Sjogren’s Syndrome in Patients with Primary Biliary Cirrhosis EPAMINONDAS v. TSIANOS,’JAYH. HOOFNAGLE,~ PHILIP c. FOX,2 MARGARET &SPAUGH,* E. ANTHONY J O N E S , ~DANIELF.SCHAFER~ AND HARALAMPOS M. MOUTSOPOULOSS ‘Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases (NIALIDK), ‘National Institute for Dental Research (NIDR), National Institutes of Health (NIH), Bethesda, Maryland 20892; 3University of Ioannina, School of Medicine, Department of Internal Medicine, 451 10 Ioannina, Greece; 4Department of Internal Medicine, Veterans Administration Medical Center, Martinez, California 94553 and 6Liver Study Unit, Veterans Administration Medical Center, Omaha, Nebraska 68105

Symptomatology and objective findings of Sjogren’s that patients with Ss associated with RA have clinical syndrome were evaluated in 38 consecutive patients (5, 8), serological (9-11) and genetic (12, 13) features with primary biliary cirrhosis. Symptoms of Sjogren’s that differ from those of patients with pSs. In particular, syndrome were present in 18 (47.4%)patients, but were pSs, unlike that associated with RA, is associated with severe enough to warrant therapy in only four (10.6%). serum autoantibodies to cellular antigens Ro(SSA) and Nineteen patients consented to evaluation for La(SSB) (10) and with the HLA-B,, -DR, and -DRwS2 Sjogren’ssyndrome, which included Schirmer’s I test, measurement of parotid flow rate and serum autoanti- alloantigens (12-14). pSs patients also tend to exhibit bodies, labial minor salivary gland biopsy and human more severe manifestations of Ss compared with paleukocyte antigen typing. Histological changes diag- tients with secondary forms of the syndrome (7, 8). In nostic of Sjogren’s syndrome were present in five contrast to RA patients with Ss, patients with propatients (26.3%).All five patients had symptoms of gressive systemic sclerosis and Ss have clinicoserological Sjogren’s syndrome and three had abnormal Schirm- features similar to those seen in pSs patients (7). er’s I tests, but none had corneal ulcerations or Ss has also been shown to be associated with PBC decreased parotid flow rates. Results of serological (15, 16). Indeed, in several studies the most common tests and human leukocyte antigen typing were not autoimmune disorder associated with PBC is Ss (17). similar to those described in patients with primary The reported prevalence of Ss in PBC patients has varied Sjogren’ssyndrome but were similar to those described in patients with rheumatoid arthritis and Sjogren’s from 69% to 81% (15, 16, 18). However, the clinical, syndrome. These findings indicate that Sjogren’s syn- serological and immunogenetic features of Ss in PBC drome associated with primary biliary cirrhosis is a have not been systematically studied. We report the results of an analysis of clinical, form of secondary Sjogren’ssyndrome resembling that biochemical, serological, immunogenetic and histoassociated with rheumatoid arthritis. (HEPATOLOGY 1990;11:730-734.) logical features of Ss in 38 consecutive patients with

Sjogren’s syndrome (Ss) is the result of lymphocytemediated destruction of exocrine glands, leading to diminished or absent glandular secretions and mucosal dryness (1). It primarily affects women and is the second most common autoimmune rheumatoid disorder worldwide, after rheumatoid arthritis (RA) (2,3).Ss can occur alone (primary, or pSs) or in association with various autoimmune diseases such as RA, systemic lupus erythematosus and progressive systemic sclerosis (secondary syndrome or Ss associated with other autoimmune disorders) (4-8). Several studies have shown Received October 2, 1989; accepted December 19, 1989. Address reprint requests to: E.V. Tsianos, M.D., Assistant Professor of Medicine/Gastroenterology, Department of Medicine, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece. 3111120065

PBC. This analysis indicates that Ss associated with PBC is probably a secondary form of the syndrome similar to that seen in RA patients. MATERIALS AND METHODS Thirty-eight consecutive patients with PBC were evaluated for symptomsof Ss (6).Each patient completed a questionnaire to evaluate clinical symptoms of xerostomia, xerophthalmia and parotid gland enlargement. These patients represented all patients with PBC admitted to the National Institutes of Health Clinical Center and followed as outpatients by the Liver Diseases Section of the National Institute of Diabetes and Digestive and Kidney Diseases between June 1979 and June 1983. All but one were female. The patients’ ages ranged from 29 to 68 yr (average = 50.1 yr). Diagnosis of PBC was based on the presence of compatible clinical, serum-biochemical, serological and hepatic histological features (19). In patients with atypical features (young age, male sex, negative tests for antimitochondrial


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FIG.1. Histological findings in minor salivary glands in a patient with PBC. A lymphocytic infiltration of the salivary glands is present, which is compatible with Ss. Similar histological findings were obtained in four more of 19 patients with PBC who had minor salivary gland biopsies (H & E, ~ 1 3 0 ) . antibodies), lesions affecting large bile ducts were excluded tears) in only four (10.5%) patients. Comparison of by cholangiography. patients with and without symptoms of Ss showed that The diagnosis of pSs was based on the presence of at least symptomatic patients tended to be older (mean two of the three following criteria: xerostomia (subjective age = 54.7 yr vs. 46 yr) (p c 0.0031, but they did not complaints and decreased stimulated parotid flow rate); have more advanced liver disease as assessed by the keratoconjunctivitis sicca (subjective complaints, Schirmer’s I test and positive slit-lamp examination after rose-bengal presence and duration of symptoms (p = N.S.), serum staining) and recurrent or persistent parotid or major gland bilirubin levels (p = N.S.) and histological stage of the enlargement. Diagnosis was confirmed by labial minor salivary liver lesion (p = N.S.) (Table 1). Serological testing revealed a similar prevalence of gland biopsies in those who signed consent forms. Nineteen of the 38 patients agreed to undergo a more autoantibodies in both groups (Table 2). Autoantibodies thorough evaluation which included Schirmer’s I test, slit- to cellular antigen La(SSB) were absent in both groups. lamp examination after rose-bengal staining (201, mea- Autoantibodies to cellular antigen Ro(SSA) tended to surement of parotid ffow rate (211 and a minor salivary gland occur more often in patients with PBC without Ss biopsy. All 19 patients were female. Their ages ranged from 34 symptoms. Overall, antimitochondrial antibodies were to 68 yr (average = 54.5 yr). Schirmer’s I test was considered present in 35 (92.1%)patients, antinuclear antibodies in abnormal if less than 5 mm of the paper strip was wet after 5 min of contact with the globe. Parotid flow rate was considered 2 (5.3%),rheumatoid factor in 5 (13.2%),anti-DNA in 7 abnormal when less than 0.5 mV5 min after stimulation with (18.4%),anti-Ro(SSA) in 4 (10.5%),anti-La(SSB) in lemon juice. Tissue sections of labial minor salivary gland none and anti-RANA in 9 (23.7%). Of the 19 patients who consented to more thorough biopsy samples were evaluated in a blinded fashion and scored from 0 to 4 + on the basis of the histological classification evaluation, only five (26.3%)had minor labial gland described by Tarpley, Anderson and White (22). Written, histological changes compatible with those seen in Ss. informed consent was obtained for salivary gland biopsy; the The histological appearance of the minor salivary glands protocol was approved by the NIDDK Clinical Research is similar to that of the bile-duct lesions seen in liver Subcommittee. Autoantibodies to cellular antigen Ro(SSA) biopsy samples from patients with PBC (Fig. 1). All five and La(SSB) and anti-RANA were measured as previously patients with abnormal salivary gland histology had Ss described (10, 23). Finally, 32 of the patients were typed for HLA-A, -B and -DR symptoms -in particular, three had abnormal Schirmer’s I tests, but none had corneal ulcerations or alloantigens (13). Data were analyzed stastically using the paired t test and the decreased parotid flow rate (Table 3). Of the 14 patients with normal salivary gland histology, six had symptoms xz methods where appropriate.

RESULTS Biochemical, histological and serological features in the 38 PBC patients are summarized in Tables 1 and 2. Symptoms of Ss were present in 18 (47.4%)patients but were severe enough to require therapy (use of artificial

of Ss, one had an abnormal Schirmer’s I test and two had decreased parotid flow rate. The presence of abnormal salivary gland histology did not correlate with severity of histological features (p = N.S.) of PBC, duration of symptoms (p = N.S.), serum bilirubin levels (p = N.S.) (Table 4) or positive serological tests (Table 5 ) .




TABLE 1. Clinical and laboratory features in 38 PBC patients with or without symptoms of Ss Mean age f S.D.

Mean PBC duration f S.D.

Mean serum-bilirubin levels f S.D. (mddl)

PBC patients



With sicca complaints (n = 18) Without sicca complaints (n = 20)

54.7 i 8.5"





* 9.2"




46.0 f 8.9




1.8 f 2.7




Mean histological

stage f S.D.

"For statistical analysis see text. bLiver biopsy w w performed in 17 patients. 'Liver biopsy was performed in 18 patients.

TABLE 2. Serological features in 38 PBC patients with or without symptoms of Ss (+) m (+)MA (+) RF Anti-DNA Anti-Ro (SSA) PBC patients n (%) n (%) n (%) n 1%) n (9'0) With sicca complaints (n = 18) Without sicca complaints (n = 20)


Anti-La (SSB) n (%)

17 (94.4)


3 (16.7)

3 (16.7)


0 (0)

18 (90)


2 (10)

4 (20)

3 (15)

0 (0)

= antimitochondrial antibodies;


= antinuclear antibodies;



rheumatoid factor.

TABLE3. Evaluation of Ss in 19 PBC patients with or without symptoms of Ss Labial histopathology

PBC patients

Abnormal Schirmer's test n (%)

Decreased PFRo


n (%)

n (%I

If n (5%)

n (%)

3 (27.3)

0 (0)

4 (36.4)

2 (18.2)

5 (45.5)


2 (25)

7 (87.5)


0 (0)

With sicca complaints (n = 11) Without sicca complaints (n = 8)

a 2+

"PFR = parotid flow rate.

TABLE 4. Correlation of clinical and histological features of PBC with labial minor salivary gland histolodcal findings ~

Lip biopsy score groupa

Mean age f S.D.

duration f 8.D.

Mean PBC

Mean serum-bilirubin level f S.D.




Mean histological etage f S.D.

55.8 f 9.2" 48.6 f 7.8

2.3 f 2.1b 2.0 2 1.7

1.0 f 1.8 f 3.0

2.0 t 1.06 2.0 f 0.8



2+ (n = 5)

C 1+ (n = 14)

"Group 3 2 + vs. Group c 1+ , p = NS. bFor statistical analysis see the text.

TABLE 5. Correlation of serological features of 19 PBC patients with or without sicca manifestationa and labial minor salivary gland histolodcal findings



antimitochondrial antibodies; ANA = antinuclear antibodies; RF = rheumatoid factor.


Vol. 11, No. 5, 1990

TABU:6. Frequency of HLA-B8 and HLA-DR specificities in 38 PBC patients with or without symptoms of Se

HLA specificity B8 DRI. DR2 DR3 DR4 DREi DR6 DRY DR8 DRw52

PBC with sicca symptoms (n = 18) (% positive)

PBC without sicca symptoms (n = 20) (% positive)

11 33 22 11 28 11 5 17 17 50

35 20 10 30 40 0 20 15 15 55


gland enlargement is uncommon and antibodies to Ro(SSA) and La(SSB) cellular antigens are infrequent (5, 8). In PBC patients in this study, presence of anti-Ro(SSA) antibodies did not correlate with the presence of histological features of Ss; anti-La(SSB) were not present. Furthermore, patients with PBC and Ss symptoms did not have increased frequency of the HLA-BB, -DR, and DRw6, alloantigens as has been shown in pSs patients (13).Thus the Ss associated with PBC appears to be a secondary form of this syndrome, similar to that seen in RA patients.

Acknowledgment: We wish to thank Mr. G.E. Papanikolaou for excellent secretarial assistance. REFERENCES

The results of HLA typing (Table 6)did not show any increase in frequency of HLA-B8 or HLA-DR alloantigens in patients with PBC and symptoms of Ss. DISCUSSION

This study of 38 patients with PBC revealed that approximately half had symptoms of keratoconjunctivitis sicca, but less than half of the patients with complaints of mouth dryness had histopathological changes compatible with Ss (22) in the labial minor salivary glands. Similar discrepancies between clinical symptoms and histological findings have been observed in patients with other autoimmune diseases such as RA and scleroderma (7, 8). There is no simple explanation for these discrepancies. However, there is a possibility of sampling errors when using small labial salivary gland biopsy samples to make the diagnosis of Ss. Furthermore, lesions in the labial minor salivary glands are not necessarily representative of pathological conditions present. in lacrimal or major salivary glands. Analysis of patients with and without Ss symptoms showed that the symptomatic group was older. Thus, Ss complaints may be attributable to aging alone (24). There were also apparent discrepancies between lacrimal and parotid flow rates and salivary gland histopathology. However, several studies have shown that flow rates depend on many factors and are not reliable for the diagnosis of Ss. Furthermore, parotid flow rates do not clearly separate Ss patients from normal controls (25,26). This study also showed that PBC patients with lymphocytic infiltrates of the labial minor salivary gland rarely have serious local sequelae. All patients tested had negative rose-bengal staining of the cornea and conjunctivae. Thus in the majority of PBC patients Ss is usually mild. It seems unlikely that the histological lesion of the labial minor salivary glands follows the typical course of the disease observed in primary Ss. Finally, patients with PBC and histology of Ss did not have the serological and immunogenetic features that characterize pSs (12,13) and thus resemble patients with RA and Ss, where eye dryness is frequent, parotid

1. Moutsopoulos HM, Chused TM, Mann DL, Klippel JH, Fauci AS, Frank MM, Lawley TJ, et al. Sjogren’s syndrome (sicca syndrome) current issues. Ann Intern Med 1980;92:212-216. 2. Bloch KJ, Buchanan WW, Wohl MJ, Bunim J J . Sjogren’s syndrome: a clinical, pathological and serological study of sixty-two cases. Medicine 1965;44:187-231. 3. Shearn MA. Sjogren’s syndrome. Med Clin North Am 1977; 61:271-282. 4. Alarcon-Segovia D, Ibanez G, Valazquez-Forero F, HernandezOrtiz J , Gonzalez-Jimenez Y. Sjogren’s syndrome in systemic lupus erythematosus. Ann Intern Med 1974;81:577-583. 5. Moutsopoulos HM, Webber BL, Vlagopoulos TP, Chused TM, Decker JL. Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis. Am J Med 1979;66733-736. 6. Moutsopoulos HM, Klippel JH, Pavlidis N, Wolf RO, Sweet JB, Steinberg AD, Chu FC, et al. Correlative histologic and serologic finding of sicca syndrome in patients with systemic lupus erythematosus. Arthritis Rheum 1980;23:36-40. 7. Drosos AA, Andonopoulos AP,Costopoulos JS, Stavropoulos ED, Papadimitriou CS, Moutsopoulos HM. Sjogren’s syndrome in progressive systemic sclerosis. J Rheumatol 1988;15:965-968, 8. Andonopoulos AP,Drosos AA, Skopouli FN, Acritidis NC, Moutsopoulos HM. Secondary Sjogren’s syndrome in rheumatoid arthritis. J Rheumatol 1987;14:1098-1103. 9. Lundwig H, Schernthaner G, Scherak 0, Kolarz G. Antibodies to pancreatic duct cells in Sjogren’s syndrome and rheumatoid arthritis. Gut 1977;18:311-315. 10. Alspaugh MA, Talal N, Tan EM. Differentiation and characterization of autoantibodies and their antigens in Sjogren’s syndrome. Arthritis Rheum 1976;19:216-222. 11. Akizuki M, Boehm-Truiff MJ, Kassan SS, Steinberg AD, Chused TM. Purifications of an acidic nuclear protein antigen and demonstration of its antibodies in subsets of patients with sicca syndrome. J Immunol 1977;119:932-938. 12. Chused TM, Kassan SS, Opelz G, Moutsopoulos HM, Terasaki PI. Sjogren’s syndrome associated with HLA-DRw,. N Engl J Med 1977;296:895-897. 13. Moutsopoulos HM, Mann DL, Johnson AH, Chused TM. Genetic differences between primary and secondary sicca syndrome. N Engl J Med 1979;301:761-763. 14. Moutsopoulos HM, Chused TM, Johnson AH, Knudsen B, Mann DL. B lymphocyte antigens in sicca syndrome. Science 1978; 199:1441-1442. 15. Alarcon-Segovia D, Diaz-Jouanen E, Fishbein E. Features of Sjogren’s syndrome in primary biliary cirrhosis. Ann Intern Med 1973;79:31-36. 16. Golding PL, Brown R, Mason AMS, Taylor E. “Sicca complex” in liver disease. Br Med J [Clin Resl 1970;4:340-342. 17. Bodenheimer HC, Schaffner F. Primary biliary cirrhosis and the immune system. Am J Gastroenterol 1979;72:285-296. 18. Crowe JP, Christensen E, Butler J, Wheeler P, Coniach D, Keenan J , Williams R. Primary biliary cirrhosis: the prevalence of



hyperthyroidism and its relationship to thyroid autoantibodies and sicca syndrome. Gastroenterology 1980;78:1437-1441. 19. Scheuer PJ, ed. Liver biopsy interpretation. 4th ed. London: Bailliere Tindall, 1988:53-62. 20. Holm S. Keratoconjunctivitis sicca and the sicca syndrome. A d a Ophthalmol Suppl (Copenh) 1949;33:1-230. 21. Sproles A, Schaeffer LD. An advanced design of the CarlsonCrittenden cup for collection of parotid fluid. Biomat Med Der Art Org 1974;2:95-101. 22. Tarpley TM, Anderson LG, White CL. Minor salivary gland involvement in Sjogren’s syndrome. Oral Surg Oral Med Oral Pathol 1974;37:64-74. 23. Alspaugh MA,Tan EM. Serum antibody in rheumatoid arthritis reactive with a cell in associated antigen: demonstration by


precipitation and immunofluorescence. Arthritis Rheum 1976; 19~711-719. 24. Drosos AA,Andonopoulos AP,Costopoulos JS, Papadimitriou CS, Moutsopoulos HM. Prevalence of primary Sjogren’s syndrome in an elderly population. Br J Rheumatol 1988;27:123-127. 25. Paschides CA, Kitsios G, Karakostas KX, Psillas C, Moutsopoulos HM. Evaluation of tear break-up time, Schirmer’s I test and rose bengal staining as confirmatory tests of keratoconjundivitis sicca. Clin Exp Rheumatol 1989;7:155-158. 26. Skopouli FN, Siouna-Fatourou HI, Ziciadis C, Moutsopoulos HM. Evaluation of unstimulated whole saliva flow rate and stimulated parotid flow as confirmatory tests for xerostomia. Clin Exp Rheumatol 1989;7:127-130.

Sjögren's syndrome in patients with primary biliary cirrhosis.

Symptomatology and objective findings of Sjögren's syndrome were evaluated in 38 consecutive patients with primary biliary cirrhosis. Symptoms of Sjög...
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