Sjögren’s disease is associated with a high burden of illness, diminished quality of life, and increased health care costs. The Sjögren’s Syndrome Foundation developed the first US clinical practice guidelines for management of the oral, ocular, and rheumatologic or systemic manifestations. Guideline recommendations were reviewed by a consensus expert panel using a modified Delphi process. This initiative should improve the quality and consistency of care for Sjögren’s disease in the United States, guide insurance reimbursement, and define areas for future study. Guidelines will be periodically reviewed and revised as new information becomes available.
Key points
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Sjögren’s disease (SD) is associated with a high burden of illness, poor quality of life, and increased health care costs.
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All SD patients with xerostomia should be given fluoride for caries prophylaxis.
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Proper treatment of dry eyes necessitates comprehensive assessment to determine severity level and the relative contributions of aqueous tear deficiency versus meibomian gland dysfunction.
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Disease-modifying antirheumatic drugs can be used to treat inflammatory musculoskeletal pain starting with hydroxychloroquine as first-line therapy.
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Fatigue is most effectively managed with self-care measures and exercise.
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Biological therapy like rituximab is best used in SD patients with serious organ manifestations who fail more conservative treatments.
Introduction
Among all the chronic autoimmune rheumatic disorders, Sjögren’s disease (SD) is among the most difficult to evaluate and manage. Clinicians are frequently challenged to differentiate symptoms related to disease activity from those that result from pre-existing damage. Additionally, the presence of multiple SD-related comorbidities, including anxiety, depression and fibromyalgia, may influence the severity of patient symptoms and further complicate the evaluation process. Furthermore, in the clinical setting, a thorough investigation of patient complaints will often reveal multiple potential causes for the same symptom.
Presently, no cure or remittive agent for SD exists. Treatment goals remain (1) symptom palliation, (2) prevention of complications and, (3) for rheumatologists, proper selection of patients for immunosuppressive therapy. In SD the frequent occurrence of oral and ocular manifestations and complications also mandates a multidisciplinary approach to optimize care. Unfortunately, the paucity of well-designed, controlled studies in the SD medical and dental literature frequently leaves the clinician with little guidance. Therefore, the approach to treating SD in the United States has differed widely among various institutions and providers.
High burden of illness
Several studies have documented that quality of life (QOL) is diminished in primary SD subjects compared with healthy controls and, in some cases, diminished to the degree seen in other subject groups, such as those with rheumatoid arthritis (RA) and/or fibromyalgia. One study found less overall end organ damage in primary SD compared with systemic lupus (SLE) but concluded that the degree of functional disability was the same for both disorders. Patients with SD may also incur increased health care costs and, not surprisingly, increased dental care costs. A study from England reported that annual health care costs in primary SD (£2188) were twice that of community controls (£949) and comparable to those of subjects with RA (£2693). Thus, the burden of illness in primary SD is quite substantial.
Introduction
Among all the chronic autoimmune rheumatic disorders, Sjögren’s disease (SD) is among the most difficult to evaluate and manage. Clinicians are frequently challenged to differentiate symptoms related to disease activity from those that result from pre-existing damage. Additionally, the presence of multiple SD-related comorbidities, including anxiety, depression and fibromyalgia, may influence the severity of patient symptoms and further complicate the evaluation process. Furthermore, in the clinical setting, a thorough investigation of patient complaints will often reveal multiple potential causes for the same symptom.
Presently, no cure or remittive agent for SD exists. Treatment goals remain (1) symptom palliation, (2) prevention of complications and, (3) for rheumatologists, proper selection of patients for immunosuppressive therapy. In SD the frequent occurrence of oral and ocular manifestations and complications also mandates a multidisciplinary approach to optimize care. Unfortunately, the paucity of well-designed, controlled studies in the SD medical and dental literature frequently leaves the clinician with little guidance. Therefore, the approach to treating SD in the United States has differed widely among various institutions and providers.
High burden of illness
Several studies have documented that quality of life (QOL) is diminished in primary SD subjects compared with healthy controls and, in some cases, diminished to the degree seen in other subject groups, such as those with rheumatoid arthritis (RA) and/or fibromyalgia. One study found less overall end organ damage in primary SD compared with systemic lupus (SLE) but concluded that the degree of functional disability was the same for both disorders. Patients with SD may also incur increased health care costs and, not surprisingly, increased dental care costs. A study from England reported that annual health care costs in primary SD (£2188) were twice that of community controls (£949) and comparable to those of subjects with RA (£2693). Thus, the burden of illness in primary SD is quite substantial.
Guidelines development
In 2010, the Sjögren’s Syndrome Foundation (SSF) enlisted the help of more than 200 professional volunteers nationwide to develop the first ever clinical practice guidelines (CPGs) for SD patients in the United States. The framework for this process is summarized in Fig. 1 . The goals were to improve the quality and consistency of care and to ease the uncertainty of providers, patients, and insurers regarding coverage and reimbursement issues. All working groups followed a highly rigorous process with guidance from major professional organizations including the Institute of Medicine, American Dental Association, American Academy of Ophthalmology (AAO), and the American College of Rheumatology (ACR). The Appraisal of Guidelines for Research and Evaluation (AGREE) was used. Overreaching methodological principles included transparency, involvement of key stakeholders, and consistency of methods. All participants completed ACR conflict of interest forms.
Defining clinical issues
All key stakeholders, including patients and providers of various disciplines, from academia and the community, were surveyed to identify pertinent clinical issues. Topics were assigned to 1 of 3 working groups: Oral, Ocular, or Rheumatologic-Systemic; prioritized; and reformatted as PICO (population, intervention, comparison, and outcome) questions. Bias was reduced as much as possible by defining a priori all methodology elements, including protocol worksheets, data extraction tables, and literature search terms.
Topic review and the Delphi consensus process
Topic review groups (TRGs) of at least 2 to 3 providers were established for each clinical question to review the medical or dental literature, complete data extraction tables, and write an evidence summary. The TRG, as a whole, rated the strength of the evidence, developed a draft recommendation, and rated the strength of the recommendation based on a variation of grading of recommendations, assessment, development, and evaluation (GRADE). For the dry eye guidelines the AAO Preferred Practice Pattern guidelines for level of evidence were also followed. Any definition of primary SD (ie, SD without an associated connective tissue disorder) based on published classification criteria were accepted for guideline development. Data on patients with secondary SD were not used in this analysis.
A consensus expert panel (CEP) of pertinent specialists, providers from other disciplines, and stakeholders provided feedback and voted on each recommendation. A modified Delphi process was used with 75% agreement required for consensus. Revision of guidelines that failed to achieve consensus was permitted up to 3 rounds before the recommendation was discarded.
Guidelines for Oral Management
Rationale
Salivary dysfunction in SD can lead to serious and costly oral health complications. Study subjects with SD have significantly more dental caries, tooth extractions, and higher lifetime dental costs then do controls. SD patients who lose their dentition often have problems with denture wear and find that dental implants provide the only viable long-term alternative. Most patients in the United States lack sufficient dental insurance to cover these expenses and pay most costs out-of-pocket. It is, therefore, incumbent on every dentist and oral medicine specialist to consider the diagnosis of SD in patients with accelerated caries and initiate a management program for caries prophylaxis early in the disease course.
Recommendations
To develop CPGs for caries prophylaxis in SD, the Oral Working Group reviewed dental literature concerning the use of fluoride, salivary stimulation, antimicrobials, and remineralizing agents. Fig. 2 is a summary of this process. Further details, including findings from extensive literature reviews, protocol worksheets, data extraction tables, and summaries of dental evidence, have been previously reported. The clinical questions and oral guidelines for caries prophylaxis in SD are summarized in Box 1 . The clinician is encouraged to consider all recommendations as potential therapies to be used either singly or in combination for the individual patient.
Use of fluoride
Clinical questions
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In primary SD patients, does the use of a topical fluoride compared with no topical fluoride reduce the incidence, arrest, or reverse coronal or root caries?
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In primary SD patients, is one topical fluoride agent more effective than another in reducing the incidence, or to arrest or reverse, coronal or root caries?
Recommendation
Topical fluoride should be used in SD patients with dry mouth.
No information was available to answer the second question.
Strength of recommendation: strong
Salivary stimulation
Clinical questions
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In primary SD patients, does salivary stimulation compared with not stimulating saliva flow reduce the incidence, arrest, or reverse coronal or root caries?
Recommendation
While no studies to date link improved salivary function in SS patients to caries prevention, it is generally understood in the oral health community that increasing saliva may contribute to decreased caries incidence. Based on its expert opinion, the TRG recommends that SD patients with dry mouth increase saliva through gustatory, masticatory stimulation, and pharmaceutical agents; for example, sugar-free lozenges and/or chewing gum, xylitol, mannitol, and the prescription medications pilocarpine and cevimeline.
Strength of recommendation: weak
Antimicrobials
Clinical questions
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In primary SD patients, does the use of antimicrobial agents compared with placebo reduce the incidence, arrest, or reverse coronal or root caries?
Recommendation
Chlorhexidine administered by varnish, gel, or rinse may be considered in SD patients with dry mouth and a high root caries rate.
Strength of recommendation: weak
Nonfluoride remineralizing agents
Clinical questions
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In primary SD patients, does the use of nonfluoride remineralization agents compared with placebo reduce the incidence, arrest, or reverse coronal or root caries?
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In primary SD patients, does the use of nonfluoride remineralization agents compared with the use of fluoride reduce the incidence, arrest, or reverse coronal or root caries?
Recommendation
Nonfluoride remineralizing agents may be considered as an adjunct therapy in SD patients with dry mouth and a high root caries rate.
Insufficient information was available to answer the second question.
Strength of recommendation: moderate
Guidelines for Ocular Management
Rationale
At least 2 prior surveys of SD patients conducted by the SSF have documented dry eye to be the single most troublesome symptom in SD. Additionally, dry eye is recognized as a debilitating symptom in the US Social Security Administration Disability Guidelines, which included SD as a specific listing for the first time in 2006. Dry eye can seriously compromise QOL and at least 1 study suggested that the impact of dry eye on QOL was comparable to that seen in patients with moderate to severe angina.
Terminology
The development of ocular guidelines for the evaluation and management of dry eyes for SD used the definition of dry eye and other terminology reported in the 2007 International Dry Eye Workshop (DEWS). The DEWS report defined terms to characterize patient subsets, as well as clinical issues, and defined dry eye as, “a multi-factorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”
Dry eye is classified into 2 categories: (1) aqueous-deficient dry eye related to decreased tear production and (2) evaporative dry eye most commonly caused by meibomian gland dysfunction (blepharitis). Both types of dry eye may occur in SD and often coexist in the same individual. Most patients are symptomatic and describe their discomfort as burning, stinging, foreign body sensation (grittiness), itching, or pain. Symptoms of visual disturbance may include fluctuation or blurring of vision, especially during reading or computer work, with transient improvement after blinking or the instillation of artificial tears. Interestingly, a recent study reported that as many as 40% of SD subjects with clear objective evidence of dry eyes had no symptoms, thus underscoring the necessity to thoroughly evaluate all SD patients for dry eye regardless of symptoms.
Evaluation
The Ocular Working Group stressed the importance of comprehensive assessment of the SD patient to determine the cause and severity of dry eye before recommending treatment. This process involves the assessment of key ocular symptoms as described previously, as well as the examination of several objective parameters, including tear production, tear film stability, tear osmolarity, lid margin disease, and ocular surface damage. A summary of the diagnostic evaluation and recommended order of tests is included in Table 1 .
| Observation or Test | What is Examined | Tools | Sign of Dry Eye |
|---|---|---|---|
| 1. Direct Observation | Tear function, tear stability and ocular surface | Corneal light reflex biomicroscope (additional instruments are available in the research setting) | Tear film instability Ocular surface irregularity |
| Meibomian gland disease | Biomicroscope | Presence of foamy debris | |
| 2. Osmolarity | Tear composition: levels of inflammatory mediators in tear film and conjunctiva | Osmometer (mostly limited to research settings but units are increasingly available for clinical practice) | Elevated osmolarity of the tear film |
| 3. Fluorescein Tear Break-Up Time | Tear film stability | Fluorescein dye Slit-lamp | Rapid tear film breakup (<10 s) |
| 4. Corneal Staining | Ocular surface evaluation | Fluorescein Rose bengal or lissamine green dye | Staining observed of mucus strands, filaments, and unprotected areas of the epithelium Staining patterns can designate severity of dry eye |
| 5. Schirmer 1 Test or Phenol Red Thread Test | Tear secretion rate | Schirmer tear test strip Small thread impregnated with phenol red dye A fluorophotometer is more sensitive than either of these but is usually not available in the clinical setting | Schirmer 1: <5–7 mm of wetting after 5 min Phenol red thread test: <10 mm of wetting after 15 s |
Recommendations
To develop SD-specific ocular CPGs, the dry eye literature was reviewed according to preselected criteria as summarized in Fig. 3 . Studies on non-SD dry eye disease also guided management whenever considered essential. The CPGs for dry eye management in SD are outlined in Table 2 and organized by type of dry eye disease (aqueous deficient vs meibomian gland dysfunction) and level of severity. The latter is determined mainly by the presence or absence of ocular surface staining and the staining pattern. Conjunctival staining usually occurs before corneal staining and medial staining often occurs before temporal conjunctival staining. Early corneal staining is most often observed in the inferonasal cornea with central staining occurring later. A classic pattern of interpalpebral staining across the medial conjunctiva, cornea, and temporal conjunctiva, or the presence of ocular filaments, indicates advanced dry eye disease. If the results of treatment of the SD patient at a given level of severity are insufficient, the eye care provider is encouraged to follow recommendations for the next level of severity.
| Diagnosis | Treatment | Severity Level 1 a | Severity Level 2 | Severity Level 3 | Severity Level 4 | Evidence b | Recommendation c |
|---|---|---|---|---|---|---|
| Dry eye disease: aqueous deficiency without meibomian gland disease | Education and environment or diet modification | — | — | — | Good | Strong |
| Elimination of offending systemic medication | Good | Strong | ||||
| Artificial tears, gels, ointments | Good | Strong | ||||
| — | Omega 3 essential fatty acid supplement | — | — | Moderate | Moderate | |
| Anti-inflammatory therapy: cyclosporine | Good | Moderate | ||||
| Anti-inflammatory therapy: pulse steroids | Good | Moderate | ||||
| Punctal plugs | Good | Moderate | ||||
| Secretagogues | Good | Moderate | ||||
| Moisture chamber spectacles | Good | Moderate | ||||
| — | — | Topical autologous serum | — | Good | Moderate | |
| Contact lenses | Good | Moderate | ||||
| Permanent punctal occlusion | Good | Moderate | ||||
| — | — | — | Systemic anti-inflammatory medication | Moderate | Weak | |
| Eyelid surgery | Good | Moderate | ||||
| Dry eye disease: aqueous deficiency with meibomian gland disease | Education and environment or diet modification | — | — | — | Good | Strong |
| Elimination of offending systemic medication | Good | Strong | ||||
| Artificial tears with lipid component | Good | Strong | ||||
| Eyelid therapy: warm compress, massage | Good | Strong | ||||
| — | Omega 3 essential fatty acid supplement | — | — | Moderate | Moderate | |
| Anti-inflammatory therapy: cyclosporine | Good | Moderate | ||||
| Anti-inflammatory therapy: topical steroids | Good | Moderate | ||||
| Topical azithromycin | Good | Moderate | ||||
| Liposomal spray | Good | Moderate | ||||
| Possible oral doxycycline | Good | Moderate | ||||
| Expression of meibomian glands | Good | Moderate | ||||
| Punctal plugs | Good | Moderate | ||||
| Secretagogues | Good | Moderate | ||||
| Moisture chamber spectacles | Good | Moderate | ||||
| — | — | Topical autologous serum | — | Good | Moderate | |
| Contact lenses | Good | Moderate | ||||
| Permanent punctal occlusion | Good | Moderate | ||||
| LipiFlow pulsed thermal compression | Insufficient | Weak | ||||
| Probing of meibomian gland | Insufficient | Weak | ||||
| — | — | — | Systemic anti-inflammatory medication | Moderate | Weak | |
| Eyelid surgery | Good | Moderate |
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