MG/DAY

\h\

12

10

. 8

. 6

4

I- 2

S09

3 4WEEKS

SEPT16

1971

2 3WEEKS

FIG. 2.Graph showing response of reticulocytes and hemoglobin to prednisoneadministration. Arrow denotes blood transfusion.

FIG. 3.Bone marrow showing a marked decrease in number of cells of the erythroidseries. x250

734 CMA JOURNAL/OCTOBER 20, 1973/VOL. 109

fever, tachycardia and tachypnea. Rightlower lobe pneumonia was diagnosed, andshe was given antibiotics; some improve¬ment followed. However, on the eveningof October 24, 1971, 20 minutes afterreceiving an oral dose of 12.5 mg. ofMytelase chloride, the patient was founddead.

At autopsy the immediate cause ofdeath was found to be bronchopneumonia.Situated in the anterosuperior mediastinumwas a white, hard, cystic mass measuring

FIG. 4A.Wall of mediastinal cysticmass showing dense connective tissuewith calcification. This represents theresiduum of the irradiated thymoma.x 12.5

2x2x1 cm. Its wall was composed ofdense collagenous connective tissue withfoci of calcification (Fig. 4A). A fewnests of epithelioid cells and lymphocyteswere present in the wall and occasionalHassaFs corpuscles were noted in im-mediately adjacent fat (Fig. 4B). Becauseof the anatomical situation of this massand the presence of both epithelioid cellsand Hassall's corpuscles, it was thoughtthat it represented the thymoma notedradiologically and subsequently destroyedby irradiation.

Muscles showed scattered atrophicfibres but frankly necrotic fibres andlymphorrhages were not seen. The bonemarrow showed a marked decrease incells of the erythroid series as well asmarked hemosiderosis. Hemosiderosiswas also present in the liver and spleen.There was no evidence of extramedullaryhematopoiesis.The right kidney weighed 120 g. and

the left 150 g. Both had moderatelygranular cortical surfaces. Basementmembrane thickening was evident in manyglomeruli. This was mild in degree inmost, but in a few, "wire-loop" forma-tions typical of lupus erythematosus were

FIG. 5.Renal glomerulus withbasement membrane thickening, showing"wire-loop" lesion typical of lupuserythematosus. x 125

noted (Fig. 5). Capsular thickening hadoccurred in some glomeruli while otherswere totally sclerotic. A few tubules con¬tained hyaline casts.The heart was increased in weight to

350 g. owing to left ventricular hyper-trophy. The aortic valve showed large fi-brinous vegetations adherent to the lateralventricular surfaces and the commissure oftwo cusps as well as to their inner surface(Fig. 6). The valve was normal other¬wise. Microorganisms were not seen inthese vegetations. Although they did notpresent the classical appearance of Lib-man-Sacks endocarditis, it was thoughtthat these organizing aortic vegetationswere related to the presence of lupuserythematosus. Fibrous pericardial adhe¬sions were noted as well as fibrous pleuraladhesions.

Other findings were a microfollicularadenoma of the left lobe of the thyroidgland with fibrosis and atrophy of therest of the thyroid parenchyma, adrenalcortical atrophy, and a small superficialulcer of the duodenum.

Discussion

The association of thymic hyper¬plasia or thymoma with various mani¬festations now thought to be of auto¬immune origin has long been known.A classical example is the associationof thymoma and myasthenia gravis.8'4Similarly, thymoma complicated byerythroblastopenic anemia has beenfrequently reported.5*6 Cases of thy¬moma and systemic lupus erythema¬tosus7 and others of myasthenia gravisand systemic lupus erythematosus8 havealso been reported.Of the four above-mentioned dis¬

eases, thymoma, myasthenia gravis,systemic lupus erythematosus and ery-throblastopenia, a combination ofthree has been recorded in only 14instances (Table I).1-2-9-20 The existenceof all four conditions in one patient, tothe best of our knowledge, has never

«¦ «-h , , d CM 1 2 3FIG. 4B.Hassall s corpuscle in adiposetissue in the cyst wall shown in Fig. 4A. FIG. 6.Organizing fibrinous endocarditis of aortic valve cusps, consistent with

x 250 Libman-Sacks endocarditis (vertical marks indicate centimetre measurements).

736 CMA JOURNAL/OCTOBER 20, 1973/VOL. 109

been well documented, although a posi¬tive LE cell test was recorded in twopatients who had the other three con¬

ditions.1'2 In several of the above-men-tioned cases various circulating anti¬bodies have been found. These in¬clude antinuclear factor,1418,20 anti-DNA antibodies,15'16'19 anti-thyroidantibodies15 and skeletal muscle anti¬bodies.14'19 No rheumatoid factor was

detected in the sera tested.1516'19Our patient first presented clinically

with myasthenia gravis confirmed byelectromyography, muscle biopsy anda remarkable response to anticholines-terase agents. Five months later an

anterior mediastinal mass was detectedand irradiated. At autopsy, remnantsof thymic tissue wth cystic formationwere seen in that area.The erythrocyte hypoplasia was do¬

cumented by several bone marrow as-

pirations. It is of interest that at theonset of the disease the administrationof steroids induced proliferation oferythrocyte precursors in the bone mar¬row and disappearance of the anemia.No such effect was observed in the latestage of the disease.

Systemic lupus erythematosus was

clinically manifested mainly by in¬

volvement of the peripheral vessels,joints and pericardium. LE cell testwas repeatedly positive except during16 months of clinical remission. Al¬though no definite evidence for renalinvolvement was present during thecourse of the disease, at autopsy typicalwire-loop lesions were seen in theglomeruli. Other findings includedpericardial and pleural adhesions andLibman-Sacks-like vegetations on theaortic valve.The pathogenesis of the association

of thymic disorders and autoimmunediseases is not yet completely under-stood. A central role for the thymus inimmune surveillance has now been sug¬gested. Fudenberg21 has postulated thatproduction of physiologic autoanti-bodies is normally under the controlof "T cells". If these thymus-derivedcells are defective then there would bean increase in production of autoanti-bodies with eventual development ofautoimmune diseases. A similar pointof view was expressed by Osoba22 whopostulated that autoimmune pheno-mena may result from genetically de¬termined immunologic disease. For ex¬

ample, recent reports have shown a

high incidence of systemic lupus ery¬

thematosus with two specific histocom-patibility antigens, HL-A-8 and W15,incidences of 33 and 40%, as com¬

pared to control population levels of16 and 10% respectively.23According to others, some autoim¬

mune diseases may have a viral etio¬logy. For example, the SLE-like dis¬ease of NZ black mice is now thoughtto be due to immune complexes withviral particles as antigen.24

Whatever the etiology, there is clear-cut evidence that some conditions fre¬quently found in association may havean immunological background. It wasshown that intraperitoneal injections ofautologous or heterologous striatedmuscle or thymus cells into guineapigs results in the release of an agentwhich can produce a neuromuscularblock similar to that found in myas¬thenia gravis.25'26 This experimentalmodel can be further supported by thefinding of anti-skeletal-muscle anti¬bodies in 30% of patients with myas¬thenia gravis.25

Half of the patients with pure ery¬throcyte hypoplasia (or erythroblasto¬penic anemia) have also a thymoma.*7Conversely, 5 to 6% of patients withthymoma eventually develop this form

Table I.Immunological abnormalities in patients with thymoma, myasthenia gravis and/or erythrocyte aplasia andsystemic lupus erythematosus

Ref.no.

Age (yrs.)/sex T MG EA SLE

LEcelltest ANF

Anti- Anti- Anti-muscle thyroid Latex DNAab* ab* test ab* Comments

48/M + ND NDNDND ND ND Transient reticulocytosisafter thymectomy andafter splenectomy,sustained response withACTH

ND = not doneANF= antinuclear factor?Circulating antibodiesT = thymoma, MG = myasthenia gravis, EA = erythrocyte aplasia, SLE = systemic lupus erythematosus

CMA JOURNAL/OCTOBER 20, 1973/VOL. 109 737

of anemia."8 The immunological back-ground of this association has been sug-gested by showing that plasma from apatient with a thymoma and erythro-cyte hypoplasia could inhibit the effectof exogenous erythropoietin in poly-cythemic mice.'9 Further studies showedthat this plasma fraction was an IgG."OField e.t aP1 and Krantz and Kao"suggested that this antibody is not di-rected specifically against erythropoi-etin, but that it exerts its activity atthe stem cell level. Our case supportsthe concept of an immune basis of theerythrocyte aplasia since the adminis-tration of prednisone restored the ery-throblastic activity of the bone marrow,at least on one occasion. The lack ofresponse on the second occasion couldbe explained by irreversible atrophy ofbone marrow elements in the advancedstage of the disease. The favourableinfluence of steroids on bone marrowchanges in erythrocyte aplasia was seenby others, and recently immunosup-pressive agents were suggested as treat-ment of this condition;'", also, splenec-tomy was found to be of value in somepatients.1' Recently the response ofbone marrow in culture to erythropoi-etin has been found to be helpful indetermining response to treatment.'3The link between systemic lupus

erythematosus and other autoimmunedisorders has been repeatedly stressed.Development of hyperplastic changesin the thymus similar to those in my-asthenia gravis and even thymomashave been reported in systemic lupuserythematosus.i'3"The similar age of onset, female

predilection and clinical pattern ofmyasthenia gravis and systemic lupuserythematosus have led several authorsto suggest an association between thesetwo entities. As well, family studies ofpatients with myasthenia gravis haveshown a higher incidence of systemiclupus erythematosus than is found ina normal population.36 It is likely,furthermore, that the thymic disorderscommon to both have pathogeneticsignificance."7,3"On review of the literature no evid-

ence could be found to implicate anti-cholinesterase agents - the only medi-cation the patient received other thanprednisone - in either the drug-in-duced systemic lupus erythematosus syn-drome or erythroblastopenic anemia.Whatever the etiological factors(s),

it seems that an association of two ormore autoimmune disorders in one pa-tient (Table I) may be more frequentthan was previously believed. A pre-existing "central" immunological de-ficiency may be the common denomi-nator.

Our thanks are expressed to Dr. D. Osobafor his critical comments and discussion

of the case, to Mrs. R. Hajdinjak for per-formance of immunological tests, to MissM. Bliss for excellent photographic as-sistance, and to Mrs. Christine Onofreyfor her diligent preparation of the manu-script.

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31. FIELD EO, CAUGHI MN, BLACKETT NM, et al:Marrow suppressing factors in the bloodin pure red cell aplasia, thymoma, andHodgkin's disease. Br J Haematol 15: 101,1968

32. KRANTZ SB, KAO V: Studies on red celiaplasia. II. Report of a second patient withan antibody to erythroblast nuclei and aremission after immunosuppressive therapy.Blood 84: 11, 1969

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35. KOUGH RH, BARNES WT: Thymoma asso-ciated with erythroid aplasia, bullous skineruption and the lupus erythematosus cellphenomenon. Report of a case. Ann InternMed 61: 308, 1964

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738 CMA JOURNAL/OCTOBER 20, 1973/VOL. 109