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Introduction

  1. Top of page
  2. Introduction
  3. AUTHOR CONTRIBUTIONS
  4. REFERENCES
  5. APPENDIX A

Of the major autoimmune connective tissue diseases, Sjögren's syndrome (SS) is perhaps the least well understood. Both primary and secondary forms of SS occur, but their phenotypes are not well defined. At least 10 sets of diagnostic/classification criteria for SS have been applied since 1965 (1–11), but none to date have been universally adopted or accepted by the American College of Rheumatology. These criteria have often identified patients with similar clinical features, but not necessarily with a common disease process. There is little longitudinal data on SS. The absence of recognized classification criteria contributes to delays in diagnosis for individual patients and hampers SS research due to small sample sizes and heterogeneously diagnosed patient populations.

To address these issues, the ongoing Sjögren's International Collaborative Clinical Alliance (SICCA) was funded under a US National Institutes of Health (NIH) contract beginning in 2003. The goals of the SICCA project are: design and implement an international SS registry for collecting and storing clinical data and biospecimens, develop standardized classification/diagnostic criteria for SS that are universally applicable, and provide these resources for future studies of SS funded by the NIH or comparable agencies.

Subjects and Methods

SICCA is an ongoing longitudinal multisite observational study that is developing and studying a large and growing cohort of uniformly evaluated individuals from ethnically diverse populations to achieve the goals previously mentioned. SICCA participants must be at least 21 years old and have at least 1 of the following: symptoms of dry eyes or dry mouth; a previous suspicion or diagnosis of SS; elevated serum antinuclear antibodies (ANA), positive rheumatoid factor (RF), anti-SSA, or anti-SSB; bilateral parotid enlargement in a clinical setting of SS; a recent increase in dental caries; or have diagnoses of rheumatoid arthritis or systemic lupus erythematosus and possibly have secondary SS. Individuals are enrolled using broad criteria to create a cohort reflecting a wide range of symptoms or signs, from possible early SS to well-established disease. However, to avoid circular reasoning in developing a new definition of SS, no diagnostic labels are used at study entry even for participants previously diagnosed with primary SS.

SICCA recruits participants using announcements in patient support group publications and public media, and from patients referred by intramural and extramural practices or clinics with populations meeting these enrollment criteria. Enrollment began in the fall of 2004 at 6 international SICCA Research Groups that recruit, enroll, and examine participants, and collect and ship biospecimens to the central repository in San Francisco. These groups are located at the University of Buenos Aires and German Hospitals, Buenos Aires, Argentina; the Peking Union Medical College Hospital, Beijing, China; the Copenhagen University Hospital, Glostrup, Denmark; Kanazawa Medical University, Ishakawa, Japan; the King's College London, London, UK; and the University of California at San Francisco. Members of the SICCA Research Groups are listed in Appendix A.

All SICCA groups use the same protocol-directed methods to provide uniform evaluations and record data from ocular, oral, and rheumatologic examinations and biospecimen collections. The latter include serum, DNA, whole and parotid saliva, tears, conjunctival cells, frozen and paraffin-embedded labial salivary gland (LSG) biopsy specimens, peripheral blood mononuclear cells, and plasma from all participants and DNA from blood-related controls. SICCA participants who have any objective measures of salivary hypofunction, ocular dryness, any focal lymphocytic infiltration in their LSG biopsy specimen, or positive anti-SSA or anti-SSB (95.3% of the cohort so far) at their baseline examination, are being recalled 2 years later to repeat all examinations and specimen collections. Participants with no positive objective tests are not recalled. This group may serve as controls in future analyses. SICCA clinical questionnaires, data collection forms, and protocols for clinical examination and specimen collection are available for review from the SICCA Web site (URL: http://sicca.ucsf.edu).

Early lessons from the SICCA project

Preliminary cohort-wide analyses of SICCA data have already provided new information about SS. Data from 1,208 baseline evaluations and 134 recall evaluations were available for these analyses. The demographic and SS-related phenotypic characteristics of the SICCA cohort at this stage are summarized in Table 1. Interestingly, positive responses to the questions, “Does your mouth feel dry?” or “Do your eyes feel dry?” were not statistically associated with the presence of focal lymphocytic sialadenitis (focus score >1), serum anti-SSA, anti-SSB, or ocular staining ≥3 (indicating keratoconjunctivitis sicca [KCS]). Responses to more specific questions such as, “Do you need to sip liquids to swallow dry foods?” or “Does your mouth feel dry when eating a meal?” (13) were associated with the presence of LSG biopsy focus scores >1 (P = 0.001 and P = 0.007, respectively), but had weaker or no associations with serum anti-SSA or anti-SSB (P = 0.03 and P = 0.08 respectively). Analysis of future followup examination data should reveal whether these symptomatic individuals develop signs of primary SS over time.

Table 1. Demographic characteristics and Sjögren's syndrome (SS)–related phenotypic characteristics in 1,208 participants enrolled in the Sjögren's International Collaborative Clinical Alliance registry as of September 15, 2008*
CharacteristicsValue
  • *

    Values are the number (percentage) unless indicated otherwise.

  • Denominators vary due to missing observations (<3%) for some variables.

  • Assessed by fluorescein staining of the cornea and lissamine green staining of the interpalpebral conjunctivae. A score ≥3 represents the presence of keratoconjunctivitis sicca.

  • §

    Based on criteria from ref. 12.

Baseline enrollment sources 
 Argentina221 (18)
 China236 (20)
 Denmark231 (19)
 Japan184 (15)
 UK (since May 2007)55 (5)
 US281 (23)
Women1,116 (93)
SS characteristics 
 Dry mouth1,093 (91)
 Dry eyes1,025 (85)
 Both dry mouth and dry eyes960 (80)
 Positive anti-SSA/Ro456 (39)
 Positive anti-SSB/La289 (25)
 Positive anti-SSA and anti-SSB285 (26)
 Positive rheumatoid factor468 (40)
 Positive antinuclear antibody titer ≥1:40787 (67)
 Positive hepatitis C antibody (repeatedly positive)15 (1)
 Hypergammaglobulinemia (IgG >1,445 mg/dl)484 (41)
 Unanesthetized Schirmer's test ≤5 mm in 5 minutes388 (33)
 Tear break-up time <10 seconds991 (83)
 Ocular staining score ≥3 (max of left and right)869 (72)
 Unstimulated whole salivary flow <0.5 ml/5 minutes666 (55)
 Labial salivary gland biopsy specimen results 
  Nonspecific/sclerosing chronic sialadenitis409 (34)
  Granulomatous inflammation/within normal limits11 (1)
  Inadequate specimen26 (2)
  Focal lymphocytic sialadenitis (n = 740)§762 (63)
   Score >1500 (68)
   Score 127 (4)
   Score <1213 (29)
Continuous variables 
 Age, median (range) years54 (21–90)
 Unstimulated whole salivary flow rate, median (25th–75th percentile) ml/5 minutes0.42 (0.13–0.93)
 Stimulated parotid flow, median (25th–75th percentile) ml/minute0.12 (0.03–0.26)

In the process of developing new classification criteria for SS, we use area-proportional Venn diagrams to visualize the interrelationship between various phenotypic characteristics of SS (14). Figure 1 illustrates the overlapping relationships of 3 objective SS signs in the cohort (72% exhibit positive ocular staining for KCS, 42% positive LSG biopsy specimen, 39% positive serum anti-SSA and/or anti-SSB, and 20% none of these). Interestingly, 3% of the participants had only an abnormal focus score, 2% had only a positive serology to anti-SSA or anti-SSB, whereas 28% had only an abnormal ocular staining score. The high proportion of participants with only abnormal ocular staining led us to compare this subgroup (termed KCS-only; n = 323) with those having KCS and at least 1 of the 2 other main phenotypic features of SS, specifically focal lymphocytic sialadenitis with a focus score >1 and/or anti-SSA or anti-SSB antibodies (termed SS-KCS; n = 510). KCS-only participants had significantly lower levels of serum autoantibodies (RF, ANA titer, IgG), better ocular physiologic tests (Schirmer's test, tear break-up time), more frequent use of anticholinergic drugs and/or cigarettes (P < 0.0001 for all), and were older (P = 0.001) compared with SS-KCS participants. This suggests that KCS-only cases may represent a distinct entity of seronegative KCS that is significantly less severe than SS-KCS. Additional recall data will allow us to explore if KCS-only subjects progress into SS-KCS or whether KCS-only is a disease entity distinct from SS.

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Figure 1. An area-proportional Venn diagram of the Sjögren's International Collaborative Clinical Alliance (SICCA) cohort (n = 1,156) illustrates the partially overlapping relationships of 3 objective signs of Sjögren's syndrome: positive serum anti-SSA or SSB, labial salivary gland (LSG) biopsy specimens with focal lymphocytic sialadenitis and a focus score >1, and an ocular surface stain score ≥3.

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Currently, 78% of baseline participants screened for followup completed the followup examinations (21% of whom declined a second biopsy), ∼10% are being scheduled or waiting for followup examination, and 12% refused further participation. In preliminary analyses of LSG biopsy specimens (n = 108) after 2 years of followup, we found marked disease progression in 2 participants. One participant progressed from focal lymphocytic sialadenitis with a focus score of 4 foci/4 mm2 at baseline to confluent follicular lymphocytic proliferation 2 years later. In the other participant, the baseline biopsy specimen demonstrated focal lymphocytic sialadenitis with a focus score of 9 foci/4 mm2 and in 2 years the participant had progressed to marginal zone/mucosa-associated lymphoid tissue lymphoma with diffuse and homogenous B cell (CD20 positive) proliferation. The number of recall specimens will continue to increase for the duration of the registry, therefore providing valuable additional data related to this important issue.

There were no significant changes in the serologic and physiologic tests (e.g., salivary flow rates, Schirmer's test, and tear break-up time) during the 2-year period between baseline and followup examinations (n = 134 patients). Overall, there was no measurable progression or regression in this group, but this is preliminary data based on small numbers and only a 2-year followup time. However, there appears to be a subgroup of participants on a faster track of progression detectable through progression of their LSG biopsy specimen.

The data from recall examinations will inform the characterization of the natural history of SS through analysis of progression of individual symptoms and signs, assessing the onset of extra glandular diseases, and supporting validation of preliminary classification criteria developed from baseline examination data. Our ultimate goal is to provide reliable data and analysis from which to describe the phenotype of primary SS, new classification criteria for identifying the disease, and uniformly well-documented biospecimens for future research on SS.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Introduction
  3. AUTHOR CONTRIBUTIONS
  4. REFERENCES
  5. APPENDIX A

Dr. Daniels had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Daniels, Criswell, C. Shiboski, S. Shiboski, Schiødt, Greenspan.

Acquisition of data. Daniels, S. Shiboski, Lanfranchi, Dong, Schiødt, Umehara, Sugai, Challacombe, Greenspan.

Analysis and interpretation of data. Daniels, Criswell, C. Shiboski, S. Shiboski, Umehara, Sugai, Greenspan.

Manuscript preparation. Daniels, Criswell, C. Shiboski, S. Shiboski, Lanfranchi, Umehara, Sugai, Greenspan.

Statistical analysis. Daniels, C. Shiboski, S. Shiboski.

REFERENCES

  1. Top of page
  2. Introduction
  3. AUTHOR CONTRIBUTIONS
  4. REFERENCES
  5. APPENDIX A
  • 1
    Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjögren's syndrome: a clinical, pathological, and serological study of sixty-two cases. Medicine (Baltimore) 1965; 44: 187231.
  • 2
    Daniels TE, Silverman S Jr, Michalski JP, Greenspan JS, Sylvester RA, Talal N. The oral component of Sjögren's syndrome. Oral Surg Oral Med Oral Pathol 1975; 39: 87585.
  • 3
    Ohfuji T. Review on research reports: annual report of the Ministry of Health and Welfare. Sjögren's disease Research Committee, Japan. 1977. p. 36.
  • 4
    Manthorpe R, Frost-Larsen K, Isager H, Prause JU. Sjögren's syndrome: a review with emphasis on immunological features. Allergy 1981; 36: 13953.
  • 5
    Skopouli FN, Drosos AA, Papaioannou T, Moutsopoulos HM. Preliminary diagnostic criteria for Sjögren's syndrome. Scand J Rheumatol Suppl 1986; 61: 225.
  • 6
    Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjögren's syndrome: proposed criteria for classification. Arthritis Rheum 1986; 29: 57785.
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    Homma M, Tojo T, Akizuki M, Yamagata H. Criteria for Sjögren's syndrome in Japan. Scand J Rheumatol Suppl 1986; 61: 267.
  • 8
    Vitali C, Bombardieri S, Moutsopoulos HM, Balestrieri G, Bencivelli W, Bernstein RM, et al, and the European Study Group on Diagnostic Criteria for Sjögren's Syndrome. Preliminary criteria for the classification of Sjögren's syndrome: results of a prospective concerted action supported by the European Community. Arthritis Rheum 1993; 36: 3407.
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    Vitali C, Bombardieri S, Moutsopoulos HM, Coll J, Gerli R, Hatron PY, et al, and the European Study Group on Diagnostic Criteria for Sjögren's Syndrome. Assessment of the European classification criteria for Sjögren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. Ann Rheum Dis 1996; 55: 11621.
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    Fujibayashi T. Revised diagnostic criteria for Sjögren's syndrome. Rheumatology 2000; 24: 4218. In Japanese.
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    Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al, and the European Study Group on Classification Criteria for Sjögren's Syndrome. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group. Ann Rheum Dis 2002; 61: 5548.
  • 12
    Daniels TE, Whitcher JP. Association of patterns of labial salivary gland inflammation with keratoconjunctivitis sicca: analysis of 618 patients with suspected Sjögren's syndrome. Arthritis Rheum 1994; 37: 86977.
  • 13
    Fox PC, Busch KA, Baum BJ. Subjective reports of xerostomia and objective measures of salivary gland performance. J Am Dent Assoc 1987; 115: 5814.
  • 14

APPENDIX A

  1. Top of page
  2. Introduction
  3. AUTHOR CONTRIBUTIONS
  4. REFERENCES
  5. APPENDIX A

PROFESSIONAL COLLABORATORS FOR THE SJÖGREN'S INTERNATIONAL COLLABORATIVE CLINICAL ALLIANCE

In addition to the authors, professional collaborators for the SICCA project and locations are the University of California, San Francisco: K. Sack, J. Whitcher, A. Wu, D. Greenspan, D. Cox, R. Jordan, Y. DeSouza, M. Rasmussen, N. McNamara, D. Lee, D. Drury, L. Scott; University of Buenos Aires and German Hospitals, Buenos Aires, Argentina: A. Heidenreich, C. Vollenweider, I. Adler, A. Smith, M. Gandolfo, P. M. Bisio, A. Keszler, A. Chirife, S. Daverio, V. Kambo; Peking Union Medical College Hospital, Beijing, China: Y. Zhao, M. Li, W. Zheng, J. Su, Q. Shi, Y. Wang, S. Tong, S. Zhang, J. Zhao, D. Du, J. Xiao, H. Wang, Q. Wu, C. Zhang, W. Meng; Copenhagen University Hospital, Glostrup, Denmark: P. Helin, S. Johansen, S. Jensen, P. Ibsen, T. Schnefeldt, A. Vang; Kanazawa Medical University, Ishikawa, Japan: K. Kitagawa, Y. Masaki, M. Tanaka, N. Ogawa, K. Shimoyama, T. Sawaki, K. Hagiwara, T. Nojima, N. Kurose, M. Hondo, M. Takahashi, T. Kawanami, K. Fujimoto; King's College London, London, UK: P. Shirlaw, B. Jacobs, B. Kirkham, G. Larkin, P. Morgan, E. Odell.