Guidelines Summary
European League Against Rheumatism guidelines
In 2019, the European League Against Rheumatism (EULAR) published guidelines on the management of Sjögren syndrome with topical and systemic therapies. [103] EULAR recommends that patients with Sjögren syndrome be managed at, or in close collaboration with, centers of expertise following a multidisciplinary approach. Specific recomendations are listed below.
Dry mouth
Baseline evaluation of salivary gland function, including measurement of whole salivary flows, and exclusion of unrelated conditions, is recommended before starting treatment for oral dryness.
The preferred first therapeutic approach for oral dryness according to salivary gland function may be as follows:
-
Mild dysfunction - Nonpharmacological stimulation (eg, sugar-free acidic candies, lozenges, xylitol, sugar-free chewing gum)
-
Moderate dysfunction - Pharmacological stimulation (eg, pilocarpine, cevimeline; anetholtrithione, bromhexine, N-acetylcysteine in cases of intolerance or non-response)
-
Severe dysfunction - Saliva substitution
The guidelines recommend against using any of the following for oral dryness:
-
Hydroxychloroquine
-
Oral glucocorticoids
-
Immunosuppressive agents
-
Rituximab
Dry eyes
The first-line therapeutic approach to ocular dryness includes the use of artificial tears and ocular gels/ointments. Refractory/severe ocular dryness may be managed in stepwise fashion, as follows:
- Topical ocular non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may be prescribed by ophthalmologists as a short-term therapeutic approach (maximum 2–4 weeks); if no response or intolerance, then
- Topical cyclosporine; if no response or intolerance, then
- Serum eye drops; if no response or intolerance, then
- Rescue therapies - Oral muscarinic agonists or plug insertion
Fatigue and/or pain:
-
Concomitant diseases should be evaluated in patients presenting with fatigue/pain, whose severity should be scored using specific tools (eg, EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI], Profile of Fatigue, Brief Pain Inventory).
-
Consider analgesics or other pain-modifying agents for musculoskeletal pain, considering the balance between potential benefits and side-effects.
Systemic disease:
-
Treatment of systemic disease should be tailored to organ-specific severity using the EULAR Sjögren's syndrome disease activity index (ESSDAI) definitions.
-
Glucocorticoids should be used at the minimum dose and length of time necessary to control active systemic disease (eg, pulses of methylprednisolone followed by doses of 0.5 mg/kg/d or lower as induction therapy in severe presentations, and doses< 0.5 mg/kg/d in moderate/less-severe presentations, with a final target of withdrawing glucocorticoids in patients with inactive disease as soon as possible or at least trying to target a maintenance dose of 5 mg/daily or less with the aid of glucocorticoid-sparing immunosuppressive agents).
-
Immunosuppressive agents (eg, leflunomide, methotrexate, azathioprine, mycophenolate, cyclophosphamide) should be mainly used as glucocorticoid-sparing agents, with no evidence supporting the choice of one agent over another.
-
B-cell–targeted therapies (eg, rituximab, epratuzumab, belimumab) may be considered in patients with severe, refractory systemic disease.
-
The systemic organ-specific therapeutic approach may follow, as a general rule, the sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics.
-
Treatment of B-cell lymphoma should be individualized according to the specific histological subtype and disease stage.
Sjögren’s Foundation guidelines
In 2016, the Sjögren’s Foundation published clinical practice guidelines for Sjögren syndrome patients in the United States. [104] The guidelines note that treatment goals remain as follows:
- Symptom palliation
- Prevention of complications
- For rheumatologists, proper selection of patients for immunosuppressive therapy
Dry mouth
Recommendations (and their strength) for Sjögren syndrome patients with dry mouth include the following:
-
Topical fluoride should be used in for caries prophylaxis (strong)
-
Saliva can be increased through gustatory, masticatory stimulation, sugar-free lozenges and/or chewing gum, xylitol, mannitol, and the prescription medications pilocarpine and cevimeline (weak)
-
Chlorhexidine administered by varnish, gel, or rinse may be considered in patients with a high root caries rate (weak)
-
Nonfluoride remineralizing agents may be considered as an adjunct therapy in patients with a high root caries rate (moderate)
Dry eye
For dry eye disease, recommendations vary according to whether meibomian gland disease is present and by the severity of eye involvement, which is determined mainly by the presence or absence of ocular surface staining and the staining pattern. Recommendations also vary according to disease severity.
For aqueous deficiency without meibomian gland disease, severity 1, recommendations are as follows:
-
Education and modification of the environment or diet
-
Elimination of offending systemic medication
-
Artificial tears, gels, ointments
For severity 2 disease, recommendations are as follows:
-
Omega 3 essential fatty acid supplement
-
Anti-inflammatory therapy with cyclosporine
-
Anti-inflammatory therapy with pulse steroids
-
Punctal plugs
-
Secretagogues
-
Moisture chamber spectacles
For severity 3 disease, recommendations are as follows:
-
Topical autologous serum
-
Contact lenses
-
Permanent punctal occlusion
For severity 4 disease, recommendations are as follows:
-
Systemic anti-inflammatory medication
-
Eyelid surgery
For aqueous deficiency with meibomian gland disease, severity 1, recommendations are as follows:
-
Education and modification of the environment or diet
-
Elimination of offending systemic medication
-
Artificial tears with lipid component
-
Eyelid therapy: warm compress, massage
For severity 2 disease, recommendations are as follows:
-
Omega 3 essential fatty acid supplement
-
Anti-inflammatory therapy with cyclosporine
-
Anti-inflammatory therapy with topical steroids
-
Topical azithromycin
-
Liposomal spray
-
Possible oral doxycycline
-
Expression of Meibomian glands
-
Punctal plugs
-
Secretagogues
-
Moisture chamber spectacles
For severity 3 disease, recommendations are as follows:
-
Topical autologous serum
-
Contact lenses
-
Permanent punctal occlusion
-
LipiFlow pulsed thermal compression
-
Probing of meibomian gland
For severity 4 disease, recommendations are as follows
-
Systemic anti-inflammatory medication
-
Eyelid surgery
Inflammatory musculoskeletal pain
The Sjögren’s Foundation guidelines advise that physicians consider the individual patient’s circumstances when weighing risks and benefits of each therapy. Insufficient evidence exists on the effectiveness of disease-modifying antirheumatic drugs (DMARDs) in the treatment of inflammatory musculoskeletal pain in primary Sjögren syndrome, so recommendations were formulated on the basis of expert opinion as guided by the consensus group process.
The following recommendations are listed in order of preference for use in the treatment of inflammatory musculoskeletal pain in primary Sjögren syndrome; if a therapy is insufficiently effective, the physician is advised to try the next recommendation in sequence, and so on:
- Hydroxychloroquine; first-line treatment
- Methotrexate
- Hydroxychloroquine plus methotrexate
- Short-term (1 month or less) corticosteroids (15 mg or less a day); long-term corticosteroids (≤15 mg/d for more than 1 month) may be useful, but efforts should be made to find a steroid-sparing agent as soon as possible
- Leflunomide
- Sulfasalazine
- Azathioprine (may be a better choice than leflunomide or sulfasalazine in patients with major organ involvement)
- Cyclosporine
Fatigue
The only strongly recommended treatment of fatigue in Sjögren syndrome was exercise. Hydroxychloroquine may be considered in selected situations
The guidelines include strong recommendations against the use of the following for fatigue:
-
Dehydroepiandrosterone (DHEA)
-
Etanercept
-
Infliximab
Insufficient evidence to issue a recommendation was found for the following therapeutic options for fatigue:
-
Interleukin-1 inhibition (anakinra)
-
Azathioprine
-
Mycophenolate
-
Zidovudine
-
Doxycycline
-
Lamivudine
-
Leflunomide
-
Abatacept
-
Belimumab
-
Epratuzumab
Biological therapies
The guidelines advise against use of tumor necrosis factor–alpha (TNF-α) inhibitors to treat sicca symptoms in patients with primary Sjögren syndrome. If TNF-α inhibition therapy is used for rheumatoid arthritis or other related overlap conditions in patients with Sjögren syndrome, health care providers should consider and monitor for the following:
-
Lymphoma and other malignancies (risk for non-Hodgkin is elevated)
-
Serious infections, including tuberculosis
-
Invasive fungal infections
-
Hepatitis B reactivation
-
Hepatotoxicity
-
Heart failure
-
Cytopenias
-
Hypersensitivity
-
Serious infusion reactions
-
Demyelinating disease
Rituximab
Rituximab may be considered as a therapeutic option for the following indications in patients with primary Sjögren syndrome:
-
Keratoconjunctivitis sicca (KCS), in patients for whom conventional therapies (eg, topical moisturizers, secretagogues, anti-inflammatory drugs, immunomodulators, punctual occlusion) have proven insufficient
-
Xerostomia, in patients with primary Sjögren syndrome with some evidence of residual salivary production and clinician-determined significant evidence of oral damage, in whom conventional therapies, including topical moisturizers and secretagogues, have proved insufficient
Rituximab may be considered as a therapeutic option for adults with primary Sjögren syndrome and any or all of the following systemic manifestations:
-
Cryoglobulinemia associated with vasculitis
-
Vasculitis
-
Severe parotid swelling
-
Inflammatory arthritis
-
Pulmonary disease
-
Peripheral neuropathy, especially mononeuritis
Patients and health care providers should be aware that, although uncommon, significant harms may be associated with the use of rituximab and should exercise caution and observe for the following when using rituximab in patients with Sjögren syndrome:
-
Infusion reactions
-
Tumor lysis syndrome in patients with non-Hodgkin lymphoma
-
Progressive multifocal leukoencephalopathy
-
Hepatitis B reactivation with possible fulminant hepatitis
-
Severe mucocutaneous reactions
-
Infections
-
Bowel obstruction and perforation
-
Cardiac arrhythmias and angina
-
Cytopenias
-
Serious bacterial, viral, or fungal infections
Other recommendations regarding rituximab included the following:
-
Particularly careful consideration of risk versus benefit is necessary in pregnant and nursing patients
-
Live vaccines should be avoided in patients taking rituximab
Pulmonary disease
The Sjögren’s Foundation published guidelines on Sjögren syndrome–related pulmonary disease in 2021. [105] Recommendations on upper and lower airway disease in patients with Sjögren syndrome included the following:
-
Evaluate patients with dry bothersome cough and absence of lower airway or parenchymal lung disease for treatable or preventable etiologies other than xerotrachea.
-
Encourage all patients to stop smoking.
-
Bronchoscopic biopsy is not recommended in patients with symptomatic small airway disease.
-
Perform complete pulmonary function testing in patients with symptomatic small airway disease.
Treatment for clinically relevant bronchiectasis:
-
Mucolytic agents/expectorants
-
Nebulized or hypertonic saline
-
Oscillatory positive expiratory pressure
-
Postural drainage
-
Mechanical high-frequency chest wall oscillation therapies
-
Long-term macrolide antibiotics (in patients without Mycobacterium colonization or infection)
Interstitial lung disease (ILD) :
-
High-resolution CT with expiratory views and oximetry testing are recommended in Sjögren syndrome patients with suspected ILD.
-
All Sjögren syndrome patients must be immunized against influenza and pneumococcal infection.
-
Long-term oxygen therapy is recommended for Sjögren syndrome patients with suspected ILD and clinically significant hypoxemia.
-
Consider mycophenolate mofetil or azathioprine in Sjögren syndrome patients with symptomatic ILD when long-term corticosteroid use is contemplated and steroid-sparing immunosuppressive therapy is required. Note that there are cautions for each of those medications.
European League Against Rheumatism guidelines
In 2019, the European League Against Rheumatism (EULAR) published guidelines on the management of Sjögren syndrome with topical and systemic therapies. [103] EULAR recommends that patients with Sjögren syndrome be managed at, or in close collaboration with, centers of expertise following a multidisciplinary approach. Specific recomendations are listed below.
Dry mouth
Baseline evaluation of salivary gland function, including measurement of whole salivary flows, and exclusion of unrelated conditions, is recommended before starting treatment for oral dryness.
The preferred first therapeutic approach for oral dryness according to salivary gland function may be as follows:
-
Mild dysfunction - Nonpharmacological stimulation (eg, sugar-free acidic candies, lozenges, xylitol, sugar-free chewing gum)
-
Moderate dysfunction - Pharmacological stimulation (eg, pilocarpine, cevimeline; anetholtrithione, bromhexine, N-acetylcysteine in cases of intolerance or non-response)
-
Severe dysfunction - Saliva substitution
The guidelines recommend against using any of the following for oral dryness:
-
Hydroxychloroquine
-
Oral glucocorticoids
-
Immunosuppressive agents
-
Rituximab
Dry eyes
The first-line therapeutic approach to ocular dryness includes the use of artificial tears and ocular gels/ointments. Refractory/severe ocular dryness may be managed in stepwise fashion, as follows:
- Topical ocular non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids may be prescribed by ophthalmologists as a short-term therapeutic approach (maximum 2–4 weeks); if no response or intolerance, then
- Topical cyclosporine; if no response or intolerance, then
- Serum eye drops; if no response or intolerance, then
- Rescue therapies - Oral muscarinic agonists or plug insertion
Fatigue and/or pain:
-
Concomitant diseases should be evaluated in patients presenting with fatigue/pain, whose severity should be scored using specific tools (eg, EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI], Profile of Fatigue, Brief Pain Inventory).
-
Consider analgesics or other pain-modifying agents for musculoskeletal pain, considering the balance between potential benefits and side-effects.
Systemic disease:
-
Treatment of systemic disease should be tailored to organ-specific severity using the EULAR Sjögren's syndrome disease activity index (ESSDAI) definitions.
-
Glucocorticoids should be used at the minimum dose and length of time necessary to control active systemic disease (eg, pulses of methylprednisolone followed by doses of 0.5 mg/kg/d or lower as induction therapy in severe presentations, and doses< 0.5 mg/kg/d in moderate/less-severe presentations, with a final target of withdrawing glucocorticoids in patients with inactive disease as soon as possible or at least trying to target a maintenance dose of 5 mg/daily or less with the aid of glucocorticoid-sparing immunosuppressive agents).
-
Immunosuppressive agents (eg, leflunomide, methotrexate, azathioprine, mycophenolate, cyclophosphamide) should be mainly used as glucocorticoid-sparing agents, with no evidence supporting the choice of one agent over another.
-
B-cell–targeted therapies (eg, rituximab, epratuzumab, belimumab) may be considered in patients with severe, refractory systemic disease.
-
The systemic organ-specific therapeutic approach may follow, as a general rule, the sequential (or combined) use of glucocorticoids, immunosuppressive agents, and biologics.
-
Treatment of B-cell lymphoma should be individualized according to the specific histologic subtype and disease stage.
-
Marked bilateral parotid gland enlargement in a patient with primary Sjögren syndrome. Sicca syndrome is a common clinical finding. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
-
Clinical photograph and photomicrograph of a 48-year-old man with Sjögren syndrome with a large left parotid mass. On biopsy, B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type was identified. Microscopic section of parotid biopsy, stained with immunoperoxidase for kappa light chains (brown-stained cells), showed monoclonal population of B cells, confirming the diagnosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
-
Photograph that demonstrates the Schirmer test, which is used to detect deficient tear production in patients with Sjögren syndrome. The filter paper strip is placed at the junction of the eyelid margins. After 5 minutes, 15 mm of paper should be moistened if tear production is normal, as shown here. Persons older than 40 years may moisten between 10 mm and 15 mm. Patients with Sjögren syndrome have less moistening. Sjögren syndrome is most common in patients with rheumatoid arthritis but may also occur without associated disease and in systemic lupus erythematosus, polyarteritis, systemic sclerosis, lymphoma, and sarcoidosis. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
-
Dryness of the mouth and tongue due to lack of salivary secretion is characteristic of xerostomia associated with Sjögren syndrome. Mouth dryness may produce a deep red tongue, as shown here, and dental caries are common. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
-
Photomicrograph of a lip biopsy specimen showing two lymphocytic foci adjacent to normal-appearing mucinous acini typical of minor salivary gland abnormalities in Sjögren syndrome. (C) 1972-2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
