Sjogren's Screened by Autoimmune Antibody Tests

Linda Roach

December 03, 2012

Testing patients for 2 autoimmune antibodies can enable ophthalmologists to find previously unsuspected cases of Sjögren's syndrome (SS) among their patients with aqueous-deficient dry eye (ADDE), according to an analysis of data from a large multicenter drug trial.

In an article published online September 21 and in the December issue of the British Journal of Ophthalmology, Melissa (Shiao Hui) Liew, MBBS, from Pfizer, and colleagues report that patients with clinically significant ADDE who were positive for rheumatoid factor (RF) or antinuclear antibody (ANA) had approximately 5 to 14 times the risk of having SS as other participants in the study (P = .009 for RF; P < .0001 for ANA).

Table. Sjögren's Risk Based on RF and ANA Levels

  Non-SS Primary SS Odds Ratio (95% Confidence Interval) P Value
RF <10 ≥10 4.8 (1.90 - 11.95) .009
ANA <1:160 ≥1:160 13.9 (5.23 - 36.82) < .0001

The researchers found that 6.4% of the 327 patients with dry eye enrolled in the trial (which was testing a dry-eye drug) had primary SS. In a quarter of these patients, the disorder had not been previously diagnosed. Another 5.2% of the participants had secondary SS, and in 29.4% of them this was a new diagnosis.

"So as ophthalmologists we should not order only tests for Sjögren-specific antibodies A and B, we should always order ANA and rheumatoid factor as well," said senior author Esen K. Akpek, MD, in an interview with Medscape Medical News. Dr. Akpek is an associate professor of ophthalmology and rheumatology at Wilmer Eye Institute, Johns Hopkins University, and associate director of the Johns Hopkins Jerome L. Greene Sjögren's Syndrome Center, Baltimore, Maryland.

Dr. Akpek noted that the study supports the recommendation this year by the American College of Rheumatology that positive RF and ANA titer higher than 1:320 be included in a proposed new Sjögren's case definition, replacing a consensus classification system that has been widely used since 2002.

Under the new system, patients with SS would meet at least 2 of 3 criteria, which are independent of specific symptomology:

  • positive serum Sjögren-specific antibody A (SSA) and/or Sjögren-specific antibody B (SSB) or positive RF and ANA antibody titer greater than 1:320,

  • an ocular staining score greater than 3, or

  • the presence of focal lymphocytic sialadenitis with a focus score greater than 1 focus/4 mm2 in labial salivary gland biopsy samples.

Her group's research represented a secondary analysis of data from a clinical phase 1/2 investigational drug study of a possible drug for dry eye. However, as a consultant to the drug company (Pfizer) at the time, Dr. Akpek said she tailored the design to gather information necessary for the secondary analysis.

"We prospectively tested the patients for Sjögren, even though it was really an investigational trial of a drug," she said. "ANA and RF, for example, were not part of the diagnostic criteria for Sjögren's, based on the 2002 diagnostic criteria set."

Only 2 of the 4 criteria in that 2002 classification system are objective tests: positive results on SSA and SSB testing and salivary gland biopsy. However, the former misses about 40% of Sjögren cases, she said, and the latter is not practical for ophthalmologists to use for screening patients with suspected Sjögren and referring them to a rheumatologist.

Early identification is important because of the organ and systemic problems the syndrome causes, including lymphoma, autoimmune hepatitis, pulmonary fibrosis, cystitis, and nephritis, Dr. Akpek said.

"The results of this study support calling for an increased index of suspicion for ophthalmologists caring for dry eye, and the recommendation that the presence of SS should be assessed in all patients with clinically significant ADDE," the authors conclude. "[A]lthough not clinical practice, patients with significant dry eye signs and symptoms plus a positive RF or ANA result should be offered diagnostic testing even if their SSA or SSB results are negative."

However, those conclusions appear to be stronger than the evidence given in the article, said Mark Willcox, PhD, professor in the School of Optometry and Vision Science at the University of New South Wales in Sydney, Australia, who was not involved in the study.

"They used 2 definitions of primary SS (pSS): those who had a previously established diagnosis of SS and no other autoimmune connective tissue disease, or patients with positive dry eye signs and symptoms, subjective dry mouth symptoms, and a positive test for SSA and/or SSB, " Dr. Willcox told Medscape Medical News. "Their conclusion...is difficult to justify from the results of the study, as they do not present results analyzed for only those pSS subjects who were SSA or SSB negative."

Dr. Akpek was a consultant to Pfizer Inc during the study, which the company sponsored, but she is no longer affiliated with the company. Three coauthors were Pfizer employees at the time of the study. Dr. Willcox has disclosed no relevant financial relationships.

Br J Ophthalmol. 2012;96:1498-1503. Abstract