Sjogren's Syndrome in Progressive Systemic Sclerosis JAMES F. CIPOLETTI, M.D.; ROBERT B. BUCKINGHAM, M.D., F.A.C.P.; E. LEON BARNES, M.D.; ROBERT L PEEL, M.D.; KHALID MAHMOOD, M.D.; FRANKLIN E. CIGNETTI, M.D.; JOHN M. PIERCE, M.D.; BRUCE S. RABIN, M.D.; and GERALD P. RODNAN, M.D., F.A.C.P.; Pittsburgh, Pennsylvania Thirty-five consecutive patients with progressive systemic sclerosis were prospectively evaluated for evidence of Sjogren's syndrome. Six of the 35 ( 1 7 % ) were judged to have the disorder. This is a higher prevalence than in most reports, but much lower than that recently reported by Alarcdn-Segovia and associates (7). An additional 17 of the 35 patients ( 4 8 % ) had significant fibrosis in the absence of sufficient mononuclear cell infiltrates to confirm the diagnosis of Sjogren's syndrome. This group had particularly aggressive scleroderma with serious visceral features, and five died after a short duration of illness. No significant abnormalities were found in biopsies from six patients with the mixed connective tissue disease syndrome, five with Raynaud's phenomenon alone, or in 2 9 autopsy control subjects who had no evidence of connective tissue disease. Fibrosis in the absence of mononuclear infiltration in minor salivary glands of patients with progressive systemic sclerosis indicates a poor prognosis.
SJOGREN'S SYNDROME is a chronic inflammatory disor-
der involving the exocrine glands, characterized by xerostomia and keratoconjunctivitis sicca. The combination of dry eyes and dry mouth has been known since the 1880s, but interest in Sjogren's syndrome increased greatly after publication by Henrick Sjogren in 1933 of a monograph stressing the relation between sicca features and rheumatoid arthritis (1). The combination of dry eyes and dry mouth occurs frequently in the absence of a connective tissue disease, in such instances being designated the sicca complex, but exists most often in conjunction with one or another of these diseases (2). There is increasing evidence of a much higher frequency of Sjogren's syndrome in rheumatoid arthritis, in other connective tissue diseases, and also in certain other disorders thought to be mediated by autoimmune reactions. Progressive systemic sclerosis has stood out as one connective tissue disease with an apparently relatively low frequency of associated Sjogren's syndrome (3-6), until a recent report by AlarconSegovia and associates (7) of the finding of sicca features in the majority of a group of such individuals studied prospectively. In a previous report on one hundred consecutive pa• From the Division of Rheumatology and Clinical Immunology, Department of Medicine, the Division of Immunopathology, and the Department of Pathology, University of Pittsburgh School of Medicine; and the Presbyterian-University Hospital; Pittsburgh, Pennsylvania.
Annals of Internal Medicine 87:535-541, 1977
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tients with progressive systemic sclerosis, we noted only two individuals with clear-cut clinical manifestations of Sjogren's syndrome (6). Realizing that the diagnosis can be easily overlooked in individuals with milder forms of the sicca syndrome, we have re-examined this question in a prospective study of individuals with progressive systemic sclerosis and certain other connective tissue diseases and in normal control groups. We have also attempted to ascertain the frequency and the prognostic significance of fibrosis in the minor salivary glands of individuals with scleroderma. Materials and Methods
Thirty-five consecutive patients who met criteria for the diagnosis of progressive systemic sclerosis (8-9) were evaluated prospectively for evidence of Sjogren's syndrome. Thirty of those studied were women, five were men; three of the women were black, and all of the remaining patients were white. All of these individuals had abnormal thickening and tightness of the skin (scleroderma), and all exhibited Raynaud's phenomenon. Fifteen of the 35 patients (two men and 13 women) represented the CREST syndrome variant. This is defined as a form of progressive systemic sclerosis in which there is relatively limited involvement of the skin (often confined to the fingers and face), prominence of calcinosis and telangiectasia, and a prolonged delay in appearance of visceral changes (10). The ages of the patients at the time of study ranged from 23 to 70 years (average, 50.8 years). Patients were interrogated carefully with respect to the history of past or current evidence of salivary gland enlargement, occular complaints characteristic of Sjogren's syndrome, and dry mouth. Schirmer and rose bengal dye tests were done on most of the patients. The Schirmer test was considered abnormal if less than 5 mm of filter paper was moistened in 5 min. The rose bengal dye study was evaluated according to the Holm's classification (types A and B were considered significant) (11). Serologic studies included the latex agglutination reaction for rheumatoid factor as described by Singer and Plotz (12), using the Hyland RA Test (Hyland Laboratories, Costa Mesa, California), antinuclear antibody (ANA) determination by indirect immunofluorescence using mouse liver as substrate, anti-DNA antibody by the ammonium sulfate precipitation reaction of Pincus (13), and antiribonucleoprotein (anti-RNP) antibody done by Dr. Gordon Sharp, University of Missouri-Columbia, Missouri. Antisalivary-gland and anti-smooth-muscle antibodies were detected by indirect immunofluorescence, using human salivary gland from a blood group 0 individual and rat stomach respectively. Antibodies to thyroglobulin and thyroid microsomes were sought for by indirect hemagglutination. Results considered significantly elevated were as follows: latex agglutination reaction titer, 1:40 or greater; ANA titer, 1:20 or greater; anti-DNA, 20% precipitation or greater; anti-RNP, 1:1000 or greater; antisalivary gland, 1:10 or greater; anti-smooth-muscle antibody, 1:10 or greater; antithyroglobulin antibody, 1:50 or greater; and antithyroid microsomal antibody, 1:100 or greater. 535
Biopsy of minor salivary glands of the lower lip was done in all 35 patients. Results were described according to the criteria of Tarplay, Anderson, and White (14), namely: Normal = well-defined acini and ducts with no round cell aggregates. 1+ = one to two round cell aggregates per lobule. An aggregate is defined as approximately 50 round cells composed of lymphocytes, plasma cells, and histiocytes. 2+ = three or more aggregates per lobule. 3+ = diffuse rather than aggregated round cell infiltration, with acinar destruction. 4+ = diffuse round cell infiltration, with complete destruction of lobular architecture. The biopsies were evaluated independently by three pathologists. Statistical analysis of the data showed no significant intraor interobserver variation. A second method of grading minor salivary gland biopsies resulting in a "focus score" as described by Greenspan and colleagues (15) was applied to a representative number of biopsies. These authors defined a focus as a discrete collection of at least 50 mononuclear inflammatory cells (lymphocytes, histiocytes, or plasma cells). The focus score is the average number of such cellular foci per 4-mm2 area of labial salivary gland tissue. A score of 10 is the highest that can be ascertained accurately; for statistical purposes, a score of 12 was arbitrarily assigned to tissue sections showing confluent infiltration in which individual foci could not be found. There was good agreement using these two methods. All biopsies graded 0-1+ by the Tarplay method had a focus score of 0-1 with a single exception. All grade 3+ and 4+ biopsies received a focus score of 10 to 12. Fibrosis was subjectively graded as absent (0), minimal (1+), moderate (2+), or severe (3+). Five patients with Raynaud's phenomenon, six with the mixed connective tissue disease syndrome, and five with the sicca complex unassociated with a connective tissue disease served as control subjects and were evaluated as described above. Criteria used for the diagnosis of mixed connective tissue disease included the presence of sclerodermatous skin changes, inflammatory myositis, clinical features characteristic of systemic lupus erythematosus, and high titers of antibody to ribonucleoprotein (16). A consecutive series of 29 autopsy cases with no evidence of connective tissue disease served as additional biopsy control subjects. Results
In the 35 patients with progressive systemic sclerosis, there were four who described recurrent salivary gland enlargement. Three of these four also described symptoms of dry eyes and dry mouth. Nine additional patients with progressive systemic sclerosis cited the presence of dry eyes and 12 described dry mouth. Three patients described symptoms of xerostomia without salivary gland enlargement or xerophthalmia. The Schirmer test was positive in nine patients (done in 32 of the 35 patients with progressive systemic sclerosis), and rose bengal dye study was positive in a total of three patients (done in 29 of the 35 patients). Only two of the patients with a positive Schirmer test also had a positive rose bengal dye study. On the basis of minor salivary gland biopsy of the 35 patients with scleroderma, three distinct groups were noted (Table 1, Groups A, B, and C). Figure la through f shows examples of the morphologic changes noted in labial minor salivary gland biopsies on the patients studied. Group A included six patients with marked mononuclear cell infiltration ( 3 - 4 + ) , and significant periductal fibrosis felt to be diagnostic of Sjogren's syndrome (Fig536
ure Id and e). Five of these six patients had clinical Sjogren's syndrome with two or more of the five clinical features assessed. Four of the six were individuals with the CREST syndrome variant of progressive systemic sclerosis. None of these patients had significant visceral involvement (other than esophageal disease) attributable to progressive systemic sclerosis despite the fact that they were the oldest (mean age, 60.5 years) and had had their disease diagnosed for the longest period of time (mean, 12.9 years). Two showed some interstitial fibrosis on chest roentgenograms together with moderate reductions in pulmonary diffusion capacities (54% and 65% of normal), but both had long cigarette-smoking histories (29 and 18 pack-years respectively) that may have accounted for these findings. Group B included 17 patients who exhibited moderateto-marked ( 2 - 3 + ) fibrosis of the minor salivary glands in the absence of significant inflammatory cell infiltrate (Figure If). This fibrosis was both perilobular and intralobular in location and in five instances was extensive and accompanied by acinar atrophy. Only three individuals in this group had two or more clinical markers of Sjogren's syndrome. Eleven of these patients had diffuse scleroderma and six had the CREST syndrome variant. Although their average age was only 52 years with a mean duration of 4.5 years since diagnosis, seven exhibited significant visceral complications of scleroderma and five have now died. Complications included pulmonary fibrosis in five, renal involvement in two, and severe gastrointestinal disease (other than esophageal dysfunction) in two. In summary, these patients had much more severe disease. Group C included 12 patients with neither inflammatory nor fibrotic changes of any significance on biopsy (Figure \a and b). Five had diffuse scleroderma and seven had the CREST syndrome variant. In this group, four patients had two or more clinical features of Sjogren's syndrome and one of these was positive for rheumatoid factor. Two patients in this group had pulmonary fibrosis on roentgenographic examination. N o other complications were noted. The average age in this group was 43.8 years with a mean period since diagnosis of 7.1 years. CONTROL SUBJECTS
Of the five patients with the sicca complex, all had clinical evidence of extensive exocrine gland disease and minor salivary gland biopsy was positive in all (Table 2). Among the six patients with mixed connective tissue disease, one had xerostomia and xerophthalmia. Minor salivary gland biopsies in these patients were interpreted as normal. Of the five patients with Raynaud's phenomenon unassociated with a connective tissue disease, two had xerostomia and xerophthalmia but salivary gland biopsies were normal in all. As stated previously, the minor salivary gland biopsy was believed to be diagnostic of Sjogren's syndrome in six of 35 patients with progressive systemic sclerosis and in all with the sicca complex alone. In the six with mixed connective tissue disease, the five with Raynaud's phe-
November 1977 • Annals of Internal Medicine • Volume 87 • Number 5
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Table 1 . Patients with Progressive Systemic Sclerosis Divided According to Findings in Salivary Gland Biopsy
Patient
Age
Sex Age at Onset
yrs
Sjogren's Syndrome
Scleroderma Duration
Type*
Associated Features
Clinical Features f
Lip Biopsy Inflammation J (0-4+)
Fibrosis§ (0-3+)
5/5 4/5
4 4
3 0
4/5 0/4 2/4
3 3 3
3 3 0
2/3
3
2
0/5
0
3
0/5 3/5
1 0
3 3
1/5 1/5
0 1
3 3
1/5 1/5 1/5 2/4
0 1 1 0
3 3 3 3
1/5 0/5 3/5 0/5 0/5 1/5 0/5
0 0 0 0 1 1 0
3 2 2 2 2 2 2
0/5
0
2
0/5 1/4 0/5 0/5 3/5 0/5 2/3 3/5
0 0 1 1 0 1 0 0
0 0 0 0 0 0 0 0
0/3 2/5 0/5 0/5
0 0 0 0
0 0 0 0
yrs
Group A: patients with progressive systemic sclerosis and Sjogren';5 syndrome 50 F 33 17 Diff 1 53 5 Pulmonary F CREST 58 2 fibrosis 5 F 63 CREST 3 68 5.5 F 64 CREST 70 4 29 Pulmonary F 34 CREST 63 5 fibrosis F 39 15 Diff 6 54 Group B: patients with progressive systemic sclerosis and sclerosis on lip biopsy F 43 2 Diff Pulmonary 57 7 fibrosis 50 Diff F 4 8 54 Diff F 43 Pulmonary 9 50 7|| fibrosis and renal 49 Diff M 52 Gastrointestinal 10 31| Diff F 55 60 Pulmonary 11 4.5|| fibrosis F 62 3 Diff 12 65 49 2 Diff 13 F 51 59 9 68 F 14 CREST 46 Diff 15 F 45 1 Pulmonary fibrosis 16 Diff 50 F 48 Renal 1.5|| 66 56 17 10 F CREST F 18 49 40 CREST Gastrointestinal 9|| 19 52 F 2 50 CREST F 3 Diff 20 45 42 40 M 8 21 32 CREST M 36 22 39 3 Diff Pulmonary fibrosis 46 F 3 Diff 23 43 Group C : patients with progressive systemic sclerosis and negative lip biopsy 24 52 F 40 12 Diff 6 25 51 F 55 CREST 26 36 F 33 3 Diff 36 27 F 4 32 CREST 28 F 53 49 4 CREST 29 23 F 22 1 CREST 30 60 F 3 57 CREST 31 53 F 39 Pulmonary 14 CREST fibrosis 32 32 F 8 Diff 24 33 35 F 33 1.5 CREST M 34 59 57 1.5 Diff 35 36 F 1.5 Diff 34 Pulmonary fibrosis
* CREST indicates calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly (limited skin involvement, often confined to fingers and face), and telangiectasia (10). Diff indicates diffuse scleroderma (progressive systemic sclerosis). t Clincial features included xerostomia, xerophthalmia, salivary gland enlargement, Schirmer's test, and rose bengal dye test. The denominator indicates the number of features evaluated. % Criteria of Tarplay, Anderson, and White (14). § Graded on a scale of 0-3+ (0 = absent). || Deceased.
nomenon not associated with a connective tissue disease, and in 29 autopsy control subjects, none had greater than 1 + changes of inflammation. However, 1 + changes were common, occurring in all six with mixed connective tissue diseases, two of five with Raynaud's phenomenon, and 13 of 29 of the autopsy control subjects. The frequency of these 1 + changes in asymptomatic and control pa-
tients raises a question concerning the validity of the 1 + category in the histopathologic confirmation of Sjogren's syndrome. When these results were compared with the "focus score" of Daniels and coworkers (17), there was good agreement between the two methods. All biopsies graded 0-1 + by the Tarplay method had a focus score of 0-1 with a single exception. When using the focus score Cipoletti
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et al. • Progressive Systemic Sclerosis
537
Figure 1 . Examples of various morphologic changes f r o m labial minor salivary gland biopsy, a. Normal, no round cell infiltrate, periductal fibrosis nor acinar atrophy. (Original magnification, x 4 4 ) . b. 1 + inflammatory changes with a single focus (arrow), of periductal mononuclear cell infiltration. (Original magnification, x 3 5 . 8 ) . c. 2 + changes with at least three foci of periductal mononuclear cell infiltration per lobule. (Original magnification, x 3 5 . 8 ) . d . 3 + changes with diffuse mononuclear cell infiltration and widespread acinar destruction. (Original magnification, x 2 7 . 5 ) . e. 4 + changes with extensive mononuclear cell infiltration, complete replacement of normal architecture and epimyoepithelial islands (arrows). (Original magnification, x 2 7 . 5 ) . f. 4 + perilobular fibrosis in the absence of mononuclear cell infiltration (arrow). Also note intralobular fibrosis with acinar destruction and duct dilatation. (Original magnification, x 4 6 . 8 ) . 5 3 8
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• Annals of Internal Medicine • Volume 87 • Number 5
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Table 2. Control Groups: Clinical Features of Sjogren's Syndrome Group
Major Salivary Gland Enlargement
Xerophthalmia
Positive Schirmer *
Positive Rose Bengal *
Xerostomia
Positive Minor Salivary Gland Biopsy
Sicca complex (5) Mixed connective tissue disease (6) Raynaud's phenomenon (5) Autopsy control subjects (29)
3 1 1
5 1 2
4/5 0/5 0/4
2/4 0/4 2/4
4 1 1
5 0 0 0
* For the Schirmer and rose bengal dye tests, the denominator indicates the total number of patients studied in each disease category. For the remaining clinical features, all patients were studied; therefore denominators are not included.
method, the presence of salivary gland involvement is considered confirmed if the minor salivary gland biopsy score is greater than 1. SEROLOGIC STUDIES
The serologic findings are shown in Table 3. With a single exception, positive latex agglutination reactions were found only in the patients with progressive systemic sclerosis within group A. In group A, five of six exhibited rheumatoid factor, and four of these six had the CREST syndrome variant. None of the 17 in group B, and only one of 12 in group C (also a patient with CREST syndrome) had positive latex agglutination tests. N o serologic marker except for the rheumatoid factor associated more commonly with either diffuse scleroderma or the CREST syndrome variant. The A N A was positive (always in a speckled pattern) in two of six in group A, six of 17 in group B, and one of 12 in group C; anti-DNA and anti-RNP studies were negative in all progressive systemic sclerosis patients. Antisalivary-gland antibody was detected in 12 of the 28 progressive patients with systemic sclerosis studied. Three of 23 patients had antithyroglobulin antibodies (two of these three also had Sjogren's syndrome), and two of 23 had antimitochondrial antibodies (one with Sjogren's syndrome). Of the patients with the sicca complex alone, A N A was detected in three of five (all speckled pattern). Four of four and five of five were negative for anti-DNA and anti-RNP antibodies respectively. Antisalivary-gland antibody was negative in five of five. In testing the various solid organ antibodies, one patient had antimicrosomal
antibody. Of the six patients with mixed connective tissue disease, all had a positive A N A (all with a speckled pattern) and high-titer anti-RNP. All were negative for anti-DNA antibodies, and one individual in this group had both antimicrosomal and antithyroglobulin antibodies. Other solid organ antibodies were not detected. Of the five patients with Raynaud's phenomenon unassociated with a connective tissue disease, one had a positive A N A . All were negative for anti-DNA and antiR N P antibodies. Antisalivary-gland antibodies were detected in one of five. For the remaining solid organ antibodies tested, one of five patients was positive for antimicrosomal antibody and anti-smooth-muscle antibody. Antimitochondrial and antithyroglobulin antibodies were not detected in any patients in this group. Discussion
Progressive systemic sclerosis is a generalized disorder of connective tissue characterized by inflammatory, fibrotic, and degenerative changes often accompanied by prominent vascular lesions in the skin, synovium, and certain internal organs. Although often classified as one of the "autoimmune" diseases, the cause and pathogenesis are obscure. The similarity between various features of progressive systemic sclerosis and rheumatoid arthritis, systemic lupus erythematosus, and polymyositis, as well as the associated occurrence of certain features of progressive systemic sclerosis in "overlap syndromes" (including the so-called mixed connective tissue disease) are reasons for considering it in the autoimmune category. Antinuclear antibodies occur frequently in patients with
Table 3. Serologic Studies Study*
Latex agglutination Antinuclear antibody Anti-DNA Anti-RNP Anti-salivary gland Anti-thyroglobulin Anti-smooth muscle Anti-microsomal Anti-mitochondrial
Group PSS-A t
PSS-B
PSS-C
Sicca Complex
MCTD J
Raynaud's Phenomenon
5/6 2/6 0/6 0/6 2/5 2/6 1/6 1/6 1/6
0/17 6/17 0/17 0/17 5/11 0/7 1/7 1/7 1/7
1/12 1/12 0/12 0/12 5/12 1/10 0/10 1/10 0/10
4/5 3/5 0/4 0/5 0/5 0/5 0/5 1/5 0/5
3/6 6/6 0/6 6/6 0/6 1/6 0/6 1/6 0/6
1/5 1/5 0/5 0/5 1/5 0/5 0/5 1/5 1/5
* See text for methods used and for titers consid ered significant. In each case the d
SJOGREN'S SYNDROME is a chronic inflammatory disor-
der involving the exocrine glands, characterized by xerostomia and keratoconjunctivitis sicca. The combination of dry eyes and dry mouth has been known since the 1880s, but interest in Sjogren's syndrome increased greatly after publication by Henrick Sjogren in 1933 of a monograph stressing the relation between sicca features and rheumatoid arthritis (1). The combination of dry eyes and dry mouth occurs frequently in the absence of a connective tissue disease, in such instances being designated the sicca complex, but exists most often in conjunction with one or another of these diseases (2). There is increasing evidence of a much higher frequency of Sjogren's syndrome in rheumatoid arthritis, in other connective tissue diseases, and also in certain other disorders thought to be mediated by autoimmune reactions. Progressive systemic sclerosis has stood out as one connective tissue disease with an apparently relatively low frequency of associated Sjogren's syndrome (3-6), until a recent report by AlarconSegovia and associates (7) of the finding of sicca features in the majority of a group of such individuals studied prospectively. In a previous report on one hundred consecutive pa• From the Division of Rheumatology and Clinical Immunology, Department of Medicine, the Division of Immunopathology, and the Department of Pathology, University of Pittsburgh School of Medicine; and the Presbyterian-University Hospital; Pittsburgh, Pennsylvania.
Annals of Internal Medicine 87:535-541, 1977
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tients with progressive systemic sclerosis, we noted only two individuals with clear-cut clinical manifestations of Sjogren's syndrome (6). Realizing that the diagnosis can be easily overlooked in individuals with milder forms of the sicca syndrome, we have re-examined this question in a prospective study of individuals with progressive systemic sclerosis and certain other connective tissue diseases and in normal control groups. We have also attempted to ascertain the frequency and the prognostic significance of fibrosis in the minor salivary glands of individuals with scleroderma. Materials and Methods
Thirty-five consecutive patients who met criteria for the diagnosis of progressive systemic sclerosis (8-9) were evaluated prospectively for evidence of Sjogren's syndrome. Thirty of those studied were women, five were men; three of the women were black, and all of the remaining patients were white. All of these individuals had abnormal thickening and tightness of the skin (scleroderma), and all exhibited Raynaud's phenomenon. Fifteen of the 35 patients (two men and 13 women) represented the CREST syndrome variant. This is defined as a form of progressive systemic sclerosis in which there is relatively limited involvement of the skin (often confined to the fingers and face), prominence of calcinosis and telangiectasia, and a prolonged delay in appearance of visceral changes (10). The ages of the patients at the time of study ranged from 23 to 70 years (average, 50.8 years). Patients were interrogated carefully with respect to the history of past or current evidence of salivary gland enlargement, occular complaints characteristic of Sjogren's syndrome, and dry mouth. Schirmer and rose bengal dye tests were done on most of the patients. The Schirmer test was considered abnormal if less than 5 mm of filter paper was moistened in 5 min. The rose bengal dye study was evaluated according to the Holm's classification (types A and B were considered significant) (11). Serologic studies included the latex agglutination reaction for rheumatoid factor as described by Singer and Plotz (12), using the Hyland RA Test (Hyland Laboratories, Costa Mesa, California), antinuclear antibody (ANA) determination by indirect immunofluorescence using mouse liver as substrate, anti-DNA antibody by the ammonium sulfate precipitation reaction of Pincus (13), and antiribonucleoprotein (anti-RNP) antibody done by Dr. Gordon Sharp, University of Missouri-Columbia, Missouri. Antisalivary-gland and anti-smooth-muscle antibodies were detected by indirect immunofluorescence, using human salivary gland from a blood group 0 individual and rat stomach respectively. Antibodies to thyroglobulin and thyroid microsomes were sought for by indirect hemagglutination. Results considered significantly elevated were as follows: latex agglutination reaction titer, 1:40 or greater; ANA titer, 1:20 or greater; anti-DNA, 20% precipitation or greater; anti-RNP, 1:1000 or greater; antisalivary gland, 1:10 or greater; anti-smooth-muscle antibody, 1:10 or greater; antithyroglobulin antibody, 1:50 or greater; and antithyroid microsomal antibody, 1:100 or greater. 535
Biopsy of minor salivary glands of the lower lip was done in all 35 patients. Results were described according to the criteria of Tarplay, Anderson, and White (14), namely: Normal = well-defined acini and ducts with no round cell aggregates. 1+ = one to two round cell aggregates per lobule. An aggregate is defined as approximately 50 round cells composed of lymphocytes, plasma cells, and histiocytes. 2+ = three or more aggregates per lobule. 3+ = diffuse rather than aggregated round cell infiltration, with acinar destruction. 4+ = diffuse round cell infiltration, with complete destruction of lobular architecture. The biopsies were evaluated independently by three pathologists. Statistical analysis of the data showed no significant intraor interobserver variation. A second method of grading minor salivary gland biopsies resulting in a "focus score" as described by Greenspan and colleagues (15) was applied to a representative number of biopsies. These authors defined a focus as a discrete collection of at least 50 mononuclear inflammatory cells (lymphocytes, histiocytes, or plasma cells). The focus score is the average number of such cellular foci per 4-mm2 area of labial salivary gland tissue. A score of 10 is the highest that can be ascertained accurately; for statistical purposes, a score of 12 was arbitrarily assigned to tissue sections showing confluent infiltration in which individual foci could not be found. There was good agreement using these two methods. All biopsies graded 0-1+ by the Tarplay method had a focus score of 0-1 with a single exception. All grade 3+ and 4+ biopsies received a focus score of 10 to 12. Fibrosis was subjectively graded as absent (0), minimal (1+), moderate (2+), or severe (3+). Five patients with Raynaud's phenomenon, six with the mixed connective tissue disease syndrome, and five with the sicca complex unassociated with a connective tissue disease served as control subjects and were evaluated as described above. Criteria used for the diagnosis of mixed connective tissue disease included the presence of sclerodermatous skin changes, inflammatory myositis, clinical features characteristic of systemic lupus erythematosus, and high titers of antibody to ribonucleoprotein (16). A consecutive series of 29 autopsy cases with no evidence of connective tissue disease served as additional biopsy control subjects. Results
In the 35 patients with progressive systemic sclerosis, there were four who described recurrent salivary gland enlargement. Three of these four also described symptoms of dry eyes and dry mouth. Nine additional patients with progressive systemic sclerosis cited the presence of dry eyes and 12 described dry mouth. Three patients described symptoms of xerostomia without salivary gland enlargement or xerophthalmia. The Schirmer test was positive in nine patients (done in 32 of the 35 patients with progressive systemic sclerosis), and rose bengal dye study was positive in a total of three patients (done in 29 of the 35 patients). Only two of the patients with a positive Schirmer test also had a positive rose bengal dye study. On the basis of minor salivary gland biopsy of the 35 patients with scleroderma, three distinct groups were noted (Table 1, Groups A, B, and C). Figure la through f shows examples of the morphologic changes noted in labial minor salivary gland biopsies on the patients studied. Group A included six patients with marked mononuclear cell infiltration ( 3 - 4 + ) , and significant periductal fibrosis felt to be diagnostic of Sjogren's syndrome (Fig536
ure Id and e). Five of these six patients had clinical Sjogren's syndrome with two or more of the five clinical features assessed. Four of the six were individuals with the CREST syndrome variant of progressive systemic sclerosis. None of these patients had significant visceral involvement (other than esophageal disease) attributable to progressive systemic sclerosis despite the fact that they were the oldest (mean age, 60.5 years) and had had their disease diagnosed for the longest period of time (mean, 12.9 years). Two showed some interstitial fibrosis on chest roentgenograms together with moderate reductions in pulmonary diffusion capacities (54% and 65% of normal), but both had long cigarette-smoking histories (29 and 18 pack-years respectively) that may have accounted for these findings. Group B included 17 patients who exhibited moderateto-marked ( 2 - 3 + ) fibrosis of the minor salivary glands in the absence of significant inflammatory cell infiltrate (Figure If). This fibrosis was both perilobular and intralobular in location and in five instances was extensive and accompanied by acinar atrophy. Only three individuals in this group had two or more clinical markers of Sjogren's syndrome. Eleven of these patients had diffuse scleroderma and six had the CREST syndrome variant. Although their average age was only 52 years with a mean duration of 4.5 years since diagnosis, seven exhibited significant visceral complications of scleroderma and five have now died. Complications included pulmonary fibrosis in five, renal involvement in two, and severe gastrointestinal disease (other than esophageal dysfunction) in two. In summary, these patients had much more severe disease. Group C included 12 patients with neither inflammatory nor fibrotic changes of any significance on biopsy (Figure \a and b). Five had diffuse scleroderma and seven had the CREST syndrome variant. In this group, four patients had two or more clinical features of Sjogren's syndrome and one of these was positive for rheumatoid factor. Two patients in this group had pulmonary fibrosis on roentgenographic examination. N o other complications were noted. The average age in this group was 43.8 years with a mean period since diagnosis of 7.1 years. CONTROL SUBJECTS
Of the five patients with the sicca complex, all had clinical evidence of extensive exocrine gland disease and minor salivary gland biopsy was positive in all (Table 2). Among the six patients with mixed connective tissue disease, one had xerostomia and xerophthalmia. Minor salivary gland biopsies in these patients were interpreted as normal. Of the five patients with Raynaud's phenomenon unassociated with a connective tissue disease, two had xerostomia and xerophthalmia but salivary gland biopsies were normal in all. As stated previously, the minor salivary gland biopsy was believed to be diagnostic of Sjogren's syndrome in six of 35 patients with progressive systemic sclerosis and in all with the sicca complex alone. In the six with mixed connective tissue disease, the five with Raynaud's phe-
November 1977 • Annals of Internal Medicine • Volume 87 • Number 5
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Table 1 . Patients with Progressive Systemic Sclerosis Divided According to Findings in Salivary Gland Biopsy
Patient
Age
Sex Age at Onset
yrs
Sjogren's Syndrome
Scleroderma Duration
Type*
Associated Features
Clinical Features f
Lip Biopsy Inflammation J (0-4+)
Fibrosis§ (0-3+)
5/5 4/5
4 4
3 0
4/5 0/4 2/4
3 3 3
3 3 0
2/3
3
2
0/5
0
3
0/5 3/5
1 0
3 3
1/5 1/5
0 1
3 3
1/5 1/5 1/5 2/4
0 1 1 0
3 3 3 3
1/5 0/5 3/5 0/5 0/5 1/5 0/5
0 0 0 0 1 1 0
3 2 2 2 2 2 2
0/5
0
2
0/5 1/4 0/5 0/5 3/5 0/5 2/3 3/5
0 0 1 1 0 1 0 0
0 0 0 0 0 0 0 0
0/3 2/5 0/5 0/5
0 0 0 0
0 0 0 0
yrs
Group A: patients with progressive systemic sclerosis and Sjogren';5 syndrome 50 F 33 17 Diff 1 53 5 Pulmonary F CREST 58 2 fibrosis 5 F 63 CREST 3 68 5.5 F 64 CREST 70 4 29 Pulmonary F 34 CREST 63 5 fibrosis F 39 15 Diff 6 54 Group B: patients with progressive systemic sclerosis and sclerosis on lip biopsy F 43 2 Diff Pulmonary 57 7 fibrosis 50 Diff F 4 8 54 Diff F 43 Pulmonary 9 50 7|| fibrosis and renal 49 Diff M 52 Gastrointestinal 10 31| Diff F 55 60 Pulmonary 11 4.5|| fibrosis F 62 3 Diff 12 65 49 2 Diff 13 F 51 59 9 68 F 14 CREST 46 Diff 15 F 45 1 Pulmonary fibrosis 16 Diff 50 F 48 Renal 1.5|| 66 56 17 10 F CREST F 18 49 40 CREST Gastrointestinal 9|| 19 52 F 2 50 CREST F 3 Diff 20 45 42 40 M 8 21 32 CREST M 36 22 39 3 Diff Pulmonary fibrosis 46 F 3 Diff 23 43 Group C : patients with progressive systemic sclerosis and negative lip biopsy 24 52 F 40 12 Diff 6 25 51 F 55 CREST 26 36 F 33 3 Diff 36 27 F 4 32 CREST 28 F 53 49 4 CREST 29 23 F 22 1 CREST 30 60 F 3 57 CREST 31 53 F 39 Pulmonary 14 CREST fibrosis 32 32 F 8 Diff 24 33 35 F 33 1.5 CREST M 34 59 57 1.5 Diff 35 36 F 1.5 Diff 34 Pulmonary fibrosis
* CREST indicates calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly (limited skin involvement, often confined to fingers and face), and telangiectasia (10). Diff indicates diffuse scleroderma (progressive systemic sclerosis). t Clincial features included xerostomia, xerophthalmia, salivary gland enlargement, Schirmer's test, and rose bengal dye test. The denominator indicates the number of features evaluated. % Criteria of Tarplay, Anderson, and White (14). § Graded on a scale of 0-3+ (0 = absent). || Deceased.
nomenon not associated with a connective tissue disease, and in 29 autopsy control subjects, none had greater than 1 + changes of inflammation. However, 1 + changes were common, occurring in all six with mixed connective tissue diseases, two of five with Raynaud's phenomenon, and 13 of 29 of the autopsy control subjects. The frequency of these 1 + changes in asymptomatic and control pa-
tients raises a question concerning the validity of the 1 + category in the histopathologic confirmation of Sjogren's syndrome. When these results were compared with the "focus score" of Daniels and coworkers (17), there was good agreement between the two methods. All biopsies graded 0-1 + by the Tarplay method had a focus score of 0-1 with a single exception. When using the focus score Cipoletti
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et al. • Progressive Systemic Sclerosis
537
Figure 1 . Examples of various morphologic changes f r o m labial minor salivary gland biopsy, a. Normal, no round cell infiltrate, periductal fibrosis nor acinar atrophy. (Original magnification, x 4 4 ) . b. 1 + inflammatory changes with a single focus (arrow), of periductal mononuclear cell infiltration. (Original magnification, x 3 5 . 8 ) . c. 2 + changes with at least three foci of periductal mononuclear cell infiltration per lobule. (Original magnification, x 3 5 . 8 ) . d . 3 + changes with diffuse mononuclear cell infiltration and widespread acinar destruction. (Original magnification, x 2 7 . 5 ) . e. 4 + changes with extensive mononuclear cell infiltration, complete replacement of normal architecture and epimyoepithelial islands (arrows). (Original magnification, x 2 7 . 5 ) . f. 4 + perilobular fibrosis in the absence of mononuclear cell infiltration (arrow). Also note intralobular fibrosis with acinar destruction and duct dilatation. (Original magnification, x 4 6 . 8 ) . 5 3 8
November 1977
• Annals of Internal Medicine • Volume 87 • Number 5
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Table 2. Control Groups: Clinical Features of Sjogren's Syndrome Group
Major Salivary Gland Enlargement
Xerophthalmia
Positive Schirmer *
Positive Rose Bengal *
Xerostomia
Positive Minor Salivary Gland Biopsy
Sicca complex (5) Mixed connective tissue disease (6) Raynaud's phenomenon (5) Autopsy control subjects (29)
3 1 1
5 1 2
4/5 0/5 0/4
2/4 0/4 2/4
4 1 1
5 0 0 0
* For the Schirmer and rose bengal dye tests, the denominator indicates the total number of patients studied in each disease category. For the remaining clinical features, all patients were studied; therefore denominators are not included.
method, the presence of salivary gland involvement is considered confirmed if the minor salivary gland biopsy score is greater than 1. SEROLOGIC STUDIES
The serologic findings are shown in Table 3. With a single exception, positive latex agglutination reactions were found only in the patients with progressive systemic sclerosis within group A. In group A, five of six exhibited rheumatoid factor, and four of these six had the CREST syndrome variant. None of the 17 in group B, and only one of 12 in group C (also a patient with CREST syndrome) had positive latex agglutination tests. N o serologic marker except for the rheumatoid factor associated more commonly with either diffuse scleroderma or the CREST syndrome variant. The A N A was positive (always in a speckled pattern) in two of six in group A, six of 17 in group B, and one of 12 in group C; anti-DNA and anti-RNP studies were negative in all progressive systemic sclerosis patients. Antisalivary-gland antibody was detected in 12 of the 28 progressive patients with systemic sclerosis studied. Three of 23 patients had antithyroglobulin antibodies (two of these three also had Sjogren's syndrome), and two of 23 had antimitochondrial antibodies (one with Sjogren's syndrome). Of the patients with the sicca complex alone, A N A was detected in three of five (all speckled pattern). Four of four and five of five were negative for anti-DNA and anti-RNP antibodies respectively. Antisalivary-gland antibody was negative in five of five. In testing the various solid organ antibodies, one patient had antimicrosomal
antibody. Of the six patients with mixed connective tissue disease, all had a positive A N A (all with a speckled pattern) and high-titer anti-RNP. All were negative for anti-DNA antibodies, and one individual in this group had both antimicrosomal and antithyroglobulin antibodies. Other solid organ antibodies were not detected. Of the five patients with Raynaud's phenomenon unassociated with a connective tissue disease, one had a positive A N A . All were negative for anti-DNA and antiR N P antibodies. Antisalivary-gland antibodies were detected in one of five. For the remaining solid organ antibodies tested, one of five patients was positive for antimicrosomal antibody and anti-smooth-muscle antibody. Antimitochondrial and antithyroglobulin antibodies were not detected in any patients in this group. Discussion
Progressive systemic sclerosis is a generalized disorder of connective tissue characterized by inflammatory, fibrotic, and degenerative changes often accompanied by prominent vascular lesions in the skin, synovium, and certain internal organs. Although often classified as one of the "autoimmune" diseases, the cause and pathogenesis are obscure. The similarity between various features of progressive systemic sclerosis and rheumatoid arthritis, systemic lupus erythematosus, and polymyositis, as well as the associated occurrence of certain features of progressive systemic sclerosis in "overlap syndromes" (including the so-called mixed connective tissue disease) are reasons for considering it in the autoimmune category. Antinuclear antibodies occur frequently in patients with
Table 3. Serologic Studies Study*
Latex agglutination Antinuclear antibody Anti-DNA Anti-RNP Anti-salivary gland Anti-thyroglobulin Anti-smooth muscle Anti-microsomal Anti-mitochondrial
Group PSS-A t
PSS-B
PSS-C
Sicca Complex
MCTD J
Raynaud's Phenomenon
5/6 2/6 0/6 0/6 2/5 2/6 1/6 1/6 1/6
0/17 6/17 0/17 0/17 5/11 0/7 1/7 1/7 1/7
1/12 1/12 0/12 0/12 5/12 1/10 0/10 1/10 0/10
4/5 3/5 0/4 0/5 0/5 0/5 0/5 1/5 0/5
3/6 6/6 0/6 6/6 0/6 1/6 0/6 1/6 0/6
1/5 1/5 0/5 0/5 1/5 0/5 0/5 1/5 1/5
* See text for methods used and for titers consid ered significant. In each case the d
