fibrosing alveolitis in polymyositisa review of histologically confirmed cases

CASE REPORTS

Fibrosing Alveolitis in Polymyositis

A Review of Histologically Confirmed Cases

PHILIP E. DUNCAN, M.D.’

JOHN P. GRIFFIN, M.D.

ABRAHAM GARCIA, M.D.

STANLEY B. KAPLAN, M.D.

Memghis, Tennessee

From the Sections of Pulmonary Disease and Rheumatology, Medical Service, Veterans Ad- ministration Hospital, and Department of Medi- cine, University of Tennessee College of Medi- cine, Memphis, Tennessee. Requests for re- prints should be addressed to Dr. John P. Griffin, VA Hospital, 1030 Jefferson Avenue, Memphis, Tennessee 38104. Manuscript accepted De- cember 27, 1973.

* Present address: Fayetteville Diagnostic Center, 675 Lollar Lane, Fayetteville. Arkansas 72701.

Fibrosing alveolitis has been reported in polymyositis. Two such cases are presented and 12 previously reported cases in which there was histologic confirmation of these diagnoses are reviewed. In half the cases, respiratory manifestations preceded

evidence of inflammatory muscle disease. In 12 of the 14 cases, respiratory signs and symptoms dominated the clinical picture and often initially masked the underlying rheumatologic disease. Patients with extensive, predominant pulmonary fibrosis fared poorly, and several did not respond to corticosteroid therapy; however, patients with actively inflamed lesions responded well. In cases of fibrosing alveolitis one should consider the possibility of an unrecognized connective tissue disorder, including polymyositis. Furthermore, pulmonary histology is useful in planning ther-

apy and in predicting prognosis.

The term fibrosing alveolitis (interstitial pneumonitis/fibrosis) has

been used to designate a spectrum of predominantly idiopathic pul-

monary diseases characterized by varying degrees of inflammation

and scarring in the interstitium and alveolar spaces of the lung [ 11.

In the broad sense, use of this term is appropriate to designate var-

ious expressions of pulmonary involvement in connective tissue

disorders. In contrast to the well documented occurrence of fibros-

ing alveolitis in systemic lupus erythematosus, scleroderma and

rheumatoid arthritis [ 2-41, its recognition in polymyositis has been

rarely reported. Only 12 histologically confirmed cases have ap-

peared in the literature over a 17 year period [ 5-151. We describe

two well studied patients with polymyositis and fibrosing alveolitis,

and discuss the implications of this association.

CASE REPORTS

Case 1. A 44 year old woman (T.M.) was admitted to the City of Mem-

phis Hospitals in June 1971 with progressive dyspnea of 3 weeks’ dura-

tion. One month prior to admission a pruritic, erythematous rash devel-

oped on her face and forearms followed by sore throat, myalgia, cough,

fever, and swelling and stiffness of her proximal interphalangeal joints.

She was treated for “bronchitis” with penicillin for 3 days; the rash and sore throat disappeared but the dry cough persisted and was followed by

the development of polyarthralgias, night sweats and progressive dysp-

nea. Her previous records included mild toxemia with pregn,ancy and the

documentation of AS hemoglobin by electrophoresis. Physical examination revealed an acutely ill, tachypneic woman with

October 1974 The American Journal of Medicine Volume 57 621

FIBROSING ALVEOLITIS IN POLYMYOSITIS-DUNCAN ET AL.

Figure 1. Case 1. Chest roentgenogram obtained on June 29, 197 1, shows diffuse pulmonary infiltration. Figure 2. Case 1. Lung biopsy specimen shows intersti-

tial thickening with edema and a mononuclear inflamma to- ry reaction and focal fibrosis. Hematoxylin and eosin stain; original magnification X 100, reduced by 45 per cent.

I

Figure 3. Case 1. Chest roentgenogram obtained on August 8, 197 1, shows a diffuse reticulonodular pattern with striking resolution of acute inflammatory infiltration.

Figure 4. Case 1. Lung biopsy specimen shows resolution of inflammatory reaction. Note considerable improvement compared to specimen shown in Figure 2. Hematox- ylin and eosin stain; original magnification X 400, reduced by 45 per cent.

Figure 5. Case 2. Chest roentgenogram shows bilateral basilar reticulonodular infiltration.

Figure 6. Case 2. Microscopic section of lung shows severe fibrosis and honeycombing, with superimposed bronchopneumonia. Hematoxylin and eosin stain; original magnification X 100.

622 October 1974 The American Journal of Medicine Volume 57

respirations 40/min, temperature 10l°F, pulse rate 1 lO/ min, restricted chest expansion, medium rales over the lower half of both lung fields, and striking weakness of the shoulder girdles. There were no skin lesions. The hemato- crit value was 35 per cent, leukocyte count 19,150/mm3 with 90 per cent neutrophils, and erythrocyte sedimentation rate 54 mm/hour (Westergren). Urinalysis, serum urea nitrogen, electrolytes, serum protein electrophoresis and serum complement were within normal limits; Latex fixation, antinuclear factor and lupus erythematosus cell tests were negative. Enzyme studies revealed creatine phos- phokinase (CPK) 580 mu/ml (normal 5 to 30), lactate de- hydrogenase (LDH) 1,200 mu/ml (normal 210 to 424), serum glutamic oxaloacetic transaminase (SGOT) 122 mu/ ml (normal 5 to 40) and aldolase 65 mu/ml (normal 1 to 8). The electrocardiogram showed sinus tachycardia. Chest roentgenogram (Figure 1) revealed diffuse and partially confluent infiltrates. Arterial blood gases showed arterial oxygen tension (Pa02) 38 mm Hg, arterial carbon dioxide tension (PaCOp) 28 mm Hg and pH 7.52. After the administration of oxygen at 10 liters/min the Pa02 increased to 65 mm Hg. Sputum gram stain revealed mixed organisms. The initial impression was acute interstitial pneumonitis. The arthralgias and muscle weakness rapidly and com- pletely subsided during the first 3 days of hospitalization. The patient was treated initially with penicillin and later with cephalothin and kanamycin without any diminution in her temperature which was sustained at about 103’F, and the leukocyte count persisted at approximately 25,000/ mm3. Bacterial cultures of sputum and blood failed to reveal pathogens, and studies for acid-fast bacilli and fungi were negative. On the 17th hospital day a trephine biopsy of the lung was performed in the right posterior axillary line. It revealed alveolar septal thickening and distortion, a marked inflammatory reaction with edema, areas of alveolar lining cell hyperplasia and focal fibrosis (Figure 2).

On the 18th hospital day, the administration of prednisone 100 mg daily was begun with a dramatic resolution of fever and improvement in oxygenation and muscle strength. On the 30th hospital day, pulmonary function studies showed vital capacity (VC) 1.5 liters, total lung capacity (TLC) 2.1 liters, forced expiratory volume at 1 second (FEV ,.,-,) 1.1 liters and maximum mid-expiratory flow rate (MMFR) 1.34 liters/set, consistent with a combined restrictive and obstructive ventilatory impairment. The sin- gle breath carbon monoxide diffusing capacity was mark- edly reduced at 10.7 ml/min/mm Hg (predicted 21.4 ml/ min/mm Hg), consistent with profound abnormality of respiratory gas exchange.

The dose of prednisone was gradualty reduced to 20 mg daily, and chest roentgenograms (Figure 3) taken 20 days after institution of therapy showed progressive clearing of the infiltrate. The striking clinical and roentgenologic improvement as wetl as better oxygenation were associated with resolution of the obstructive ventilatory defect (FEV,,o 1.6 liters, MMFR 2.9 liters/set) without improvement in the restrictive impairment. Enzyme levels were persistently elevated including a CPK of 290 mu/ml, SGOT 54 mu/ml and aldolase 41 mu/ml.

The patient was readmitted in October 1971 for persis- tent symptoms of fatigue and dyspnea on moderate exer-


tion. Repeat trephine lung biopsy (Figure 4) in the same

location showed a marked resolution in the acute inflammatory reaction and focal areas of fibrosis.

During further reduction of the prednisone dose to 10 mg daily she experienced progressive generalized myalgia, polyarthralgias and muscle weakness in her shoulders and hips. Fever, with temperatures to 104OF, with night sweats and associated dyspnea ensued, and she was readmitted to the hospital in January 1972. Physical examination revealed generalized muscle tenderness, marked proximal muscle weakness, and effusions in the left elbow and knee. Fine rales were heard at the bases of both lungs. The blood leukocyte count was 16,000/mm3 with 84 per cent neutrophils and the erythrocyte sedimentation rate was 76 mm/hour (Westergren), but latex fixation, antinuclear factor and lupus erythematosus tests remained negative. PaOa had decreased to 55 mm Hg. Aspiration of the left knee revealed a turbid fluid with a white blood cell count of 31 ,800/mm3 and a glucose level of 80 mg/lOO ml. There was striking deterioration of enzymes with CPK 4,270 mu/ml, LDH 2,100 mu/ml and SGOT 570 mu/ml. Chest roentgenogram revealed no increase in\ infiltration. An electromyogram revealed changes consistent with polymyositis. A biopsy specimen of the deltoid muscle revealed the typical histologic appearance of polymyositis: endomysial, perimysial and perivascular acute and chronic inflammatory exudate with foci of degeneration and regen- eration within groups of fibers. Electron micrography confirmed the findings by light microscopy. A profound weakness of the muscles of respiration was evident, with a concomitant deterioration in pulmonary function (VC 1.2 ti- ters, FEVlo 0.9 liter, MMFR 1.04 liters/set). Increasing the dose of prednisone to 60 mg daily resulted in resolution of fever and considerable gain in muscle strength, with some diminution in enzyme abnormalities. The patient continues to exhibit moderate proximal muscle weakness, fatigue and dyspnea on exertion.

In this case the diagnosis of a severe acute interstitial

pneumonitis by lung biopsy and its successful treat-

ment with corticosteroids overshadowed the underly-

ing rheumatologic disease. Only during reduction of

steroid dosage was the full blown picture of polymy-

ositis evident.

Case 2. A 39 year old woman (L.S.) experienced inter- mittent swelling, heat and soreness in both knees in July 1968. She was hospitalized in November of that year with a 1 month history of nonproductive cough, low grade fever and dyspnea on exertion without orthopnea. A chest roentgenogram (Figure 5) showed infiltrates at the base of both lungs. Work-up failed to reveal an etiology of the pulmonary problem. After treatment with antibiotics the fever subsided, but the cough and pulmonary infiltrates persisted. Muscle weakness in the shoulder girdles began in Jan- uary 1969 accompanied by gradual weight loss. By April of that year the patient was experiencing fever daily and Raynaud’s phenomenon had developed. By June she had lost 40 pounds in weight and required rehospitalization. Physical findings included respirations 26/min, temperature 10i°F, fine rales at the bases of both lungs, and



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proximal muscle weakness and tenderness. The chest roentgenogram showed no interval change. Laboratory data included a normal hemogram, urinalysis and renal function studies; numerous lupus erythematosus cell prep- arations and antinuclear factor tests were negative, but latex fixation was positive at a titer of 1:2560. Enzyme studies revealed CPK 165 mu/ml, LDH 1,200 mu/ml and SGOT 177 mu/ml. An electromyogram showed changes consistent with polymyositis. A biopsy specimen of the deltoid muscle revealed the changes of polymyositis. Pul- monary function studies showed VC 1.84 liters, TLC 3.14 liters and FEVI.~ 1.31 liters; these findings were considered indicative of restrictive ventilatory impairment. The resting PaOp was 78 mm Hg, PaCOp 28 mm Hg and pH 7.49. After exercise the Pa02 fell to 69 mm Hg; after the administration of 100 per cent oxygen for 7 minutes the ‘Pa02 rose to 525 mm Hg. These data were interpreted as consistent with a defect in diffusion.

After treatment with corticosteroids there was resolution of fever and marked improvement in muscle strength; however, the pulmonary infiltration did not change.

In August 1969 the patient was readmitted with hemop- tysis, increasing dyspnea at rest, respirations 30/min and temperature IOl’F. Chest examination revealed medium rales over the lower half of both lung fields and an increased pulmonic component of the second heart sound. Chest roentgenograms revealed a marked increase in pulmonary infiltration consistent with a complicating bronchopneumonia. The Pa02 had decreased to 58 mm Hg. The steroid dose was increased, and antibiotics were administered without significant improvement. On the 20th hospital day there was a spike in temperature to 105“F followed by progressive deterioration and death 3 days later. Blood cultures revealed Klebsiella pneumoniae, Pro- teus mirabilis and Listeria monocytogenes. Postmortem examination disclosed chronic polymyositis, cardiac fibrosis and diffuse interstitial pulmonary fibrosis with superimposed suppurative bronchopneumonia (Figure 6).

In this case a chronic pulmonary infiltration associ-

ated with symptoms of dyspnea and cough preceded

the development of polymyositis. After corticosteroid

treatment the manifestations of polymyositis dimin-

ished although the pulmonary abnormalities were un-

changed. At autopsy the lungs showed the typical

changes of fibrosing alveolitis.

COMMENTS

The thoracic manifestations in polymyositis are of

three general types: (1) secondary bronchopneumo-

nia, (2) involvement of the respiratory musculature, and (3) diffuse interstitial pneumonitis and fibrosis.

The first two complications are not specific for

polymyositis but may be observed in any chronic neuromuscular disorder. Interstitial pneumonitis and

fibrosis (fibrosing alveolitis) is a well documented fea-

ture of various connective tissue disorders including

systemic lupus erythematosus, scleroderma and rheumatoid arthritis [2-41; however, there are very


few cases on record associated with polymyositis. In

a review of 133 cases of polymyositis, Pearson [ 161

noted pulmonary involvement in only two. Further-

more, Medsger et al. [ 171 found only 3 of 118 cases of polymyositis in which bilateral basilar interstitial in-

filtration might be considered consistent with the

roentgenologic changes of fibrosing alveolitis. Since

the first reported case of fibrosing alveolitis in

polymyositis by Mills [5] in 1956, this form of associ-

ated pulmonary involvement has been histologically

confirmed in only 12 cases in the English literature

[5- 151. Pertinent features of these cases and the

two reported herein are listed in Table I. Histologic study of muscle in every case showed

the typical changes of polymyositis. Electromyo-

graphic findings were consistent with polymyositis in

the seven patients in whom it was performed, and

muscle-related enzymes were elevated in the 12 pa-

tients in whom they were measured. The mean age

of patients in this series was 48 years (range 37 to

65 years). As is the usual experience in polymyositis

there was a predominance of females (11 of 14). In

seven patients the first symptom of their illness was

respiratory; in seven others the initial symptoms

were rheumatologic. Respiratory manifestations

were predominant in 12 of the 14 patients, and often

there was complicating respiratory failure. All pa-

tients had cough and dyspnea, usually with rales in

conjunction with the demonstrated pulmonary involvement. Chest roentgenograms usually showed

either a basilar or more generalized interstitial infiltra-

tion. Histologic study of the lung showed varying de-

grees of alveolar wall thickening and distortion, fibro-

sis and infiltration with lymphocytes and plasma cells.

Three patients had medial or intimal thickening of the

small pulmonary arteries and arterioles consistent

with changes of pulmonary hypertension, but vasculi-

tis was seen in only one specimen. The most impor-

tant clinicopathologic correlation was found between

the amount of fibrous tissue present and long-term

prognosis. Of the 10 patients with moderate to se-

vere pulmonary fibrosis, 8 died, 5 with respiratory

failure. Four of the eight who died were treated with

corticosteroids with no evidence of pulmonary improvement, although two patients did show a diminu-

tion in rheumatologic manifestations. Of the five pa-

tients who were alive at the time of reporting, lung bi-

opsy in three showed a predominantly active inflam-

matory reaction with minimal fibrosis. This was in dis-

tinct contrast to the fatal cases. These patients responded to corticosteroid therapy with resolution of

pulmonary infiltration as well as rheumatologic im-

provement. One patient with proved polymyositis, but with sclerodermatous features, failed to respond to

the administration of corticosteroids and at autopsy


showed predominantly pulmonary vasculitis [ 91. In

another patient, showing largely fibrosis, pulmonary

function improved with corticosteroid therapy, but

there was no change on the chest film [ 141. A final

patient had fibrosis and chronic inflammation [ 151.

After treatment there was improvement both in pul-

monary function and on the chest roentgenogram.

In addition to these histologically confirmed cases

of fibrosing alveolitis in polymyositis, the literature

does contain several reports in which no pulmonary

pathologic material was available. Some of these

cases do warrant mention. Dubowitz and Dubowitz

[ 181 described a 5 year old child with polymyositis

and a severe respiratory distress syndrome. A diffuse

pulmonary infiltration was visible on the chest roent-

genogram. Corticosteroid therapy produced a striking

clinical response with resolution of the abnormalities

noted on roentgenograms. Camp and a.ssociates

[ 191 described a 39 year old woman with derma-

tomyositis and progressive exertional dyspnea.

Roentgenograms of the chest revealed bilateral

widespread interstitial infiltrations. A dramatic clinical

response occurred with corticosteroid therapy. De-

spite the absence of pulmonary pathology. the re-

sponse to corticosteroids, including resolution of the

findings on chest roentgenograms, suggests a more

acute, inflammatory pulmonary lesion in t.hese two

patients. Hepper and colleagues [20] described a 56

year old woman with polymyositis and progressive

dyspnea for several months. Following steroid thera-

py her pulmonary symptoms subsided, and pulmo-

nary function testing and chest roentgenograms re-

vealed some improvement. In a less detailed report,

Brundin [21] described three patients with derma-

tomyositis, with dyspnea at work or rest and with pul-

monary crepitations and abnormalities on chest

roentgenograms. No treatment data were reported.

Four other cases recorded in the foreign literature

were not reviewed [ 22-251.

Rheumatoid factor, lupus erythematosus cell prep-

arations and serum antinuclear factor are reported in

Table I. In three of nine cases studied for rheumatoid

factor results were positive, but all tests for lupus er-

ythematosus cells and antinuclear factor were nega-

tive. The significance of these so-called “tests of au-

toimmunity” in this group of patients is uncertain.

Several studies have demonstrated the variable pres-

ence of these factors not only in diseases such as

systemic lupus erythematosus, scleroderma, rheu-

matoid arthritis and polymyositis [26], but also in fi-

brosing alveolitis without evidence of any coexisting

connective tissue disorder [27-291. However, any role of such factors in the causation of these diseas-

es is purely speculative at present. It has lbeen theo- rized that when fibrosing alveolitis is associated with

the collagen-vascular disorders, the pulmonary lesibn


FIBROSING ALVEOLITIS IN POLYMYOSITIS-DUNCAN ET AL

might represent a manifestation of systemic immune

complex disease due to localization of materials such as antinuclear factor in the lungs. However, immu-

nofluorescence studies for deposited immunoglobulin

in the lung were negative in the one patient with fi-

brosing alveolitis in polymyositis so tested [ 121.

It appears that patients with fibrosing alveolitis as-

sociated with polymyositis are of two general types:

In one type there is a chronic progressive course,

and histologically pulmonary fibrosis is predominant.

These patients show a poor response to corticoste-

roids as exemplified by our patient (Case 2) who, although showing a rheumatologic response to this

treatment, shawed no pulmonary improvement. In

the other type there is generally a more acute

course, and histologically alveolar wall thickening,

distortion and acute inflammatory infiltration but little

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

fibrosis are evident. These patients usually have a

good response to corticosteroid therapy as shown by

our patient (Case 1) in whom the inflammatory reac-

tion resolved with only focal fibrosis remaining evi-

dent on post-treatment biopsy.

In the desperately ill patient, corticosteroid therapy

should be instituted empirically. Otherwise, a lung bi-

opsy is recommended in that the type of pathology

will provide a useful guideline for therapy. A reaction

showing active inflammation should be treated ag-

gressively with corticosteroids. However, the use of

corticosteroids in the presence of predominant, extensive fibrosis would not be expected to improve

respiratory insufficiency, and if administered in large

doses and for extended periods might be expected to

greatly increase the probability of complicating bron-

chopneumonia.

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fibrosing alveolitis in polymyositisa review of histologically confirmed cases

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