Clinical Practice Guidelines for Oral Management of Sjogren Disease

PRACTICE GUIDELINES

Clinical practice guidelines for oral management of Sjögren disease Dental caries prevention

Domenick T. Zero, DDS, MS; Michael T. Brennan, DDS, MHS; ABSTRACT Troy E. Daniels, DDS, MS; Athena Papas, DMD, PhD; Carol Stewart, DDS, MS; Andres Pinto, DMD, MPH, MSCE; Background. Salivary dysfunction in Sjögren disease can Ibtisam Al-Hashimi, BDS, MS, PhD; Mahvash Navazesh, lead to serious and costly oral health complications. Clin- DMD; Nelson Rhodus, DMD, MPH; James Sciubba, DMD, ical practice guidelines for caries prevention in Sjögren PhD; Mabi Singh, DMD, MS; Ava J. Wu, DDS; disease were developed to improve quality and consistency Julie Frantsve-Hawley, RDH, PhD; Sharon Tracy, PhD; of care. Philip C. Fox, DDS; Theresa Lawrence Ford, MD; Methods. A national panel of experts devised clinical Stephen Cohen, OD; Frederick B. Vivino, MD, MS; questions in a Population, Intervention, Comparison, Katherine M. Hammitt, MA; for the Sjögren’s Syndrome Outcomes format and included use of fluoride, salivary Foundation Clinical Practice Guidelines Committee stimulants, antimicrobial agents, and nonfluoride remineralizing agents. The panel conducted a systematic search of the literature according to pre-established parameters. alivary dysfunction can have serious adverse At least 2 members extracted the data, and the panel rated effects on the oral health of patients with Sjögren the strength of the recommendations by using a variation disease (formerly known as Sjögren syndrome), of grading of recommendations, assessment, development, making it paramount that the oral clinician uses and evaluation. After a Delphi consensus panel was con- S ducted, the experts finalized the recommendations, with a every means possible to prevent complications. Patients with Sjögren disease have significantly higher levels of minimum of 75% agreement required. dental caries, require more tooth extractions, and report Results. Final recommendations for patients with higher dental expenses over their lifetime than do con- Sjögren disease with dry mouth were as follows: topical 1 fluoride should be used in all patients (strong); although no trols. Sjögren disease fl clearly is associated study results link improved salivary ow to caries preven- with a high burden tion, the oral health community generally accepts that of disease, including increasing saliva may contribute to decreased caries inci- 2 5 diminished quality of life - and increased health care dence, so increasing saliva through gustatory, masticatory, 5 7 5 costs, - especially high dental care costs. or pharmaceutical stimulation may be considered (weak); chlorhexidine administered as varnish, gel, or rinse may be Sjögren disease is the second most common auto- fl immune connective tissue disease, affecting up to 3.1 considered (weak); and non uoride remineralizing agents million Americans according to the National Arthritis may be considered as an adjunct therapy (moderate). 8 Data Workgroup, or approximately 1 in 70 people. This Conclusions and Practical Implications. The incidence of caries in patients with Sjögren disease can be number represents those with Sjögren disease alone fl (traditionally referred to as primary Sjögren disease); the reduced with the use of topical uoride and other pre- number affected approximately doubles if those with ventive strategies. Key Words. Sjögren syndrome; xerostomia; practice another major autoimmune or rheumatic disease in fl fl addition to Sjögren disease are included. Although guidelines; uoride; antimicrobial; salivary ow; remineralization. JADA 2016:-(-):--- http://dx.doi.org/10.1016/j.adaj.2015.11.008 Copyright ª 2016 American Dental Association. All rights reserved.

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Sjögren disease is a systemic disease and can affect any of this article). At least 2 TRG members extracted the body organ or system, dry mouth and dry eyes are chief data, and the TRG as a whole rated the strength of the 4 9 symptoms. , Sjögren disease causes chronic inflam- evidence, developed a draft recommendation, and rated mation and dysfunction and, ultimately, damages the the strength of the recommendation. We based grading salivary glands. of the evidence and strength of the recommendation The Sjögren’s Syndrome Foundation (SSF) set about largely on grading of recommendations, assessment, 15 establishing the first-ever clinical practice guidelines for development, and evaluation, which rates the quality Sjögren disease to improve consistency and quality of of the evidence on the basis of study limitations, care for assessing and managing the disease. It is critical inconsistency of results, indirectness of evidence, for oral health care professionals to identify patients imprecision, and publication bias (very low quality potentially having Sjögren disease and ensure that they to high quality). We rated the strength of the recom- obtain a correct diagnosis and start appropriate man- mendation on the basis of quality of evidence, balance agement to prevent caries. Care must be coordinated by a of benefits and harms, values and preferences, and costs team of health care professionals that includes a dentist, (strong or weak both for and against). For the strength rheumatologist, and ocular specialist. The SSF clinical of the recommendation, we used a variation of grading practice guidelines for caries prevention address clinical of recommendations, assessment, development, and questions pertaining to the use of fluoride, salivary evaluation that was developed by the American Society 16 stimulants, antimicrobial agents, and nonfluoride remi- of Clinical Oncology. (Appendix 4 provides defini- neralizing agents. tions used for the strength recommendations, and Appendix 5 provides the guidelines statement regarding METHODS decision on grading the quality of evidence; available The SSF followed a highly transparent and rigorous online at the end of this article). process in developing clinical practice guidelines. We followed a Delphi-type process to ascertain level Guideline protocols and principles were based on those of agreement from practitioners and other stakeholders defined by the American College of Rheumatology, the before finalizing recommendations. The TRGs sum- Institute of Medicine, and the Appraisal of Guidelines marized the data and rationale for the recommenda- for Research and Evaluation and involved participation tions they drafted, and we provided these documents by the American Dental Association (ADA) evidence- (Appendix 6, available online at the end of this article, 10 13 based dentistry staff. - Overarching methodological provides clinical rationales and evidence summaries), principles were transparency, involvement of key stake- the data extraction tables, and a summary outlining holders, and consistency. All participants completed the process to the consensus expert panel (CEP) that American College of Rheumatology conflict of interest reviewed the recommendations. The CEP, made up forms. of key stakeholders (listed in Appendix 7,available Methodological process. We established topic review online at the end of this article), voted on each groups (TRGs) for each caries prevention topic. To recommendation by using a 6-point Likert scale with reduce bias as much as possible, we predefined all the following ratings: completely agree, mostly agree, methodology elements, starting with completion of slightly agree, slightly disagree, mostly disagree, and guidelines protocol worksheets (Appendix 1, available completely disagree. Forty-two to 45 CEP members online at the end of this article) for each TRG that voted and added comments for TRG consideration. delineated clinical questions in the patient population, A minimum of 75% agreement was required and clearly intervention, comparison, outcome format and defined met with 1 round of voting for each topic. However, parameters for literature searches and data extraction for because of comments received on the strength of the all selected articles. The ADA conducted a systematic recommendation on fluoride, a second round of literature search by using predetermined terms and pa- consensuswasheldforthisspecific question, leading rameters. A minimum of 2 TRG members reviewed all to CEP agreement to increase the level for the abstracts and selected articles for further review. See the strength of the recommendation. Participants included Preferred Reporting Items for Systematic Reviews and dentists and dental hygienists from academia and 14 Meta-Analyses flow diagrams, Figures 1 through 4, for community practice, oral medicine experts, clinical literature search details; Appendix 2 (available online at researchers, and patientswithSjögrendisease. the end of this article) provides search terms. An ADA guidelines expert and librarian (S.T.) executed the systematic literature search. We prepared data extraction tables that included ABBREVIATION KEY. ADA: American Dental Association. details on study characteristics, sample and disease CD-CP: Casein derivative and calcium phosphate. information, evidence, and study quality for each CEP: Consensus expert panel. SSF: Sjögren’s Syndrome publication (Appendix 3, available online at the end Foundation. TRG: Topic review group.

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Records identified through searching Additional records identified through MEDLINE, PubMed, and Cochrane Library— updated literature search on first search executed March 20, 2013, April 21, 2015 and going back to January 1, 1960 (n = 26) (n = 122) Identification

Abstracts after duplicates removed (n = 136)

Required Parameters for Study Design Abstracts Records excluded • Meta-analyses, systematic

Screening (n = 136) (n = 123) reviews, randomized controlled trials (ideal); cohort and case-control studies • Minimum of 12 months' Full-text articles assessed for eligibility duration (less duration Full-text articles excluded, (n = 25) acceptable for pilocarpine with reasons Reduced after thorough hydrochloride and (n = 2) cevimeline trials) review Eligibility • Primary outcomes: reduction (n = 13) in the incidence, arrest, or reversal of coronal or root Required Parameters for caries Literature Search • Assessed for reproducible Studies deemed • English language only methodology, adequate acceptable and data • Patients: randomization, concealed extracted for full 18 years and older allocation, sufficient sample analysis and Any sex, race, ethnicity, and Included size, comparable groups, grading of the evidence menopausal status validated and reliable (n = 11) Diagnosed with primary Sjögren measures, adequate follow- disease according to any up, appropriate analyses, published criteria accurate results, and Flow rates consistent with nonsignificant conflicts of xerostomia from any cause interest and risk of bias • Interventional agent: fluoride

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses ﬂow diagram: ﬂuoride topic review group. Source: Moher and colleagues.14

Appendix 8 (available online at the end of this article) disease with xerostomia to inform discussions better. provides the CEP votes. Finally, the lack of consistency in outcome measures and the way they were assessed made comparison of the CHALLENGES studies difficult. Numerous challenges existed in the development of the CLINICAL QUESTIONS AND RECOMMENDATIONS recommendations. The dearth of studies meeting pre- The table presents clinical (population, intervention, selected criteria meant there were few available studies comparison, outcome) questions, recommendations for to inform the committee. The oral working group caries prevention in patients with Sjögren disease, and accepted any published criteria for diagnosing Sjögren the strength of each recommendation. disease, meaning that comparing study populations was difficult because diagnosis was made according CLINICAL RATIONALES AND EVIDENCE SUMMARIES to different clinical or classification criteria. The TRGs View the full clinical rationale and evidence sum- considered studies involving patients without Sjögren maries for all topic areas provided to the CEPs

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Abstracts after duplicates removed (n = 136)

Required Parameters for Study Design

Screening Abstracts Records excluded • See Figure 1 for study design (n = 136) (n = 136) parameters

In addition: • Interventional agent: any salivary stimulation agent Full-text articles assessed for eligibility (n = 0) Eligibility

Studies deemed Required Parameters for acceptable and data Literature Search extracted for full • English language only analysis and • Patients: Included grading of the evidence 18 years and older (n = 0) Any sex, race, ethnicity, and menopausal status Diagnosed with primary Sjögren disease according to any published criteria Flow rates consistent with xerostomia from any cause

Figure 2. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram: salivary stimulation topic review group. Source: Moher and colleagues.14 in Appendix 6 (available online at the end of this provided with fluoride products. In the studies from article). which we extracted data, most used fluoride daily. A review of all 136 abstracts found in the systematic FLUORIDE literature review led to the final selection of 13 studies Although evidence is greatly limited on the effectiveness that we determined to be relevant to the clinical question of any intervention available to manage dry mouth, more and that also met the preset study parameters. Despite evidence exists to encourage use of topical fluoride in the high number of studies available, the evidence for patients with dry mouth than any other tool available. fluoride use is weak because investigators in only 1 17 Therefore, the TRG recommends the use of topical study of the 13 looked specifically at patients with fluoride as a first line of defense in patients with Sjögren Sjögren disease. Investigators in 9 studies focused on 18 26 disease who have dry mouth. The TRG declined to make patients undergoing head and neck radiation - and 27 29 a recommendation about preferred topical fluorides or in 3 on other causes of dry mouth. - frequency of use because of lack of evidence. The latter The only study including patients with Sjögren disease 17 also would depend on the types (brush on, gel, rinse, or was published by Hay and Thomson in 2002. In the varnish) of fluoride used and individual assessment for trial, they compared the effectiveness of casein derivative caries risk; a baseline recommendation already is and calcium phosphate (CD-CP) with sodium fluoride in

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Abstracts after duplicates removed (n = 136)

Required Parameters for Study Design

Screening Abstracts Records excluded • See Figure 1 for study design (n = 136) (n = 127) parameters

In addition: • Secondary outcome measures were added for Full-text articles assessed Full-text articles excluded, decreased Streptococcus for eligibility with reasons (n = 9) (n = 6)

Eligibility mutans, lactobacilli, and plaque, and increased unstimulated whole salivary flow rates • Interventional agent: Studies deemed Required Parameters for chlorhexidine acceptable and data Literature Search extracted for full • English language only analysis and • Patients: Included grading of the evidence 18 years and older (n = 3) Any sex, race, ethnicity, and menopausal status Diagnosed with primary Sjögren disease according to any published criteria Flow rates consistent with xerostomia from any cause

Figure 3. Preferred Reporting Items for Systematic Reviews and Meta-Analyses ﬂow diagram: antimicrobial agents topic review group. Source: Moher and colleagues.14

138 patients with dry mouth, 56 from Sjögren disease and standards, this seminal study brought widespread 82 from radiation therapy. They assessed coronal and recognition of the importance of fluoride. Investi- root caries as primary outcomes, and follow-up data gators in 3 additional studies in patients undergoing 19 21 collection took place 1 year later. They did not specify head and neck radiation - concluded that fluoride diagnostic criteria for Sjögren disease, and results were was beneficial for caries prevention; all were rated of not statistically significant, although the caries incidence moderate quality with intermediate risk of bias. Three was slightly lower in the CD-CP group. The TRG remaining studies were deemed of weak quality with 22 24 designated the study quality as moderate with an inter- high risk of bias. - mediate risk of bias. Three additional studies involved patients with 18 Dreizen and colleagues were the first to demon- xerostomia from other causes, including those with 27 strate that patients with xerostomia due to head and medication-induced xerostomia, elderly people who 28 neck radiotherapy could prevent caries with daily use were institutionalized, and patients with unclassified 29 of topical fluoride gel. The profound benefitofusing xerostomia. The first 2 studies were rated of moderate fluoride was evident whether the patient followed a quality and intermediate risk of bias and the third of weak cariogenic diet or not. Although determined to be quality with high risk of bias. Results from all 3 showed of weak quality with high risk of bias by today’s fluoride beneficial.

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Abstracts after duplicates removed (n = 136)

Required Parameters for Study Design

Screening Abstracts Records excluded • See Figure 1 for study design (n = 136) (n = 113) parameters

In addition: • Secondary outcome measures were added for Full-text articles assessed Full-text articles excluded, decreased Streptococcus for eligibility with reasons (n = 23) (n = 21)

Eligibility mutans, lactobacilli, and plaque, and increased unstimulated whole salivary flow rates • Interventional agent: Studies deemed Required Parameters for nonfluoride remineralizing acceptable and data Literature Search agents extracted for full • English language only analysis and • Patients: Included grading of the evidence 18 years and older (n = 2) Any sex, race, ethnicity, and menopausal status Diagnosed with primary Sjögren disease according to any published criteria Flow rates consistent with xerostomia from any cause

Figure 4. Preferred Reporting Items for Systematic Reviews and Meta-Analyses ﬂow diagram: nonﬂuoride remineralization topic review group. Source: Moher and colleagues.14

We included 2 studies for data extraction and discus- of its 8-month duration, it provides some evidence for sion, but we did not include them in the final selection for the use of high fluoride concentration toothpaste in an 25 evidence. We did not include the Papas and colleagues elderly population, some of whom had oral dryness. article from 1999 because it was underpowered and an Fluoride: strength of the recommendation. The interim analysis, and the TRG included the final results TRG originally rated the strength of the recommenda- 19 later published as Papas and colleagues in 2008.The tion as moderate. While acknowledging that evidence is second study the TRG eliminated (Al-Joburi and col- weak, the TRG also recognized that more evidence exists 26 leagues ) was rated as low quality with high risk of bias, demonstrating the benefitoffluoride in patients with dry and the TRG noted that the test product currently is not mouth than any other intervention. Accordingly, the marketed and is of little value to the clinician. TRG upgraded the strength of the recommendation to We identified 1 study after an updated literature strong on the basis of CEP comments and TRG high search conducted April 21, 2015. This study involved confidence that the recommendation reflects best prac- elderly people with disabilities living in nursing homes tice on the basis of the following: good evidence exists for 30 (Ekstrand and colleagues ). Although this study was not a true net effect (that is, benefits exceed harms) for included in developing the fluoride recommendation and fluoride use in dry mouth, the compelling consideration does not meet the predefined inclusion criteria because that expert experience and studies outside of Sjögren

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disease indicate that fluo- TABLE ride is highly effective in Clinical questions and recommendations for caries preventing caries in dry mouth, and the extent of prevention. agreement by the TRG TOPIC AREA CLINICAL QUESTIONS AND RECOMMENDATIONS STRENGTH OF and CEP that the recom- RECOMMENDATION mendation meets the SSF’s Fluoride Clinical Questions: Strong - In patients with primary Sjögren disease, does the use of a topical clinical practice guidelines fluoride compared with no topical fluoride reduce the incidence, definition for making a arrest, or reverse coronal or root caries? strong recommendation. - In patients with primary Sjögren disease, is one topical fluoride agent more effective than another in reducing the incidence, arresting, or reversing coronal or root caries? (No information SALIVARY STIMULATION available to answer the second question.) Reduction in salivary Recommendation: Topical fluoride should be used in patients gland function, lack with Sjögren disease with dry mouth. of oral clearance, and Salivary Clinical Question: Weak Stimulation - In patients with Sjögren disease, does stimulating saliva flow reduced amounts of compared with not stimulating saliva flow reduce the incidence, bioavailable calcium and arrest, or reverse coronal or root caries? phosphate place patients Recommendation: Although no studies to date link improved salivary function in patients with Sjögren disease to caries with Sjögren disease at prevention, the oral health community generally understands increased risk of demin- that increasing saliva may contribute to decreased caries eralization of teeth and incidence. On the basis of its expert opinion, the topic review group recommends that patients with Sjögren disease with development of dental dry mouth increase saliva through gustatory or masticatory caries and erosion. stimulation and pharmaceutical agents—for example, sugar-free Reduction in salivary lozenges or chewing gum, xylitol, mannitol, and the prescription medications pilocarpine hydrochloride and cevimeline. output is regarded as a Antimicrobial Clinical Question: Weak key component of any Agents - In patients with primary Sjögren disease, does the use of anti- comprehensive assess- microbial agents compared with placebo reduce the incidence, ment for caries risk arrest, or reverse coronal or root caries? 31 Recommendation: Chlorhexidine administered as varnish, gel, assessment. or rinse may be considered in patients with Sjögren disease Salivary stimulation: with dry mouth and a high root caries rate. strength of the recom- Nonfluoride Clinical Questions: Moderate mendation. Of 136 unique Remineralizing - In patients with Sjögren disease, does the use of nonfluoride Agents remineralization agents compared with placebo reduce the inci- articles found in the liter- dence, arrest, or reverse coronal or root caries? ature review, the salivary - In patients with Sjögren disease, does the use of nonfluoride stimulation TRG found remineralization agents compared with the use of fluoride reduce the incidence, arrest, or reverse coronal or root caries? (Insufficient none that addressed its information available to answer the second question.) clinical question. As a Recommendation: Nonfluoride remineralizing agents may be result, the strength of the considered as an adjunct therapy in patients with Sjögren recommendation was disease with dry mouth and a high root caries rate. rated as weak. CEP members noted, however, that salivary stimulation for caries prevention in patients with to 3. None of these studies involved patients with Sjögren Sjögren disease with dry mouth is accepted widely and disease as the study population. should be recognized as a core therapeutic measure on the Results of the first study, a multicenter randomized 32 basis of strong anecdotal evidence and clinical experience. clinical trial, indicated that both root caries and total caries were reduced significantly in the chlorhexidine ANTIMICROBIAL AGENTS group compared with placebo. Coronal caries also were In addition to the decline in salivary flow rate, changes in reduced, but the difference between the 2 groups did not the composition of saliva alter its antimicrobial proper- reach statistical significance. The investigators reported ties and lead to an accumulation of oral pathogens, no significant differences in caries increment between the resulting in severe tooth decay and tooth loss, even with chlorhexidine and placebo groups, a finding attributed to proper oral hygiene. After reviewing 136 abstracts, we unanticipated antimicrobial properties of the placebo selected for data extraction 9 studies in which the in- treatment. vestigators examined the efficacy of antimicrobial agents. Investigators in a second randomized controlled 28 A subsequent decision to restrict the intervention agent trial examined the efficacy of chlorhexidine-thymol to chlorhexidine reduced the number of relevant studies varnish in a sample of 102 frail elderly patients with root

JADA -(-) http://jada.ada.org - 2016 7 PRACTICE GUIDELINES caries. Caries lesions in the placebo group increased predetermined criteria for determining the efficacy of significantly and were significantly closer to the gingival nonfluoride remineralizing agents. Investigators in 1 margin compared with baseline, but clinical severity of study addressed the clinical question of comparing lesions in the test group remained unchanged. The third nonfluoride remineralizing agents versus fluoride; no 33 study was a short-term randomized controlled trial study investigators examined nonfluoride remineralizing with results that indicated that, although a significant agents versus placebo. arrest of caries occurred in both groups, the addition The first study, a randomized but open-label clinical 17 of chlorhexidine did not enhance the effectiveness of trial, already has been described in the section con- the fluoride rinse alone. cerning fluoride. The results were not statistically sig- 34 The TRG declined to include a fourth study in nificant, although the incidence of coronal caries was developing its recommendation. Although the in- slightly lower in the CD-CP group. The study investigators in this study reported that chlorhexidine gel vestigators concluded that use of CD-CP might hold in trays was superior to polishing teeth with chlorhexi- promise in reducing caries in patients with dry mouth. 38 dine in reducing the prevalence of Streptococcus mutans The second study was a retrospective cohort study. in patients with xerostomia—a topic of interest as a Patients used a saturated calcium phosphate rinse 3 or secondary outcome—the investigators did not use 4 times a day with sodium fluoride (1.1%sodiumfluoride) at carious lesions (the TRG’s primary outcome) as an night. The 134 patients included those with Sjögren disease, end point. We extracted data for 5 additional studies those with medically induced xerostomia, and those un- not used in the final selection for evidence because the dergoing head and neck radiation. Although fluoride use 19 25 27 35 36 required primary outcome was not used. , , , , presented a confounding factor, the TRG noted that the use 37 An additional study by Wyatt and colleagues of prescription-strength fluoride in addition to the calcium discovered after the literature search and CEP voting phosphate rinse was significantly more beneficial. has been added to the evidence summary. In this ran- We did not include xylitol-containing products in the domized controlled trial, the investigators concluded that literature search because they were just coming into use no substantial effect on the preservation of sound tooth when the guidelines initiative started. Only weak evi- 39 43 structure in older adults resulted from use of a 0.12% dence exists for its use in caries prevention. - In their 43 chlorhexidine rinse. The study should be recognized, 2015 Cochrane review, Riley and colleagues confirmed but did not change the recommendation and, in fact, the weak evidence for xylitol but stated that fluoridated confirmed the strength of the recommendation. toothpaste with xylitol appeared to be more effective Chlorhexidine: side effects. Chlorhexidine mouth- than toothpaste with fluoride alone in preventing caries rinse has a number of side effects, the most common in the permanent teeth of children. of which is a brownish staining of the teeth. Staining Nonfluoride remineralizing agents: strength of the is reported in up to one-half of patients but is removable recommendation. This recommendation was rated as once the mouthrinse is discontinued. Chlorhexidine moderate. While acknowledging that the evidence is may cause an increase in calculus development. Other based on limited studies, the ratings allow for inclusion less frequently reported side effects include altered taste, of the strength of expert opinion (Appendix 4,avail- which can persist for several hours after use, oral able online at the end of this article). The TRG burning, and development of lesions and ulcerations concluded that clinicians should consider the use of of the gingival mucosa. It also has a strong, unpleasant nonfluoride remineralizing agents as worthy of their taste that most patients find objectionable. attention and consideration. Emphasis is placed on Antimicrobial agents: strength of the recom- all recommendations for caries prevention in Sjögren mendation. Because available evidence for recom- disease being viewed in aggregate—that is, the clinician mending chlorhexidine use for caries prevention is weak, should consider all recommendations as potential the strength of the recommendation was rated as weak. therapies to be used as deemed necessary for an indi- Although the TRG is confident that the recommendation vidual patient and most likely in conjunction with one is valid in the circumstances cited and offers the best another. guidance for practice, the group’s confidence is diminished by the potential side effects, the experts’ opinions, SELECT AVAILABLE GUIDELINES FOR THE 37 and the study by Wyatt and colleagues. POPULATION AT HIGH CARIES RISK The ADA has supported a number of systematic reviews NONFLUORIDE REMINERALIZING AGENTS that provided a summary of the level of evidence for Nonfluoride remineralizing agents may be considered for caries prevention strategies. Although they are not use by patients with Sjögren disease with dry mouth to related directly to patients with Sjögren disease with dry prevent caries. A review of 136 abstracts led to the se- mouth, they can help inform clinical decisions about lection of 23 studies for data extraction. After thorough which preventive interventions may be of the greatest review, the TRG decided that only 2 studies met the benefit. Clinical practice guidelines that provide

8 JADA -(-) http://jada.ada.org - 2016 PRACTICE GUIDELINES summaries of the evidence are available at the ADA Dr. Zero is a director, Oral Health Research Institute, and professor, Center for Evidence-Based Dentistry website for topical Department of Cariology, Operative Dentistry, and Dental Public Health, 44 45 Indiana University School of Dentistry, 415 Lansing St., Indianapolis, IN fluoride agents, nonfluoride caries preventive agents, 46202 46 , e-mail [email protected]. Address correspondence to Dr. Zero. and pit-and-fissure sealants. Dr. Brennan is a professor and chair, Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC. Dr. Daniels is a professor of oral medicine and pathology, Department of FUTURE DIRECTIONS FOR RESEARCH Orofacial Sciences, Schools of Dentistry and Medicine, University of Cali- Patients with Sjögren disease with dry mouth must be fornia, San Francisco, San Francisco, CA. Dr. Papas is a Johansen Professor of Dental Research and head, Division considered as being at high risk of developing caries, and of Oral Medicine, Division of Geriatric Dentistry, School of Dental Medi- the need for evidence-based preventive intervention is cine, Tufts University, Medford, MA. of paramount importance. On the basis of the extensive Dr. Stewart is a professor, Department of Oral and Maxillofacial Diag- literature search, an unexpected lack of well-controlled nostic Sciences, College of Dentistry, University of Florida, Gainesville, FL. fi Dr. Pinto is a chairman and associate professor, Department of Oral and studies exists that provide scienti c evidence for the most Maxillofacial Medicine and Diagnostic Sciences, School of Dental Medicine, effective preventive interventions in this patient popu- Case Western Reserve University, Cleveland, OH. lation. A need for standardization of clinical outcome Dr. Al-Hashimi is a professor, Department of Periodontics, Baylor College fi of Dentistry, Dallas, TX. measures is critical so that ndings across studies can Dr. Navazesh is a professor, Division of Diagnostic Sciences, School of be interpreted properly by using advanced methods such Dentistry, University of Southern California, Los Angeles, CA. as meta-analyses. Dr. Rhodus is a Morphse Distinguished Professor, Division of Oral While recognizing the need for clinical trials in Medicine, Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN. patients with Sjögren disease with dry mouth in which Dr. Sciubba is a professor (Ret) and consultant, Johns Hopkins Head and investigators evaluate the role of fluoride for caries pre- Neck Center, Greater Baltimore Medical Center, Baltimore, MD. vention, the authors also recognize that fluoride remains Dr. Singh is an associate professor and director, Dry Mouth Clinic, Department of Diagnostic Sciences, School of Dental Medicine, Tufts the criterion standard for preventing caries in patients University,Medford,MA. with xerostomia, and all patients ethically should receive Dr. Wu is a clinical professor, Department of Orofacial Sciences, School of fluoride. No data exist, however, on whether one topical Dentistry, University of California, San Francisco, San Francisco, CA. fl Dr. Frantsve-Hawley is an executive director, American Association of uoride is more effective than another in preventing Public Health Dentistry, Springfield, IL; and editor-in-chief, The Interna- caries in patients with Sjögren disease, and the TRG tional Journal of Evidence-Based Practice for the Dental Hygienist, Hanover encourages future studies to elucidate any differences. Park, IL. In particular, studies are needed in which the in- Dr. Tracy was an assistant director, Center for Evidence-Based Dentistry, fl Science Division, American Dental Association, Chicago, IL when this vestigators compare professionally applied uoride article was written. She now is a principal researcher, Materials Science, products, such as fluoride varnish treatments, with and Steelcase Inc, Grand Rapids, MI. without added nonfluoride remineralizing agents. Also, Dr. Fox is president, PC Fox Consulting, Assisi, Italy. fi fl Dr. Ford is the chief executive officer and medical director, North Georgia assessing the bene ts of prescription-strength uoride Rheumatology Group, PC, Lawrenceville, GA. toothpaste compared with regular toothpaste in patients Dr. Cohen is a doctor of optometry, Doctor My Eyes, Scottsdale, AZ. with Sjögren disease is necessary. Future clinical trials Dr. Vivino is the chief, Division of Rheumatology, Penn Presbyterian ’ in patients with Sjögren disease to assess agents to be Medical Center; the director, Penn Sjogren s Center; and a professor of fl clinical medicine, Perelman School of Medicine, University of Pennsylvania, used as adjuncts to ongoing uoride clearly are needed to Philadelphia, PA. evaluate the role of salivary stimulation products or Ms. Hammitt is a vice president of medical and scientific affairs, Sjögren’s pharmaceutical agents, chlorhexidine and other antimi- Syndrome Foundation, Bethesda, MD. fl crobials, and non uoride remineralizing agents. Disclosure. Dr. Zero had or has consulting relationships with and serves as a principal investigator on studies sponsored by GlaxoSmithKline, Johnson & CONCLUSIONS Johnson, Unilever, and C3 Jian, but none directly related to this article. Dr. Brennan has consulting relationships with Daiichi Sankyo. Dr. Stewart has Based on limited evidence, incidence of caries in patients consulting relationships with Parion Sciences. Dr. Wu has stock options with with Sjögren disease can be reduced with the use of AbbVie and Schering-Plough but none directly related to this article. Dr. Ford topical fluoride, and all patients with Sjögren disease is on the advisory board for Bausch & Lomb, is a member of the board of fl fi directors for the national Sjögren’s Syndrome Foundation, and is chair of the should receive uoride as the rst line of therapy. Other international Sjögren’s Syndrome Clinical Trials Consortium. Dr. Ford also preventive strategies, including salivary stimulation, an- has consulting relationships with AbbVie, Actelion, Amgen, Bristol-Myers timicrobials such as chlorhexidine, and nonfluoride Squibb, Horizon, Mallinckrodt, Pfizer, Takeda, and UCB but none directly related to this article. Dr. Vivino has a consulting relationship with Biogen remineralizing agents, can be considered as adjunctive Idec, Takeda, and Immco Diagnostics, but none are directly related to this treatments. Research studies specifically in patients with article. None of the other authors reported any disclosures. Sjögren disease are clearly needed for all of these caries ’ n The Sjögren s Syndrome Foundation clinical practice guidelines initiative preventive interventions. is funded fully by the Sjögren’s Syndrome Foundation with no corporate or pharmaceutical industry support. SUPPLEMENTAL DATA The Sjögren’s Syndrome Foundation (SSF) thanks the members of the oral Supplemental data related to this article can be found at working group for volunteering their time and expertise to develop the SSF http://dx.doi.org/10.1016/j.adaj.2015.11.008. clinical practice guidelines for oral management of Sjögren disease; members

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of the consensus expert panel who volunteered their time to comment and 20. Spak CJ, Johnson G, Ekstrand J. Caries incidence, salivary flow rate vote on the recommendations and review the clinical rationale and evidence and efficacy of fluoride gel treatment in irradiated patients. Caries Res. summaries and tables for each recommendation; the American Dental As- 1994;28(5):388-393. sociation, which was invaluable in contributing expertise in evidence-based 21. Horiot JC, Schraub S, Bone MC, et al. Dental preservation in patients research and conducting the literature searches; Patricia Hurley, MSc, irradiated for head and neck tumours: a 10-year experience with topical methodology consultant, who helped devise the overall methodological fluoride and a randomized trial between two fluoridation methods. processes for all SSF clinical practice guidelines working groups; the Amer- Radiother Oncol. 1983;1(1):77-82. ican College of Rheumatology for advising the SSF from the start of and 22. Chambers MS, Fleming TJ, Toth BB, et al. Erratum to “Clinical throughout its pursuit of clinical practice guideline development; and the SSF evaluation of the intraoral fluoride releasing system in radiation-induced board of directors, who supported this initiative. SSF clinical practice xerostomic subjects, part 2: Phase I study.” Oral Oncol. 2007;43(1):98-105. guidelines encompass working groups for oral, ocular, and rheumatological, 23. Epstein JB, van der Meij EH, Lunn R, Stevenson-Moore P. Effects of and systemic manifestations of Sjögren disease. A list of members can be compliance with fluoride gel application on caries and caries risk in pa- found in Appendix 9 (available online at the end of this article). tients after radiation therapy for head and neck cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;82(3):268-275. 1. Christensen LB, Petersen PE, Thorn JJ, Schiodt M. Dental caries and 24. Keene HJ, Fleming TJ, Toth BB. Cariogenic microflora in patients dental health behavior of patients with primary Sjogren syndrome. Acta with Hodgkin’s disease before and after mantle field radiotherapy. Oral Odontol Scand. 2001;59(3):116-120. Surg Oral Med Oral Pathol. 1994;78(5):577-582. 2. Strömbeck B, Ekdahl C, Manthorpe R, Wikström I, Jacobsson L. 25. Papas A, Russell D, Singh M, et al. Double blind clinical trial of a Health-related quality of life in primary Sjögren’s syndrome, rheumatoid remineralizing dentifrice in the prevention of caries in a radiation therapy arthritis and fibromyalgia compared to normal population data using population. Gerodontology. 1999;16(1):2-10. SF-36. Scand J Rheumatol. 2000;29(1):20-28. 26. Al-Joburi W, Clark C, Fisher R. A comparison of the effectiveness of 3. Valtýsdóttir ST, Gudbjörnsson B, Lindqvist U, Hällgren R, Hetta J. two systems for the prevention of radiation caries. Clin Prev Dent. 1991; Anxiety and depression in patients with primary Sjögren’s syndrome. 13(5):15-19. J Rheumatol. 2000;27(1):165-169. 27. Papas A, He T, Martuscelli G, Singh M, Bartizek RD, 4. Segal B, Bowman SJ, Fox PC, et al. Primary Sjögren’s syndrome: health Biesbrock AR. Comparative efficacy of stabilized stannous fluoride/ experiences and predictors of health quality among patients in the United sodium hexametaphosphate dentifrice and sodium fluoride/triclosan/ States. Health Qual Life Outcomes. 2009;7:46. copolymer dentifrice for the prevention of periodontitis in xerostomic 5. Fox PC, Bowman SJ, Segal B, et al. Oral involvement in primary patients: a 2-year randomized clinical trial. J Periodontol. 2007;78(8): Sjögren’s syndrome. JADA. 2008;139(12):1592-1601. 1505-1514. 6. Bowman SJ, St Pierre Y, Sutcliffe N, et al. Estimating indirect costs in 28. Brailsford SR, Fiske J, Gilbert S, Clark D, Beighton D. The effects of primary Sjögren’s syndrome. J Rheumatol. 2010;37(5):1010-1015. the combination of chlorhexidine/thymol- and fluoride-containing var- 7. Callaghan R, Prabu A, Allan RB, et al; UK Sjögren’s Interest Group. nishes on the severity of root caries lesions in frail institutionalised elderly Direct healthcare costs and predictors of costs in patients with primary people. J Dent. 2002;30(7-8):319-324. Sjögren’s syndrome. Rheumatology (Oxford). 2007;46(1):105-111. 29. Haveman CW, Summitt JB, Burgess JO, Carlson K. Three restorative 8. Helmick CG, Felson DT, Lawrence RC, et al. National Arthritis Data materials and topical fluoride gel used in xerostomic patients: a clinical Workgroup. Estimates of the prevalence of arthritis and other rheumatic comparison. JADA. 2003;134(2):177-184. conditions in the United States, part I. Arthritis Rheum. 2008;58(1):15-25. 30. Ekstrand KR, Poulsen JE, Hede B, Twetman S, Qvist V, Ellwood RP. 9. Sjögren’s Syndrome Foundation Breakthrough Goal Survey. 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41. Rethman MP, Beltrán-Aguilar ED, Billings RJ, et al; American Dental 44. ADA Center for Evidence-Based Dentistry. Topical fluoride for caries Association Council on Scientific Affairs Expert Panel on Nonfluoride prevention. Available at: http://ebd.ada.org/en/evidence/guidelines/topical- Caries-Preventive Agents. Nonfluoride caries-preventive agents: executive fluoride. Accessed December 17, 2015. summary of evidence-based clinical recommendations. JADA. 2011;142(9): 45. ADA Center for Evidence-Based Dentistry. Non-fluoride agents 1065-1071. for caries prevention. Available at: http://ebd.ada.org/en/evidence/ 42. Bader JD, Vollmer WM, Shugars DA, et al. Results from the Xylitol guidelines/non-fluoride-caries-preventive-agents. Accessed December 17, for Adult Caries Trial (X-ACT). JADA. 2013;144(1):21-30. 2015. 43. Riley P, Moore D, Ahmed F, Sharif MO, Worthington HV. Xylitol- 46. ADA Center for Evidence-Based Dentistry. Pit-and-fissure sealants containing products for preventing dental caries in children and adults. for caries prevention. Available at: http://ebd.ada.org/en/evidence/ Cochrane Database Syst Rev. 2015;3:CD010743. guidelines/pit-and-fissure-sealants. Accessed December 17, 2015.

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