7

Sjögren’s Disease/Syndrome

Sjögren’s disease is a chronic inflammatory autoimmune disease also referred to as Sjögren’s syndrome (SS) (Baer and Hammitt, 2021). The field is moving toward the “Sjögren’s disease” terminology to highlight the fact that patients afflicted with this disease do not have a collection of random symptoms, but rather have a distinct pattern of disease including specific laboratory markers and histopathologic features. However, because most of the literature referred to in this chapter was published using the Sjögren’s syndrome terminology, this chapter will refer to the disease as Sjögren’s syndrome. The primary disease pathogenesis includes exocrine gland inflammation and eventual dysfunction resulting in decreased tear and saliva production. The hallmark clinical manifestations of SS are xerostomia (dry mouth) and keratoconjunctivitis (dry eyes), which are termed sicca symptoms. Sicca symptoms are present in almost all adults at the time of diagnosis. Musculoskeletal pain and fatigue are also present in the majority of patients (Romão et al., 2018). In addition, some patients with SS experience a variety of extra-glandular symptoms which can potentially affect any organ system in the body. For example, neurologic conditions are common, and most often take the form of peripheral neuropathies.

SS affects between 1 million and 4 million people in the United States, or 0.5–1.0 percent of the population. It is the most common autoimmune disease after rheumatoid arthritis (Carsons and Patel, 2021; Qin et al., 2015). The diagnosis is typically made in patients after their fifth decade of life, and 90 percent of cases occur in women. There is a higher prevalence of the disease in Caucasian populations (particularly in European cohorts) and a lower prevalence in Hispanic populations (Brito-Zerón et al., 2017).

SS is likely underdiagnosed either because a physician does not recognize the features of this systemic condition or the patient does not feel that it is necessary to visit the doctor for dry eyes and mouth (Sandhya et al., 2017).

This chapter will discuss the clinical features, classification, disease course, and treatments for SS in adults, then briefly describe how the disease affects children.

CLINICAL FEATURES, DIAGNOSIS, AND DISEASE COURSE

The classic presentation of SS involves a middle-aged woman with dry eyes, oral dryness, and joint pain (Brito-Zerón et al., 2017; Jonsson et al., 2018). Primary Sjögren’s syndrome (pSS) is sometimes distinguished in the literature from secondary Sjögren’s syndrome (sSS) (Stefanski et al., 2017). However, more recently, there has been debate about whether the terms primary and secondary represent an appropriate differentiation. There are no distinguishable pathologic features, nor are there differences in outcomes between the two, and the differentiation has unfortunately led to exclusion of many patients from clinical trials (Kollert and Fisher, 2020). Furthermore, there is disagreement on accepted diagnostic criteria for secondary disease, leading to some subjectivity. As a result, the classification of primary versus secondary might fall out of favor in the coming years. This section will describe the clinical features, diagnosis, and disease course of Sjögren’s syndrome, specifically pSS, also known as Sjögren’s disease.

Clinical Features

SS is a chronic, incurable disease with a wide range of presentations. It can damage vital organs and may remain stable, worsen, or go into remission. The primary features of SS are keratoconjunctivitis (dry eyes) and xerostomia (dry mouth), as the immune system targets the salivary glands, which produce saliva, and the lacrimal glands, which produce tears. Those symptoms (dry mouth and dry eyes) are collectively referred to as sicca. Patients also may experience organ-specific systemic symptoms, known as extra-glandular disease, as well as general symptoms including fatigue, depression, and chronic musculoskeletal pain.

Sicca is present in approximately 90 percent of patients at the time of SS diagnosis (Brito-Zerón et al., 2017). There are varying degrees of dryness at the time of diagnosis, which may be related to duration of disease prior to diagnosis, though dryness can also be severe in patients with aggressive short disease duration. Patients may not report dryness directly, but may describe evidence of it when asked follow-up questions about experiencing a gritty sensation in their eyes, a sensation of something stuck in their eyes, the need for frequent artificial tear application, red eyes, eye discomfort,

or blurred vision (Sandhya et al., 2017). Similarly, dry mouth may present with salivary gland swelling (parotid, sublingual, or submandibular), hoarseness, difficulty swallowing food, patients requiring water at their bedside, or a disproportionate number of dental caries for the patient’s level of dental hygiene.

SS-related dry eye is progressive and has a major negative impact on the quality of life of affected patients. Such patients experience, on a daily basis, significant vision fluctuation with blinking, blurred vision, eye fatigue, and difficulty reading, which in turn can have a negative impact on employment and workplace productivity. Additionally, SS can cause corneal melt and perforation, uveitis, scleritis, retinal vasculitis, and optic neuritis (Akpek et al., 2019).

Some patients with SS may experience only mild symptoms of dry eyes and mouth, while others undergo cycles of good health followed by severe disease. Many patients treat symptoms only when they flare up and are bothersome. Others, however, have blurred vision, constant eye discomfort, recurrent mouth infections, swollen parotid glands, hoarseness, and difficulty swallowing and eating. SS also may cause skin, nose, and vaginal dryness and may affect other organs including the kidneys, blood vessels, lungs, pancreas, and brain. Dry skin is present in about half of patients (Villon et al., 2021). Vaginal dryness, an often-overlooked manifestation of SS, can result in decreased sexual health and dysmenorrhea (Haga et al., 2005; Piccioni et al., 2020).

In addition to dryness, the clinical presentation of SS includes asthenia and arthralgia as well as general symptoms. Arthritis occurs in approximately 16 percent of SS patients and typically involves proximal interphalangeal joints (35 percent), metacarpal-phalangeal joints (35 percent), and wrists (30 percent), though any joint can be involved (Both et al., 2017). The severity of inflammatory musculoskeletal pain in SS ranges from mild arthralgia and myalgia to synovitis with chronic pain (Carsons et al., 2017). Joint pain in SS is usually moderate, affecting fewer than five joints, though it can be more severe in the case of overlap with rheumatoid arthritis (Parisis et al., 2020).

The most prevalent general symptom in SS is fatigue, which occurs in approximately 70–80 percent of SS patients. SS patients’ scores on the multidimensional fatigue inventory were twofold worse on all dimensions than for healthy controls. Additionally, chronic pain is also seen, often due to accompanying fibromyalgia and or polyarthralgia. Care must be taken to differentiate this from peripheral neuropathy, in particular sensory neuropathy, which occurs in 20 percent of patients and can lead to functionally debilitating chronic neuropathic pain (Jones et al., 1972). Depression and anxiety are also more common in SS patients than in healthy controls (Both et al., 2017). These general systemic symptoms may be the

most troublesome for patients, as they can lead to significant disability and quality of life impairment. Further discussion of general symptoms such as fatigue, pain, and depression can be found in Chapter 2.

Systemic Manifestations

Although the most typical symptom of SS is sicca, approximately three-quarters of patients with SS also present with constitutional symptoms (Both et al., 2017; Parisis et al., 2020) such as fatigue, dry skin, and musculoskeletal pain. Extra-glandular involvement with direct immune-mediated disease (for example, inflammation in a specific organ) is present in approximately 25 percent of patients (Asmussen et al., 1996; García-Carrasco et al., 2002). Common manifestations in individuals with SS include cutaneous, musculoskeletal, pulmonary, renal, hematologic, and neurologic involvement. Table 7-1 describes each systemic manifestation and notes its estimated prevalence, clinical manifestations, and method of diagnosis. The prevalences of systemic manifestations are estimated based on data from cohort studies and may range widely.

Skin involvement is relatively common, and manifestations include xeroderma, eyelid dermatitis, annular erythema/subacute cutaneous lupus-like lesions, and vascular purpura (Both et al., 2017; Parisis et al., 2020). Pulmonary manifestations are seen in 10–20 percent of patients and are more prevalent in female than male patients (Both et al., 2017; Flament et al., 2016). The most typical are chronic interstitial lung disease (ILD) and tracheobronchial disease (Flament et al., 2016). ILD is a significant cause of death in SS, while tracheobronchial disease sometimes causes a chronic cough that can be crippling and decrease quality of life (Both et al., 2017; Flament et al., 2016). The most common phenotype of ILD in SS is nonspecific interstitial pneumonia, which is present in 45 percent of SS patients (Both et al., 2017).

Renal involvement is uncommon (less than 10 percent) and includes a spectrum of manifestations, interstitial nephritis being the most prevalent. Electrolyte disturbances can develop, most notably distal renal tubular acidosis, but diabetes insipidus and Gitelman syndrome¹ (François and Mariette, 2016) are also possible. End-stage renal disease is rare (less than 1 percent) (Lin et al., 2020).

Neurologic involvement can affect both the central and peripheral nervous systems (Both et al., 2017; Parisis et al., 2020). The prevalence of neuropathy is estimated to be between 10 and 19 percent (Both et al., 2017).

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¹ Gitelman syndrome is a kidney disorder that causes an imbalance of potassium, magnesium, and calcium ions. The signs and symptoms of Gitelman syndrome usually appear in late childhood or adolescence.

TABLE 7-1 Systemic Manifestations in Primary Sjögren’s Syndrome

NOTE: CSF = cerebrospinal fluid; CT = computed tomography; EMG = electromyography; MRI = magnetic resonance imaging.

SOURCE: Both et al., 2017, with permission.

Peripheral neuropathies are the most common form, with axonal sensory and sensorimotor neuropathies more prevalent than small fiber disease. Central nervous system disease includes headaches, cognitive impairment, encephalitis, seizures, and inflammatory demyelinating disease including optic neuritis, transverse myelitis, multiple-sclerosis like disease, and neuromyelitis optica spectrum disorders (Both et al., 2017). Cognitive dysfunction (“brain fog”), restless leg syndrome, and psychiatric abnormalities are classically linked to SS (Parisis et al., 2020).

Anemia is present in 20 percent of SS cases, usually normochromic or normocytic. Leukopenia is found in 15 percent of patients and corresponds to lymphocytopenia. CD4-lymphocytopenia is mainly found in anti-Ro-SSA positive patients and is associated with an increased risk of non-Hodgkin’s lymphoma (Parisis et al., 2020).

Clinical Diagnosis and Professionally Accepted Classification Criteria

The diagnosis of SS involves a combination of taking a medical history, a physical examination, the measurement of tear production, blood tests, and a salivary gland assessment which may include the measurement of saliva production, a gland biopsy, and salivary gland imaging (Romão et al., 2018). It is performed in a multidisciplinary fashion typically involving rheumatologists, radiologists, dentists, ophthalmologists, and otolaryngologists. The key to diagnosis is finding objective evidence of decreased salivary and lacrimal gland function (the key feature of the disease) along with unique histopathologic or serologic evidence pointing to glandular dysfunction. SS can be difficult to diagnose, particularly in patients without dryness or serologic evidence of disease (anti-Ro/SSA), and in some cases a diagnosis may be delayed by more than 10 years. Sicca, fatigue, and nonspecific musculoskeletal pain can be mistaken for manifestations of age, mental health disorders, or menopause in people with SS. The diagnosis is ultimately made through the judgment of an expert clinician (Parisis et al., 2020).

Assessments of sicca symptoms and glandular function are the first step in diagnosing SS. Dry eyes can be evaluated with a simple ophthamologic examination. The Schirmer test involves positioning a small strip of filter paper inside the inferior fornix of each eye. The eyes are then closed for 5 minutes, after which the strips are removed, and the amount of tears absorbed by capillary action is measured in millimeters from the edge of the strip in contact with the ocular surface. Dryness is significant if the test reads less than or equal to 5 millimeters per 5 minutes. Tear film stability may be evaluated next to assess for Meibomian gland dysfunction resulting in evaporative dryness. While this can occur with SS, it can also occur independently of SS and may explain dryness in patients who do not have

SS. Finally, damage to the conjunctiva and cornea related to decreased tear production can be identified by ocular surface staining techniques such as fluorescein, cornea staining, and lissamine green conjunctiva staining. The anomalies are scored using standardized scores. Scores of 4 or greater on the van Bijsterveld scale or of 5 or greater on the SICCA Ocular Staining Score are suggestive of SS (Parisis et al., 2020).

The salivary glands can be evaluated using sialometry. Sialometry involves measuring the unstimulated whole salivary flow rate (UWSF) or the stimulated whole salivary flow rate (SWSF). UWSF is assessed by asking the patient, after fasting for 2 hours, to drain all saliva produced into a jar for 15 minutes. The saliva volume and weight in the jar are then measured. A UWSF of less than 0.1 mL per minute (mL/min) is suggestive of SS. SWSF is measured in the presence of mechanical stimulation—for example, by asking the patient to chew gum or a cloth—with the resulting saliva weighed and measured. A SWSF score of no more than 0.5–0.7 mL/min is suggestive of SS (Parisis et al., 2020).

In addition to evaluating for sicca symptoms and glandular dysfunction, a diagnostic evaluation should include histopathologic and serologic evidence. One major element of SS diagnosis is the antinuclear antibodies (ANA) profile, which involves the detection of anti-Ro/SSA or anti-La/SSB autoantibodies (Parisis et al., 2020). Most SS patients have a positive ANA, and many have an elevated rheumatoid factor and hypergammaglobulinemia (Martín-Nares and Hernández-Molina, 2019; Parisis et al., 2020). In addition to ANA testing, serologic evaluation is important in confirming SS. The initial workup may include assessing for diseases that may coexist with SS and evaluating the unique manifestations of SS in the patient. That may include: a complete blood count; a coagulation profile with antiphospholipid panel; urea/creatinine dosage and urine sediment and 24-hour urine protein or urine protein/creatinine levels; Na+/K+/HCO3−/Cl−/uric acid levels to investigate renal tubulopathy; hepatic enzymes levels; creatine phosphokinase to investigate myositis; C3/C4/CH50 levels, rheumatoid factor, cyclic citrullinated peptide antibodies, Coombs test; serum protein electrophoresis and total IgG, IgM, and IgA levels to investigate the presence of polyclonal hypergammaglobulinemia or monoclonal gammapathy; HCV serology; VDRL/TPHA; free T4 levels, angiotensin-converting enzyme to screen for sarcoidosis; thyroid-stimulating hormone; and anti-thyroid peroxidase, anti-thyroglobulin, anti-mitochondrial, anti-smooth muscle, and anti-gastric parietal cell antibodies in case of associated auto-immune diseases (Parisis et al., 2020). Rheumatoid factor and elevated IgG are present in more than 50 percent of patients with SS (Maślińska et al., 2021).

Evaluation for extra-glandular disease involvement is tailored to a patient’s specific symptoms and signs of disease as well as the invasiveness of testing. As an example, it is standard practice to screen for renal disease

on baseline laboratory testing. That is due to the higher frequency of renal involvement and the ease of urine and blood sample collection. However, cross-sectional imaging, pulmonary function testing, and lung biopsy would only be considered when there is concern for ILD (Both et al., 2017).

The American–European Consensus Group (AECG) and the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) provide classification criteria that serve as a useful guide for diagnosing SS. In practice, a diagnosis by a clinician is usually less stringent than would be accomplished using the full AECG or ACR/EULAR criteria and includes clinical experience and judgment. As an example, early in the disease course patients may have preserved gland function that would not meet the established threshold of positivity (Jonsson et al., 2018).

The AECG consensus criteria for SS include subjective evidence of disease, objective measures of a decrease in salivary and lacrimal gland function, salivary gland biopsy, and Sjögren-specific autoantibodies (Table 7-2). According to the AECG guidelines, SS is diagnosed when four out of the six items are present, including salivary gland pathology or the presence of autoantibodies against SS-A/SS-B (Both et al., 2017). The 2016 ACR/EULAR criteria differ from the AECG classification and focus more on objective measurements of disease activity. They do not include the subjective symptoms of ocular and oral dryness or the anti-SS-B antibody as part of the classification criteria (Table 7-2). A score of four or more out of nine possible points is required for classification.

In a study of 646 subjects comparing the ACR/EULAR and AECG criteria on characteristics such as sensitivity and specificity, the AECG criteria scored better than the ACR/EULAR criteria on all test characteristics (Rasmussen et al., 2014). A separate study of 290 subjects found the ACR/EULAR criteria to be slightly more sensitive, allowing patients lacking sicca to be classified as having the disease (Le Goff et al., 2017). Table 7-2 summarizes both sets of criteria (Both et al., 2017).

TABLE 7-2 Comparison of the Revised American–European Consensus Group (AECG) Classification Criteria and the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) Classification Criteria for Sjögren’s Syndrome.

NOTES: Classification rules for AECG criteria: pSS may be diagnosed when: the presence of any four of the six items is indicative of pSS, as long as either item 4 (histopathology) or 6 (serology) is positive. Classification rules for ACR/EULAR criteria: pSS may be diagnosed when the classification of SS, which applies to individuals with signs/symptoms that may be suggestive of SS, will be met in patients who have at least two of the three objective features previously described.

SOURCE: Reproduced from Both et al., 2017, with permission.

Disease Course, Outcomes, and Variability

SS is slowly progressive. Patients accrue advancing gland damage leading to varying levels of decreased exocrine gland function, and they may also accumulate additional autoimmune diagnoses. An observational study of 152 SS patients with mean follow-up of 12 years reported that 49 percent of the participants eventually developed another autoimmune diagnosis (autoimmune thyroiditis being the most common) and 28 percent developed a malignancy. Specifically, 10 percent of the patients developed non-Hodgkin’s lymphoma (Abrol et al., 2014). As with other immune-mediated disorders, disease activity can fluctuate over time and progress between flares and remissions. In the case of salivary gland swelling, patients may experience episodic disease flares. If gland function is preserved, they may have little if any dryness symptoms between flares. It is generally accepted that once damage occurs to the gland architecture, complete disease remission is not attainable. Typically, manifestations due to lymphocytic infiltration around an epithelium of a target organ (such as salivary gland and pulmonary disease) follow a more predictable course, while those linked to immune complex deposition or autoantibodies have a more unpredictable course (Parisis et al., 2020).

There is no cure for Sjögren’s disease, and treatment generally focuses on managing symptoms without the expectation of complete disease remission. Patients typically experience stable symptoms or, at most, a mild continued progression of glandular disease, the main feature of Sjögren, with lifelong symptoms. The glandular inflammation is usually mild and chronic; however, some patients do experience acute episodes of painful salivary gland swelling. At some point the inflammation will result in gland destruction. Gland destruction eventually leads to a progressive loss of gland function and increasing dryness symptoms. After gland destruction has occurred, there is little hope for damage reversal. Decreased tear and saliva production have significant impacts on quality of life and function which require daily management for both symptom relief and prevention of secondary complications. In particular, patients with dry eyes may experience significant vision fluctuation with blinking, blurred vision, eye fatigue, and difficulty reading on a daily basis, which has a negative impact on employment and workplace productivity (Akpek et al., 2019). The complications of dryness include corneal ulcers, oral candidiasis, and expedited dental decay.

A significant proportion of SS patients (50–70 percent) experience systemic symptoms or extra-glandular manifestations at the time of glandular onset or within 6 months (Parisis et al., 2020). Patients who experience extra-glandular manifestations have a varied disease course which is

dependent on the specific organ system involvement. Both the treatment and functional limitations in these patients vary widely. Constitutional symptoms including fatigue and arthralgia can improve with pharmacologic and non-pharmacologic therapy, but those symptoms are often chronic. Some organ-specific manifestations, such as hematologic conditions, can be successfully treated; in other cases, such as for ILD, the goal of therapy is to prevent further progression. Patients with significant systemic disease activity are generally those with early-onset disease, ANA positivity with a higher frequency of anti-Ro/SSA (with or without anti-La/SSB), low C3, low C4, and cryoglobulinemia (Parisis et al., 2020).

Patients with SS have a substantially increased risk of lymphoma, estimated to be 6.5- to 44-fold higher than in the general population (Smedby et al., 2008). Among all autoimmune diseases, SS has the highest prevalence of lymphoma (Sandhya et al., 2017). A diagnosis of lymphoma can be made concurrently at the time of SS diagnosis, but this is not common. Lymphoma develops at a median of 7.5 years after SS diagnosis (Sandhya et al., 2017). There are several known risks factors for lymphoma among patients with SS, including persistent salivary gland enlargement, lymphadenopathy, cryoglobulinemia, higher focus score at diagnosis, and nephritis (Sandhya et al., 2017). It is not known if that risk can be lowered with treatment, but there is limited evidence that suggests that the administration of rituximab may decrease lymphoproliferation and be protective in patients who carry known risk factors (Dong et al., 2013; Quartuccio et al., 2009).

SS is not associated with an increased risk in all-cause mortality (Singh et al., 2015), although there are subsets of patients with extra-glandular involvement (including vasculitis, hypocomplementemia, and cryoglobulinema) who may have an increased risk of mortality. Patients who develop lymphoma do have a greater risk of death. Once lymphoma is diagnosed, the standardized mortality ratio of a patient with SS increases from 2.86 to 7.89. Risk factors (clinical and biological) for lymphoma and organ involvement should be frequently assessed (Both et al., 2017; Parisis et al., 2020). The leading causes of death in SS patients are cardiovascular events followed by solid-organ and lymphoid malignancies and infections. The risk factors associated with increased mortality include an advanced age at diagnosis, male sex, parotid enlargement, abnormal parotid scintigraphy, extra-glandular involvement, vasculitis, anti-SSB positivity, low C3 and C4, and cryoglobulinaemia (Parisis et al., 2020).

Finally, pregnant patients with Sjögren-specific antibodies (SSA and SSB), even those who do not have a diagnosis of SS or systemic lupus erythematosus (SLE), carry a risk of transmission of neonatal lupus to their offspring. That is the result of transplacental passage of antibodies to the fetus, which results in a transient syndrome which leads to cutaneous and

cardiac injury as well as hematologic and hepatic injury in some patients. The maternal antibodies wane, and the symptoms resolve in most patients. However, there is a risk of congenital heart block developing in utero, which occurs in 2 percent of women with SSA/SSB antibodies (Brucato et al., 2011). Moreover, there are three forms of congenital heart block, with complete heart block being irreversible (85–90 percent of cases are related to neonatal lupus). Cardiac disease may be prevented by the administration of hydroxychloroquine to the pregnant mother. Therefore, women with SS who become pregnant will require more frequent fetal monitoring and possibly a change in treatment of their SS during pregnancy (Barsalou et al., 2017).

TREATMENT AND MANAGEMENT

There is no known cure for SS, nor is there a specific treatment to restore gland secretion. Unfortunately, irreparable glandular damage often has occurred at the time of sicca development, and therefore return of glandular function is not anticipated. Treatment is aimed at slowing or preventing further glandular damage, alleviating symptoms of dryness, and considering immune modulation in the case of extra-glandular disease (Ramos-Casals et al., 2020).

Clinical Practice Guidelines for Receiving Treatments

Treatment is individualized according to the extent of sicca and extra-glandular manifestations. Management is provided by a multidisciplinary team of specialists including those in the fields of rheumatology, ophthalmology, dental, otolaryngology, and psychology, and it may include other specialists such as neurologists, hematologists, and oncologists for extra-glandular disease and cancers. The treatment includes pharmacologic and non-pharmacologic interventions and can be divided into local and systemic therapy. Treatment is decided on an individual basis based on disease activity and the presence and extent of systemic manifestations (Stefanski et al., 2017).

Sicca

Ocular dryness is addressed by limiting tear loss (wearing glasses, avoiding dry or windy environments), avoiding medications that may precipitate decreased tear production, using interventions to increase tear production with medication (e.g., cyclosporine, immune suppression) or punctual plugs, and replacement with artificial tears and lubrication. A

similar approach is used for dry mouth, including gustatory stimulation (e.g., chewing gum), hydration, salivary stimulants (oral sweeteners, prescription pilocarpine, or cevimeline), and using moisture replacement (Both et al., 2017; Romão et al., 2018). Dry skin is often addressed with a regular moisturizing regimen. Vaginal dryness is treated with topical moisturizers and, in some cases, vaginal estrogen application.

The administration of systemic immune modulation lacks strong supportive evidence of efficacy in sicca symptoms, but some patients do report improvement, so this may be employed. The most commonly used medications include hydroxychloroquine and rituximab. Those medications are generally reserved for extra-glandular involvement, recurrent painful glandular swelling, or cases when general symptoms such as arthralgia cannot be managed with local treatment and lifestyle adjustments (Both et al., 2017; Stefanski et al., 2017).

Systemic Symptoms

Hydroxychloroquine is used as a first-line treatment for general symptoms, including sicca, arthralgia, and musculoskeletal pain. Methotrexate can be used in cases in which hydroxychloroquine is ineffective (Both et al., 2017; Carsons et al., 2017). Glucocorticoids are commonly used for episodes of salivary gland swelling as well as for more severe manifestations including severe cutaneous, pulmonary, renal, musculoskeletal, or neurological involvement. When longer-term immune modulation is indicated, DMARDs (mycophenolate mofetil, cyclosporine A, azathioprine) are commonly used to limit glucocorticoid toxicity (Both et al., 2017). The use of biologicals such as rituximab is indicated for severe disease with proven organ damage that is resistant to non-biologic immunosuppressant drugs or when conventional therapies are insufficient (Both et al., 2017; Carsons et al., 2017). Rituximab should be considered as a treatment option for adults with pSS and any of the following manifestations: vasculitis, severe parotid swelling, inflammatory arthritis, pulmonary disease, or peripheral neuropathy, especially mononeuritis multiplex (Carsons et al., 2017).

Many clinicians treat systemic effects of SS based on EULAR’s recommendations for the management of SS with topical and systemic therapies (Ramos-Casals et al., 2020). Those treatment indications are summarized in Table 7-3.

ILD is usually treated with glucocorticoids or other immunosuppressive drugs, such as azathioprine, mycophenolate mofetil, cyclophosphamide, or cyclosporine (Both et al., 2017). There is no standardized treatment for renal involvement in SS, though glucocorticoids are the mainstay for tubulointerstitial nephritis. Studies show that other immunosuppressive drugs

TABLE 7-3 Drugs Indicated for Treatment of Active Systemic Symptoms of Sjögren’s Syndrome

NOTES: *Specifically, neuromyelitis optica antibodies. IVIG = intravenous immunoglobulin.

SOURCE: Ramos-Casals, 2020.

are not effective or only moderately effective in SS-related renal involvement. For patients with neurological involvement, intravenous corticosteroids are the first-line therapy. Cyclophosphamide or intravenous immunoglobulins can also be used if patients do not improve with corticosteroids (Both et al., 2017).

The treatment of general symptoms such as fatigue should also be considered in patients with SS. Therapy includes self-care measures such as advice about using exercise to reduce fatigue. Hydroxychloroquine can be used in some cases to treat fatigue in SS, as it has shown efficacy in treating fatigue in SLE patients, though the quality of evidence for use in SS patients is low (Carsons et al., 2017). Nevertheless, hydroxychloroquine remains the most widely prescribed treatment for fatigue in SS in the United States (Carsons et al., 2017).

Likelihood of Improvement Given Treatment

As mentioned above, there is no known treatment to restore glandular function. Once gland damage occurs, there is usually little chance that normal function will return with treatment. The disease course of SS is, at best, stable over time, but it is more likely to slowly worsen. Patients require regular monitoring to assess the progression of symptoms and the development of systemic manifestations, additional autoimmune disease, and transformation to lymphoma. There is usually no remission of most symptoms. There are no data in the literature that provide information on likelihood of improvement with treatment, though researchers continue to explore ways to decrease complications through studies that include drug trials and finding better methods of gauging disease activity and severity.

Secondary Impairments from Treatment

Secondary impairments from treatment are described in Chapter 2 for patients with immune disorders generally. Patients with SS may experience a worsening of their sicca while using anticholinergic medications for other diseases for which they are being treated. In addition, patients with SS have a higher risk of lymphoma. It is uncertain whether immune modulation increases the risk of lymphoma in SS patients (Fragkioudaki et al., 2016). There is hope that the anti–B-cell agent, rituximab, may decrease the risk of lymphoma but this has not been investigated to date.

Defining Disease Activity and Severity

In the past decade, the EULAR SS task force has developed two validated clinical tools with which to assess systemic disease activity and

severity in pSS: the EULAR Sjögrens Syndrome Disease Activity Index (ESSDAI) and the EULAR Sjögrens Syndrome Patient Reported Index (ESSPRI). ESSDAI is used as a gold standard to measure disease activity in clinical studies. It includes 12 domains: cutaneous, respiratory, renal, articular, muscular, peripheral nervous system, central nervous system, hematological, glandular, constitutional, lymphadenopathic, and biological. Each domain is divided into three or four disease activity levels that are specific to that domain (Seror et al., 2015). For example, Table 7-4 shows the disease activity levels for the muscular domain.

Features that are stable for at least 12 months are considered irreversible and are given a score of 0 (Seror et al., 2015). The total ESSDAI score is calculated by summing the scores in the 12 domains. Low disease activity has been defined as an ESSDAI score of less than 5, with moderate disease activity being an ESSDAI score of between 5 and 13, and high disease activity being an ESSDAI score of 14 or more (Seror et al., 2015). Additionally, a threshold has been proposed for minimal clinically important improvement, defined as a decrease of at least 3 points in the ESSDAI score (Seror et al., 2015). Those thresholds have been used in randomized controlled trials.

ESSPRI translates the most common patient-reported symptoms—pain, dryness, and fatigue—into a score between 0 and 10. Seror and colleagues (2015) suggest that a score of 5 or more constitutes an unsatisfactory symptom state and that a 1-point increase in score is a meaningful improvement.

These tools provide useful definitions of disease activity states and clinically meaningful improvement, including a version that is meant for clinician use. They have been incorporated both into clinical research and into clinical

TABLE 7-4 Muscular Domain in the EULAR Sjögrens Syndrome Disease Activity Index

NOTES: Exclude weakness due to corticosteroids. EMG = electromyogram; MRI = magnetic resonance imaging.

SOURCE: Seror et al., 2015, with permission.

practice and show promise for improving patient care by trending scores over time as an indication of disease progress, regression, or stability, which may prompt a change in management (Romão et al., 2018).

Drug use can also be an indicator of disease severity. As discussed in the treatments section, mild cases of SS are generally treated with lifestyle modifications and local drugs such as pilocarpine and cyclosporine, possibly with the addition of nonsteroidal anti-inflammatory drugs for mild arthralgia. More severe cases with arthralgia are usually treated with hydroxychloroquine. Moderately severe cases may involve the addition of non-biologic immunosuppressant drugs such as methotrexate to treat systemic involvement. Severe cases with proven organ damage that are resistant to non-biologics often are treated with biological immunosuppressive drugs such as rituximab (Both et al., 2017).

Select Treatments Currently in Clinical Trials

Drug approvals for treating SS have lagged behind approvals for other immune disorders such as rheumatoid arthritis. Scientists designing clinical trials for SS have encountered a number of challenges, including patient selection (e.g., how to capture a heterogeneous group of patients in varying disease stages), the assessment of treatment efficacy (which is confounded by, e.g., corticosteroid use), and the identification of therapeutic targets (Leverenz and St. Clair, 2019; Narain et al., 2020).

A search of the National Institutes of Health’s (NIH’s) National Library of Medicine website on October 22, 2021, found 91 studies for Sjögren’s disease in the United States. Although clinical trials are under way to study potential therapies, several targeted therapies have not performed as expected in large phase III trials. ESSDAI and ESPRI have been used as outcome measures in clinical trials and are the gold standard; however, one challenge is that patients with a diversity of organ system involvement might not have the same chance of improving their score because of differences in the responsiveness of their particular symptoms to therapy compared with other symptoms which may be more reversible (Leverenz and St. Clair, 2019).

As of yet, no DMARDs have been approved by the U.S. Food and Drug Administration (FDA) specifically for SS, and DMARDs used to treat Sjögren’s are considered off-label (as they are typically approved by FDA to treat immune arthritis rather than SS) (Leverenz and St. Clair, 2019). Clinical trials of traditional DMARDs and biologics for use in SS, including hydroxychloroquine and rituximab, have failed to show improvement in symptoms (Fox and Fox, 2016; Leverenz and St. Clair, 2019). Despite the failure of rituximab to show a benefit in SS treatment in two recent clinical trials, it is well tolerated in SS patients, and treatment guidelines continue

to endorse rituximab in the management of select cases (van den Hoogen and van Laar, 2020). B cells and T cells remain a focus of interest in SS treatment and continue to be studied in clinical trials.

Recently, a number of novel drugs to target B cells in SS have shown promise in clinical trials, including belimumab, ianalumab, and iscalimab (Narain et al., 2020; van den Hoogen and van Laar, 2020). Belimumab is a monoclonal antibody directed against B-cell activating factor (BAFF) which has been approved for use in SLE but has not been studied extensively in SS. However, in one study, 30 patients with SS who were treated with belimumab at 0, 2, and 4 weeks (and followed once every 4 weeks) showed improvements in their ESSDAI scores and in dryness after 28 weeks, and a 6-month extension of the study found persisting improvements (De Vita et al., 2015; Mariette et al., 2015). Placebo-controlled studies designed to corroborate those results are under way. Ianalumab is another novel BAFF-targeting antibody that has recently been tested in patients with SS. In a phase II clinical trial involving 190 patients, inanlumab given at 300 mg per month led to a significant improvement in ESSDAI scores compared with controls (Bowman et al., 2022). Other BAFF-targeting treatments that were unsuccessful in tests against SLE, such as tabalumab, blisbimod, and atacicept, have not been assessed in SS (van den Hoogen and van Laar, 2020). Iscalimab is a monoclonal antibody against CD40, which is involved in the interaction between B cells and T cells. Two placebo-controlled cohort studies of SS patients treated with iscalimab found an improvement in ESSDAI scores (Fisher et al., 2020).

DISEASE-SPECIFIC FUNCTIONAL LIMITATIONS

SS can be disabling and can also be accompanied by significant functional status impairment related to the symptoms of dry eye, reduced visual function, pain, fatigue, anxiety, depression, and systemic disease activity. Patients with SS experience difficulty with reading, which in turn has a negative impact on workplace productivity (Akpek et al., 2019). SS can also lead to serious ocular impairments, including decreased vision, or chronic inflammation of the eye (Akpek et al., 2019). Corneal scarring can also be a significant cause of functional disability. Unfortunately, visual function is rarely measured. ESSPRI, which is one of the most commonly used instruments for assessing patient symptoms in SS, includes only one item that addresses the severity of overall dryness, and it does not measure either dry eye specifically or vision-related quality of life (Akpek et al., 2019).

Beyond these vision-related limitations, patients with SS report that general symptoms such as fatigue, pain, and cognitive dysfunction are

the greatest cause of disability (Romão et al., 2018). Fatigue is reported in up to 70–80 percent of patients with pSS and has been well studied using the multidimensional fatigue inventory (Both et al., 2017). Patients report that fatigue is the symptom experienced as most distressing, though nonspecific complaints such as fatigue and diffuse pain can be difficult to evaluate (Stefanski et al., 2017; see chapter 3 for further discussion). A systematic review that included two cohort studies indicated that the functional disorders related to pSS included headache, cognitive disorders, and mood disorders. Those functional disorders were associated with SS-induced encephalopathy, aseptic meningitis, and cerebral white matter and spinal cord lesions as confirmed by histopathological assessment (Sumida et al., 2018). Depression and anxiety are also more common in patients with SS than in healthy controls (Both et al., 2017).

A study in working-age Swedish SS patients found that after 2 years with SS, approximately 40 percent of the patients received work disability, which was related to fibromyalgia pattern, age, and incapacity for work at diagnosis (Mandl et al., 2017). Another study in a population of working-age Dutch SS patients found that approximately 47 percent received work disability, which was related to male sex, high educational level, a higher number of systemic manifestations, and the use of artificial saliva or hydroxychloroquine (Meijer et al., 2009).

CHILDHOOD SJÖGREN’S SYNDROME

Juvenile SS is rare and poorly defined (and perhaps underdiagnosed), affecting children and adolescents with a mean age at diagnosis of 10 years. Not enough published data exist to determine the prevalence of SS in pediatric populations, although approximately 5 percent of adult SS patients report having had symptoms prior to age 12 (Smolik et al., 2017). As with adults, the hallmarks of the disease involve exocrine gland inflammation with an eventual loss of function along with the potential for extra-glandular disease. It is not known if children represent an early presentation of adult type disease or if it is a different entity, as is the case for other autoimmune diseases. The differences between presenting symptoms in children and adults suggest it is the latter. A critical consideration is that the diagnosis is often made in adults when gland dysfunction already has been established due to years of inflammation. Since children have not had the opportunity to experience decades of disease, there may be the potential to suppress glandular inflammation and regain some glandular function or prevent glandular damage before it has occurred.

A variety of organ systems may be affected, which may result in numerous manifestations, including neurological, dermatological,

musculoskeletal, vascular, gastrointestinal, respiratory, renal, and hematological (Brokstad et al., 2018). Extra-glandular symptoms have been reported in 51.3 percent of those with juvenile SS. The diagnosis, treatment, and follow-up are generally based on clinical symptoms and the presence of autoantibodies. Further, patients with juvenile SS often present with swelling of the major salivary glands. Parotid swelling often precedes regular oral and ocular symptoms, although serological finding may be absent. Salivary gland ultrasonography shows features typical of primary SS/juvenile SS which can add useful information in diagnosing. In juvenile SS, parotid swelling usually precedes regular oral and ocular symptoms, although typical serological findings may not be present (Brokstad et al., 2018). Unique aspects of childhood SS are a lower prevalence of sicca and a higher incidence of recurrent or persistent parotitis (Basiaga et al., 2021). Lymphoma risk has not been studied in children, though it is possible that the lifetime relative risk of developing lymphoma is higher in children than in adults with SS given that they will accrue more years with the disease.

Diagnosis of juvenile SS is similar to that of adult disease. There are no accepted pediatric-specific diagnostic or classification criteria for children. The 2016 ACR/EULAR criteria are often applied to children; however, they were validated in adults and may not be sensitive in children. When those adult criteria were applied to a large cohort of 300 children with the disease, the calculated sensitivity was only 23 percent (Basiaga et al., 2021). There have been proposed pediatric-specific criteria (Bartůňková et al., 1999) that have not been widely accepted. A review article reported that when they were applied to a small series of children retrospectively, the proposed pediatric criteria had 76 percent sensitivity (Houghton et al., 2005). However, when the proposed pediatric criteria were applied to a larger cohort of 300 children, they had just 55 percent sensitivity (Basiaga et al., 2021). Therefore, the diagnosis is often made by subspecialists experienced in the disease. It is not unusual for children to have SS, diagnosed by an expert subspecialist, but not fulfill adult criteria yet. This is partly because the adult criteria rely on evidence of gland damage that can take years to accrue.

Treatment of juvenile SS follows the same course of treatment in adult disease, though all of the treatment efficacy studies were performed in adults. Similar to adult disease, treatment for juvenile SS usually shows little benefit in terms of improving glandular function, although medication may be more beneficial in children, as most have not yet experienced glandular destruction.

There are no longitudinal studies in children that have described the disease course or outcomes.

SUMMARY

SS, now also known as Sjögren’s disease, is a systemic autoimmune disease characterized by glandular dysfunction resulting in sicca symptoms (dryness, usually in the eyes and mouth), fatigue, chronic musculoskeletal pain, and possible systemic disease with a significant risk of progression to non-Hodgkin’s lymphoma. Although it is often reduced to its sicca syndrome, SS remains a systemic disease that can affect virtually all organs. It is the second most common autoimmune disorder after rheumatoid arthritis.

Diagnosis requires evidence of glandular dysfunction and serologic or pathologic evidence that SS is the cause of the glandular dysfunction. SS may be difficult to recognize, and, because of that, diagnosis can be delayed by more than 10 years. Classification criteria exist for use in cohort studies, although they should be used only as a guide and are not designed as sensitive diagnostic criteria for clinical practice. The pathogenesis of SS is not well understood, but an increase in the activation of B cells followed by immune complex formation and autoantibody production is thought to be involved.

The disease course of SS is slowly progressive and unlikely to improve, with the exception of extra-glandular involvement. Patients will accrue advancing gland damage which leads to varying levels of decreased exocrine gland function, and they can also accumulate additional autoimmune diagnoses; for example, SS patients are at an increased risk of non-Hodgkin’s lymphoma. As with other immune disorders, disease activity can fluctuate over time and progress between flares and remissions, particularly in the case of salivary gland inflammation. Once gland disease develops, it is generally accepted that disease remission is not attainable and that symptoms of dryness may be static.

There are no treatments to cure SS, and treatment research lags behind that of other autoimmune disorders. Management involves improving the quality of life by reducing dryness, fatigue, and chronic pain and by treating systemic manifestations to prevent damage accrual, which will worsen the vital and functional prognosis. The treatment of manifestations of sicca, fatigue, and pain mainly involves symptomatic measures and rehabilitation, and generally immunosuppressants are not recommended to treat those symptoms. The treatment of manifestations related to inflammatory disease activity is based on scarce evidence. Therapy must be tailored to organ-specific involvement and the severity of the disorder. Mild manifestations can be treated with hydroxychloroquine or local corticosteroids, while moderate to severe systemic involvement will require the use of systemic corticosteroid therapy often combined with steroid-sparing immune modulation. Methotrexate, azathioprine, and rituximab may be first-line immune modulation based on the organ systems involved. Despite targeted

therapies having revolutionized rheumatology in recent years, and despite the impressive number of molecules tested so far in SS, the technology has not revolutionized SS treatment as it has for rheumatoid arthritis.

SS is associated with significant functional impairment, which is due to the symptoms of reduced visual function, pain, fatigue, anxiety, and depression. Cohort studies in Swedish and Dutch populations showed that 40–47 percent of working-age adults with SS received work disability. Those studies found that the risk factors for work disability included the presence of fibromyalgia, male sex, older age, a higher number of systemic manifestations, and the use of artificial saliva. Although SS is not associated with an increased risk of mortality, patients with extra-glandular involvement (including vasculitis, hypocomplementemia, and cryoglobulinema) and those with lymphoma do have a greater risk of death.

Juvenile SS is a rare and poorly defined disease with a mean age at diagnosis of 10 years. As with adults, the hallmarks of the disease involve exocrine gland inflammation with an eventual loss of function along with the potential for extra-glandular disease. It is not known if children represent an early presentation of adult-type disease or if it is a different entity, as is the case for other autoimmune diseases. Differences in presenting symptoms between children and adults suggests it is the latter. A variety of organ systems may be affected, which may result in numerous manifestations, including neurological, dermatological, musculoskeletal, vascular, gastrointestinal, respiratory, renal, and hematological. Diagnosis, treatment, and follow-up are generally based on clinical symptoms and the presence of autoantibodies. Unique aspects of childhood SS are a lower prevalence of sicca and a higher incidence of recurrent or persistent parotitis.

REFERENCES