pulmonary fibrosis in generalized scleroderma · pulmonary fibrosis-in generalized sclerodermaadmit...

Thorax (1948), 3, 241.

PULMONARY FIBROSIS IN GENERALIZED SCLERODERMA

REVIEW OF THE LITERATURE AND REPORT OF FOUR FURTHER CASES

BY

W. E. LLOYD AND R. D. TONKINFrom the Westminster Hospital, 'London

Generalized scleroderma is not a disease of theskin alone. This was originally shown by Lewinand Heller as early as 1894, when they produceda monograph on the subject, and reviewed the451 cases which had been recorded in the litera-ture before that date. As regards the respiratorysystem, several cases were recorded in whichdyspnoea was a prominent symptom, but theauthors correlated this with sclerodermatouschanges in the skin and muscles of the chest wall,and it is of interest to note that there is no recordof any case in which involvement of the lungsthemselves was detected clinically. This is inaccord with the general experience that symptomsof respiratory insufficiency are not commonlyencountered, even in those cases in which grosspulmonary fibrosis has subsequently been shownto be present. However, in their post-mortemseries of twenty-four cases, there is mention of atleast two in which generalized pulmonary fibrosiswas found.

Since that time there have been many casereports recording involvement of various viscerain cases of generalized scleroderma, notably thelung, the myocardium, and the oesophagus, butalso the thyroid, the kidneys, and other organs.Hekteon in 1897 reported a case in which thethyroid and the myocardium were involved andin which there were also changes in the pituitary.Masugi (1938) and Talbott and others (1939)recorded involvement of the kidneys. In 1943Weiss and others thoroughly reviewed the subjectof myocardial fibrosis in association with general-ized scleroderma, and reported nine additionalcases. Lindsay and others in the same year dealtwith the oesophageal changes, describing five casesand reviewing the literature from that aspect.Bevans in 1945 reported two cases in which the

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process of fibrosis extended throughout the wholeof the intestinal tract, and in which were presentboth pulmonary and myocardial fibrosis and alsochanges in the thyroid gland.On the subject of pulmonary fibrosis in associa-

tion with generalized scleroderma there are fewerreports. Although the association of the two iswell-recognized, search of the available literaturereveals only seventeen cases. In most of these thecondition was proved to be present by examinationof post-mortem material, but in four cases theevidence was radiological only. Lewin andHeller (1894), as has been noted above, did notreport any cases in which the pulmonary fibrosiswas actually recognized during life, but in at leasttwo of the 24 autopsies reviewed by them therewas macroscopic and histological evidence of it.Matsui (1924), in his description of the clinicaland post-mortem findings in six cases of general-ized scleroderma, reported three in which pulmon-ary fibrosis was found to be present. In additionhe made mention of the histological findings inone museum specimen of the disease, and thisalso showed a degree of generalized fibrosis. Innone of these cases were there any significantclinical symptoms of pulmonary involvement.

Since that time cases showing the associationof the two conditions have been reported byMurphy and others (1941), Linenthal and Talkov(1941), Weiss and others (1943), Jackman (1943),Bevans (1945), and Getzowa (1945). It is ofinterest to note, although not particularly surpris-ing, that in three cases at least (Bevans, 1945 ;.and Weiss and others, 1943) the radiograph of thechest during life did not reveal any significantabnormality even though histological evidence ofwidespread fibrosis was found in the post-mortemmaterial.

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W. E. LLOYD AND R. D. TONKIN

THE PRESENT SERIESThe four cases which form the basis of this

report show a remarkable similarity in their chestradiographs. The appearances are those of adiffuse fibrosis which is obviously generalized andyet at the same time predominantly basal in distri-bution. Before outlining the case histories, itmight be profitable to consider the natural historyof the average case of generalized scleroderma.

Generalized scleroderma is twice as common inwomen as in men. It usually begins between thethird and fourth decade, and is usually precededby the Raynaud syndrome. The course may bzrapid or slow, progressing to death in a matter ofmonths or extending over many years. Spon-taneous recovery is recorded but is rare. At firstthere is oedema and induration of the dermis, andonly later does this progress to the more widelyrecognized shiny atrophic skin, which frequentlyshows pigmented areas. In the early stages muscleweakness is a prominent feature, and there mayalso be myalgia and arthralgia. As the active stagepasses, the more familiar musc!e wasting and con-tractures develop, together with the shiny andinelastic skin.

In the three women seen by us scleroderma wasfairly advanced. It was preceded for several yearsin all three by the Raynaud phenomenon, and inone by calcinosis. In the one man, the sclero-derma was definite though early.

CASE I.-This patient, a single woman, was firstseen by us in June, 1943, when she was 45 years oldand when Raynaud's disease had been progressing forthree years. During that time she had also feltincreasing breathlessness on exertion, and had lostover 42 lb. (19 kg.) in weight. The hands wereswollen and somewhat cyanosed, and the skin showedearly changes characteristic of generalized scleroderma.No abnormal physical signs were discovered in thechest, but the radiograph showed some basal fibrosis.In May, 1946, owing to an increase in the severityof the Raynaud symptoms, a right cervical pre-ganglionic sympathectomy was performed. This re-sulted in improvement in the symptoms, and twomonths later sympathectomy was in consequence per-formed on the left side. The skin at this time showedvery definite sclerodermatous changes, which weremost severe in the hands but which also involved theface and arms. Apart from some increase in theexertional dyspnoea, there were no symptoms refer-able to the chest. The radiograph showed consider-able increase in shadowing throughout both lungfields. Since that time the patient has been remark-ably free from symptoms of the Raynaud type, butboth the skin and the lung changes have steadilyprogressed. The vital capacity is now 27 per cent ofnorrnal, and the radiograph (Plate XXIVa) reveals

very considerable fibrosis, most severe in the lowerzones. Many rales are audible throughout the lungs,and the patient is only able to walk along the leveland at a very slow rate, owing to the great dyspnoearesulting from the slightest effort. Repeated and ex-haustive search for evidence of tuberculosis through-out the whole period of her observation has revealednothing. The Mantoux reaction is negative to 1 mg.O.T. The possibility of the effects of chronic lungirritants has also been excluded.

CASE 2. This patient, an unmarried woman, wasfirst seen in June, 1938, when she was 48 years old.She had been suffering for twenty years from attacksof the Raynaud phenomenon. On examination therewere trophic ulcers on the fingers, and the skin ofthe hands was smooth and atrophic. Radiographsof the limbs revealed large masses of calcium in themuscles of the calves and forearms. A diagnosis ofRaynaud's phenomenon with sclerodactylia and cal-cinosis was made, and on account of the severity ofthe symptoms a right cervical sympathectomy wasperformed. This resulted in considerable relief ofsymptoms, and in consequence the operation was per-formed on the left side six months later. Blood cal-cium and phosphorus were within normal limits, aswas the calcium balance. A radiograph of the chestshowed some basal fibrosis.

In March, 1939, the patient began to have Raynaudsymptoms in the legs, and in consequence a bilaterallumbar sympathectomy was performed which againresulted in considerable relief. She was not seen againuntil June, 1946, when she said she had suffered fromgeneral debility and lassitude for the past year. Shealso complained of exertional dyspnoea. She haddifficulty in swallowing unless her food was fluid orfinely divided. Her skin was atrophic and thin, andthere were abnormal areas of both pigmentation anddepigmentation over the hands and forearms. A fewsmall subcutaneous nodules were present over themiddle third of the left ulna; these discharged chalkymaterial from time to time. Apart from the skinchanges, there were no significantly abnormal physicalsigns. A radiograph (Plate XXIVb) of the chestshowed the fibrosis, which was known to have beenpresent in 1938, to have increased considerably; itwas generalized, although still predominant at thebases. The sputum was negative for tubercle bacilli.The erythrocyte sedimentation rate (Westergren) was5 mm. in the first hour. The blood Wassermann andKahn tests were negative. The patient died at homesoon after discharge from hospital. No post-mortemexamination was obtained.

CASE 3.-A man, aged 55 years, in October, 1947,complained of gradually increasing exertional dys-pnoea over a period of three years. He had alsonoticed loss of weight over the same period, whichhe thought amounted to 2 or 3 st. (12 to 19 kg.).He coughed a little, sputum was scanty only, and therewas no haemoptysis. The texture of the skin hadchanged, but only on direct questioning did the patient

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PLATE XXIV. (a) Radio-graph of Case 1, showingconsiderable fibrosis.(b) Radiograph of Case2, showing generalizedfibrosis.

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PLATE XXV.-(a) Radio-graph of Case 3,showing widespreadinterstitial fibrosispredominantly basalin distribution, and acalcified primary com-plex in the right lung.(b) Radiograph ofCase 4, showinggeneralized fibrosis,predominant in thelower zones.

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PULMONARY FIBROSIS- IN GENERALIZED SCLERODERMA

admit that temperature changes affected his hands,which readily became blue and cold in the winter.The full Raynaud syndrome was not present. Therewere no other symptoms. The skin of the face andhands-was firm and leathery, with loss of the sub-cutaneous fat. The skin just above and below theclavicles and above the pubis showed lesser degreesof this same change. The feet and legs were slightlyaffected and the back was spared. There were alsoareas of increased pigmentation with depigmentedspots below the clavicles. There was sorne clubbingof fingers and toes. There was also some diminutionof the percussion note and air entry at the basesof both lungs. A radiograph (Plate XXVa) showedevidence of widespread interstitial fibrosis which waspredominantly basal in distribution; a calcifiedprimary complex was present in the right lung.Sputum was negative for tubercle bacilli. The Man-toux reaction was positive to 0.0002 mg. purifiedprotein derivative. The blood Wassermann and Kahntests were negative.

CASE 4.-A Polish Jewess, married and aged 48years, first noticed thirteen years before the presentexamination that The tips of her fingers becamebleached on stretching the fingers, and that littlefestering spots appeared. Since that time the skinhad become progressively tight. Soon after this thesymptom complex became more definitely of theRaynaud type. Five years before examination shenoticed her lips becoming thin, and about the sametime she began to feel some shortness of breath onexertion.She was found to be a very nervous individual, and

she said she had always been "highly strung." Whenasked about her health she concentrated upon hermental illness and appeared somewhat indifferent tothe physical changes in the skin.The skin of the hands, forearms, face, and neck

showed generalized scleroderma. The trunk was alsoaffected, but less so. Legs and feet were relativelyclear. Examination of the chest revealed a fewscattered rales only. Radiography,, however, showedgeneralized fibrosis, predominant in the lower zones,and similar to that found in the other cases (PlateXXVb).

DISCUSSIONIt seems likely that, in those cases of generalized

scleroderma in which radiography reveals a diffuseirregular shadowing throughout both lung fields,there is an increase in the pulmonary connectivetissue which represents a visceral manifestation ofthe disease. The majority of the recorded caseshave no pulmonary symptoms apart from progres-sive exertional dyspnoea, which may becomeextreme in the terminal stages.That the pulmonary condition can exist in the

absence of detectable dermatological changes, orat least may precede these changes, is suggested

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by the fact that an exactly comparable radiologicalpicture has been observed in cases in which theclinical picture is that of the Raynaud pheno-menon only (Linenthal and Talkov, 1941). Thisis a point of the greatest importance in the inter-pretation of chest radiographs in cases exhibitingthe Raynaud phenomenon, and possibly also inthose which reveal generalized fibrosis for whichthere is no other satisfactory aetiologicalexplanation.

Generalized scleroderma is by no means a singleclear-cut disease, even if its occurrence as anoccasional sequel to the Raynaud phenomenon betaken into account. Many authors have shownits association with several other conditions,notably calcinosis (Thibierge and Weissenbach,1911; Durham, 1928; Prosser Thomas, 1942) anddermatomyositis (Dowling and Griffiths, 1939;Banks, 1941). Dowling (1940) in a most con-vincing paper discussed the arguments in favour ofconsidering generalized scleroderma and dermato-myositis as expressions of the same disease. Hestressed the fact that in both conditions generalizedmyasthenia is a prominent symptom, progressingto muscle wasting and subsequent fibrosis. That amyopathic state exists in both is supported by theraised creatinine output which is to be found insome cases of both conditions. On this lineDowling goes even further and offers the sugges-tion, with some supporting evidence, that thyroiddyscrasia may also bear a close relationship togeneralized scleroderma, calcinosis, and dermato-myositis.

If the association of these three conditions isaccepted, the question arises whether generalizedpulmonary fibrosis may occur in conjunction withall of them. Search of the available literature hasnot revealed any reports of pulmonary fibrosishaving been noted in conjunction with dermato-myositis, nor in any case of pure calcinosis(Brooks, 1934); pulmonary changes have beenreported only in cases which later developedscleroderma. However, the possibility of itsoccurrence should be borne in mind.The occurrence of arthralgia as a not uncommon

feature in the course of the development ofscleroderma is of interest to us in view of the factthat we have a further case whose chest radiographbears a striking similarity to those of the fourcases described above, showing generalized fibrosiswhich is somewhat more marked in the lowerzones. It is not accompanied by symptoms orsigns referable to the chest, with the exception ofvery marked clubbing of the fingers and toes.This patient has progressive arthritis of the rheu-matoid type, which is of considerable severity,

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but he shows no evidence of generalized- scle'o-derma. A further point of interest is that he hada thyroidectomy performed for Graves' diseasesome eight years previously. He still retains hisexophthalmos.

SUMMARY

The association of progressive pulmonaryfibrosis with generalized scleroderma is wellrecognized. The literature on this association isreviewed and four further cases are described.

We are greatly indebted to Dr. E. H. Hudson for theuse of his records of Case 2, and to Dr. Dudley Hartand Dr. Altmann for Case 4.

REFERENCESBanks, B. M. (1941). New Engi. J. Med., 225, 433.Bevans, M. (1945). Amer. J. Path., 21, 25.Brooks, W. D. W. (1934). Quart. J. Med., 27, 293.

Dowling, G. B. (1940). -Brit. J. Derm. Syph., 52, 242.Dowling, G. B., and Griffiths, W. J. (1939). Lancet, 1,

1424.Durham, R. (1928). Arch. int. Med., 42, 467.Getzowa, S. (1945). Arch. Path., 40, 99.Hekteon, L. (1897). J. Amer. med. Ass., 28, 1240.Jackman, J. (1943). Radiology, 40, 163.Lewin, G., and Heller, J. (1894). Charite-Annalen, 19,

763.Lindsay, J. R., Templeton, F. E., and Rothman, S. (1943).

J. Amer. med. Ass., 123, 745.Linenthal, H., and Talkov, R. (1941). New Engl. J. Med.,

224, 682.Masugi, M. Ya-Shu (1938). Virchow. Arch. path. Anat.,

302, 39.Matsui, S. (1924). Mitt. med. Fakult, Univ. Tokyo, 31, 55.Murphy, J. R., Krainin, P., and Gerson, it. J. (1941).

J. Amer. med. Ass., 116, 499.Prosser Thomas, E. W. (1942). Lancet, 2, 389.Talbott, J. H., Gall, E. A., Consolazio, W. V., and

Coombs, F. S. (1939). Arch. int. Med., 63, 476.Thibierge, G., and Weissenbach, A. (1911). Ann. Derm.

Syph., Paris, 2, 129.Weiss, S., Stead& E. A., Warren, J. V., and Bailey, 0. T.

(1943). Arch. int. Med., 71, 749.

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