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370

PULMONARY MANIFESTATIONS IN THESYSTEMIC COLLAGEN DISEASES*

By PHILIP ELLMAN, M.D., F.R.C.P.Conslultant Phlysician in Diseases of-the Chest, North-East Metropolitan Regional Hospital Board; and

Consultant Physician to the South-West Metropolitan Regional Hospital Board

(From St. Stephen's Hospital and Plaistow Hospital Chest Unit, London)

During the past decade, interest in the so-calledsystemic collagen diseases,' which are more

accurately described as connective tissue diseases,has spread and increased. The present conceptof them requires a brief explanation by way ofintroduction.

It is generally tunderstood that the connectivetissues of the body arise from the mesentchyme,and constitute most of the supporting structureswhich themselves include various serous mem-branes. Connective tissue varies in compositionin different sites, but is usually composed ofbundles of fibres (collagenous material) embeddedin mucoid ground substance (composed of muco-polysaccharides). Robb Smith (I954) has de-scribed the modern concept of disease of collagenbut the term was used by Klemperer (I950) tomean all the extra-cellular components of con-nective tissue. Klemperer held that the termreferred to the fact that alterations of the extra-cellular portions of the connective tissue wereprominent and systemic in various diseases. Itwould seem to embrace, as Banks (I941), amongothers, has suggested, such hitherto undiffer-entiated conditions as disseminated lupus ery-thematosus, polyarteritis nodosa, scleroderma,rheumatic fever and rheumatoid arthritis. Klem-perer considered these were related clinically andpathologically, as diffuse vascular and mesenchy-mal diseases. The typical lesion common to thegroup is 'fibrinoid change in connective tissue.'Klinge, in I933, first reported its occurrence inrelation to rheumatic fever, believing that itspathogenesis was an allergic tissue reaction, andthat fibrinoid degeneration of connective tissuewas a characteristic lesion in tissue hypersensi-tivity. To many observers, there is no doubt that

the unifying principle for the systemic collagendiseases is the assumed allergic aetiology of theseconditions, and the role of hypersensitivity inhuman disease is being explored and extended,particularly in relation to. this group of diseases.The similarity of their histopathology would

suggest a common pathogenesis, but a unitaryconcept for the widely differing clinical mani-festations is upheld by some observers, and notaccepted by others.There would, however, appear to be some unity

of vascular pathology founded upon an apparentlyuniform and diffuse arteritis. These diseasesoften show some common clinical manifestations,viz. fever, polyarthralgia, polyarthritis, anaemia,high sedimentation rate and, to a lesser extent,purpura, a Raynaud phenomenon, polyserositis,renal and pulmonary lesions. Of recent years,the development of steroids has opened the gateto further therapeutic possibilities.

I propose to confine my attention to the pleuraland pulmonary lesions, which are fairly commonin diffuse collagen disorders, and which haveinterested me for some years. In such conditions,one encounters changes varying from pleuraleffusions, partial consolidation, widespread reticu-lation, miliary mottling to chronic fibrosis andsclero-cystic lung disease (Ellman and Cud-kowicz, 1954). These lesions must be integratedwith the systemic clinical picture which involvesthe whole of general medicine.

Let us, therefore, first review the pleural andpulmonary lesions of disseminated systemic lupuserythematosus, and illustrate some of them by caserecords. The natural history of the disease, areview of the literature, the clinical picture of theacute, subacute and more chronic discoid type(with the latter little or no constitutional disorder)have been admirably described by Cohen andCadman (1953), who stress the close relationshipand gradation between these three types. Allinterested in the general aspects of this subject are

*Being the subject of an opening paper at a meetingof the British 'I'uberculosis Association in London onFebruary 17, I956. Iorld Cohen of Birkenhead was alsoan opening speaker at this meeting and his paper willbe published in a subsequenlt number of this journal.

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August 1956 ELLMAN : Pulmonary Manifestations in the Systemic Collagen Diseases 371

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referred to this comprehensive paper with itsrecord of i6 cases of the disease. Osler, in I895,recognized not only the systemic manifestationsof the disease, but the fact that pleuro-pulmonarylesions were among the visceral changes. Pleurallesions, both dry and moist, are indeed quitecommon, but pure' lupus pulmonary parenchymallesions' can and do occur, and have to be care-fully differentiated from secondary pulmonarybacterial infections which may complicate theterminal stages of the disease.

Various types of lung parenchymal involvementwere observed in 46 of I05 cases studied byHarvey et al. (I954). Israel (I953), recognizingthat the pulmonary manifestations of systemiclupus erythematosus may occasionally dominatethe clinical picture, urged the importance of care-ful search for the typical L.E. cells in the peri-pheral blood or marrow. These were firstdescribed by Hargraves et al. (I948). The typicalL.E. cell, which is more commonly found in acutecases, consists of a large mature polymorpho-nuclear neutrophil containing within its cellmembrane round or oval homogeneous (inclusionbody) material. The segments of the nucleus aredisplaced to the periphery, and only a thincrescent of cytoplasm can be seen. Around theedge of the mass ' rosettes,' aggregates of poly-morphonuclear neutrophils surrounding massesof homogeneous material, are frequently found, inassociation with cells. The absence of L.E. cellsfrom one single preparation is of little significance.

We have encountered these cells in acute pleural,pericardial and synovial effusions (Fig. i).

In cases that have come to autopsy, the lupuslung lesions are found to simulate closely those in' rheumatic pneumonia,' polyarteritis nodosa, theso-called 'anaphylactic pneumonitis,' and the lungsin 'serum sickness,' with such histological changesas focal necrosis of the alveolar walls with capillarythrombi, areas of organizing interstitial pneu-monia and haemorrhage and metaplasia of thebronchial epithelium.A brief comment on the clinical and radio-

logical aspects of three cases is perhaps instructive.Case I. S.W., typist, aged 35, with a 17-year

history of R.A., experienced in 1950 a suddensevere inspiratory pain in the left chest; shebecame rapidly dyspnoeic and developed a highpyrexia (temperature range 99-I04.6). She wasadmitted under my care with high swinging tem-perature, tachypnoea and acute swelling of theknees. She was wasted, her face and breastsshowed marked erythematous patches and manysmall telangiectases. She had marked cyanosis ofthe lips and fingers. The breath sounds werediminished at both bases, especially the right,crepitations were very audible at the left base andpericardial friction was well heard at the base ofthe heart. X-ray examination of the chest showeda right basal effusion with bilateral basal reticu-lation (Fig. 2). There was an effusion into bothknees, and a rheumatoid type of arthritic lesion.Blood cultures were negative. There was a poly-morphonuclear leucocytosis. Antibiotics had noeffect on the high pyrexia. L.E. cells were foundin the marrow and blood, and, in view of thegrave condition of the patient, she was givenACTH (90-60 mg. per day) which had to be dis-continued on the ninth day, despite subjectiveimprovement, because of a purpuric rash on thebuttocks and over the lumbar spine, and becauseof a rise in temperature. It was then decided totry the effect of o00 mg. of cortisone per day.Her rash disappeared rapidly, the temperaturesubisded, and she improved remarkably. Thelungs, however, showed little change clinically orradiologically. She subsequently kept reasonablywell, with occasional recurrences, which alwaysresponded to cortisone until she developed a

progressive renal lesion for which steroids pro-duced no remission, and she died on January 14of this year.

Case 2. J.M., female, aged 32. She complainedof sudden onset of swelling of the right knee andthe proximal interphalangeal joints of both handsin November, 1952. In April, 1954, she wasadmitted to hospital with left basal pleurisy.Subsequently, she had transient attacks of poly-arthritis and Raynaud's disease. On August I2,

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372 POSTGRADUATE MEDICAL JOURNAL August, 1956

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FIG. z.-X-ray chest from Case 2 of disseminated lupus erythematosus(D.L.E.) showing elevation of diaphragm, right basal effusion andreticulation at the bases.

i955, she was admitted to my chest unit as anemergency, with high pyrexia. Investigationrevealed pain in the chest, pleurisy at the leftbase, pericarditis, severe anaemia, marked leuco-penia, no thrombocytopenia, normal plasma pro-teins, although electrophoresis showed a slightexcess of gamma globulin. Blood culture andblood agglutinins were negative. The left basalpleurisy and pericarditis were confirmed radio-logically, and were associated with a character-istically high diaphragm. No L.E. cells werefound in the blood or marrow on repeatedexaminations, until mid-September, when shewas given Ioo units of ACTH daily, with rapidsystemic improvement. In October a butterflytransient erythematous rash over the face wasobserved. The dose was gradually reduced to15 units of Gel every third day. On December 17,1955, the equivalent dose of delta cortisone (pred-nisone) was administered, and she was dischargedfrom hospital on December 31 on a maintenancedose (io mg.) of this drug every third day. Sheremains entirely free from symptoms.Disseminated Lupus Erythematosus

Case 3. V.B., housewife, aged 29, complainedon April 6, I953, of vaginal bleeding, followingfour months of amenorrhoea. Fourteen days latershe complained of persistent vomiting; she hadmarked swelling of her face, and was very anaemicwith a haemoglobin of 50 per cent. The erythro-cyte sedimentation rate was 80. On April I3 shedeveloped an erythematous butterfly rash on the

face. She had a left basal effusion with some con-solidation of the left upper lobe (Fig. 3). Shewas gravely ill with high pyrexia and signs ofmeningeal irritation. L.E. cells were found in theperipheral blood. She responded well to full dosesof ACTH in hospital; her lung and other lesionssubsided (Fig. 4). Subsequently she was givenmaintenance doses of oral cortisone as an out-patient. This was discontinued in November,I953, since when her condition has been good.No L.E. cells have been found in the blood, andin November, I955, she had no anaemia and herE.S.R. was normal. I am indebted to my col-league, Mr Philip Harvey, under whose care thispatient was, for permission to include this case.

In all three cases involvement of the pleuraoccurred; in two of them with accompanyingeffusion, which is usually small, but was certainlymoderate in Case 2. In all three cases the episodesof pleurisy occurred at various periods during theillness.The striking feature in Case i was the tachy-

pnoea during the febrile stage, the progressivedyspnoea and cyanosis, the persistent crepitationsat the bases, and the evidence of acute pulmonaryinsufficiency. -There were some very dramaticremissions between 1950 and the time of herdemise on January 14, 1956. Fever, anaemia,leucopenia, polyarthritis, polyserositis, skin lesionson the face and breasts, and terminal nephriticlesions characterized her illness at various periods.This case, like many others, illustrates the markedelevation and fixation of both diaphragms with



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areas of plate-like atelectasis where crepitationsare heard in abundance. For the most part, theclinical and radiological signs are basal. Thedifferential diagnosis between tuberculous pleurisyand lupus pleurisy and virus and bacterial lunglesions is of clinical significance. In reaching adiagnosis, failure to respond to antibiotics and agood response to steroid therapy is helpful. Ihave been amazed at the clinical improvement inthe pleural and pulmonary lesions in the earlystages of the acute disease, usually within the firstweek of the initiation of steroid therapy. Inkeeping with the experience of most observers,the more acute the disease, the better the responseto steroid therapy, the introduction of which has,as Cohen and Cadman indicate, proved to be alandmark in the history of the condition. Further,like Cohen and Cadman, it has been my experi-ence that of all the collagen diseases, systemiclupus erythematosus secures the most favourableresponse to steroid therapy. Cortisone, deltacortisone and ACTH in sufficient dosage may allinduce therapeutic remissions of varying lengths,but they do not cure the condition, although thepatient is subjectively much more comfortable.Some regression of the pulmonary signs, althoughrarely complete, may occur, as well as a fall intemperature and an improvement in the sedi-mentation rate and the anaemia. The developmentand persistence of renal involvement is, in myexperience, a bad sign.The literature of lung changes in disseminated

lupus erythematosus has received attention else-where (Ellman and Cudkowicz, I954).Pulmonary Polyarteritis Nodosa

Although the disease was described almost ahundred years ago by Kussmaul and Maier, it islittle more than ten years since it was diagnosedclinically, and now at least 50 per cent. of casesare diagnosed ante-mortem. The pathologicallesion is that of a patchy, inflammatory, necrotizingarteritis with fibrinoid necrosis, involving all coatsof the small and medium sized arteries andreflected by symptoms dependent on the specificorgans involved. The weakened and necroticarterial wall may granulate and form multiplesmall aneurysms which sometimes give rise topalpable swellings beneath the skin or mucousmembrane. The clinical manifestations may be aconstitutional illness with local manifestationsresulting from arterial occlusion. Toxic mani-festations and multiple infarctions will accountfor the widespread polymorphic nature of thedisease.The onset is often acute, with high pyrexia

which fails to respond to antibiotics. Almost anysystem may be involved, including the kidneys,heart, lungs, nervous system, joints and ali-mentary tract. As Grant (I940) has stated, acomplete list of symptoms of the establisheddisease would covet almost the whole field of



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374 POSTGRADUATE MEDICAL JOURNAL August I956

medicine. The pulmonary manifestations to whichwe shall confine our attention are of considerableclinical interest, and may present problems indifferential diagnosis.Lung changes may precede those in other

organs by months or even years, and the clinicalpresentation may be that of ' asthma,' bronchitis,pleurisy or pulmonary infarction, or a pneumonicor broncho-pneumonic episode of miliary pattern.The lesion may closely simulate pulmonarytuberculosis, as was the case in at least three casesto be described here, and may go on to fibrosis,bronchiectasis, caseation and even cavitation.

G. A. Rose (1956) has carefully investigated forthe Medical Research Council some IIo cases ofpolyarteritis nodosa, and some 40 cases havepresented with a pulmonary manifestation whichhas usually manifested certain features not charac-teristic of polyarteritis as a whole. These aregenerally associated with high blood eosinophilia,nasal granulomata and pathologically a range ofnecrotizing and granulomatous lesions not demon-strably related to the arteries.

Klinge (I931), Wegener (1936) and others havereported combined necrotizing granulomatouslesions in the lungs, kidneys, nose, etc., which areborderline types of polyarteritis, sometimes withmassive necrosis in the lungs. In some cases fociof necrosis surrounded by palisaded cells withjoint lesions have been interpreted as rheumatoidlesions. Indeed, necrotizing arteritis and giant cellformation in the lungs has been thought by Pagel(1951), in a paper on polyarteritis nodosa and therheumatic diseases,' to represent a close relation-

ship. The radiological picture can vary fromscattered areas of consolidation to miliary infiltra-tion, fibro-caseous disease closely simulating thatof pulmonary tuberculosis, and pleural effusion,usually in combination with a pleural eosinophilia.As already noted, Rose (I955) has shown that thepulmonary cases may precede systemic poly-arteritis nodosa by periods varying from one toseven years, and the high blood eosinophilia ofour own cases has also been observed. He classi-fied this group under the title ' eosinophilic poly-arteritis,' and there would appear to be consider-able clinical support for this designation or that ofpulmonary polyarteritis, where the presentinglesion is pulmonary in type.My experience of a limited number of cases

originating with symptoms in the respiratorytract, frequently asthmatic in nature, has shownthat eosinophilia was almost invariable and thatbronchial or pulmonary lesions were common.In such cases, pulmonary polyarteritis shouldcertainly be suspected, and the relationship ofthis type of polyarteritis with that of pulinonary

eosinophilia (Crofton et al., 1954) appears veryclose.

Case i. A.E., housewife, aged 41, seen by mein I943. She presented with attacks of breathless-ness and wheeziness, polyarthralgia, petechae onthe face, chest and fingers, and bouts of bloodydiarrhoea. She was febrile, the chest symptomswere predominant and a competent radiologisthad reported tuberculous infiltration of the rightupper zone in response to which an enterprisinggeneral practitioner was about to induce a rightartificial pneumothorax. The patient, however,had second thoughts, and I was asked to see herin consultation. It is true that the lung infiltrationwould, on radiological appearances, have beencompatible with pulmonary tuberculosis, but thehistory and clinical examination showed suchpleomorphic changes that I unhesitatingly calledfor further investigations before instituting theA.P.To summarize: The fever, anaemia, a leuco-

cytosis of 33,000 with an eosinophilia of 6i percent., an E.S.R. of 41 and the findings alreadynoted were responsible for the diagnosis of poly-arteritis nodosa on clinical grounds. The diag-nosis was subsequently confirmed by Sir ArthurHurst and Professor Witts, a course of N.A.B.was recommended and this produced a temporaryremission. The lung infiltration resolved, but waslater followed by a pericardial effusion.

Case 2. P.T., housewife, aged 40, complainedof polyarthralgia and polymyalgia of several years'duration. She had left-sided pleurisy in I951.She was admitted to sanatorium in September,I955, following an attack of influenza, as a case ofacute pulmonary tuberculosis with radiologicalevidence of infiltration and cavitation in the leftupper zone, the infiltration extending into the leftmiddle zone.

In view of the acute lesio n, she was immediatelyput on a course of daily streptomycin, I g., andPAS, 20 g., without any real improvement.Numerous sputum examinations were negative.The history showed that for the previous 18months she had had a cough with a little muco-purulent sputum as well as nocturnal wheezing forat least six months. Because of this wheezing, herhusband insisted on her going to the chest clinic.I saw her in consultation after seven weeks ofsanatorium treatment. The sputum was per-sistently negative for A.F.B. and showed numerouseosinophils and Charcot Leyden crystals. Theblood count showed no anaemia, but a leucocytosisof I8,500 with 53 per cent. of eosinophils. Elec-trophoresis of plasma proteins showed slight excessof gamma globulin. The Mantoux test waspositive.She was admitted to my chest unit. The blood



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of left upper and middle zones with cavitationsimulating pulmonary tuberculosis with no responseto antibiotics.

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eosinophilia persisted and although, apart fromthe polyarthralgia and myalgia, the lesion wasconfined to the lung, I regarded this as a case ofpulmonary polyarteritis. The response to steroidtherapy has been dramatic, producing relief ofsymptoms, almost complete resolution of the lung



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376 POSTGRADUATE MEDICAL JOURNAL August 1956

lesion and a dramatic fall in the eosinophilia(Figs. 5-8).

Case 3. S.L., housewife, aged 32. She wasadmitted to hospital in April, 1955, complainingof breathlessness in paroxysms, wheeziness, sweat-ing, cough and the expectoration of a drachm ofmucoid sputum for the past six weeks. She hadalso lost 2 stone in weight. In November, I954,she had had an attack of what her doctor called'asthma' and which lasted two days. She hadno further attack until six weeks before admission,when attacks of breathlessness were repeated.She had a high temperature (97-o10). There wasno significant past or family history.On clinical examination she looked ill and toxic,

she was breathless and wheezy, and there werescattered rhonchi throughout both lung fields.Her sputum was negative for A.F.B. by directsmear and culture, and the agglutinins were nega-tive. The serum proteins showed a total of 4 g.per cent., albumin 2.2 g. per cent., globulini.8 per cent., A.G. ratio 1.2 per cent. L.E. cellswere not found. The blood count showed aleucocytosis with persistent eosinophilia (seechart).X-ray of the chest showed scattered infiltration

of both lungs. She failed to respond to strepto-mycin and PAS, and was changed to izoniazid

and PAS. Her E.S.R. remained Ioo. On May 7I955, she was put on cortisone, ioo mg. daily,and dramatic clinical improvement took place.After 14 days the daily dose was reduced to 75 mg.By July 30, I955, her E.S.R. had dropped to 3,and her eosinophils were normal, she was asymp-tomatic and gained I stone in weight. She was

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FIG. I.--Chart of same case showing response ofeosinophilia to cortisone.



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August I956 ELLMAN : Pulmonary Manifestations in the Systemic Collagen Diseases 377

discharged on August 30, I955, on a maintenancedose of 121 mg. of cortisone with dipasic 200 mg.t.i.d. She has since been seen at monthly intervals,and remains asymptomatic. She has gained 2 stonein weight (Figs. 9-II).

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Case 4. R.G., housewife, aged 42, was treatedfor rheumatoid arthritis for I8 years. I first sawher in November, I953, when she was acutely illwith fever, anaemia, purpura, polyarthritis, amassive pericardial effusion, some basal pleuralinvolvement and, finally, glomerulo-nephritis.We came to the conclusion that she was a case ofpolyarteritis nodosa with joint, serous and renalchanges. L.E. cells were never found in herblood, marrow, joint, or pericardial fluid, andwhen she eventually died of uraemia autopsyexamination showed the characteristic changes,and histology confirmed the diagnosis of poly-arteritis nodosa, the lung histology being typical.The interesting feature in this case of apparentlylong-standing rheumatoid arthritis is its emergence18 years later as a polyarteritis nodosa.

Case 5. A.K.G., female, aged 55, single, hadsevere 'asthma' in May, I954. She was admittedto hospital under my care as a case of pulmonarytuberculosis with severe bronchospasm, anaemia,fever (temperature I02), cough and a table-spoonful of mucopurulent sputum in 24 hours.She had physical signs of a bronchitic naturethroughout both lungs and dullness and diminishedair entry at the left base, where she had a pleuraleffusion. X-ray examination showed a transientinfiltration in both lungs with a left pleural effusion.The blood count showed a haemoglobin of 70 percent., a white cell count of I4,600, and an eosino-

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FIG. 14.-Same case-almost complete resolution whichhas been maintained on a maintenance dose ofsteroid therapy.



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phil count of 40 to i8 per cent.; the E.S.R.was io. The pleural fluid showed a markedpleural eosinophilia. Numerous sputum examina-tions were negative for tubercle bacilli. Therewas a past history of polyarthralgia, and theresponse to ACTH was dramatic. For the past18 months it has been necessary to keep her ona maintenance dose to avoid relapse (Figs. I2-14).

Pulmonary SclerodermaFinlay (1891) recognized the association be-

tween pulmonary fibrosis and generalized sclero-derma; Goetz (i945), in view of the widespreadand sclerotic nature of the disease, has used theterm ' progressive systemic sclerosis'; Matsui(I924) described three patients with pulmonaryfibrosis and scleroderma in whom the total pul-monary artery bed was reduced and the rightventricle was enlarged. Varying degrees of diffusepulmonary fibrosis, fine nodulation and cystformation (sometimes almost becoming a honey-comb lung), as well as pleural fibrosis, may all beencountered in this disease. Interstitial thickeningof the alveolar basement membranes is commonlyrecognized.We have not encountered any case with a

pleural effusion clinically or radiologically. Hyper-tension in the pulmonary circuit was a feature ofa few cases. Radiologically, the diffuse mottlingand interlacing linear shadows, commencing inthe lower zones and advancing to a netlike shadow-ing in the middle zones, is characteristic. Hilarinvolvement is uncommon, but occurred in onecase, illustrated here with pulmonary hypertension.

Clinically our cases with ' pulmonary sclero-derma' have presented with progressive dyspnoearecurring after the disease as a whole had beenrecognized. All the cases showed sclerodactylia,accompanied sometimes by calcinosis circum-scripta, telangiectasis and widespread skin involve-ment by the time the patient became breathless.The physical signs were comparatively scanty, butchest expansion and vital capacities were di-minished. Our experience tallies with that ofLloyd and Tonkin (1948), who described theclinical sequence in scleroderma lung disease asexertional dyspnoea, dry cough and reduction invital capacity, associated radiologically with diffusepulmonary fibrosis and, in some cases, fine nodu-lation, fibrocystic change and pleural fibrosis.The pulmonary fibrosis starts at the bases andmay spread to the middle and even the upperzones, leaving the apices almost invariably free.In one of our cases, dermatomyositis and sclero-dermatous lesions appeared to merge into eachother. Pagel and Treip (I955) have shown howthe clinical and histological features of thesesystemic collagen diseases may sometimes overlap

... .....

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FIG. 15.-X-ray chest showing gross pulmonary fibrosis.

sufficiently to render differential diagnosis almostimpossible. They have suggested that such inter-mediate forms should be grouped under the nameof' viscero-cutaneous collagenosis.'

In one such case under my care rheumatoiddisease with a Felty's syndrome and Sj6gren'sdisease was complicated by a scleroderma merginginto dermatomyositis.

Case I. O.F., housewife, aged 65 (seen bycourtesy of my colleague, Dr. Francis Bach). Herhistory was of I8 years' duration, the onset havingbeen insidious with coldness and hardness of thefinger tips. The skin remained normal until fouryears ago, when she noticed a few ' red spots' onher face, cough and progressive breathlessness,with tightness of the skin of her face and aroundher mouth and gross pulmonary fibrosis (Fig. 15).She showed a satisfactory response to ACTH.There was nothing abnormal in the sputum; theblood count and E.S.R. were normal.

Case 2. A.S., ex-R.A.F. N.C.O., aged 33, beganwith Raynaud's disease in I945, for which he hada bilateral cervical sympathectomy with no appre-ciable benefit. I first saw him in July, I950, whenhe had sclerodactylia, telangiectasis and a wide-spread skin sclerosis. At this time, he began tocomplain of breathlessness, his chest expansionwas restricted, and within i8 months his vitalcapacity was reduced from 4.2 to 2.6 litres. Thebreath sounds were diminished at both bases,



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FIG. i6a.-Sclerodactylia with absorption of the terminal flanges.

where fine crepitation and pleural friction couldbe heard.

Serial X-ray examination of his chest (1950-53)has shown a progressive fibrosis, starting at thebases and gradually spreading to the middle zoneswith some fine honeycombing, especially at theright base. During his period of observation hehad developed dysphagia, nausea, vomiting anddiarrhoea, with definite involvement of his gastro-intestinal tract, as well as cardiac enlargement.He eventually died of ischaemic heart disease(Figs. i6a, I6b).

Case 3. B.R., male, aged 66, had had sclero-derma for over 20 years, with obvious sclero-dactylia, widespread skin sclerosis, multiple telan-giectasia and dysphagia. At this time he alsocomplained of breathlessness, effort, chest painand haemoptysis. His lung fields showed bilateralpleural fibrosis, his heart was markedly enlarged,his blood pressure was 220/I Io, and the pulmonaryarteries were very prominent. After repeatedattacks of heart failure he died, 22 years after theonset of his disease. Unfortunately, a post-mortem was refused.

Case 4. B.B., housewife, aged 46, was first seenin November, 1952, with swellings of the proximalinterphalangeal joints of the hands, and a Raynaudphenomenon as well as early thyrotoxicosis. Shecame under my care 12 months later when, inaddition to these manifestations, she had developedsome periarticular thickening of the wrists, and atendency to clawing of the fingers, which hadbecome progressively worse. Within a year, theskin of her fingers had begun to ulcerate over the

a.

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FIG. I6b.-X-ray chest of same case showing a typicalarea of pulmonary fibrosis in the right lower lobe.



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knuckles, and the skin over the front of her chestand around the angles of the mouth had alsobecome tight, so that she had increasing difficultyin opening her mouth.

She soon developed a typical sclerodactyliawith calcinosis, dysphagia, early basal lung changesconsistent with pulmonary fibrosis. In October,I954, she developed increasing breathlessness andischaemic chest pain, and skin and muscle changesin her arms, compatible with dermatomyositis,complicated by a carcinoma of the left breast.She died from heart failure on December I, 1954,and at autopsy sclerodermatous changes wereseen in the heart, lungs, skin and oesophagus.Her response to several courses of steroid therapywas on the whole unsatisfactory.

Pulmonary Manifestations in RheumatoidDisease

Finally, I must refer to certain pulmonarymanifestations which I have encountered in whatI prefer to call 'rheumatoid disease.'We have already noted the complex clinical

problems which may arise in patients with mergingpatterns of some systemic collagen diseases.'Rheumatoid disease,' whose principal localclinical manifestation is arthritis, is a systemic aswell as a local disease. Its systemic nature can bemanifested by widespread pathological changes ofmesenchymal connective tissue which may occurin various tissues and organs, including the skin,with cutaneous and subcutaneous nodules,muscles, tendons, peripheral nerves, serous struc-tures including the synovia, pleura and peri-cardium and, in some cases, extending into thelungs and heart.

It is, of course, true that both the pleural andpulmonary lesions in rheumatoid disease are rare.The occurrence of nodular lung and pleurallesions (structurally indistinguishable from thesubcutaneous rheumatoid nodule) has been de-scribed by Bennet et al. (I940), Bagenstoss andRosenberg (I941, I943, I944), Gruenwald (I948),Raven et al. (I948), Ellman et al. (I954), andChristie (I954). Caplan (I953) described in coal-miners a syndrome of nodular lung fibrosis asso-ciated in over 50 per cent. of the cases withrheumatoid arthritis. Miall et al. (1953) sug-gested that the prevalence of rheumatoid arthritiswas increased where there was a complicatingpneumokoniosis. The question of an associationbetween rheumatoid arthritis and pulmonarytuberculosis was raised by Miall (1955), whonoted the frequency of tuberculosis in the rheu-matoid arthritic group. He suggested from hisdata that there may be a relationship betweenthe two diseases, due perhaps to some alteration

in tissue reaction, genetic in origin, and possiblya component of the so-called rheumatoid diathesis.Gough and his colleagues (1955), basing their

work on extensive pathological studies, found that,in contrast to ordinary lungs, the pneumokonioticlungs of coalminers appear exceptionally vulner-able to the rheumatoid process. Gough suggeststhat they are sometimes more vulnerable than thejoints and like Miall and his colleagues, heencountered characteristic X-ray appearances inthe chest and lung lesions which seemed typicalof the' rheumatoid' pneumokoniotic type. Therewere, however, no joint changes and these othermanifestations may precede the appearance ofjoint lesions.

Christie (I954) has shown that rheumatoiddisease affects the respiratory tract in the pleura(probably the commonest site), the bronchi, thepulmonary and bronchial vessels and the alveolarwalls. The lesions he found in the lungs were asvaried and widespread as those in other organs,and ranged from acute exudative foci to chronicscars of loose or dense texture. In size theyvaried from minute connective tissue buds to agiant nodule 7 cm. in diameter, structurally indis-tinguishable from the familiar subcutaneous rheu-matoid nodule. Much of the fibrosis found byChristie was non-specific, although such areasusually contained more advanced foci, recognizableas rheumatoid nodules.The respiratory manifestations of rheumatoid

disease that we have encountered can be classifiedas:

(I) Pleural lesions which may be (a) nodular,(b) diffuse. A dry or wet pleurisy may beencountered.

(2) Pulmonary lesions: (a) nodular, (b) diffuse.The nodular lesions in the lungs and pleura arealmost identical histologically with those of therheumatoid subcutaneous nodules, showing a cen-tral fibrinoid necrosis, surrounded by an encirclingcorona of closely-packed mesenchymal cells, thegreat majority of which are fibroblasts and externalto this is a zone of inflammatory tissue (Collins,I937). The interstitial changes at the peripheryof the nodules closely resemble those that havebeen described in the diffuse parenchymal lunglesions (Ellman and Ball, 1948; Christie, 1954).

It would appear from the cases encounteredthat the rheumatoid changes in the lungs orpleura (or both) may occur early or late in therheumatoid process, and when they occur, theymay be silent (when they are not discovered) orsymptomatic. The nodules can sometimes bedemonstrated radiologically and by tomography.The diffuse pulmonary lesions show a reticularpattern. The diagnosis cannot be made in theabsence of arthritis as Spence (1955) has shown,



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FIG. I7.-X-ray chest from a case of acute rheumatoidjoint disease showing diffuse reticulation of bothlungs.

and we would agree with Aronoff and his colleagues(I955) (who have found no example of' rheuma-toid lung' in what they describe as a compara-tively small group of patients) that the problemof differential diagnosis of lung lesions in rheuma-toid arthritis can be most difficult.

It is important to separate this apparently rarecondition from unrelated pulmonary disease, ase.g. pulmonary tuberculosis, the pneumonias, sar-coidosis, carcinoma of the lung, etc. The lunglesions in the systemic collagen diseases alreadynoted must also be carefully eliminated.The occurrence of nodular lung and pleural

lesions is generally accepted. We, like otherworkers, have also recorded interstitial lungchanges, both at autopsy and during life. Usingroutine chest X-rays for all patients with rheuma-toid disease, we have on occasion noted pleuraleffusions and peripheral lung shadows which theclosest possible clinical scrutiny has led us toregard as lung and pleural manifestations ofrheumatoid disease. We have suggested that thenon-specific interstitial lung changes may representthe end stages of acute lung lesions which at somestage in the patient's life may well have been ofthe nodular variety (Ellman and Cudkowicz, 1955).Indeed, in view of the presumably asymptomaticnature of some of the pleural and pulmonary

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FIG. i 8.-Same case showing dramatic response tosteroid therapy in lungs (with complete resolution)as well as joints.

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FIG. 20.-Macroscopic photograph of lung following autopsy showing pleural and pulmonarynodulation and fibrosis.

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FIG. 2i.--Microphotograph of a section of the lungshowing gross pleural thickening and a subpleuralrheumatoid nodule radiating into the lung paren-chyma and surrounded by fibrosis.

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FIG. 22.-Photomicrograph of section of left auricularmyocardium and endocardium showing two rheuma-toid nodules in the endocardium (multiplied tentimes).



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FIG. 23b.-X-ray hands from same case of acute rheumatoiddisease showing active joint changes in the P.I.P. and carpaljoints.

nodular lesions, we do not know how commonlythese lesions occur nor what are the end-effectsupon the adjacent lung in patients who haveexperienced lung remissions from the rheumatoidprocess.Much support for this viewpoint is obtained

from the pathological work of Christie (I954) andis confirmed by Spence (1956).A review of the literature on the pulmonary

manifestations of rheumatoid disease and a record

of cases has been given elsewhere (Ellman, 1947;Ellman and Ball, I948; Ellman and Cudkowicz,I954).Through the courtesy of Dr. G. E. Beaumont

and G. D. Hadley of the Middlesex HospitalI was recently asked to see two cases (sincerecorded by Spence, 1955) of the pulmonarymanifestations of rheumatoid disease. One was aman, J.H., aged 47, with 14 years of inactiverheumatoid arthritis and subcutaneous nodules.



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FIG. 24.-X-ray chest showing widespread infiltrationin both lungs.

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FIG. 25.-Further X-ray of same case showing goodresolution following steroid therapy.

Symptomless subpleural nodules (seen radio-logically in the right mid-zone, 14 mm. in dia-meter) and very evident on tomography appearedafter some 14 years of his illness. The roundedopacities were in close relation to the pleura.Eight months later, when the nodule had increasedin size to 17 mm., a pleural effusion, filling theright costo-phrenic angle, developed.The second case was a man, aged 29, who, after

an acute exacerbation of a relatively mild rheu-matoid arthritis of six years' duration, developedfever and cough with a diffuse patchy reticulationof both lungs. The response to steroid therapyin both the joint and lung lesions was striking.(Figs. 17 and i8.)We have records of a large number of cases of

this type of lung reticulation.We have recently recorded (Ellman, Cudkowicz

and Elwood, 1954) a case which illustrates the co-existence of multiple subcutaneous rheumatoidnodules, involving the scalp, the left olecranonprocess, the ulnar borders of both forearms andthe ischial tuberosities, with widespread involve-ment of viscera, including the lungs and pleurae.This was confirmed by autopsy.The patient, a male, aged 63, had had rheuma-

toid arthritic disease for 17 years with widespreadrheumatoid nodules involving subcutaneous tissue,sclera, dura mater synovia, myocardium, allvalves, pericardium, intima of the ascending part

of the aorta, the lungs and pleura. These lesionswere all associated clinically, in addition to poly-arthritis, with a left pleural effusion (Fig. 19),heart block and Jacksonian epilepsy. The initialreponse to steroid therapy was satisfactory, thesubcutaneous nodules showing signs of regression.Eventually, however, the patient succumbed, andcame to autopsy. (Figs 20, 21 and 22.)Rheumatoid ArthritisAmong further cases are the following:M.H.C., aged 54, male, farm labourer. Ten

years' history of transient polyarthritis. In AprilI953 he had acute exacerbation of the joint lesionswhich settled down after three months. InNovember of that year he developed an acutefebrile illness, cough with severe breathlessnessand flare-up of his joint lesions. There werewidespread physical signs throughout both lungsand an X-ray examination of his chest showedmottling of all zones of both lungs. There wasno response to antibiotics. All investigations fortubercle, carcinoma, sarcoid, etc., were negative.A lung biopsy was done for me by Mr. W. Cleland.The sections were examined by Dr. J. W. Cleggand Professor Gough, and showed evidence offibrosing pneumonitis (non-specific). Joint andlung lesions responded well to steroid therapy.(Figs. 23a, 23b, 24 and 25.)



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FIG. 26.-X-ray of hands from a case of active rheumatoid jointdisease.

H.L., paint sprayer, aged 59, presented in 1951with a long-standing history of rheumatoidarthritis, dating to the First World War. He hadhad a long remission, and this acute exacerbationof his joints responded well to treatment.

Nothing was seen of him again until NovemberI954, when he developed a severe respiratoryinfection and acute polyarthritis, (Fig. 26). He hadpronounced crepitations at both bases with markedfinger-clubbing. X-ray examination of his chestshowed a hilar adenopathy with increased reticu-lation of both lungs, especially at the bases (Fig.27). All investigations for pulmonary tubercle,carcinoma, sarcoid, etc., were negative.

In February 1955 Mr. Cleland performed aleft lateral thoracotomy through the seventh inter-space. The lingula appeared fairly normal, buthigher up the fissure, the lung fringe exhibitedsmall nodules not much larger than a pinhead.Higher still, the nodular change seemed even moremarked. Unfortunately, these nodules were notbiopsied, but the lingular biopsy showed a non-specific fibrosis. Professor Gough has informedme (personal communication, I955) that he hasrecently had a sudden death in a woman withactive extensive rheumatoid arthritis. He foundwhitish areas in the lung which histologicallyshowed focal nodular changes.

A.L., aged 47, night watchman, has had rheu-matoid arthritis for 20 years. In August 1953, hewas admitted to my chest unit with an acuteexacerbation of his joint lesions, fever, and acough with 2 ounces of frothy white sputum.He also had progressive dyspnoea and a severe

laryngeal stridor. There was widespread lymph-adenopathy, and there were nodules in botholecranon bursae. The lungs showed diffusereticulation in both mid-zones. The spleen and

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FIG. 27.-X-ray of chest from same case showingbilateral hilar adenopathy and basal reticulation.



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:·

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FIG. 28.-X-ray chest from a case of active rheumatoidjoint disease. Diffuse reticulation in both mid-zones.

liver were not felt. Sputum was repeatedlynegative for tubercle bacilli, and showed repeatedlysome non-haemolytic streps and M. catarrhalis.There was no anaemia; there were no L.E. cells

in the blood; the E.S.R. Westergren (50-30);plasma proteins were normal; bronchoscopy andliver biopsy were normal; bronchography showedno evidence of bronchiectasis, and cold agglutina-tion tests were negative.

Investigations showed no evidence of lungcarcinoma, tubercle, sarcoid, virus pneumonia ormycosis. The lung and joint lesions finally sub-sided, but on June i8, I954, he had a furtherrelapse with intense laryngeal stridor, acute poly-arthritis and lymphadenopathy with widespreadphysical signs in both lungs, expiratory rhonchithroughout both lungs, and basal crepitations.The laryngeal stridor was so pronounced that itnecessitated urgent tracheotomy. Careful investi-gations at the Institute of Laryngology favouredthe diagnosis of crico-artenoid arthritis. Thejoint and lung lesions are now in remission, andthe radiological picture of the joints and chest areshown (Figs. 28 and 29).

In conclusion, it would seem, from a review ofthe literature, that the lung lesions of the systemiccollagen diseases are confined in varying degreesto the pleura, the interlobular septa and thealveolar supporting membranes, the smallerbronchi and peri-bronchial tissues, and, in somecases, to the walls of the pulmonary artery. Thesesupporting structures of the lungs receive theirblood supply from the bronchial arteries (Cud-kowicz, I952). If it is accepted, as Miller (I949)believes, that a panarteritis underlies the mani-festation of collagen disease, the diffuse lung and

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FIG. 29.-X-ray of hands and wrists from same case showingadvanced rheumatoid joint changes.



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pleural changes can be explained by ischaemicchanges in the bronchial circulation which is thesole arterial blood supply to these structures.The close relationship of these diseases and

their response to steroid therapy, producing vary-ing degrees of remission, make their diagnosis amatter of clinical significance.

BIBLIOGRAPHYARONOFF, A., BYWATERS, E. G. L., and FEARNLEY, G. R.

(xi95), Brit. med. J., ii, 228.BAGGENSTOSS, A. H., and ROSENBERG, E. F. (I941), Arch.

int. Med., 67, 241.BAGGENSTOSS, A. H., and ROSENBERG, E. F. (I943), Arch.

Path. Chicago, 35, 503.BAGGENSTOSS, A. H., and ROSENBERG, E. F. (1944), Ibid.,

37, 54.BENNETT, G. A., ZELLER, J. W., and BAUER, W. (1940)Ibid., 30, 70.CAPLAN, A. (I953), Thorax, 8, 29.CHRISTIE, S. G. (1954), Australasian Ann. Med., 3, 49.COHEN, H., and CADMAN, E. F. B. (I953), Lancet, ii, 305.COLLINS, D. H. (1937), J. Path. Bact., 45, 07.CROFTON, J. W., LIVINGSTONE, J. E., OSWALD, N. C., and

ROBERTS, A. T. M.(I952), Thorax, I, i.CUDKOWICZ, L. (I952), Thorax, 7, 720.ELLMAN, P. (1947), Proc. Roy. Soc. Mtd., 40, 332.ELLMAN, P., and BALL, R. E. (I948), Brit. mred. J., ii, 8I6.ELLMAN, P., CUDKOWICZ, L., and ELWOOD, J. S. (1954),y. Chin. Path., 7, 230.

ELLMAN, P., and CUDKOWICZ, L. (1954), Thorax, 9, 46.ELLMAN, P., and CUDKOWICZ, L. (i955), Brit Med. J,.2, 325.FINLAY, D. W. I891), (Middx. Hosp. Rep., 29.GOETZ, R. H. (I945), Clin. Proc., 4, 337.GOUGH, J., RIVERS, D., and SEAL, R. M. E. (1955), Thorax,

I0, I.

GRANT, R. I. (1940), Clin. Sci., 4, 245.GRUENWALD, P. (1948), Arch. Path., 46, 59.HARGRAVES, M. M., RICHMOND, H., and MORTON, R.(1948), Proc. Staff Meet. Mayo Clin., 23, 25.ISRAEL, H. L. (1953), Amer. J. med. Sci., 226, 387.KLEMPERER, P. (1950), Amer. J. Path., 26, 505.KLINGE, F. (1933), Ergebn. allg. Path. path. Anat., 83, i86.KUSSMAUL, A., and MAIER, R. (i866), Deutsch. Arch. Klin.Med., I, 484.LLOYD, W. E., and TONKIN, R. D. (1948), Thorax, 3, 24I.LOVELL, R. R. H., and ROSE, G. A. (1955), Postgrad. med. J.,31, 382.MATSUI, S. (1924), Mitt. Med. Fak. Tokio, 31, 55.MIALL, W. E., CAPLAN, A., COCHRANE, A. L., KIL-PATRICK, G. S., and OLDHAM, P. D. (1953), Brit. med. J.,ii, 123I.MIALL, W. E. (1955), Ann. Rheum. Dis., I4, 150.MILLER, H. G. (1949), Proc. Roy. Soc. Med., 42, 497.OSLER, W. (1895), Amer. J. med. Sci., IIo, 629.PAGEL, W. (1x95), J. Clin. Path., 4, 137.PAGEL, W., and TREIP, C. S. (I955), Ibid., 8, i.RAVEN, R. W., WEBER, F., PARKES, and PRICE, L. W. (1948),Ann. Rheum. Dis., 7, 63.ROBB SMITH, A. H. T. (1954), Practitioner, 173, 117.ROSE, G. A., In the press.SPENCE, H. P. (1955), Arch. Middx. Hosp., 5, 95.WEGENER, F. (1936), Verhalt. d. deutsch. Path. Geselsch., 29, 202

CARCINOMA OF THE BRONCHUS(Postgraduate Medical Journal)

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INTRODUCTORY UNUSUAL MANIFESTATIONSMaurice Davidson, D.M., F.R.C.P. J. Smart, M.D., F.R.C.P.

THE INCIDENCE AND AETIOLOY COOG ICAL EXANATION OF THEPRIMARY CARCINOMA OF THE LUNG SPUTUM AND PLEURAL EFFUSIONC. E. Drew, M.V.O., F.R.C.S. J. L. Pinniger, D.M., M.R.C.P.

MEDICAL ASPECTS THE SCOPE OF RADIOTHERAPYJ. Anderson, M.D., F.R.C.P. Gwen Hilton, D.M.R.E., F.F.R.

SURGERY OF CARCINOMA OF THERADIOLOGICAL ASPECTS BRONCHUSG. Simon, M.D., D.M.R.E., F.F.R. L. L. Bromley, M.Chir., F.R.C.S.

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