Version May 2024
INTRODUCTION — Sjögren's disease (SjD) is a chronic, multisystem autoimmune rheumatic disease characterized by lacrimal and salivary gland inflammation, with resultant dryness of the eyes and mouth and occasional glandular enlargement. In addition, a variety of systemic (so-called "extraglandular") manifestations may occur, including fatigue, musculoskeletal pain, rashes, and internal organ (eg, pulmonary, renal, hepatic, and neurologic) disease. There is also increased risk of non-Hodgkin B-cell lymphoma.
SjD occurs in a primary form, not associated with other autoimmune rheumatic diseases, and in an associated or overlap form, in which there is a concomitant second systemic autoimmune rheumatic disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, and, less commonly, polymyositis/dermatomyositis.
The treatment of salivary gland enlargement, extraglandular manifestations affecting other organs and tissues, and constitutional symptoms will be reviewed here. An overview of the systemic treatment and prognosis of SjD, the clinical manifestations and diagnosis of SjD, and the treatment of dry eyes, dry mouth (including the use of muscarinic agonists such as pilocarpine and cevimeline as secretagogues), and other nonocular sicca symptoms, as well as neurologic manifestations of SjD, are described in detail separately. (See "Overview of the management and prognosis of Sjögren's disease" and "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Diagnosis and classification of Sjögren’s disease" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease" and "Neurologic manifestations of Sjögren's disease".)
OVERVIEW OF MANAGEMENT — An overview of the management and prognosis of Sjögren's disease (SjD) is presented separately (see "Overview of the management and prognosis of Sjögren's disease"). Key elements are reviewed briefly here together with the evidence supporting our approach to drug therapy. (See 'Approach to drug therapy' below and 'Therapy for organ-based disease and constitutional symptoms' below and 'Therapeutic rationale and evidence overview' below and 'Efficacy of specific therapeutic agents' below.)
Treatment goals and principles — The goals of therapy in patients with SjD are to ameliorate symptoms of dry eye and mouth, prevent complications of mucosal dryness (such as dental decay, corneal ulceration, or oral candidal infection), and detect and manage systemic manifestations and glandular and lymphoproliferative disease.
General principles that apply to the management of patients with SjD include care by a multidisciplinary team; the necessity of a thorough pretreatment evaluation; and treatment tailored to the individual patient with attention to the particular manifestations, severity of symptoms, and disease complications. These principles are described in greater detail separately. (See "Overview of the management and prognosis of Sjögren's disease", section on 'Treatment goals and principles'.)
Pretreatment evaluation — The pretreatment evaluation should include the following elements, which are described in detail separately (see "Overview of the management and prognosis of Sjögren's disease", section on 'Pretreatment evaluation'):
●Confirmation of the diagnosis of SjD and that the clinical manifestation targeted for treatment is due to SjD (see "Overview of the management and prognosis of Sjögren's disease", section on 'Confirmation of the diagnosis')
●Assessment of disease activity, based upon features of the history and physical examination, laboratory testing, and histopathologic findings (see "Overview of the management and prognosis of Sjögren's disease", section on 'Assessment of disease activity and severity')
●Clinical determination of the disease subset, depending upon the presence or absence of glandular enlargement and the degree of systemic involvement (see "Overview of the management and prognosis of Sjögren's disease", section on 'Determining disease subset')
Nonpharmacologic and preventive interventions — All patients should receive nonpharmacologic and preventive interventions, including patient education and vaccinations. Several nonpharmacologic measures and other interventions are typically employed, as described in detail separately. (See "Overview of the management and prognosis of Sjögren's disease", section on 'Nonpharmacologic and preventive interventions'.)
Approach to drug therapy — Choice of therapy varies according to the organ manifestations and disease severity:
●Dry eye, dry mouth, and other sicca symptoms – SjD patients with sicca symptoms but without glandular enlargement or other organ involvement do not require systemic therapy other than secretagogues since ocular and oral symptoms generally do not improve with the use of systemic immunosuppressive agents. The treatment of dry eyes and of dry mouth and other nonocular sicca symptoms is described in detail separately. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)
●Organ-based disease and constitutional symptoms – The approach to extraglandular manifestations such as skin rashes, arthritis, vasculitis, and pulmonary and renal manifestations is generally similar to that used for systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), depending upon the manifestation and its severity. Treatment of glandular lymphoproliferation and more severe extraglandular manifestations generally includes the use of glucocorticoids; antimalarials (hydroxychloroquine); conventional nonbiologic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, leflunomide, azathioprine, sulfasalazine, mycophenolic acid, and cyclosporine; and other potent agents, including the alkylating agent cyclophosphamide and the anti-CD20 antibody rituximab, which targets B cells. (See 'Therapy for organ-based disease and constitutional symptoms' below.)
There is only limited direct evidence to support this approach, which is based upon clinical practice guidelines, case series, limited clinical trial data for a few agents, our clinical experience, expert opinion, and indirect evidence from the use of these agents in other autoimmune rheumatic disorders. Recommendations for the management of SjD with systemic therapies have been published by the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [1], the Sjögren's Foundation [2], British Society of Rheumatology [3], and Japan College of Rheumatology [4] as well as in a French National Diagnostic and Care Protocol [5]. (See 'Therapeutic rationale and evidence overview' below and 'Efficacy of specific therapeutic agents' below.)
THERAPY FOR ORGAN-BASED DISEASE AND CONSTITUTIONAL SYMPTOMS — In addition to the sicca symptoms, therapy may also require attention to glandular, lymphoproliferative, and systemic disease manifestations. The specific treatment depends upon the severity of involvement, the organs and tissues specifically affected, and the prior response to therapy.
Salivary gland enlargement — Enlargement of the major salivary glands may develop at any point during the disease course; may be unilateral, bilateral, acute and intermittent, or chronic; and regresses spontaneously in some patients.
We take the following approach:
●Acute unilateral glandular swelling – Sudden painful unilateral salivary gland swelling with fever and erythema overlying the involved site should prompt concern for acute bacterial sialadenitis. Initial management includes the use of broad-spectrum antibiotics, hydration, and milking of the salivary glands to culture an infectious organism. Imaging by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) is used to rule out ductal obstruction and/or abscess formation. (See "Suppurative parotitis in adults".)
An episode of acute unilateral glandular swelling and discomfort without signs of infection is initially managed symptomatically with hot compresses, analgesics, milking of the affected salivary gland, and sucking on lemon drops. The swelling is often triggered by eating and can occur from ductal obstruction due to sialolithiasis or sialostenosis with mucus plugs. (See "Salivary gland stones".)
Recurrent episodes should be managed prophylactically with therapeutic doses of secretagogues (eg, pilocarpine, cevimeline) to increase salivary flow as well as regular milking of the salivary glands [6,7]. Sialoendoscopy may also be used to alleviate major salivary duct obstruction in refractory cases [6].
●Major salivary glandular enlargement – Intermittent subacute major salivary glandular enlargement most often affects the parotid glands and is caused by autoimmune sialadenitis. In the experience of the authors and other experts, this problem can be effectively managed with short courses of glucocorticoids (prednisone 20 mg/day for one week followed by a gradual taper to finish a two-week course) [8].
Chronic persistent salivary gland enlargement related to autoimmune sialadenitis is often difficult to manage, but patients can be reassured that the enlargement may sometimes resolve spontaneously over time. The enlargement is usually bilateral, although it may be asymmetric. It may be relapsing and remitting or persistent. Patients who report intermittent swelling often have chronically enlarged glands that do not cause other symptoms [9].
Systemic treatment is generally reserved for those patients with cosmetic concerns, glandular pain, or systemic involvement that would otherwise justify this therapeutic approach. We frequently use daily hydroxychloroquine or weekly methotrexate in doses equivalent to those used for rheumatoid arthritis (RA) to manage this problem (see "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'). Rituximab may be effective for autoimmune sialadenitis but is usually reserved for SjD patients with more serious organ involvement [2,10]. In a survey of North American pediatric rheumatologists, respondents reported prescribing hydroxychloroquine, corticosteroids, and methotrexate for the majority of pediatric SjD cases with recurrent parotitis. Rituximab, mycophenolate mofetil, abatacept, azathioprine, and belimumab were used in a minority of patients [11].
●Persistent major salivary gland swelling for more than 12 weeks – Major salivary gland swelling that persists for more than 12 weeks despite therapy should prompt concern for non-Hodgkin B-cell lymphoma, especially in circumstances where the involvement is unilateral and/or the gland feels indurated, nodular, or is associated with regional adenopathy [12]. Bilateral parotid gland enlargement, sometimes massive, is a less common presentation of salivary gland lymphoma.
Such patients should undergo evaluation for glandular lymphoma or other neoplasm, which typically includes MRI or computed axial tomography of the neck and referral to an otolaryngologist or ultrasound radiologist for a fine-needle aspiration or ultrasound-guided core-needle biopsy [13,14]. In the evaluation of suspected lymphoma, it is important to collect specimens for flow cytometry (core-needle specimens and/or fine-needle aspirates) in addition to a core-needle biopsy for histopathologic analysis. Excisional biopsy may be required if the diagnosis remains indeterminate. An approach to treatment of lymphoma in SjD is described below. (See 'Lymphoma' below.)
In SjD patients on chronic glucocorticoids, persistent parotid gland swelling may occur due to fatty infiltration, and management includes discontinuation of glucocorticoids in favor of other immunosuppressive therapies (if still needed) and weight-loss counseling.
●Lacrimal gland enlargement – Clinically overt enlargement of the lacrimal glands is uncommon in SjD. Its presence in a patient presenting for evaluation of possible SjD should prompt concern for alternative diagnoses, such as sarcoidosis and IgG4-related disease. In addition, lacrimal gland enlargement may be a presenting feature of lymphoma affecting the ocular adnexa in SjD.
Musculoskeletal pain — Treatment for musculoskeletal pain depends upon the cause of the symptoms, their severity, and the response to therapy; the spectrum of inflammatory musculoskeletal pain in SjD ranges from mild arthralgias and myalgias to frank synovitis and chronic pain. Additionally, age-related osteoarthritis and fibromyalgia may also contribute to musculoskeletal pain in SjD patients.
●Arthralgia and arthritis – Patients with mild joint symptoms, including those with mild arthritis and those with arthralgia and myalgia but lacking definite inflammatory synovitis, may be managed with nonsteroidal antiinflammatory drugs (NSAIDs) in antiinflammatory doses given daily or as needed depending upon symptom frequency.
Patients with an inadequate response to NSAIDs after a one- to two-month trial or with moderate to severe symptoms usually require a traditional nonbiologic disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine or low-dose weekly methotrexate, depending upon the severity of symptoms, in doses typically used for RA [1-3,15-20]. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye examinations'.)
Our approach is consistent with clinical practice guidelines for the use of DMARDs in inflammatory musculoskeletal pain in SjD that were issued in 2017 by a national consensus panel and that reaffirmed the use of hydroxychloroquine as initial therapy followed by methotrexate and other agents, if needed. Choice of therapy also depends on the patient's other medical problems and careful consideration of the risk-benefit ratio [2]. These guidelines were based upon uncontrolled studies, similarity to the approach used to treat systemic lupus erythematosus (SLE) and mild RA, and the expert opinion of the consensus panel. Treatment-refractory cases, especially SjD patients with overlapping features of RA, may occasionally require biologic therapy with rituximab or a tumor necrosis factor (TNF) alpha inhibitor [2].
●Fibromyalgia – Up to 40 percent of SjD patients may also develop fibromyalgia as a comorbid illness and cause of musculoskeletal pain; thus, attention to sleep hygiene, treatment of nocturnal dryness, aerobics, and stretching exercises may alleviate symptoms. Management is very similar to fibromyalgia in patients without SjD, except that the use of medications with anticholinergic side effects is best avoided; these agents may exacerbate nighttime dryness and further disrupt sleep. The treatment of fibromyalgia is described in detail separately. (See "Treatment of fibromyalgia in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Systemic lupus erythematosus and Sjögren's disease'.)
In SjD patients with musculoskeletal pain of uncertain etiology, a two-week course of low-dose prednisone (15 mg/day) followed by a rapid taper can sometimes help differentiate inflammatory from noninflammatory causes. A positive response may justify further treatment with immunosuppressive therapy.
Fatigue — As seen in other connective tissue disease patients, fatigue occurs frequently in SjD and can occasionally be severe and disabling. It is often multifactorial, and other related or coincidental causes of fatigue may contribute to patient symptoms. Thus, the initial approach to management includes a thorough evaluation to identify the etiology or etiologies of fatigue in the individual patient.
In patients with SjD, the major potential causes, in addition to the disease itself, include:
●A sleep disturbance (especially restless legs syndrome and obstructive sleep apnea) [21,22]
●Fibromyalgia
●Depression
●Hypothyroidism
●Dysautonomia
●Severe deficiencies of vitamin B12 and/or vitamin D
●Anemia
An approach to the evaluation of the adult patient with fatigue is presented in detail separately. (See "Approach to the adult patient with fatigue".)
In patients with fatigue that is largely related to the SjD itself, we suggest a low-impact aerobic exercise program and various psychoeducational interventions (eg, cognitive behavioral therapy, mindfulness, stress reduction, motivational counseling) as first-line therapy for all patients. In patients with fatigue refractory to exercise and other lifestyle changes, we use hydroxychloroquine in a fashion similar to the approach utilized for SLE. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Treatment of specific SLE manifestations'.)
This approach is consistent with clinical practice guidelines for management of fatigue in SjD that have been developed by a national consensus panel in the United States, which strongly recommended aerobic exercise as first-line therapy for all patients [2]. The efficacy of nonpharmacologic interventions is supported by a systematic review that informed the 2023 European Alliance of Associations for Rheumatology (EULAR) recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases [23]. The choice of other therapies is customized for every individual depending on the results of the evaluation.
For those patients with disabling fatigue refractory to hydroxychloroquine, we sometimes use a positive response to a two-week course of prednisone 15 mg/day as evidence to support treatment with additional immunosuppressive therapy, including chronic low-dose or alternate-day prednisone, conventional DMARDs, or biologic agents such as rituximab (see "Overview of the management and prognosis of Sjögren's disease"). Given the potential hazards of immunosuppressive therapy, these agents should only be continued in patients who demonstrate significant improvement of fatigue following treatment over a six-month trial period.
Cutaneous manifestations — Several different skin manifestations may occur in patients with SjD and require distinct management approaches:
Pruritus — Pruritus in SjD is common and often exacerbated by xeroderma [24]. It may be treated by the use of oilated soaps and shampoos, less frequent bathing, the application of body oils or skin lotions (eg, 12% ammonium lactate lotion) to wet skin immediately after bathing, and, whenever possible, the discontinuation of medications with anticholinergic effects (see "Pruritus: Therapies for generalized pruritus", section on 'Xerosis (dry skin)'). Pruritus can be an occasional symptom of a small-fiber sensory neuropathy in SjD.
In the authors' experience, dermatographic urticaria also occurs in SjD, can exacerbate chronic pruritus, and can cause migratory cutaneous stinging and burning sensations that mimic neuropathic pain. Symptoms are frequently exacerbated by exposure to tartrazine dyes (ie, Food, Drug, and Cosmetic [FD&C] yellow #5) [25,26]. Treatment with a tartrazine-free and salicylate-free diet, dye-free fexofenadine (60 mg twice/day), and a dye-free famotidine (20 mg twice daily) is effective. Short courses of low-dose oral glucocorticoids (prednisone 15 mg/day or less for two to three months) may be useful in treatment-resistant cases. (See "Physical (inducible) forms of urticaria", section on 'Overview of treatment approach'.)
In patients with pruritus refractory to these treatments, screening for primary biliary cholangitis (primary biliary cirrhosis) is indicated. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)
Annular erythema — Annular erythema may occur in SjD (especially in patients with anti-SSA/Ro antibodies) and resembles subacute cutaneous lupus. This cutaneous eruption is characterized by annular polycyclic lesions with a wide elevated border and central pallor [27]. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Annular erythema'.)
Initial treatment options include topical steroids, tacrolimus, or pimecrolimus; in patients with more extensive and severe skin involvement, treatment may require oral glucocorticoids (eg, prednisone 5 to 30 mg/day) [28-30] in combination with hydroxychloroquine.
For recurrent skin lesions, we use systemic therapies that have benefit in cutaneous lupus, including hydroxychloroquine (with or without concomitant quinacrine) or low-dose weekly methotrexate. SjD patients with treatment-refractory skin lesions should be referred to a dermatologist for skin biopsy, confirmation of the diagnosis, and consideration of other therapies. Additional options include low-dose cyclosporine, mycophenolate mofetil, dapsone, thalidomide or its analogs, and azathioprine [30,31]. (See "Overview of cutaneous lupus erythematosus", section on 'Management' and "Initial management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus" and "Management of discoid lupus erythematosus and subacute cutaneous lupus erythematosus refractory to antimalarial therapy".)
Cutaneous vasculitis — Cutaneous vasculitis in SjD, which presents as palpable or nonpalpable purpura, erythematous macules or papules, urticarial-like lesions, cutaneous ulcers, and, rarely, digital necrosis [32], is most often caused by leukocytoclastic vasculitis and may occur with or without cryoglobulinemia. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Cutaneous vasculitis'.)
SjD patients with cutaneous vasculitis should be evaluated for other organ involvement, especially that of the kidneys, joints, and peripheral nervous system; such testing should include serum cryoglobulins, complement levels, and testing for hepatitis C (see "Diagnosis and classification of Sjögren’s disease", section on 'Diagnostic testing'). The presence or absence of serum cryoglobulins in an SjD patient with palpable purpura serves to differentiate two broad categories of cutaneous vasculitis with prognostic implications [33].
Patients with recurrent flat, petechial or small purpuric lesions on the lower extremities (often termed "benign hypergammaglobulinemic purpura of Waldenström") [34,35] (see "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Cutaneous vasculitis') can be effectively managed with compression stockings, avoidance of prolonged standing, and hydroxychloroquine [36] (see "Antimalarial drugs in the treatment of rheumatic disease"). In the absence of cryoglobulins, this form of vasculitis is generally not associated with systemic manifestations of vasculitis, such as neuropathy and nephritis [33]. Colchicine 0.6 mg twice/day [37] may also be effective in suppressing the lesions. Patients who are refractory to standard therapies or have more severe symptoms may require a two- to three-week course of prednisone 15 to 30 mg/day followed by rapid taper.
Individuals with treatment-refractory attacks, or whose biopsies demonstrate involvement of medium-sized muscular arteries, should also be evaluated for the presence of cryoglobulins. They are treated with oral DMARDs (eg, methotrexate, leflunomide [38], azathioprine) or intravenous (IV) rituximab at doses typically used to manage RA [2,34] or with longer courses of glucocorticoids (eg, prednisone <30 mg/day). (See "Initial treatment of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Patients with severe cutaneous ulceration, digital necrosis, or life-threatening organ involvement may require treatment with plasma exchange, high-dose oral or IV pulse glucocorticoids, cyclophosphamide, or rituximab [2,39].
Cryoglobulinemic vasculitis warrants special consideration and is treated according to the severity of the skin disease and extent/severity of internal organ involvement (eg, peripheral neuropathy, glomerulonephritis, etc). It is often associated with underlying or evolving lymphoma. Additionally, hepatitis C must be excluded since its presence would mandate consideration of antiviral therapy. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Cutaneous vasculitis' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Vasculitis' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Cryoglobulins' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Lymphoma' and "Mixed cryoglobulinemia syndrome: Treatment and prognosis".)
Raynaud phenomenon — Raynaud phenomenon is common, especially in the subset of patients with anticentromere antibodies, and is treated as it is in other rheumatic diseases. (See "Treatment of Raynaud phenomenon: Initial management".)
Cardiopulmonary manifestations
●Interstitial lung disease – Interstitial lung disease (most commonly nonspecific interstitial pneumonitis) occurs in approximately 10 percent of SjD patients and is often more successfully treated with corticosteroids than lung disease in RA and systemic sclerosis. In the 2021 Sjogren’s Foundation consensus guidelines for the evaluation and management of pulmonary disease in SjD, it was recommended that all patients be screened for pulmonary disease with a baseline chest radiograph and pulmonary function testing for lung volumes, spirometry, and bronchodilators [40]. Symptomatic patients should also undergo high-resolution computerized axial tomography of the chest. Comprehensive management of interstitial pneumonitis and pulmonary manifestations of SjD is reviewed elsewhere. (See "Interstitial lung disease associated with Sjögren's disease: Management and prognosis".)
●Xerotrachea – Xerotrachea related to exocrine gland dysfunction may also contribute to the patient symptoms (eg, cough) and may, in the authors' experience, be alleviated with therapeutic doses of secretagogues or guaifenesin.
●Pulmonary hypertension – Pulmonary hypertension is treated according to paradigms established for other connective tissue diseases, such as SLE and systemic sclerosis [41]. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis" and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Treatment'.)
●Pleuropericarditis – Pleuritis and pericarditis are rare in SjD and should always prompt evaluation for SLE, an overlap syndrome, or other causes. Treatment approaches parallel those used in SLE. Depending upon the specific problem and severity, useful agents to treat one or both of these manifestations may include NSAIDs, colchicine 0.6 mg twice/day, glucocorticoids, or azathioprine. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults", section on 'Pericardial disease' and "Pulmonary manifestations of systemic lupus erythematosus in adults".)
Kidney — The principal types of renal involvement are interstitial nephritis (IN) with renal tubular acidosis (RTA) and, less commonly, membranoproliferative glomerulonephritis (GN) [27]. The renal manifestations of SjD and their management are described separately. (See "Kidney disease in primary Sjögren's disease".)
Other renal problems include thrombotic glomerulopathy as in the antiphospholipid syndrome (APS) (see "Antiphospholipid syndrome and the kidney" and "Management of antiphospholipid syndrome"). The treatment of APS-causing thrombotic glomerulopathy in SjD is the same as for patients with SLE. (See "Antiphospholipid syndrome and the kidney", section on 'Kidney disease in APS associated with systemic lupus erythematosus' and "Management of antiphospholipid syndrome".)
Gastrointestinal
●Gastroesophageal reflux – Many patients have symptoms of gastroesophageal reflux disease (GERD), with resultant laryngotracheal irritation. Treatment of these problems with proton pump inhibitors, H2 blockers, promotility agents, and dietary modification is similar to that for patients with GERD without SjD. The use of secretagogues to stimulate saliva flow and neutralize stomach acid may also be beneficial. (See "Medical management of gastroesophageal reflux disease in adults" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease", section on 'Inadequate response to salivary stimulation and substitutes'.)
●Dysphagia – Dysphagia may occur due to dryness, reflux, esophageal dysmotility, or, less commonly, the presence of a Zenker's diverticulum or esophageal web. Upper endoscopy and/or a barium swallow with video esophagogram will usually reveal the cause and facilitate treatment. Use of secretagogues may alleviate dysphagia related to dryness. (See "Approach to the evaluation of dysphagia in adults" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease", section on 'Inadequate response to salivary stimulation and substitutes'.)
●Atrophic gastritis – Atrophic gastritis and associated pernicious anemia may require parenteral or sublingual vitamin B12 supplementation [42]. We exclude Helicobacter pylori as a potential cause of the gastritis in these patients. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Gastrointestinal tract' and "Treatment of vitamin B12 and folate deficiencies".)
●Celiac disease – The incidence of celiac disease may be higher in SjD than in the general population [43], and treatment for this problem may prevent neurologic manifestations that mimic SjD, including ataxic peripheral neuropathies and nutritional deficiencies. (See "Management of celiac disease in adults".)
●Primary biliary cholangitis and autoimmune hepatitis – Primary biliary cholangitis (primary biliary cirrhosis) and chronic active autoimmune hepatitis may be associated with SjD and are treated as detailed separately [44,45]. (See "Overview of the management of primary biliary cholangitis" and "Management of autoimmune hepatitis".)
●Diarrhea – Diarrhea in the SjD patient may occur as a side effect of secretagogue use, small intestinal bacterial overgrowth syndrome (SIBO) [46], concomitant celiac disease [43], or lymphocytic colitis [47]. Treatment depends upon the specific diagnosis and is the same as in patients without SjD. (See "Management of celiac disease in adults" and "Approach to the adult with acute diarrhea in resource-abundant settings" and "Approach to the adult with chronic diarrhea in resource-abundant settings".)
Neurologic manifestations — Management of the neurologic manifestations of SjD varies depending upon the particular form of neurologic involvement and is discussed in detail separately. (See "Neurologic manifestations of Sjögren's disease".)
Hematologic — Hematologic manifestations are common in SjD and include cytopenias, monoclonal gammopathies, and non-Hodgkin B-cell lymphoma [48]. (See 'Cytopenias' below and 'Monoclonal gammopathy' below and 'Lymphoma' below.).
Cytopenias
●Leukopenia – The majority of patients with leukopenia, including those with neutropenia, are asymptomatic and do not require specific therapy. The use of antibiotics is reserved for those with infections. In patients with severe infections or those requiring surgery, treatment may include glucocorticoids, intravenous immune globulin (IVIG), or granulocyte-stimulating factors [49,50]. We use glucocorticoids with or without IVIG before granulocyte-stimulating factor. Case reports highlight the potential benefit of mycophenolate mofetil [51], but not methotrexate [50], as chronic therapy for agranulocytosis. T-cell large granular lymphocytic leukemia is a rare cause of neutropenia in SjD and has a specific treatment protocol [52]. (See "Treatment of large granular lymphocyte leukemia".)
●Thrombocytopenia – Immune thrombocytopenia in SjD is often mild and clinically silent. Severe cases are treated as in other systemic rheumatic diseases, with glucocorticoids and IVIG or rituximab. (See "Initial treatment of immune thrombocytopenia (ITP) in adults".)
●Anemia – The most common form is a mild normochromic normocytic anemia of chronic inflammation, which does not require specific treatment. Other forms include hemolytic anemia, pure red cell aplasia, and pernicious anemia. Treatment should be tailored to the cause and is the same as it would be for a patient without SjD. (See "Acquired pure red cell aplasia in adults", section on 'Management' and "Treatment of vitamin B12 and folate deficiencies" and "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'.)
Monoclonal gammopathy — Monoclonal proteins are present in up to 20 percent of patients, and occasionally herald the onset of a plasma cell dyscrasia or lymphoma. We evaluate these according to guidelines recommended for monoclonal gammopathy of undetermined significance (see "Diagnosis of monoclonal gammopathy of undetermined significance") and monitor relevant laboratory studies (eg, serum-free light chain ratio, immunoglobulin levels) on an annual basis unless specific symptoms arise suggesting the development of a hematologic malignancy. In addition, monoclonal proteins may be an indication of cryoglobulinemia [53]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)
Lymphoma — The treatment of lymphomas seen in patients with SjD [54], including marginal zone lymphomas (MZL; both extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue [MALT lymphoma] and nodal MZL) and large B-cell lymphoma, uses the same regimens as in patients without SjD. (See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)" and "Initial treatment of limited stage diffuse large B cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell lymphoma".)
However, the management of MALT lymphoma in SjD involves unique considerations, including its usual noninfectious etiology, frequent occurrence with SjD systemic disease manifestations, and potential for specific therapy-related complications. Approaches to the management of MALT lymphoma of the parotid gland in SjD have been outlined by two sets of investigators [55,56]. The initial staging evaluation should include MRI or CT of the head and neck to define the extent of salivary gland involvement and the presence of enlarged regional lymph nodes. The need for CT of the chest and abdomen, bone marrow biopsy, and upper gastrointestinal endoscopy is debated and depends on the patient's clinical presentation. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)
For patients with localized MALT and mild extraglandular disease, a strategy of watchful waiting may be adopted. This approach may also apply to some asymptomatic patients with disseminated disease but low SjD activity. Indications for treatment include cosmetic concerns or pain associated with the parotid enlargement. We do not use low-dose involved field radiotherapy to treat enlarged salivary glands, because it has the potential to aggravate xerostomia if a significant amount of salivary gland tissue is included in the radiation field.
The primary indications for treatment of MALT lymphoma are disseminated (bone marrow or nodal) disease and adverse prognostic markers (eg, International Prognostic Index score>1 (see "Prognosis of diffuse large B cell lymphoma")) and those with severe extraglandular SjD disease activity. The favored treatment regimens include rituximab, either alone or with additional chemotherapy.
THERAPEUTIC RATIONALE AND EVIDENCE OVERVIEW — Our approach is based upon case series, clinical trial data, our clinical experience, and expert opinion, including consensus guidelines [1-5,15,16,40,57-62]. It is also supported by indirect evidence from the use of these agents in other autoimmune rheumatic disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), which sometimes overlap with Sjögren's disease (SjD). (See "Overview of the management and prognosis of systemic lupus erythematosus in adults" and "General principles and overview of management of rheumatoid arthritis in adults".)
There is inadequate evidence of efficacy and safety to justify use of systemic immunosuppressants to treat sicca symptoms alone or use of immunosuppressive drugs or biologic agents as long-term disease suppressants. The use of these agents in patients with SjD is thus primarily supported by indirect evidence, including their benefit for clinical manifestations of SLE or features of SjD in patients with RA. Clinical trials assessing the efficacy of therapeutic agents for cardinal disease manifestations of SjD, such as dryness, pain, and fatigue, have been severely limited by the absence of ideal primary endpoints, disease heterogeneity, the challenge of distinguishing between disease activity and permanent damage, and uncertainty as to the best inclusion criteria and trial duration [63]. Accordingly, randomized trials of most agents studied have yielded negative results, and efforts to define better clinical trial endpoints and outcome measures are ongoing [64-67]. Thus, none of the traditional disease-modifying antirheumatic drugs (DMARDs) or biologic agents used for treatment of SjD have been approved by the US Food and Drug Administration (FDA) specifically for use in SjD.
EFFICACY OF SPECIFIC THERAPEUTIC AGENTS
Glucocorticoids — There have been no large trials addressing the potential benefit of glucocorticoids for the glandular manifestations of Sjögren’s disease (SjD). In a small randomized, controlled trial, neither prednisone (30 mg every other day) nor piroxicam (20 mg/day) treatment, compared with placebo, resulted in significant improvement of salivary and lacrimal gland function or salivary gland histopathology after six months [68]. By contrast, in an uncontrolled open-label trial involving 20 SjD patients, prednisolone therapy (mean starting dose of 15 mg/day, tapering to 5 to 7.5 mg/day after 12 months and 5 mg/day after 30 months) was associated with a significant increase in whole saliva flow compared with baseline starting at one month and sustained to the end of the trial at 48 months [69]. The authors use brief courses of glucocorticoids for acute episodes of noninfectious sialadenitis but have not observed any significant benefit from prolonged glucocorticoids for treatment of sicca.
Long-term use of glucocorticoids in SjD is also tempered by concern for potential side effects, including osteoporosis, hyperglycemia, weight gain, agitation, and increased risk of infections, as in rheumatoid arthritis (RA) and other diseases (see "Major adverse effects of systemic glucocorticoids"). In SjD patients, an increased risk of oral candidiasis and acceleration of dental decay further limit the prolonged use of glucocorticoids at higher dose [70].
Glucocorticoids are sometimes used to treat systemic manifestations of SjD in a manner similar to that in other systemic rheumatic and autoimmune diseases [15]. In an analysis of 1120 Spanish patients with primary SjD, low-dose glucocorticoids (equivalent to prednisone ≤20 mg/day) were used for this purpose in 19 percent of such patients [71].
Conventional immunosuppressive drugs and nonbiologic DMARDs — Disease-modifying antirheumatic drugs (DMARDs) are primarily used to treat specific organ manifestations in a manner similar to systemic lupus erythematosus (SLE), particularly to taper or replace glucocorticoids. Their utility for the treatment of glandular manifestations of the disease has been disappointing. Briefly, clinical trials of these agents have included the following:
●Hydroxychloroquine – Therapy with hydroxychloroquine is largely based upon its efficacy in SLE [17,18]. Small, open-label trials and observational studies have found improvement in arthralgias, myalgias, acute phase reactants, and hypergammaglobulinemia [19,72-74]. In a three-year longitudinal analysis of the Korean Initiative SS cohort (KISS) of 256 patients, the use of hydroxychloroquine was associated with a significant lowering of serum IgG levels and less solid organ damage [75]. However, a 24-week randomized trial involving 120 patients did not reach its primary endpoint of 30 percent or greater reduction in two of three numeric analog scales evaluating fatigue, pain, or dryness [76].
●Methotrexate – A one-year pilot study of methotrexate (0.2 mg/kg weekly) in 17 patients with primary SjD showed improvement in dry mouth and eye symptoms, arthralgias, arthritis, and the frequency of parotid gland enlargement and purpura. However, no improvement in objective parameters of dry eyes and dry mouth was observed [77]. A retrospective case review of articular manifestations in a large French cohort also reported benefit in 11 of 12 SjD patients treated with methotrexate for musculoskeletal pain [74].
●Azathioprine – In a randomized trial of low-dose azathioprine (1 mg/kg/day) in 25 patients with primary SjD, there was no significant change in disease activity over a period of six months [78]. However, azathioprine at higher doses is commonly used in the management of specific extraglandular involvement, such as interstitial pneumonitis, myelopathy, and chronic active autoimmune hepatitis.
●Leflunomide – In an open-label pilot study, leflunomide (20 mg/day) provided only modest benefits for 15 patients with early and active primary SjD [79]. However, there was notable improvement in leukocytoclastic vasculitis in three patients. The treatment was associated with the development of lupus-like skin lesions in five patients. In a study of RA, leflunomide therapy was associated with worsening of eye dryness in a group of 45 patients with RA with secondary SjD as compared with 30 without secondary SjD [38]. A small, controlled, randomized 24-week trial of combination therapy with leflunomide (20 mg/day) and hydroxychloroquine (400 mg/day) showed significant clinical efficacy (improvement of European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] scores versus baseline) when compared with placebo alone in a study involving 29 patients; these results need verification in a larger study [80].
●Mycophenolate – In an open-label pilot study of 11 patients with primary SjD, mycophenolate in doses up to 1440 mg/day for six months did not improve objective measures of ocular or oral dryness but did lead to significant reductions in hypergammaglobulinemia and rheumatoid factor (RF) and an increase in complement and white blood count levels [81]. A small retrospective case series from France reported benefit or stabilization of SjD-related sensory ganglionopathy in 11 of 12 SjD patients following treatment with mycophenolate mofetil and glucocorticoids or mycophenolate alone [82]. A case report documented thatthis medication was also effective in treating refractory agranulocytosis in a patient with primary SjD [51].
●Cyclosporine – In a randomized trial, cyclosporine (5 mg/kg/day) resulted in symptomatic improvement of dry mouth at six months, compared with placebo, but no change in dry eye symptoms or objective parameters of ocular and oral dryness [83]. In an open-label extension, labial gland histopathology worsened at 12 months in cyclosporine-treated patients [84]. In an open-label trial of low dose cyclosporine (2mg/kg/day) in 30 SjD patients with active articular involvement, there was a significant reduction in tender and swollen joints after 16 weeks of treatment [85].
Rituximab — Rituximab, a chimeric monoclonal antibody directed against the CD20 cell surface marker on B cells and their precursors, has been studied extensively as a treatment option [86]. The findings have been variable, as illustrated by a number of reports, including randomized trials, open-label studies, and retrospective case reports and series [87-91]. In the two largest randomized trials of rituximab, the primary outcome measures, reduction of patient-reported dryness and fatigue, were not met, although the suitability of these outcome measures has been questioned [89,92,93]. The drug has been reported to be of benefit for specific extraglandular manifestations in retrospective case series and registry analyses.
●Randomized trials
•The Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS) trial was a multicenter 24-week trial of rituximab versus placebo for dryness and fatigue (given in two infusions over two weeks) [89]. It enrolled 120 SjD patients and demonstrated some symptomatic improvement at weeks 6 and/or 16 in disease activity, fatigue, and dryness. However, the study failed to document a statistically significant difference in the primary study endpoint at six months, defined as at least 30 mm improvement in two of four visual analog scales for global disease, pain, fatigue, and dryness. Limitations of the study included low disease activity at baseline and a primary outcome that may have been insensitive to detecting clinically important changes [92].
•A study of anti-B-cell therapy in patients with primary SjD, called the TRACTISS trial, was a multicenter 48-week trial of rituximab versus placebo for fatigue and dryness (given as infusions at 0, 2, 24, and 26 weeks). Among 133 randomized patients, there were no significant differences in any outcome measures except unstimulated salivary flow, where placebo-treated patients showed a modest decline in flow relative to rituximab-treated patients [94].
•In a randomized trial, 30 patients with SjD and measurable baseline salivary flow (ie, stimulated salivary flow rate ≥0.15 mL/minute) were assigned to receive rituximab (20 patients) or placebo (10 patients) [91]. All patients received intravenous (IV) methylprednisolone before infusion and a tapering course of oral prednisolone afterward. There was significant improvement in salivary secretion and visual analog scales for oral and ocular dryness in the rituximab treatment group. These benefits were observed between 12 and 36 weeks after treatment but not at the 48-week endpoint of the trial.
•In a randomized trial involving 17 patients, rituximab did not reduce fatigue, the primary outcome measure (≥20 percent improvement in fatigue visual analog scale), compared with placebo [90]. Both the drug and placebo groups showed improvement, which could be attributed to glucocorticoid usage.
●Open-label trials – Open-label trials that each included small numbers of patients have been conducted with administration of rituximab either alone or in comparison with conventional DMARDs. Modest improvements in salivary gland function and patient-reported symptoms of fatigue, quality of life, and dryness were observed, but only in patients with residual salivary gland function [87,95-97]. The ESSDAI also decreased, mainly due to improvements in constitutional, glandular, hematologic, and biologic domains [88,98].
In a prospective, two-center follow-up study of 41 patients with early active SjD, unstimulated saliva flow rates significantly improved at 120 weeks in the 19 patients who received rituximab treatments every 24 weeks, compared with the 22 patients who received conventional DMARD therapy [98]. There was also a significant decrease in labial salivary gland lymphocytic infiltration (as measured by focus score) in the rituximab-treated patients. These findings need to be reproduced in a randomized trial but suggest that prolonged therapy with rituximab in early active disease is needed to realize significant clinical benefit.
●Retrospective case series and registry analyses – Parotid swelling, arthritis/arthralgias, cryoglobulinemic vasculitis, peripheral neuropathy, and scleritis have been treated successfully with rituximab in a number of observational studies [99-106].
●Safety of rituximab in Sjögren's syndrome
•Several reports have included a small number of patients who experienced adverse effects of rituximab therapy for extraglandular SjD, including serum-sickness-like reactions [107,108], infusion reactions [89], and interstitial lung disease [109]. In other conditions, such as SLE treated with rituximab, progressive multifocal encephalopathy has been reported [110,111].
•The use of methylprednisolone 100 mg as a premedication before IV rituximab infusion is associated with a low risk of infusion or serum-sickness-like reactions [87,89-91].
•In our experience, a slower rate of infusion is preferred, particularly during the initial infusions (over three to four hours), although the rate may be increased during subsequent infusions if there are no infusion reactions [112].
Other biologic agents
●Tumor necrosis factor inhibitors – Several small studies and randomized trials of both infliximab and etanercept failed to demonstrate benefit in patients with SjD [113-115]. In one randomized trial involving 103 patients who received infliximab or placebo, there were no significant differences in the change from baseline in pain, fatigue, or sicca symptoms or in objective measures of salivary flow, swollen joints, tender joints, erythrocyte sedimentation rate (ESR), or C-reactive protein (CRP) [113]. Similarly, no benefit was seen in a trial involving 28 patients who were randomly assigned to receive either etanercept or placebo, despite a 19 percent decrease in the ESR over the 12-week study in the etanercept group [115]. A previous study, which had reported benefit from treatment with infliximab, was subsequently retracted [116-118].
●Belimumab – Belimumab, a monoclonal antibody directed against B-cell activating factor, was evaluated in an open-label trial of 30 primary SjD patients, which found a modest reduction in symptoms of dryness but not in fatigue at 28 and 52 weeks [119,120]. Saliva flow, Schirmer testing, and salivary biopsy focus score results did not change. However, there was improvement in nonmalignant parotid enlargement, arthritis/arthralgia, and in B-cell biomarker values, including serum immunoglobulin and RF levels.
●Abatacept – Abatacept, a T cell costimulation blocker approved for the treatment of RA, showed promising results in two small open-label studies [121,122]. However, it was not more efficacious than placebo in the treatment of moderate to severe primary SjD in two large randomized trials. The first was a single-center study of 80 patients in which treatment with subcutaneous abatacept (125 mg each week) was associated with a greater improvement than placebo in systemic disease activity (as measured by the ESSDAI) at week 12, but not at week 24, the primary outcome measure [123]. The second study was a global, multicenter randomized trial of 187 patients. There was no statistically significant difference between abatacept and placebo in terms of change in ESSDAI or patient-reported severity of pain, fatigue, or dryness (using the EULAR SjD Patient-Reported Index [ESSPRI] scale) at day 169 [124]. In both trials, there was evidence of biologic activity of abatacept, but a robust placebo response may have obscured evidence of clinical efficacy.
●Tocilizumab – Tocilizumab, an interleukin 6 (IL-6) receptor inhibitor, was assessed for clinical benefit in primary SjD in a multicenter randomized trial involving 110 patients and lasting 24 weeks. Tocilizumab treatment, relative to placebo, was not associated with any greater improvement in systemic involvement and symptoms [125].
Other agents in clinical trials — A number of other therapeutic approaches have been tried or are under investigation in SjD. In randomized placebo-controlled clinical trials, the primary outcome of a significant reduction in systemic disease activity (as measured by the ESSDAI) was achieved for remibrutinib (a Bruton tyrosine kinase inhibitor) [126], low-dose IL-2 [127]; ianalumab (BAFF receptor inhibitor and B-cell depleter) [128], iscalimab (CD40 blockade) [129], telitacicept (BAFF and APRIL inhibitor) [130], and dazodalibep (CD40 ligand antagonist) [131]. These positive results await verification in larger phase 3 trials. Further clinical testing was not pursued due to side effects or inefficacy for thalidomide, oromucosal interferon alfa [132], anakinra [133], baminercept [134], seletalisib [135], prezalumab [136], petesicatib [137], and efalizumab [138]. Information concerning ongoing trials in the United States can be found at www.clinicaltrials.gov.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sjögren's disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Sjögren's disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Overall approach – Evaluation and management of Sjögren's disease (SjD) should be provided by a multidisciplinary team. Patients should undergo a thorough pretreatment evaluation to confirm the diagnosis and determine the severity and extent of disease and the disease subset. The approach to management is generally the same for primary or secondary SjD. (See 'Treatment goals and principles' above and 'Pretreatment evaluation' above.)
●Nonpharmacologic interventions – All patients should receive nonpharmacologic and preventive interventions, including patient education regarding self-care measures and the benefits of smoking cessation, counseling regarding diet and medication use, routine preventive care and immunizations, and pregnancy counseling. (See 'Nonpharmacologic and preventive interventions' above.)
●Sicca management – In patients with mild SjD, which includes those with sicca symptoms alone, without glandular enlargement or other organ involvement, treatment generally does not require systemic therapy other than secretagogues, in addition to local treatment for ocular, oral, and other symptoms of dryness, monitoring of the condition, and usual medical and dental preventive care. (See "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease".)
●Approach to other disease manifestations – Management of patients with moderate to severe involvement depends on the clinical manifestation, tissues, and organ system affected, and may involve systemic medical therapy, including the use of immunosuppressives and biologic agents. Treatment has been influenced by the approach for other systemic rheumatic diseases, particularly systemic lupus erythematosus (SLE) as well as rheumatoid arthritis (RA). (See 'Approach to drug therapy' above and 'Therapy for organ-based disease and constitutional symptoms' above and 'Therapeutic rationale and evidence overview' above and 'Efficacy of specific therapeutic agents' above.)
We generally use the following approach:
•Salivary gland enlargement – Symptomatic treatment may be sufficient for some patients with salivary gland enlargement, particularly those with acute unilateral involvement. For patients with major salivary glandular enlargement who have an inadequate response to symptomatic management, we suggest a short course of glucocorticoids (Grade 2C). A typical regimen is prednisone 20 mg/day for one week followed by a gradual taper to finish a two-week course. Patients with recurrent obstructive symptoms related to sialolithiasis or sialostenosis can be managed prophylactically with secretagogues. Patients with acute salivary gland swelling and fevers due to bacterial sialadenitis require broad-spectrum antibiotics. Recurrent episodes of glucocorticoid-responsive autoimmune sialadenitis can be prevented with the use of hydroxychloroquine or methotrexate. Patients with major salivary gland swelling that persists for more than 12 weeks despite therapy should undergo evaluation for malignancy, especially when the gland feels indurated, nodular, or is associated with regional adenopathy. (See 'Salivary gland enlargement' above.)
•Musculoskeletal pain – In patients with mild joint symptoms, including mild arthritis and/or arthralgia and myalgia, we suggest nonsteroidal antiinflammatory drugs (NSAIDs) in antiinflammatory doses given daily or as needed depending upon symptom frequency (Grade 2C). For patients with an inadequate response to NSAIDs or with moderate to severe symptoms, we suggest a traditional nonbiologic disease-modifying antirheumatic drug (DMARD), such as hydroxychloroquine or low-dose weekly methotrexate in doses typically used for RA (Grade 2C). Fibromyalgia is treated in the same fashion as in patients without SjD except that we attempt to minimize the use of agents with strong anticholinergic properties. (See 'Musculoskeletal pain' above and "Treatment of fibromyalgia in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Treatment'.)
•Fatigue – In patients with fatigue that is largely related to the SjD itself, we treat initially with a low-impact aerobic exercise program and energy conservation measures. In patients with fatigue refractory to exercise and other lifestyle changes, we suggest hydroxychloroquine in a fashion similar to the approach utilized for SLE, rather than glucocorticoids or a DMARD (Grade 2C). Other comorbidities that can cause fatigue in SjD patients should be identified and treated separately. (See 'Fatigue' above.)
•Cutaneous manifestations – Treatment of cutaneous manifestations of SjD varies by the condition. Pruritus is largely managed symptomatically. Annular erythema is treated initially with topical steroids or topical calcineurin inhibitors, or with oral glucocorticoids (prednisone 5 to 30 mg/day) for more severe or widespread disease; for recurrent skin lesions, we use systemic therapies that have benefit in cutaneous lupus, such as hydroxychloroquine or low-dose weekly methotrexate. Treatment of cutaneous vasculitis depends upon the cause and whether an associated illness is present and may include local measures, colchicine, glucocorticoids, or nonbiologic or biologic DMARDs. (See 'Pruritus' above and 'Annular erythema' above and 'Cutaneous vasculitis' above.)
•Raynaud phenomenon – Raynaud phenomenon is treated as it is in other rheumatic diseases. (See 'Raynaud phenomenon' above and "Treatment of Raynaud phenomenon: Initial management".)
•Cardiopulmonary disease – The treatment of most cardiopulmonary manifestations, including interstitial lung disease, pulmonary hypertension, and pleuropericarditis, is approached in the same way as in patients with other systemic rheumatic disorders, such as SLE or systemic sclerosis. (See 'Cardiopulmonary manifestations' above.)
•Renal disease – The management of interstitial nephritis (IN) with renal tubular acidosis (RTA) and glomerulonephritis (GN) are described separately. The treatment of thrombotic glomerulopathy caused by antiphospholipid syndrome (APS) in SjD is the same as for patients with SLE. (See "Kidney disease in primary Sjögren's disease".)
•Gastrointestinal disorders – Treatment of any of the various gastrointestinal disorders associated with SjD requires a careful diagnostic evaluation and appropriate therapeutic interventions for the primary disorder (eg, gastroesophageal reflux or dysmotility) and for aspects of the SjD that may be contributing to the disorder (eg, treatment with secretagogues to improve salivary flow). Associated conditions (eg, celiac disease or primary biliary cholangitis [cirrhosis]) should be identified and treated as in patients without SjD. (See 'Gastrointestinal' above.)
•Neurologic manifestations – The treatment of neurologic manifestations differs depending upon the specific involvement. (See 'Neurologic manifestations' above and "Neurologic manifestations of Sjögren's disease".)
•Hematologic abnormalities – Hematologic manifestations include cytopenias, monoclonal gammopathies, and non-Hodgkin B-cell lymphoma. (See 'Hematologic' above.)
-The majority of patients with leukopenia do not require specific therapy. Specific intervention (which may include glucocorticoids, intravenous immune globulin (IVIG), or granulocyte-stimulating factors) is reserved for patients with severe infections or those requiring surgery. (See 'Cytopenias' above.)
-Severe immune thrombocytopenia is treated as in other rheumatic diseases. (See "Initial treatment of immune thrombocytopenia (ITP) in adults".)
-We evaluate monoclonal proteins according to guidelines recommended for monoclonal gammopathy of undetermined significance and monitor relevant laboratory studies on an annual basis unless specific symptoms arise suggesting the development of a hematologic malignancy. (See 'Monoclonal gammopathy' above.)
-The treatment of lymphomas seen in patients with SjD uses the same regimens as in patients without SjD, although the management of extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) in SjD involves unique considerations. (See 'Lymphoma' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to earlier versions of this topic review.
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