How novel autoantibodies may improve screening dry eye patients for Sjogren's syndrome

This article was reviewed by Vatinee Bunya, MD, MSCE.

The addition of data on novel autoantibodies related to Sjogren’s syndrome (SS) may improve screening dry eye patients for SS, according to research presented at the recently held annual meeting of the Association for Research in Vision and Ophthalmology.

The study, funded by the National Eye Institute, was led by Vatinee Bunya, MD, MSCE, and was presented by Kennedy Johnson, a clinical research coordinator at the Scheie Eye Institute at the University of Pennsylvania in Philadelphia.

Sjogren's syndrome is an underdiagnosed autoimmune disease in which the diagnosis is often delayed by a few years, and dry eye is one of the most common symptoms of SS, explained Johnson. However, because dry eye is such a prevalent condition, it is not feasible to work up all patients with dry eye for SS, she noted.

“Because dry eye is one of the most common symptoms of the disease (SS), ophthalmologists often see these patients first and are therefore in a unique position to screen dry eye patients for Sjogren’s syndrome,” said Johnson.

There are traditional antibodies to check for SS and they include Anti-Sjogren’s-syndrome-related antigen A and B (SSA, SSB), antinuclear antibody (ANA), and rheumatoid factor (RF) related antigen A and B, but Johnson noted that these traditional antibodies are not specific to SS and that they are not always found in every SS patient.

Previous research¹ that evaluated dry eye patients for SS found that half of the patients required a minor salivary gland biopsy to reach a definitive diagnosis because of the lack of positive antibody testing, noted Johnson.

“We believe it’s important to identify new serological biomarkers that could better characterize Sjogren’s syndrome and overcome the limitations of traditional antibodies,” said Johnson. “Many studies have explored novel antibodies for Sjogren’s syndrome.”

One of those studies concluded that antibodies to salivary protein, parotid secretory protein, and carbonic anhydrase isoenzyme VI (CA-6) may be novel markers for SS, said Johnson. Moreover, in mouse studies these novel antibodies were detected earlier in the disease process.²

Other research has revealed that anti-CA6 is associated with younger age and more severe disease,³ noted Johnson. In addition, other studies have found that autoantibodies SP-1 IgM and PSP had an increased prevalence in patients with SS and that SP-1 may be a marker of worse ocular surface disease.^4,5

The research suggests that autoantibodies may not only help detect patients with SS but detect SS patients with more severe disease, explained Johnson.

Bunya and her team at Scheie Eye Institute had previously developed a screening questionnaire including ocular examination findings such as tear film break-up time and lissamine green staining of the conjunctiva to help detect patients with dry eye who may also have underlying SS. The sensitivity of the algorithm was 78% and the specificity 66%.⁶

Since then, the team has sought to refine the diagnostic ability of the tool and increase the sensitivity and specificity by incorporating novel autoantibody data. They launched a study including patients with dry eye who were more than 18 years of age, with no previous diagnosis of SS or any other autoimmune disease.

They also excluded patients with a history of corneal refractive surgeries, head or neck radiation, chemotherapy, pre-existing lymphoma and patients who are taking a topical glaucoma medication. In terms of the definition of SS, they used classification criteria as developed by the American College of Rheumatology and the European League Against Rheumatism, noted Johnson.

Apart from completion of the questionnaire, subjects in the study also underwent an ocular surface exam, an unstimulated salivary flow rate test, and serological testing. A subset of subjects also underwent a labial salivary gland biopsy if indicated.

Interestingly, investigators did find that the percentage of positive subjects in specific immunoglobulin groups of SP IgA, PSP IgM, and CA-VI IgM was significantly higher in those with SS than in those without SS.

“We had 25.4% in the absence of Sjogren’s syndrome and 61.1% in the presence of Sjogren’s syndrome,” said Johnson, noting the inclusion of autoantibodies SP IgA, PSP IgM, and CA-VI IgM demonstrated an improvement in the performance of the previously developed algorithm.

The study, however, has to be conducted in larger and more diverse population to ensure the generalizability of the screening method, said Johnson.

“Our study has some limitations,” said Johnson. “Our sample size was small and only involved a single center with the majority of patients being older Caucasian females. In the future, we would like to include additional sites and a more diverse patient population to increase the generalizability of our screening tool. Future studies may also involve the analysis of tear and saliva samples, which were collected during our study to further examine the presence of these autoantibodies and other biomarkers in patients with or without Sjogren’s syndrome.”

The likelihood scoring system that Johnson and colleagues have developed can be implemented using the brief series of questions alone, or combined with standard ocular surface signs and novel autoantibody testing for improved performance.

“In the future, once the algorithm has been validated, it may serve as an effective screening tool to identify patients with Sjogren’s syndrome at a younger age, thus leading to earlier diagnosis,” Johnson said.

References

1. Akpek EK, Klimava A, Thorne JE, Martin D, Lekhanont K, Ostrovsky A. Evaluation of patients with dry eye for presence of underlying Sjögren’s syndrome. Cornea. 2009;28(5):493–497.
2. Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjogren’s syndrome. Clin Immunol. 2012;145(3):251-255.
3. Karakus S, Baer AN, Agrawal D, Gurakar M, Massof RW, Akpek EK. Utility of novel autoantibodies in the diagnosis of Sjogren’s syndrome among patients with dry eye. Cornea. 2018;37(4):405-411.
4. Bunya VY, Ying G, Maguire MG, et al. Prevalence of novel candidate Sjogren’s syndrome autoantibodies in the dry eye assessment and management (DREAM) study. Cornea. 2018;37(11):1425-1430.
5. Bunya VY, Masaro-Giordano M, Vivino FB, et al. Prevalence of novel candidate Sjogren syndrome autoantibodies in the Penn Sjogren’s International Collaborative Clinical Alliance Cohort. Cornea. 2019;38(12):1500-1505.
6. Bunya VY, Maguire MG, Akpek EK, et al. A new screening questionnaire to identify patients with dry eye with a high likelihood of having Sjogren syndrome. Cornea. 2021;40(2):179-187.

Vatinee Y. Bunya, MD, MSCE

E: vatinee.bunya@pennmedicine.upenn.edu

Bunya is co-director, Penn Dry Eye and Ocular Surface Center, and associate professor of ophthalmology at the Hospital of the University of Pennsylvania. She did indicate any proprietary interest in the subject matter.