airway disease in a subset of nonsmoking rheumatoid patients: characterization of the disease and...

Airway Disease in a Subset of Nonsmoking

Rheumatoid Patients

Characterization of the Disease and Evidence for an

Autoimmune Pathogenesis

RAYMOND BEGIN, M.D. SERGE MASSi, M.D. ANDRE CANTIN, M.D. HENRI-A MiNARD, M.D. MICHEL-A BUREAU, M.D.

Sherbrooke, Quebec, Canada

From the Unite de Recherche Pulmonaire and Unite des Maladies Rhumatismales, Departement de MtMecine et Pathologie, Centre Hospitalier Universitaire, Universite de Sherbrooke, Sher- brooke, Quebec. This work was supported in part by the Canadian Arthritis Society and the Conseil de la Recherche en Santg du Quebec. R Begin is a scholar of the Canadian Life Insurance Com- panies Association. Requests for reprints should be addressed to Dr. Raymond Begin, Unite de Recherche Pulmonaire, Centre Hospitalier Uni- versitaire, UniversiU de Sherbrooke, Sherbrooke, Quebec, Canada JlH 5N4. Manuscript accepted October 29, 1982.

Prevtous investigations of airway disease in rheumatoid patients have been oriented toward establishing the prevalence of the disease, but the pathogenesis and the time course of the airflow obstruction in rheumatoid disease are still unclear. In this study, we analysed the clinical, serial pulmonary function and histlbpathologic data of six rheumatoid pabents who had never smoked but who had airflow limitatlons documented repeatedly up to 10 years previously. We have attempted to characterize the site, nature and evolution of the chronic airway disease in this group of patknts. Bronchtectasts was excluded in all patients by bilateral bronchography. Clhrical and histopathologic evidence of the Sjogren autoimmune exocrinopathy was documented in five of the patients, and the sixth patient had lymphopksmocytk Mtrates of the labial glands wlthout obstructton of the lumen or destruction. By pulmonary function tests and hlsto- pathologic examination of four open lung biopsies, the airway dls- ease was found to be located predominantly in the peripheral alrways of the lung. On each Mopsy, the lestons were in d&went stages of activity, but on all specimens there was a definite predilection for selective bronchiolar injury. Early stage lesions were characterized by mononuclear cell tnflltrates of the peribronchiolar tlssue which led to deformation of airway lumen, focal mucosal extension and ulceration. Subsequently, the inflammatory reaction was replaced by fibroblastic proliferation, and in the end stage of the disease, there was complete obliteration of many bronchioles by collagenized fibroblastic tissue. From regression analyses of serial pulmonary function tests of these patients, it was concluded that (1) the airway disease in our patients who did not smoke progressed inevitably but not uniformly and (2) detertoration of pulmonary functbns was more rapid in our patients than It was in the cigarette smokers who had chronic obstructive lung disease. This study also documents major dysfunctions of the chest wall mechanics which appear to contribute to the restriction of lung volumes in some rheumatoid pattents.

In patients with rheumatoid disease, much of the early research on lung involvement [l-6] has focused on the study of the prevalence and nature of pleuropulmonary disease, but evaluation of airway function has been limited. Indeed, most investigators have either at- tributed airflow obstruction in rheumatoid disease to smoking and aging

May 1982 The American Journal of Medicine Volume P2 743

AIRWAY DISEASE IN RHEUMATOID PATIENTS-BEGIN ET AL

TABLE I Clinical Data Df The Six Patients With Rheumatoid Disease (RD)

Age Age Age al

Age al Onset Rheumatoid ARA at onset ROW Labial Onset of

Patient in 1981 uf Rheumatoid Disease RD Nodule Functional of S]dpren Syndrome Bchlnner’s Bengal Parotid Gland Dyepnea Dyepnea

No. (yr) (yr) Titer Biopsy Class (yr) Test Teef Scan Biopsy (yr) Grade’

1 60 30 1:640 + Ill ? - - - + 49 415

2 58 46 I:2560 + IV 55 + + + + 54 515

3 66 41 1:1280 + Ill 66 + - + 61 215

4 57 53 1:2560 ND II 55 : + - + 56 315

5 49 40 1:2560 + IV 49 + + + + 48 515

6 65 62 1:640 + Ill 61 + + + + 63 315

RD = rheumatoid disease; ARA = American Rheumatism Association; SS = Sjbgren syndrome; ND = not done; + = positive; - = nega- tive. * According to Crofton and Douglas [43].

or have simply discarded the information from their reports. Recently, however, clear evidence of a distinct airway disease in patients with rheumatoid disease has been presented by Geddes and associates [7] who described six patients with rheumatoid disease who had rapidly progressive airway obliteration in the absence of chronic bronchitis or emphysema. Subsequently, prevalence studies [&lo] have established that in such patients there is a 30 percent incidence of airflow obstruction in those who do not smoke cigarettes and 60 percent in those who do smoke. These studies have further documented that airway obstruction may well be the most common pulmonary manifestation of rheumatoid disease, but little information is yet available on the nature and evolution of this airway disease.

volume curve, expiratory flow rate, diffusing capacity (Dt+,), sitting blood gas and maximal mouth pressure studies were carried out according to standard methods [ 13,141, as previously applied in our laboratory [ 15- 171. As suggested [ 141, maximal mouth pressure was taken as the mean of maximal expiratory pressure at total lung capacity and maximal inspiratory effort at residual volume [ 16,171. The tests were carried out seven times over a lo-year period in Patient 1, eight times over a four-year period in Patient 2, three times over a one-and-a-half-year period in Patient 3, three times over a six-month period in Patient 4, two times over a five- year period in Patient 5 and three times over a three-month period in Patient 6.

We have, therefore, investigated a group of 12 patients with rheumatoid disease who were referred to us with respiratory complaints. Six of them were cigarette smokers, and because of the established relationship between smoking habit and airway disease, they were excluded from this report. The six lifetime nonsmokers

who did not have bronchiectasis were selected in order

to evaluate the site and time course of their airflow

obstruction, and also to gain some insight into the

pathogenesis of the chronic airway disease in this

subset of patients with rheumatoid disease.

Furthermore, at the time of their last visit, flow-volume curves were obtained while breathing room air and a mixture of 80 percent helium, 20 percent oxygen, to detect the major site (large or small airways) of airflow limitation [ 18-211. Lung Biopsies. Open lung biopsies were carried out in four of the patients, at a time when their expiratory flow rates were mildly to severely reduced. Biopsy specimens of the lung were obtained for diagnostic purposes in our first two patients and in two others with restrictive lung volumes, to eliminate fibrosing alveoiitis. The average morphologic severity of airway disease was evaluated without knowledge of pulmonary function results. During surgery, a specimen of intercostal muscle was obtained for histopathologic examination in Patient 1. In addition, a biopsy specimen of a quadriceps muscle was obtained from Patient 6.

MATERIALS AND METHODS RESULTS

Subjects. The six patients of this study had classic rheumatoid disease as defined by the American Rheumatism Association [ 1 l]. All had chronic erosive disease with sub- cutaneous nodules and high titer rheumatoid factors. They were evaluated for progressive breathlessness and persistent cough. All were lifetime nonsmokers and had no history of exposure to toxic gases or any recent pulmonary viral in- fection. None fulfilled the diagnostic criteria of asthma or chronic bronchitis as suggested by the American Thoracic Society [ 121. The mean age of the patients at the onset of arthritis was 45 years (range 30 to 62 years) and at the onset of dyspnea, 55 years (range 49 to 63 years). Pulmonary Function Tests. The lung volume, pressure-

Clinical Data. In Table I, the clinical features of the six rheumatoid patients are presented. None of the patients had major clinical flare-ups of their arthritis or dyspnea at the time of data collection. All had classic rheumatoid

arthritis for an average of 10 years duration before the start of breathlessness. In all patients, rheumatoid factor was positive.

During the course of joint replacement surgery, five

patients had excision of rheumatoid nodules and in all, the classic histopathoiogic criteria for the disease were fulfilled. All patients had been treated with the usual

anti-inflammatory drugs before initial pulmonary diag-

744 May 1982 The American Journal of Medicine Volume 72

AIRWAY DISEASE IN RHEUMATOID PATIENTS-BEGIN ET AL.

TABLE II Pulmonary Function of the Six Patients

Total Functional

Lung Vital Residual Residual Patient Date of Capacily Capacity Capacity Volume FEV, FEV,/FVC Vmax 50 Pa02 Pa,,2

No. Test@ (% prediction) (% prediction) (% prediction) (56 prediction) (% prediction) (% prediction) ( % prediction) (torr) (torr)

10/21/71 06/04/75 1 l/07/79 04/29/80 08/26/ao lo/lo/a0 01/2ofal 03128177 I ii07178 12fl5/78 01/12/79 02127179 04/05/79 ol/oa/ao 09/16/80 04127176 01/16/81 06/05/80 loi27iao 01/09ial 0711 ii80 loioliao oli20/81 loi2oiao 12il2iao 01/23/al

90 100 102 100 - - - 136 128 125 120 112 121 117 -

102 100

68 - -

71 - -

86 97 a4

73 74 75 62 60 55 63

104 a3 74 73 73 70 61 56 90

107 40 47 42 53 60 55 54 72 68

100 120 109 148 116 148 115 116 - - - - 152 153 154 151 133 155 153 - 100 aa a2 a2 - al - - 118 121 105

- - 195 209 217 205 la3 214 220 -

123 a9

118 - -

107 - - 137 138 109

49 50 43 44 33 35 27 39 30 39 26 38 27 38 43 47 23 34 26 35 20 32 23 34 20 31 20 28 19 29 78 75 73 71 34 61 33 58 30 60 25 50 28 41 20 31 70 80 56 70 55 69

la 20

5 5 3 3

30 10 - - - -

4 4

48 40 12

9 a 4 5 4

51 28 15

68 74 a1 - - - - 73 75 75 - 75 74 64 - 76 80 57 68

30 29 28 - - - -

31 31 32 -

33 35 36 _-

28 38 33 39

67 33 - - 71 66 70

-

38 32 39

FEVl = forced expiratory volume in 1 second; FVC = forced vital capacity; FEV,/FVC, % = FEV, percent forced vital capacity; \imax 50: maximal expired flow rate at 50% forced vital capacity; Pao2 = arterial oxygen pressure; PacoP = arterial carbon dioxide pressure.

nosis, and only Patient 5 had received a four-month course of penicillamine therapy one year before respiratory symptoms developed. Eight years earlier, this patient had received a total of 2.1 grams of gold administered intramuscularly and, following her pulmonary diagnosis, a three-month course of chloroquine. Patient 4 also received 1 gram of gold administered intramuscularly two years before initial pulmonary diagnosis, and a six-month course of chloroquine therapy one year before. Patient 2 has been receiving chloroquine therapy since February 1980.

Five of the six patients had symptoms suggestive of an associated autoimmune exocrinopathy: dry eyes, dry mouth, positive Schirmer test and rose bengale test [ 22-251. Parotid scintigraphy was abnormal in three of the patients. Labial gland biopsies showed lymphoplasmocytic infiltration with obstruction and destruction of the gland [26,27] in five patients. The lip biopsy of Patient 1 showed a few foci of periglandular lymph+ plasmocytic infiltrate without gland obstruction or destruction. This latter patient (Patient 1) did not complain of dry mouth or dry eyes and had “normal” Schirmer and rose bengale tests. Pulmonary Function. The results of selected expira-

tory flow rate, lung volume and blood gas tests obtained serially in these patients are presented in Table II. From these data, a gradual reduction of expiratory flow rates was seen over time and was associated with a progressive increase in the residual lung volume; these rates were associated with chronic mild hypoxemia and respiratory alkalosis. The air-helium flow volume curves demonstrated in all patients high isoflow volumes and little to no influence of low density gas on expiratory flow rates. Figure 1 presents, in addition to the air- helium flow volume curve of a normal 55 year old woman, the curves of three of our patients at various stages of airway disease. Finally, to obtain some information on the time course of this airway obstruction, the forced expiratory volume in one second to the percent forced vital capacity (FEVJFVC [percent]) data of each patient over time were fitted in linear regression equations (regression greater than 0.9 in all) (Figure 2, left panel). We also averaged those of Patients 1 through 5 which had been measured for over six months to allow comparisons with the time course of this parameter in a healthy nonsmoking population [ 151 and with the long-term course of the same parameter in chronic obstructive pulmonary disease [28] (Figure 2, right

May 1962 The American Journal of Medicine Volume 72 745


4 Volume CL)

6. 6.

4. Volume CL1 4 Volume CL)

4 Volume CL)

L . . _ -, . . . . , Ffgure 7. I ne air-net/urn (- - - - , . . . L *. * . . .

respecrrvery) now-volume curves or a nealu 55 year old woman are presented in the upper left panel. The curves of Patient are presented in the upper right panel. The lower left panel shows the curves of Patient 5 and the lower right panel demonstrates the curves of Patient 2. On these flow-volume curves, the isoflow volume is the lung volume (percent forced vital capacity) at which the air and helium curves meet and the changs in maximal expired flow rate at 50 percent forced vital capacity is the difference between flow rates at 50 percent forced vital capacity during air and helium breathing. In all patients, the isoflow volume was above 80 percent and the change in maximal expired fluorate at 50 percent forced vital capacity below 5 percent.

panel). In this figure, it can be seen that airway obstruction in our patients had a variable course but, on the average, progressed much more rapidly than in patients with chronic obstructive pulmonary disease.

In Figure 3 selected pulmonary function data per- taining to the diffusion capacity and the respiratory mechanics in these patients are presented. Although Patients 4, 5, and 6 had reduced total lung capacities, they were not associated with low diffusion capacities nor with increases in maximal pleural pressure at total lung capacity, changes which have been previously linked to interstitial lung disease [ 131. However, max-

imal mouth pressure, the maximal pressure generated by the respiratory system against an occluded airway, was reduced in all patients to an average 59 percent prediction. In the three patients without reduction in lung volumes, maximal mouth pressure averaged 77 percent, whereas in those with small lung volumes, it averaged 34 percent. Histopathology. Representative lesions seen at lung biopsy are presented in Figure 4. They show selective bronchiolar injury at different stages without evidence of inflammatory or fibrotic disease in adjacent lung parenchyma. Figure 4A and B show early bronchiolar

749 May 1982 The American Journal of Medicine Volume 72


r

30 50 70

AGE (yr)

- . . _ . _. . . . . . . _

WA PI\TIENTS

50 AGE(Yr)

COPD ‘&%whv7nl,

70

i /gum z. me trme course or a/rrlow rrmrtatron or our patients witn rheomatoid disease is

presented in terms of the change of the forced expiratory volume in 7 second at the percent forced vital capacity (FEV,l FVC, percent) in comparison to a healthy nonsmoking population (air patients) and a population of patients suffering from chronic obstructive pulmonary disease (COPD). In the left panel, c&eta of each patient (identified by number) are presented. In the right panel, the averaw regession line of the five patients followed for over six months, is presented. The shaded areas represent 2 standard error of the estimate in each panel.

injury characterized by a dense lymphoplasmocytic infiltrate, at times nodular in a peribronchiolar location. This lesion produced variable degrees of luminal distortion and narrowing. Figure 4C and D show intermediate stages of the disease. Here, the mononuclear infiltrate is less dense, but there is mucosal destruction, granulation tissue and scarring of the bronchiolar wall. Figure 4E shows a late-stage lesion characterized by complete fibrous obliteration of the bronchiolar lumen

in the absence of inflammatory activity. In Figure 4F, an intercostal muscle biopsy specimen shows myositis with nodular infiltration by lymphoplasmocytic cells with germinal centers. A peripheral muscle biopsy in Patient 6 revealed similar findings.

The biopsy specimens of the lung presented herein were obtained within a few days following pulmonary function testing. Figures 4A and B represent the average airway disease of Patient 1 at the time of her first pulmonary function tests which are presented in Table II (forced expiratory volume in 1 second [FEV,] = 50 percent forced vital capacity [FVC]). Figures 4C and D are from Patient 5, who at the time of biopsy, had a FEV, of 41 percent FVC. Figure 4E of Patient 2, who had the most severe airflow obstruction (FEV, = 32 percent FVC), at the time of biopsy, shows severe fibrous obliteration of the airway which was seen only in this patient. On all four lung biopsies of our patients with rheumatoid disease, the average morphologic severity of airway disease was well reflected on the degree of expiratory airflow reduction.

DL/VA Pp,max TLC Pmmax

r@rn? 3. Seiected pulmomuy tirnctkm data of each patient are presented in consecutive order, in terms of diffusrng capacity (DL f VA), maximal pleural pressure at fult inspiration (Pprmax), total lung capacitv (TLC) and maximal pressure generated at the nkn4th a&nst an airway occlusion (P,max). P,,,max is the mean of P,,,max generated at TLC during an expiratory effort and of P,,,max generatedat residual volume during an inspiratory effort. The high LX VA in some of these patients is likely an effect of the correction for lung volume, since diffusing capacity uncorrected was within f 30 percent prediction in all patients.



Figure 4. Photomicrographs of lung and muscle biopsy specimens. A, early stage lesion of Patient 1 with peribronchiolar mononuciear infiltration and slight distortion of bronchiole (ff and E; magnification X 700, reduced by 50 percent). 6, ear/y stage lesion of Patient 7 showing more severe distortion and narrowing of bronchiole by a nodular inflammatory infiltrate with few, if any, abnormalities of ao”cent parenchyma (Hand E; magnification X 700, reduced by 50 percent). Insert shows perforation of mucosa by a lymphoplasmocytic exudate (H and E; magnification X 250, reduced by 50 percent). C, intermediate stage lesion on lung biopsy of Patient 5, with foci of mucosal damage and cellular accumulation in bronchiolar lumen (Hand E; magnification X 100). Insert shows intraluminal foamy histiocytes, residual tymphoplasmocytic exudation and granulation tissue with fibroblastic proliferation extending to the lumen (t-t and E; original magnification X 250, reduced by 50 percent). D, advanced stage lesion on biopsy of Patient 5 with narrowing of &men and thickening of the bronchiolar wait (Masson; magnification X 250, reduced by 50 percent). Insert shows mucosal remnants, intraiuminal histiocytes, scarring and thickening of the sub-muwsa (h&son; original magnification X 400, reduced by 50 percent). E, final stage lesion on biopsy of Patient 2 with total obliteration of the bronchiole in the absence of parenchymal exudation or fibroblastic lesion (Hand E; magnification X 100, reduced by 50 percent). insert shows fibroblastic luminal obliteration, absence of inflammation and residual smooth muscle bundle (H and E; original magnification X 250 reduced by 50 percent). F, intercostal muscle biopsy from Patient 1 showing a nodular lymphoid infiltrate with germinal center (Hand E; magnification X 250, reduced by 50 percent).

740 May 1982 The American Journal ol Medlclne Volume 72

COMMENTS

In this paper, we describe six patients who were lifetime nonsmokers with classic rheumatoid disease, who had no exposure to toxic gases, no symptoms of asthma, chronic bronchitis or bronchiectasis but who did have clear evidence of airway obstruction. These patients had moderate to severe classic rheumatoid arthritis and high titers of rheumatoid factor documented, on the average, 10 years before respiratory symptoms began to develop. Only two patients had received gold or penicillamine therapy many months before initial respiratory symptoms, thus eliminating the possible reia- tionship of the airway disease to the use of these drugs [ 8,29-341. However, five of the patients had definite evidence of advanced autoimmune exocrinopathy, and the sixth patient had lymphopiasmocytic infiltration of the labial glands which was suggestive of an early stage of Sjdgren disease. This tatter patient, as well as Patient 5, both had symptomatic airflow limitations many months before the exocrinopathy was suspected; an observation which is in line with the recent reports of Moutsopoulos et al. [35] and Martinez-lavin et al. [36], both of which emphasized the multisystemic nature of Sjogren syndrome often in the absence of the sicca symptoms. This suggests therefore, that airflow limitation may well be an early presentation of the Sjijgren syndrome, a manifestation which has only recently been described in 11 patients, two of whom also had rheumatoid disease [37]. The incidence of this autoimmune airway disease in patients with rheumatoid disease is currently unknown.

To elucidate the nature of this airway disease, all patients underwent bronchography which excluded the presence of bronchiectasis. At open lung biopsy, the disease was characterized by a lymphoplasmocytic infiltration of the wall of the small airway which ap- peared to gradually narrow the airway lumen, destroy the bronchiolar wail, invade the lumen and replace the bronchiole by a fibrous scar in the advanced stage of the disease. Although the larger airways were not bi- opsied in our patients, it is likely that similar lymphoplasmocytic infiltration of the bronchial wall would have been observed [23]. But, as seen on bronchography, the disease of the larger airways did not obliterate the airway lumen. Furthermore, we have used pulmonary function tests which correlate well with the structural abnormalities seen at lobectomy or autopsy [38-411. The data of isoflow volume and the change in maximal expired flow rate at 50 percent forced vital capacity in our patients clearly suggest that the major location of airflow limitation in the disease is in the peripheral airways. Thus, the airway disease in our patients appears to be caused by an autoimmune process

AIRWAY DISEASE

that predominantly tion.

IN RHEUMATOID PATIENTS-BEGIN ET AL.

alters the peripheral airway func-

To define the time course of this airflow limitation, we analysed the pulmonary functions of our patients who had been tested for up to 10 years (Figure 2). The analyses demonstrated that airway obstruction in our patients is invariably progressive but generally at a much faster pace (FEVr of 9 percent FVC per year [percent decrease]) than the established progression of the airway disease in cigarette smokers (FEV, of 2 percent FVC per year) [28]. Thus, the serial pulmonary function data in our subpopulation of patients with rheumatoid disease, although limited by the number of subjects, suggest that this autoimmune airway disease could, on the average, lead to respiratory insufficiency some 12 to 15 years after the onset of the rheumatic disease. In addition, the present study has documented major reductions in maximal mouth pressure (Figure 3) which can contribute to the restriction of lung volumes in patients with rheumatoid disease. In our patients, maximal mouth pressure could have been reduced by alteration of the chest wall relaxation characteristics, as seen in ankylosing spondyiitis [42] or by weakening of the respiratory muscles, as seen in muscular diseases [ 16,171. In our patients with severe rheumatoid disease, the process affecting most peripheral joints could conceivably restrict the mobility of the chest wall, thereby interfering with the generation of normal maximal mouth pressure. Furthermore, weakening of the respiratory muscles in patients with rheumatoid disease could be caused by inflammatory muscle disease as documented on biopsy in two patients.

At the present time, the contribution of these two mechanisms in the reduction of maximal mouth pressure and on the reduction of lung volumes in some patients with rheumatoid disease cannot be clearly defined, but detailed studies of these alterations of the respiratory mechanics are currently underway in our laboratory.

in conclusion, we have documented a clearly progressive obstructive disease of the peripheral airways in six rhematoid patients who were lifetime nonsmokers. This airway disease is caused by a lymphoplasmocytic infiltration of the peribronchidlar tissue, which gradually invades and destroys the small airways in a manner similar to the parotid gland involvement seen in the Sjogren syndrome. This airway disease in two of our patients clearly preceded the other manifestations of autoimmune exocrinopathy. In addition, major dysfunctions of the chest wail mechanics con- tributed to the restrictive lung syndrome seen in some of these patients.


AIRWAY DISEASE IN RHEUMATOID PATIENTS-&GIN ET AL.

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750 May 1982 The American Journal of Medlclne Volume 72

airway disease in a subset of nonsmoking rheumatoid patients: characterization of the disease and...

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