干燥综合征2012ACR诊断标准

American College of Rheumatology Classification Criteria for Sjo¨gren’s Syndrome: A Data-Driven, Expert Consensus Approach in the Sjo¨gren’s International Collaborative Clinical Alliance Cohort S. C. SHIBOSKI,1 C. H. SHIBOSKI,1 L. A. CRISWELL,1 A. N. BAER,2 S. CHALLACOMBE,3 H. LANFRANCHI,4 M. SCHIØDT,5 H. UMEHARA,6 F. VIVINO,7 Y. ZHAO,8 Y. DONG,9 D. GREENSPAN,1 A. M. HEIDENREICH,4 P. HELIN,5 B. KIRKHAM,3 K. KITAGAWA,6 G. LARKIN,3 M. LI,9 T. LIETMAN,1 J. LINDEGAARD,10 N. MCNAMARA,1 K. SACK,1 P. SHIRLAW,3 S. SUGAI,6 C. VOLLENWEIDER,4 J. WHITCHER,1 A. WU,1 S. ZHANG,9 W. ZHANG,11 J. S. GREENSPAN,1 AND T. E. DANIELS,1 FOR THE SJO¨GREN’S INTERNATIONAL COLLABORATIVE CLINICAL ALLIANCE (SICCA) RESEARCH GROUPS This criteria set has been approved by the American College of Rheumatology (ACR) Board of Directors as Provisional. This signifies that the criteria set has been quantitatively validated using patient data, but it has not undergone validation based on an external data set. All ACR-approved criteria sets are expected to undergo intermittent updates. The American College of Rheumatology is an independent, professional, medical and scientific society which does not guar- antee, warrant, or endorse any commercial product or service. Objective. We propose new classification criteria for Sjo¨gren’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. Methods. Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjo¨gren’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. Results. 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. Conclusion. 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. INTRODUCTION Sjo¨gren’s syndrome (SS) is a multisystem autoimmune disease characterized by hypofunction of the salivary and lacrimal glands. It is among the group of diseases overseen by rheumatologists; however, its diagnosis and manage- ment require 3 areas of specialty practice: rheumatology, ophthalmology, and oral medicine. The multidisciplinary Supported by the NIH (National Institute for Dental and Craniofacial Research, National Eye Institute, and Office of Research on Women’s Health; contract N01-DE32636). 1S. C. Shiboski, PhD, C. H. Shiboski, DDS, MPH, PhD, L. A. Criswell, MD, MPH, DSc, D. Greenspan, BDS, DSc, ScD, T. Lietman, MD, N. McNamara, OD, PhD, K. Sack, MD, J. Whitcher, MD, MPH, A. Wu, DDS, J. S. Greenspan, BDS, PhD, FRCPath, T. E. Daniels, DDS, MS: University of Cali- fornia, San Francisco; 2A. N. Baer, MD: Johns Hopkins Uni- versity, Baltimore, Maryland; 3S. Challacombe, BDS, PhD, Arthritis Care & Research Vol. 64, No. 4, April 2012, pp 475–487 DOI 10.1002/acr.21591 © 2012, American College of Rheumatology SPECIAL ARTICLE 475 aspect of the disease represents a challenge for the defini- tion and validation of classification criteria because there is no single gold standard test for diagnosing SS, and it is not feasible to use a single clinician’s diagnosis for the case/control definition. The closest substitute is based on expert assumptions about the characteristics of SS, specifically that it: 1) is a systemic, multiorgan autoim- mune disease, 2) has a chronic or progressive course, and 3) is characterized by, but not limited to, secretory dys- function. While there have been 11 classification or diagnostic criteria published for SS since 1965 (1–11), none have been endorsed by the American College of Rheumatol- ogy (ACR) or the European League Against Rheumatism (EULAR). The American–European Consensus Group (AECG) criteria (11) have better specificity than their pre- decessor (9), as they require evidence of autoimmunity from positive anti-SSA/Ro and/or anti-SSB/La serology or focal lymphocytic sialadenitis (FLS) with a focus score (FS) �1 in a labial salivary gland (LSG) biopsy sample. However, they have been criticized for including subjec- tive tests (symptoms), physiologic measures that lack spec- ificity, and alternate objective tests that are not diagnosti- cally equivalent. For example, Schirmer’s test may be used instead of the rose bengal ocular stain, even though they differ in sensitivity and specificity (11). Further, the inclu- sion of symptoms of dry mouth and/or eyes can lead to misclassification of asymptomatic patients. In addition, physiologic measures, such as unstimulated whole sali- vary (UWS) flow, unanesthetized Schirmer’s test, and sal- ivary scintigraphy, are useful for assessment of salivary or tear function, but lack specificity for SS. The need for new classification criteria is clear consid- ering the current lack of standardization inherent to the use of multiple older criteria in the field and the emer- gence of biologic agents as potential treatments. Consider- ing the potentially serious adverse effects and comorbidi- ties of these agents, criteria used for enrollment into clinical trials will need to be clear, easy to apply, and have high specificity. They also must rely upon well-estab- lished objective tests that are clearly associated with the systemic/autoimmune, oral, and ocular characteristics of the disease, and include alternate tests only when they are diagnostically equivalent. Furthermore, it is desirable for new classification criteria for SS to be endorsed by profes- sional rheumatology organizations across the world (such as the ACR and EULAR) to increase their credibility and maximize standardization when enrolling participants into clinical trials. The Sjo¨gren’s International Collaborative Clinical Alli- ance (SICCA) is funded by the National Institutes of Health (12) to develop new classification criteria for SS, better define the SS phenotype, and collect/store clinical data and biospecimens to support future research. We propose new classification criteria for SS, following the ACR guide- lines (13) to the extent possible for a condition requiring multiple clinical specialties for diagnosis. Below we de- scribe our approach to criteria development and valida- tion. MATERIALS AND METHODS We used a consensus methodology derived from the nom- inal group technique (14) to: 1) define the target popula- tion to whom the classification criteria should apply; 2) identify the initial list of criteria components that have face validity, would be measured as part of the SICCA project, and could be considered in the classification criteria (item generation and reduction); and 3) select preliminary classification criteria. We then engaged in a series of validation exercises. Our overall approach relied on analyses of current SICCA data and consisted of 4 phases. FDSRCS, FRCPath, FMedSci, B. Kirkham, MD, FRCP, FRACP, G. Larkin, FRCoPath, P. Shirlaw, BDS, FDRCPS: King’s College London, London, UK; 4H. Lanfranchi, DDS, PhD, A. M. Heidenreich, MD, C. Vollenweider, MD: Univer- sity of Buenos Aires, Buenos Aires, Argentina; 5M. Schiødt, DDS, P. Helin, MD, PhD: Rigshospitalet, Copenhagen, Den- mark; 6H. Umehara, MD, PhD, K. Kitagawa, MD, PhD, S. Sugai, MD: Kanazawa Medical University, Ishikawa, Japan; 7F. Vivino, MD: Penn Presbyterian Medical Center and Uni- versity of Pennsylvania, Philadelphia; 8Y. Zhao, MD: PUMC Hospital, Beijing, China; 9Y. Dong, MD, M. Li, MD, S. Zhang, MD: Peking Union Medical College Hospital, Beijing, China; 10J. Lindegaard, MD, PhD: Glostrup Hospital, Glostrup, Den- mark; 11W. Zhang, MD: Chinese Academy of Medical Sci- ence and Peking Union Medical College Hospital, Beijing, China. Collaborators of the Sjo¨gren’s International Collab- orative Clinical Alliance are shown in Appendix A. Drs. S. C. Shiboski and C. H. Shiboski contributed equally to this work. Dr. Vivino has received consultant fees and/or honoraria (less than $10,000 each) from Daiichi-Sankyo and Parion Sciences. Dr. Wu owns stock and/or stock options in Isis Pharmaceuticals and Schering-Plough. Dr. J. S. Greenspan has received consultant fees (less than $10,000) from GlaxoSmithKline. Address correspondence to S. C. Shiboski, PhD, Uni- versity of California, San Francisco, Department of Epi- demiology and Biostatistics, Division of Biostatistics, 185 Berry Street, Lobby 5, Suite 5700, San Francisco, CA 94107. E-mail: steve@biostat.ucsf.edu. Submitted for publication March 31, 2011; accepted in revised form December 20, 2011. Significance & Innovations ● New classification criteria for Sjo¨gren’s syndrome are needed to better support etiologic and genetic research and therapeutic trials for this prevalent autoimmune disease. ● Criteria used for enrollment into clinical trials need to be clear, be easy to apply, and have high specificity, considering the potentially serious ad- verse effects and comorbidities of biologic agents. ● We propose classification criteria for Sjo¨gren’s syndrome that are developed from registry data collected using standardized instruments and di- agnostic tests, and are based entirely on objective measures. 476 Shiboski et al Phase 1: expert panel member selection and item gen- eration. Expert panel member selection. We first identi- fied panel members who were experts in the relevant clin- ical specialties (rheumatology, ophthalmology, or oral medicine) and constituted a heterogeneous group with respect to geographic area, sex, and seniority/level of ex- pertise. The panel included 20 experts: 7 rheumatologists, 6 ophthalmologists, and 7 experts in oral medicine. Nine members (45%) were from the US, and the rest were from 4 countries on 3 continents. All of the panel experts prac- ticed their specialty within a university-affiliated medical center. Sixteen (80%) were senior investigators at the pro- fessor level, 20% were at the associate professor level, and 40% were women. All of the investigators had been se- lected for their experience with SS within their clinical specialty and for geographic representation. Expert panel first face-to-face meeting: review of evi- dence-based literature and item generation. In February 2004, the panel of experts gathered for a face-to-face meet- ing moderated by a statistician (SCS) and an epidemiolo- gist (CHS). The goal of this meeting was to obtain consen- sus (at least 80%) on the target population to whom the classification criteria would apply, and the initial list of variables or criteria items that would be collected as part of SICCA. The meeting began with presentation of a compre- hensive literature review by one of the senior investigators (TED) of the 11 previous classification and diagnostic cri- teria for SS that had been published in the past 40 years, none of which had been endorsed by the ACR or EULAR. There was consensus among the panel that the criteria should apply to the population of patients who may be referred to a specialist because of signs and/or symptoms possibly suggesting SS. Recruitment strategies and eligi- bility criteria are described below. The rationale for select- ing this target population is that a given patient would not be evaluated for SS unless she/he had signs or symptoms suggesting this diagnosis. There was also consensus that if asked to select cases and controls for validation of new classification criteria, panel members would use objective tests (e.g., specific serum measures of autoimmunity, ocu- lar staining reflecting lacrimal hypofunction, and LSG bi- opsy reflecting FLS) that would likely be part of the new classification criteria, leading to circularity. Therefore, it was agreed that no diagnostic labels would be used for enrollment, and that all of the participants would undergo the same set of standardized objective tests and question- naires capturing various signs and symptoms. The panel agreed upon the examinations and tests used to assess ocular and oral signs and symptoms, tear and salivary function, LSG biopsy results, and various serum measures of autoimmunity. The list created was based both on published results and on the clinical experience of panel members. There was discussion among the rheuma- tologists regarding which extraglandular manifestations possibly associated with SS should be captured, and con- sensus was achieved regarding a list of signs/symptoms that would be measured through a targeted rheumatologic examination, review of systems, careful medical history, and serologic laboratory measures. Similarly, the oral medicine specialists agreed on a list of tests measuring salivary function (both stimulated parotid and UWS flow rates) and salivary gland expression of autoimmunity through biopsy of LSG, examining them for the presence of FLS, and measuring FS accordingly as described in detail elsewhere (15). The ophthalmologists agreed on tests eval- uating participants for the presence of keratoconjunctivitis sicca (KCS). There was consensus that, while rose bengal had been widely used for grading conjunctival and corneal damage in patients with KCS, it is inherently toxic to epithelial cells and very painful for patients. Therefore, fluorescein was selected to grade the cornea and lissamine green was selected to grade the bulbar conjunctiva. Effec- tiveness for grading KCS is established for both (16). They agreed on a standardized quantitative grading system that would be easily reproducible and could be used in clinical practice in the future (17). The ocular staining score (OSS) is the sum of a 0–6 score for fluorescein staining of the cornea and a 0–3 score for lissamine green staining of both the nasal and temporal bulbar conjunctivae, yielding a total score ranging from 0–12. Alternative established tests for dryness used in prior criteria, such as tear breakup time (TBUT) and unanesthetized Schirmer’s test, were also included. The final list of criteria items that was agreed upon by the end of the first meeting included nearly all those pre- viously reported in the relevant literature. It has been described previously (12) and is available online at http:// sicca.ucsf.edu. Phase 2: item reduction. Expert panel second face-to- face meeting: review of preliminary SICCA data analyses. Following 2 years of standardized data collection, includ- ing the criteria components selected in phase 1, another face-to-face panel meeting was convened in April 2006. Data analysis summaries were presented to the group by the epidemiologist and statistician who moderated the initial meeting, and the panel was divided into small spe- cialty-specific focus groups to review evidence-based re- sults for each clinical specialty. The goals of these explor- atory analyses included understanding the relationship between variables representing the oral/salivary, ocular, and systemic features of the disease; defining cutoff values for particular tests that could be used as components of the classification criteria; and assessing the value of tests that could serve as surrogates for primary objective tests in alternate criteria sets. Methods used included frequency tables, binary regression, and classification trees. We also used area-proportional Venn diagrams to visualize the overlapping relationships of 3 variables simultaneously, each representing one of the primary disease features (18). Phase 3: candidate SS criteria. Expert panel third face- to-face meeting: data-driven, consensus-based selection of preliminary classification criteria for SS. The panel met in May 2009 to decide on preliminary classification criteria. Additional analyses were presented, including longitudi- nal assessment of the stability of criteria components over time (based on results from scheduled 2-year followup visits that mirrored baseline assessments). Results from a statistical classification based on latent class analysis (LCA) (19) were presented (approach further described New Classification Criteria for Sjo¨gren’s Syndrome 477 below). The data presented to the panel represented a subset of participants (n � 1,107) consecutively enrolled as of April 1, 2009. Following presentation of results by the statistician, a discussion among panel members was moderated by the epidemiologist and statistician. The goal of the discussion was for members to select, based on their understanding of the data analyses presented and on their clinical experi- ence, which objective test(s) they believed was/were the most specific for SS within their own specialty. Further- more, various preliminary classification criteria were dis- cussed, and panel members were asked to select which criteria they believed would best classify patients with SS. Following this third face-to-face meeting, a report summa- rizing the data analyses was circulated among the panel members and a questionnaire was distributed by e-mail. The questionnaire was designed to assess consensus among the expert panel members regarding the prelimi- nary classification criteria. It also measured the level of consensus within each specialty regarding which criteria component was thought to have the highest level of face validity within that specialty. The response to each ques- tion was on a scale of 1–5, with 1 indicating strong dis- agreement and 5 indicating strong agreement. SICCA registry cohort. The participants in the SICCA cohort have been enrolled since 2004 in 5 collaborating academically-based research groups, located in Argentina, China, Denmark, Japan, and the US, and directed from the University of California, San Francisco (12) (Table 1). Sub- sequently, additional research groups joined the SICCA project: in 2007 from the UK and in 2009 from India and 2 additional sites in the US. To be eligible for the SICCA registry, participants must be at least 21 years of age and have at least 1 of the following: symptoms of dry eyes or dry mouth; a previous suspicion or diagnosis of SS; elevated serum antinuclear antibody (ANA) titer, positive rheumatoid factor (RF), or anti-SSA and/or anti-SSB; bilateral parotid enlargement in a clinical setting of SS; a recent increase in dental caries; or diagnoses of rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and any of the above. The rationale for these eligibility criteria is that only patients with such characteristics would be evaluated for SS or considered for enrollment in a clinical trial designed to evaluate a poten- tial therapeutic agent for SS. Therefore, our classification criteria target individuals with signs and symptoms that may be suggestive of SS, not the general population. Participants are recruited through local or national SS patient support groups, health care providers, public me- dia, and populations served by all 9 SICCA research groups. Exclusion criteria include known diagnoses of hepatitis C, human immunod