Version May 2024
INTRODUCTION — Sjögren's disease (SjD) is a chronic, multisystem autoimmune disorder 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.
SjD occurs in a primary form, not associated with other autoimmune rheumatic diseases, and in an associated form, in which classification criteria for a second systemic autoimmune rheumatic disease, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or systemic sclerosis, are fulfilled.
An overview of the systemic treatment and prognosis of SjD will be reviewed here. 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), other nonocular sicca symptoms, and manifestations affecting other organs and tissues are described in detail separately. (See "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 "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)
TREATMENT GOALS AND PRINCIPLES — The goals of therapy in patients with Sjögren's disease (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. The following general principles apply to the management of patients with SjD:
●Evaluation and management should be provided by a multidisciplinary team; a rheumatologist, an eye care professional, and a dentist or oral medicine specialist are often required for optimal care [1].
●Patients should undergo a thorough pretreatment evaluation to determine the severity and extent of disease. (See 'Pretreatment evaluation' below.)
●The approach to management is generally the same for primary or associated SjD and depends upon the severity of symptoms and the response to therapy (see 'Assessment of disease activity and severity' below and 'Determining disease subset' below):
•All patients benefit from nonpharmacologic and preventive interventions, including patient education regarding self-care measures, benefits of smoking cessation, counseling regarding diet and medication use, routine preventive care and immunizations, and pregnancy counseling. (See 'Nonpharmacologic and preventive interventions' below.)
•Patients with mild SjD, in whom sicca manifestations alone are present, without systemic manifestations and without glandular enlargement, may only require local treatment for ocular, oral, and other symptoms of dryness, in addition to monitoring of their 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".)
•Patients with moderate to severe SjD, including extraglandular involvement, may also benefit from systemic therapies, including the use of secretogogues, immunosuppressive and/or biologic agents.
PRETREATMENT EVALUATION — The pretreatment evaluation should include:
●Confirmation of the diagnosis of Sjögren's disease (SjD) and that the clinical manifestation targeted for treatment is due to SjD (see 'Confirmation of the diagnosis' below)
●Assessment of disease activity, based upon features of the history and physical examination, laboratory testing, and histopathologic findings (see 'Assessment of disease activity and severity' below and 'Laboratory evaluation' below and 'Additional studies' below)
●Clinical determination of the disease subset, depending upon the presence or absence of glandular enlargement and the degree of systemic involvement (see 'Determining disease subset' below)
Confirmation of the diagnosis — Before initiating systemic immunomodulatory or immunosuppressive therapies for clinical manifestations of SjD, the underlying diagnosis of SjD should be confirmed and other causes excluded by performing a comprehensive evaluation, as described separately. (See "Diagnosis and classification of Sjögren’s disease".)
There are potential pitfalls in the evaluation of this disease that can lead to an incorrect diagnosis. As examples, these include incorrect interpretation of the labial minor salivary gland biopsy [2], reliance upon low titer test results for anti-SSA/Ro, or the finding of anti-SSB/La antibodies alone [3]. SjD is frequently misdiagnosed as other disorders such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), based upon the presence of a positive antinuclear antibody (ANA) or a positive rheumatoid factor (RF), even in clinical centers with great expertise in SjD [4]. (See "Diagnosis and classification of Sjögren’s disease", section on 'Diagnostic testing'.)
Certain systemic and organ-based manifestations, such as chronic fatigue, joint and muscle pain, orthostatic intolerance, gastrointestinal dysmotility, and neuropathic pain, also need thorough evaluation with respect to their differential diagnosis and presumed etiology. Key considerations include:
●Recognition that SjD commonly overlaps with other autoimmune disorders that may cause additional morbidity. Examples include antisynthetase antibody in a patient with interstitial lung disease, anti-aquaporin-4 antibodies in a patient with myelitis, and an elevated thyroid-stimulating hormone (TSH) in a patient with fatigue from coexistent Hashimoto thyroiditis. (See "Transverse myelitis: Etiology, clinical features, and diagnosis" and "Disorders that cause hypothyroidism", section on 'Chronic autoimmune (Hashimoto's) thyroiditis' and "Clinical manifestations of Sjögren’s disease: Extraglandular disease" and "Clinical manifestations of dermatomyositis and polymyositis in adults".)
●Knowledge that autoantibodies generally thought of as characteristic of other disorders such as anticyclic citrullinated peptide (anti-CCP), anticentromere, and anti-RNP antibodies occur in a small subset of primary SjD patients and may impact disease phenotype and/or portend the later development of a second rheumatic disease or overlap syndrome. This information can affect the choice of treatment. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Autoantibodies' and "Diagnosis and classification of Sjögren’s disease".)
●Awareness that the extraglandular manifestation presumed to be due to SjD may sometimes arise from unrelated comorbid conditions rather than SjD itself. One example is the finding of white matter lesions on magnetic resonance imaging (MRI) of a patient with neurologic symptoms (eg, "brain fog," headache), which are more likely related to age or coincidental hypertension, migraine headaches, hyperlipidemia, or another process. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Differential diagnosis'.)
Assessment of disease activity and severity — Disease activity may be difficult to assess in most patients for whom the clinical course, dominated by sicca manifestations, is relatively stable. It is best judged by the history and physical examination (including serial objective assessment of dry eyes and dry mouth). Markers of activity include inflammatory arthritis, internal organ involvement, intractable and incapacitating fatigue, salivary and/or lacrimal gland enlargement, cutaneous eruptions of annular erythema or palpable purpura, new sensory loss, and leg ulcers.
Certain symptoms and laboratory markers, while useful, need to be interpreted with caution because they lack sensitivity and specificity (see 'Laboratory evaluation' below). Common laboratory abnormalities such as hypergammaglobulinemia, elevated erythrocyte sedimentation rate (ESR), and RF are not always consistent and reliable markers of disease activity.
Fever, weight loss, severe anemia, splenomegaly, and/or clinically apparent generalized lymphadenopathy are uncommon manifestations of SjD and should prompt concern for lymphoproliferative disease or, alternatively, another systemic rheumatic disease (such as systemic lupus) or intercurrent complication (such as infection, coincidental malignancy, or drug toxicity).
ESSPRI and ESSDAI — For clinical trials, disease severity and activity may also be quantified with validated research tools: one assesses the patient's self-report of symptom severity, including dryness, pain, and fatigue, and is termed the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) Sjögren's Syndrome Patient Reported Index (ESSPRI) (form 1). The other scores the extent of exocrine glandular enlargement, organ-specific manifestations, and certain laboratory abnormalities, and is termed the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (table 1) [5]. The ESSPRI is a validated measure of symptom severity, whereas the ESSDAI is a validated measure of disease activity [6]. These measures have been developed for research purposes and are not used in routine clinical practice. The two measures are often not congruent since the subjective experience of dryness, fatigue, and pain correlates poorly with systemic markers of disease activity (eg, serologic testing) and the presence of extraglandular disease.
Laboratory evaluation — In addition to obtaining a detailed clinical history and performing a thorough physical exam, laboratory tests may be used to help assess disease activity and prognosis and monitor organ-specific complications (such as renal or hematologic). Since there is no single marker of disease activity, clinicians must interpret the laboratory results in the appropriate clinical context.
Testing for all patients at initial evaluation — We obtain the following tests for all patients at the initial evaluation for SjD:
●Complete blood count with differential – Leukopenia, anemia, and thrombocytopenia are closely associated with systemic disease activity [7].
●Acute phase reactants – The ESR is often elevated in SjD as a manifestation of hypergammaglobulinemia. A high-sensitivity assay for C-reactive protein CRP levels (hsCRP) may be utilized to assess the risk of cardiovascular disease, which is increased in SjD, as in systemic lupus [8]. (See "C-reactive protein in cardiovascular disease".)
●Chemistry panel – Hypokalemia and low serum bicarbonate are manifestations of renal tubular acidosis; the serum creatinine may be elevated due to nephritis. Elevated liver function tests provide a clue to concurrent autoimmune liver disease or hepatitis C, a potential SjD mimic.
●Urinalysis with examination of urinary sediment – Proteinuria or cellular casts and hematuria may be due to nephritis.
●Serologies – We measure ANA, anti-SSA/Ro, anti-SSB/La, and RF as initial screening tests for SjD. Anti-SSA/Ro antibodies are a key component for the classification of SjD as outlined in the 2016 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) criteria [9]. ANA tests performed by immunofluorescence assay are preferred over those done by solid phase assay since they are more sensitive and the immunofluorescent staining pattern may serve to identify specific ANAs, such as anticentromere antibodies, which are relevant to SjD disease subset. Anti-SSA/Ro and anti-SSB/La antibodies can be detected in patients with negative ANA tests; thus, the algorithm for screening for SjD is different than what is recommended in "Choosing Wisely" test algorithms for other systemic rheumatic diseases [10].
●Exclusion of disease mimics – We routinely obtain serologic testing for hepatitis C in all patients and for human immunodeficiency virus (HIV) in at-risk individuals. We evaluate for immunoglobulin (Ig)-G4-related disease and sarcoidosis with appropriate tests in patients with clinical findings suggestive of these disorders. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis" and "Clinical manifestations and diagnosis of IgG4-related disease".)
Vitamin A deficiency should be excluded in patients with severe dry eye and night blindness or risk factors for nutritional deficiency. (See "Overview of vitamin A", section on 'Deficiency'.)
Testing in confirmed Sjögren's disease to define subset, activity, and prognosis — In a patient with a confirmed diagnosis of SjD, we obtain the following tests to define disease subsets, activity, and prognosis (see 'Determining disease subset' below):
●Complement levels (C3 and C4) – Low complement values are associated with systemic disease activity and can be markers of an increased risk of non-Hodgkin B-cell lymphoma [7].
●Rheumatoid factor – An elevated level of rheumatoid factor, found in approximately 60 percent of patients, is a marker of more severe disease and an increased risk of lymphoma development [11-14].
●Serum protein electrophoresis – Hypergammaglobulinemia and the presence of monoclonal proteins are markers of immune activation. An IgM kappa monoclonal protein is a particular risk factor for lymphoma [15].
●Serum cryoglobulins – These have a strong association with systemic disease activity and risk of non-Hodgkin B-cell lymphoma [15].
●C-reactive protein – CRP levels are often elevated in SjD patients with interstitial lung disease [16-18].
●Other autoimmune serologic tests – We obtain additional autoimmune serologic tests based upon clinical features that might point to an alternative rheumatic disease diagnosis or overlap syndrome. These include anti-DNA, -Sm, and -Sm/RNP antibodies to screen for lupus in patients with serositis, photosensitive rash, oral ulcers, or prominent cytopenia; anticentromere antibodies in those with prominent Raynaud phenomenon, sclerodactyly, or mat telangiectasia; anti-CCP antibodies in those with inflammatory arthritis; and antisynthetase antibodies in those with myositis or interstitial lung disease.
●Creatine kinase – Myositis is a rare complication of the disease.
●Spot (untimed) urine protein: creatinine ratio – Quantification of proteinuria helps assess the severity of glomerular disease and/or detect low molecular weight proteinuria that is easily missed with routine dipstick testing in early cases of tubulointerstitial nephritis [19].
●TSH and vitamin B12 levels – These studies should be obtained in patients with fatigue.
●Celiac disease antibody panel – These studies should be obtained in SjD patients with chronic diarrhea or other symptoms of celiac disease. (See "Diagnosis of celiac disease in adults".)
Additional studies
●Role of minor salivary gland biopsy – We recommend a labial minor salivary gland biopsy to confirm a diagnosis of SjD in those patients lacking or with low titer anti-SSA/Ro antibodies or with anti-SSB/La antibodies alone. Such disease confirmation is important for those patients with systemic manifestations for whom immunosuppressive therapies are being considered. The biopsy also offers useful prognostic information, since the presence of germinal center-like structures and/or a focus score >3 per 4 mm2 (ie, at least three periductal lymphoid aggregates per 4 mm2 of glandular tissue section) are associated with an increased risk of lymphoma [20,21]. It may also identify alternative diagnoses, including mucosa-associated lymphoid tissue (MALT) marginal zone lymphoma, sarcoidosis, amyloidosis, and IgG4-related disease.
●Role of major salivary gland ultrasonography – Ultrasonography of the major salivary glands is emerging as a useful diagnostic tool for SjD at specialized centers. Various abnormalities characterize the sialadenitis of SjD, including heterogeneity and altered echogenicity of the glandular parenchyma with ovoid hypoechoic foci, hyperechoic bands, disappearance of the posterior glandular border, punctate calcifications, increased number of intraparotid lymph nodes, and changes in glandular size [22]. Scoring systems may tabulate the severity of each of these abnormalities or focus primarily on the extent of the hypoechoic foci [22]. A semi-quantitative four-grade scoring system has been developed through consensus by the Outcomes Measures in Rheumatology (OMERACT) task force and is gaining widespread use [23,24].
An abnormal salivary gland ultrasound score correlates with the presence of anti-SSA/Ro antibodies, positive labial or parotid gland biopsy, and more severe disease [25,26]. In a meta-analysis, the pooled sensitivity of salivary gland ultrasound for the diagnostic assessment of SjD was 80 percent (95% CI 77-83 percent), and specificity was 90 percent [27]. Given that patients with SjD may have a negative ultrasound, it does not necessarily replace the invasive labial gland biopsy as a diagnostic tool. The technique is also useful for the evaluation of SjD patients with enlargement or masses of the major salivary glands [28,29].
●Radiographs – Radiographs of symptomatic joints may help identify patients with SjD with overlapping features (eg, erosions) of RA or differentiate joint pain due to inflammatory arthritis from coincidental age-associated degenerative joint disease.
Determining disease subset — SjD patients can generally be grouped into three subsets at the time of presentation, based upon their degree of disease activity. These patient subsets have different disease prognoses and thus different requirements for systemic therapies. These include:
●Sicca manifestations alone, without systemic manifestations and without glandular enlargement
●Predominant sicca manifestations with glandular enlargement and/or a mild systemic manifestation, such as joint pain, fatigue, hypergammaglobulinemia, or mild leukopenia
●Sicca with moderate to severe systemic organ manifestations
In the Sjögren Big Data Consortium of 10,007 primary SjD patients, only 18 percent had no systemic activity and no glandular enlargement at the time of diagnosis [30]. In our experience, as well, most patients fall within the second or, less commonly, third categories.
NONPHARMACOLOGIC AND PREVENTIVE INTERVENTIONS — All patients should receive nonpharmacologic and preventive interventions, including patient education and vaccinations. Several nonpharmacologic measures and other medical interventions are typically employed, although high-quality studies to support their efficacy for the treatment of Sjögren's disease (SjD) specifically are lacking [31].
●Self-care of sicca manifestations – The large degree of self-care that is required mandates comprehensive patient education. There should be particular attention to self-management strategies for tear conservation, effective use of artificial tears, treatment of dry mouth symptoms, oral hygiene, and recognition of symptoms requiring medical attention. These issues are described in detail separately. Patient education materials are available from the Sjögren's Syndrome Foundation, Inc. (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".)
●Immunizations – Patients should receive appropriate immunizations prior to the institution of immunosuppressive therapies in order to ensure optimal therapeutic response and avoid infectious complications of live virus vaccines (table 2) [32]. There is no evidence that certain vaccines, such as coronavirus disease 2019 (COVID-19), herpes zoster, or pneumococcal, can aggravate the underlying disease. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
●Smoking cessation – Patients should be counseled against smoking cigarettes and/or recreational or medical cannabis. In addition to the inherent risks of these activities, they may exacerbate dry mouth and dry eye symptoms and augment the risk of dental decay and other oral complications. Smoking may diminish the efficacy of medications, including hydroxychloroquine [33,34]. Cigarette smoking can also potentially aggravate small airway disease in SjD. (See "Overview of smoking cessation management in adults".)
●Diet and nutrition – We counsel patients regarding the potential benefit of over-the-counter dietary supplements rich in flaxseed oil and/or other sources of omega-3 fatty acids for dry eye disease and/or inflammatory arthritis [35,36] (see "Treatment of moderate to severe dry eye in Sjögren’s disease", section on 'Dietary fatty acid supplements'). Similarly, adherence of the Mediterranean diet, with increased fish consumption, may be beneficial [37]. We do not discourage patients who wish to try "antiinflammatory" and gluten-free diets for SjD, but we counsel patients regarding the limited data regarding their efficacy.
●Issues with specific medications and therapies – Medications with anticholinergic (table 3) and other drying side effects should be avoided, if medically possible, in patients with SjD since these treatments can aggravate sicca symptoms (see "Drug prescribing for older adults", section on 'Anticholinergic activity'). The use of immune checkpoint inhibitors that block the interaction between the programmed cell death protein and one of its ligands (PD-1, PD-L1) is associated with the development of SjD or an SjD-like illness in patients being treated for neoplastic disease [38,39]. The long-term efficacy, safety, and tolerability of these novel therapies in patients with established SjD is unclear at the present time. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy", section on 'Sicca syndrome/other ocular disorders'.)
●Pregnancy and contraception – Women should be counseled concerning pregnancy and fetal outcomes in SjD. The most significant adverse fetal outcome is congenital heart block (see "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis"), occurring in infants born to mothers with high titers of anti-SSA/Ro and/or anti-SSB/La antibodies. Other pregnancy outcomes, such as fetal loss, intrauterine growth retardation, and premature delivery, appear to be more common in women with SjD as compared with controls. This may relate to their more advanced age during gestation or the more severe disease that is present in younger women with SjD [40,41]. Hormonal contraception is contraindicated if the patient has antiphospholipid antibodies or a history of thrombosis.
GENERAL APPROACH TO DRUG THERAPY — Choice of therapy varies according to the organ manifestations and disease severity:
●Dry eye, dry mouth, and other sicca symptoms – In patients with Sjögren's disease (SjD), the treatment of sicca symptoms alone, without glandular enlargement or other organ involvement, generally does not require systemic therapy other than secretagogues. Changes in the patient's other medications to eliminate or minimize drying side effects is also useful. The treatment of dry eyes and of dry mouth and other nonocular sicca symptoms (including the use of muscarinic agonists such as pilocarpine and cevimeline as secretagogues) 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.)
The evidence supporting this approach is described in more detail separately. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations" and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Approach to drug therapy' and "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations", section on 'Therapeutic rationale and evidence overview'.)
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. Treatment depends upon the clinical manifestation, tissues, and organ system affected. Treatment of these glandular, constitutional, and systemic manifestations affecting other organs and tissues is described in detail separately. (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)
SPECIAL CONSIDERATIONS
Management during pregnancy — Management of Sjogren's disease (SjD) during pregnancy is largely the same as in the general population. SjD commonly has overlapping features with systemic lupus erythematosus (SLE), which may raise additional treatment considerations. Use of hydroxychloroquine may improve pregnancy outcomes [18]. (See "Pregnancy in women with systemic lupus erythematosus".)
In patients with positive anti-SSA/Ro and/or anti-SSB/La antibodies, routine care by a perinatologist and increased surveillance for congenital heart block is recommended. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Fetal surveillance for heart block' and "Pregnancy in women with systemic lupus erythematosus", section on 'Presence of anti-Ro and anti-La antibodies'.)
Past reports have described adverse outcomes in SjD pregnancies (eg, fetal loss, intrauterine growth retardation, and premature delivery). However, a controlled study casts doubt on these earlier observations. In a prospective study of 1944 pregnancies among women with SjD, adverse outcomes occurred in six pregnancies (ie, 7 percent) [42]. These adverse outcomes included intrauterine growth retardation, intrauterine fetal death, preeclampsia, placental abruption, and small-for-gestational-age birthweight. When compared with 420 matched control pregnancies, SjD was not associated with adverse pregnancy outcomes (odds ratio [OR] 1.31, 95% CI 0.25-2.98).
General anesthesia — Patients with SjD are at increased risk of complications from any surgery requiring general anesthesia [43]. Responsible factors include the use of anticholinergic drugs, which further reduce tear production, and the low-humidity environment of the operating theater. These factors may predispose to ocular surface damage from reduced tear production and mucosal or dental damage from decreased oral tracheal secretions. The reduction in airway secretions in SjD increases the risk of inspissated mucus and postoperative atelectasis, while oral dryness may increase the difficulty of taking oral medications. Management may include prophylactic use of ocular lubricants, humidified oxygen, and chest physiotherapy to mobilize secretions. Recommendations for the usage and dosing of immunosuppressives during the perioperative period of elective surgery generally follow those for patients with SLE and rheumatoid arthritis (RA) [44]. (See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren’s disease" and "Treatment of dry eye in Sjögren’s disease: General principles and initial therapy", section on 'Perioperative management'.)
PROGNOSIS — The natural history of Sjögren's disease (SjD) has been conceptualized as a series of stages, including stage 0 (pre-disease) where serologic abnormalities exist without clinical involvement, stage 1 with strictly glandular involvement, stage 2 with additional extraglandular involvement, and stage 3 with lymphoma development [45]. This sequencing of the stages is not routinely observed in clinical practice and patients may first come to medical attention in any of the four stages. Extraglandular involvement and other autoimmune diseases accrue during the course of SjD in roughly one third to one half of patients [46,47]. In a study of 140 Dutch SjD patients, the cumulative incidence of new extraglandular manifestations or associated autoimmune diseases was 30.7 percent over a period of 23 years. These included interstitial lung disease, arthritis, lesions of cutaneous lupus, polyneuropathy, and Hashimoto's thyroiditis [47]. Similarly, 49 percent of 152 patients in the University College of London Sjögren's cohort, evaluated retrospectively, developed other autoimmune diseases, including autoimmune thyroid disease, pulmonary fibrosis, and vasculitis, over a period of 25 years [46]. Non-Hodgkin lymphoma occurs in approximately 5 percent of SjD patients and this prevalence increases with disease duration [48].
In large epidemiologic studies and meta-analyses, an increased incidence of certain comorbidities relevant to SjD has been detected. These include malignancy (apart from lymphoma), infections, and cardiovascular disease [49].
Reduced quality of life was illustrated in a study that used the Short Form 36 (SF-36) to compare patients with primary SjD with a control population [50]. The SjD patients showed significantly lower scores than controls in all SF-36 domains. Patients with extraglandular involvement had lower scores for vitality, social functioning, bodily pain, and general health compared with patients without extraglandular features.
Despite the association between SjD and lymphoproliferative disorders, there is contradictory evidence regarding overall survival of patients with this disorder:
●In a retrospective study, 723 patients with primary SjD were followed for a mean of six years, with mortality rates that were compared with a sex- and age-matched segment of the same population [51]; a trend towards a small increase in the standardized mortality ratio (SMR) for those with primary SjD was not statistically significant (SMR 1.15, 95% CI 0.86-1.73).
●In a study of 1045 consecutive SjD patients, lymphoma and end-stage organ damage due to lung or renal involvement and vasculitis were found to confer increased mortality risk [52].
●In a 2015 systematic review and meta-analysis of cohort studies, the pooled SMR was 1.38 (95% CI 0.94-2.01) [53]. Certain subsets of patients had higher risk factors for increased mortality, including those with vasculitis, hypocomplementemia, and cryoglobulinemia.
Certain laboratory or clinical findings have prognostic implications. As an example, severe exocrine gland disease is associated with increased risk of lymphoma. In addition, patients with cutaneous vasculitis are more likely than those lacking vasculitis to develop other extraglandular manifestations, including lymphoma, and to die of disease-related complications [54-56].
Hypocomplementemia also appears to be an independent risk factor for premature death. In one study, among a variety of clinical and laboratory variables examined, only a depressed serum C4 complement level remained a significant risk factor for a shortened lifespan after multivariate analysis (hazard ratio [HR] 4.39, 95% CI 2.18-8.83) [51]. The association between poor prognosis and depressed complement level has been independently confirmed [57].
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
●Evaluation and management of Sjögren's disease (SjD) should be provided by a multidisciplinary team, usually including a rheumatologist, an eye care professional, and a dentist or oral medicine specialist. Patients should undergo a thorough pretreatment evaluation to confirm the diagnosis and determine the severity and extent of disease and the disease subset, based upon the history, physical examination, laboratory testing, and histopathologic findings. The approach to management is generally the same for primary or secondary SjD. (See 'Treatment goals and principles' above and 'Pretreatment evaluation' above.)
●All patients benefit from 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 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 'General approach to drug therapy' above 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".)
●Patients with moderate to severe involvement generally require systemic medical therapy, including the use of immunosuppressives and biologic agents, depending upon the clinical manifestation, tissues, and organ system affected. Treatment has been influenced by the approach for other systemic rheumatic diseases, particularly systemic lupus erythematosus (SLE) as well as rheumatoid arthritis (RA). (See "Treatment of Sjögren's disease: Constitutional and non-sicca organ-based manifestations".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Creamer, MD, who contributed to earlier versions of this topic review.
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