Nodular pleuropulmonary rheumatoid disease

Nodular

Pleuropulmonary

Rheumatoid

Disease*

Report of Two Cases and Review of Literature Err

H. RUBIN,

M.D., MORRIS

GORDON,

M.D. and WILLIAM

L. THEL~IO.

N.D

New York, New York

0

F

Described herein are two patients with nodular rheumatoid pleuropulmonary disease confirmed at autopsy. In neither was there an occupational history to suggest Caplan’s syndrome. In one, a sixty-two year old man, symptoms and roentgenographic findings of diffuse interstitial pulmonary fibrosis, in keeping with the Hamman-Rich syndrome, were present three years before the onset of joint complaints, the latter evolving into a crippling rheumatoid arthritis. In the other, a seventy-one year old woman, advanced rheumatoid arthritis had been present for more than twenty years before discovery of the pulmonary lesions. The course of the disease in the man was featured by recurrent spontaneous pneumothoraces, and repeated attempts at closure of the bronchopleural fistulas. Thirty-two previousl>- reported cases of nodular, nonpneumoconiotic rheumatoid disease are tabulated and several others cited, with special reference to certain relationships of the manifestations of joint and lung involvement. On the basis of the present study and previous observations it is concluded that in some cases the Hamman-Rich syndrome reflerts a rheumatoid disease even in the absence of accompanying symptoms of joint involvement.

interstitial pulmonary fibrosis was found on a chest roentgenogram three years before the onset of the symptoms of joint involvement. The lung lesions progressed,’ giving rise to recurrent bilateral spontaneous pneumothoraces. Rheumatoid granulomas were also found in the epicardium. In the second patient, rheumatoid arthritis had been present for about twenty years prior to recognition of the pulmonary lesions. Pleuropulmonary rhertrrlatoid granulomas were discovered at autops)..

THE several types of pulmonary lesions that may occur as part of rheumatoid disease, interstitial pulmonary fibrosis has received considerable attention because the lesions closely resemble those characterizing the Hamman-Rich syndrome. Another type of lung involvement is represented in nodular lesions duplicating the subcutaneous nodules of rheulnatoid arthritis. Nodular lesions are not uncommon in workers with rheumatoid arthritis who are exposed to certain dusty occupations (Caplan’s syndrome) but are comparatively rare in those without pneumoconiosis. The nodules favor the corticopleural layer of the lungs and at times it is difficult to determine whether the pleura or lung is primarily affected. This may explain why pleural effusions are frequent [39]. This report deals with two patients who had nodular, rheumatoid pleuropulmonary lesions confirmed at autopsy, unassociated with pneunloconiosis. In one the presence of diffuse

CASE 1. In this sixty-two year old white male storekeeper (J.T.) cough, expectoration. fever, rightsided chest pain and shortness of breath developed early in 1960. He consulted one of us (E.H.R.) on September 7, 1960. He denied ever having been seriously ill. He had given up smoking ten years previously. Physical examination disclosed a heavy set person, 67 inches tall and weighing- 155 pounds, with a blood pressure of 120/80 mm. Hg. He was short of breath on exertion. There was no clubbing 01 the fingers, no signs of lymph node enlargement

* From the Divisions of Pulmonary Medicine and Laboratories, York, New York. Manuscript received June 15, 1966. VOI..

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56?

Montefiorr

Hospital

and Medical

Ccntcr,

New

568

Nodular

Pleuropulmonary

Rheumatoid

Disease-Rubin

et al.

1A

FIG. 1. Case 1. Chest roentgenograms. A, September 7, 1960, diffuse interstitial reticulations, more pronounced in right lung. B, shows detail in right lung. C, April 6, 1964, shows increase in reticulations, also small densities in both lower lung fields. D, July 7, 1965, bilateral pneumothorax showing both lungs partially collapsed with a small effusion at the base of right lung.

On percussion and auscultation of the chest no abnormalities were elicited. Chest roentgenograms revealed normal heart size. There were diffuse reticulations throughout both lungs, more marked on the right side (Fig. 1A and IB). A chest roentgenogram

taken on April 26, 1960, and available for review, revealed no abnormalities. The diffuseness of the lung lesions, their recent development and the complaint of increasing shortness of breath, suggested interstitial pulmonary fibrosis, presumably the HamAMERICAN

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man-Rich syndrome. Further studies were suggested but declined. The patient continued the antibiotic treatment which he had received previously. He continued to work until the middle of 1963 when pain and swelling of the joints developed, including the ankles, knees, fingers, shoulders, elbows and jurists. l‘reatment during the following months consisted of aspirin, phenylbutazone, paramethasone acetate and gold sodium thiomalate given intramuscularly. The arthritic and pulmonary symptoms became more severe and he was hospitalized from April 0 to April 28, 1964. The same medications were continued, including antibiotics. In April and May 1964 the patient came under the care of the Chest Clinic of the Department of Health. His cough and expectoration had in the meantime become more severe, he had lost weight and was now “crippled by arthritis.” .4 chest roentgenogram showed considerable increase in the interstitial lesions in both lungs and, in addition, patchy areas of consolidation more marked in the lower lobes (Fig. 1C). Hospitalization was recommended. On July 4, 1964, the patient was admitted to the Montefiore Hospital and Medical Center. Examination revealed a cyanotic, dyspneic man. Temperature ranged from 100’ to 102°F.; there was 3+ clubbing of digits; the joints, ankles. wrists, knees and feet were red, hot, swollen and painful. The patient also complained of pain in the spine. On auscultation rales were heard in the lower part of the chest. The chest roentgenogram showed little change. A partial compression in the body of seventh thoracic vertebrae was noted and mild spondylitis deformans. Roentgenograms of the knees revealed minimal arthritic changes. A barium swallow and x-ray series of the gastrointestinal tract failed to demonstrate any abnormalities. Other laboratory tests showed serum total protein 5.4 gm. per cent (albumin 2.6 gm. per cent, globulin 2.8 gm. per cent). Serological tests for syphilis were negative, as were tests for lupus erythrmatosus. The latex fixation titer was 1: 1280 on one occasion. The electrophoretic pattern was normal. The sputum showed no acid-fast bacilli but contained a mixture of Klebsiella, Staphylococcus albus and streptococci. Arterial oxygen studies 39.4 mm. Hg, showed pH 7.45, PC02 (electrode) 02 saturation 89.4 per cent, ~02 (electrode) 60.1 mEq. per L. Treatment consisted of oxygen inhalation with the Bird respirator and postural drainage. The patient was also given prednisone, 2.5 mg. daily, and 80 units of ACTH twice weekly for one month, tetracycline, 1 gm. daily, physiotherapy, acetylsalicylic acid and diuretics. After subsidence of the fever, bronchography revealed moderate cylindric bronchiectasis of the basal segments of the lower lobes. At discharge on August 7, 1964, the swelling of the ankles and feet had decreased greatly and the patient was able to walk. The expectoration was less but the rales in the lungs persisted. The administration of VOL.

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1967

Disease--/
rt a/.

.%I’)

oral and injectible corticosteroicis and ar:tibiotics was continued. The patient was readmitted to 111~ blontefiore Hospital and Medical Center on Apri! 23, 1065, stating that in the preceding two months the cough, expectoration, joint and back pain and shortness of breath had increased and that night s\veats and weight loss had developed. For thy folloivinq six weeks the temperature ranged between 101” to 102’~. The pain and swelling of the ankles, knees and small joints subsided but the back pain persisted, requiring a brace for relief. Genrralizrd muscular atrophy developed. Roentgenograms revealed demineralization of the dorsolumbar spine and a compression fracture of the twelfth thoracic vrrtebrae, ascribed to the prolonged corticosteroid medication. The chest roentgenograms showed littl(b change in the interstitial fibrosis and basal densit& but there was now blunting of the right costophrenic sinus. Pertinent laboratory examinations included hematocrit 29 per cent increasing to 35 per cent: white blood cell count 16,000 per cu. mm. decreasing to 9,200 per cu. mm., with a normal differential; bone marrow examination was negative; aspirated pleural fluid from the right side of the chest revealed no growth; lupus erythematosus tests were negative; blood culture was negative. The serum total protein was 6.8 gm. per cent with albumin 2.6 gm. per cent and $obulin 4.2 gm. per cent. Serum electrolytes \\ere normal. Serologic test for syphilis (VDRL) wab negative. The patient was treated at various times \vith prednisone, 10 mg. daily ; ACTH, 80 units twice weekly ; sedatives and antibiotics but he continued to have cough, purulent expectoration, recurring periods of fever and pain in the chest, back and joints. When, in 1965 the findings, including the chest roentgenograms, were compared with those five years before it was evident that considerable progression had occurred in the extent of the diffuse interstitial fibrosis. and the recent development of rheumatoid arthritis suggested that the course of the illness was in keeping with rheumatoid ltmg disease. On June 27, 1965, a routine chest roentgenogram disclosed a spontaneous pneumothorax on the left side, with a small effusion. There were no accompanying symptoms. About two weeks later a similar episode occurred on the right side (Fig. ID). There were mild pressure symptoms. Air was aspirated from both pleural cavities and closed water-seal drainage instituted. After a month of drainage the tubes were removed and the patient was discharged on July 25, 1965, with minimal amounts of air still present in both pleural cavities. Antibiotics, prednisone, sedatives and narcotics were given during this period. On September 14, 1965, severe chest pain and marked dyspnea developed. The patient was seen by his physician (M.G.) at home who removed approximately 5 L. of air from the left side of the chest and sent the patient to the Emergency Room of the

570

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Montefiore Hospital and Medical Center. Examination revealed the patient to be in acute respiratory distress. The temperature was 98.6’~., pulse rate 96 and regular; blood pressure 115/70 mm. Hg, respiration 28 per minute. The breath sounds were suppressed on both sides. The chest roentgenogram revealed the presence of bilateral pneumothorax now showing greater collapse of both lungs than at the time of discharge. Both pleural cavities were cannulated, underwater-seal drainage was instituted, and the patient admitted to the surgical service. On September 22 a left partial pleurectomy, decortication and oversewing of a bronchopleural fistula was performed. Subcutaneous emphysema was noted within thirty-six hours. The emphysema became widespread and continued unabated for about three months; it subsided gradually but never disappeared completely. The draining tube was removed on the seventeenth postoperative day. By the twenty-eighth postoperative day there was still a leak on the left side and a small pneumothorax on the right. On October 21 another tube thoracotomy was performed on the right. The patient became progressively hyponatremic, refused medication, food and liquids and had to be treated with intravenous fluids. On October 25, successful closure of the bronchopleural fistula was accomplished after exploration of the chest on the left. On October 31 the tubes in the left side of the chest were removed. However, the right pneumothorax kept recurring and increasing. On November 11 a right pleurectomy and closure of the bronchopleural fistula was performed but an air leak persisted, requiring a third tube thoracotomy on the right. Surgical specimens of the pleura removed at the several thoracotomies showed areas of caseating granuloma compatible with tuberculosis. However, stains for acid-fast bacilli were negative and repeated cultures of fluid and specimens from both pleural cavities were consistently negative for acid-fast bacilli, fungi and, initially, negative for all bacteria. Later, the right-sided empyema grew out hemolytic Staphylococcus albus and enterococci. The air leak from the right side decreased gradually. On December II, 1965, a right basal empyema was noted and drained by thoracotomy tubes. During the ensuing weeks the empyema cavity drained slightly; the temperature ranged from lOlo to 102’F. and at times the patient was disoriented. During this period of hospitalization, which covered three major thoracotomies, two on the left clnd one on the right side, and many tube insertions, the patient received sedatives and, at various times, streptomycin and isoniazid in addition to a battery of other drugs, including procaine penicillin, mandelamine, erythChloromycetin,@ mycostatin, staphcillin, romycin, oxacillin, keflin, prednisone, prednisolone and SoluMedrol@ by various routes and in various strengths. In the latter part of December the patient’s condition

Disease-Rubin

et al.

deteriorated, he became increasingly disoriented, and died on December 28, 1965. At autopsy the body was that of a well developed. poorly nourished elderly white man measuring 65 inches in length and weighing an estimated 110 pounds. There was no jaundice, edema, cyanosis or peripheral lymphadenopathy. About 50 cc. of purulent exudate was present in each pleural cavity. There were extensive fibrous and fibrinous adhesions to the parietal pleura and diaphragm. Both lungs were poorly aerated and enveloped by markedly thickened grayish white pleura. Several sutures were noted on the anterior surfaces of both upper lobes at the sites of previous attempted closures of bronchopleural fistulas. The lungs in these locations disclosed necrosis with cavitation which varied from 0.5 to 1 cm. in size. On section the corticopleural layer contained firm, small nodules measuring 0.3 to 0.4 cm., the adjacent lung having a honeycombed appearance (Fig. 2A). The gray-pink parenchyma was speckled with moderate amounts of anthracotic pigment. The central portions of the lobes were less diseased. In addition to the necrotic nodules in both upper lobes, most marked in the corticopleural layer, there was subpleural fibrosis with loculated small abscesses in both lower lobes. A small amount of mucopurulent material was expressed from the cut surfaces. The trachea and bronchi were patent and contained some mucopurulent exudate. The pulmonary arteries and veins were patent and free of emboli. The hilar and tracheobronchial lymph nodes were enlarged and on cut section showed no tumor. The pericardial sac contained 20 cc. of greenish yellow exudate, with extensive adhesions between the pericardium and epicardium. The epicardial fat disclosed necrosis with several granulomas on the anterior aspect of the left atrium. The heart was otherwise not remarkable. The diaphragm was extensively adherent to the base of both lower lobes so that it was impossible to separate the diaphragm from the lungs without tearing bits of lung tissue. Microscopic examination of the lungs disclosed intrapleural granulomas showing central necrosis. There was adjacent interstitial fibrosis with abundant macrophages in the alveoli (Fig. 2B). In the zones of dense fibrosis, arteriolar sclerosis was noted (Fig. 2C) as well as bronchiolectasis with papillary formation. Most of the dilated bronchioles were filled with leukocytic exudation composed of polymorphonuclear cells and macrophages with necrotic debris (Fig. 2D). The individual nodules were composed of a central ulcerated zone rimmed by proliferating fibroblasts showing a palisading arrangement in some areas. These in turn were surrounded by dense fibrous tissue with scant lymphocytes and plasma cells (Fig. 3A). Some granulomas showed central cavitation. A few multinucleated giant cells of both the Langhan’s and foreign body type were present in the granulomas AMERICAN

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Nodular

Pleuropulmonary

Rheumatoid

1Xsease-

Kuhin rf rd.

.iT 1

2A

2c

sclrrosis

but

no etldartcritis.

Original

magnification

(Fig. 3B). The smallest qranuloma seen (perhaps the earliest lesion noted) consisted of small conglomerates of epithelioid ceils and proliferating fibroblasts without necrosis (Fig. 3C). Foci of calcification were found in the corticopleural layer (Fig. 3D). Acidfast and periodic acid-Schiff stains were negative. Examination of the tissue with polarizing lens revealed no foreign bodies or silica crystals. Cultures and guinea pig inoculation for hlycobacterium tuberculosis were negative. The pericardium revealed deposition of eosinophilic fibrinous and fibrinoid material associated with proliferating and sometimes palisading fibroblasts. Sections taken from the left atrium showed granulomatous lesions in the epicardiumcharacterized by central necrosis rimmed by proliferating fibroblasts with a tendency to palisade arrangement in some areas perpendicular to the granulomas. The myocardium was uninvolved. The remaining organs, including the brain and spinal cord, revealed no lesions pertinent to the rheumatoid disease. The ribs and vertebrae were excalvarium, sternum, var..

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Y 120. amined and appeared to be within normal limits. There was no evidence of osteoarthritis in the vertebrae. The intervertebral discs and the .joints were not remarkable. The muscles disclosed no atrophy. CASE 2. This seventy-one year old white widowed housewife (S.S.) had been suffering from rheumatoid arthritis since the age of fifty, deformities gradually involving the spine, shoulders, hands, knees and feet. Over the years she had been treated with gold, steroids, salicylates and other drugs. She was hospitalized on December 12, 1956, after sustaining a fracture of the neck of the right femur. The fracture was treated with traction but it remained ununired and there was considerable osteoporosis of the bones. The patient was admitted to the Beth Abraham Home on October 7, 1957. Examination revealed an emaciated elderly woman with deforming arthritis of the hands, elbows and knees. She was unable to move without help. There were decubitus ulcers which had developed during her recuperation from the fracture. The laboratory examinations revealed anemia and

572

Nodular

Pleuropulmonary

Rheumatoid

Disease-Rubin

et al.

3A

3B

3c

3D

FIG. 3. Case 1. Microscopic pathology. A, circumscribed rheumatoid granuloma with central necrosis, admixed with some anthracotic pigment, rimmed by a belt of proliferating fibroblasts showing a tendency to palisade arrangement. Acid-fast bacilli and periodic acid-Schiff stains were negative; polariscopic study showed no foreign bodies or silica crystals. Original magnification X 60. B, elongated rheumatoid lesion showing slit-like area of necrosis, surrounded by proliferating fibroblasts showing palisade arrangement; surrounding inflammatory zone. Original magnification X 120. C, two small granulomas, the upper larger lesion showing amorphous material surrounded by epithelioid cells and fibroblasts with tendency to lamellation. Van Giesen stain showed no elastic fibers. The lower granuloma, the smallest seen and perhaps the earliest lesion, consists of epithelioid cells and some fibroblasts in the periphery with no evidence of necrosis. Original magnification X 170. D, dense fibrotic layer at periphery of lung containing focus of calcification; part of a large ulcerating rheumatoid nodule is visible. Original magnification X 16.

slight leukocytosis; the latex fixation titer was 1: 320; other tests were noninformative. In the Spring of 1960 gangrene of the second and third toes of the left foot developed and the patient was transferred to the Montefiore Hospital and Medical Center on June 13, 1960. In addition to the advanced generalized rheumatoid arthritis, there was demineralization of the left foot with destruction of the normal joint spaces between the first metatarsal and first phalanx although no definite osteomyelitic focus could be identified. Chest roentgenograms revealed hyperillumination of both lungs. On June 20, 1960, amputation above the left knee was carried out. The patient did well postoperatively and was transferred back to the Beth Abraham Home on July 14, 1960. Occult blood was found in her stools. Roentgenograms of the gastrointestinal tract revealed hiatus hernia with ulceration, probably at the esoph-

agogastric junction. She was treated with antacid, soft diet and antibiotics. From 1960 to 1965 repeated chest roentgenograms showed prominent interstitial striations and in the later films small nodulations more marked in the upper lobe of the right lung. No particular significance was ascribed to these changes because it was difficult to position the patient adequately for roentgenography. On August 10, 1965, fever developed. A chest roentgenogram disclosed a hazy infiltrate at the level of the second and third ribs on the right side. On August 17 the patient vomited coffee-ground material. Death occurred on December 29, 1965. At autopsy the body was that of a well developed, emaciated, elderly white women, measuring 45 inches in length and weighing an estimated 80 pounds. There was no jaundice, edema, cyanosis, clubbing or peripheral lymphadenopathy. There were extreme AMERICAN

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Nodular

Pleuropulmonarv

Rheumatoid

I Xseasee

li’lrhin rl N/.

4B

4A

flexion hands

abduction deformities and kvrists. Ankylosis

of the fingers of both of the right knee was

noted and the left leg had an above-knee amputation. l‘he levels of the leaflets of the diaphragm were at the fifth intercostal space anteriorly. The pleural cavities were free of fluid and adhesions. The parietal pleura was smooth, glistening and translucent. The lungs together weighed 700 gm. They were normally aerated. with basal atelectasis and occasional areas of emphysema. Except for a focal area of fibrosis on the anterior- surface of the upper lobe of the right lung, the pleural surfaces were smooth, glistening and translucent. On palpation the lungs were hypercrepitant in areas but hypocrepitant in the bases. There were no areas of consolidation, masses or cavities. Cut section disclosed gray-pink parenchyma, speckled with moderate amounts of anthracotic pigment. The area of fibrosis in the upper lobe of the right lung was noted to be subpleural with a few nodules measuring 0.3 to 0.4 cm. in diameter. Examination of the left lung disclosed occasional raised, granular whitish areas. A copious amount of pinkish, frothy fluid was expressed from the cut surfaces. The trachea and bronchial tree were patent and not remarkable, as were the pulmonary arteries and veins. The hilar and tracheobronchial lymph nodes appeared normal. The esophagus was patent throughout; its mucosa and wall were normal. There were no varices or diverticula. The periesophageal lymph nodes were not enlarged. About 2 cm. of the stomach was pulled through the hiatal opening of the diaphragm, comprising the hiatus hernia. Examination of the stomach disclosed some erosion of the mucosa which was herniated through the hiatal opening; however, no definite ulcerations were found. On examination, the sternum. ribs and vertebrae were normal. A section of the right hand was taken because of arthritic VOI..

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deformity. ‘There was some spurring of the anterior lips of the vertebral bodies. The inLervcrtebra1 discs appeared normal. The right knee was partly ankylosed and the wrist and fingers showed sevrre Aexionabduction deformities. Microscopic examination of the lungs revealed granulomatous lesions amidst subpleural fibrotic areas. The granulomas were characterized by central necrosis admixed with some inflammatory cells, mostly polymorphonuclear cells and macrophages. These were rimmed by a belt of proliferating fibroblasts with a tendency to palisading arrangement perpendicular to the granulomas. These in turn were surrounded by varying degrees of dense fibrous tissue with scant lymphocytes and plasma cells. Some granulomas showed central necrosis with palisading fibroblasts and scattered giant cells (Fig. 4-4 and 4B). In zones of peripheral pulmonary fibrosis there was arteriolar sclerosis as well as peribronchiolar fibrosis and bronchiolectasis. Other random sections revealed alveolar distention and thinning of the alveolar walls consistent with emphysema. Acid-fast and periodic acid-Schiff stains showed no abnormalities. Polariscopic study revealed no foreign bodb- or silica crystals. Examination of the remaining organs revealed no lesions pertinent to the rheumatoid diurase except for diffuse atrophy of the muscles of the cxtrcmitirs and thighs. COMMENTS

In 1948 Ellman and Ball [ 71 described three patients with rheumatoid disease involving joints and lungs, of which two were examined at autopsy and the lungs showed diffuse nonspecific fibrosis. Similar cases were subsequently reported by others with and without histologic confirmation. In 1953 Caplan [2] drew atten-

574

Nodular

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Rheumatoid

tion to the occasional presence of rounded, discrete densities in the chest roentgenograms of coal miners with rheumatoid arthritis. The lesions were found to develop in crops, and evolved rapidly, at times undergoing cavitation. The nodules were found three times as often in miners with rheumatoid arthritis as in those without arthritis. The combination has since been encountered in workers with rheumatoid arthritis exposed to inhalations of dusts from sandblasting, brass, iron, pottery, boiler scaling and asbestos. Mattingly [27] quotes Caplan to the effect that some 600 cases of the syndrome have been reported. Relatively few cases have been recorded in the American literature [3]. Pneumoconiotic rheumatoid nodules consist of concentric layers of partially necrotic colincluding foci lagen and dust, occasionally of tuberculosis and nonspecific inflammation [4]. It has been suggested that an altered host response, possibly genetically determined, may play a role in Caplan’s syndrome. Miall and his colleagues [S] noted that in most cases the onset of arthritic symptoms coincided with the development of the lung lesions. In some cases the characteristic roentgenologic appearances preceded the arthritis by several years and one case was cited in which rheumatoid arthritis developed in a miner six years before his first chest roentgenogram was taken; this showed simple pneumoconiosis. The next film, taken five years later, showed the “typical” rheumatoid appearances. A somewhat similar experience was reported by Snoek, Raab and Appelman [6]. A sixty-year old coal miner, after thirtyeight years of underground work, had shown no evidence of pneumoconiosis roentgenologically. Following a seizure of rheumatoid arthritis, nodular shadows were seen on a chest roentgenogram. The patient died and at autopsy nodules were found in the lungs with necrotic centers containing coal pigment but no particles of silica. Nodular pleuropulmonary rheumatoid disease unassociated with pneumoconiosis is probably not as rare as generally believed. We have been able to find reports of thirty-two histologically proved cases: fourteen discovered at autopsy, fourteen at thoracotomy and four on pleural biopsy. The demonstration ofrheumatoid nodules in the pleura or lungs duplicating the histology of the subcutaneous nodule leaves little doubt of the nature of the disease [7]. Except for the presence of rheumatoid gran-

Disease-Rubin

et al.

ulomas and the occasional accompaniment of minute cystic spaces, the histology of the lesion is quite monotonous in a.ppearance. Like its counterpart in subcutaneous tissues, the rheumatoid granuloma is composed of three usually recognizable layers: (1) a central zone of fibrinoid degeneration or necrosis, the larger nodules showing slit-like ulceration or gross cavitation; (2) an intermediate zone consisting of proliferating cellular elements, chiefly fibroblasts which often show radial orientation (palisading), and (3) a peripheral zone of inflamed tissue. These and several other features of the rheumatoid lung are represented in the several illustrations and in the summaries of the pathologic findings of previously reported cases (Table I) [7-321. The thirty-two previously reported cases include twenty-two men and ten women. Only five were forty years of age or less. With few exceptions the symptoms of joint involvement antedated the pulmonary manifestations by many years. But there is reason to believe that pulmonary lesions had existed in practically every case for a long time. Christie [ 771 noted that typical rheumatoid nodules occurred in the severe grades of chronic pulmonary lesions. In some of the reported cases an intercurrent pleural effusion or a chance roentgenogram led to the discovery of thoracic disease. The spontaneous pneumothoraces in Case 1 were caused by necrotizing lesions at the lung surface which ruptured the organs. Cases of spontaneous pneumothorax with bronchopleural fistulas, although not as dramatic as in the present instance, have been reported [27,29,30]. Several others have also noted the necrotizing nature of the lesions and the tendency to regional involvement of bronchi and pleura, the latter often showing a reactive pleuritis or localized collections of fluid (see Table I). Although non-necrobiotic lesions do not have the same degree of specificity, there is,evidence to indicate that diffuse nonspecific interstitial pulmonary lesions occurring in a patient with rheumatoid disease are also part of the basic disturbance, unless another cause is found. At thoracic times, manifestations precede the symptoms of joint involvement or appear at approximately the same time. Not infrequently an attack of pleurisy heralds an exacerbation of the disease [33,34]. Price and Skelton [35] described a middle-aged woman who complained of mild chest pains for possibly a year AMERlCAN

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n‘odular

Pleuropulmonary

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bcforc rhrrullatoid arthritis de\;eloped. Autopsy cotnplexes,” thickening of disclosed ‘.nodular alveolar Lvalls, nodules of osteoid tissue and a striking dcgrec of arteritis and bronchiolitis which were considered to be basic processes in the development of rheumatoid lung. Thr occlu-rence of pulmonary disease, usually interstitial fibrosing lesions, for significant periods prior to the appearance of joint manifcstations has been recorded by others. Edge and Rickards [Xi] described a fifty-two year old housewife in whom cough and dyspnea developed in February 1956. A chest roentgenograin was normal. The dyspnea progressed so that by January 1957 the patient was breathless on climbing one flight of stairs. At this time she first noted pain in the small joints of the hands, feet, knees and ankles. A chest roentgenogram at this time showed scattered nodular shadows at the periphery- and lower half of each lung field. A biopsy specimen of the lung showed diffuse fibrosis of a nonspecific character and dense areas of collagenous fibrosis. A striking feature was the dense accumulation of plasma cells and lymphocytes. Doctor and Snider [37] described a fifty-five year old man whose pulmonary disease was discovered in 1953 on a survey chest roent,qenogram. The lungs showed diffuse haz), and nodular infiltrations in both lung fields. There was blunting of the left costophrenic sinus. After being followed in the outpatient department for four years, in May 1957 he was admitted with complaints of painful swelling of the left wrist and right ankle and stiffness of the finger joints in both hands. A biopsy specimen of the lung revealed pleural fibrosis on both sides, interstitial pneumonia, thickened alveolar septums, dilatation of bronchioles and infiltration with chronic inflammatar)- cells; also marked pulmonary arteriosclerosis. The finding of diffuse interstitial fibrosis on the chest roentgenogram in Case 1, three years before the appearance of rheumatoid arthritis, approximately five years before death, and the demonstration at autopsy of an advanced degree of interstitial pulmonary fibrosis as well as nodrllar lesions, is a unique experience. The exact nature of the pulmonary lesions could not be ascertained initially. The presence of the Halnman-Rich syndrome was suspected on the basis of comparative chest roentgenograms and the patient’s complaints of increasing breathlessness. A definitive diagnosis of the

I >&ease --~Kuhin et 01.

.575

Hamiilan-Rich syndronle rcquircks histologic proof and confirmatory functional tc,stiny bllt since one is not always in a position to obtain such evidence, a tcntativc diagnosis based 011 the course of events is permissible rlnd~r certain circumstances [.38]. The course of events in Case 1. as well as ii1 the several cases cited, is in kecpinq \j.ith crrtain observations made by one of 11s in 19.55 [,YJ] and with the late Dr. Ruth Lublinc~r [Jo] ill which attention was drawn to the close resemblance of the interstitial pulmonar); lesions accompanying rheumatoid disease and those characterizing the Hamman-Rich svndrome. Similar opinions were later expressed b!- others [76,37,41]. The similarity of the histologic findings does not necessarily indicate a conm~on etiology since the lungs possess limited ability to react specifically to the man)’ irritants to which they are exposed. However, the probability that such lesions in some cases represent a pulmonary form of rheumatoid disease is supported by certain serologic tests to be discussed. The fact that the Hamnlan-Rich syndrolne in its acute stage is almost invariably proqressi1.r and fatal whereas the rheumatoid lung pursues an indolent course is probably explainable blthe tempo of the respective diseases. The event leading to a fatal outcome in the HammanRich syndrome is often the superimposition of acute lesions on chronic ones. Perhaps this explains the rather paradoxical designation originally applied to the disease by Halurnan and Rich [-L3], namely, “acute diffuse interstitial @rosin of the lungs.” Arn01~g more than thirtyhistologically verified cases of the HalimlanRich syndrome, one of us (E.H.R.) has encountered several in which pulmonar!- s)mptolns were relatively mild initially, the lesions showing little change on successive chest roentgenograms until the sudden appearance of increasiiig air hunger and a rapidly fatal evolution. ,4 comparison of the findings in six patients with successive lung biopsies, in some of whorl1 specimens were obtained at autopsy, showed that the intense fibrosis, shrinkage and hone);combing of the lungs represented the natural transformation of acute lesions into chronic ones [42]. Cruickshank [Ifi] notes that in the majority of cases of early rheuinatoid lung disease thP lesions represent a nonspecific interstitial pneumonitis and at this stage the process is reversible. Early lesions of the Hamman-Rich syndroine also under70 resolution

576

Nodular

Pleuropulmonary

Rheumatoid TABLE

CASE

REPORTS

OF NODULAR

et al.

Disease-Rubin

I

PLEUROPULMONARY

RHEUMATOID

DISEASE

Symptoms Involvement

Bennett

et al. 1940

of Joint (duration)

56,M

3 yr.

57,M

6 yr.

Pleuropulmonary Manifestations

.

VI Zrucnwald

Raven

1948

[8]

et al. 1948

Bevans et al. 1954

Christie

(Care

Pathologic

A: Pleura

..

62,M

[701

46,F

15 yr.

Pleural tion

57,M

15 yr.

Fluid

53,F

35 yr.

Density in upper lobe of left lung; later round density 6 cm. in upper lobe of right lung

63,M

17 yr.

Left pleural

64,F

21 yr.

Nodular pulmonary lesions simulating tuberculosis

I) 1954

and consolida-

base of right

lung

[771

Christie

(Case III) 1954

I771

8

Ellman

et al. 1954

Maher

1954

1721

[73]

rheumatoid

nodules

A:

191

effusion

showed

Findings*

effusion

Granulomas of arthritis in right atrium, tricuspid valve, pleura and capsule of spleen; partial fibrous obliteration of pericardial and pleural cavities; several larger granulomas in the pleura, underneath and protruding on surface of pleura, some showing necrosis A: Both lungs adherent; necrobiosis of pleura with peripheral palisading of cells, giant cells inconspicuous; typical nodules in heart; pericarditis, mediastinitis A: Circumscribed yellow necrotic nodules, about 3 mm. in diameter deep in upper lobe of left lune: subolcural tubercle of same diameter; small granulomas about periphery of large nodule A: Firm white subpleural nodules; 2 on left and 3 on right; largest were necrotic; hyalinized rheumatoid nodule in one hilar lymph node; fibrous pericardium A: Round encapsulated mass 5 cm. in upper lobe of right lung; nodule showed palisading fibroblasts immediately adjacent inner z&e; giant cells of foreign body type; diffuse oerivascular and oeribronchial fibrosis A: N&erous peripheial and subpleural nodules; abscess cavity within pleura; rheumatoid lesions in pleura, endocardium, valves, and ascending aorta A: Nodules in lungs 1 cm. in diameter, some with necrotic centers; necrosis into small bronchus; nodules in bronchial lymph nodes, heart, sclera, dura, subcutaneous

tissue Skogrand (Case 1956 [74]

I)

41,M

10 yr.

Skogrand (Case 1956 1741 Skogranh (&se 1956 [74]

II)

43,F

5 mo.

III)

52,M

4 yr.

57,M

21 yr.

Gresham, Kellaway 1958 [75] Cruickshank

Contin,

Heller

16

Flatley

1959

Oka 1966

et al. 1956

1959

18

ludkowicz

pains

since

teenage

at bases of both lungs

[76]

58,M

1771

52,F

23 yr.

Linear and nodular densities in both lower lung fields; one lesion showed cavitation

[78]

56,M

2 mo.

Pleural effusion, small infiltratt in upper lobe of right lung

62,M

Zmcurrent rheumatoid arthritis and small leftsided pleural effusion of 10 yr. duration

57,M

7 yr.

Diffuse density left base; thickened pleura and fluid

63.M

12 yr.

Rilateral

[79]

Lee et al. 1959

Joint

Densities

[ZO]

et al. 1961

Diffuse interstitial reticulations; progressive in mid and lower zones

Later infiltration left lung

pleural

lower

lobe ot

effusions

[271

* A =

autopsy.

T

=

thoracotomy.

PB

=

pleural

A: Granulomas in lungs displaying three different zones: a few aiant cells: similar granulomas in liver, ipleen &l lymph nodes A: Various sized granulomas; granulomas in hilar lymph nodes A: Pin-head to pea-sized nodules; rheumatoid granulomas in pericardium, heart and valves A: Diffuse tiny subpleural cysts in all lobes; rheumatoid granulomas and adjacent cysts in upper lobe of left lung A: Fibrous pleural adhesions: scattered small rheumatdid granulomas, most numerous in subpleural &ox; occasional multinuclcated giant cells A: Masses in both lunes showing central cavitation, also small nodules; granulomas showed palisading, giant cells, arteritis; granulomas in heart and meninges T: Pleuritis with characteristic palisading of histiocytes under a layer of fibrinoid degeneration T: Frozen section of &ion in lower lobe of left lung suggested cancer; lobectcmy of lower lobe of left lung; microscopic, rheumatoid subspleural nodules in fibrotic parenchyma, fibrous thickening pleura; one lung nodule T: Pleural biopsy: nodule in thickened pleura with palisading of cells: lymphocytic infiltration T: Lung biopsy showed firm nodules over middle lobe; pleural and subpleural nodules with multiple areas of central necrosis; palisade arrangement; 4 mo. later, after period of cortisone treatment, spontaneous pneumothorax with empyema and bronchopleurai fistula

biopsy. AMERICAN

J”URNAL

OF

MEDICINE

Nodular

Pleuropulmonary

Rheumatoid

TABLE CASE

REPORTS

CaSC NO

20

Symptoms Involvrment

‘rirniewir~ 1962

ct 41. (C.tv [-‘i]

(I

‘Grnic\~ icz (Case 1962 [23] l)uma

II

et al. 1963

/ Noonan

of Joint (duration)

[_71]

1 yr.

Multiple nodules in periphery of both lower lungs; one nodule in right lung larger neoplasm suspected; later cavitation in one nodule

43.F

6 yr.

~ 51,bl

5 yr.

[27]

~ 53,M

Recent onset; positive tests for rheumatoid arthritis 9 yr.

40.M

Rheumatic fever at 16; polyarthritis 18 ma.

37,F

5 yr.

Thickened pleura, cloudy pleural fluid; biopsy of pleura and lung showed nodular granulomas with central necrosis similar to subcutaneous nodule; Lung nodule was a large granuloma showing n little cavitation T: Nodular lesion 2.5 cm. in tip of middle lobe; grayish exudate over lobe revealed an opening into another nodule behind pleura, presumably ruptured contents into pleura; wedge resection showed nodules with necrotic centers bounded by palisading fibroblasts T: Thickened pleura; necrotic nodule, palisading of fibrobkas

Nodular lesions in upper lobes of both lungs, also right pleural effusion Multiple lung densities, no symptoms; later cavitation in both upper lobes; after thoracotomy residual scarring without nod&&y Initially left pleural reaction; later multi& well circumscribed nodules in both lunes peripherally and subpIe:rally suggestive metastatic; s”me showed cavitation Routine chest roentgenogram -rounded opacity in upper lobe of right lung with cavitation Mass in upper right lung simnlating carcinoma

T:

Much of middle lobe resected; area of necrosis beneath pleura surrounded by fibrous tissue; histologically not typical of rheumatoid nodule; considered rheumatoid lung with cavity formation T: Two nodules removed from upper lobe of left lung revealed rheumatoid granuloma with central areas of necrosis; ash assay, no silica cOntent

T:

Excision of mass; pus escaped from center; sterile; necrobiotic rheumatoid nodule with surrounding layer of palisading cells; no giant cells T: Sterile lung abscess filled with necrotic material with palisading of cells in the wall similar to that seen in a nrcrobiotic rheumatoid nodule T: Biopsy of left lung 5 yr. before death showed chronic diffuse interstitial pneumonitis: autopsy revealed fibrous pleural adhesions, cystic spaces visible through pleura (2 t” 15 mm. in diameter); lung showed honeycomb appearance; numerous necrobiotic nodules in parenchyma T: For reexpansion of lung; white nodules in visceral pleura showing central necrosis, palisade arrangement similar to rheumatoid nodule; rupture of cavitatrd rheumatoid nodule; pyopneumothorax T: Empyema drained; later excised, also wedge resection of lung which revealed necrotic nodule 2 cm. in diameter containmg typical rheumatoid nodule; also thick ~rnall nodules in walls of bronchioles PB: .4rea of necrosis surrounded by epithelioid cells arranged in palisade fashion compatible with rheumatoid nodule P.B.: Area of necrosis surrounded by spindle epithelioid ccIIs; compatible with rheumatoid nodule PB: Suggestive of rheunutoid nodule

Diffuse bilateral infiltrations; lesions progressed over a period of 5 yr.

Increasing effusion in right side of chest; 2 pleural nodules; later hydropneumothorax; suspected of cancer of lung No

abnormalities on initial chest roentgenograms; later left pleuritis and subsequently air and fluid in chest

Schools, (Case

hlikkelsen I) 1962 1371

35,hl

15 mo

30

Schools, (Case

hiikkelsen II) 1962 1.311

66,M

4 mo.

31

Schools, (Case

hfikkclscn III) 1962 [.3l]

41,F

2 yr.

32

Lassiter.

Tassv

1965

43,M

4 yr.

33

[321 Present

(Cast

1, 1966

62,M

Chest roentgenogram showed diffuse pulmonary fibrosis 3 yr. before symptoms of joint involvement

Progression of lesions in lungs; recurrent bilateral spontane“us pneumothorax

34

Prcsrnr

Car

71,F

20 yr.

Prominent interstitial Ftriations and nondescript nodulations

Pleural lung

effusion

base

of right

Bilateral pleural effusions with“ut evidence of parenchymal involvement Multiple pulmonary nodules and bilateral pleural effusions Bilateral pleural effusions

PB: A:

VOL.

42.

APRIL

1967

Granulomatous

inflammation

Ulcerating and cavitating rheumatoid granulomns showing palisade appearance in corticopleural layer of lungs; multinucleated giant cells; foci of calcification: polariscopic study showed no foreign bodies or silica crystals; rheumatoid eranuloma in eoicardium 1 A: Ulcerating rheumatoid granulomas, showing palisade appearance. peribronrhialar fibrosis and hronchiolectasis; polariscopic study showed no foreign body i or sllicd crystals

,

3

l;indrngs*

T:

41,M

5 yr.

1964

Pathologic

Diffuse irregularly sized nodules both lungs, suggesting metastatic disease

1 mo.

UISXASb

Pleur”pulm”nary Manifestations

14 In”

24

&fatting11

RIIEUMA’I‘OID

54,hl

30,F

577

et crl.

I (continued) PLEUROPUIXONARY

:

/

et al. 1963

[25]

25

OF NODULAR

Disease--K&Gz

I 1

578

Nodular

Pleuropulmonary

Rheumatoid

after corticosteroid treatment as evidenced by roentgenographic and functional studies [&I. There are several disparities in the appearance of the lesions in rheumatoid lung disease and in the Hamman-Rich syndrome which are probably related to the stage of the disease in which the two diseases are recognized, also the severity of the inflammatory process and speed with which it develops. The nature of the physiological adjustments may also play a part. The corticopleural localization of lesions in rheumatoid lung does not have an exact counterpart in the Hamman-Rich syndrome. However, And& [&a] noted that when idiopathic interstitial fibrosis of the lungs developed a honeycomb pattern, the tendency was to concentrate in the apical and peripheral parts of the lungs. Likewise small but often persistent pleural effusions encountered in rheumatoid disease are rarely seen in uncomplicated Hamman-Rich syndrome. Yet it is inconceivable that the thickened, often adherent pleura covering the Hamman-Rich lung was at no time associated with free fluid. Small pleural effusions are easily overlooked, especially in patients too ill to allow frequent roentgenographic examinations. The following cases illustrate the important role which tempo plays in the evolution of the disease and possibly explain certain differences in the appearances of the lesions. In a case presented at a clinicopathologic conference at Mt. Sinai Hospital [45] “classic” histologic features of the Hamman-Rich syndrome were found in a seventy-two year old Negro laborer who was admitted with a two months’ history of acute rheumatoid arthritis. Late in the disease chest roentgenograms revealed diffuse interstitial striations in both lungs, chiefly the right. The patient died. The postmortem examination showed the alveolar septums to be diffusely thickened, with some of the alveoli showing hyaline membrane formation, and also diffuse interstitial fibrosis. Nowhere was there evidence of nodular rheumatoid disease. As in the case of Edge and Rickards [36], cited previously, an unusual finding was an accompanying plasmacytosis. An entirely different course is illustrated in a case described by Patterson, Harville and Pierce [28]. A twenty-four year old woman had a history of rheumatoid arthritis of nine years’ duration. The chest roentgenogram revealed diffuse interstitial lesions. A biopsy specimen of the lung showed chronic diffuse

Disease-Rubin

et al.

interstitial pneumonitis. There were numerous inflammatory cells, chiefly lymphocytes and plasma cells in the alveolar septums which tended to form lymphoid follicles but without nodular formation. The pulmonary symptoms progressed. Cor pulmonale developed and the patient died five years after the diagnostic lung biopsy. Autopsy revealed nodules throughout the pleura and honeycombing of the lungs. The nodules had the characteristic features of necrobiotic granulomas of rheumatoid disease. Our Case 1 is analogous in some respects to this case except that pulmonary lesions, in keeping with diffuse interstitial fibrosis, were discovered roentgenologically three years prior to the appearance of symptoms of joint involvement. A biopsy specimen of the lung was not available. Interstitial and nodular lesions were found at autopsy. It cannot be claimed that in every case rheumatoid lung disease and the Hamman-Rich syndrome are one and the same disease. But there is little doubt that in an appreciable number of the latter the pulmonary lesions represent rheumatoid disease even in the absence of joint manifestations. We agree with Doctor and Snider [37] that until more is known of the Hamman-Rich syndrome the latter designation should be restricted to patients with diffuse interstitial fibrosis of undetermined etiology, unassociated with rheumatoid arthritis. These workers were impressed with the fact that for each four cases in which interstitial pulmonary fibrosis occurred as an isolated finding (116 collected cases) there was one case in which the pulmonary fibrosis was associated with joint disease (thirty-one collected cases), a correlation which seemed more than a coincidence, considering the comparative rarity of both. It is significant that a sizable percentage of patients with interstitial pulmonary fibrosis without arthritis have been found to have seropositive tests for rheumatoid arthritis. Franklin, Zucker-Franklin and McEwen [46] found positive rheumatoid factors in about 50 per cent of patients with diffuse interstitial pulmonary fibrosis in the absence of overt rheumatoid arthritis. In three of their patients arthralgias developed subsequently without deformities and in one of these a subcutaneous nodule appeared which on biopsy had the histologic appearance of an early rheumatoid nodule. Positive serologic tests in patients with diffuse interstitial pulmonary fibrosis in the absence

Nodular

Pleuropulmonary

Rheumatoid

of rhelllnatoid arthritis have been reported by others [37,-N]. Tomasi, Fudenberg and Finby [49] obtained positive reactions to serologic tests for rheumatoid factor in 61 per cent of eighteen patients with idiopathic pulmonary fibrosis. These investigators postulated that the factor itself may play a role in the pathogenesis of rheumatoid lung disease. These observations are in keeping with studies by Dixon [50] who was able to demonstrate the localization of antigen and presumably antibody specifically in the sites of lesions of allergic disease and simllltaneously with their development. The findings seemed to indicate that “the antigenantibody complex per se was an established pathogenetic villain.” That antigen-antibody complexes are probably- directly involved in the pulmonary lesions of certain hypersensitivity diseases in man is suggested by fluorescent antibody studies [51]. A recent communication by Turner-Warwick [52] on the results of lung biopsies in patients with interstitial pulmonary fibrosis, examined by immunofluorescent technics using conjugated also revealed in three cases anticomplement, bright fluorescence of the alveolar wall suggestive of intramural deposition of antigenantibody complexes. The possibility that an autoimmune phenomenon may be involved in the Hamman-Rich syndrome and that the latter may be included among the collagen diseases has been discussed elsewhere [53]. Although the Hamman-Rich syndrome in some cases represents a rheumatoid disease, in most instances one is dealing with what appears to be a primary pneumonia possibly caused by an aerogenous agent. Recent studies suggest that the Hamman-Rich syndrome represents an autoilnmune disease, possibly one caused by an infective agent. Intensive studies have been directed to the Myco@lasma pneumoniae group of organisms [54]. Sharp [55] suggests that special attention be given to cases of arthritis occurring in association with primary atypical pneumonia and idiopathic respiratory tract infections. The fact that pleuropulmonary lesions may precede, accompany or follow rheumatoid disease and that the Hamman-Rich syndrome is allied to the latter in some cases, suggests additional avenues of study of the cause or causes of both diseases. ADDENDUM

Since submitting this article, additional cases of rheumatoid disease have been reported in VOL.

42,

APRIL

1967

Disease-PKnhin

et ni.

570

which histologic examination of p1~1ra ar~cl ‘or lung showed nodular l~le~~ropr~lll~o~l;~r~lesions [5&fi.?]. Acknowledgment: LC’e wish 10 express ollr appreciation to Dr. Harry M. Zimlnrarr tlan, Chief’ of the Laboratory Division of the 1lontcfiore Hospital and Medical Center for his help in the interpretation of the postmortem findings in the two cases and to Dr. Morris Rllbin of the Thoracic Surgical Department for supplying pertinent information on the slqical findings in Case 1. REFERENCES 1. ELLMAN, P. and BALL, R. E. “Rheumatoid disease” with joint and pulmonary manifestations. Rrit.

M. J., 2: 816, 1948. 2. CAPLAN, A. Certain unusual

radiological appearances in the chest of coal-miners suffering from rheumatoid arthritis. Thorax, 8: 29, 1953. 3. RAMIREZ-R, J., LOPEZ-MAJANO, V. and SCHULTZE, G. Caplan’s syndrome: a clinicopathologic study.

Am. J. Med., 37: 643, 1964. 4. GOUGH, J., RIVERS, D. and SEAL, R.

M. E. Pathological studies of modified pneumoconiosis in coalminers with rheumatoid arthritis (&plan’s syndrome). Thorax, 10: 9, 1955. 5. MIALL, W. E., CAPLAN, A., COCHRANE, A. L., KILPATRICK, G. S. and OLDHAM, P. D. An epidemiological study of rheumatoid arthritis associated with characteristic chest x-ray appearances in coal-workers. Brit. M. J., 2: 1231, 1953. 6. SNOEK, D. W. Th., RAAB, Th. and APPELMAN, A. C. Silicose na primair chronisch reuma (syndroom van Caplan). 1Vedwl. tljdschr. ,gencusk., 109 : 11, 1965. 7. BENNETT, G. A., ZELLER, J. W. and BAUER, LY. Subcutaneous nodules of rheumatoid arthritis and rheumatic fever: a pathologic study. -4rch. Path.,

30: 70, 1940. 8. GRUENW?ILD, P. Visceral lesions in a casr of rhcumatoid arthritis. Arch. Path. 46: 59, 1948. 9. RAVEN, R. W., WEBER, F. P. and PRIGI:: L. 1%‘. ‘The necrobiotic nodules of rheumatoid arthritis: case in which the scalp, abdominal wxll (involving striped muscle), larynx, pericardiunl (involving myocardium), pleurae (involving lungs), and peritoneum were affected. :lnn. Rheunrat. ZXs., 7 :

63, 1948. 10. BEVANS, M., NADELL, J., DEMAR.TINI, F. and KAGAN,

11. 12.

13. 14. 15.

C. The systemic lesions of malignant rheumatoid arthritis. .Jm. .I. Med., 16: 197. 1954. CHRIS-TIE, G. S. Pulmonary lesions in rheumatoid arthritis. Australasian Ann. ‘Med., 3: 49, 1954. ELLMAN, P., CUOKOWICZ, L. and EL.\~ooD, J. S. Widespread serous membrane involvement by rheumatoid nodules. J. Clin. Path., 7, 239, 1354. MAHER, J. A. Dural nodules in rheumatoid arthritis; report of case. Arch. Path., 58: 354, 1954. SKOGRAND, A. Visceral 1esic;ns in rheumatoid arthritis. Acta rhmmat. scandinm., 2: 17. 1956. GRESHAM, G. A and KELLAWAI., T. II. Rheuma-

Nodular Pleuropulmonary Rheumatoid

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26. 27. 28.

29.

30. 31. 32.

33.

34. 35. 36. 37.

38.

toid disease in the larynx and lung. Ann. Rheumat. D~F., 17: 286, 1958. CRUICKSHANK,B. Interstitial pneumonia and its consequences in rheumatoid disease. Brit. J. Dis. Chest, 53: 226, 1959. CONTIN,J. U. and OKA, M. Unusual cardiac, pulmonary and meningeal involvement in rheumatoid arthritis. Dis. Chest, 49: 552, 1966. HELLER, P., KELLOW, W. F. and CHOMET,B. Needle biopsy of the parietal pleura. New England J. Med., 255: 684, 1956. FLATLEY, F. J. Rheumatoid pulmonary disease: report of a case. New En,&nd J. Med., 261: 1105, 1959. LEE, P. R., Sox, H. C., NORTH, F. S. and WOOD, G. A. Pleurisv with effusion in rheumatoid arthritis. Arch. Znt. bed., 104: 634, 1959. CVDKOWICZ, L., MADOFF, I. M. and ABELMANN, W. H. Rheumatoid lung disease: a case report which includes respiratory function studies and a lung biopsy. Brit. J. Dis. Chest, 55: 35, 1961. ROBERTSON, J. L. and BRINKMAN, G. L. Nodular rheumatoid lung disease. Am. J. Med., 31: 483, 1961. SIENIEWICZ,D. J., MARTIN, J. R., MOORE, S. and MILLER, A. Rheumatoid nodules in the lung. J. Canad. A. Radial., 13: 73, 1962. DUMAS, L. W., GREGORY, R. L. and OZER, F. L. Case of rheumatoid lung with cavity formation. Brit. M. J., 1: 383, 1963. NOONAN, C. D., TAYLOR, F. B., JR. and ENGLEMAN, E. P. Nodular rheumatoid disease of the lung with cavitation. Arthritis &2 Rheumat., 6: 232, 1963. YATES, D. A. H. Cavitation of a rheumatoid lung nodule. Ann. Phys. Med., 7 : 105, 1963. MATTINGLY, S. The lungs and rheumatoid arthritis. Ann. Phys. Med., 7: 185, 1964. PATTERSON, C. D., HARVILLE, W. E. and PIERCE, J. A. Rheumatoid lung disease. Ann. Znt. Med., 62 : 685, 1965. HINDLE, W. and YATES, D. A. H. Pyopneumothorax complicating rheumatoid lung disease. Ann. Rheumat. Dir., 24: 57, 1965. DAVIES, D. Pyopneumothorax in rheumatoid lung disease. Thorax, 21: 230, 1966. SCHOOLS,G. S. and MIKKELSEN,W. M. Rheumatoid pleuritis. Arthritis & Rheumat., 5 : 369, 1962. LASSITER,G. S. and TASSY, F. T. Malignant rheumatoid disease with aortic stenosis. Arch. Znt. Med., 116: 930, 1965. HORLER, A. R. and THOMPSON,M. The pleural and pulmonary complications of rheumatoid arthritis. Ann. Znt. Med., 51: 1179, 1959. WARD, R. Pleural effusion and rheumatoid disease. Lancet, 2: 1336, 1961. PRICE, T. M. L. and SKELTON, M. 0. Rheumatoid arthritis with lung lesions. Thorax, 11 : 234, 1956. EDGE, J. R. and RICKARDS, A. G. Rheumatoid arthritis with lung lesions. Thorax, 12: 352, 1957. DOCTOR, L. and SNIDER, G. L. Diffuse interstitial pulmonary fibrosis associated with arthritis: with comments on the definition of rheumatoid lung disease. Am. Rev. Resp. Dis., 85: 413, 1962. RUBIN, E. H. and RUBIN, M. Lung biopsy for diffuse pulmonary lesions: value and limitations. Dis. Chest, 46: 635, 1964.

Disease---Z&bin et al.

39. RUBIN, E. H. Pulmonary lesions in “rheumatoid disease” with remarks on diffuse interstitial pulmonary fibrosis. Am. J. Med., 19: 569, 1955. 40. RUBIN, E. H. and LUBLINER,R. The Hamman-Rich syndrome: review of the literature and analysis of 15 cases. Medicine, 36: 397, 1957. 41. LEE, F. I. and BRAIN, A. T. Chronic diffuse interstitial pulmonary fibrosis and rheumatoid arthritis. Lancet, 2: 693, 1962. 42. RUBIN, E. H. and SOIFER, I. Unpublished data. 43. HAMMAN, L. and RICH, A. R. Acute diffuse interstitial fibrosis of the lungs. Bull. Johns Hopkins Hosp., 74: 177, 1944. 44. (a) AND~R, L. Idiopathic interstitial fibrosis of the lungs. I. Prognosis as indicated by radiological findings. Acta med. scandinau., 178: 47, 1965. (b) MALMBERG, R., BERGLUND,E. and ANDBR, L. Idiopathic interstitial fibrosis of the lungs. II. Reversibility of respiratory disturbances during steroid administration. Acta med. scandinav., 178: 59, 1965. 45. SCHAFFNER, F. (Ed.) Clinico-Pathological Conference. Polyarthritis, fever and late onset of pulmonary findings. J. Mt. Sinai Hosp., 29 : 528, 1962. 46. FRANKLIN, E. C., ZUCKER-FRANKLIN,D. and McEWEN, C. Some observations on patients with interstitial pulmonary fibrosis. Arch. Interamerican Rheumat., 2: 250, 1959. 47. STRETTON, T. B. and LEEMING,J. T. Diffuse interstitial pulmonary fibrosis in patients with a positive sheep cell agglutination test. Thorax, 19: 79, 1964. 48. WARD, R. and STALKER, R. Sheep cell agglutination test in chronic interstitial pulmonary fibrosis. Ann. Rheumat. Dis., 24: 246, 1965. 49. TOMASI, T. B., JR., FUDENBERG,H. H. and FINBY, N. Possible relationship of rheumatoid factors and pulmonary disease. Am. J. Med., 33: 243, 1962. 50. DIXON, F. J. The role of antigen-antibody complexes in disease. Harvey Lect., 58: 21, 1963. 51. BOTTINO, A. J., BROWN, A. L., JR. and DIVERTIE, M. B. The pulmonary lesion in a patient with Goodpasture’s syndrome: as studied with the electron microscope. Am. J. C&n. Path., 42: 387, 1964. 52. TURNER-WARWICK, M. Immuno-fluorescent studies in lung biopsies. Proceedings of the Thoracic Society. Thorax, 21: 290, 1966. 53. RUBIN, E. H. Rheumatic diseases as related to pulmonary medicine. Bull. Washington Hosp. Center, 2: 3, 1966. 54. MUFSON, M. A., SANDERS, V., WOOD, S. C. and CHANOCK,R. M. Primary atypical pneumonia due to Mycoplasma pneumoniae (Eaton agent). Report of a case with a residual pleural abnormality. New England J. Med., 268: 1109, 1963. 55. SHARP, J. T. The mycoplasmataceae (PPLO) as causes of joint infections. Arthritis @ Rheumat., 7: 437, 1964. 56. BEROER,H. W. and SECKLER,S. G. Pleural and pericardial effusions in rheumatoid disease. Ann. Znt. Med., 64: 1291, 1966. 57. BRUNK,J. R., DRASH, E. C. and SWINEFORD,O., JR. Rheumatoid pleuritis successfully treated with decortication. Report of a case and review of the literature. Am. J. M. SC., 251: 545, 1966. AMERICAN

JOURNAL

OF

MEDICINE

Nodular 58.

Ihmso~.

W.

effusion port

tT. and

Pleuropulmonary

HOLLINGSWORTH,

in rheumatoid

of glucose.

arthritis:

Rheumatoid

J. LY. Pleural impaired trans-

.\‘Pw England ./. Med., Cholesterol lung disease.

pleural

C.

rhrumatoid MORGAN,

Thorax,

effusion

21 :

in

VOL.

42,

and

62.

in rheumatoid

98: 334. 1966.

APRIL

1967

disease

and 697,

GKACX,

\1.

with cavitary

eosinophilia.

Ycrt

A..

JR.

I<~ICUIII;I-

nwl~~l~~~,;x,t~~moF!!‘ian!,/

1. .\IPn’.

1966.

RAMIREZ-K., J. Rheulnatoid cavitation.

577,

D. A. The lungs arthritis. 4772. J. Roent-

\VOLFEL,

lung

thor,w

63. \Y. Ii. C.


ynol..

toid

275: 1337,

1966. 60.

61. POR.I.NER, M. M. ;II~

275:

1966. 59. FP.KGUSON, G.

i81

IXsease---h)~~hin rl ni.

Dzs. C/ze.r/,50

disease UI IIIV LIII~ \vith 1900.

: 544,

Srwicxx. B. F., ~V,\.I.SON, R. K. iltld D.wI.I~,(;. K. .J. Pullnonary rheumatoid nodule 1, ith (‘,I\ itation and chronic lipid effusion. ./..1..11..-1.. 198: 1263. 1966