Treatment of Sjögren's Syndrome - Constitutional and Non-Sicca Organ-Based Manifestations - UpToDate

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Treatment of Sjögren's syndrome: Constitutional and

non-sicca organ-based manifestations
Authors: Alan N Baer, MD, MACR, Frederick B Vivino, MD, MS, FACR
Section Editor: Robert Fox, MD, PhD
Deputy Editor: Philip Seo, MD, MHS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2023. | This topic last updated: Feb 24, 2022.
INTRODUCTION
Sjögren's syndrome (SS) is a chronic, multisystem autoimmune 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 symptoms,
rashes, and internal organ (eg, pulmonary, renal, hepatic, and neurologic) disease. There is
also increased risk of non-Hodgkin B-cell lymphoma.
SS occurs in a primary form, not associated with other autoimmune rheumatic diseases, and
in a secondary form, often associated with 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 SS, the clinical manifestations and diagnosis of SS, 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 SS, are described in detail separately. (See "Overview of the
management and prognosis of Sjögren's syndrome" and "Clinical manifestations of Sjögren's
syndrome: Exocrine gland disease" and "Clinical manifestations of Sjögren's syndrome:
Extraglandular disease" and "Diagnosis and classification of Sjögren's syndrome" and
"Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy" and
"Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome" and
"Neurologic manifestations of Sjögren's syndrome".)
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OVERVIEW OF MANAGEMENT
An overview of the management and prognosis of Sjögren's syndrome (SS) is presented

separately (see "Overview of the management and prognosis of Sjögren's syndrome"). 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 SS 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 SS 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 syndrome",
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 syndrome", section on 'Pretreatment evaluation'):
● Confirmation of the diagnosis of SS and that the clinical manifestation targeted for
treatment is due to SS (see "Overview of the management and prognosis of Sjögren's
syndrome", 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 syndrome", 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 syndrome", 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 syndrome", 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 – SS 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 syndrome: General principles and
initial therapy" and "Treatment of dry mouth and other non-ocular sicca symptoms in
Sjögren's syndrome".)
● 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 SS with
systemic therapies have been published by the European Alliance of Associations for
Rheumatology (EULAR; formerly known as European League Against Rheumatism) [1],
Sjögren's Foundation [2], and British Society of Rheumatology [3]. (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 [4,5]. Sialoendoscopy may also be used to alleviate major
salivary duct obstruction in refractory cases [4].
● 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) [6].
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
are not of cosmetic concern or do not cause other symptoms [7].
Systemic treatment is generally reserved for those patients with cosmetic concerns,
glandular pain, or systemic involvement that would otherwise warrant it. 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 SS patients with more serious organ involvement [2,8].
● 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. 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 [9,10]. 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 SS is described below. (See 'Lymphoma' below.)
In SS 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.
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 SS ranges from mild arthralgias and myalgias to frank synovitis and
chronic pain.
● 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 [1-3,11-16]. (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 SS 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, depending 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 SS 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 SS patients may also develop fibromyalgia as a

comorbid illness and a contributor to musculoskeletal pain; thus, attention to sleep
hygiene, nocturnal dryness, aerobics, and stretching exercises may alleviate symptoms.
Management is very similar to fibromyalgia in patients without SS, 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 "Initial treatment of fibromyalgia in adults" and
"Treatment of fibromyalgia in adults not responsive to initial therapies".)
In SS 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.
Fatigue — As with other connective tissue disease patients, fatigue in SS can occasionally be
severe and disabling but is often multifactorial, and other related or coincidental causes of
fatigue may contribute to the symptoms. The initial step in managing fatigue in patients
with SS is a thorough evaluation to identify the etiology of fatigue in the individual patient.
In patients with SS, the major potential causes, in addition to the disease itself, include:
● A sleep disturbance (especially restless legs syndrome and obstructive sleep apnea)
[17,18]
● 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 SS itself, we suggest a low-impact
aerobic exercise program and energy conservation measures 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 SS
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 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 syndrome"). 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 SS and require distinct management approaches:
Pruritus — Pruritus in SS is common and often exacerbated by xeroderma. 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)'.)
In the authors' experience, dermatographic urticaria also occurs in SS, 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) [19,20]. 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 SS (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
[21]. (See "Clinical manifestations of Sjögren's syndrome: 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) [22-24].
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. SS 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 [24,25]. (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 SS, which presents as palpable or

nonpalpable purpura, erythematous macules or papules, urticarial-like lesions, cutaneous
ulcers, and, rarely, digital necrosis [26], is most often caused by leukocytoclastic vasculitis
and may occur with or without cryoglobulinemia. (See "Clinical manifestations of Sjögren's
syndrome: Extraglandular disease", section on 'Cutaneous vasculitis'.)
SS 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 syndrome", section on 'Diagnostic testing'). The presence or
absence of serum cryoglobulins in an SS patient with palpable purpura serves to
differentiate two broad categories of cutaneous vasculitis with prognostic implications [27].
Patients with recurrent flat, petechial or small purpuric lesions on the lower extremities
(often termed "benign hypergammaglobulinemic purpura of Waldenström") [28,29] (see
"Clinical manifestations of Sjögren's syndrome: Extraglandular disease", section on
'Cutaneous vasculitis') can be effectively managed with compression stockings, avoidance of
prolonged standing, and hydroxychloroquine (dosing of which is described separately) [30]
(see "Antimalarial drugs in the treatment of rheumatic disease", section on 'Routine eye
examinations'). In the absence of cryoglobulins, this form of vasculitis is generally not
associated with systemic manifestations of vasculitis, such as neuropathy and nephritis [27].
Colchicine 0.6 mg twice/day [31] 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 [32], azathioprine) or
intravenous (IV) rituximab at doses typically used to manage RA [2,28] 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 [2,33].
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 syndrome:
Extraglandular disease", section on 'Cutaneous vasculitis' and "Clinical manifestations of
Sjögren's syndrome: Extraglandular disease", section on 'Vasculitis' and "Clinical
manifestations of Sjögren's syndrome: Extraglandular disease", section on 'Cryoglobulins'
and "Clinical manifestations of Sjögren's syndrome: 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 SS patients and is often
more successfully treated than lung disease in RA and systemic sclerosis.
Comprehensive management of interstitial pneumonitis and pulmonary manifestations
of SS is reviewed elsewhere. (See "Interstitial lung disease associated with Sjögren
syndrome: 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 [34]. (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 SS 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)
[21]. The renal manifestations of SS and their management are described separately. (See
"Kidney disease in primary Sjögren syndrome".)
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
SS 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
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with proton pump inhibitors, H2 blockers, promotility agents, and dietary modification
is similar to that for patients with GERD without SS. 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 syndrome", 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 syndrome", 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 [35]. We exclude Helicobacter
pylori as a potential cause of the gastritis in these patients. (See "Clinical manifestations
of Sjögren's syndrome: 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 SS than in the general
population [36], and treatment for this problem may prevent neurologic manifestations
that mimic SS, including ataxic 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 SS and are treated as detailed separately [37,38]. (See "Overview of the
management of primary biliary cholangitis" and "Autoimmune hepatitis: Treatment".)
● Diarrhea – Diarrhea in the SS patient may occur as a side effect of secretagogue use,
small intestinal bacterial overgrowth syndrome (SIBO) [39], concomitant celiac disease
[36], or lymphocytic colitis [40]. Treatment depends upon the specific diagnosis and is
the same as in patients without SS. (See "Management of celiac disease in adults" and
"Approach to the adult with acute diarrhea in resource-rich settings" and "Approach to
the adult with chronic diarrhea in resource-abundant settings".)
Neurologic manifestations — Management of the neurologic manifestations of SS varies

depending upon the particular form of neurologic involvement and is discussed in detail
separately. (See "Neurologic manifestations of Sjögren's syndrome".)
Hematologic — Hematologic manifestations are common in SS and include cytopenias,

monoclonal gammopathies, and non-Hodgkin B-cell lymphoma [41]. (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 [42,43]. We use glucocorticoids with
or without IVIG before granulocyte-stimulating factor. Case reports highlight the
potential benefit of mycophenolate mofetil [44], but not methotrexate [43], as chronic
therapy for agranulocytosis.
● Thrombocytopenia – Immune thrombocytopenia in SS 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 SS. (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, most often in the absence 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 [45]. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and
diagnosis".)
Lymphoma — The treatment of lymphomas seen in patients with SS [46], 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 SS. (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 SS involves unique considerations,

including its usual noninfectious etiology, frequent occurrence with SS systemic disease
manifestations, and potential for specific therapy-related complications. Approaches to the
management of MALT lymphoma of the parotid gland in SS have been outlined by two sets
of investigators [47,48]. 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 SS 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 SS 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 [1-3,11,12,49-54]. 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 syndrome (SS). (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
SS is thus primarily supported by indirect evidence, including their benefit for clinical
manifestations of SLE or features of SS in patients with RA. Clinical trials assessing the
efficacy of therapeutic agents for cardinal disease manifestations of SS, such as dryness,
pain, and fatigue, have been severely limited by the absence of ideal primary endpoints,
disease heterogeneity, and uncertainty as to the best inclusion criteria and trial duration
[55]. Accordingly, randomized trials of most agents studied have yielded negative results,
and efforts to define better clinical trial endpoints and outcome measures are ongoing [56-
59]. Thus, none of the traditional disease-modifying antirheumatic drugs (DMARDs) or
biologic agents used for treatment of SS have been approved by the US Food and Drug
Administration (FDA) specifically for use in SS.
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 syndrome (SS). In our
experience, however, some benefit for glandular enlargement but not for sicca symptoms
may be observed. In a small randomized 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 [60].
Long-term use of glucocorticoids in SS 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 side effects of
systemic glucocorticoids"). In SS patients, an increased risk of oral candidiasis and
acceleration of dental decay further limit the prolonged use of glucocorticoids at higher
dose [61].
Glucocorticoids are sometimes used to treat systemic manifestations of SS in a manner

similar to that in other systemic rheumatic and autoimmune diseases [11]. In an analysis of
1120 Spanish patients with primary SS, low-dose glucocorticoids (equivalent to prednisone
≤20 mg/day) were used for this purpose in 19 percent of such patients [62].
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 [13,14]. Small, open-label trials and observational studies have found
improvement in arthralgias, myalgias, acute phase reactants, and

hypergammaglobulinemia [15,63-65]. However, a randomized trial involving 120
patients did not show benefit for fatigue, pain, or dryness [66].
● Methotrexate – A one-year pilot study of methotrexate (0.2 mg/kg weekly) in 17

patients with primary SS 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 [67]. A retrospective case review of articular manifestations in a large French
cohort also reported benefit in 11 of 12 SS patients treated with methotrexate for
musculoskeletal pain [65].
● Azathioprine – In a randomized trial of low-dose azathioprine (1 mg/kg/day) in 25

patients with primary SS, there was no significant change in disease activity over a
period of six months [68]. 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 SS [69]. 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 SS as compared with 30 without
secondary SS [32]. Combination therapy with leflunomide (20 mg/day) and
hydroxychloroquine (400 mg/day) had 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 24-week randomized trial involving 29 patients; these results need
verification in a larger study [70].
● Mycophenolate – In an open-label pilot study of 11 patients with primary SS,

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 [71]. A small retrospective case series from France
reported benefit or stabilization of SS-related sensory ganglionopathy in 11 of 12 SS
patients following treatment with mycophenolate mofetil and glucocorticoids or
mycophenolate alone [72]. This medication was effective in treating agranulocytosis in
a patient with primary SS [44].
● 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 [73]. In
an open-label extension, labial gland histopathology worsened at 12 months in
cyclosporine-treated patients [74].
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 [75]. The findings have been variable, as illustrated by a number of reports, including
randomized trials, open-label studies, and retrospective case reports and series [76-80]. 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 [78,81,82]. 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) [78]. It enrolled 120 SS 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 [81].
• A study of anti-B-cell therapy in patients with primary SS, 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 [83].
• In a randomized trial, 30 patients with SS 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) [80]. 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 [79]. 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 [76,84-86]. The ESSDAI also decreased,
mainly due to improvements in constitutional, glandular, hematologic, and biologic
domains [77,87].
In a prospective, two-center follow-up study of 41 patients with early active SS,

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 [87]. 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 [88-
95].
● 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 SS, including serum-sickness-like
reactions [96,97], infusion reactions [78], and interstitial lung disease [98]. In other
conditions, such as SLE treated with rituximab, progressive multifocal
encephalopathy has been reported [99,100].
• 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
[76,78-80].
• 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 [101].
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 SS [102-104]. 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) [102]. 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 [104]. A previous study, which had reported benefit
from treatment with infliximab, was subsequently retracted [105-107].
● Belimumab – Belimumab, a monoclonal antibody directed against B-cell activating

factor, was evaluated in an open-label trial of 30 primary SS patients, which found a
modest reduction in symptoms of dryness but not in fatigue at 28 and 52 weeks
[108,109]. 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 [110,111]. However, it was
not more efficacious than placebo in the treatment of moderate to severe primary SS 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 [112]. The
second study was a global, multicenter randomized trial of 187 patients. In a
preliminary report, 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 SS Patient-Reported Index [ESSPRI] scale) at day 169 [113].
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 SS in a multicenter randomized trial involving 110 patients
and lasting 24 weeks. In a preliminary report, relative to placebo, tocilizumab treatment
was not associated with any greater improvement in systemic involvement and
symptoms [114].
Other agents in clinical trials — A number of other therapeutic approaches have been
tried or are under investigation in SS. Further clinical testing was not pursued due to side
effects or inefficacy for thalidomide, oromucosal interferon alfa [115], anakinra [116],
baminercept [117], and efalizumab [118]. 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
syndrome".)
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 syndrome (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Evaluation and management of Sjögren's syndrome (SS) 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
SS. (See 'Treatment goals and principles' above and 'Pretreatment evaluation' above.)
● 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.)
● In patients with mild SS, 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 syndrome:
General principles and initial therapy" and "Treatment of dry mouth and other non-
ocular sicca symptoms in Sjögren's syndrome".)
● 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 SS except that we
attempt to minimize the use of agents with strong anticholinergic properties. (See
'Musculoskeletal pain' above and "Initial treatment of fibromyalgia in adults".)
• Fatigue – In patients with fatigue that is largely related to the SS 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 SS patients should be identified and treated separately. (See
'Fatigue' above.)
• Cutaneous manifestations – Treatment of cutaneous manifestations of SS 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 SS is
the same as for patients with SLE. (See "Kidney disease in primary Sjögren
syndrome".)
• Gastrointestinal disorders – Treatment of any of the various gastrointestinal

disorders associated with SS requires a careful diagnostic evaluation and
appropriate therapeutic interventions for the primary disorder (eg,
gastroesophageal reflux or dysmotility) and for aspects of the SS 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 SS. (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 syndrome".)
• 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 thrombocytopenic purpura 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 SS uses the same regimens
as in patients without SS, although the management of extranodal marginal
zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)
in SS involves unique considerations. (See 'Lymphoma' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to earlier
versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
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Topic 113735 Version 8.0
Contributor Disclosures
Alan N Baer, MD, MACR Grant/Research/Clinical Trial Support: Viela Bio [Sjögren's syndrome].
Consultant/Advisory Boards: Bristol-Myers Squibb [Sjögren's syndrome]. All of the relevant financial
relationships listed have been mitigated. Frederick B Vivino, MD, MS, FACR Grant/Research/Clinical
Trial Support: Immco Diagnostics [Sjögren's syndrome]. Consultant/Advisory Boards: Bristol Myers
Squibb [Sjögren's syndrome]; Horizon Therapeutics [Sjögren's syndrome]; ICON plc [Sjögren's
syndrome]; Immco Diagnostics [Sjögren's syndrome]; Novartis [Sjögren's syndrome]. All of the relevant
financial relationships listed have been mitigated. Robert Fox, MD, PhD Consultant/Advisory Boards:
Celgene [Sjögren's syndrome]; Novartis [Sjögren's syndrome]. All of the relevant financial relationships
listed have been mitigated. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible
companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
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Treatment of Sjögren's syndrome: Constitutional and

Sjögren's syndrome (SS) is a chronic, multisystem autoimmune disease characterized by

The treatment of salivary gland enlargement, extraglandular manifestations affecting other

An overview of the management and prognosis of Sjögren's syndrome (SS) is presented

Treatment goals and principles — The goals of therapy in patients with SS are to

Pretreatment evaluation — The pretreatment evaluation should include the following

Nonpharmacologic and preventive interventions — All patients should receive

employed, as described in detail separately. (See "Overview of the management and

Approach to drug therapy — Choice of therapy varies according to the organ

● Organ-based disease and constitutional symptoms – The approach to

THERAPY FOR ORGAN-BASED DISEASE AND CONSTITUTIONAL SYMPTOMS

Salivary gland enlargement — Enlargement of the major salivary glands may develop at

We take the following approach:

● Acute unilateral glandular swelling – Sudden painful unilateral salivary gland

An episode of acute unilateral glandular swelling and discomfort without signs of

Recurrent episodes should be managed prophylactically with therapeutic doses of

● Major salivary glandular enlargement – Intermittent subacute major salivary

Chronic persistent salivary gland enlargement related to autoimmune sialadenitis is

In SS patients on chronic glucocorticoids, persistent parotid gland swelling may occur

Musculoskeletal pain — Treatment for musculoskeletal pain depends upon the cause of

modifying antirheumatic drug (DMARD) such as hydroxychloroquine or low-dose

● Fibromyalgia – Up to 40 percent of SS patients may also develop fibromyalgia as a

In SS patients with musculoskeletal pain of uncertain etiology, a two-week course of low-

For those patients with disabling fatigue refractory to hydroxychloroquine, we sometimes

Cutaneous manifestations — Several different skin manifestations may occur in patients

Pruritus — Pruritus in SS is common and often exacerbated by xeroderma. It may be

Annular erythema — Annular erythema may occur in SS (especially in patients with anti-

Initial treatment options include topical steroids, tacrolimus, or pimecrolimus; in patients

Cutaneous vasculitis — Cutaneous vasculitis in SS, which presents as palpable or

Individuals with treatment-refractory attacks, or whose biopsies demonstrate involvement of

Patients with severe cutaneous ulceration, digital necrosis, or life-threatening organ

Cryoglobulinemic vasculitis warrants special consideration and is treated according to the

Raynaud phenomenon — Raynaud phenomenon is common, especially in the subset of

● Interstitial lung disease – Interstitial lung disease (most commonly nonspecific

● Xerotrachea – Xerotrachea related to exocrine gland dysfunction may also contribute

● Pulmonary hypertension – Pulmonary hypertension is treated according to

Other renal problems include thrombotic glomerulopathy as in the antiphospholipid

● Gastroesophageal reflux – Many patients have symptoms of gastroesophageal reflux

● Primary biliary cholangitis and autoimmune hepatitis – Primary biliary cholangitis

Neurologic manifestations — Management of the neurologic manifestations of SS varies

Hematologic — Hematologic manifestations are common in SS and include cytopenias,

● Leukopenia – The majority of patients with leukopenia, including those with

● Thrombocytopenia – Immune thrombocytopenia in SS is often mild and clinically

● Anemia – The most common form is a mild normochromic normocytic anemia of

Monoclonal gammopathy — Monoclonal proteins are present in up to 20 percent of

Lymphoma — The treatment of lymphomas seen in patients with SS [46], including

However, the management of MALT lymphoma in SS involves unique considerations,

THERAPEUTIC RATIONALE AND EVIDENCE OVERVIEW

There is inadequate evidence of efficacy and safety to justify use of systemic

EFFICACY OF SPECIFIC THERAPEUTIC AGENTS

Glucocorticoids — There have been no large trials addressing the potential benefit of

Glucocorticoids are sometimes used to treat systemic manifestations of SS in a manner

Conventional immunosuppressive drugs and nonbiologic DMARDs — Disease-modifying

● Hydroxychloroquine – Therapy with hydroxychloroquine is largely based upon its

improvement in arthralgias, myalgias, acute phase reactants, and

● Methotrexate – A one-year pilot study of methotrexate (0.2 mg/kg weekly) in 17

● Azathioprine – In a randomized trial of low-dose azathioprine (1 mg/kg/day) in 25

● Leflunomide – In an open-label pilot study, leflunomide (20 mg/day) provided only

● Mycophenolate – In an open-label pilot study of 11 patients with primary SS,

● Cyclosporine – In a randomized trial, cyclosporine (5 mg/kg/day) resulted in

Rituximab — Rituximab, a chimeric monoclonal antibody directed against the CD20 cell