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Figure.
Cumulative Number of Patients With Primary Sjögren Syndrome With Autoantibodies Before Clinical Onset
Cumulative Number of Patients With Primary Sjögren Syndrome With Autoantibodies Before Clinical Onset
Table.  
Presence of Autoantibodies Before Symptom Onset in 44 Patients With Primary Sjögren Syndrome and 44 Matched Controlsa
Presence of Autoantibodies Before Symptom Onset in 44 Patients With Primary Sjögren Syndrome and 44 Matched Controlsa
1.
Vitali  C, Bombardieri  S, Jonsson  R,  et al; 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(6):554-558.
PubMedArticle
2.
Jonsson  R, Bolstad  AI, Brokstad  KA, Brun  JG.  Sjögren’s syndrome—a plethora of clinical and immunological phenotypes with a complex genetic background. Ann N Y Acad Sci. 2007;1108:433-447.
PubMedArticle
3.
Theander  E, Henriksson  G, Ljungberg  O, Mandl  T, Manthorpe  R, Jacobsson  LT.  Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796-803.
PubMedArticle
4.
Pukkala  E, Andersen  A, Berglund  G,  et al.  Nordic biological specimen banks as basis for studies of cancer causes and control—more than 2 million sample donors, 25 million person years and 100,000 prospective cancers. Acta Oncol. 2007;46(3):286-307.
PubMedArticle
5.
Mignogna  MD, Fedele  S, Lo Russo  L, Lo Muzio  L, Wolff  A.  Sjögren’s syndrome: the diagnostic potential of early oral manifestations preceding hyposalivation/xerostomia. J Oral Pathol Med. 2005;34(1):1-6.
PubMedArticle
6.
Jonsson  R, Bowman  SJ, Gordon  T. Sjögren’s syndrome. In: Koopman  WJ, Moreland  LW, eds. Arthritis and Allied Conditions: A Textbook of Rheumatology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1681-1705.
Research Letter
November 6, 2013

Autoantibodies Present Before Symptom Onset in Primary Sjögren Syndrome

Author Affiliations
  • 1Broegelmann Research Laboratory, University of Bergen, Bergen, Norway
  • 2Department of Rheumatology, Lund University, Malmö, Sweden
  • 3Department of Laboratory Medicine Malmö, Lund University, Malmö, Sweden
JAMA. 2013;310(17):1854-1855. doi:10.1001/jama.2013.278448

Autoantibodies are characteristic of primary Sjögren syndrome1 and may be involved in its pathogenesis.2 We investigated autoantibodies present before symptom onset in patients with Sjögren syndrome because data on this issue are limited.

Methods

All patients with primary Sjögren syndrome at Malmö University Hospital (Malmö, Sweden) have been included in a registry since 1984.3 To obtain presymptomatic serum samples, the registry was linked with 3 biobanks containing specimens from 625 000 individuals submitted for microbiological analyses or population-based studies of healthy individuals.4

Date of symptom onset was determined retrospectively from the patient during the first office visit at which Sjögren syndrome was diagnosed. All cases provided written informed consent at inclusion in the registry. The study was approved by the ethics committee at Lund University.

All patients with available samples who met consensus criteria for Sjögren syndrome1 were included. When multiple samples were available for a single patient, the earliest positive sample was used. Controls were randomly selected from the biobanks and matched by sex, age, and date of earliest sampling (within 60 days before or after) to each case. None of the controls were diagnosed with Sjögren syndrome. Those serum samples that were obtained from the microbiology biobank had been submitted due to symptoms unrelated to Sjögren syndrome (eg, pregnancy screening, suspected influenza). Samples were collected from 1976 through 2001 and Sjögren syndrome was diagnosed through 2011.

Autoantibodies against Ro60/SSA, Ro52/SSA, La/SSB, Sm, RNP, Scl-70, Jo-1, ribosome P, and chromatin were detected using a multiplex immunobead assay (QUANTA Plex SLE Profile 8, INOVA Diagnostics) and analyzed on a Luminex 100 instrument (Luminex Corp). Antinuclear antibodies (ANAs) were analyzed by immunofluorescence with HEp-2 cells as the antigens. Immunoglobulin M-class rheumatoid factor (RF) was analyzed with an in-house enzyme-linked immunosorbent assay.

Descriptive statistics and a 2-sided Friedman test were used for statistical analysis (Statistics version 20.0; IBM SPSS). P < .05 was considered statistically significant.

Results

Of 360 cases in the registry, 44 (41 women and 3 men; mean [SD] age, 53 [13] years [range, 25-78 years] at symptom onset) provided 64 presymptomatic serum samples obtained a mean (SD) of 7 (5.5) years (range, 1-23 years) before symptom onset. They were representative of the whole registry cohort based on age, sex, and disease severity (eg, positive salivary gland biopsy, postdiagnostic presence of anti-Ro/SSA and anti-La/SSB antibodies, and systemic involvement).

The mean duration between symptom onset and the first office visit was 3.7 (median, 3.0) years. Forty-four controls (41 women and 3 men; mean [SD] age, 53 [13] years) provided 44 serum samples.

In 29 cases (66%), autoantibodies were detected before symptom onset (primarily ANA, followed by RF, anti-Ro60/SSA, anti-Ro52/SSA, and anti-La/SS-B; Table and Figure). All 29 cases had autoantibodies in their earliest available serum sample, as early as 18 years before symptom onset (median, 5 [interquartile range {IQR}, 3.0-7.5] years for ANA, 6 [IQR, 3.0-13.0] years for RF, 4 [IQR, 2.25-7.75] years for antibodies against Ro60/SSA, 5 [IQR, 3.0-8.0] years for antibodies against Ro52/SSA, and 4 [IQR, 2.75-9.0] years for antibodies against La/SSB).

There was no statistically significant difference in the time between a positive test result and symptom onset between autoantibodies (P = .41). The odds ratio (OR) for developing Sjögren syndrome was high for both anti-Ro60/SSA (OR, 15.0; 95% CI, 1.9-118.5) and anti-La/SSB (OR, 10.0; 95% CI, 1.2-81.5) antibodies (Table). For anti-Ro52/SSA, none of the controls vs 15 cases were reactive.

Discussion

To our knowledge, this is the first systematic investigation of presymptomatic autoantibodies in Sjögren syndrome. Most cases produced autoantibodies many years before clinical onset of the disease; the median time of 4 to 6 years is an underestimate because all seropositive cases had autoantibodies in their earliest available serum sample.

A limitation of the study is the wide confidence intervals that reflect the small sample size and may indicate unstable estimates. Also, we cannot eliminate the possibility that seropositive controls may have had undiagnosed Sjögren syndrome (3-11 years diagnostic delay has been reported)5,6 or may develop the disease in the future.

Autoantibody profiling may identify individuals at risk many years before disease onset. However, the significance of these presymptomatic autoantibodies for determining prognosis and treatment remains to be determined.

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Article Information
Section Editor: Jody W. Zylke, MD, Senior Editor.

Corresponding Author: Gunnel Henriksson, MD, PhD, Lund University, Jan Waldenströms St 59, 20502 Malmö, Sweden (gunnel.henriksson@med.lu.se).

Author Contributions: Dr Henriksson 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. Drs Jonsson and Theander contributed equally to the article.

Study concept and design: Jonsson, Theander, Henriksson.

Acquisition of data: Jonsson, Theander, Sjöström, Brokstad, Henriksson.

Analysis and interpretation of data: Jonsson, Theander, Sjöström, Brokstad, Henriksson.

Drafting of the manuscript: Jonsson, Theander, Brokstad, Henriksson.

Critical revision of the manuscript for important intellectual content: Jonsson, Theander, Sjöström, Brokstad, Henriksson.

Statistical analysis: Theander, Sjöström.

Obtained funding: Jonsson, Theander, Henriksson.

Administrative, technical, or material support: Jonsson, Theander, Sjöström, Brokstad, Henriksson.

Study supervision: Jonsson, Theander, Henriksson.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Theander reported serving on advisory boards for Roche and Pfizer; receiving payment for lectures from Roche; and receiving reimbursement for travel expenses from Roche and Pfizer. No other disclosures were reported.

Funding/Support: This study was supported by grants from the Malmö University Hospital Foundation, the Malmö University Hospital Cancer Foundation, the Swedish Rheumatism Association, the Strategic Research Program at Helse Bergen, the Regional Health Authority for Western Norway, the Broegelmann Foundation, and the Foundations of Kock, Österlund, and Gustaf V.

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are grateful to Peter Olsson, MD (Department of Rheumatology, Lund University, Malmö, Sweden), for assistance with acquisition of data and Bo Cederholm, MD, PhD (Clinical Immunology Laboratory, Skåne University Hospital, Lund, Sweden), for access to laboratory facilities for the analysis of rheumatoid factor. No compensation was received by either of these individuals.

References
1.
Vitali  C, Bombardieri  S, Jonsson  R,  et al; 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(6):554-558.
PubMedArticle
2.
Jonsson  R, Bolstad  AI, Brokstad  KA, Brun  JG.  Sjögren’s syndrome—a plethora of clinical and immunological phenotypes with a complex genetic background. Ann N Y Acad Sci. 2007;1108:433-447.
PubMedArticle
3.
Theander  E, Henriksson  G, Ljungberg  O, Mandl  T, Manthorpe  R, Jacobsson  LT.  Lymphoma and other malignancies in primary Sjögren’s syndrome: a cohort study on cancer incidence and lymphoma predictors. Ann Rheum Dis. 2006;65(6):796-803.
PubMedArticle
4.
Pukkala  E, Andersen  A, Berglund  G,  et al.  Nordic biological specimen banks as basis for studies of cancer causes and control—more than 2 million sample donors, 25 million person years and 100,000 prospective cancers. Acta Oncol. 2007;46(3):286-307.
PubMedArticle
5.
Mignogna  MD, Fedele  S, Lo Russo  L, Lo Muzio  L, Wolff  A.  Sjögren’s syndrome: the diagnostic potential of early oral manifestations preceding hyposalivation/xerostomia. J Oral Pathol Med. 2005;34(1):1-6.
PubMedArticle
6.
Jonsson  R, Bowman  SJ, Gordon  T. Sjögren’s syndrome. In: Koopman  WJ, Moreland  LW, eds. Arthritis and Allied Conditions: A Textbook of Rheumatology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:1681-1705.
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