Review article

The Diagnosis and Treatment of Sjögren’s Syndrome

Dtsch Arztebl Int 2017; 114(20): 354-61; DOI: 10.3238/arztebl.2017.0354

Stefanski, A; Tomiak, C; Pleyer, U; Dietrich, T; Burmester, G R; Dörner, T

Background: Sjögren’s syndrome is one of the more common inflammatory rheumatological diseases, with a prevalence of at least 0.4% in Germany.

Methods: This review is based on pertinent articles retrieved by a selective search in PubMed. Special attention is drawn to updated classification criteria and current treatment recommendations.

Results: Sjögren’s syndrome has a wide variety of presentations, ranging from the local involvement of exocrine glands with keratoconjunctivitis sicca and xerostomia (the leading signs of the disease) to the systemic, extraglandular involvement of multiple organs. Fatigue also markedly worsens the patients’ quality of life. Serologic testing reveals antinuclear auto-antibodies (anti-Ro/SSA and anti-La/SSB) as well as rheumatoid factors. The histological hallmark of the disease is focal lymphocytic infiltration in otherwise normal-appearing glandular acini. The disease also markedly elevates the risk of non-Hodgkin lymphoma of the B-cell series, which arises in about 5% of patients. Primary Sjögren’s syndrome (pSS) differs from the secondary form (sSS), which appears in the setting of another autoimmune disease, particularly systemic lupus erythematosus (15–36%), rheumatoid arthritis (20–32%), and limited or progressive systemic sclerosis (11–24%). Disease-modifying therapy is reserved for patients with systemic involvement; there is limited evidence for its efficacy. Because of the complexity of this disease, some of its clinical manifestations may require interdisciplinary treatment.

Conclusion: The main considerations in the interdisciplinary care of patients with Sjögren’s disease are measures to improve quality of life, pharmacological and non-pharmacological treatments to keep disease activity in check, and management of the risk of lymphoma. Future therapeutic approaches must take the heterogeneity of the disease into account.

Sjögren’s syndrome is a chronic inflammatory autoimmune disease of unknown origin, attacking in particular the tear and salivary glands. Sicca symptoms are the hallmarks of the disease which may also present with various organ manifestations. Due to the wide variety of signs and symptoms, patients with Sjögren’s syndrome may see a diverse range of healthcare practitioners, including family physicians, ophthalmologists, ENT specialists, and dentists, at the first consultation. Thus, it is crucial for physicians of various specialties to be informed about current aspects of clinical manifestations of the disease, the revised classification criteria, and current treatment options.

Primary Sjögren’s syndrome (pSS) is distinguished from secondary Sjögren’s syndrome (sSS) which occurs as a part of other autoimmune diseases. sSS coexists especially with systemic lupus erythematosus (15–36%), rheumatoid arthritis (20–32%) as well as limited and progressive systemic sclerosis (11–24%), less frequently with multiple sclerosis and autoimmune hepatitis and thyreoiditis (1). Here, the term “secondary” does not describe a chronological sequence of disease manifestation: The underlying condition may initially present with sicca symptoms and only later reveal itself over the course of the disease. Establishing the diagnosis is often challenging in patients with overlapping disease entities. Given the distinct courses of disease (including prognosis), it is important to differentiate between the primary and secondary form of Sjögren’s syndrome.

Epidemiology

The heterogeneity of the available prevalence and incidence data for Sjögren’s syndrome is explained by differences in study design and classification criteria. The global prevalence calculated for the rarer pSS is 61 per 100 000 inhabitants, with the highest prevalence encountered in Europe (2). Women develop Sjögren’s syndrome significantly more frequently than men; the sex difference ranges between 9:1 to 19:1. Mean age at time of first diagnosis of pSS is 56 years, with another peak occurring between 20 and 40 years. However, first symptoms may occur years before diagnosis. As yet, there is a lack of reliable epidemiological data for Germany. The overall prevalence of Sjögren’s syndrome, including the more common secondary form of the disease, is assumed to be at least 0.4% (3).

Clinical manifestation

According to the largest cohort published so far, sicca symptoms are the most common manifestation of Sjögren’s syndrome, with up to 98% of cases (4). Patients with keratoconjunctivitis sicca (KCS) complain about foreign-body sensation, burning or soreness of the eyes and increased sensitivity to light. Marked xerostomia as a sign of stomatitis sicca presents clinically as difficulties when talking for extended periods of time and while chewing or insalivating dry food. Compared with the general population, the prevalence of dental caries and early tooth loss is about twice as high in patients with Sjögren’s syndrome and their oral health-related quality of life is significantly reduced. Recurrent oral infections with Candida albicans occur 10 times more frequently than in the general population (5). On the other hand, sicca symptoms are commonly reported with advancing age and polypharmacy: Approximately 5% to 35% of the general population suffer from dry eyes (6), and approximately 20% of dental patients experience dry mouth (7). Thus, a thorough medical history, including medications, and physical examination, followed by special function tests, is crucial for the interpretation of these complaints. Table 1 lists the differential diagnoses for glandular complaints. In addition, attention should be paid to other sicca symptoms, such as dry cough in tracheobronchitis sicca or sicca symptoms in the nasopharynx or genital tract, manifesting as an increased susceptibility to infection or as dyspareunia.

Up to 34% of patients with Sjögren’s syndrome report episodic or chronic, typically bilateral swelling of the parotid glands (9). Here, it is essential to exclude malignant non-Hodgkin lymphoma (NHL) of B cell lineage which occurs in about 5% of patients with pSS (10) who are at a significantly increased risk of developing NHL compared with the general population (risk ratio [RR]: 13.7). Key predictors for the development of NHL include low complement levels (RR: 8.3), cryoglobulinemia (RR: 6.8), lymphadenopathy (RR: 3.7), histological finding of ectopic germinal center-like structures, permanent swelling of parotid gland, and skin vasculitis (10, 11). These patients belong to a high-risk group and require monitoring at closer intervals and, if necessary, further diagnostic investigations, such as chest radiography and abdominal ultrasound; however, valid recommendations for lymphoma screening are not available.

The most common extraglandular manifestations are arthralgia and a usually non-erosive polyarthritis which occur in approximately 50% of patients (9). Pulmonary involvement beyond the sicca complex typically manifests as interstitial lung disease or follicular bronchiolitis, normally after many years of disease activity (9–12%) (9, 12). About 10% of patients have cutaneous lesions, the majority in form of a vasculitis with involvement of small and medium vessels of the lower limbs. In addition, other less common skin manifestations may occur, such as annular erythema, urticarial vasculitis, or hypergammaglobulinemic purpura (9). Renal involvement, which is found in approximately 5% of patients, is usually associated with tubulointerstitial changes which frequently go along with distal renal tubular acidosis (RTA type 1) with hypokalemic muscular hypotonia; glomerulonephritis is rare in patients with pSS (9, 13).

Also of clinical relevance is the involvement of the peripheral nervous system, especially later in the course of the disease, typically manifesting as sensory neuropathy (10–25%) (9, 14). Rarer and more challenging to identify are CNS manifestations; for example, the differential diagnosis of multifocal CNS lesions on MRI includes multiple sclerosis lesions which are difficult to distinguish from pSS lesions (15). In this context, the coexistence of pSS with neuromyelitis optica spectrum disorders (NMOSD), which are characterized by autoantibodies to aquaporin-4, is of importance (4). If patients test positive for this antibody, this is of great differential therapeutic significance.

By contrast, nonspecific complaints such as fatigue and diffuse pain are more difficult to evaluate. However, fatigue is the symptom experienced as most distressing by the patient, determining physician visit frequency, quality of life as well as fitness for work (16, e1). Other conditions in the differential diagnosis of fatigue, such as hypothyroidism, anemia and sleep disorders, should be excluded and difficulties in coping with the disease should also be taken into account.

Anti-Ro/SSA- and anti-La/SSB-positive women desiring to have children require special counseling. Placental transmission of these antibodies can cause inflammation with subsequent sclerosis of the atrioventricular (AV) node which carries the risk of the fetus developing a congenital heart block. In 80% of cases, complete irreversible heart block occurs and in 20% fetal mortality is significantly increased (17). Weekly ultrasonographic monitoring of the cardiac rhythm of the fetus between 16 and 31 weeks’ gestation is essential for both prognostic evaluation and management.

Prognosis

Overall, the prognosis of Sjögren’s syndrome is favorable. The life expectancy of pSS patients is comparable with that of the general population (18). However, the patients’ quality of life is reduced by the diverse manifestations of the disease. Cardiovascular disease, infections, solid tumors, and lymphoma are the main causes of death. In patients with sSS, life expectancy is determined by the primary disease.

Pathogenesis

As with most autoimmune diseases, the etiology of Sjögren’s syndrome is not yet fully understood (e2e5, 19). Current concepts of its pathogenesis are summarized in the eFigure.

Classification criteria and diagnostic evaluation

Since the 1970s, various classification criteria have been established and evaluated. Recently, the existing US criteria from 2012 were for the first time integrated in the current classification by the major societies, ACR (American College of Rheumatology) and EULAR (European League Against Rheumatism). In patients having experienced sicca symptoms for at least 3 months, these are based on further function tests (e.g. the Schirmer’s test) or serological (Anti-Ro/SSA) and histological examinations (labial salivary gland biopsy). Among these investigations, anti-Ro/SSA antibodies and an abnormal labial salivary gland biopsy have the highest specificity; consequently, they are the criteria with the highest values. A minimum score of 4 allows for classification as Sjögren’s syndrome (Box). The Figure shows a diagnostic algorithm for Sjögren’s syndrome, based on the revised classification criteria and the various disease manifestations.

Figure 1

Objective tests for sicca symptoms

Schirmer’s test and Saxon’s test are easy to perform, but their results do not correlate well with patient complaints and should be evaluated in the overall context. Here, cooperation with the ophthalmology department is crucial: Topical application of vital stains (lissamine green or fluorescein) is used to visualize and grade corneal and conjunctival lesions associated with keratoconjunctivitis sicca. Direct measurement of salivation is the diagnostic gold standard, but it is time consuming in daily clinical practice. Parotid sialography and salivary gland scintigraphy lack sufficient specificity. As a noninvasive method, ultrasonography of the major salivary glands is an integral part of daily clinical practice. However, the method is not yet sufficiently validated to be include in the classification criteria (21).

Laboratory testing

Immunofluorescence testing for antinuclear antibodies (ANA) is highly relevant for the diagnosis of connective tissue disorders. Up to 83% of patients with pSS test positive for ANA (22). However, low-titer (<1:160) and unspecific ANA patterns are also found in 5% to 20% of the general healthy population (23). In patients with positive ANA titers, a fine speckled fluorscence pattern is strongly indicative of anti-Ro/SSA and/or anti-La/SSB antibodies, which is revealed in approximately 40% to 75% and 23% to 52% of pSS patients, respectively (24). With the recent increase in diagnostic value assigned to anti-Ro/SSA antibodies in the current classification system, it can be expected that significantly more newly classified Sjögren’s syndrome patients will have elevated antibody levels compared with historical cohorts. Positive antibody titers correlate with early onset of disease, more intense tissue infiltration, and higher prevalence of extraglandular manifestations. However, patients with other connective tissue disorders may also test positive for anti-Ro/SSA antibodies. Here, the clinical context is vital, especially to differentiate between overlapping disease entities. Interestingly, serological autoimmune phenomena have been detected up to 20 years before the appearance of the first signs and symptoms of the disease (25). Other serological abnormalities include the presence of rheumatoid factors (60–75%) as well as polyclonal hypergammaglobulinemia as a sign of increased B cell activity.

The development of biomarkers, providing prognostic information and a means to monitor disease progression, has now reached the establishment phase. An increase in beta2-microglobulin and free light chains of immunoglobulins is associated with an increased risk of lymphoma (26). Siglec-1 has recently emerged as a new biomarker. This indirect interferon marker correlates with a high level of disease activity as well as extraglandular manifestations (27).

Histopathology

The histopathological finding of focal periductal localized lymphocytic infiltrates in exocrine glandular tissue along with otherwise intact acinar units is pathognomonic for Sjögren’s syndrome. These infiltrations mostly consists of CD4+ T cells, with some additional CD8+ T cells and CD19+ B cells, plasma cells and dendritic cells. Deep expertise in line with international recommendations on the interpretation of histopathological findings is required to differentiate Sjögren’s syndrome from other disease entities (28). A minimum number of 50 monocytic cells/4 mm² was defined as a focus score (FS) of 1. A focus score ≥1 correlates with the phenotypical characteristics of Sjögren’s syndrome.

Management

Despite continued advances in our understanding of the mechanisms involved in the pathogenesis of the disease, a targeted treatment of Sjögren’s syndrome is not available at present. Treatment is decided on an individual basis according to disease activity and the presence and extent of extraglandular manifestations. In patients with sSS, the indication for treatment is based on the underlying disease. In general, treatment should be provided by an interdisciplinary team, including family physicians, rheumatologists, ophthalmologists and ETN specialists, as well as dentists. Subject to the organ(s) involved and the presenting symptoms, consultation of other specialists (gynecologists, pulmonologist, neurologists, etc.) may be required. Disease-modifying therapy is reserved for patients with extraglandular involvement. To measure systemic disease activity, the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) was developed and validated (29, e7).

Management of sicca symptoms

In most patients, the main aim of therapy is to improve quality of life by treating the sicca and fatigue symptoms. At the same time, this is a very challenging task for physicians as evidence-based treatment options are scarce and most therapeutic approaches are only symptomatic (Table 2). Patient education plays an important role, focusing on compliance with everyday behavioral rules (30)—targeting environmental factors (e.g., air humidification), prevention (e.g., fluoride for caries prevention, quit smoking), and avoidance of factors that increase fatigue (e.g., sleep hygiene) as well as physical fitness (aerobic endurance training to fight fatigue).

Various tear substitutes are available to treat keratoconjunctivitis sicca. The composition of the tear substitutes varies in accordance with the complex physiology of the three-layered preocular tear film (lipid layer, aqueous layer, and mucin layer). Since immune-mediated mechanisms play a central role in the pathogenesis of dry eye, anti-inflammatory treatment with cyclosporine A eye drops has gained significant importance. Their efficacy has been proven in randomized controlled trials (RCTs) and, based on data from these studies, 0.1% cyclosporine A cationic emulsion received marketing authorization from the European Medicines Agency (31). Additional measures significantly increasing the quality of life of these patients include the use of punctal plugs and the fitting of extra-large contact lenses (“scleral lenses”) with water storage function (32). Thus, cooperation with ophthalmologists is essential.

Xerostomia is treated jointly by dentists and otolaryngologists. The oral mucosal surface is comparatively large and different structures in the oral cavity need to be moistened (tongue, teeth, gum, oral mucosa). In addition, saliva composition varies with function and time of day. Optimal therapeutic compensation of the complex functions of saliva cannot be achieved. Two systematic reviews on topical/non-pharmacological treatments arrive at the conclusion that, while symptoms can be alleviated, the flow of saliva cannot be increased (33, 34). Dental care for patients with xerostomia is particularly challenging, as the lack of saliva reduces the tolerability of removable dental restorations. By contrast, in patients with Sjögren’s syndrome good outcomes are achieved with dental implant treatment (35).

Disease-modifying therapy

The decision to intensify treatment is dependent on disease activity and the organ system involved. However, the few RCTs evaluating the use of conventional disease-modifying antirheumatic drugs (DMARDs) or biologic agents in patients with Sjögren’s syndrome did not provide conclusive evidence supporting their efficacy (30, 36). Treatment decisions are frequently based on experiences with related rheumatic disease entities, such as systemic lupus erythematosus. Analog to other connective tissue disorders, hydroxychloroquine, an agent with a favorable side-effect profile, is the drug of choice for various mild to moderate systemic manifestations, such as arthralgia, arthritis, cutaneous lesions, and fatigue. The example of hydroxychloroquine highlights the challenges with regard to study design and the selection of patients who may benefit from treatment. A randomized controlled trial on pSS found no difference between hydroxychloroquine und placebo regarding sicca symptoms, pain and fatigue after 24 weeks (37). However, this study had significant limitations: The disease activity in these patients was low, the follow-up period short, and the primary endpoint not validated. To increase the validity of future RCTs investigating this heterogeneous disease, it is essential to recruit representative patient groups and select robust primary endpoints.

With regard to fatigue, a pilot study demonstrated moderate efficacy for rituximab (38). Unfortunately, this was not confirmed by a large RCT conducted some years later (39).

Treatment recommendations with regard to immunosuppression vary according to organ involvement (Table 3). In patients with severe organ manifestations, the use of high-dose methylprednisolone and cyclophosphamide is of proven effectiveness. For severe vasculitis, especially with concomitant cryoglobulinemia, rituximab or plasmapheresis are the recommended treatment options. In patients with NHL, treatment is chosen based on subentity and stage according to current guidelines on the treatment of hemato-oncological disorders.

The recommended treatment for pregnant women with Sjögren’s syndrome and a high risk for congenital heart block is hydroxychloroquine to minimize risk; however this recommendation is solely based on evidence from retrospective studies (40).

New treatment approaches, targeting pathophysiological mechanisms, are currently being evaluated in RCTs with validated instruments (ESSDAI): modulation of B-cell hyperactivity (e.g., belimumab), antagonizing T-cell co-stimulation (e.g., abatacept), effector cytokines (e.g., interleukin-6-receptor/tocilizumab; interferon α/anifrolumab), as well as prevention of the formation of ectopic germinal center-like structures (e.g., lymphotoxin-βR blockade). These studies face the challenge to demonstrate efficacy for the three symptom complexes—sicca, fatigue, and extraglandular manifestations.

Conflict of interest statement
Prof. Dörner received consultancy fees from UCB, Novartis and Roche as well as financial support for the conduct of clinical studies from UCB and Novartis.

Prof. Pleyer received consultancy and lecture fees from Santen, Théa, and Allergan.

Prof. Burmester received financial support for the conduct of clinical studies from Novartis, UCB and Roche.

Dr. Stefanski, Dr. Tomiak and Prof. Dietrich declare that no conflict of interest exists.

Manuskript received on 13 December 2016; revised version accepted on 14 March 2017

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Dr. med. Ana-Luisa Stefanski
Charite Universitatsmedizin Berlin
Rheumatologie und klinische Immunologie
Charitéplatz 1
10117 Berlin, Germany
Ana-Luisa.Stefanski@charite.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref2017

eFigure:
www.aerzteblatt-international.de/17m0354

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Charité Center for Internal Medicine, Medical Department—Division of Rheumatology and Clinical Immunology, Berlin, Germany: Prof. Dr. med. Burmester, Dr. med. Stefanski, Prof. Dr. med. Dörner
University Clinic of Rheumatology, Immunology and Allergology, Inselspital Bern, Bern, Switzerland: Dr. med. Stefanski
BfA Wendelstein Rehabilitation Clinic, Rheumatology Center, AHB Clinic, Bad Aibling, Germany:
Dr. med. Tomiak
Department of Ophthalmology, Charité Campus Virchow, Berlin, Germany: Prof. Dr. med. Pleyer
Oral Surgery, The School of Dentistry, University of Birmingham, United Kingdom: Prof. Dr. med. Dr. med. dent. Dietrich
1. Tomiak C, Dorner T: Sjogren‘s syndrome. Current aspects from a rheumatological point of view. Z Rheumatol 2006; 65: 505–17 CrossRef MEDLINE
2.Qin B, Wang J, Yang Z, et al.: Epidemiology of primary Sjögren‘s syndrome: a systematic review and meta-analysis. Ann Rheum Dis 2015; 74: 1983–9 CrossRef MEDLINE
3.Westhoff G, Zink A: Epidemiology of primary Sjogren‘s syndrome. Z Rheumatol 2010; 69: 41–9 CrossRef MEDLINE
4.Brito-Zeron P, Theander E, Baldini C, et al.: Early diagnosis of primary Sjögren‘s syndrome: EULAR-SS task force clinical recommendations. Expert Rev Clin Immunol 2016; 12: 137–56 CrossRef MEDLINE
5.Fox PC, Bowman SJ, Segal B, et al.: Oral involvement in primary Sjögren syndrome. J Am Dent Assoc 2008; 139: 1592–601 CrossRef MEDLINE
6.Bron AJ, Tomlinson A, Foulks GN, et al.: Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf 2014; 12: 1–31 CrossRef MEDLINE
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