International Collaborative Clinical Alliance Research Articles

The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome

ObjectiveTo determine whether the Sjögren's syndrome B (SSB)-positive/Sjögren's syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS.MethodsAmong registrants in the Sjögren's International Collaborative Clinical Alliance (SICCA)...

Reliability of 4 Clinical Grading Systems for Corneal Staining

To determine the interobserver and intraobserver reliability of 4 clinical grading systems for corneal staining. Retrospective, observational study. One hundred twenty-two photographs of corneal erosions from variable ocular surface diseases were graded by 11 ophthalmologists. Each image was graded with 4 grading systems: the Oxford scheme, the National Eye Institute-recommended system, the area-density combination index, and the Sjögren's International Collaborative Clinical Alliance ocular staining score. Grading was repeated after 1week to evaluate repeatability. Interobserver and intraobserver reliability were evaluated using intraclass correlation coefficients (ICCs). To determine the degree of agreement based on the severity of corneal staining, the relationship between the variance and the score using each grading system was evaluated with linear regression. Interobserver reliability for the 4 grading systems was excellent, with ICCs ranging from 0.981 to0.991. The intraobserver repeatability of the 4 gradingsystems also was excellent, with ICCs ranging from 0.939 to 0.998. The National Eye Institute-recommended system showed the best reliability and repeatability. There was no definite correlation between variance and score in the Oxford scheme (Y= 0.006X+ 0.284; R(2)= 0.002) or the Sjögren's International Collaborative Clinical Alliance ocular staining score grading system (Y=-0.068X+ 0.595; R(2)= 0.109). However, there was a significant correlation between variance and score in the National Eye Institute-recommended system (Y= 0.210X+ 0.965; R(2)= 0.144) and in the area-density combination index (Y= 0.187X+ 0.279; R(2)= 0.178); the variance increased with the corneal staining score. The 4 grading systems may be usefulfor evaluation of corneal staining independent of diseaseconditions and grading individuals.

Classification criteria of Sjögren's syndrome

Sjögren's syndrome (SS) is a chronic, systemic autoimmune disease that affects typically the exocrine glands causing mucosal dryness. Dry eyes and mouth are considered by far the most common and early symptoms of the disease but systemic complications may also occur. In 1993, the preliminary European criteria were proposed and widely accepted, consisting of both subjective and objective criteria. Almost ten years later, these classification criteria were revised by introducing more stringent rules and precise diagnostic procedures leading to the currently used American-European Consensus Group (AECG) criteria. The AECG criteria have been largely employed to conduct epidemiologic and clinical studies of patients with SS and proved to be more specific compared to the preliminary European criteria. The recent American College of Rheumatology/Sjögren's International Collaborative Clinical Alliance (ACR/SICCA) criteria that are based exclusively on objective tests, the stringency of the AECG criteria and the potential therapeutic use of biologic agents in SS clearly set the need for new classification criteria. Whether the new diagnostic approach will further encompass subclinical and early forms of the disease remains to be addressed by the scientific community.

New advances in the classification, pathogenesis and treatment of Sjogren's syndrome

In the current review, we summarize the newly proposed classification criteria for Sjogren's syndrome, recent findings of Sjogren's syndrome pathogenesis and the latest achievements in disease management. A new set of Sjogren's syndrome classification criteria has been recently proposed by an expert consensus panel of the American College of Rheumatology-Sjögren's International Collaborative Clinical Alliance. Recent findings reveal new aspects in the activation of innate and adaptive immune pathways and novel animal models - highly reminiscent of human Sjogren's syndrome-are described. Of particular note, apoptosis of epithelial cells as a result of deficient IκBζ, previously shown to be a modulator of NFκB activity, has been suggested as a central pathogenetic event. Mechanistic data on anti-B-cell therapies, gene transfer approaches aimed to restore secretory function, as well mesenchymal stem cell transplantation in mice and humans are also discussed. Over the last year, a new set of classification criteria for Sjogren's syndrome has been suggested, new Sjogren's syndrome-like animal models have been described and significant progress has been made in understanding the activation of innate and adaptive immune responses. New therapeutic approaches have been also implemented with variable success.

Primary Sjogren’s Syndrome: Time for Prospective Cohorts

Many important clinical questions concerning primary Sjögren's syndrome (pSS) remain, that can only be adequately addressed by prospective cohorts. Thus, a better knowledge of the clinical outcome, the course of disease activity and the risk factors of lymphoma requires the setting up of cohorts with biobanks. The homogeneous collection of clinical data, disease activity, patient-related outcome, and biological samples, including DNA, RNA and serum, is definitively mandatory to determine new biological prognostic factors and identify disease activity markers. Three large prospective cohorts have already started to enroll patients with pSS. This will be highly invaluable for scientists and clinicians to gain a better insight into the pathogenesis of pSS, as well as to identify prognostic markers and new therapeutic targets.

Primary Sjögren's syndrome as a systemic disease: A study of participants enrolled in an International Sjögren's syndrome registry

To study the prevalence of extraglandular manifestations in primary Sjögren's syndrome (SS) among participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry. A total of 1,927 participants in the SICCA registry were studied, including 886 participants who met the 2002 American-European Consensus Group (AECG) criteria for primary SS, 830 "intermediate" cases who had some objective findings of primary SS but did not meet AECG criteria, and 211 control individuals. We studied the prevalence of immunologic and hematologic laboratory abnormalities, specific rheumatologic examination findings, and physician-confirmed thyroid, liver, and kidney disease, as well as lymphoma among SICCA participants. Laboratory abnormalities, including hematologic abnormalities, hypergammaglobulinemia, and hypocomplementemia, frequently occurred among primary SS cases and were more common among the intermediate cases than among control participants. Cutaneous vasculitis and lymphadenopathy were also more common among primary SS cases. In contrast, the frequency of physician-confirmed diagnoses of thyroid, liver, and kidney disease and lymphoma was low and only primary biliary cirrhosis was associated with primary SS case status. Rheumatologic and neurologic symptoms were common among all SICCA participants, regardless of case status. Data from the international SICCA registry support the systemic nature of primary SS, manifested primarily in terms of specific immunologic and hematologic abnormalities. The occurrence of other systemic disorders among this cohort is relatively uncommon. Previously reported associations may be more specific to select patient subgroups, such as those referred for evaluation of certain neurologic, rheumatologic, or other systemic manifestations.

American College of Rheumatology classification criteria for Sjögren's syndrome: A data‐driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance Cohort

We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American–European Consensus Group (AECG) criteria, a model-based “gold standard”obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants

To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS). The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

A Simplified Quantitative Method for Assessing Keratoconjunctivitis Sicca From the Sjögren's Syndrome International Registry

To describe, apply, and test a new ocular grading system for assessing keratoconjunctivitis sicca (KCS) using lissamine green and fluorescein. Prospective, observational, multicenter cohort study. The National Institutes of Health-funded Sjögren's Syndrome International Registry (called Sjögren's International Collaborative Clinical Alliance [SICCA]) is developing standardized classification criteria for Sjögren syndrome (SS) and is creating a biospecimen bank for future research. Eight SICCA ophthalmologists developed a new quantitative ocular grading system (SICCA ocular staining score [OSS]), and we analyzed OSS distribution among the SICCA cohort and its association with other phenotypic characteristics of SS. The SICCA cohort includes participants ranging from possibly early SS to advanced disease. Procedures include sequenced unanesthetized Schirmer test, tear break-up time, ocular surface staining, and external eye examination at the slit lamp. Using statistical analyses and proportional Venn diagrams, we examined interrelationships between abnormal OSS (>or=3) and other characteristics of SS (labial salivary gland [LSG] biopsy with focal lymphocytic sialadenitis and focus score >1 positive anti-SS A antibodies, anti-SS B antibodies, or both). Among 1208 participants, we found strong associations between abnormal OSS, positive serologic results, and positive LSG focus scores (P < .0001). Analysis of the overlapping relationships of these 3 measures defined a large group of participants who had KCS without other components of SS, representing a clinical entity distinct from the KCS associated with SS. This new method for assessing KCS will become the means for diagnosing the ocular component of SS in future classification criteria. We find 2 forms of KCS whose causes may differ.

An early view of the international Sjögren's syndrome registry.

Of the major autoimmune connective tissue diseases, Sjoren’s syndrome (SS) is perhaps the least well understood. Both primary and secondary forms of SS occur, but their phenotypes are not well defined. No less than 10 sets of diagnostic/classification criteria for SS have been applied since 1965 (1–11), but none have been universally adopted or accepted by the American College of Rheumatology. These criteria have often identified patients with similar clinical features, but not necessarily with a common disease process. There is scant longitudinal data on SS. The absence of recognized classification criteria contributes to delays in diagnosis for individual patients and hampers research into SS due to small sample sizes and heterogeneously diagnosed patient populations. To address these issues, the ongoing Sjoren’s International Collaborative Clinical Alliance (SICCA) was funded under a US National Institutes of Health contract beginning in 2003. The SICCA project has the goals of 1) designing and implementing an international SS registry for collecting and storing clinical data and biospecimens; 2) developing standardized classification/diagnostic criteria for SS that are universally applicable; and 3) providing these resources for future studies of SS funded by the NIH or comparable agencies.