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Sjögren Syndrome: Clinical Manifestations, Diagnosis, and Management

Volume 58 - Issue 9 - September 2018

Authors:
Maryam Jadeed, MD, and Samer Nuhaily, MD

Citation:
Jadeed M, Nuhaily S. Sjögren syndrome: clinical manifestations, diagnosis, and management. Consultant. 2018;58(9):229-241.

 

ABSTRACT: Sjögren syndrome (SS) is a systemic autoimmune disease characterized mainly by the presence of keratoconjunctivitis sicca and xerostomia. Patients also may experience inflammation of the joints, muscles, nerves, lungs, gastrointestinal tract, thyroid, lymph nodes, or any other organ of the body, as well as fatigue, disturbed sleep, and memory problems. The etiology and pathophysiology of SS are not well understood, and diagnosis presents a challenge. Although there is no cure, management includes pharmacologic and nonpharmacologic interventions with the goal of improving quality of life by treating the sicca and fatigue symptoms.

KEYWORDS: Sjögren syndrome, keratoconjunctivitis sicca, xerostomia

 

Sjögren syndrome (SS) is a systemic autoimmune disease characterized mainly by keratoconjunctivitis sicca (dry eyes) and xerostomia (dry mouth).1 The clinical manifestations are often vague; patients may experience inflammation of the joints, muscles, nerves, lungs, gastrointestinal tract, thyroid, lymph nodes, or any other organ of the body. Patients also report fatigue, disturbed sleep, and memory problems.2,3

SS can occur as a solitary condition (primary or sicca syndrome) in the absence of other autoimmune diseases. In contrast, secondary SS develops alongside or as a consequence of other autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and scleroderma.4

The etiology and pathophysiology of SS are complex and are not well understood.5 Numerous genetic, environmental, and hormonal factors have been postulated to establish the condition (Table 1).4

Sjögren Table 1

SS is the second most prevalent chronic rheumatic autoimmune disease (after RA).1,6 The mean age of onset is in the 4th or 5th decade, with a prevalence of approximately 0.5% in the general population. It is estimated that 0.4 million to 3.1 million individuals are affected in the United States alone,7 with a female to male ratio of 9 to 1.7,8 However, males present with a more severe form of the disease.9

SS has distressing physical, emotional, and financial impacts on patients. In 2017, a survey conducted to measure these effects concluded that more than half of patients (53%) with severe dryness also experienced fatigue.3 The survey revealed that SS adds significant burdens to patients’ lives, relationships with friends, families, and sexual partners. Moreover, 28% of patients had to stop work, reduce their working hours, or take a lighter job due to their disease.3

NEXT: Etiology

ETIOLOGY

The exact cause of SS is still obscure, but it involves (as do all autoimmune diseases) several interacting factors rather than a single individual factor. The key features of the pathogenesis  of SS include lymphocytic infiltration of the exocrine glands (predominantly the lacrimal and salivary glands), the release of inflammatory mediators and cytokines, and the production of autoantibodies.6

CLINICAL MANIFESTATIONS

The clinical manifestations of the disease can be divided into glandular and extraglandular features.

A retrospective study of 80 patients with primary SS followed for a median of 7.5 years reported that all patients experienced dry eyes and dry mouth, and this was the only manifestation in 31% of the patients.10 Extraglandular involvement occurred in 25% of the patients included in the study. Moreover, 2.5% developed non-Hodgkin lymphoma (NHL).10

Glandular manifestations include dry mouth, dry eyes, salivary and lacrimal gland enlargement (which occurs in approximately 50% of patients during the course of the disease10), and vaginal dryness and associated dyspareunia. Patients with keratoconjunctivitis sicca report a sensation of foreign body and burning in the eyes. Xerostomia results in difficulty swallowing and talking. The patient’s oral health is significantly affected; they are 10 times prone to dental caries and recurrent oral Candida albicans infection compared with the general population.11

Approximately 5% to 10% of all primary SS patients would eventually develop NHL of B-cell lineage,10 arising from mucosal associated lymphoid tissue, lymph nodes, and exocrine glands, particularly the parotid gland (Figure 1).12 Based on 2 series, the transition to lymphoma occurred 6.5 to 7.5 years after the diagnosis of SS.13 It is essential to rule out malignant NHL when a SS patient presents with a swollen salivary gland.

Sjögren Fig 1

Multiple extraglandular organs may be affected in patients with SS, including the skin, joints, blood vessels, lungs, kidneys, gynecologic system, and nervous system.2

Patients with SS also experience fatigue and sleep disorders,3 which are attributed to the disruption caused by xerostomia stimulating polydipsia with resultant polyuria.14 Depression is highly prevalent among SS patients, occurring 5 times more often compared with healthy control patients as indicated in a large meta-analysis.15 A cohort study evaluating the cognitive aspects of SS patients also concluded that 33% to 49% have depression.16 Fibromyalgia is present in 22% to 33% of patients with primary SS.17

NEXT: Diagnosis

DIAGNOSIS

Diagnosing SS is somewhat complicated, since patients manifest a wide range of symptoms that are similar to those of many other diseases. Patients are often seen by different specialists for their symptoms, and this makes the diagnosis challenging. There is no single diagnostic test for SS. The diagnosis is made in the presence of compatible clinical and laboratory findings after the exclusion of all the other possible diagnoses.

Available SS diagnostic criteria such as those issued by the American-European Consensus Group and of the American College of Rheumatology were not designed to be used in routine clinical practice; instead, they are mainly for scientific communication and research purposes.18 Nevertheless, these criteria can be helpful in making the clinical diagnosis if they are used appropriately.

The diagnostic evaluation starts with a thorough history and physical examination of patients with suspected cases, including those with persistent dry eyes and/or dry mouth on a daily basis for 3 or more months,11 parotid gland enlargement, and recurrent dental caries. The history and physical examination should be focused on the features of SS and other rheumatic and connective tissue diseases.

In addition, basic initially laboratory tests should be obtained, including a complete blood cell count with differential, which might reveal anemia, leukopenia, and thrombocytopenia; an erythrocyte sedimentation rate; a comprehensive metabolic panel; assessment of globulin level, looking for hyperglobulinemia; and urinalysis to check for hematuria and proteinuria.18 All patients should be evaluated for systemic autoimmunity.

All patients should be examined by an ophthalmologist to evaluate for an objective marker of dry eyes. The Schirmer test, done by applying a sterile filter paper in the lower eyelid while the eye is gently closed for 5 minutes, measures the reflux tears in each eye without the use of topical anesthesia (Figure 2). In the normal population, more than 10 mm of the filter paper should be wetted with tears. Wetting of less than 5 mm indicates aqueous tear deficiency and is considered a diagnostic criterion of SS.18 Moreover, a slit lamp examination is done to evaluate tear breakup time, which is a measure of tears’ quality.18 Ocular surface stains are used to highlight devitalized tissues and damaged conjunctiva and corneal epithelial cells and include the rose bengal, fluorescein, and lissamine stains.18 These tests also aid in diagnosing and treating other causes of ocular dryness and irritation.

Sjögren Fig 2

NEXT: Diagnosis (Continued)

Many patients do not require further tests beyond basic blood investigations and an ocular examination.

If ophthalmic examination does not reveal sufficient information to make the diagnosis of SS, or if the salivary gland symptoms predominate, the patient should undergo evaluation of salivary gland function, including sialometry and imaging studies for structural abnormalities. The most commonly used imaging modalities are magnetic resonance imaging and ultrasonography (US).18 Five large studies done between 2013 and 2015 showed that US has a sensitivity from 55% to 66% and a specificity from 93% to 98%,19 which make it a promising tool for evaluating glandular parenchymal abnormalities.20

All patients should be evaluated for systemic autoimmunity. Results of tests for anti-SSA/Ro antibodies, anti-SSB/La antibodies, antinuclear antibodies, and rheumatoid factor all support the diagnosis of SS. Approximately 60% to 80% of persons with SS have anti-SSA/Ro antibodies, anti-SSB/La antibodies, or both.18 Anti-SSB/La antibody is by far more specific, and it is found in persons with SS and SLE.21 Weak positive results should be interpreted with caution, since 10% and 12.5% of the general population will test positive for anti-SSA/Ro and anti-SSB/La antibodies, respectively.11 Anticentromere antibodies can be positive in up to 5% of SS patients, particularly in those with features of systemic sclerosis such as Raynaud phenomenon. Anti-cyclic citrullinated peptide antibodies, which are very specific for RA, can also be found in persons with SS, especially those with predominantly articular involvement.18 However, more specific tests are guided by the signs and symptoms of other rheumatic diseases. Clinicians should keep in mind that many causes contribute to sicca symptoms in elderly individuals, such as age-related sicca syndrome, sarcoidosis, hepatitis C, HIV infection, systemic vasculitis, and malignancy.17 These conditions should be assessed for in the diagnostic workup in patients presenting with classic dry eyes and dry mouth.

Minor salivary gland biopsy is conducted only when no evidence exists of concomitant autoimmune disease or relevant antibodies, weakly positive anti-SSA/Ro and anti-SSB/La antibodies, or when only anti-SSB/La antibody is positive in the absence of anti-SSA/Ro antibody.18 Labial biopsy also reveals structural abnormalities seen in other conditions. Moreover, it provides information regarding disease prognosis, since a higher grade of lymphoid infiltration and the presence of germinal centers predicts a greater risk of development of NHL.21

Figure 3 illustrates the steps in diagnosing SS.

Sjögren fig 3

NEXT: Management

MANAGEMENT

Patients with SS respond best to treatment provided by a multidisciplinary team, including family physicians, dentists, rheumatologists, ophthalmologists, otorhinolaryngologists, psychiatrists, and other specialists depending on patients’ symptoms. Treatment should be individualized based on disease activity, extraglandular organ involvement, and the presence of underlying or associated autoimmune diseases.11 Managing this chronic condition requires using evidence-based pharmacologic and nonpharmacologic interventions, often in combination. Although there is no cure for primary SS,22 the primary goal of treatment is to improve patients’ quality of life by treating the sicca and fatigue symptoms.11 Patients must be educated about their disease and the importance of adherence to their treatment regimen and behavioral modifications.

Due to the promising advances in the management of SS, the overall survival of patients does not differ from that of the general population.23 Symptomatic treatment is usually sufficient and appropriate for sicca symptoms, whereas systemic medications, including disease-modifying therapies, are reserved for systemic extraglandular disease.

TOPICAL TREATMENT FOR DRY EYES

Sodium hyaluronate eye drops. Sodium hyaluronate eye drops increase corneal wettability, reduce the tear evaporation rate, and reduce the healing time of corneal epithelium.24 A meta-analysis conducted in 2012 showed marked improvement in xeropthalmia compared with baseline measurements following the use of sodium hyaluronate–containing eye drop solutions.22 A double-blind randomized controlled trial (RCT) indicated that artificial tears containing hyaluronate are superior to normal saline artificial drops in terms of improvement of dry eye symptoms; it also proved hyaluronate to be safe and well tolerated.25 A hypotonic formulation was shown to have better effects than isotonic preparations.22

Cyclosporine A eye drops. Because immune-mediated mechanisms play a major role in the pathogenesis of xeropthalmia, the role of cyclosporine A to suppress the underlying inflammation has gained significant importance. Cyclosporine A eye drops were approved by the Food and Drug Administration in 2002 to treat dry eyes disease,22 and clinical evidence has been supportive of efficacy and safety. The authors of 1 RCT concluded that cyclosporine A cationic emulsion is superior to hyaluronate sodium in terms of patients’ subjective symptoms of moderate to severe dry eyes disease.26 Another RCT showed that cyclosporine A cationic emulsion improved patients’ severe to moderate dry eyes over a period of 6 months.27 An RCT enrolling 877 patients with moderate to severe dry eyes compared the 2 novel doses of cyclosporine A (0.1% and 0.05%) with placebo.28 The results showed that patients who received cyclosporine (0.1% and 0.05%) treatment for 6 months had better Schirmer test scores; however, patients receiving cyclosporine, 0.05%, had fewer corneal abrasions on corneal stains, less ocular discomfort, and less artificial tears usage. Hence, cyclosporine, 0.05%, is considered the recommended dosing regimen. Neither formulation was associated with major topical or systemic adverse effects (AEs).

Nonsteroidal anti-inflammatory drug (NSAID) eye drops. Data regarding the use of NSAID eye drops to treat dry eye disease, including SS, are limited and inconsistent. An uncontrolled comparative study with 22 SS patients showed improvement of dry eyes symptoms in those treated with eye drops containing diclofenac or indomethacin, with greater benefit observed for diclofenac.22 On the other hand, a small RCT found no significant difference between diclofenac and normal saline.22 The major concern with ocular NSAIDs is the associated AEs, which have been reported to include corneal perforation, ulceration, and severe keratitis.22

Corticosteroid eye drops. Compared with placebo, fluorometholone and methylprednisolone have demonstrated significant clinical benefits. Corticosteroids also have been found superior to NSAIDs in a randomized prospective study.22 However, clinicians must consider the associated AEs before prescribing ocular corticosteroids. Increased intraocular pressure and the development or worsening of preexisting cataracts occurred in 14% of patients treated with topical methylprednisolone.22 NSAID and corticosteroid topical drops are to be prescribed only by ophthalmologists and for the shortest possible duration, since the AEs frequently are reported after 2 weeks of treatment.22

NEXT: Topical Treatment for Dry Mouth

TOPICAL TREATMENT FOR DRY MOUTH

Salivary substitutes and stimulants. The first step to improving oral dryness is the use of mechanical gustatory stimulation and/or salivary substitutes.22 The primary motive for administering salivary substitutes is to improve lubrication and hydration of the oral cavity.29 Clinical studies evaluating various salivary substitutes have yielded conflicting results. Some RCTs concluded that while some oral dryness symptoms can be improved, the salivary flow rate cannot be increased. Moreover, the authors of a large systematic review of 36 RCTs of topical interventions, substitutes, and stimulants, such as lozenges, sprays, mouth rinses, gels, oils, chewing gum, and toothpastes for the treatment of dry mouth symptoms, reported the absence of strong evidence of the effectiveness of any of these topical measures in relieving dry mouth symptoms.30

Dental hygiene is an important concern in patients with SS, and topical fluoride is proven effective in preventing dental caries.11 In 1 study, 205 women with SS, 32 (17%) of whom had dental implants, participated in an oral health questionnaire; 75% of the patients were highly satisfied with the implants, and 97% would recommend them to other patients with SS.31

SYSTEMIC TREATMENT FOR DRY EYES AND DRY MOUTH

If topical interventions are not effective, systematic therapy is indicated.22 The muscarinic acetylcholine receptor agonists (pilocarpine and cevimeline) are approved agents to treat sicca symptoms.22 These medications bind to the muscarinic receptors on the glands and stimulate secretion of saliva and tears.11 One study compared placebo with pilocarpine and noted significant improvement in tears and salivary flow rates.32 Another RCT also emphasized the positive effect of pilocarpine on oral, ocular, nasal, vaginal, and skin dryness.33 The effectiveness of cevimeline also has been evaluated in a number of RCTs, and it has been shown to result in improvement in overall dryness.34

The most common related AEs that should be discussed with the patient include sweating, flushing, headache, nausea, and urinary frequency.11

NEXT: Managing Extraglandular Symptoms

MANAGING EXTRAGLANDULAR SYMPTOMS

The cornerstone of managing the general symptoms of SS, after excluding other differential diagnoses, is mild immunosuppressant hydroxychloroquine (HCQ). It is considered the drug of choice for mild to moderate systemic manifestations such as arthralgia, arthritis, cutaneous lesions, and fatigue.11 Based on the results of a recent meta-analysis, significant improvement occurred in general manifestations such as arthralgia and myalgia after treatment with HCQ.35 Also, baseline inflammatory markers (erythrocyte sedimentation rate and C-reactive protein level), autoantibody levels, and disease activity all decreased. Although none of the available studies reported associated retinal toxicity or any significant AEs,22 patients taking HCQ should undergo annual ophthalmology follow-up visits.11 In contrast, the meta-analysis showed that HCQ is not superior to placebo in controlling sicca symptoms and is less effective than placebo for managing fatigue.35 HCQ is also the recommended therapy for SS in pregnant women.11

One RCT of 17 patients with primary SS taking rituximab measured the reduction of fatigue as the primary desired outcome. Significant improvement from baseline in patient-reported fatigue was observed in the rituximab group in contrast to the placebo group, consistent with the view that fatigue in SS is immune-mediated.36 A more recent study, the TRACTISS trial, which is the largest RCT evaluating the role of rituximab in improving fatigue symptoms, found no significant difference compared with placebo.37

The decision to escalate treatment largely depends on disease severity and the involved organs. Management is organ-specific, using mainly corticosteroids and immunosuppressive agents.22 Corticosteroids should be used at the minimum dose and length of time necessary. No conclusive evidence supports the efficacy of disease-modifying antirheumatic drugs and biologic agents in the treatment of SS.11

Methylprednisolone and cyclophosphamide are used for severe organ manifestations in life-threatening situations. Rituximab or plasmapheresis work best for vasculitis and concomitant cryoglobulinemia. Treating NHL should be based on hematology-oncology treatment guidelines according to the grade and stage of the tumor.11

Figure 4 illustrates the proposed therapy for the main extraglandular manifestations of SS.11,22

Sjögren Fig 4

NEXT: Nonpharmacologic Interventions

NONPHARMACOLOGIC INTERVENTIONS

Nonpharmacologic interventions include patient education; environmental modification such as air humidification; elimination of the use of anticholinergic drugs; increased water intake; tobacco cessation; and the use of fluoride-containing toothpaste to prevent dental caries.11

Studies have shown that avoiding factors that provoke fatigue, establishing sleep hygiene, and aerobic endurance training are effective in fighting fatigue.11

A systematic review of 9 studies that evaluated nonpharmacologic techniques to alleviate dry mouth symptoms included 366 patients with dry mouth of various causes including SS.38 Nonpharmacologic interventions included acupuncture, electrostimulation devices, and power toothbrushes. The studies were of poor quality, and all failed to find a statistically significant benefit of improvement in dry mouth symptoms.

Table 2 summarizes the recommended pharmacologic and nonpharmacologic interventions used in the clinical treatment of patients with SS.

Sjögren Table 2

 

Maryam Jadeed, MD, is a family practice resident at Salmaniya Medical Complex in Manama, Bahrain.

Samer Nuhaily, MD, is a consultant rheumatologist and medical director at American Medical Center in Manama, Bahrain.

 

NEXT: References

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