Sjögren's syndrome in progressive systemic sclerosis (scleroderma)

Sjiigren’s Syndrome in Progressive Systemic Sclerosis (Scleroderma)

DONATO

ALARCCN-SEGOVIA,

M.D.

GRACIELA IBANEZ, M.D. JORGE HERNANDEZ-ORTlZ, FRANCISCO YOLANdA

M.D.

VELAZQUEZ-FORERO,

M.D.

GONZ~LEZJlM6NEZ

M6xico City, Mtxico

Sicca features of Sjogren’s syndrome were investigated in 25 consecutive patients with progressive systemic sclerosis by means of clinical examination, Schirmer’s tests, rose bengal staining tests, secretory parotid sialographies, scintillation scanning of salivary glands with s9+“Tc pertechnetate, radionuclide salivary excretion studies and lip biopsies for study of minor salivary glands. All 25 patients had at least one abnormal test and all but 3 patients had more than two abnormal tests. Pathologic findings in minor salivary glands included both lymphocytic infiltration and duct cell proliferation characteristic of Sjogren’s syndrome, as well as collagen infiltration and disruption attributable to scleroderma. However, the finding of lacrimal and major salivary gland involvement indicates that Sjogren’s syndrome does occur in the majority of patients with progressive systemic sclerosis. Because Sjogren’s syndrome coexists almost exclusively with autoimmune disorders, our findings support the contention that progressive systemic sclerosis is related to autoimmunity. Of all connective tissue disorders, progressive systemic sclerosis (scleroderma) has proved to be the most elusive. Markers of autoimmunity, found in most other connective tissue diseases, have not been demonstrated systematically in progressive systemic

From the Departments of Immunology and Rheumatology, Radiology, Pathology and Nuclear Medicine, lnstituto National de la Nutrition, Mexico City, Mexico. Requests for reprints should be addressed to Dr. Donato AlarconSegovia, Department of Immunology and Rheumatology, lnstituto National de la Nutricibn, Mexico 22, D.F., Mexico. Manuscript accepted November 13, 1973.

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sclerosis. Sjogren’s syndrome has been occasionally reported in patients with progressive systemic sclerosis [l-4]. Inasmuch as Sjogren’s syndrome seems to result from an immunologic alteration second only in its complexity to that which occurs in systemic lupus erythematosus [5], its occurrence in progressive systemic sclerosis would strongly suggest that autoimmunity is implicated in the pathogenesis of scleroderma. We investigated sicca features of Sjbgren’s syndrome in 25 patients with progressive systemic sclerosis by conventional methods as well as by more sensitive methods of study recently described.

MATERIAL AND METHODS Patients. Twenty-five consecutive patients with progressive systemic sclerosis were studied. Their ages, at the time of the study, ranged from 20 to 72 years (average 44.6 years). Twenty were female.

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SYNDROME IN SCLERODERMA-ALARCbN-SEGOVIA

The clinical features of this group of patients are presented in Table I. No patient had evidence of rheumatoid arthritis, systemic lupus erythematosus, polymyositis, chronic active hepatitis or primary biliary cirrhosis. Studies of Features of SjBgren’s Syndrome. All patients were questioned and examined for ocular and salivary features of Sjogren’s syndrome. Schirmer’s tests were performed in all and were considered abnormal when wetting of the paper was 5 mm or less in 5 minutes. Tests were carried out when the patients were adequately hydrated and were not receiving drugs that could affect results. None of 30 normal subjects and only 1 of 24 patients with other diseases studied as controls had an abnormal Schirmer’s test at a 5 mm endpoint. Rose bengal ocular staining tests were performed in 22 patients. Only type A and B staining of Holm’s classification were considered positive

TABLE

[61.

* Association of calcinosis, dermg and telangiectasia.

Bilateral parotid secretory sialography was performed in all but one patient who could not open his mouth enough for its performance. Results were interpreted at the filling and se.cretory phases as well as at 24 hours by the criteria of Rubin and Holt [7]. Scintiscans of salivary glands after the intravenous administration of 5 mCi of gg-mT~pertechnetate were performed as previously described [8]. Criteria of abnormality were (1) diminished uptake by salivary glands, both absolute and as compared to the thyroid (in the presence of a normal thyroid function), and (2) asymmetric uptake by the parotid and/or the submandibular glands. In all but one patient who could not produce enough saliva for its study, counts were made in saliva obtained 15 and 60 minutes after the injection of gg-mT~pertechnetate. An increase in radioactivity per unit volume of saliva, from the 15 to the 60 minutes sample after isotope injection, was considered abnormal [8]. Biopsy of minor salivary glands of the lip was performed in 20 patients. Results were interpreted according to the criteria of Chisholm and Mason [9] and of Morgan and Castleman [ 10 1. RESULTS

In all 25 patients with progressive systemic sclerosis, results of at least one of the tests performed for the detection of sicca features of Sjogren’s syndrome (Table II) were abnormal, and in 22 patients results of more than 2 of the various tests were abnormal (Figure 1). When questioned about it, 18 patients described ocular symptoms suggestive of diminished tear output. Ten had abnormal Schirmer’s tests, and all IO complained of ocular symptoms. Rose bengal staining revealed conjunctival and/or cornea1 deposition of the dye in 11 patients. All but 1 of these 11 had ocular symptoms, but 5 of the patients with dye deposits had normal Schirmer’s tests. On the whole, only two patients who complained of ocular symptoms had no detectable abnormalities by Schirmer’s and/or rose bengal staining tests. In another patient (PCA), who complained of ocular symptoms, the

I

ET AL.

Summary of Clinical Features of 25 Patients with Progressive Systemic Sclerosis Included in This Study

Feature

No.of Patients

Cutaneous involvement Generalized Acrosclerosis Raynaud’s phenomenon Esophageal involvement Calcinosis Telangiectasia Intestinal involvement Pulmonary involvement Renal involvement CRST syndrome*

25 21 4 24 21 13 11 9 7 2 8

Raynaud’s

phenomenon,

sclero-

Schirmer’s test was normal, but the rose bengal staining test was not performed. On direct questioning 21 patients said they had significant dryness of the mouth, and 21 were found to have parotid and/or submandibular gland enlargement. Of these, only one (JSE) denied having xerostomia. Conversely, only one patient who complained of xerostomia (JGS) did not have major salivary gland enlargement. Abnormalities were found in 18 of the 24 patients in whom parotid sialograms were obtained (Figure 2). Ten had globular and 8 had punctate sialectasia. In all of these retention of the dye was detected on roentgenograms taken 24 hours after its instillation. Only one patient (TMP) with an abnormal parotid sialogram had neither clinical xerostomia nor major salivary gland enlargement. Scintillation scans of salivary glands were interpreted as abnormal in 22 patients with progressive systemic sclerosis (Figure 3). Thirteen of these 22 patients, and none of the 3 with normal scintiscans, had abnormal radionuclide excretion in saliva as judged from counts obtained at 15 and 60 minutes after injection of gg-mT~ (Figure 4). Of the three patients who had neither xerostomia nor salivary gland enlargement, two had abnormal scintiscans. One of these two also had an abnormal parotid sialogram. Five patients with normal sialograms had abnormal scintiscans, whereas two of the three patients with normal scintiscan had abnormal sialogram. Table Ill summarizes the pathologic findings on lip biopsy in 20 patients. In 18 biopsy specimens, abnormalities were found which could be distinctly divided into two main groups. Inflammatory infiltrates of various degrees, such as are found in Sjogren’s syndrome, were present in 13 specimens (Figures 5a to 5e). Increased collagen deposition in and around

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TABLE II

Patient

Progressive Systemic Sclerosis-Lacrimal in 25 Patients

Symptoms

+ + + -

CSG JGS TMP TRC AAR TGR EBV LMC MVA JHR EHG ERB JPB MDC VOL RDC CLR FPD MPF PCA FFV CMR JLC GAK JSE

Schirmer Test

+ -

+ + -

+ + -

+ -

+ -

+ + -

+ + + + + + + + + + -

Rose Bengal Staining*

Salivary Gland Involvement

Salivary

Xerostomia

+ ... + ... + + ++ + ... + + ... + ++ + ...

+ -

and/or

Enlargement

+ + -

+ -

+ + + -

+ + + -

+ + + + + + + + + + + + + + + + -

+ + + + + + + + + + -

as Detected

Glands Radionuclide Excretion

Parotid Sialographyt

+ +

++ + + -

Scintiscan

+

+ + + + -

++ ++ ++ + ++ -

+ + + +

+ + . *. ++* ++ ++ ++ + + +

. -t .. -

..I

+

.

+

Pathologic

Findings on Lip Biopsy in 20 Patients

with Progressive

+

Patient

Increased Collagen in Glands

JGS TRC AAR LMC MVA

3+ 2+ 1+ 3+ 4+

4+ 0

JHR EHG

+

.

.

.

+

.

.

.

+

+

+

+

+

+

+

+

+

+

+

+

+

+

+

-

+

+

+

+

+

+ + + -

+

+

+

+

.

+

+

+

-

+

+

Systemic

Sclerosis

Ductular Changes

Lymphocyte/Plasma Cell Infiltrate

1+ 1+ 1+ 0 0

0

2+ 3+ 2+

4+ 3+ 2+ 3+ 2+

2+ 0

0 1+

0 1+

0 0

1+ 0

ERB JPB MDC VOL

3+ 1+ 2+ 0

2+ 2+ 1+ 0

1+ 2+ 1+ 0

0

RDC CLR FPD MPF PCA CMR JLC GAK JSE

3+ 1+ 1+ 2+ 0

I.+ 1+ 1+ 1+ 2+ 2+ 0

1+ 2+ 2+ 1+ 2+ 2+ 0

1+ 0

2+ 4+ 1+ 0 0

2+ 1+ 1+ 3+ 0

2+ 2+ 1+ 2+ 3+ 0

2+

1+ 2+

1+ 2+

1+ 3+

2+ 1+

15

16

17

12

13

Total abnormal * Graded in scale of l+

to 4+;

0 = no abnormality.

.

+

Glandular Atrophy

1+ 0 0

.

+

Abnormality* Increased Collagen in Submucosa

.

+

- = negative, normal or absent; . . . = not done. NOTE: f = present or abnormal: I * + = type B; ++ = type A, Holm’s classification [6]. t + = punctate sialectasia; ++ = globular sialectasia, criteria of Rubin and Holt 171. $ Could not produce enough saliva for study.

TABLE III

Lip %iopsy

+

+

++ -

+ + + + + + +

by Various Methods

3+ 1+ 0

1+ 1+ 0 0

SJbGREN’S

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ET AL.

LACRIMAL SYMPTOMS SCHIRMER’S ROSE

BENGAL

TEST

I

STAINING

SALIVARY XEROSTOMIA ENLARGEMENT SIALOGRAPHY RADIONUCLIDE

EXCRETION SCINTIS LIP

>

2 ABNORMAL

CAN BIOPSY

TESTS

II

I,,,,,

I

3

,,,I,1

5

7

9

,,,,,,,,,,

II

13

15

-

17

19

21

23

25

PATIENTS

Figure 1. Abnormalities of function and/or structure of lacrimal and/or salivary glands as detected by various methods in 25 patients with progressive systemic sclerosis. minor salivary glands, attributable to progressive systemic sclerosis, was found in 16 biopsy specimens (Figures 5a, 5c to 5f). Inflammatory changes were more striking than collagen deposition in the minor salivary glands in four biopsy specimens, whereas in the other nine specimens showing inflammatory changes there was also prominent collagen deposition. In three specimens with increased collagen deposition, no significant inflammatory infiltrate was evident (Figure 5f). Glandular atrophy, which could be the result of either inflammatory infiltrate or collagen was found in 17 biopsy specimens. deposition,

Twelve patients had ductular changes characteristic of Sjogren’s syndrome (Figures 5a and 5b). Three patients, in whom biopsy disclosed abnormalities of the minor salivary glands, had normal scintiscans. In two of them parotid sialography disclosed abnormalities, whereas in the other one all studies of Sjogren’s syndrome, other than lip biopsy, were normal. In two patients with normal findings on lip biopsy, findings on both scintiscan and parotid sialography were abnormal. There was no relationship between lacrimal and/or salivary gland involvement or its severity with any

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s~ikREN3

SYNDROME IN SCLERODERMA-ALARCON-SEGOVIA ET AL.

b

C Figure 3. Scintillation scans of salivary glands in patients with progressive systemic sclerosis. (a) Normal scintiscan (patient FPD): P = parotids, S = submandibular, T = thyroid, 0 = oral cavity. (b) Diminished uptake by the left submandibular gland in patient PCA (arrow). (c) Diminished uptake by both parotid glands and submandibular glands but more noticeable in the latter (patient VOL). (d) Diminished uptake by all major salivary glands. Only the parotr d glands are barely noticeable (patient JPB).

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particular volvement.

progressive

systemic

sclerosis

organ

SYNDROME IN SCLERODERMA-ALARCON-SEGOVIA

ET AL.

in-

900,000

COMMENTS Few cases of Sjogren’s syndrome associated with progressive systemic sclerosis have been described [l-4]. Larger series of Sjogren’s syndrome usually include a few cases of scleroderma: 7 in the 248 cases of keratoconjunctivitis sicca and Sjogren’s syndrome reviewed by Stoltze and her co-workers [ 111, 3 in the 62 cases of Sjogren’s syndrome discussed by Bloch et al. [5] and 4 in the 80 cases of Sjogren’s syndrome reported by Shearn [ 121. Conversely, series of progressive systemic sclerosis also include a few cases of Sjogren’s syndrome: 7 in the 727 cases of Tuffanelli and Winkelmann [ 131, and 2 in the 100 cases of Rodnan [ 141. No systematic investigation of the sicca features of Sjbgren’s syndrome has been conducted in patients with progressive systemic sclerosis, and the recent availability of newer tests for the diagnosis of salivary gland involvement made it possible for us to assess its true incidence in progressive systemic sclerosis. This study shows that lacrimal and/or salivary gland involvement in Sjogren’s syndrome is found, when looked for, in most patients with progressive systemic sclerosis. Salivary gland involvement appears to be more frequent than lacrimal gland involvement in patients with progressive systemic sclerosis. However, the difference may reflect the higher number of tests that are available for the study of salivary gland functional and organic damage. It may also derive from the fact that, of the tests employed for the study of lacrimal glands, Schirmer’s test is rather gross and the rose bengal staining test reflects the result of decreased tear production on the conjunctiva and cornea rather than gland damage proper. Tests used for the study of salivary glands give information about the functional and pathologic status of the glands themselves rather than of its reflection on other buccal structures. Differences in findings obtained with the various tests employed for the study of salivary glands reflect their different sensitivity, the different parameters they measure as well as the irregularity and asymmetry of salivary gland involvement in Sjbgren’s syndrome. Thus, parotid sialography gives information about ductal changes of major glands which occur after inflammation has already caused retraction and dilatation of the major ducts; scintillation scanning evidences functional abnormalities of the parenchyma proper, by its inability to adequately concentrate elements of periodic group VII. Delayed radionuclide excretion in saliva probably reflects abnormalities of such a concentrating mechanism as well as of transport of the radionu-

800,000

‘;’

700,000

2 f

600,000

%

2

500,000

5 s

400,000

9 F z

300,000

s 2

200,000

I00,000

0.

I

PSS

MINUTES

AFTER

CONTROLS k--------i I5 RADI~IuuCLI~E

60

INJECTION

Radioactive counts in saliva at 15 and 60 minutes after injection of gg-mTc pertechnetate in patients with progressive systemic sclerosis (24 patients; 1 patient could not produce enough saliva for counting) and in normal control subjects (2 1 studies).

Figure 4.

elide from the acini to saliva, and diminished salivary flow. Histologic study of minor salivary glands reveals the various stages of IymphocyticIplasma cell infiltration and ductular cell proliferation leading to damage of the glands. In the particular case of scleroderma, the abnormalities in collagen deposition found in the minor salivary glands, which do not usually occur in Sjbgren’s syndrome, may be due to their proximity to the site of major involvement in progressive systemic sclerosis. It is thus apparent that although xerostomia may be caused by two different mechanisms in patients with progressive systemic sclerosis, namely, collagen deposition in minor salivary glands and Sjogren’s syndrome proper, both may be present in the minor salivary glands. It is unlikely, however, that collagen deposition can also mimick the picture of Sjogren’s syndrome in roentgenographic and radionuelide studies of the major salivary glands. However, to determine if the major salivary glands are similarly affected by collagen deposition, biopsy of major salivary glands would be required.

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ET AL.

Pathologic findings in minor salivary glands obtained at lip biopsy in patients with progressive systemic sclerosis. (a) Patient JPB Lymphocytic and plasma cell infiltration in an area in which prominent intraductular cell proliferation, including an epi-myoepithelial island of Morgan and Castleman [IO] (arrow), gives a histologic picture characteristic of Sjogren’s syndrome. Increased collagen deposition can be seen penetrating into the gland at the right hand lower corner. (b) Patient JPB. Massive lymphocyte and plasma cell infiltration with prominent ductular changes. (c) Patient ERB. A minor salivary gland surrounded by collagen which tends to penetrate into the gland and disrupt its acini (arrows). Notice pockets of lymphocytic infiltration. (d) Patient FPD. .The larger of two minor salivary glands shows an area of lymphocytic and plasma cell infiftration whereas the other one is embedded in collagen. (e) Patient MVA. Collagen fibers surround the salivary gland, engulf its Iimitating septa and penetrate into the gland disrupting its architecture. There is dilatation of ducts and some lymphocytic and plasma cell infiltration. (f) Patient JGS. Near total disruption of a salivary gland by collagen deposition has occurred here. Acini are atrophied and spreaded apart by collagen, ductules are dilated and also spreaded apart by collagen. No significant inflammatory infiltrate is seen. Hematoxylin and eosin stain; original magnification X 100 (a, b, c, e, f) and X 40 (d), reduced by 27 per cent.

Figure 5.

a4

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.SJ&FiEN’S SYNDROME IN SCLERODERMA-ALARCON-SEGOVIA ET AL.

Although some of the changes found in minor salivary glands seem to be due to progressive systemic sclerosis rather than to an associated SjGgre$s’syndrome, the presence of an inflammatory infiltrate, of characteristic ductular changes in the same minor glands, as well as of lacrimal and major salivary gland involvement as detected by the ,other tests employed, indicates that besides the occurrence of collagen deposition in the minor salivary glands, true SjSgren’s syndrome does occur in most patients wit‘h progressive systemic sclerosis.

Because Sjiigren’s syndrome has been found to occur almost exclusively in association with diseases in which autoimmunity has been implicated, such as rheumatoid arthritis [5,11], systemic lupus erythematosus [ 151, polymyositis [ 161, chronic active hepatitis [ 171 and primary biliary cirrhosis [ 161, its occurrence in association with progressive systemic sclerosis, with a frequency that rules out coincidence, suggests that autoimmunity is implicated in the pathogenesis of this, the most baffling of the connective tissue disorders.

REFERENCES 1. 2. 3. 4. 5.

6. 7.

8.

9.

Harrington AB, Dewar HA: Case of Sjbgren’s disease with scleroderma. Br Med J 1: 1302, 1951. Ramage JH, Kinnear WF: Keratoconjunctivitis sicca and the collagen diseases. Br J Ophthalmol 40: 4 16, 1956. Shearn MA: SjBgren’s syndrome in association with scleroderma. Ann Intern Med 52: 1352, 1960. Denko CW. Jacob WO: Myopathy in the sicca syndrome. Am J Clin Pathol 51: 631, 1969. Bloch KJ, Buchanan WW. Wohl MJ, Bunim JJ: Sjbgren’s syndrome: a clinical, pathological and serological study of 62 cases. Medicine (Baltimore) 44: 187, 1965. Holm S: Keratoconjunctivitis sicca and the sicca syndrome. Acta Ophthalmol (Kbh) 33 (suppl): 1, 1949. Rubin P. Holt JF: Secretory sialography in diseases of the major salivary glands. Am J Roentgen01 Radium Ther Nucl Med 77: 575, 1957. Alar&n-Segovia D, Gonzhlez-JimBnez Y, Garza LR, Maisterrena J: Radioisotopic evaluation of salivary gland dysfunction in Sjbgren’s syndrome. Am J Roentgen01 Radium Ther Nucl Med 112: 373, 1971. Chisholm DM, Mason DIC: Labial salivary gland biopsy in Sjbgren’s syndrome. J Clin Pathol21: 656, 1968.

10. 11.

12. 13. 14. 15.

16. 17. 18.

Morgan WS, Castleman B: a clinicopathologic study of “Mickulicz’s disease.” Am J Pathol 29: 47 1, 1953. Stoltze CA, Hanlon DG, Pease GL: Keratoconjunctivitis sicca and SjGgren’s syndrome. Systemic manifestations and hematologic and protein abnormalities. Arch Intern Med 106: 513, 1960. Shearn MA: Sjbgren’s Syndrome, Philadelphia, W. B. Saunders Co., 1971, p 114. Tuffanelli DL, Winkelmann RK: Systemic scleroderma. Arch Dermatol 84: 359, 1961. Rodnan GP: The natural history of progressive systemic sclerosis. Bull Rheum Dis 13: 301, 1963. Steinberg AD, Talal N: Coexistence of Sjbgren’s syndrome and systemic lupus erythematosus. Ann Intern Med 74: 55. 1971. Silberberg DH, Drachman DA: Late life myopathy occurring in Sjbgren’s syndrome. Arch Neurol 6: 428, 1962. Gokling PL, Bown R, Mason AMS: “Sicca complex” in liver disease. Br Med J 2:, 340, 1970. Alar&n-Segovia D, Diaz-Jouanen E, Fishbein E: Features of Sjbgren’s syndrome in primary biliary cirrhosis. Ann Intern Med 79: 3 1, 1973.

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