Challenges with screening dry eye patients for Sjögren’s syndrome

Reviewed by Dr Vatinee Bunya.

Additional data on novel autoantibodies related to Sjögren’s syndrome (SS) may improve screening of dry eye patients for SS, according to research presented at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. The study, funded by the National Eye Institute, was led by Dr Vatinee Bunya and presented by Kennedy Johnson, a clinical research coordinator at the Scheie Eye Institute at the University of Pennsylvania in Philadelphia, United States.

SS is an underdiagnosed autoimmune disease in which the diagnosis is often delayed by a few years. “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 SS,” Ms Johnson said. However, because this symptom is so prevalent, it is not feasible to screen all patients with dry eye for SS, she noted.

Use of antibodies for screening

There are traditional antibodies used to check for SS. These include anti-SS-related antigens A and B (SSA, SSB), antinuclear antibody (ANA) and rheumatoid factor (RF)-related antigens A and B; however, Ms Johnson noted that these antibodies are not specific to SS and are not found in every patient with SS. Previous research¹ to evaluate dry eye patients for SS found that half required a minor salivary gland biopsy to reach a definitive diagnosis because of the lack of positive antibody testing, Ms Johnson explained.

“We believe it is important to identify new serological biomarkers that could better characterise SS and overcome the limitations of traditional antibodies,” she added. “Many studies have explored novel antibodies for SS.”

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

Other research has revealed that anti-CA-VI is associated with younger age and more severe disease,³ noted Ms Johnson. Studies have found that autoantibodies SP-1 IgM and PSP had increased prevalence in patients with SS and that SP-1 may be a marker of worse ocular surface disease.^4,5 She pointed to research which suggests that autoantibodies may not only help detect patients with SS but also detect those with more severe disease.

Dr 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 older than 18 years and had no previous diagnosis of SS or any other autoimmune disease.

They excluded patients with a history of corneal refractive surgeries, head or neck radiotherapy, chemotherapy or pre-existing lymphoma, and patients taking a topical glaucoma medication. Ms Johnson stated that as a definition of SS, they used classification criteria as developed by the American College of Rheumatology and the European League Against Rheumatism.

In addition to completing the questionnaire, subjects in the study also underwent an ocular surface examination, an unstimulated salivary flow rate test and serological testing. A subset of subjects also underwent a labial salivary gland biopsy if indicated.

Investigators found that the percentage of positive subjects in the 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 SS and 61.1% in the presence of SS,” said Ms Johnson.

She noted that including the autoantibodies SP IgA, PSP IgM and CA-VI IgM produced an improvement in the performance of the previously developed algorithm. However, she stated that the study must be conducted in a larger, more diverse population to ensure that the screening method can effectively be generalised.

“Our study has some limitations,” she said. “Our sample size was small and only involved a single centre, with the majority of patients being older Caucasian females.”

She added that in the future, investigators would like to include additional sites and a more diverse patient population to increase the generalisability of the 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 SS,” she said.

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Vatinee Y. Bunya, MD, MSCE

E: vatinee.bunya@pennmedicine.upenn.edu

Dr Bunya is co-director of the Penn Dry Eye and Ocular Surface Center and associate professor of ophthalmology at the Hospital of the University of Pennsylvania, US. She did not indicate any proprietary interest in the subject matter.

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References

1. Akpek EK, Klimava A, Thorne JE, Martin D, Lekhanont K, Ostrovsky A. Cornea. Evaluation of patients with dry eye for presence of underlying Sjögren’s syndrome. 2009;28:493–497.

2. Shen L, Suresh L, Lindemann M, et al. Novel autoantibodies in Sjogren’s syndrome. Clin Immunol. 2012;145:251-255.

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;37:405-411.

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;37:1425-1430.

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;38:1500-1505.

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;40:179-187.