In this paper, we describe the OSS, a new quantitative simplified method of grading KCS in patients with primary Sjögren's syndrome. Previous grading systems have been simplified, standardized, and combined to produce the OSS, which is then subjected to validation by non-ocular data collected from patients with primary Sjögren's syndrome or its partial phenotype. With 1208 participants as of September 15, 2008, the SICCA Registry is a large, and ethnically and geographically diverse, ongoing cohort of women and men with suspected Sjögren's syndrome. Most of the participants (85%) reported symptoms of dry eyes, and among those, nearly half reported having these symptoms for more than 5 years. An unexpected finding was the high number of participants (n = 323) with objective clinical signs of KCS in the absence of any other phenotypic features of Sjögren's syndrome while 510 participants () had KCS together with at least one of the two other main phenotypic features of Sjögren's syndrome (focal lymphocytic sialadenitis with a focus score > 1 and/or a positive serology to anti-SS-A or B antibodies). The presence of clinical KCS in the absence of any other phenotypic features of Sjögren's syndrome (and without any associated lid or conjunctival disease) represents an interesting and unexpected finding that will require additional study.
One of the primary goals of the SICCA Registry is to establish standardized classification criteria for the diagnosis of Sjögren's syndrome. For the eye, this entails developing a KCS grading scheme that is simple, quantitative, reproducible, and straight forward enough to be universally adopted by eye care providers. A unique innovation of the OSS is the use of two different vital dyes to grade different areas of the ocular surface: fluorescein to grade the cornea and lissamine green to grade the bulbar conjunctiva. Previous grading schemes have used rose Bengal or lissamine green exclusively to grade both the cornea and the conjunctiva. While both of these dyes primarily stain goblet cells, keratinized epithelial cells, and devitalized cells, rose Bengal has been the dye of choice for grading conjunctival damage in patients with KCS. Interestingly, rose Bengal is not a true vital dye and is inherently toxic to epithelial cells. This is especially true in KCS where the protective function of the preocular tear film is disrupted12
and the dye becomes so irritating that many investigators recommend prior instillation of a topical anesthetic.9
This is in direct contrast to lissamine green; a true, non-irritating vital dye.13
Fluorescein is also nontoxic, nonirritating and is the most useful dye for staining the precorneal tear film and those areas of the cornea where the epithelium is absent or eroded.14
Under cobalt blue illumination, fluorescein is extraordinarily sensitive in delineating individual epithelial cell loss and PEE. We used a solution of 0.5% because it routinely produces the most reliable corneal staining pattern during the four to eight minute time interval following instillation.
To develop a quantitative, reproducible and reliable KCS grading system, we used a modification of the Oxford grading scheme proposed by Bron, et al in 2003.9
By quantitatively grading both the cornea and bulbar conjunctiva, and giving equal weight to clinical findings in both areas, the OSS provides a simplified, non-irritating, quantitative grading system that is easily applicable to clinical practice without the need for specialized equipment other than a slit lamp. Its reliability was confirmed by the observation that 80% of participants in the study had an OSS with a difference between the two eyes of 1 or less, while both the TBUT and Schirmer tests had skewed distributions with a higher variability between the two eyes. While Vesura, et al.15,16
promotes using a combination of tests to diagnose KCS, he also acknowledges that the ocular staining pattern with lissamine green is unquestionably of greatest importance. The SICCA study confirms this assertion and promotes the OSS as the key ocular diagnostic parameter for KCS.
Even with the development of the OSS, the diagnosis of Sjögren's syndrome remains problematic. Sjögren's syndrome is defined as an autoimmune exocrinopathy characterized by lymphoid infiltration and functional deterioration of exocrine glands, especially of lachrymal and salivary glands. Sjögren's syndrome may develop in the absence (primary SS) or in the presence (secondary SS) of another autoimmune disease.17
Although the true incidence is not known, the diagnosis of primary SS by primary care physicians in a defined population has been reported to be as infrequent as 4 per 100,000.18
This figure is undoubtedly low because it is based on a core of patients with primary SS in a community setting rather than on a case detection survey where there are well-established lines of referral. Higher physician awareness and simplified classification criteria for primary SS would lead to more frequent identification and less misclassification of cases in the population.19
Paradoxically, KCS is one of the most frequently made diagnoses in an ophthalmic practice. Studies indicate that up to 20% of adults aged 45 or older experience dry eye symptoms in varying degrees of severity.20
This disparity between the large number of symptomatic patients who are being diagnosed with KCS and the relatively small number of patients with primary SS has never been explained.21
With this in mind, an intriguing finding of the SICCA study to date is the documentation of two different forms of KCS. Over the course of study, a group of KCS patients emerged that have all of the ocular diagnostic parameters, but none of the non-ocular characteristics of Sjögren's syndrome (KCS-only). The surprising size of this group (323 of 920 patients or 35 %) is best appreciated in the proportional Venn diagram (), where overlapping areas are exactly proportional to the number of patients with the specified characteristics. The lower “bulge” in the diagram represents the large number of patients who have KCS as confirmed by a positive OSS and supported by decreased TBUT and low Schirmer values, but who do not have abnormal LSG focus scores and/or a positive serology for anti-SS-A and/or B antibodies. The “bulge” does not change substantially in size (260 of 857 patients or 30%) when the OSS grade is raised from 3 to 4 (). The other group, consisting of individuals with a positive OSS and at least one of the two other diagnostic characteristics for SS also remains stable when the OSS changes from 3 to 4. Further comparison of the two groups reveals that they have several different characteristics that are statistically significant ( and ). For example, those with KCS-only had significantly higher scores for other ocular tests commonly used in the evaluation of Sjögren's syndrome (Schirmer test and TBUT), as well as greater unstimulated whole saliva flow rates. They had significantly lower levels of specific markers of autoimmunity (e.g., rheumatoid factor, ANA, and IgG), were significantly older, more likely to be current smokers and more likely to be taking anti-cholinergic medications. Yet, there was no difference between the KCS-only and SS-KCS groups with respect to dry-eye or dry-mouth symptoms, duration of dry-eye symptoms, or presence of specific diseases of the lids and conjunctiva (e.g., blepharitis and meibomitis). These findings suggest that KCS-only and SS-KCS may represents separate clinical entities with clear characteristic differences between the two patient populations.
For decades ophthalmologists have acknowledged anecdotally that a form of KCS exists that is not related to Sjögren's syndrome and for which there is no obvious biological explanation. In a long-term follow up study, Kruize, et al17
alluded to this form of isolated KCS but did not fully characterize the small group of patients. It was noted, however, that none of the patients with isolated KCS or secondary SS developed lymphoproliferative disease over a 10 to 12 year period, while 10% of the primary SS patients died of lymphoma. This suggests that patients with isolated KCS represent a distinct clinical population that is much more common and milder than SS-KCS and likely accounts for the majority of dry eye patients seen in ophthalmic practices. The authors of the NEI-sponsored DEWS (Dry Eye Workshop) Reports22, 23
in 2007 also discussed this clinical entity, calling it non-Sjögren's syndrome (NSS) KCS, but data were not presented. The only way to prove that these “NSS-KCS” patients do not eventually develop SS-KCS is to follow them over time. The SICCA Registry provides the opportunity to follow these patients over time and to answer the following questions: 1) do patients with KCS-only eventually convert to SS-KCS on follow up? 2) do both forms become clinically worse over time? or 3) do two distinct disease processes exist that follow different courses and ultimately have different outcomes?
In the process of developing the OSS for the purpose of establishing new universal classification criteria for the diagnosis of SS, we have identified a large subset of dry eye patients, who have clinical characteristics that are distinctly different from those patients with SS-KCS. The underlying cause of this condition is at present unknown and represents a new and interesting area for future study that we hope to investigate with the large data base that is currently being collected as part of the SICCA Registry.